PKS762refs.MYD ~?yEgan, M. F. Goldberg, T. E. Kolachana, B. S. Callicott, J. H. Mazzanti, C. M. Straub, R. E. Goldman, D. Weinberger, D. R.2001\Effect of COMT Val(108/158) Met genotype on frontal lobe function and risk for schizophrenia 6917-6922OProceedings of the National Academy of Sciences of the United States of America9812JunAbnormalities of prefrontal cortical function are prominent features of schizophrenia and have been associated with genetic risk, suggesting that susceptibility genes for schizophrenia may impact on the molecular mechanisms of prefrontal function. A potential susceptibility mechanism involves regulation of prefrontal dopamine, which modulates the response of prefrontal neurons during working memory. We examined the relationship of a common functional polymorphism (Va(108/158) Met) in the catechol-O-methyltransferase (COMT) gene, which accounts for a 4-fold variation in enzyme activity and dopamine catabolism, with both prefrontally mediated cognition and prefrontal cortical physiology. In 175 patients with schizophrenia, 219 unaffected siblings, and 55 controls, COMT genotype was related in allele dosage fashion to performance on the Wisconsin Card Sorting Test of executive cognition and explained 4% of variance (P = 0.001) in frequency of perseverative errors. Consistent with other evidence that dopamine enhances prefrontal neuronal function, the load of the low-activity Met allele predicted enhanced cognitive performance. We then examined the effect of COMT genotype on prefrontal physiology during a working memory task in three separate subgroups(n = 11-16) assayed with functional MRI, Met allele load consistently predicted a more efficient physiological response in prefrontal cortex. Finally, in a family-based association analysis of 104 trios, we found a significant increase in transmission of the Val allele to the schizophrenic offspring. These data suggest that the COMT Val allele, because it increases prefrontal dopamine catabolism, impairs prefrontal cognition and physiology. and by this mechanism slightly increases risk for schizophrenia.://000169151500070 Times Cited: 512ISI:000169151500070NIMH, Clin Brain Disorders Branch, Bethesda, MD 20892 USA. NIAAA, Neurogenet Lab, Rockville, MD 20852 USA. Virginia Commonwealth Univ, Med Coll Virginia, Dept Psychiat, Richmond, VA 23298 USA. Egan, MF, NIMH, Clin Brain Disorders Branch, Bldg 10,Ctr Dr, Bethesda, MD 20892 USA.?aHariri, A. Mattay, V. Tessitore, A. Kolachana, B. Fera, F. Goldman, D. Egan, M. Weinberger, D. R.2002OSerotonin transporter genetic variation and the response of the human amygdala.400-403Science297$~?QHariri, A. R. Mattay, V. S. Tessitore, A. Fera, F. Smith, W. G. Weinberger, D. R.2002>Dextroamphetamine modulates the response of the human amygdala 1036-1040Neuropsychopharmacology276Dec(Amphetamine, a potent monoaminergic agonist, has pronounced effects on emotional behavior in humans, including the generation of fear and anxiety. Recent animal studies have demonstrated the importance of monoamines, especially dopamine, in modulating the response of the amygdala, a key brain region involved in the perception of fearful and threatening stimuli, and the generation of appropriate physiological and behavioral responses. We have explored the possibility that the anxiogenic effect of amphetamine in humans reflects the drug's influence on the activity of the amygdala. In a double-blind placebo controlled study, fMRI revealed that dextroamphetamine potentiated the response of the amygdala during the perceptual processing of angry and fearful facial expressions. Our results provide the first evidence of a specific neural substrate for the anxiogenic effects of amphetamine and are consistent with animal models of dopaminergic activation of the amygdala. (C) 2002 American College of Neuropsychopharmacology. Published by Elsevier Science Inc.://000179156900015 Times Cited: 23ISI:000179156900015NIMH, Clin Brain Disorders Branch, Intramural Res Program, NIH, Bethesda, MD 20892 USA. Hariri, AR, NIMH, Clin Brain Disorders Branch, Intramural Res Program, NIH, 10 Ctr Dr,Room 3C108, Bethesda, MD 20892 USA.(~?DHariri, A. R. Tessitore, A. Mattay, V. S. Fera, F. Weinberger, D. R.2002LThe amygdala response to emotional stimuli: A comparison of faces and scenes317-323 Neuroimage171SepPAs a central fear processor of the brain, the amygdala initiates a cascade of critical physiological and behavioral responses. Neuroimaging studies have shown that the human amygdala responds not only to fearful and angry facial expressions but also to fearful and threatening scenes such as attacks, explosions, and mutilations. Given the relative importance of facial expressions in adaptive social behavior, we hypothesized that the human amygdala would exhibit a stronger response to angry and fearful facial expressions in comparison to other fearful and threatening stimuli. Twelve subjects completed two tasks while undergoing fMRI: matching angry or fearful facial expressions, and matching scenes depicting fearful or threatening situations derived from the International Affective Picture System (IAPS). While there was an amygdala response to both facial expressions and IAPS stimuli, direct comparison revealed that the amygdala response to facial expressions was significantly greater than that to IAPS stimuli. Autonomic reactivity, measured by skin conductance responses, was also greater to facial expressions. These results suggest that the human amygdala shows a stronger response to affective facial expressions than to scenes, a bias that should be considered in the design of experimental paradigms interested in probing amygdala function.://000178102000023 Times Cited: 63ISI:000178102000023NIMH, Clin Brain Disorders Branch, Intramural Res Program, NIH, Bethesda, MD 20892 USA. Hariri, AR, NIMH, Clin Brain Disorders Branch, Intramural Res Program, NIH, Bethesda, MD 20892 USA.~?OLangheim, F. J. P. Callicott, J. H. Mattay, V. S. Duyn, J. H. Weinberger, D. R.20027Cortical systems associated with covert music rehearsal901-908 Neuroimage164AugMusical representation and overt music production are necessarily complex cognitive phenomena. While overt musical performance may be observed and studied, the act of performance itself necessarily skews results toward the importance of primary sensorimotor and auditory cortices. However, imagined musical performance (IMP) represents a complex behavioral task involving components suited to exploring the physiological underpinnings of musical cognition in music performance without the sensorimotor and auditory confounds of overt performance. We mapped the blood oxygenation level-dependent fMRI activation response associated with IMP in experienced musicians independent of the piece imagined. IMP consistently activated supplementary motor and premotor areas, right superior parietal lobule, right inferior frontal gyrus, bilateral mid-frontal gyri, and bilateral lateral cerebellum in contrast with rest, in a manner distinct from fingertapping versus rest and passive listening to the same piece versus rest. These data implicate an associative network independent of primary sensorimotor and auditory activity, likely representing the cortical elements most intimately linked to music production.://000177444900005 Times Cited: 13ISI:000177444900005NIMH, Intramural Res Program, Clin Brain Disorders Branch, NIH, Bethesda, MD 20892 USA. NINDS, Lab Funct & Mol Imaging, IRP, NIH, Bethesda, MD 20892 USA. Callicott, JH, NIMH, Intramural Res Program, Clin Brain Disorders Branch, NIH, Bethesda, MD 20892 USA.?rMattay, V. Tessitore, A. Callicott, J. H. Bertolino, A. Goldberg, T. E. Chase, T. N. Hyde, T. M. Weinberger, D. R.2002S Dopaminergic modulation of cortical function in patients with Parkinson's disease.156-164 Ann Neurol512~?]Mattay, V. S. Fera, F. Tessitore, A. Hariri, A. R. Das, S. Callicott, J. H. Weinberger, D. R.2002LNeurophysiological correlates of age-related changes in human motor function630-635 Neurology584FebBackground: There are well-defined and characteristic age-related deficits in motor abilities that may reflect structural and chemical changes in the aging brain. Objective: To delineate age-related changes in the physiology of brain systems subserving simple motor behavior. Methods: Ten strongly right-handed young (<35 years of age) and 12 strongly right-handed elderly (>50 years of age) subjects with no evidence of cognitive or motor deficits participated in the study. Whole-brain functional imaging was performed on a 1.5-T MRI scanner using a spiral pulse sequence while the subjects performed a visually paced "button-press" motor task with their dominant right hand alternating with a rest state. Results: Although the groups did not differ in accuracy, there was an increase in reaction time in the elderly subjects (mean score +/- SD, young subjects = 547 +/- 97 ins, elderly subjects = 794 280 ms, p < 0.03). There was a greater extent of activation in the contralateral sensorimotor cortex, lateral premotor area, supplementary motor area, and ipsilateral cerebellum in the elderly subjects relative to the young subjects (p < 0.001). Additional areas of activation, absent in the young subjects, were seen in the ipsilateral sensorimotor cortex, putamen (left > right), and contralateral cerebellum of the elderly subjects. Conclusions: The results of this study show that elderly subjects recruit additional cortical and subcortical areas even for the performance of a simple motor task. These changes may represent compensatory mechanisms invoked by the aging brain, such as reorganization and redistribution of functional networks to compensate for age-related structural and neurochemical changes.://000174012600022 Times Cited: 46ISI:000174012600022NIMH, Clin Brain Disorders Branch, Intramural Res Program, NIH, Bethesda, MD 20892 USA. Mattay, VS, Bldg 10,Ctr Dr,Rm 4S-235, Bethesda, MD 20982 USA.~?ZSt Lawrence, K. S. Ye, F. Q. Lewis, B. K. Weinberger, D. R. Frank, J. A. McLaughlin, A. C.2002wEffects of indomethacin on cerebral blood flow at rest and during hypercapnia: An arterial spin tagging study in humans628-635%Journal of Magnetic Resonance Imaging156JunPurpose: To investigate using an arterial spin tagging (AST) approach the effect of indomethacin on the cerebral blood flow (CBF) response to hypercapnia. Materials and Methods: Subjects inhaled a gas mixture containing 6% CO2 for two 5-minute periods, which were separated by a 10-minute interval, in which subjects inhaled room air. In six subjects, indomethacin (i.v., 0.2 mg/ kg) was infused in the normocapnic interval between the two hypercapnic periods. Results: Indomethacin reduced normocapnic gray matter CBF by 36 +/- 5% and reduced the CBF increase during hypercapnia from 43 +/- 9% to 16 +/- 5% in gray matter (P < 0.001) and from 48 +/- 11% to 35 +/- 9% in white matter (P < 0.025). Conclusion: The results demonstrate that an AST approach can measure the effects of indomethacin on global CBF increases during hypercapnia and suggest that an AST approach could be used to investigate pharmacological effects on focal CBF increases during functional activation.://000175918300002 Times Cited: 4ISI:000175918300002NIH, Lab Diagnost Radiol Res, Clin Ctr, Bethesda, MD 20892 USA. St Lawrence, KS, NIH, Lab Diagnost Radiol Res, Clin Ctr, Bldg 10 Rm B1N 256 10 Ctr Dr MSC 1074, Bethesda, MD 20892 USA.~? jTessitore, A. Hariri, A. R. Fera, F. Smith, W. G. Chase, T. N. Hyde, T. M. Weinberger, D. R. Mattay, V. S.2002UDopamine modulates the response of the human amygdala: A study in Parkinson's disease 9099-9103Journal of Neuroscience2220OctVIn addition to classic motor signs and symptoms, Parkinson's disease (PD) is characterized by neuropsychological and emotional deficits, including a blunted emotional response. In the present study, we explored both the neural basis of abnormal emotional behavior in PD and the physiological effects of dopaminergic therapy on the response of the amygdala, a central structure in emotion processing. PD patients and matched normal controls (NCs) were studied with blood oxygenation level-dependent functional magnetic resonance imaging during a paradigm that involved perceptual processing of fearful stimuli. PD patients were studied twice, once during a relatively hypodopaminergic state (i.e., greater than or equal to12 hr after their last dose of dopamimetic treatment) and again during a dopamine-replete state. The imaging data revealed a robust bilateral amygdala response in NCs that was absent in PD patients during the hypodopaminergic state. Dopamine repletion partially restored this response in PD patients. Our results demonstrate an abnormal amygdala response in PD that may underlie the emotional deficits accompanying the disease. Furthermore, consistent with findings in experimental animal paradigms, our results provide in vivo evidence of the role of dopamine in modulating the response of the amygdala to sensory information in human subjects.://000178686600035 Times Cited: 28ISI:000178686600035NIMH, Clin Brain Disorders Branch, NIH, Bethesda, MD 20892 USA. NINDS, Expt Therapeut Branch, NIH, Bethesda, MD 20892 USA. Mattay, VS, NIMH, Clin Brain Disorders Branch, NIH, 10 Ctr Dr,Room 3C108, Bethesda, MD 20892 USA. ~? Weinberger, D. R. McClure, R. K.2002zNeurotoxicity, neuroplasticity, and magnetic resonance imaging morphometry - What is happening in the schizophrenic brain?553-558Archives of General Psychiatry596JunIn an era of dramatic discoveries in neuroscience and genetics, it is likely that many popular theories and formulations about mental illness will need to be revised, if not discarded. The "neurodevelopmental hypothesis" is one of the popular theories about the origins of schizophrenia, which posits that abnormalities of early brain development increase risk for the subsequent emergence of the clinical syndrome.(1-3) An early piece of evidence in support of this hypothesis was the apparent lack of progression of cerebral ventricular enlargement observed with computed tomography during illness.(4-9) An important assumption of the neuro developmental hypothesis is that the putative primary pathologic condition of the brain is a reflection of abnormalities of early development. The neuro developmental hypothesis thus assumes that developmental neuropathologic conditions should arrest early in life and not continue to progress. The computed tomography results showing no apparent progression seemed consistent with this assumption. However, a recent series of magnetic resonance imaging (MRI) studies has called into question this assumption, by revealing changes in measurements of brain structures over short periods in patients who have been ill for varying durations and at various stages of life. These recent studies'(10-14) have generated enthusiasm for a "neurodegenerative hypothesis," harkening back to proposals of Kraepelin and other neuropathologists during the first quarter of the 20th century that there is destruction of neural tissue associated with psychosis. In fact, results of MRI measurements have been cited as support for a much broader conceptual revolution in psychiatry, a "neurotoxicity hypothesis" for many psychiatric illnesses, including affective disorders(15,16) and anxiety and stress disorders(17-19) and even jet lag.(20) This recent trend has been bolstered by basic discoveries about the adaptability of neuronal connections(21) and the viability and reproducibility of neurons in the adult brain (eg, apoptosis and neurogenesis).(22,23) These developments have led some to opine that the neurodegenerative hypothesis of schizophrenia may have been unjustly overshadowed by the ascendancy of the neuro developmental hypothesis.(24)://000176055400010 Times Cited: 62ISI:000176055400010NIMH, Clin Brain Disorders Branch, Intramural Res Program, NIH, Bethesda, MD 20892 USA. Weinberger, DR, NIMH, Clin Brain Disorders Branch, Intramural Res Program, NIH, 10 Ctr Dr,Bldg 10,Room 3C-101,MSc 1255, Bethesda, MD 20892 USA. %~? eCallicott, J. H. Egan, M. F. Mattay, V. S. Bertolino, A. Bone, A. D. Verchinksi, B. Weinberger, D. R.2003zAbnormal fMRI response of the dorsolateral prefrontal cortex in cognitively intact siblings of patients with schizophrenia709-719American Journal of Psychiatry1604AprObjective: The identification of neurobiological intermediate phenotypes may hasten the search for susceptibility genes in complex psychiatric disorders such as schizophrenia. Earlier family studies have suggested that deficits in executive cognition and working memory may be related to genetic susceptibility for schizophrenia, but the biological basis for this behavioral phenotype has not been identified. Method: The authors used functional magnetic resonance imaging (fMRI) during performance of the N-back working memory task to assess working memory-related cortical physiology in nonschizophrenic, cognitively intact siblings of patients with schizophrenia. They compared 23 unaffected siblings of schizophrenic patients to 18 matched comparison subjects. As a planned replication, they studied another 25 unaffected siblings and 15 comparison subjects. Results: In both cohorts, there were no group differences in working memory performance. Nevertheless, both groups of siblings showed an exaggerated physiological response in the right dorsolateral prefrontal cortex that was qualitatively similar to results of earlier fMRI studies of patients with schizophrenia. Conclusions: These fMRI data provide direct evidence of a primary physiological abnormality in dorsolateral prefrontal cortex function in individuals at greater genetic risk for schizophrenia, even in the absence of a manifest cognitive abnormality. This exaggerated fMRI response implicates inefficient processing of memory information at the level of intrinsic prefrontal circuitry, similar to earlier findings in patients with schizophrenia. These data predict that inheritance of alleles that contribute to inefficient prefrontal information processing will increase risk for schizophrenia.://000182096300019 Times Cited: 57ISI:000182096300019NIMH, Clin Brain Disorders Branch, IRP, NIH, Bethesda, MD 20892 USA. Callicott, JH, NIMH, Clin Brain Disorders Branch, IRP, NIH, Bldg 10,Ctr Dr,Rm 4D-20 MSC1389, Bethesda, MD 20892 USA. 1~? ZCallicott, J. H. Mattay, V. S. Verchinski, B. A. Marenco, S. Egan, M. F. Weinberger, D. R.2003TComplexity of prefrontal cortical dysfunction in schizophrenia: More than up or down 2209-2215American Journal of Psychiatry16012Dec5Objective: Numerous neuroimaging studies have examined the function of the dorsolateral prefrontal cortex in schizophrenia; although abnormalities usually are identified, it is unclear why some studies find too little activation and others too much. The authors' goal was to explore this phenomenon. Method: They used the N-back working memory task and functional magnetic resonance imaging at 3 T to examine a group of 14 patients with schizophrenia and a matched comparison group of 14 healthy subjects. Results: Patients' performance was significantly worse on the two-back working memory task than that of healthy subjects. However, there were areas within the dorsolateral prefrontal cortex of the patients that were more active and areas that were less active than those of the healthy subjects. When the groups were subdivided on the basis of performance on the working memory task into healthy subjects and patients with high or low performance, locales of greater prefrontal activation and locales of less activation were found in the high-performing patients but only locales of underactivation were found in the low-performing patients. Conclusions: These findings suggest that patients with schizophrenia whose performance on the N-back working memory task is similar to that of healthy comparison subjects use greater prefrontal resources but achieve lower accuracy (i.e., inefficiency) and that other patients with schizophrenia fail to sustain the prefrontal network that processes the information, achieving even lower accuracy as a result. These findings add to other evidence that abnormalities of prefrontal cortical function in schizophrenia are not reducible to simply too much or too little activity but, rather, reflect a compromised neural strategy for handling information mediated by the dorsolateral prefrontal cortex.://000186881900021 Times Cited: 56ISI:000186881900021NIMH, Clin Brain Disorders Branch, NIH, Bethesda, MD 20892 USA. Callicott, JH, NIMH, Clin Brain Disorders Branch, NIH, Bldg 10,Rm 4D-20,MSC 1389, Bethesda, MD 20892 USA.~? Egan, M. F. Kojima, M. Callicott, J. H. Goldberg, T. E. Kolachana, B. S. Bertolino, A. Zaitsev, E. Gold, B. Goldman, D. Dean, M. Lu, B. Weinberger, D. R.2003uThe BDNF val66met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function257-269Cell1122JanBrain-derived neurotrophic factor (BDNF) modulates hippocampal plasticity and hippocampal-dependent memory in cell models and in animals. We examined the effects of a valine (val) to methionine (met) substitution in the 5' pro-region of the human BDNF protein. In human subjects, the met allele was associated with poorer episodic memory, abnormal hippocampal activation assayed with fMRI, and lower hippocampal n-acetyl aspartate (NAA), assayed with MRI spectroscopy. Neurons transfected with met-BDNF-GFP showed lower depolarization-induced secretion, while constitutive secretion was unchanged. Furthermore, met-BDNF-GFP failed to localize to secretory granules or synapses. These results demonstrate a role for BDNF://000181191600014 Times Cited: 284ISI:000181191600014NICHHD, Sect Neural Dev & Plast, NIH, DHHS, Bethesda, MD 20892 USA. NIMH, Clin Brain Disorders Branch, Bethesda, MD 20892 USA. NIAAA, Neurogenet Lab, Rockville, MD 20857 USA. NCI, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. Natl Inst AIST, Cell Dynam Res Grp, Osaka 5638577, Japan. Japan Sci & Technol Corp, CREST, Kawaguchi 3320012, Japan. Lu, B, NICHHD, Sect Neural Dev & Plast, NIH, DHHS, Bldg 49-6A67, Bethesda, MD 20892 USA.&~?kHariri, A. R. Goldberg, T. E. Mattay, V. S. Kolachana, B. S. Callicott, J. H. Egan, M. F. Weinberger, D. R.2003Brain-derived neurotrophic factor val(66)met polymorphism affects human memory-related hippocampal activity and predicts memory performance 6690-6694Journal of Neuroscience2317JulBDNF plays a critical role in activity-dependent neuroplasticity underlying learning and memory in the hippocampus. A frequent single nucleotide polymorphism in the targeting region of the human BDNF gene (val (66)met) has been associated with abnormal intracellular trafficking and regulated secretion of BDNF in cultured hippocampal neurons transfected with the met allele. In addition, the met allele has been associated with abnormal hippocampal neuronal function as well as impaired episodic memory in human subjects, but a direct effect of BDNF alleles on hippocampal processing of memory has not been demonstrated. We studied the relationship of the BDNF val (66)met genotype and hippocampal activity during episodic memory processing using blood oxygenation level-dependent functional magnetic resonance imaging and a declarative memory task in healthy individuals. Met carriers exhibited relatively diminished hippocampal engagement in comparison with val homozygotes during both encoding and retrieval processes. Remarkably, the interaction between the BDNF val (66)met genotype and the hippocampal response during encoding accounted for 25% of the total variation in recognition memory performance. These data implicate a specific genetic mechanism for substantial normal variation in human declarative memory and suggest that the basic effects of BDNF signaling on hippocampal function in experimental animals are important in humans.://000184469200003 Times Cited: 90ISI:000184469200003NIMH, Clin Brain Disorders Branch, Intramural Res Program, NIH,US Dept HHS, Bethesda, MD 20892 USA. Weinberger, DR, NIMH, Clin Brain Disorders Branch, Intramural Res Program, NIH,US Dept HHS, 10 Ctr Dr,Room 4S235, Bethesda, MD 20892 USA.~?DHariri, A. R. Mattay, V. S. Tessitore, A. Fera, F. Weinberger, D. R.2003BNeocortical modulation of the amygdala response to fearful stimuli494-501Biological Psychiatry536Mar{Background: The cortical circuitry involved in conscious cognitive processes and the subcortical circuitry involved in fear responses have been extensively studied with neuroimaging, but their interactions remain largely unexplored. A recent functional magnetic resonance imaging (fMRI) study demonstrated that the engagement of the right prefrontal cortex during the cognitive evaluation of angry and fearful facial expressions is associated with an attenuation of the response of the amygdala to these same stimuli, providing evidence for a functional neural network for emotional regulation. Methods: In the current study, we have explored the generalizability of this functional network by using threatening and fearful non-face stimuli derived from the International Affective Picture System (IAPS), as well as the influence of this network on peripheral autonomic responses. Results: Similar to the earlier findings with facial expressions, blood oxygen level dependent fMRI revealed that whereas perceptual processing of IAPS stimuli was associated with a bilateral amygdala response, cognitive evaluation of these same stimuli was associated with attenuation of this amygdala response and a correlated increase in response of the right prefrontal cortex and the anterior cingulate cortex. Moreover, this pattern was reflected in changes in skin conductance. Conclusions: The current results further implicate the importance of neocortical regions, including the prefrontal and anterior cingulate cortices, in regulating emotional responses mediated by the amygdala through conscious evaluation and appraisal. (C) 2003 Society of Biological Psychiatry.://000181569900004 Times Cited: 90ISI:000181569900004NIMH, Clin Brain Disorders Branch, Intramural Res Program, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. Hariri, AR, NIMH, Clin Brain Disorders Branch, Intramural Res Program, NIH,Dept Hlth & Human Serv, 10 Ctr Dr,Rm 3C108, Bethesda, MD 20892 USA.~?Hariri, A. R. Weinberger, D. R.2003Imaging genomics259-270British Medical Bulletin65;The recent completion of a working draft of the human genome sequence promises to provide unprecedented opportunities to explore the genetic basis of individual differences in complex behaviours and vulnerability to neuropsychiatric illness. Functional neuroimaging, because of its unique ability to assay information processing at the level of brain within individuals, provides a powerful approach to such functional genomics. Recent fMRI studies have established important physiological links between functional genetic polymorphisms and robust differences in information processing within distinct brain regions and circuits that have been linked to the manifestation of various disease states such as Alzheimer's disease, schizophrenia and anxiety disorders. Importantly, all of these biological relationships have been revealed in relatively small samples of healthy volunteers and in the absence of observable differences at the level of behaviour, underscoring the power of a direct assay of brain physiology like fMRI in exploring the functional impact of genetic variation.://000182080300019 Times Cited: 47ISI:000182080300019NIMH, Clin Brain Disorders Branch, Intramural Res Program, NIH, Bethesda, MD 20892 USA. Weinberger, DR, NIMH, Clin Brain Disorders Branch, Intramural Res Program, NIH, 10 Ctr Dr,Room 4S235, Bethesda, MD 20892 USA.~?>Heinz, A. Romero, B. Gallinat, J. Juckel, G. Weinberger, D. R.2003JMolecular brain imaging and the neurobiology and genetics of schizophrenia S152-S157Pharmacopsychiatry36NovIt has been hypothesized that schizophrenia is related to dysfunction in temporolimbic-prefrontal neuronal networks, which is acquired early in an individual's development. After puberty, relatively reduced prefrontal control of striatal dopaminergic neurotransmission may lead to unmodulated striatal dopamine (DA) activity, and the positive symptoms of acute psychosis. Brain imaging studies support the notion of prefrontal dysfunction in schizophrenia and correlated upregulation of presynaptic striatal DA activity. Recent molecular brain imaging studies have combined genetic assessments with a multimodal neuroimaging approach to further refine our understanding of the pathophysiologic architecture of the disorder. We review the literature on functional brain imaging in schizophrenia and discuss genotype effects on core psychotic symptoms. A promising research strategy is the identification of genetic and environmental factors that contribute to intermediate phenotypes such as working memory deficits in schizophrenia. Molecular brain imaging can help to unravel the complex interactions between genes and environment and its association with neuronal network dysfunction in schizophrenia.://000188081200002 Times Cited: 6 Suppl. 3ISI:000188081200002Charite Univ Med Berlin, Dept Psychiat & Psychotherapy, D-10117 Berlin, Germany. NIMH, Clin Brain Disorders Branch, NIH, Bethesda, MD 20892 USA. Heinz, A, Charite Univ Med Berlin, Dept Psychiat & Psychotherapy, CCM, Schumannstr 20-21, D-10117 Berlin, Germany. andreas.heinz@charite.de~?Mattay, V. S. Goldberg, T. E. Fera, F. Hariri, A. R. Tessitore, A. Egan, M. F. Kolachana, B. Callicott, J. H. Weinberger, D. R.2003pCatechol O-methyltransferase val(158)-met genotype and individual variation in the brain response to amphetamine 6186-6191OProceedings of the National Academy of Sciences of the United States of America10010May\Monamines subserve many critical roles in the brain, and monoaminergic drugs such as amphetamine have a long history in the treatment of neuropsychiatric disorders and also as a substance of abuse. The clinical effects of amphetamine are quite variable, from positive effects on mood and cognition in some individuals, to negative responses in others, perhaps related to individual variations in monaminergic function and monoamine system genes. We explored the effect of a functional polymorphism (val(158)-Met) in the catechol O-methyltransferase gene, which has been shown to modulate prefrontal dopamine animals and prefrontal cortical function in humans, on the modulatory actions of amphetamine on the prefrontal cortex. Amphetamine enhanced the efficiency of prefrontal cortex function assayed with functional MRI during a working memory task in subjects with the high enzyme activity val/val genotype, who presumably have relatively less prefrontal synaptic dopamine, at all levels of task difficulty. In contrast, in subjects with the low activity met/met genotype who tend to have superior baseline prefrontal function, the drug had no effect on cortical efficiency at low-to-moderate working memory load and caused deterioration at high working memory load. These data illustrate an application of functional neuroimaging in pharmacogenomics and extend basic evidence of an inverted-"U" functional-response curve to increasing dopamine signaling in the prefrontal cortex. Further, individuals with the met/met catechol O-methyltransferase genotype appear to beat increased risk for an adverse response to amphetamine.://000182939400110 Times Cited: 125ISI:000182939400110NIMH, Clin Brain Disorders Branch, NIH, Dept Hlth & Human Serv, Bethesda, MD 20982 USA. Weinberger, DR, NIMH, Clin Brain Disorders Branch, NIH, Dept Hlth & Human Serv, Bldg 10,Ctr Dr,Room 4S-235, Bethesda, MD 20982 USA.~?IScamvougeras, A. Kigar, D. L. Jones, D. Weinberger, D. R. Witelson, S. F.2003eSize of the human corpus callosum is genetically determined: an MRI study in mono and dizygotic twins91-94Neuroscience Letters3382FebThe factors determining the large variation seen in human corpus callosum (CC) morphology are as yet unknown. In this study heritability of CC size was assessed by comparing the concordance of CC midsagittal area in 14 monozygotic and 12 dizygotic twin pairs with a mean age of 27 years, using magnetic resonance imaging and various methods of calculating trait heritability. Heritability was high regardless of method of assessment. The application of a structural equation model resulted in the estimate that 94% of the variance in CC midsagittal size is attributable to the genome. This indicates that under normal conditions and before the effects of normal aging, there is very modest influence of the environment on CC morphology. The results suggest that correlates of CC size, such as the pattern of cerebral lateralization, cognitive abilities and neuropsychiatric dysfunction may be associated with the genetic determinants of CC morphology. (C) 2002 Published by Elsevier Science Ireland Ltd.://000181014300001 Times Cited: 6ISI:000181014300001McMaster Univ, Albert Einstein Irving Zucker Chair Neurosci, Dept Psychiat & Behav Neurosci, Hamilton, ON L8N 3Z5, Canada. Univ British Columbia, Dept Psychiat, Neuropsychiat Unit, Vancouver, BC, Canada. NIMH, Clin Brain Disorders Branch, Intramural Res Program, NIH, Bethesda, MD 20892 USA. Witelson, SF, McMaster Univ, Albert Einstein Irving Zucker Chair Neurosci, Dept Psychiat & Behav Neurosci, 1200 Main St W, Hamilton, ON L8N 3Z5, Canada.~?^Scarabino, T. Bertolino, A. Burroni, M. Popolizio, T. Duyn, J. Weinberger, D. R. Salvolini, U.2003wWhite matter lesions in phenylketonuria: Evaluation with magnetic resonance Imaging and magnetic resonance spectroscopy251-261Rivista Di Neuroradiologia162Apr.Phenylketonuria (PKU) is a congenital metabolic autosomic recessive disease, caused by a deficit in the liver of phenyl-alanine hydroxylase, the enzyme responsible for conversion of phenyl-alanine (PHE) into tyrosine. Reduction of this enzymatic activity is responsible for increased phenyl-alanine in blood and tissues and, above all, in brain. Accumulation of PHE causes neural damage which produces a typical clinical picture with mental retardation, psychiatric symptoms and epilepsy. It is now possible to diagnose this disease early (with neonatal screening), before irreversible clinical symptoms reflecting central nervous system injury appear. Early diagnosis allows timely onset of therapy (the only possible) consisting of a special diet with reduced intake of PHE (integrated with a mix of aminoacids) whose objective is to keep levels of PHE low in the blood (3-6 mg/dl). Magnetic Resonance Imaging (MRI) is the elective diagnostic tool to evaluate in vivo the involvement of the brain in PKU. Previous MRI morphological studies in patients with PKU have reported various focal symmetrical lesions in periventricular white matter (especially parieto-occipital) of patients with PKU with PHE blood values higher than 10 mg/dl. These lesions, whose importance is not yet clear, seem to represent a reversible structural alteration of myelin, since they regress if blood PHE decreases. Proton magnetic resonance spectroscopy (H-1-MRS) can measure in vivo brain metabolites which could help determine the nature of white matter lesions. In particular, changes in NAA (a marker of neuronal integrity) or mI (a potential astrocytic marker) could point to possible neurochemical dysfunction, whereas Cho levels may parallel the degree of the tissue myelination. The purpose of the present study was to evaluate morphologically and biochemically the regional specificity of white matter lesions with structural MRI and with H-1-MRSI. The study included 12 patients with PKU ten to 42 years of age. All patients underwent structural MRI scans while eight of them were also studied with H-1-MRSI. Structural MRI lesions in white matter were analyzed both qualitatively (signal intensity) and quantitatively (location and extension). H-1-MRSI metabolites were measured as the ratio of the area under each peak: NAA/Cr, NAA/Cho, Cho/Cr. Analysis of location and extension of the lesion on structural MRI data showed limited involvement of parieto-occipital white matter in three cases (with isointense or vaguely hypointense lesions in T1, and moderately hyperintense lesions in T2); medium involvement in six cases (with fairly hypointense or isointense lesions in T1, fairly or moderately hyperintense lesions in T2); serious involvement in three cases (with isointense or fairly hypointense lesions in T1, and fairly hyperintense lesions in T2). As for H-1-MRSI data, ANOVA showed a significant reduction of NAA/Cho and increase in Cho/Cr in white matter lesions, but no change in NAA/Cr. No correlation was found between clinical parameters and morphological or spectroscopic data. In conclusion, our morphological MRI data confirmed the presence of multiple signal alterations, focal and symmetrical, in deep periventricular white matter (especially posterior), with occasional involvement of subcortical white matter. However, these lesions do not seem to be strongly predictive of clinical outcome. H-1-MRSI data suggest increased Cho levels in white matter lesions. Since Cho is thought to reflect membrane turnover, these data may support the demyelinating nature of lesions, consistent with earlier post mortem studies.://000184842000003 Times Cited: 0ISI:000184842000003_Casa Sollievo Sofferenza Sci Inst, Dept Neuroradiol, San Giovanni Rotondo, Italy. Univ Bari, Dept Neurol & Psychiat Sci, Psychiat Neurosci Grp, Bari, Italy. Gen Hosp, Dept Neuropsychiat, Fano, Italy. NIH, Lab Diagnost Radiol Res, Bethesda, MD USA. NIMH, Clin Brain Disorders Branch, NIH, Bethesda, MD USA. Univ Ancona, Dept Neuroradiol, Ancona, Italy.b~?FWinterer, G. Coppola, R. Egan, M. F. Goldberg, T. E. Weinberger, D. R.2003WFunctional and effective frontotemporal connectivity and genetic risk for schizophrenia 1181-1192Biological Psychiatry5411DecBackground: Functional neuroimaging and electrophysiologic studies have found disturbed frontotemporal interaction in schizophrenia. We sought to determine whether abnormalities of frontotemporal connectivity are trait markers of genetic risk for schizophrenia. Methods: We investigated 64 schizophrenia patients, 79 of their clinically unaffected siblings, and 88 unrelated normal controls with an auditory oddball electroencephalogram (EEG) evoked potential paradigm. We measured: 1) frontotemporal event-related EEG-coherence (i.e. a measure of functional connectivity); and 2) we performed structural equation modeling of the effective connectivity between the frontal P300 and temporoparietal P300-amplitude. Results: Schizophrenic patients and their siblings showed a reduction of frontotemporal coherence. At peak activation during the P300 time-window, a negative ("inhibitory") frontotemporal path coefficient was found in normal controls, whereas a positive coefficient was seen in schizophrenic patients with siblings being intermediate. Intra-class correlations between sib-pairs and relative risk estimates of the applied connectivity measures were non-significant. Topographic correlation matrix analyses suggested that the altered functional and effective frontotemporal connectivity indirectly reflect regional abnormalities of increased activation variance. Conclusions: Impaired interaction of the frontotemporal macro-circuit indirectly reflects genetically determined abnormalities of frontal and temporoparietal microcircuits. The reasons why frontotemporal connectivity appears to be a poor predictor of genetic risk for schizophrenia are discussed.://000186792300007 Times Cited: 23ISI:000186792300007NIMH, Clin Brain Disorders Branch, NIH, Bethesda, MD 20892 USA. Winterer, G, Univ Mainz, Psychiat Klin & Poliklin, Untere Zahlbacher Str 8, D-55131 Mainz, Germany. :~?Bertolino, A. Blasi, G. Caforio, G. Latorre, V. De Candia, M. Rubino, V. Callicott, J. H. Mattay, V. S. Bellomo, A. Scarabino, T. Weinberger, D. R. Nardini, M.2004yFunctional lateralization of the sensorimotor cortex in patients with schizophrenia: Effects of treatment with olanzapine190-197Biological Psychiatry563AugBackground: Earlier cross-sectional studies with functional magnetic resonance imaging (fMRI) in treated patients with schizophrenia have reported abnormalities of cortical motor processing, including reduced lateralization of primary sensory motor cortex. The objective of the present longitudinal study was to evaluate whether such cortical abnormalities represent state or trait phenomena of the disorder. Methods: Seventeen acutely ill, previously untreated patients were studied after 4 weeks and after 8 weeks of olanzapine therapy. Seventeen matched healthy subjects served as control subjects. All subjects underwent two fMRI scans 4 weeks apart during a visually paced motor task using a simple periodic block design. Functional magnetic resonance imaging data were analyzed in Statistical Parametric Mapping (SPM99). Region of interest analyses were used to determine a laterality quotient (an index of lateralization) of motor cortical regions. Results: The fMRI data indicated that patients bad reduced activation of the primary sensory motor cortex at 4 weeks but not at 8 weeks; however, the laterality quotient in the primary sensory motor cortex was reduced in patients at both time points. Conclusions: These results suggest that some cortical abnormalities during motor processing represent state phenomena, whereas reduced functional lateralization of the primary sensory motor complex presents an enduring trait of schizophrenia.://000222878800009 Times Cited: 9ISI:000222878800009Univ Bari, Dipartimento Sci Neurol & Psichiat, Grp Neurosci Psichiat, Sez Clin Malattie Mentali, I-70124 Bari, Italy. Univ Foggia, Dept Psychiat, Foggia, Italy. Inst Ricovero & Cura Carattere Sci, Dept Neuroradiol, San Giovanni Rotondo, Foggia, Italy. NIMH, Clin Brain Disorders Branch, Natl Inst Hlth, Bethesda, MD 20892 USA. Bertolino, A, Univ Bari, Dipartimento Sci Neurol & Psichiat, Grp Neurosci Psichiat, Sez Clin Malattie Mentali, Piazza Giulio Cesare 9, I-70124 Bari, Italy. ~?Egan, M. F. Straub, R. E. Goldberg, T. E. Yakub, I. Callicott, J. H. Hariri, A. R. Mattay, V. S. Bertolino, A. Hyde, T. M. Shannon-Weickert, C. Akil, M. Crook, J. Vakkalanka, R. K. Balkissoon, R. Gibbs, R. A. Kleinman, J. E. Weinberger, D. R.2004UVariation in GRM3 affects cognition, prefrontal glutamate, and risk for schizophrenia 12604-12609OProceedings of the National Academy of Sciences of the United States of America10134AugGRM3, a metabotropic glutamate receptor-modulating synaptic glutamate, is a promising schizophrenia candidate gene. in a family-based association study, a common GRM3 haplotype was strongly associated with schizophrenia (P = 0.0001). Within this haplotype, the A allele of single-nucleotide polymorphism (SNP) 4 (hCV11245618) in intron 2 was slightly overtransmitted to probands (P = 0.02). We studied the effects of this SNP on neurobiological traits related to risk for schizophrenia and glutamate neurotransmission. The SNP4 A allele was associated with poorer performance on several cognitive tests of prefrontal and hippocampal function. The physiological basis of this effect was assessed with functional MRI, which showed relatively deleterious activation patterns in both cortical regions in control subjects homozygous for the SNP4 A allele. We next looked at SNP4's effects on two indirect measures of prefrontal glutamate neurotransmission. Prefrontal N-acetylaspartate, an in vivo MRI measure related to synaptic activity and closely correlated with tissue glutamate, was lower in SNP4 AA homozygotes. In postmortem human prefrontal cortex, AA homozygotes had lower mRNA levels of the glial glutamate transporter EAAT2, a protein regulated by GRM3 that critically modulates synaptic glutamate. Effects of SNP4 on prefrontal GRM3 mRNA and protein levels were marginal. Resequencing revealed no missense or splice-site SNIPS, suggesting that the intronic SNP4 or related haplotypes may exert subtle regulatory effects on GRM3 transcription. These convergent data point to a specific molecular pathway by which GRM3 genotype alters glutamate neurotransmission, prefrontal and hippocampal physiology and cognition, and thereby increased risk for schizophrenia.://000223596200039 Times Cited: 34ISI:000223596200039NIMH, Clin Brain Disorders Branch, Intramural Res Program, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. Baylor Coll Med, Dept Mol & Human Genet, Human Genome Sequencing Ctr, Houston, TX 77030 USA. Univ Bari, Clin Psichiatr 2, I-70121 Bari, Italy. ES Cell Int Pte Ltd, Melbourne, Vic 8008, Australia. Weinberger, DR, NIMH, Clin Brain Disorders Branch, Intramural Res Program, NIH,Dept Hlth & Human Serv, Bldg 10,Ctr Dr,Room 45-227,MSC 1384, Bethesda, MD 20892 USA. weinberd@intra.nimh.nih.gov~?OKnutson, B. Bjork, J. M. Fong, G. W. Hommer, D. Mattay, V. S. Weinberger, D. R.20040Amphetamine modulates human incentive processing261-269Neuron432JulResearch suggests that psychostimulants can physiologically alter dopamine kinetics in the ventral striatum (VS) and psychologically enhance mood and attention. Using event-related functional magnetic resonance imaging (fMRI), we conducted a within-subject, double-blind, placebo (PLAC)-controlled study of the effects of oral dextroamphetamine (AMPH, 0.25 mg/kg) treatment on brain activity and affect during incentive processing. In two counterbalanced scanning sessions 60-180 min after ingesting AMPH or PLAC, 8 healthy volunteers played a game involving anticipation and receipt of monetary gains and losses. Group and volume of interest analyses suggested that by enhancing tonic over phasic activation, AMPH treatment "equalized" levels of VS activity and positive arousal during anticipation of both gain and loss. These findings suggest that therapeutic effects of amphetamine on incentive processing may involve reducing the difference between anticipation of gains and losses.://000222905400014 Times Cited: 11ISI:000222905400014Stanford Univ, Dept Psychol, Stanford, CA 94305 USA. NIAAA, Clin Studies Lab, Bethesda, MD 20892 USA. NIMH, Clin Brain Disorders Branch, Bethesda, MD 20892 USA. Knutson, B, Stanford Univ, Dept Psychol, Stanford, CA 94305 USA. knutson@psych.stanford.edu5?Pezawas, L. Verchinksi, B. Mattay, V. Callicott, J. H. Kolachana, B. Straub, R. E. Egan, M. Meyer-Lindenberg, A. Weinberger, D. R.2004i The brain-derived neurotrophic factor val66met polymorphism and variation in human cortical morphology. 10099-10102Journal of Neuroscience2545 ~?Bertolino, A. Arciero, G. Rubino, V. Latorre, V. De Candia, M. Mazzola, V. Blasi, G. Caforio, G. Hariri, A. Kolachana, B. Nardini, M. Weinberger, D. R. Scarabino, T.2005xVariation of human amygdala response during threatening stimuli as a function of 5'HTTLPR genotype and personality style 1517-1525Biological Psychiatry5712JunBackground: In the brain, processing of fearful stimuli engages the amygdala, and the variability of its activity is associated with genetic factors as well as with emotional salience. The objective of this study was to explore the relevance of personality style for variability of amygdala response. Methods. We studied two groups (n = 14 in each group) of healthy subjects categorized by contrasting cognitive styles with which they attribute salience to fearful stimuli: so-called phobic prone subjects who exaggerate potential environmental threat versus so-called eating disorders prone subjects who tend to be much, less centered around fear. The two groups underwent functional magnetic resonance imaging (fMRI) at 3T during performance of a perceptual task of threatening stimuli and they were also matched for the genotype of the 5'variable number tandem repeat (VNTR) polymorphism in the serotonin transporter Results. The fMRI results indicated that phobic prone results indicated that phobic prone subjects selectively recruit the amygdala to a larger extent than eating disorders prone subjects. Activity in the amygdala was also independently predicted by personality style and genotype of the serotonin transporter. Moreover, brain activity during a working memory task did not differentiate the two groups. Conclusions. The results of the present study suggest that aspects of personality style are rooted in biological responses of the fear circuitry associated with processing of environmental information.://000230007700007 Times Cited: 9ISI:000230007700007PUniv Bari, Dipartimento Sci Neurol & Psichiatriche, Sect Mental Disorders, I-70124 Bari, Italy. Univ Bari, Psychiat Neurosci Grp, I-70124 Bari, Italy. Ist Psicoterapia & Postrazionalista, Rome, Italy. NIMH, Clin Brain Disorders Branch, NIH, Bethesda, MD 20892 USA. IRCCS Casa Sollievo Sofferenza, Dept Neuroradiol, San Giovanni Rotondo, Italy. Univ Pittsburgh, Sch Med, Dept Psychiat, Dev Imaging Genom Program, Pittsburgh, PA USA. Bertolino, A, Univ Bari, Dipartimento Sci Neurol & Psichiatriche, Sect Mental Disorders, Piazza Giulio Cesare,9, I-70124 Bari, Italy. bertolia@psichiat.uniba.it9~?Blasi, G. Mattay, V. S. Bertolino, A. Elvevag, B. Callicott, J. H. Das, S. Kolachana, B. S. Egan, M. F. Goldberg, T. E. Weinberger, D. R.2005REffect of catechol-O-methyltransferase val(158)met genotype on attentional control 5038-5045Journal of Neuroscience2520MayThe cingulate cortex is richly innervated by dopaminergic projections and plays a critical role in attentional control ( AC). Evidence indicates that dopamine enhances the neurophysiological signal-to-noise ratio and that dopaminergic tone in the frontal cortex is critically dependent on catechol-O-methyltransferase ( COMT). A functional polymorphism ( val(158)met) in the COMT gene accounts for some of the individual variability in executive function mediated by the dorsolateral prefrontal cortex. We explored the effect of this genetic polymorphism on cingulate engagement during a novel AC task. We found that the COMT val(158)met polymorphism also affects the function of the cingulate during AC. Individuals homozygous for the high-activity valine ("val") allele show greater activity and poorer performance than val/methionine ("met") heterozygotes, who in turn show greater activity and poorer performance than individuals homozygous for the low-activity met allele, and these effects are most evident at the highest demand for AC. These results indicate that met allele load and presumably enhanced dopaminergic tone improve the "efficiency" of local circuit processing within the cingulate cortex and thereby its function during AC.://000229203600016 Times Cited: 18ISI:000229203600016NIMH, Clin Brain Disorders Branch, NIH, Dept Hlth & Human Serv,Gene Cognit & Psychosis Pr, Bethesda, MD 20892 USA. Univ Bari, Dept Neurol & Psychiat Sci, Neurosci Psychiat Grp, I-70124 Bari, Italy. Ist Ricovero & Cura Carattere Sci Casa Sollievo S, Dept Neuroradiol, I-71013 San Giovanni Rotondo, Italy. Weinberger, DR, NIMH, Clin Brain Disorders Branch, NIH, Dept Hlth & Human Serv,Gene Cognit & Psychosis Pr, Bldg 10,Ctr Dr,Room 4S-235, Bethesda, MD 20892 USA. weinberd@mail.nih.gov?Callicott, J. H. Straub, R. E. Pezawas, L. Egan, M. Mattay, V. Hariri, A. Verchinksi, B. Meyer-Lindenberg, A. Balkissoon, R. Kolachana, B. Goldberg, T. E. Weinberger, D. R.2005cVariation in DISC1 affects hippocampal structure and function and increases risk for schizophrenia. 8627-8632OProceedings of the National Academy of Sciences of the United States of America102244?Fera, F. Weickert, T. Goldberg, T. E. Tessitore, A. Hariri, A. Das, S. Lee, S. Zoltick, B. Meeter, M. Myers, C. E. Gluck, M. A. Weinberger, D. R. Mattay, V.2005MNeural mechanisms underlying probabilistic category learning in normal aging. 11340-11348Journal of Neuroscience2549?ZHariri, A. Drabant, E. M. Munoz, K. E. Kolachana, B. Mattay, V. Egan, M. Weinberger, D. R.2005WA susceptibility gene for affective disorders and the response of the human amygdala. 142-152Arch Gen Psychiatry622C?Pezawas, L. Meyer-Lindenberg, A. Drabant, E. M. Verchinksi, B. Munoz, K. E. Kolachana, B. Egan, M. Mattay, V. Hariri, A. Weinberger, D. R.2005y 5-HTTLPR polymorphism impacts human cingulate-amygdala interactions: a genetic susceptibility mechanism for depression. 828-834Nature Neuroscience86 ~? YTessitore, A. Hariri, A. R. Fera, F. Smith, W. G. Das, S. Weinberger, D. R. Mattay, V. S.2005`Functional changes in the activity of brain regions underlying emotion processing in the elderly9-18 Psychiatry Research-Neuroimaging1391MayAging is associated with a decline in both cognitive and motor abilities that reflects deterioration of underlying brain circuitry. While age-related alterations have also been described in brain regions underlying emotional behavior (e.g., the amygdala), the functional consequence of such changes is less clear. To this end, we used blood oxygenation-level dependent (BOLD) functional magnetic resonance imaging (fMRI) to explore age-related changes in brain regions underlying emotion processing. Twelve young (age < 30 years) and 14 elderly subjects (age > 60 years) were studied with BOLD fMRI during a paradigm that involved perceptual processing of fearful and threatening stimuli. Consistent with previous reports, direct group comparisons revealed relatively increased BOLD fMRI responses in prefrontal cortical regions, including Broca's area, and relatively decreased responses in the amygdala and posterior fusiform gyri in elderly subjects. Importantly, additional analyses using an elderly-specific brain template for spatial normalization of the elderly BOLD fMRI data confirmed these divergent regional response patterns. While there was no difference between groups in accuracy on the task, elderly subjects were significantly slower (delayed reaction times) in performing the task. Our current data suggest that elderly subjects engage a more distributed neocortical network during the perceptual processing of emotional facial expressions. In light of recent converging data froth two other studies, our observed effects may reflect age-related compensatory responses and/or alternative strategies in processing emotions, as the elderly appear to engage cognitive/linguistic systems in the context of reduced sensory and/or limbic responses. (c) Published by Elsevier Ireland Ltd.://000230603600002 Times Cited: 2ISI:000230603600002NIMH, Clin Brain Disorders Branch, Genes Cognit & Psychosis Program, NIH, Bethesda, MD 20892 USA. Univ Naples 2, Dept Neurosci, Div Neurol 2, I-80138 Naples, Italy. Univ Pittsburgh, Sch Med, Dept Psychiat, Pittsburgh, PA 15213 USA. CNR, Inst Neurol Sci, Lab Neuroimaging, I-87050 Cosenza, Italy. Mattay, VS, NIMH, Clin Brain Disorders Branch, Genes Cognit & Psychosis Program, NIH, Bethesda, MD 20892 USA. vsm@helix.nih.gov~?!Bertolino, A. Caforio, G. Petruzzella, V. Latorre, V. Rubino, V. Dimalta, S. Torraco, A. Blasi, G. Quartesan, R. Mattay, V. S. Callicott, J. H. Weinberger, D. R. Scarabino, T.2006pPrefrontal dysfunction in schizophrenia controlling for COMT Val(158)Met genotype and working memory performance221-226 Psychiatry Research-Neuroimaging1472-3OctEarlier studies with functional imaging in schizophrenia have demonstrated dysfunction of the dorsolateral prefrontal cortex during working memory. Controlling for behavioral performance and for catechol-O-methyltransferase (COMT) Val(158)Met genotype, we here demonstrate in a functional magnetic resonance imaging paradigm that patients recruit greater neuronal resources in prefrontal cortex during working memory, suggesting that this phenotype is a core functional trait of the disease. We also replicated earlier findings that the Val allele of the COMT polymorphism is associated with greater engagement of the prefrontal cortex. (c) 2006 Elsevier Ireland Ltd. All rights reserved.://000241326800013 Times Cited: 0ISI:0002413268000131Univ Bari, Dipartimento Sci Neurol & Psichiatr, Sect Mental Disorders, Psychiat Neurosci Grp, I-70124 Bari, Italy. Univ Bari, Dept Med Biochem & Mol Biol, I-70124 Bari, Italy. Univ Perugia, Dept Clin & Expt Med, I-06100 Perugia, Italy. NIMH, Clin Brain Disorders Branch, NIH, Bethesda, MD 20892 USA. IRCCS Casa Sollievo Sofferenza, Dept Neuroradiol, San Giovanni Rotondo, FG, Italy. Bertolino, A, Univ Bari, Dipartimento Sci Neurol & Psichiatr, Sect Mental Disorders, Psychiat Neurosci Grp, Piazz Giulio Cesare 9, I-70124 Bari, Italy. bertolia@psichiat.uniba.itk~?"Bertolino, A. Rubino, V. Sarnbataro, F. Blasi, G. Latorre, V. Fazio, L. Caforio, G. Petruzzella, V. Kolachana, B. Hariri, A. Meyer-Lindenberg, A. Nardini, M. Weinberger, D. R. Scarabino, T.2006`Prefrontal-hippocampal coupling during memory processing is modulated by COMT Val158met genotype 1250-1258Biological Psychiatry6011DecBackground: Studies in humans and in animals have demonstrated that a network of brain regions is involved in performance of declarative and recognition memory tasks. This network includes the hippocampal formation (HF) as well as the ventrolateral prefrontal cortex (VLPFC). Studies in animals have suggested that the relationship between these brain regions is strongly modulated by dopamine. Methods. Using fMRI in healthy humans matched for a series of demographic and genetic variables, we studied the effect of the COMT val158met polymorphism on function of HF and VLPFC as well as on their functional coupling during recognition memory. Results: The COMT Val allele was associated with: relatively poorer performance at retrieval; reduced recruitment of neuronal resources in HF and increased recruitment in VLPFC during both encoding and retrieval; and unfavorable functional coupling between these two regions at retrieval. Moreover, functional coupling during retrieval was predictive of behavioral accuracy. Conclusions: These results shed new light on individual differences in responsivity and connectivity between HE and VLPFC related to genetic modulation of dopamine, a mechanism accounting at least in pan for individual differences in recognition memory performance.://000242278700011 Times Cited: 1ISI:000242278700011Univ Bari, Psychiat Neurosci Grp, Sect Mental Disorders, Dept Psychiat & Neurol Sci, Bari, Italy. NIMH, Genes Cognit & Psychosis Program, NIH, Bethesda, MD 20892 USA. Univ Bari, Dept Med Biochem & Med Biol, Bari, Italy. IRCCSS Casa Sollievo Sofferenza, Dept Neuroradiol, San Giovanni Rotondo, Italy. Bertolino, A, Univ Bari, Dipartimento Sci Neurol & Psichiat, Piazza Giulio Cesare 9, I-70124 Bari, Italy. bertolia@psichiat.uniba.it ~?#Blasi, G. Goldberg, T. E. Weickert, T. Das, S. Kohn, P. Zoltick, B. Bertolino, A. Callicott, J. H. Weinberger, D. R. Mattay, V. S.2006XBrain regions underlying response inhibition and interference monitoring and suppression 1658-1664 European Journal of Neuroscience236MarMResponse inhibition and interference monitoring and suppression are two important aspects of cognitive control. Previous functional imaging studies have suggested a common network of brain regions underlying these cognitive processes; the dorsolateral prefrontal cortex (DLPFC), the ventrolateral prefrontal cortex (VLPFC), the dorsal cingulate (dACC), and the parietal cortex (PC). The relative contribution of these regions to these cognitive subprocesses, however, has not been determined. Based on previous findings supporting a role for dACC in the monitoring of conflicting information within a stimulus, we hypothesized greater activity in this cortical region during interference monitoring and suppression relative to response inhibition. On the other hand, as response inhibition is characterized by differential cognitive processes such as control implementation, top down modulation of the response, expectancy, and inhibition of behavioural response, we hypothesized increased activity in the other cortical nodes of the cognitive control network relative to interference monitoring and suppression. To this end, we conducted an event-related functional magnetic resonance imaging (fMRI) study in 57 healthy volunteers using a task preferentially involving either interference monitoring and suppression or response inhibition. Accuracy for response inhibition was lower than for interference monitoring and suppression. Imaging data showed activation in DLPFC, dACC, VLPFC, PC for both conditions. Comparisons between the two conditions indicated greater activation bilaterally in DLPFC, VLPFC and PC during response inhibition, and greater activation in the dACC during interference monitoring and suppression. These results extend previous findings by suggesting regional functional specialization within a cortical network supporting cognitive control.://000236176000027 Times Cited: 0ISI:000236176000027@NIMH, CBDB, GCAP, NIH,Dept Hlth & Human Serv, Bethesda, MD 20982 USA. Univ Bari, Psychiat Neurosci Grp, Dept Neurol & Psychiat Sci, Bari, Italy. IRCCS Casa Sollievo Sofferenza, San Giovanni Rotondo, Italy. Mattay, VS, NIMH, CBDB, GCAP, NIH,Dept Hlth & Human Serv, Bldg 10,Ctr Dr, Bethesda, MD 20982 USA. vsm@mail.nih.gov!?$oDrabant, E. M. Hariri, A. Meyer-Lindenberg, A. Munoz, K. E. Mattay, V. Kolachana, B. Egan, M. Weinberger, D. R.2006sCatechol O-methyltransferase val158met genotype and neural mechanisms related to affective arousal and regulation. 1396-1406Arch Gen Psychiatry63 ~?%}Goldberg, T. E. Straub, R. E. Callicott, J. H. Hariri, A. Mattay, V. S. Bigelow, L. Coppola, R. Egan, M. F. Weinberger, D. R.2006EThe G72/G30 gene complex and cognitive abnormalities in schizophrenia 2022-2032Neuropsychopharmacology319SepA recently discovered gene complex, G72/G30 (hereafter G72, but now termed DAOA), was found to be associated with schizophrenia and with bipolar disorder, possibly because of an indirect effect on NMDA neurotransmission. In principle, if G72 increases risk for psychosis by this mechanism, it might impact with greater penetrance those cortically based cognitive and neurophysiological functions associated with NMDA signaling. We performed two independent family-based association studies (one sample contained more than 200 families and the other more than 65) of multiple SNPs in the G72 region and of multiple SNPs in the gene for (D)amino acid oxidase (DAAO), which may be modulated by G72. We examined the relationship between select cognitive measures in attention, working memory, and episodic memory and a restricted set of G72 SNPs in over 600 normal controls, schizophrenic patients, and their nonpsychotic siblings using mixed model ANOVAs. We also determined genotype effects on neurophysiology measures in normal controls using the fMRI BOLD response obtained during activation procedures involving either episodic memory or working memory. There were no significant single G72 SNP associations and clinical diagnosis in either sample, though one approached significance (p = 0.06). Diagnosis by genotype interaction effects for G72 SNP 10 were significant for cognitive variables assessing working memory and attention (p = 0.05), and at the trend level for episodic memory, such that in the schizophrenia group an exaggerated allele load effect in the predicted directions was observed. In the fMRI paradigms, a strong effect of G72 SNP 10 genotype was observed on BOLD activation in the hippocampus during the episodic memory paradigm. Tests of association with DAAO were consistently nonsignificant. We present evidence that SNP variations in the G72 gene region increase risk of cognitive impairment in schizophrenia. SNP variations were not strongly associated with clinical diagnosis in family-based analyses.://000239920400019 Times Cited: 0ISI:000239920400019NIMH, Clin Brain Disorders Branch, IRP, NIH, Bethesda, MD USA. Goldberg, TE, Hillside Hosp, Div Psychiat Res, 75 59 263rd St, Glen Oaks, NY 11004 USA. tgoldber@nshs.edu~?&`Marenco, S. Rawlings, R. Rohde, G. K. Barnett, A. S. Hone, R. A. Pierpaoli, C. Weinberger, D. R.2006FRegional distribution of measurement error in diffusion tensor imaging69-78 Psychiatry Research-Neuroimaging1471JunnThe characterization of measurement error is critical in assessing the significance of diffusion tensor imaging (DTI) findings in longitudinal and cohort studies of psychiatric disorders. We studied 20 healthy volunteers, each one scanned twice (average interval between scans of 51 +/- 46.8 days) with a single shot echo planar DTI technique. Intersession variability for fractional anisotropy (FA) and Trace (D) was represented as absolute variation (standard deviation within subjects: SDw), percent coefficient of variation (CV) and intraclass correlation coefficient (ICC). The values from the two sessions were compared for statistical significance with repeated measures analysis of variance or a non-parametric equivalent of a paired t-test. The results showed good reproducibility for both FA and Trace (CVs below 10% and ICCs at or above 0.70 in most regions of interest) and evidence of systematic global changes in Trace between scans. The regional distribution of reproducibility described here has implications for the interpretation of regional findings and for rigorous preprocessing. The regional distribution of reproducibility measures was different for SDw, CV and ICC. Each one of these measures reveals complementary information that needs to be taken into consideration when performing statistical operations on groups of DT images. Published by Elsevier Ireland Ltd.://000239973800006 Times Cited: 0ISI:000239973800006aNIMH, CBDB, Genes Cognit & Psychosis Program, IRP, Bethesda, MD 20892 USA. NIAAA, Sect Brain Electrophysiol & Imaging, LCS, IRP, Bethesda, MD USA. NICHD, Sect Tissue Biophys & Biomimet, LIMB, IRP, Bethesda, MD USA. Marenco, S, NIMH, CBDB, Genes Cognit & Psychosis Program, IRP, 10 Ctr Dr,Bldg 10,Room 4S235, Bethesda, MD 20892 USA. marencos@mail.nih.gov ~?'Mattay, V. S. Fera, F. Tessitore, A. Hariri, A. R. Berman, K. F. Das, S. Meyer-Lindenberg, A. Goldberg, T. E. Callicott, J. H. Weinberger, D. R.2006ONeurophysiological correlates of age-related changes in working memory capacity32-37Neuroscience Letters3921-2JanCognitive abilities such as working memory (WM) capacity decrease with age. To determine the neurophysiological, correlates of age-related reduction in working memory capacity, we studied 10 young subjects (<35 years of age; mean age = 29) and twelve older subjects (>55 years of age; mean age = 59) with whole brain blood oxygenation-level dependent (BOLD) fMRI on a 1.5 T GE MR scanner using a SPIRAL FLASH pulse sequence (TE = 24 ms, TR = 56 ms, FA = 60 degrees, voxel dimensions = 3.75 mm(3)). Subjects performed a modified version of the "n" back working memory task at different levels of increasing working memory load (I-Back, 2-Back and 3-Back). Older subjects performed as well as the younger subjects at 1-Back (p = 0.4), but performed worse than the younger subjects at 2-Back (p < 0.01) and 3-Back (p = 0.06). Older subjects had significantly longer reaction time (RT) than younger subjects (p < 0.04) at all levels of task difficulty. Image analysis using SPM 99 revealed a similar distribution of cortical activity between younger and older subjects at all task levels. However, an analysis of variance revealed a significant group x task interaction in the prefrontal cortex bilaterally; within working memory capacity, as in I-Back when the older subjects performed as well as the younger subjects, they showed greater prefrontal cortical (BA 9) activity bilaterally. At higher working memory loads, however, when they performed worse then the younger subjects, the older subjects showed relatively reduced activity in these prefrontal regions. These data suggest that, within capacity, compensatory mechanisms such as additional prefrontal cortical activity are called upon to maintain proficiency in task performance. As cognitive demand increases, however, they are pushed past a threshold beyond which physiological compensation cannot be made and, a decline in performance occurs. (C) 2005 Elsevier Ireland Ltd. All rights reserved.://000234268400007 Times Cited: 3ISI:000234268400007NIMH, Clin Brain Disorders Branch, Cognit & Psychosis Program, NIH, Bethesda, MD 20892 USA. Mattay, VS, Bldg 10,Ctr Dr,Rm 3C-108, Bethesda, MD 20982 USA. vsm@mail.nih.gov?(VMcClure, R. K. Phillips, I. Jazayerli, R. Barnett, A. S. Coppola, R. Weinberger, D. R.2006^Regional change in brain morphometry in schizophrenia associated with antipsychotic treatment.121-132Biological Research148V~?)Meyer-Lindenberg, A. Buckholtz, J. W. Kolachana, B. Hariri, A. R. Pezawas, L. Blasi, G. Wabnitz, A. Honea, R. Verchinski, B. Callicott, J. H. Egan, M. Mattay, V. Weinberger, D. R.2006HNeural mechanisms of genetic risk for impulsivity and violence in humans 6269-6274OProceedings of the National Academy of Sciences of the United States of America10316AprNeurobiological factors contributing to violence in humans remain poorly understood. One approach to this question is examining allelic variation in the X-linked monoamine oxidase A (MAOA) gene, previously associated with impulsive aggression in animals and humans. Here, we have studied the impact of a common functional polymorphism in MAOA on brain structure and function assessed with MRI in a large sample of healthy human volunteers. We show that the low expression variant, associated with increased risk of violent behavior, predicted pronounced limbic volume reductions and hyperresponsive amygdala during emotional arousal, with diminished reactivity of regulatory prefrontal regions, compared with the high expression allele. In men, the low expression allele is also associated with changes in orbitofrontal volume, amygdala and hippocampus hyperreactivity during aversive recall, and impaired cingulate activation during cognitive inhibition. Our data identify differences in limbic circuitry for emotion regulation and cognitive control that may be involved in the association of MAOA with impulsive aggression, suggest neural systems-level effects of X-inactivation in human brain, and point toward potential targets for a biological approach toward violence.://000236999000039 Times Cited: 6ISI:000236999000039US Dept HHS, Unit Syst Neurosci Psychiat, NIMH, NIH, Bethesda, MD 20892 USA. US Dept HHS, Neuroimaging Core Facil, NIMH, NIH, Bethesda, MD 20892 USA. US Dept HHS, Clin Brain Disorders Branch, NIMH, Genes Cognit & Psychosis Program,NIH, Bethesda, MD 20892 USA. Meyer-Lindenberg, A, US Dept HHS, Unit Syst Neurosci Psychiat, NIMH, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. andreasml@nih.gov7~?*Meyer-Lindenberg, A. Nichols, T. Callicott, J. H. Ding, J. Kolachana, B. Buckholtz, J. Mattay, V. S. Egan, M. Weinberger, D. R.2006CImpact of complex genetic variation in COMT on human brain function867-877Molecular Psychiatry119Sep:Catechol-O-methyltransferase (COMT) has been shown to be critical for prefrontal dopamine flux, prefrontal cortex-dependent cognition and activation. Several potentially functional variants in the gene have been identified, but considerable controversy exists regarding the contribution of individual alleles and haplotypes to risk for schizophrenia, partly because clinical phenotypes are ill-defined and preclinical studies are limited by lack of adequate models. Here, we propose a neuroimaging approach to overcome these limitations by characterizing the functional impact of ambiguous haplotypes on a neural system-level intermediate phenotype in humans. Studying 126 healthy control subjects during a workingmemory paradigm, we find that a previously described risk variant in a functional Val158Met (rs4680) polymorphism interacts with a P2 promoter region SNP (rs2097603) and an SNP in the 30 region (rs165599) in predicting inefficient prefrontal working memory response. We report evidence that the nonlinear response of prefrontal neurons to dopaminergic stimulation is a neural mechanism underlying these nonadditive genetic effects. This work provides an in vivo approach to functional validation in brain of the biological impact of complex genetic variations within a gene that may be critical for its clinical association.://000240043100010 Times Cited: 3ISI:000240043100010NIMH, Neuroimaging Core Facil, NIH, DHHS, Bethesda, MD 20892 USA. NIMH, Unit Syst Neurosci Psychiat, NIH, DHHS, Bethesda, MD 20892 USA. NIMH, Clin Brain Disorders Branch, NIH, DHHS,Cognit & Psychosis Program, Bethesda, MD 20892 USA. Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA. Meyer-Lindenberg, A, NIMH, Neuroimaging Core Facil, NIH, DHHS, 10-3C103,9000 Rockville Pike, Bethesda, MD 20892 USA. andreasml@nih.gov !~?+vTan, H. Y. Sust, S. Buckholtz, J. W. Mattay, V. S. Meyer-Lindenberg, A. Egan, M. F. Weinberger, D. R. Callicott, J. H.2006RDysfunctional prefrontal regional specialization and compensation in schizophrenia 1969-1977American Journal of Psychiatry16311NovObjective: It has been suggested that in healthy persons higher-order cognitive processing engaged by incremental working memory load hierarchically employs more dorsal than ventral prefrontal resources in healthy individuals. Given that working memory performance is impaired in schizophrenia, especially at higher executive loads, the authors investigated how this prefrontal functional organization might be altered in disease, independent of performance deficits. Method: Using N-back working memory functional magnetic resonance imaging (fMRI) data, the authors studied 15 patients with schizophrenia and 26 healthy comparison subjects. Subgroups based on median performance accuracy at 2-back were analyzed; high performers included eight schizophrenia patients and 14 comparison subjects, and low performers included seven patients and 12 comparison subjects. Results: High-performing but not low-performing comparison subjects responded to incremental working memory executive load with disproportionately greater dorsal but not ventral prefrontal cortex activation, which also predicted performance accuracy. In the high-and low-performing patient groups, incremental working memory load caused a disproportionate increase in ventral but not dorsal prefrontal cortex activation relative to the respective comparison group, which also correlated with accuracy. Functional connectivity between the ventral prefrontal cortex and posterior parietal cortex was relatively greater in patients, whereas comparison subjects had greater functional connectivity between the dorsal prefrontal cortex and posterior parietal cortex. Conclusions: The hierarchical organization of the prefrontal cortex may be compromised in schizophrenia, resulting in loss of functional specialization and integration at the dorsal prefrontal cortex and in compensatory activation from the ventral prefrontal cortex, which may ultimately affect working memory and executive cognition.://000241669900021 Times Cited: 0ISI:000241669900021 NIMH, Unit Funct MRI, Clin Brain Disorders Branch, Intramural Res Program, Bethesda, MD 20892 USA. Callicott, JH, NIMH, Unit Funct MRI, Clin Brain Disorders Branch, Intramural Res Program, 10 Ctr Dr,Rm 4C-216,MSC 1364, Bethesda, MD 20892 USA. callicottj@mail.nih.gov~?,vWinterer, G. Musso, F. Beckmann, C. Mattay, V. Egan, M. F. Jones, D. W. Callicott, J. H. Coppola, R. Weinberger, D. R.2006<Instability of prefrontal signal processing in schizophrenia 1960-1968American Journal of Psychiatry16311Nov Objective: Prefrontal dysfunction is considered a fundamental characteristic of schizophrenia. Recent electrophysiological evidence points to a major instability of signal processing in prefrontal cortical microcircuits because of reduced phase-synchronization (i.e., an increased stimulusrelated variability [noise] of single-trial responses in the spatial and time domain). The authors used functional magnetic resonance imaging (fMRI) during a visual two-choice reaction task in order to measure, with higher topographic accuracy, signal stability in patients with schizophrenia and its relationship to more traditional measures of activation. Method: Twelve clinically stable inpatients with schizophrenia and 16 matched comparison subjects were evaluated. Event-related blood-oxygen-level-dependent responses were subjected to an analysis of residual noise variance and to independent data dimension independent component analysis in the medial prefrontal cortex. Results: In patients with schizophrenia, the authors found increased residual noise variance of the blood-oxygen-level-dependent response that predicted the level of prefrontal activation in these subjects. In the left hemisphere, residual noise variance strongly correlated with psychotic symptoms. Independent component analysis revealed a "fractionized" and unfocussed pattern of activation in patients. Conclusions: These findings suggest that unstable cortical signal processing underlies classic abnormal cortical activation patterns as well as psychosis in schizophrenia.://000241669900020 Times Cited: 0ISI:000241669900020dNIH, Genes Cognit & Psychosis Program, NIMH, Bethesda, MD 20892 USA. Univ Mainz, Dept Psychiat, Lab Mol Neuroimaging & Electrophysiol, D-6500 Mainz, Germany. Oxford Ctr Funct Magnet Resonance Imaging Brain, Oxford, England. Weinberger, DR, NIH, Genes Cognit & Psychosis Program, NIMH, 10 Ctr Dr,MSC 1379, Bethesda, MD 20892 USA. weinberd@intra.nimh.nih.gov ^~?-oWinterer, G. Musso, F. Vucurevic, G. Stoeter, P. Konrad, A. Seker, B. Gallinat, J. Dahmen, N. Weinberger, D. R.2006SCOMT genotype predicts BOLD signal and noise characteristics in prefrontal circuits 1722-1732 Neuroimage324OctObjective: Prefrontal dopamine (DA) is catabolized by the COMT (catechol-O-methyltransferase) enzyme. Literature suggests that the Val/Met single nucleotide polymorphism (SNP) in the COMT gene predicts executive cognition in humans with Val carriers showing poorer performance due to less available synaptic DA. Recent fMRI studies are thought to agree with these studies having demonstrated prefrontal hyperactivation during n-back and attention-requiring tasks. This was interpreted as "less efficient" processing due to impaired signal-to-noise ratio (SNR) of neuronal activity. However, electrophysiological studies of neuronal SNR in primates and humans imply that prefrontal cortex should show a diminished prefrontal BOLD response in Val carriers. In the present study, we addressed the question of whether the prefrontal SNR of the BOLD response is decreased in Val carriers using a visual oddball task and an approach to analysis of fMRI data that maximizes noise characterization. Methods: We investigated N=17 homozygous Met carriers compared with N=24 Val carriers matched for age, sex, education, IQ, reaction time (variability) and head motion. Event-related fMRI was conducted presenting 160 visual stimuli (40 targets, checkerboard reversal). Subjects had to respond as quickly as possible to targets by button press. In the fMRI GLM [y(t)=beta* x(t)+c+e(t)] analysis, voxel-by-voxel 'activation' [y(t)] as well as residual noise variance [e(t)=sigma(2)] were calculated using a conservative full-width half maximum (FWHM=6 mm). Results: As compared to Val carriers, we observed a stronger and more extended BOLD responses in homozygous Met carriers in left supplementary motor area (SMA) extending to ACC and dorsolateral prefrontal cortex. Vice versa, increased levels of noise were seen in Val carriers surrounding the peak activation maximum. Discussion: In line with our expectations from prior electrophysiological studies, we observed a diminished BOLD response and increased noise in Val carriers. This suggests that the DA stabilizes cortical microcircuits by sharpening the signal and suppressing surrounding noise. (c) 2006 Elsevier Inc. All rights reserved.://000240969200018 Times Cited: 0ISI:000240969200018Univ Dusseldorf, Dept Psychiat, D-40629 Dusseldorf, Germany. Univ Mainz, Inst Neuroradiol, D-6500 Mainz, Germany. Univ Mainz, Dept Psychiat, D-6500 Mainz, Germany. Charite Berlin, Berlin, Germany. NIMH, Genes Cognit & Psychosis Program, Bethesda, MD 20892 USA. Winterer, G, Univ Dusseldorf, Dept Psychiat, Bergische Landstr 2, D-40629 Dusseldorf, Germany. georg.winterer@uni-duesseldorf.de?.nAltamura, M. Elvevag, B. Blasi, G. Bertolino, A. Callicott, J. H. Weinberger, D. R. Mattay, V. Goldberg, T. E.2007SDissociating the effects of Sternberg working memory demands in prefrontal cortex. 103-114Psychiatry Research1542.?/Apud, J.A. Mattay, V. Chen, J. Kolachana, B. Callicott, J. H. Rasetti, R. Alce, G. Iudicello, J.E. Akbar, N. Egan, M. Goldberg, T. E. Weinberger, D. R.2007ZTolcapone improves cognition and cortical information processing in normal human subjects. 1011-1020Neuropharmacology32*?0{Blasi, G. Goldberg, T. E. Elvevag, B. Rasetti, R. Bertolino, A. Cohen, J. Alce, G. Zoltick, B. Weinberger, D. R. Mattay, V.2007eDifferentiating allocation of resources and conflict detection within attentional control processing.594-602 European Journal of Neuroscience25Y?1Buckholtz, J. Meyer-Lindenberg, A. Honea, R. Straub, R. E. Pezawas, L. Egan, M. Vakkalanka, R. K. Kolachana, B. Verchinksi, B. Sust, S. Mattay, V. Weinberger, D. R. Callicott, J. H.2007]Allelic variation in RGS4 impacts functional and structural connectivity in the human brain. 1584-1593Journal of Neuroscience277>F?2Buckholtz, J. Callicott, J. H. Kolachana, B. Hariri, A. Goldberg, T. E. Genderson, M. Egan, M. Mattay, V. Weinberger, D. R. Meyer-Lindenberg, A.in press{Genetic variation in MAOA modulates ventromedial prefrontal circuitry mediating individual differences in human personalityMolecular PsychiatryF?3rBuckholtz, J. Sust, S. Tan, H. Y. Mattay, V. Straub, R. E. Meyer-Lindenberg, A. Weinberger, D. R. Callicott, J. H.in press<fMRI evidence for functional epistasis between COMT and RGS4Molecular PsychiatryMF?4Honea, R. Meyer-Lindenberg, A. Hobbs, K. B. Pezawas, L. Mattay, V. Egan, M. Verchinksi, B. Passingham, R. E. Weinberger, D. R. Callicott, J. H.in pressIs gray matter volume an intermediate phenotype for schizophrenia? A VBM study of patients with schizophrenia and their healthy siblings.Biological Psychiatry?F?5Straub, R. E. Lipksa, B. K. Egan, M. Goldberg, T. E. Callicott, J. H. Mayhew, M. B. Vakkalanka, R. K. Kolachana, B. Kleinman, J. E. Weinberger, D. R.in presswAllelic variation in GAD1 (GAD67) is associated with schizophrenia and influences cortical function and gene expressionMolecular PsychiatryMF?6vTan, H. Y. Chen, Q. Sust, S. Buckholtz, J. Egan, M. Mattay, V. Meyer-Lindenberg, A. Weinberger, D. R. Callicott, J. H.in pressiEvidence of biologic epistasis between COMT and GRM3 on human prefrontal function during working memory. OProceedings of the National Academy of Sciences of the United States of AmericaF?7MWinterer, G. Carver, F. W. Musso, F. Mattay, V. Weinberger, D. R. Coppola, R.in pressnComplex relationship between BOLD signal and synchronization/desynchronization of human brain MEG oscillationsHuman Brain MappingQ* it increases prefrontal dopamine catabolism, impairs prefrontal cognition and physiology. and by this mechanism slightly increases risk for schizophrenia.://000169151500070 Times Cited: 512ISI:000169151500070NIMH, Clin Brain Disorders Branch, Bethesda, MD 20892 USA. NIAAA, Neurogenet Lab, Rockville, MD 20852 USA. Virginia Commonwealth Univ, Med Coll Virginia, Dept Psychiat,k ?c/Harezlak, J. Ryan, L. M. Giedd, J. N. Lange, N.2005[Individual and population penalized regression splines for accelerated longitudinal designs 1037-1048 Biometrics614^http://www.scopus.com/scopus/inward/record.url?eid=2-s2.0-32644444942&partnerID=40&rel=R6.5.0 CCited By (since 1996): 1 Export Date: 19 August 2007 Source: ScopusTNle predicted enhanced cognitive performance. We then examined the effect of COMT genotype on prefrontal physiology during a working memory task in three separate subgroups(n = 11-16) assayed with functional MRI, Met allele load consistently predicted a more efficient physiological response in prefrontal cortex. Finally, in a family-based association analysis of 104 trios, we found a significant increase in transmission of the Val allele to the schizophrenic offspring. These data suggest that the COMT Val allele<Qrtical physiology. In 175 patients with schizophrenia, 219 unaffected siblings, and 55 controls, COMT genotype was related in allele dosage fashion to performance on the Wisconsin Card Sorting Test of executive cognition and explained 4% of variance (P = 0.001) in frequency of perseverative errors. Consistent with other evidence that dopamine enhances prefrontal neuronal function, the load of the low-activityT of prefrontal function. A potential susceptibility mechanism involves regulation of prefrontal dopamine, which modulates the response of prefrontal neurons during working memory. We examined the relationship of a common functional polymorphism (Va(108/158) Met) in the catechol-O-methyltransferase (COMT) gene, which accounts for a 4-fold variation in enzyme activity and dopamine catabolism, with both prefrontally mediated cognition and prefU01\Effect of COMT Val(108/158) Met genotype on frontal lobe function and risk for schizophrenia 6917-6922OProceedings of the National Academy of Sciences of the United States of America9812JunAbnormalities of prefrontal cortical function are prominent features of schizophrenia and have been associated with genetic risk, suggesting that susceptibility genes for schizophrenia may impact on the molecular m~?9DJiang, Y. Haxby, J. V. Martin, A. Ungerleider, L. G. Parasuraman, R.2000JComplementary neural mechanisms for tracking items in human working memory643-646Science2875453JanRecognition of a specific visual target among equally familiar distracters requires neural mechanisms for tracking items in working memory. Event-related functional magnetic resonance imaging revealed evidence for two such mechanisms: (i) Enhanced neural responses, primarily in the frontal cortex, were associated with the target and were maintained across repetitions of the target. (ii) Reduced responses, primarily in the extrastriate visual cortex, were associated with stimulus repetition, regardless of whether the stimulus was a target or a distracter, These complementary neural mechanisms track the status of familiar items in working memory, allowing for the efficient recognition of a currently relevant object and rejection of irrelevant distracters.://000084989400045 Times Cited: 60ISI:000084989400045NIMH, Lab Brain & Cognit, Bethesda, MD 20892 USA. Catholic Univ Amer, Cognit Sci Lab, Washington, DC 20064 USA. Jiang, Y, NIMH, Lab Brain & Cognit, Bethesda, MD 20892 USA.~?:+Kastner, S. De Weerd, P. Ungerleider, L. G.2000FTexture segregation in the human visual cortex: A functional MRI study 2453-2457Journal of Neurophysiology834Apr*Texture segregation in the human visual cortex: a functional MRI study. J. Neurophysiol. 83: 2453-2457, 2000. The segregation of visual scenes based on contour information is a fundamental process of early vision. Contours can be defined by simple cues, such as luminance, as well as by more complex cues, such as texture. Single-cell recording studies in monkeys suggest that the neural processing of complex contours starts as early as primary visual cortex. Additionally, lesion studies in monkeys indicate an important contribution of higher order areas to these processes. Using functional MRI, we have investigated the level at which neural correlates of texture segregation can be found in the human visual cortex. Activity evoked by line textures, with and without texture-defined boundaries, was compared in five healthy subjects. Areas V1, V2/VP, V4, TEO, and V3A were activated by both kinds of line textures as compared with blank presentations. Textures with boundaries forming a checkerboard pattern, relative to uniform textures, evoked significantly more activity in areas V4, TEO, less reliably in V3A, but not in V1 or V2/VP. These results provide evidence that higher order areas with large receptive fields play an important role in the segregation of visual scenes based on texture-defined boundaries.://000086598900057 Times Cited: 37ISI:000086598900057NIMH, Lab Brain & Cognit, NIH, Bethesda, MD 20892 USA. Univ Arizona, Coll Social & Behav Sci, Dept Psychol, Tucson, AZ 85721 USA. Kastner, S, NIMH, Lab Brain & Cognit, NIH, Bldg 49,Rm 1B80, Bethesda, MD 20892 USA. 4~?;UKastner, S. De Weerd, P. Pinsk, M. A. Elizondo, M. I. Desimone, R. Ungerleider, L. G.2001dModulation of sensory suppression: Implications for receptive field sizes in the human visual cortex 1398-1411Journal of Neurophysiology863Sep Neurophysiological studies in monkeys show that when multiple visual stimuli appear simultaneously in the visual field, they are not processed independently, but rather interact in a mutually suppressive way. This suggests that multiple stimuli compete for neural representation. Consistent with this notion, we have previously found in humans that functional magnetic resonance imaging (fMRI) signals in V1 and ventral extrastriate areas V2, V4, and TEO are smaller for simultaneously presented (i.e., competing) stimuli than for the same stimuli presented sequentially (i.e., not competing). Here we report that suppressive interactions between stimuli are also present in dorsal extrastriate areas V3A and MT, and we compare these interactions to those in areas V1 through TEO. To exclude the possibility that the differences in responses to simultaneously and sequentially presented stimuli were due to differences in the number of transient onsets, we tested for suppressive interactions in area V4, in an experiment that held constant the number of transient onsets. We found that the fMRI response to a stimulus in the upper visual field was suppressed by the presence of nearby stimuli in the lower visual field. Further, we excluded the possibility that the greater fMRI responses to sequential compared with simultaneous presentations were due to exogeneous attentional. cueing by having our subjects count T's or L's at fixation, an attentionally demanding task. Behavioral testing demonstrated that neither condition interfered with performance of the T/L task. Our previous findings suggested that suppressive interactions among nearby stimuli in areas V1 through TEO were scaled to the receptive field (RF) sizes of neurons in those areas. Here we tested this idea by parametrically varying the spatial separation among stimuli in the display. Display sizes ranged from 2 x 2 degrees to 7 X 7 degrees and were centered at 5.5 degrees eccentricity. Based on the effects of display size on the magnitude of suppressive interactions, we estimated that RF sizes at an eccentricity of 5.5 degrees were <2 in V1, 2-4 degrees in V2, 4-6 degrees in V4, larger than 7 degrees (but still confined to a quadrant) in TEO, and larger than 6 degrees (confined to a quadrant) in V3A. These estimates of RF sizes in human visual cortex are strikingly similar to those measured in physiological mapping studies in the homologous visual areas in monkeys.://000171024400031 Times Cited: 44ISI:000171024400031APrinceton Univ, Ctr Study Brain Mind & Behav, Dept Psychol, Princeton, NJ 08544 USA. NIMH, Neuropsychol Lab, NIH, Bethesda, MD 20892 USA. Univ Arizona, Dept Psychol, Coll Social & Behav Sci, Tucson, AZ 85721 USA. Kastner, S, Princeton Univ, Ctr Study Brain Mind & Behav, Dept Psychol, Green Hall, Princeton, NJ 08544 USA.?<LDoyon, J. Song, A. W. Karni, A. Lalonde, F. Adams, M. M. Ungerleider, L. G.2002TExperience-dependent changes in cerebellar contributions to motor sequence learning. 1017-1022OProceedings of the National Academy of Sciences of the United States of America99~?=)Ishai, A. Haxby, J. V. Ungerleider, L. G.2002PVisual imagery of famous faces: Effects of memory and attention revealed by fMRI 1729-1741 Neuroimage174Dec\Complex pictorial information can be represented and retrieved from memory as mental visual images. Functional brain imaging studies have shown that visual perception and visual imagery share common neural substrates. The type of memory (short- or long-term) that mediates the generation of mental images, however, has not been addressed previously. The purpose of this study was to investigate the neural correlates underlying imagery generated from short- and long-term memory (STM and LTM). We used famous faces to localize the visual response during perception and to compare the responses during visual imagery generated from STM (subjects memorized specific pictures of celebrities before the imagery task) and imagery from LTM (subjects imagined famous faces without seeing specific pictures during the experimental session). We found that visual perception of famous faces activated the inferior occipital gyri, lateral fusiform gyri, the superior temporal sulcus, and the amygdala. Small subsets of these face-selective regions were activated during imagery. Additionally, visual imagery of famous faces activated a network of regions composed of bilateral calcarine, hippocampus, precuneus, intraparietal sulcus (IPS), and the inferior frontal gyrus (IFG). In all these regions, imagery generated from STM evoked more activation than imagery from LTM. Regardless of memory type, focusing attention on features of the imagined faces (e.g., eyes, lips, or nose) resulted in increased activation in the right IPS and right IFG. Our results suggest differential effects of memory and attention during the generation faces.://000179969800007 Times Cited: 42ISI:000179969800007wNIMH, Lab Brain & Cognit, NIH, Bethesda, MD 20892 USA. Ishai, A, NIMH, Lab Brain & Cognit, NIH, Bethesda, MD 20892 USA.~?>=Pessoa, L. Gutierrez, E. Bandettini, P. A. Ungerleider, L. G.2002TNeural correlates of visual working memory: fMRl amplitude predicts task performance975-987Neuron355Aug~We used fMRI to investigate how moment-to-moment neural activity contributes to success or failure on individual trials of a visual working memory (WM) task. We found that different nodes of a distributed cortical network were activated to a greater extent for correct compared to incorrect trials during stimulus encoding, memory maintenance during delays, and at test. A logistic regression analysis revealed that the fMRI signal amplitude during the delay interval in a network of frontoparietal regions predicted successful performance on a trial-by-trial basis. Differential delay activity occurred even for only those trials in which BOLD activity during encoding was strong, demonstrating that it was not a simple consequence of effective versus ineffective encoding. Our results indicate that accurate memory depends on strong sustained signals that span the delay interval of WM tasks.://000177779800018 Times Cited: 41ISI:000177779800018xNIMH, Lab Brain & Cognit, NIH, Bethesda, MD 20892 USA. Pessoa, L, NIMH, Lab Brain & Cognit, NIH, Bethesda, MD 20892 USA.~??)Pessoa, L. Kastner, S. Ungerleider, L. G.2002FAttentional control of the processing of neutral and emotional stimuli31-45Cognitive Brain Research151DecA typical scene contains many different objects that compete for neural representation due to the limited processing capacity of the visual system. At the neural level, competition among multiple stimuli is evidenced by the mutual suppression of their visually evoked responses and occurs most strongly at the level of the receptive field. The competition among multiple objects can be biased by both bottom-up sensory-driven mechanisms and top-down influences, such as selective attention. Functional brain imaging studies reveal that biasing signals due to selective attention can modulate neural activity in visual cortex not only in the presence but also in the absence of visual stimulation. Although the competition among stimuli for representation is ultimately resolved within visual cortex, the source of top-down biasing signals likely derives from a distributed network of areas in frontal and parietal cortex. Competition suggests that once attentional resources are depleted, no further processing is possible, Yet, existing data suggest that emotional stimuli activate brain regions,automatically,' largely immune from attentional control. We tested the alternative possibility, namely, that the neural processing of stimuli with emotional content is not automatic and instead requires some degree of attention. Our results revealed that, contrary to the prevailing view, all brain regions responding differentially to emotional faces, including the amygdala, did so only when sufficient attentional resources were available to process the faces. Thus, similar to the processing of other stimulus categories, the processing of facial expression is under top-down control, Published by Elsevier Science B.V.://000179798900003 Times Cited: 35ISI:000179798900003NIMH, Lab Brain & Cognit, Bethesda, MD 20892 USA. Princeton Univ, Dept Psychol, Ctr Study Brain Mind & Behav, Princeton, NJ 08544 USA. Pessoa, L, NIMH, Lab Brain & Cognit, 49 Convent Dr,Bldg 49,Room 1B80, Bethesda, MD 20892 USA. ~?@7Pessoa, L. McKenna, M. Gutierrez, E. Ungerleider, L. G.20027Neural processing of emotional faces requires attention 11458-11463OProceedings of the National Academy of Sciences of the United States of America9917AugCAttention gates the processing of stimuli relatively early in visual cortex. Yet, existing data suggest that emotional stimuli activate brain regions automatically, largely immune from attentional control. To resolve this puzzle, we used functional magnetic resonance imaging to first measure activation in regions that responded differentially to faces with emotional expressions (fearful and happy) compared with neutral faces. We then measured the modulation of these responses by attention, using a competing task with a high attentional load. Contrary to the prevailing view, all brain regions responding differentially to emotional faces, including the amygdala, did so only when sufficient attentional resources were available to process the faces. Thus, the processing of facial expression appears to be under top-down control.://000177606900091 Times Cited: 136ISI:000177606900091NIMH, Lab Brain & Cognit, Bethesda, MD 20892 USA. Pessoa, L, NIMH, Lab Brain & Cognit, Bldg 10,Room 4C104, Bethesda, MD 20892 USA.~?A&Ungerleider, L. G. Doyon, J. Karni, A.20024Imaging brain plasticity during motor skill learning553-564#Neurobiology of Learning and Memory783NovThe search for the neural substrates mediating the incremental acquisition of skilled motor behaviors has been the focus of a large body of animal and human studies in the past decade. Much less is known, however, with regard to the dynamic neural changes that occur in the motor system during the different phases of learning. In this paper, we review recent findings, mainly from our own work using fMRI, which suggest that: (i) the learning of sequential finger movements produces a slowly evolving reorganization within primary motor cortex (M I) over the course of weeks and (ii) this change in M1 follows more dynamic, rapid changes in the cerebellum, striatum, and other motor-related cortical areas over the course of days. We also briefly review neurophysiological and psychophysical evidence for the consolidation of motor skills, and we propose a working hypothesis of its underlying neural substrate in motor sequence learning. (C) 2002 Elsevier Science (USA).://000179527900007 Times Cited: 61ISI:0001795279000072NIMH, Lab Brain & Cognit, NIH, Bethesda, MD 20892 USA. Univ Montreal, Dept Psychol, Montreal, PQ H3C 3J7, Canada. Univ Haifa, Fac Sci, IL-31999 Haifa, Israel. Univ Haifa, Fac Educ, IL-31999 Haifa, Israel. Ungerleider, LG, NIMH, Lab Brain & Cognit, NIH, 10 Ctr Dr,Bldg 10,Room 4C104, Bethesda, MD 20892 USA.?B)Pessoa, L. Kastner, S. Ungerleider, L. G.2003]Neuroimaging studies of attention: from modulation of sensory processing to top-down control. 3990-3998Journal of Neuroscience23~?CPessoa, L. Ungerleider, L. G.2003MNeuroimaging studies of attention and the processing of emotion-laden stimuli171-182Roots of Visual Awareness144Because the processing capacity of the visual system is limited, selective attention to one part of the visual field comes at the cost of neglecting other parts. In this paper, we review evidence from single-cell studies in monkeys and functional magnetic resonance imaging (fMRI) studies in humans for neural competition and how competition is biased by, attention. We Suggest that, at the neural level, an important consequence of attention is to enhance the influence of behaviorally relevant stimuli at the expense of irrelevant ones, providing a mechanism for the filtering of distracting information in Cluttered visual scenes. Psychophysical evidence suggests that processing outside the focus of attention is attenuated and may be even eliminated under some conditions. A major exception to the critical role of attention may be in the neural processing of emotion-laden stimuli, which are reported to be processed automatically, namely. without attention. Contrary to this prevailing view, in a recent study we found that all brain regions responding differentially to faces with emotional content, including the amygdala, did so only when sufficient resources were available to process those faces. After reviewing our findings, we discuss their implications, in particular (1) how emotional stimuli can bias competition for processing resources; (2) the source of the biasing signal for emotional stimuli: (3) how Visual information reaches the amygdala; and finally (4) the relationship between attention and awareness.://000187421400012 Progress in Brain ResearchTimes Cited: 0ISI:000187421400012NIMH, Lab Brain & Cognit, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. Pessoa, L, NIMH, Lab Brain & Cognit, NIH, Dept Hlth & Human Serv, 49 Convent Dr,Bldg 49,Room 1B80, Bethesda, MD 20892 USA.?D@Heekeren, H. R. Marrett, S. Bandettini, P. A. Ungerleider, L. G.2004FA general mechanism for perceptual decision-making in the human brain.859-562Nature431431o~?E4Ishai, A. Pessoa, L. Bikle, P. C. Ungerleider, L. G.20047Repetition suppression of faces is modulated by emotion 9827-9832OProceedings of the National Academy of Sciences of the United States of America10126JunzSingle-unit recordings and functional brain imaging studies have shown reduced neural responses to repeated stimuli in the visual cortex. By using event-related functional MRI, we compared the activation evoked by repetitions of neutral and fearful faces,which were either task relevant (targets) or irrelevant (distracters). We found that within the inferior occipital gyri, lateral fusiform gyri, superior temporal sulci, amygdala, and the inferior frontal gyri/insula, targets evoked stronger responses than distracters and their repetition was associated with significantly reduced responses. Repetition suppression, as manifested by the difference in response amplitude between the first and third repetitions of a target, was stronger for fearful than neutral faces. Distracter faces, regardless of their repetition or valence, evoked negligible activation, indicating top-down attenuation of behaviorally irrelevant stimuli. Our findings demonstrate a three-way interaction between emotional valence, repetition, and task relevance and suggest that repetition suppression is influenced by high-level cognitive processes in the human brain.://000222405600056 Times Cited: 22ISI:000222405600056Natl Inst Mental Hlth, Lab Brain & Cognit, NIH, Bethesda, MD 20892 USA. Ishai, A, Univ Zurich, Brain Res Inst, Winterthurerstr 190, CH-8057 Zurich, Switzerland. ishai@hifo.unizh.ch B~?FPessoa, L. Ungerleider, L. G.2004SNeural correlates of change detection and change blindness in a working memory task511-520Cerebral Cortex145May|Detecting changes in an ever-changing environment is highly advantageous, and this ability may be critical for survival. In the present study, we investigated the neural substrates of change detection in the context of a visual working memory task. Subjects maintained a sample visual stimulus in short-term memory for 6 s, and were asked to indicate whether a subsequent, test stimulus matched or did not match the original sample. To study change detection largely uncontaminated by attentional state, we compared correct change and correct no-change trials at test. Our results revealed that correctly detecting a change was associated with activation of a network comprising parietal and frontal brain regions, as well as activation of the pulvinar, cerebellum, and inferior temporal gyrus. Moreover, incorrectly reporting a change when none occurred led to a very similar pattern of activations. Finally, few regions were differentially activated by trials in which a change occurred but subjects failed to detect it (change blindness). Thus, brain activation was correlated with a subject's report of a change, instead of correlated with the physical change per se. We propose that frontal and parietal regions, possibly assisted by the cerebellum and the pulvinar, might be involved in controlling the deployment of attention to the location of a change, thereby allowing further processing of the visual stimulus. Visual processing areas, such as the inferior temporal gyrus, may be the recipients of top-down feedback from fronto-parietal regions that control the reactive deployment of attention, and thus exhibit increased activation when a change is reported (irrespective of whether it occurred or not). Whereas reporting that a change occurred, be it correctly or incorrectly, was associated with strong activation in fronto-parietal sites, change blindness appears to involve very limited territories.://000220895500006 Times Cited: 9ISI:000220895500006Brown Univ, Dept Psychol, Providence, RI 02912 USA. NIMH, Lab Brain & Cognit, Bethesda, MD 20892 USA. Pessoa, L, Brown Univ, Dept Psychol, 89 Waterman St, Providence, RI 02912 USA. pessoa@brown.edu~?GQVan Boven, R. W. Ingeholm, J. E. Beauchamp, M. S. Bikle, P. C. Ungerleider, L. G.20057Tactile form and location processing in the human brain 12601-12605OProceedings of the National Academy of Sciences of the United States of America10235AugTo elucidate the neural basis of the recognition of tactile form and location, we used functional MRI while subjects discriminated gratings delivered to the fingertip of either the right or left hand. Subjects were required to selectively attend to either grating orientation or grating location under identical stimulus conditions. Independent of the hand that was stimulated, grating orientation discrimination selectively activated the left intraparietal sulcus, whereas grating location discrimination selectively activated the right temporoparietal junction. Hence, hemispheric dominance appears to be an organizing principle for cortical processing of tactile form and location.://000231675900057 Times Cited: 3ISI:000231675900057NIMH, Lab Brain & Cognit, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. Ungerleider, LG, NIMH, Lab Brain & Cognit, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. ungerlel@mail.nih.gov ~?HLHeekeren, H. R. Marrett, S. Ruff, D. A. Bandettini, P. A. Ungerleider, L. G.2006zInvolvement of human left dorsolateral prefrontal cortex in perceptual decision making is independent of response modality 10023-10028OProceedings of the National Academy of Sciences of the United States of America10326JunPerceptual decision making typically entails the processing of sensory signals, the formation of a decision, and the planning and execution of a motor response. Although recent studies in monkeys and humans have revealed possible neural mechanisms for perceptual decision making, much less is known about how the decision is subsequently transformed into a motor action and whether or not the decision is represented at an abstract level, i.e., independently of the specific motor response. To address this issue, we used functional MRI to monitor changes in brain activity while human subjects discriminated the direction of motion in random-dot visual stimuli that varied in coherence and responded with either button presses or saccadic eye movements. We hypothesized that areas representing decision variables should respond more to high- than to low-coherence stimuli independent of the motor system used to express a decision. Four areas were found that fulfilled this condition: left posterior dorsolateral prefrontal cortex (DLPFC), left posterior cingulate cortex, left inferior parietal lobule, and left fusifom/parahippocampal gyrus. We previously found that, when subjects made categorical decisions about degraded face and house stimuli, left posterior DLPFC showed a greater response to high- relative to low-coherence stimuli. Furthermore, the left posterior DLPFC appears to perform a comparison of signals from sensory processing areas during perceptual decision making. These data suggest that the involvement of left posterior DLPFC in perceptual decision making transcends both task and response specificity, thereby enabling a flexible link among sensory evidence, decision, and action.://000238872900050 Times Cited: 1ISI:000238872900050NIMH, Lab Brain & Cognit, NIH, Bethesda, MD 20892 USA. Max Planck Inst Human Dev, D-14195 Berlin, Germany. Max Planck Inst Human Cognit & Brain Sci, D-04103 Leipzig, Germany. Charite Univ Med Berlin, Berlin Neuroimaging Ctr, D-10117 Berlin, Germany. NIMH, Funct MRI Facil, NIH, Bethesda, MD 20892 USA. Ungerleider, LG, NIMH, Lab Brain & Cognit, NIH, 10 Ctr Dr MSC 1366,Bldg 10,Room 4C104, Bethesda, MD 20892 USA. ungerlel@mail.nih.gov~?I)Ishai, A. Bikle, P. C. Ungerleider, L. G.20060Temporal dynamics of face repetition suppression289-295Brain Research Bulletin704-6Oct3Single-unit recordings and functional brain imaging studies have shown reduced neural responses to repeated stimuli in the visual cortex. Using MEG, we compared responses evoked by repetitions of neutral faces to those evoked by fearful faces, which were either task relevant (targets) or irrelevant (distracters). Faces evoked a bi-phasic response in extrastriate cortex, peaking at 160-185 ms and at 220-250 ms, with stronger responses to neutral faces at the earlier interval and stronger responses to fearful faces at the later interval. At both latencies, repetitions of neutral and fearful targets resulted in reduced amplitude of the MEG signal. Additionally, we found that the context in which targets were presented affected their processing: fearful distracters increased the responses evoked by both neutral and fearful targets. Our data indicate that valence enhancement and context effects can be detected in extrastriate visual cortex within 250 ms and that these processes likely reflect feedback from other regions. (c) 2006 Elsevier Inc. All rights reserved.://000241546500004 Times Cited: 0ISI:000241546500004Univ Zurich, Inst Neuroradiol, CH-8057 Zurich, Switzerland. NIMH, Lab Brain & Cognit, Bethesda, MD 20892 USA. Ishai, A, Univ Zurich, Inst Neuroradiol, Winterhurerstr 190, CH-8057 Zurich, Switzerland. ishai@hifo.unizh.ch~?J3Pessoa, L. Japee, S. Sturman, D. Ungerleider, L. G.2006STarget visibility and visual awareness modulate amygdala responses to fearful faces366-375Cerebral Cortex163MarThe goals of the present study were twofold. First, we wished to investigate the neural correlates of aware and unaware emotional face perception after characterizing each subject's behavioral performance via signal detection theory methods. Second, we wished to investigate the extent to which amygdala responses to fearful faces depend on the physical characteristics of the stimulus independently of the percept. We show that amygdala responses depend on visual awareness. Under conditions in which subjects were not aware of fearful faces flashed for 33 ms, no differential activation was observed in the amygdala. On the other hand, differential activation was observed for 67 ms fearful targets that the subjects could reliably detect. When trials were divided into hits, misses, correct rejects, and false alarms, we show that target visibility is an important factor in determining amygdala responses to fearful faces. Taken together, our results further challenge the view that amygdala responses occur automatically.://000235277500008 Times Cited: 2ISI:000235277500008Brown Univ, Dept Psychol, Providence, RI 02912 USA. NIMH, Lab Brain & Cognit, Bethesda, MD USA. Pessoa, L, Brown Univ, Dept Psychol, 89 Waterman St, Providence, RI 02912 USA. pessoa@brown.edu ~?KXGaillard, W. D. Hertz-Pannier, L. Mott, S. H. Barnett, A. S. LeBihan, D. Theodore, W. H.2000[Functional anatomy of cognitive development - fMRI of verbal fluency in children and adults180-185 Neurology541JanObjective: To identify age-dependent activation patterns of verbal fluency with functional MRT (fMRI), Background: Few fMRI language studies have been performed in children, and none provide comparison data to adult studies. Normative data are important for interpretation of similar studies in patients with epilepsy. Methods: A total of 10 normal children (5 boys, 5 girls; mean age, 10.7 years; range, 8.1 to 13.1 years) and 10 normal adults (5 men, 5 women; mean age, 28.7 years; range, 19.3 to 48 years) were studied on a 1.5-T Sigma MRI scanner using BOLD echo planar imaging of the frontal lobes with a verbal fluency paradigm, covert word generation to letters. Studies were analyzed with a cross-correlation algorithm (r = 0.7). A region-of-interest analysis was used to determine the extent, magnitude, and laterality of brain activation. Results: Children and adults activated similar regions, predominantly in left inferior frontal cortex (Broca's area) and left, middle frontal gyrus (dorsolateral prefrontal cortex). Children had, on average, 60% greater extent of activation than adults, with a trend for greater magnitude of activation. Children also had significantly more right hemisphere and inferior frontal gyrus activation than adults. Conclusions. In a test of verbal fluency, children tended to activate cortex more widely than adults, but activation patterns for fluency appear to be established by middle childhood. Thus, functional MRI using verbal fluency paradigms may be applied to pediatric patient populations for determining language dominance in anterior brain regions. The greater activation found in children, including the right inferior frontal gyrus, may reflect developmental plasticity for the ongoing organization of neural networks, which underlie language capacity.://000084727900031 Times Cited: 106ISI:0000847279000319Childrens Natl Med Ctr, Dept Neurol, Washington, DC 20010 USA. NINDS, Epilepsy Res Branch, NIH, Bethesda, MD 20892 USA. NIH, Ctr Clin, Bethesda, MD 20892 USA. NINDS, Neuroimaging Branch, NIH, Bethesda, MD 20892 USA. Gaillard, WD, Childrens Natl Med Ctr, Dept Neurol, 111 Michigan Ave NW, Washington, DC 20010 USA.4~?LGaillard, W. D. Theodore, W. H.20004Mapping language in epilepsy with functional imaging390-400Neuroscientist65Oct Surgery is an important therapeutic alternative for patients with uncontrolled epilepsy. Preoperative identification of brain regions important for language is important to reduce the risk of functional impairment after surgery, The Wada test suffers from several technical and clinical disadvantages and provides hemispheric data at best. More invasive methods such as intraoperative or chronic subdural cortical mapping have more limited application. New approaches using neuroimaging methods offer the opportunity to localize, as well as lateralize, language. In addition, normal volunteers can be studied with the same techniques, providing comparative and control data. Although most normal studies have been reported as group data, it is important for individual scans to be available for comparison with patient studies to understand the normal range of interindividual variability. Two techniques, PET with O-15-water-PET and fMRI, have been used. Both detect signal changes associated with increased regional blood flow during neuronal activity. Usually, scans performed during a language task are compared with those obtained during control conditions. It is important to choose activation tasks carefully, to make sure one is imaging activation associated with the particular process of interest. PET has advantages, including a fully diffusible tracer, standardized analytic methods, a more comfortable environment, and less sensitivity to movement artifact. On the other hand, it involves a cyclotron-produced tracer, radiation exposure, and is more difficult to repeat. FMRI over represents the effects of large vascular structures and is very sensitive to movement but uses widely available equipment and has no limitation on the number of studies. For both studies, it is important to understand the potential effects of such factors as attention, fatigue, and familiarity with the material. Several studies comparing O-15-water-PET and fMRI to the Wada test found that the former are at least as accurate for language lateralization. In addition, we compared O-15-water-PET to direct subdural electrode cortical stimulation and found that regions showing increased cerebral blood flow during naming tasks co-registered with subdural electrodes that disrupted language during electrical stimulation. In this and other studies, PET detected more regions than electrical stimulation techniques. The whole brain cannot be covered with electrodes, but some areas participating in a task may not be crucial for it. FMRI is particularly useful for children. We compared cortical activation patterns in normal children, adolescents, and adults. The activation patterns, and laterality of language dominance, in children 8 years and above, were similar to adults, although some differences could reflect maturation and evolving focality of cognitive processes. In children with epilepsy, fMRI successfully identified language laterality and provided data on intrahemispheric localization. Studies also showed the effects of the epileptic focus on normal activation patterns for several tasks. Neuroimaging functional mapping is an important tool, still in the process of development and evolution. Although potentially of great clinical and scientific value, it should be used and interpreted cautiously.://000089436300020 Times Cited: 2ISI:000089436300020bNIH, Clin Epilepsy Sect, Bethesda, MD 20892 USA. Childrens Natl Med Ctr, Washington, DC 20010 USA.~?M[Spanaki, M. V. Kopylev, L. Liow, K. DeCarli, C. Fazilat, S. Gaillard, W. D. Theodore, W. H.2000`Relationship of seizure frequency to hippocampus volume and metabolism in temporal lobe epilepsy 1227-1229 Epilepsia419SepNPurpose: To examine the relationship between frequency of complex partial (CPS) and secondarily generalized tonic-clonic seizures (sGTCS) on hippocampal volume (HV) temporal lobe metabolism. Methods: We performed volumetric magnetic resonance imaging (MRI) and positron emission tomography with (18)fluorodeoxyglucose ((18)FDG-PET) in 32 patients with epilepsy. Temporal lobe foci were localized by ictal video-EEG. Results: We did not find any association between CPS frequency or lifetime number of sGTCS and HV or metabolism ipsilateral to electroencephalographic focus. Conclusion: The progress of metabolic or pathologic abnormalities of temporal lobe epilepsy may not be altered by adequate seizure control. The presence of an epileptic focus might be associated with progressive neuronal injury even in clinically well-controlled patients.://000089128200019 Times Cited: 10ISI:000089128200019 NINDS, Clin Epilepsy Sect, ERB, Bethesda, MD 20892 USA. NINDS, Biostat Branch, NIH, Bethesda, MD 20892 USA. Childrens Natl Med Ctr, Washington, DC 20010 USA. Theodore, WH, NINDS, Clin Epilepsy Sect, ERB, Bldg 10,Room 5N-250,10 Ctr Dr,MSC 1408, Bethesda, MD 20892 USA.u~?NATheodore, W. H. Gaillard, W. D. De Carli, C. Bhatia, S. Hatta, J.2001IHippocampal volume and glucose metabolism in temporal lobe epileptic foci130-132 Epilepsia421JanPurpose: Reports conflict on the relation of glucose metabolism to hippocampal volume in temporal lobe foci. Previous studies usually have used side-side ratios rather than regional metabolic rates. Methods: We measured hippocampal volume and glucose metabolism in 37 patients with temporal epileptogenic zones identified by ictal video-EEG telemetry. Metabolic rates were normalized to global brain mean. Results: Both 18-fluoro-2-deoxyglucose-PET and volumetric MRI lateralized the epileptic focus determined by ictal video-EEG. There were significant correlations between left-right metabolic asymmetry and hippocampal formation volume left-right ratios. Comparisons between normalized metabolism and hippocampal formation volume, ignoring the side of the epileptic focus, showed significant relations between left hippocampal volume and left inferior lateral temporal metabolism, right hippocampus and right inferior mesial temporal, and left hippocampus and left inferior mesial temporal metabolism. In contrast, when normalized metabolism was compared with hippocampal volume in the epileptic focus, no relation was found. Conclusions. Our study suggests that the relation between hippocampal volume and glucose metabolism breaks down in epileptic foci and that hypometabolism is not dependent on neuronal loss. It is consistent with data suggesting that hypometabolism is an independent predictor of surgical outcome.://000166914800018 Times Cited: 18ISI:000166914800018NINDS, Clin Epilepsy Sect, Epilepsy Res Branch, NIH, Bethesda, MD 20892 USA. Theodore, WH, NINDS, Clin Epilepsy Sect, Epilepsy Res Branch, NIH, Bldg 10,Room 5N-250,10 Ctr Dr,MSC 1408, Bethesda, MD 20892 USA.~?OvXu, B. Grafman, J. Gaillard, W. D. Ishii, K. Vega-Bermudez, F. Pietrini, P. Reeves-Tyer, P. DiCamillo, P. Theodore, W.2001Conjoint and extended neural networks for the computation of speech codes: The neural basis of selective impairment in reading words and pseudowords267-277Cerebral Cortex113Mar(The computation of speech codes (i.e, phonology) is an important aspect of word reading. Understanding the neural systems and mechanisms underlying phonological processes provides a foundation for the investigation of language in the brain. We used high-resolution three-dimensional positron emission tomography (PET) to investigate neural systems essential for phonological processes. The burden of neural activities on the computation of speech codes was maximized by three rhyming tasks (rhyming words, pseudowords and words printed in mixed letter cases). Brain activation patterns associated with these tasks were compared with those of two baseline tasks involving visual feature detection. Results suggest strong left lateralized epicenters of neural activity in rhyming irrespective of gender. Word rhyming activated the same brain regions engaged in pseudoword rhyming, suggesting conjoint neural networks for phonological processing of words and pseudowords. However, pseudoword rhyming induced the largest change in cerebral blood flow and activated more voxels in the left posterior prefrontal regions and the left inferior occipital-temporal junction. In addition, pseudoword rhyming activated the left supramarginal gyrus, which was not apparent in word rhyming. These results suggest that rhyming pseudowords requires active participation of extended neural systems and networks not observed for rhyming words, The implications of the results on theories and models of visual word reading and on selective reading dysfunctions after brain lesions are discussed.://000167286100008 Times Cited: 55ISI:000167286100008NINDS, Epilepsy Res Branch, NIH, Bethesda, MD 20892 USA. NINDS, Cognit Neurosci Sect, NIH, Bethesda, MD 20892 USA. Childrens Natl Med Ctr, Dept Neurol, Washington, DC 20010 USA. Xu, B, NINDS, Epilepsy Res Branch, NIH, 5N 250 Bldg 10 Ctr Dr, Bethesda, MD 20892 USA. ~?PGaillard, W. D. Balsamo, L. Xu, B. Grandin, C. B. Braniecki, S. H. Papero, P. H. Weinstein, S. Conry, J. Pearl, P. L. Sachs, B. Sato, S. Jabbari, B. Vezina, L. G. Frattali, C. Theodore, W. H.2002TLanguage dominance in partial epilepsy patients identified with an fMRI reading task256-265 Neurology592Jul Background: fMRI language tasks readily identify frontal language areas; temporal activation has been less consistent. No studies have compared clinical visual judgment to quantitative region of interest (ROI) analysis. Objective: To identify temporal language areas in patients with partial epilepsy using a reading paradigm with clinical and ROI interpretation. Methods: Thirty patients with temporal lobe epilepsy, aged 8 to 56 years, had 1.5-T fMRI. Patients silently named an object described by a sentence compared to a visual control. Data were analyzed with ROI analysis from t-maps. Regional asymmetry indices (AI) were calculated ([L-R]/[L+R]) and language dominance defined as >0.20. t-Maps were visually rated by three readers at three t thresholds. Twenty-one patients had intracarotid amobarbital test (IAT). Results: The fMRI reading task provided evidence of language lateralization in 27 of 30 patients with ROI analysis. Twenty-five were left dominant, two right, one bilateral, and two were nondiagnostic; IAT and fMRI agreed in most patients, three had partial agreement, none overtly disagreed. Interrater agreement ranged between 0.77 to 0.82 (Cramer V; p < 0.0001); agreement between visual and ROI reading with IAT was 0.71 to 0.77 (Cramer V; p < 0.0001). Viewing data at lower thresholds added interpretation to 12 patients on visual analysis and 8 with ROI analysis. Conclusions: An fMRI reading paradigm can identify language dominance in frontal and temporal areas. Clinical visual interpretation is comparable to quantitative ROI analysis.://000176875400020 Times Cited: 43ISI:000176875400020;George Washington Univ, Sch Med, Childrens Natl Med Ctr, Dept Neurosci, Washington, DC USA. George Washington Univ, Sch Med, Childrens Natl Med Ctr, Dept Radiol, Washington, DC USA. Natl Inst Neurol Disorders & Stroke, Epilepsy Res Branch, Bethesda, MD USA. NIH, Speech Language Pathol Sect, Dept Rehabil Med, Ctr Clin, Bethesda, MD USA. Uniformed Serv Univ Hlth Sci, Dept Neurol, Bethesda, MD USA. Univ Catholique Louvain, St Luc Univ Hosp, Dept Radiol, Brussels, Belgium. Gaillard, WD, Childrens Natl Med Ctr, Dept Neurol, 111 Michigan Ave NW, Washington, DC 20010 USA.?Q_Xu, B. Grafman, J. Gaillard, W. D. Spanaki, M. V. Ishii, K. Balsamo, L. Makale, M. Theodore, W.2002WNeuroimaging reveals automatic speech coding during perception of written word meaning.859-870 Neuroimage17 ~?RGaillard, W. D. Balsamo, L. Xu, B. McKinney, C. Papero, P. H. Weinstein, S. Conry, J. Pearl, P. L. Sachs, B. Sato, S. Vezina, L. G. Frattali, C. Theodore, W. H.2004EfMRI language task panel improves determination of language dominance 1403-1408 Neurology638OctsBackground: fMRI language tasks reliably identify language areas in presurgical epilepsy patients, but activation using single paradigms may disagree with the intracarotid amobarbital test (IAT). Objective: To determine whether a panel of fMRI tasks targeting different aspects of language processing increases accuracy in determining hemisphere language dominance. Methods: Twenty-six patients age 12 to 56 years, predominantly with temporal lobe epilepsy, were studied using whole-brain 1.5 T fMRI (echo planar imaging, blood oxygenation level-dependent) with three task categories using a block design: verbal fluency, reading comprehension, and auditory comprehension. fMRI t maps were visually rated at three thresholds. All patients had assessment of language lateralization by IAT. Results: fMRI showed left dominance in 21 patients, right dominance in 2, and bilateral activation in 2; raters disagreed over a left vs right bilateral rating in 1 patient. There was full agreement between IAT and fMRI in 21 of 25 patients ( IAT failed in 1). In three instances of partial disparity with IAT, the fMRI panel showed consistent findings across raters. Agreement between raters was excellent ( partial disagreement in only one patient); the panel of tasks was superior to any single task for interrater agreement (Cramer V 0.93 [range 0.91 to 1.0] vs 0.72 [range 0.60 to 0.86]). Conclusions: A panel of fMRI language paradigms may be more accurate for evaluating partial epilepsy patients than a single task. A panel of tasks reduces the likelihood of nondiagnostic findings, improves interrater reliability, and helps confirm language laterality.://000224732400013 Times Cited: 15ISI:000224732400013George Washington Univ, Sch Med, Childrens Natl Med Ctr, Dept Neurosci, Washington, DC USA. George Washington Univ, Sch Med, Childrens Natl Med Ctr, Dept Radiol, Washington, DC USA. NINDS, Clin Epilepsy Sect, Bethesda, MD 20892 USA. NIH, Speech Language PAthol Sect, Dept Rehabil Med, Ctr Clin, Bethesda, MD 20892 USA. Gaillard, WD, Childrens Natl Med Ctr, Dept Neurol, 111 Michigan Ave NW, Washington, DC 20010 USA. gaillardw@ninds.nih.gov~?S8Theodore, W. H. Kelley, K. Toczek, M. T. Gaillard, W. D.2004DEpilepsy duration, febrile seizures, and cerebral glucose metabolism276-279 Epilepsia453Mar1Purpose: Studies using magnetic resonance imaging have shown that reduced hippocampal volume is associated with a history of febrile seizures, the duration of epilepsy. and the number of generalized tonic-clonic seizures. It is uncertain whether these factors have the same influence on functional as on structural measures of the integrity of the epileptogenic zone. Methods: We used positron emission tomography (PET) with fluorine IS 2-deoxyglucose to study 91 patients with temporal lobe seizure foci localized by ictal video-EEG. PET was performed in the awake interictal resting state with ears plugged and eyes patched. We recorded surface EEG during injection (5 mCi) and the 30-min uptake period. We used a standard template to analyze PET scans. Results: A significant negative relation was found between the duration of epilepsy and hippocampal glucose metabolism ipsilateral to the epileptic focus. Patients with a history of either any febrile seizures, or complex. or prolonged febrile seizures, did not have greater hypometabolism ipsilateral to the epileptic focus than did patients without a febrile seizure history. We found no effect of generalized tonic-clonic seizure history. Conclusions: Longer epilepsy duration is associated with greater hypometabolism. Suggesting that epilepsy is a progressive disease.://000220193000012 Times Cited: 8ISI:000220193000012NIH, Clin Epilepsy Sect, Bethesda, MD 20892 USA. Childrens Natl Med Ctr, Dept Neurol, Washington, DC 20010 USA. Theodore, WH, NIH Bldg 10,Room 5N-250, Bethesda, MD 20892 USA. theodorw@ninds.nih.gov ~?TBerl, M. M. Balsamo, L. M. Xu, B. Moore, E. N. Weinstein, S. L. Conry, J. A. Pearl, P. L. Sachs, B. C. Grandin, C. B. Frattali, C. Ritter, F. J. Sato, S. Theodore, W. H. Gaillard, W. D.2005ASeizure focus affects regional language networks assessed by fMRI 1604-1611 Neurology6510NovrObjective: To investigate the degree of language dominance in patients with left and right hemisphere seizure foci compared to normal volunteers using a fMRI reading comprehension task. Methods: Fifty patients with complex partial epilepsy, aged 8 to 56 years and 33 normal volunteers, aged 7 to 34 had fMRI ( 1.5 T) and neuropsychological testing. Participants silently named an object described by a sentence compared to a visual control. Data were analyzed with region of interest (ROI) analysis based on t maps for inferior frontal gyrus (IFG), midfrontal gyrus (MFG), and Wernicke area (WA). Regional asymmetry indices (AIs) were calculated [( L - R)/( L - R)]; AI > 0.20 was deemed left dominant and AI < 0.20 as atypical language. Results: Left hemisphere focus patients had a higher likelihood of atypical language than right hemisphere focus patients (21% vs 0%, chi(2) < 0.002). Left hemisphere focus patients, excluding those with atypical language, had lower regional AI in IFG, MFG, and WA than controls. Right hemisphere focus patients were all left language dominant and had a lower AI than controls in WA and MFG, but not for IFG. AI in MFG and WA were similar between left hemisphere focus/left language patients and right hemisphere focus patients. Patients activated more voxels than healthy volunteers. Lower AIs were attributable to greater activation in right homologous regions. Less activation in the right-side WA correlated with better verbal memory performance in right focus/left hemisphere-dominant patients, whereas less strongly lateralized activation in IFG correlated better with Verbal IQ in left focus/left hemisphere-dominant patients. Conclusions: Patients had lower asymmetry indices than healthy controls, reflecting increased recruitment of homologous right hemisphere areas for language processing. Greater right hemisphere activation may reflect greater cognitive effort in patient populations, the effect of epilepsy, or its treatment. Regional activation patterns reflect adaptive efforts at recruiting more widespread language processing networks that are differentially affected based on hemisphere of seizure focus.://000233428100018 Times Cited: 1ISI:000233428100018George Washington Univ, Dept Neurosci, Childrens Natl Med Ctr, Sch Med, Washington, DC 20010 USA. NINDS, Clin Epilepsy Sect, NIH, Bethesda, MD 20892 USA. NIH, Speech Language Pathol Sect, Dept Rehabil Med, Ctr Clin, Bethesda, MD 20892 USA. Minnesota Epilepsy Grp, St Paul, MN USA. Gaillard, WD, George Washington Univ, Dept Neurosci, Childrens Natl Med Ctr, Sch Med, 111 Michigan Ave NW, Washington, DC 20010 USA. wgaillar@cnmc.orgF?UjGaillard, W. D. Weinstein, S. Conry, J. Pearl, P. L. Fazilat, S Vezina, L. G. Reeves-Tyer, P. Theodore, W.2007EPrognosis of children with partial epilepsy: MRI and serial 18FDG-PET Neurology68655-659\F?VGaillard, W. D. Berl, M. M. Moore, E. A. Ritzl, E. K. Rosenberger, L. R. Weinstein, S. L. Conry, J. A. Pearl, P. L. Ritter, F. F. Sato, S. Vezina, L. G. Vaidya, C. J. Wiggs, E. Fratalli, C. Risse, G. Ratner, N. B., Giooa, G. Theodore, W.in pressGAtypical language in lesional and non-lesional complex partial epilepsy Neurology?WZhang, Y. Marenco, S. Shen, J.2007yCorrection of frequency and phase variations induced by eddy currents in localized spectroscopy with multiple echo times.174-178Magnetic Resonance in Medicine58?XyPine, D. S. Fyer, A. Grun, J. Phelps, E. A. Szeszko, P. R. Koda, V. Ardekani, B. Maguire, E. A. Burgess, N. Bilder, R. M.2001?Methods for developmental studies of fear conditioning circuity225-258Emotion50F?YbPine, D. S. Grun, J. Fyer, A. Zarahn, E. Koda, V. Szeszko, P. R. Ardekani, B. Li, W. Bilder, R. M.2001aCortical brain regions engaged by masked emotional faces in adolescents and adults: an fMRI studyEmotion1137-47 ~?ZiPine, D. S. Grun, J. Maguire, E. A. Burgess, N. Zarahn, E. Koda, V. Fyer, A. Szeszko, P. R. Bilder, R. M.2002NNeurodevelopmental aspects of spatial navigation: A virtual reality fMRI study396-406 Neuroimage152FebNavigation in spatial contexts has been studied in diverse species, yielding insights into underlying neural mechanisms and their phylogenetic progression. Spatial navigation in humans is marked by age-related changes that may carry important implications for understanding cortical development. The emergence of "allocentric" processing, reflecting that ability to use viewer-independent spatial abstractions, represents an important developmental change. We used fMRI to map brain regions engaged during memory-guided navigation in a virtual reality environment in adolescents and adults. Blood oxygen level-dependent (BOLD) signal was monitored in eight adolescents and eight adults in a 1.5-T MRI scanner during three conditions: (1) memory-guided navigation (NAV); (2) arrow-guided navigation (ARROW); and (3) fixation (FIX). We quantified navigation ability during scanning and allocentric memory after scanning, based on subjects' ability to label a previously unseen, aerial view of the town. Adolescents and adults exhibited similar memory-guided navigation ability, but adults exhibited superior allocentric memory ability. Memory-guided navigation ability during scanning correlated with BOLD change between NAV/ARROWS in various regions, including a right frontal and right-anterior medial temporal lobe region. Age group and allocentric memory together explained significant variance in BOLD change in temporoparietal association cortex and the cerebellum, particularly in the left hemisphere. Consistent with developmental models, these findings relate maturation in the coding of spatial information to functional changes in a distributed, left-lateralized neural network. (C) 2002 Elsevier Science.://000173692500009 Times Cited: 16ISI:000173692500009NIMH, Intramural Res Program, Bethesda, MD 20892 USA. New York State Psychiat Inst & Hosp, New York, NY 10032 USA. Hillside Hosp, New York, NY USA. Nathan S Kline Inst Psychiat Res, Ctr Adv Brain Imaging, Orangeburg, NY 10962 USA. Univ Coll London, Dept Anat, London, England. Univ Coll London, Inst Cognit Neurosci, London, England. Univ Coll London, Inst Neurol, Wellcome Dept Cognit Neurol, London, England. Pine, DS, NIMH, Intramural Res Program, Bldg 10,Room 4N-222,MSC1381, Bethesda, MD 20892 USA.5~?[sMonk, C. S. Grillon, C. Baas, J. M. P. McClure, E. B. Nelson, E. E. Zarahn, E. Charney, D. S. Ernst, M. Pine, D. S.2003<A neuroimaging method for the study of threat in adolescents359-366Developmental Psychobiology434DecLittle is understood about the brain basis of anxiety, particularly among youth. However, threat paradigms with animals are delineating the relationship between anxietylike behaviors and brain function. We adapted a threat paradigm for adolescents using functional magnetic resonance imaging. The aim was to examine amygdala activation to fear. The threat was an aversive air blast directed to the larynx. Participants were explicitly informed that they might receive the air blast when viewing one stimulus (threat condition) and would not receive the blast when viewing the other stimulus (safe condition). Participants provided fear ratings immediately after each trial. Based on the relatively mild nature of the air blast, we expected participants to report varying degrees of fear Those who reported increased fear showed right amygdala activation during the threat condition and left amygdala activation in the safe condition. These procedures offer a promising tool for studying youth with anxiety disorders. (C) 2003 Wiley Periodicals, Inc.://000187030900009 Times Cited: 3ISI:000187030900009NIMH, Mood & Anxiety Disorders Program, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. Columbia Univ, Dept Psychiat, New York, NY 10032 USA. Monk, CS, 15K N Dr,Room 204,MSC 2670, Bethesda, MD 20892 USA. ~?\uMonk, C. S. McClure, E. B. Nelson, E. E. Zarahn, E. Bilder, R. M. Leibenluft, E. Charney, D. S. Ernst, M. Pine, D. S.2003[Adolescent immaturity in attention-related brain engagement to emotional facial expressions420-428 Neuroimage201SepVSelective attention, particularly during the processing of emotionally evocative events, is a crucial component of adolescent development. We used functional magnetic resonance imagining (fMRI) with adolescents and adults to examine developmental differences in activation in a paradigm that involved selective attention during the viewing of emotionally engaging face stimuli. We evaluated developmental differences in neural activation for three comparisons: (1) directing attention to subjective responses to fearful facial expressions relative to directing attention to a nonemotional aspect (nose width) of fearful faces, (2) viewing fearful relative to neutral faces while attending to a nonemotional aspect of the face, and (3) viewing fearful relative to neutral faces while attention was unconstrained (passive viewing). The comparison of activation across attention tasks revealed greater activation in the orbital frontal cortex in adults than in adolescents. Conversely, when subjects attended to a nonemotional feature, fearful relative to neutral faces influenced activation in the anterior cingulate more in adolescents than in adults. When attention was unconstrained, adolescents relative to adults showed greater activation in the anterior cingulate, bilateral orbitofrontal cortex, and right amygdala in response to the fearful relative to neutral faces. These findings suggest that adults show greater modulation of activity in relevant brain structures based on attentional demands, whereas adolescents exhibit greater modulation based on emotional content. (C) 2003 Elsevier Inc. All rights reserved.://000185746400038 Times Cited: 33ISI:000185746400038NIMH, Sect Dev & Affect Neurosci, Dept Hlth & Human Serv, NIH, Bethesda, MD 20892 USA. NIMH, Mood & Anxiety Disorders Program, Dept Hlth & Human Serv, NIH, Bethesda, MD 20892 USA. Columbia Univ, Dept Psychiat, New York, NY 10032 USA. Univ Calif Los Angeles, Sch Med, Dept Psychiat & Biobehav Sci, Los Angeles, CA 90095 USA. NIMH, Pediat & Dev Neuropsychiat Branch, Dept Hlth & Human Serv, NIH, Bethesda, MD 20892 USA. Monk, CS, 15K North Dr,Room 204,MSC 2670, Bethesda, MD 20892 USA.$?]UNelson, E. E. McClure, E. Monk, C. S. Zarahn, E. Leibenluft, E. Pine, D. S. Ernst, M.2003yDevelopmental differences in neuronal engagement during implicit encoding of emotional faces: an event related fMRI study 1015-1024*Journal of Child Psychology and Psychiatry44 ~?^Ernst, M. Nelson, E. E. McClure, E. B. Monk, C. S. Munson, S. Eshel, N. Zarahn, E. Leibenluft, E. Zametkin, A. Towbin, K. Blair, J. Charney, D. Pine, D. S.20047Choice selection and reward anticipation: an fMRI study 1585-1597Neuropsychologia4212We examined neural activations during decision-making using fMRI paired with the wheel of fortune task, a newly developed two-choice decision-making task with probabilistic monetary gains. In particular, we assessed the impact of high-reward/risk events relative to low-reward/risk events on neural activations during choice selection and during reward anticipation. Seventeen healthy adults completed the study. We found, in line with predictions, that (i) the selection phase predominantly recruited regions involved in visuo-spatial attention (occipito-parietal pathway), conflict (anterior cingulate), manipulation of quantities (parietal cortex), and preparation for action (premotor area), whereas the anticipation phase prominently recruited regions engaged in reward processes (ventral striatum); and (ii) high-reward/risk conditions relative to low-reward/risk conditions were associated with a greater neural response in ventral striatum during selection, though not during anticipation. Following an a priori ROI analysis focused on orbitofrontal cortex, we observed orbitofrontal cortex activation (BA-11 and 47) during selection (particularly to high-risk/reward options), and to a more limited degree, during anticipation. These findings support the notion that (1) distinct, although overlapping, pathways subserve the processes of selection and anticipation in a two-choice task of probabilistic monetary reward; (2) taking a risk and awaiting the consequence of a risky decision seem to affect neural activity differently in selection and anticipation; and thus (3) common structures, including the ventral striatum, are modulated differently by risk/reward during selection and anticipation. Published by Elsevier Ltd.://000224047600001 Times Cited: 28ISI:000224047600001NIMH, Mood & Anxiety Disorders Program, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. Ernst, M, NIMH, Mood & Anxiety Disorders Program, NIH, Dept Hlth & Human Serv, 15K N Dr, Bethesda, MD 20892 USA. ernstm@intra.nimh.nih.gov~?_uMcClure, E. B. Monk, C. S. Nelson, E. E. Zarahn, E. Leibenluft, E. Bilder, R. M. Charney, D. S. Ernst, M. Pine, D. S.2004aA developmental examination of gender differences in brain engagement during evaluation of threat 1047-1055Biological Psychiatry5511JuntBackground: Females appear to be more sensitive and responsive to social cues, including threat signals, than are males. Recent theoretical models suggest that developmental changes in brain functioning play important roles in the emergence of such gender differences. Methods: We used functional magnetic resonance imaging to examine developmental and gender differences in activation of neural structures thought to mediate attention to emotional faces depicting varying degrees of threat. Analyses focused on the orbitofrontal cortex, amygdala, and anterior cingulate cortex during the evaluation of threat conveyed by faces. Healthy adolescents (n = 17.53% male) and adults (n = 17; 53% male) were scanned while they rated how threatening pictures of neutral and emotional (angry, fearful, or happy) faces appeared. Results: Results indicate significant interactions among aged, gender, and,face type for activation during explicit threat monitoring. In particular adult women activated orbitofrontal cortex and amygdala selectively to unambiguous threat (angry) cues, while adult men showed a less discriminating pattern of activation. No gender differences were evident for adolescents, who as a group resembled adult males. Conclusions: These findings suggest that there are gender differences in patterns of neural responses to emotional laces that are not fully apparent until adulthood.://000221605800001 Times Cited: 20ISI:000221605800001Univ Calif Los Angeles, Dept Psychiat & Biobehav Sci, Los Angeles, CA 90024 USA. Columbia Univ, Dept Psychiat, New York, NY USA. NIMH, Mood & Anxiety Disorders Program, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. NIMH, Sect Dev & Affect Neurosci, Dept Hlth & Human Serv, NIH, Bethesda, MD 20892 USA. NIMH, Mood & Anxiety Disorders Program, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. McClure, EB, NIMH, NIH, MAP, 15K North Dr,MSC 2670, Bethesda, MD 20892 USA.\~?`Monk, C. S. Nelson, E. E. Woldehawariat, G. Montgomery, L. A. Zarahn, E. McClure, E. B. Guyer, A. E. Leibenluft, E. Charney, D. S. Ernst, M. Pine, D. S.2004iExperience-dependent plasticity for attention to threat: Behavioral neurophysiological evidence in humans607-610Biological Psychiatry568OctBiased attention to threat represents a key feature of anxiety disorders. This bias is altered by therapeutic or stressful experiences, suggesting that the bias is plastic. Charting on-line behavioral and neurophysiological changes in attention bias may generate insights on the nature of such plasticity. We used an attention-orientation task with threat cites to examine bow healthy individuals alter their response over time to such cites. In Experiments 1 through 3, we established that healthy individuals demonstrate an increased attention bias away from threat over time. For Experiment 3, we used functional magnetic resonance imaging to determine the neural bases for this phenomenon. Gradually increasing attention bias away from threat is associated with increased activation in the occipitotemporal cortex. Examination of plasticity of attention bias with individuals at risk for anxiety disorders way reveal how threatening stimuli come to be categorized differently in this population over time.://000224538800011 Times Cited: 5ISI:000224538800011NIMH, Bethesda, MD 20892 USA. US Dept Hlth & Human Serv, NIH, Bethesda, MD 20892 USA. Columbia Univ, Dept Psychiat, New York, NY USA. Monk, CS, 15K N Dr,Room 204, Bethesda, MD 20892 USA. christopher.monk@nih.gov?akEaster, J. McClure, E. Monk, C. S. Dhanani, M. Hodgdon, H. Leibenluft, E. Charney, D. Pine, D. S. Ernst, M.2005`Emotion recognition deficits in pediatric anxiety disorders: implications for amygdala research.563-567$Journal of Child Adolesc Psychopharm15 &~?bbErnst, M. Nelson, E. E. Jazbec, S. McClure, E. B. Monk, C. S. Leibenluft, E. Blair, J. Pine, D. S.2005fAmygdala and nucleus accumbens in responses to receipt and omission of gains in adults and adolescents 1279-1291 Neuroimage254MayAdolescents' propensity for risk-taking and reward-seeking behaviors suggests a heightened sensitivity for reward, reflected by greater feedback-related activity, changes in reward circuitry (e.g., nucleus accumbens), ane/or a lower sensitivity to potential harm reflected by weaker feedback-related activity changes in avoidance circuitry (e.g., amygdala) relative to adults. Responses of nucleus accumbens and amygdala to valenced outcomes (reward receipt and reward omission) were assayed using an event-related functional magnetic resonance imaging procedure paired with a monetary reward task in 14 adults and 16 adolescents. Bilateral amygdala and nucleus accumbens showed significantly greater activation when winning than when failing to win in both groups. Group comparisons revealed stronger activation of left nucleus accumbens by adolescents, and of left amygdala by adults. When examining responses to reward receipts and to reward omissions separately. the most robust group difference was within the amygdala during reward omission. The reduction of the fMRI BOLD signal in the amygdala in response to reward omission was larger for adults than for adolescents. Correlations showed a close link between negative emotion and amygdala decreased BOLD signal in adults, anti between positive emotion and nucleus accumbens activation in adolescents. Overall, these findings support the notion that the signal differences between positive and negative outcomes involve the nucleus accumbens more in adolescents than in adults, and the amygdala more in adults than in adolescents. These developmental differences, if replicated, may have important: implications for the development of early-onset disorders of emotion and motivation. Published by Elsevier Inc.://000229011200026 Times Cited: 10ISI:000229011200026NIMH, Mood & Anxiety Disorders Program, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. Ernst, M, NIMH, Mood & Anxiety Disorders Program, NIH, Dept Hlth & Human Serv, 15K N Dr, Bethesda, MD 20892 USA. ernstm@intra.nimh.nih.gov~?clMilham, M. P. Nugent, A. C. Drevets, W. C. Dickstein, D. P. Leibenluft, E. Ernst, M. Charney, D. Pine, D. S.2005nSelective reduction in amygdala volume in pediatric anxiety disorders: A voxel-based morphometry investigation961-966Biological Psychiatry579MayGBackground Significant controversy has emerged concerning pediatric anxiety disorders. Some researchers question the justification for diagnosing and treating pediatric anxiety disorders, owing to concerns about the inappropriate medicalization of social problems. Others note the importance of diagnosis and treatment, given that pediatric anxiety disorders represent a strong risk factor for serious adult mental disorders. We examine the neural correlates of pediatric anxiety disorders, to consider the validity of the categorization scheme used in recent treatment studies. Methods: Using inclusion criteria derived from recent treatment trials, we compared gray matter volume throughout the brain in children with and without anxiety. Morphometric analyses used optimized voxel-based morphometry, an automated method for examining structural changes throughout the brain. Results: Reductions in left amygdala gray matter volume were noted for patients with anxiety disorders relative to comparison subjects. Conclusions: We discuss implications of these findings for current controversies.://000228611900002 Times Cited: 3ISI:000228611900002NIMH, Sect Dev & Affect Neurosci, Mood & Anxiety Disorders Program, Bethesda, MD 20892 USA. Univ Illinois, Beckman Inst, Urbana, IL 61801 USA. Milham, MP, NYU, Sch Med, 150 E 30th St,Apt 5A, New York, NY 10016 USA. milham01@med.nyu.edu~?dGuyer, A. E. Nelson, E. E. Perez-Edgar, K. Hardin, M. G. Roberson-Nay, R. Monk, C. S. Bjork, J. M. Henderson, H. A. Pine, D. S. Fox, N. A. Ernst, M.2006dStriatal functional alteration in adolescents characterized by early childhood behavioral inhibition 6399-6405Journal of Neuroscience2624Jun7The temperamental style of behavioral inhibition has been characterized by exaggerated behavioral and neural responses to cues signaling threat. Virtually no work, however, has addressed whether behavioral inhibition may also confer heightened brain activation in response to positively valenced incentives. We used event-related functional MRI (fMRI) and a monetary incentive delay task to examine whether the neural response to incentives is also greater in adolescents characterized as behaviorally inhibited early in life compared with those characterized as non-inhibited. Whereas task performance did not differ between groups, fMRI revealed greater striatal activation to incentives in behaviorally inhibited adolescents than in non-inhibited adolescents. This was regardless of whether the incentive was an anticipated gain or loss. Alteration in neural systems underlying behavior modulated by both negative and positive contingencies may represent a correlate of behavioral inhibition that also underlies vulnerability to various forms of developmental psychopathology.://000238375900002 Times Cited: 1ISI:000238375900002NIMH, Emot Dev & Affect Neurosci Branch, NIH, Bethesda, MD 20892 USA. Univ Maryland, Dept Human Dev, College Pk, MD 20742 USA. Virginia Commonwealth Univ, Dept Psychiat, Richmond, VA 23284 USA. Univ Michigan, Dept Psychol, Ann Arbor, MI 48109 USA. NIAAA, Lab Clin & Translat Studies, NIH, Bethesda, MD 20892 USA. Univ Miami, Dept Psychol, Coral Gables, FL 33146 USA. George Mason Univ, Dept Psychol, Fairfax, VA 22030 USA. Guyer, AE, 15K North Dr,Room 208, Bethesda, MD 20892 USA. amandaguyer@mail.nih.gov ~?e[Krain, A. L. Hefton, S. Pine, D. S. Ernst, M. Castellanos, F. X. Klein, R. G. Milham, M. P.2006lAn fMRI examination of developmental differences in the neural correlates of uncertainty and decision-making 1023-1030*Journal of Child Psychology and Psychiatry4710OctLBackground: Maturation of prefrontal circuits during adolescence contributes to the development of cognitive processes such as decision-making. Recent theories suggest that these neural changes also play a role in the shift from generalized anxiety disorder (GAD) to depression that often occurs during this developmental period. Cognitive models of the development of GAD highlight the role of intolerance of uncertainty (IU), which can be characterized behaviorally by impairments in decision-making. The present study examines potential developmental differences in frontal regions associated with uncertain decision-making, and tests the impact of IU on these circuits. Methods: Twelve healthy adults (ages 19-36) and 12 healthy adolescents (ages 13-17) completed a decision-making task with conditions of varied uncertainty while fMRI scans were acquired. They also completed measures of worry and IU, and a questionnaire about their levels of anxiety and certainty during the task. Results: Combined group analyses demonstrated significant linear effects of uncertainty on activity within anterior cingulate cortex (ACC). Region of interest (ROI)-based analysis found a significant interaction of group and IU ratings in ACC. Increased IU was associated with robust linear increases in ACC activity only in adolescents. An ROI analysis of feedback-related processing found that adolescents demonstrated greater activation during incorrect trials relative to correct trials, while the adults showed no difference in neural activity associated with incorrect and correct feedback. Conclusions: This decision-making task was shown to be effective at eliciting uncertainty-related ACC activity in adults and adolescents. Further, IU impacts ACC activity in adolescents during uncertain decision-making, providing preliminary support for a developmental model of GAD.://000241625200007 Times Cited: 0ISI:000241625200007NYU, Sch Med, NYU Child Study Ctr, New York, NY 10012 USA. NIMH, Sect Dev & Affect Neurosci, Bethesda, MD 20892 USA. Krain, AL, NYU, Sch Med, NYU Child Study Ctr, 550 1St Ave, New York, NY 10012 USA. krain@med.nyu.edu ~?fMonk, C. S. Nelson, E. E. McClure, E. B. Mogg, K. Bradley, B. P. Leibenluft, E. Blair, R. J. R. Chen, G. Charney, D. S. Ernst, M. Pine, D. S.2006Ventrolateral prefrontal cortex activation and attentional bias in response to angry faces in adolescents with generalized anxiety disorder 1091-1097American Journal of Psychiatry1636JunObjective: While adolescent anxiety disorders represent prevalent, debilitating conditions, few studies have explored their brain physiology. Using event-related functional magnetic resonance imaging (fMRI) and a behavioral measure of attention to angry faces, the authors evaluated differences in response between healthy adolescents and adolescents with generalized anxiety disorder. Method: In the primary trials of interest, 18 adolescents with generalized anxiety disorder and 15 comparison subjects of equivalent age/gender/IQ viewed angry/neutral face pairs during fMRI acquisition. Following the presentation of each face pair, subjects pressed a button to indicate whether a subsequent asterisk appeared on the same (congruent) or opposite (incongruent) side as the angry face. Reaction time differences between congruent and incongruent face trials provided a measure of attention bias to angry faces. Results: Relative to the comparison subjects, patients with generalized anxiety disorder manifested greater right ventrolateral prefrontal cortex activation to trials containing angry faces. Patients with generalized anxiety disorder also showed greater attention bias away from angry faces. Ventrolateral prefrontal cortex activation differences remained evident when differences in attention bias were covaried. Finally, in an examination among patients of the association between degree of anxiety and brain activation, the authors found that as ventrolateral prefrontal cortex activation increased, severity of anxiety symptoms diminished. Conclusions: Adolescents with generalized anxiety disorder show greater right ventrolateral prefrontal cortex activation and attentional bias away from angry faces than healthy adolescents. Among patients, increased ventrolateral prefrontal cortex activation is associated with less severe anxiety, suggesting that this activation may serve as a compensatory response.://000237972300023 Times Cited: 0ISI:000237972300023]Univ Michigan, Dept Psychol, Ann Arbor, MI 48109 USA. Univ Michigan, Ctr Human Growth & Dev, Ann Arbor, MI 48109 USA. NIMH, Bethesda, MD 20892 USA. Univ Southampton, Southampton SO9 5NH, Hants, England. Mt Sinai Sch Med, New York, NY USA. Monk, CS, Univ Michigan, Dept Psychol, 2000 East Hall,530 Church St, Ann Arbor, MI 48109 USA. csmonk@umich.edu~?gRoberson-Nay, R. McClure, E. B. Monk, C. S. Nelson, E. E. Guyer, A. E. Fromm, S. J. Charney, D. S. Leibenluft, E. Blair, J. Ernst, M. Pine, D. S.2006tIncreased amygdala activity during successful memory encoding in adolescent major depressive disorder: An fMRI study966-973Biological Psychiatry609NovuBackground: Although major depressive disorder (MDD) represents one of the most serious psychiatric problems afflicting adolescents, efforts to understand the neural circuitry of adolescent MDD have lagged behind those of adult MDD. This study tests the hypothesis that adolescent MDD is associated with abnormal amygdala activity during evocative-face viewing. Methods: Using functional magnetic resonance imaging (fMRI), between-group differences among MDD (n = 10), anxious (n = 11), and non-psychiatric comparisons (n = 23) were examined during successful vs. unsuccessful face encoding, with encoding success measured post-scan. Results: Compared to healthy adolescents, MDD patients exhibited poorer memory for faces. fMRI analyses accounted for this performance difference through event-related methods. In an analysis comparing successful vs. unsuccessful face encoding, MDD patients exhibited greater left amygdala activation relative to healthy and anxious youth. Conclusions. Given prior findings among adults, this study suggests that adolescent and adult MDD may involve similar underlying abnormalities in amygdala functioning.://000241691600010 Times Cited: 0ISI:000241691600010NIMH, Sect Dev & Affect Neurosci, Intramural Res Program, Bethesda, MD 20892 USA. NIMH, Mood & Anxiety Disorders Program, Intramural Res Program, Bethesda, MD 20892 USA. Mt Sinai Sch Med, Dept Psychiat, New York, NY USA. Mt Sinai Sch Med, Dept Neurosci, New York, NY USA. Mt Sinai Sch Med, Dept Pharmacol, New York, NY USA. Mt Sinai Sch Med, Dept Biol Chem, New York, NY USA. NIMH, Unit Affect Disorders, Pediat & Dev Neuropsychiat Branch, Intramural Res Program, Bethesda, MD 20892 USA. NIMH, Unit Affect Cognit Neurosci, Intramural Res Program, Bethesda, MD 20892 USA. Roberson-Nay, R, Virginia Commonwealth Univ, Dept Psychiat, Commonwealth Inst Child & Family Studies, Richmond, VA 23298 USA. rrobersonnay@vcu.edu8?hErnst, M. Maheu, F. S. Schroth, E. Hardin, J. Golan, L. Cameron, J. Allen, R. Holzer, S. Nelson, E. E. Pine, D. S. Merke, D. P.2007{Amygdala function in adolescence with congenital adrenal hyperplasia: a model for the study of early steroid abnormalities. 2104-2113Neuropsychologia45?i=Eshel, N. Nelson, E. E. Blair, R. J. R. Pine, D. S. Ernst, M.2007Neural substrates of choice selection in adults and adolescents: development of the ventrolateral prefrontal and anterior cingulate cortices. 1299-1309Neuropsychologia455?jMcClure, E. Monk, C. S. Nelson, E. E. Parrish, J.M. Alder, A. Blair, R. J. R. Fromm, S. J. Charney, D. S. Leibenluft, E. Ernst, M. Pine, D. S.2007`Abnormal attention modulation of fear circuit function in pediatric generalized anxiety disorder97-106Archives of General Psychiatry64?knMcClure, E. B. Adler, A. Monk, C. S. Cameron, J. Smith, S. Nelson, E. E. Leibenluft, E. Ernst, M. Pine, D. S.2007CfMRI predictors of treatment outcome in pediatric anxiety disorders225-231Psychopharmacol32?lPerez-Edgar, K. Roberson-Nay, R. Hardin, J. Poeth, K. Guyer, A. E. Nelson, E. E. McClure, E. Henderson, H. A. Fox, N. A. Pine, D. S. Ernst, M.2007ZAttention alters neural responses to evocative faces in behaviorally inhibited adolescents 1538-1456 Neuroimage35F?m[Krain, A. L. Gotimer, K. Hefton, S. Ernst, M. Castellanos, F. X. Pine, D. S. Milham, M. P.in pressJAn fMRI investigation of uncertainty in adolescents with anxiety disordersBiological PsychiatryF?nKMaheu, F. S. Merke, D. P. Keil, M. Stratakis, C. A. Pine, D. S. Ernst, M.in presssAltered amygdala and hippocampus function in adolescents with hypercortisolemia: an fMRI study of Cushing Syndrome.Dev. and PsychopathsF?oMonk, C. S. Klein, R. G. Telzer, E. H. Schroth, E. A. Mannuzza, S. Moutlon, J. L. III Guardino, M. Masten, C. L. McClure, E. B. Fromm, S. J. Blair, R. J. R. Pine, D. S. Ernst, M.in pressAmygdala and nucleus accumbens activation to emotional facial expressions in children and adolescents at risk for major depressionAmerican Journal of Psychiatry~?p'Chang, L. C. Jones, D. K. Pierpaoli, C.2005:RESTORE: Robust estimation of tensors by outlier rejection 1088-1095Magnetic Resonance in Medicine535MaySignal variability in diffusion weighted imaging (DWI) is influenced by both thermal noise and spatially and temporally varying artifacts such as subject motion and cardiac pulsation. In this paper, the effects of DWI artifacts on estimated tensor values, such as trace and fractional anisotropy, are analyzed using Monte Carlo simulations. A novel approach for robust diffusion tensor estimation, called RESTORE (for robust estimation of tensors by outlier rejection), is proposed. This method uses iteratively reweighted least-squares regression to identify potential outliers and subsequently exclude them. Results from both simulated and clinical diffusion data sets indicate that the RESTORE method improves tensor estimation compared to the commonly used linear and nonlinear least-squares tensor fitting methods and a recently proposed method based on the Geman-McClure M-estimator. The RESTORE method could potentially remove the need for cardiac gating in DWI acquisitions and should be applicable to other MR imaging techniques that use univariate or multivariate regression to fit MRI data to a model. Published 2005 Wiley-Liss, Inc.(dagger)://000228796900014 Times Cited: 4ISI:000228796900014.NICHHD, Sect Tissue Biophys & Biomimet, Lab Integrat Med & Biophys, NIH, Bethesda, MD 20892 USA. Inst Psychiat, Ctr Neuroimaging Sci, London, England. Pierpaoli, C, NICHHD, Sect Tissue Biophys & Biomimet, Lab Integrat Med & Biophys, NIH, Bldg 13,Room 3W16,South Dr, Bethesda, MD 20892 USA. cp1a@nih.gov~?qJones, D. K. Pierpaoli, C.2005iConfidence mapping in diffusion tensor magnetic resonance imaging tractography using a bootstrap approach 1143-1149Magnetic Resonance in Medicine535MayThe bootstrap technique is an extremely powerful nonparametric statistical procedure for determining the uncertainty in a given statistic. However, its use in diffusion tensor MRI tractography remains virtually unexplored. This work shows how the bootstrap can be used to assign confidence to results obtained with deterministic tracking algorithms. By invoking the concept of a "tract-propagator," it also underlines the important effect of local fiber architecture or architectural milieu on tracking reproducibility. Finally, the practical advantages and limitations of the technique are discussed. Not only does the bootstrap allow any deterministic tractography algorithm to be used in a probabilistic fashion, but also its model-free inclusion of all sources of variability (including those that cannot be modeled) means that it provides the most realistic approach to probabilistic tractography. Magn Pleson Med 53:1143-1149, 2005. Published 2005 Wiley-Liss, Inc.://000228796900021 Times Cited: 8ISI:000228796900021Inst Psychiat, Ctr Neuroimaging Sci, London SE5 8AF, England. NICHHD, Sect Tissue Biophys & Biomimet, Lab Integrat Med & Biophys, Bethesda, MD 20892 USA. Jones, DK, Inst Psychiat, Ctr Neuroimaging Sci, P089,De Crespigny Pk, London SE5 8AF, England. d.jones@iop.kcl.ac.uk*~?r4Kim, S. Chi-Fishman, G. Barnett, A. S. Pierpaoli, C.2005ZDependence on diffusion time of apparent diffusion tensor of ex vivo calf tongue and heart 1387-1396Magnetic Resonance in Medicine546DecThe time dependence of the apparent diffusion tensor of ex vivo calf heart and tongue was measured for diffusion times (tau(d)) between 32 and 810 ms. The results showed evidence of restricted diffusion in the muscle tissues of both organs. In regions where the myofibers are parallel, the largest eigenvalue (lambda(1)) of the diffusion tensor remained the same for all diffusion times measured, while the other eigenvalues (lambda(2), lambda(3)) decreased by 29-36% between tau(d) = 32 ms and tau(d) = 400 ms. In regions where the fibers cross, the lambda(1) also changed, decreasing by 17% between tau(d) = 32 ms and tau(d) = 400 ms. The restricting compartment size and volume fraction were effectively estimated by fitting the time courses of the eigenvalues to a model consisting of a nonrestricted compartment and a cylindrically restricted compartment. To our knowledge, this study is the first demonstrating diffusion time dependence of measured water diffusion tensor in muscular tissue. With improvement in scanning technology, future studies may permit noninvasive, in vivo detection of changes in muscle myoarchitecture due to disease, treatment, and exercise. Magn Reson Med 54:1387-1396, 2005. Published 2005 Wiley-Liss, Inc.dagger://000233655200009 Times Cited: 0ISI:000233655200009NIH, Phys Disabil Branch, Dept Rehabil Med, Clin Res Ctr, Bethesda, MD 20892 USA. NIMH, NIH, Bethesda, MD 20892 USA. NICHHD, NIH, Bethesda, MD 20892 USA. Kim, S, NIH, Phys Disabil Branch, Dept Rehabil Med, Clin Res Ctr, 10-6c416,10 Ctr Dr, Bethesda, MD 20892 USA. sungheonk@cc.nih.gov1~?sCRohde, G. K. Barnett, A. S. Basser, P. J. Marenco, S. Pierpaoli, C.2004XComprehensive approach for correction of motion and distortion in diffusion-weighted MRI103-114Magnetic Resonance in Medicine511JanPatient motion and image distortion induced by eddy currents cause artifacts in maps of diffusion parameters computed from diffusion-weighted (DW) images. A novel and comprehensive approach to correct for spatial misalignment of DW imaging (DWI) volumes acquired with different strengths and orientations of the diffusion sensitizing gradients is presented. This approach uses a mutual information-based registration technique and a spatial transformation model containing parameters that correct for eddy current-induced image distortion and rigid body motion in three dimensions. All parameters are optimized simultaneously for an accurate and fast solution to the registration problem. The images can also be registered to a normalized template with a single interpolation step without additional computational cost. Following registration, the signal amplitude of each DWI volume is corrected to account for size variations of the object produced by the distortion correction, and the b-matrices are properly recalculated to account for any rotation applied during registration. Both qualitative and quantitative results show that this approach produces a significant improvement of diffusion tensor imaging (DTI) data acquired in the human brain. Published 2003 Wiley-Liss, Inc.://000188041500014 Times Cited: 19ISI:000188041500014NICHD, NIH, Bethesda, MD 20892 USA. NIMH, NIH, Bethesda, MD 20892 USA. Univ Maryland, Appl Math & Sci Computat Program, College Pk, MD 20742 USA. Rohde, GK, NICHD, NIH, Bldg 13,Rm 3W16,13 South Dr, Bethesda, MD 20892 USA. rohdeg@helix.nih.gov#~?t7Rohde, G. K. Barnett, A. S. Basser, P. J. Pierpaoli, C.2005eEstimating intensity variance due to noise in registered images: Applications to diffusion tensor MRI673-684 Neuroimage263JulImage registration techniques which require image interpolation are widely used in neuroimaging research. We show that signal variance in interpolated images differs significantly from the signal variance of the original images in native space. We describe a simple approach to compute the signal variance in registered images based on the signal variance and covariance of the original images, the spatial transformations computed by the registration procedure, and the interpolation or approximation kernel chosen. The method is general and could handle various sources of signal variability, such as thermal noise and physiological noise, provided that their effects can be assessed in the original images. Our approach is applied to diffusion tensor (DT) MRI data, assuming only thermal noise as the source of variability in the data. We show that incorrect noise variance estimates in registered diffusion-weighted images can affect DT parameters, as well as indices of goodness of fit such as chi-square maps. In addition to DT-MRI, we believe that this methodology would be useful any time parameter extraction methods are applied to registered or interpolated data, such as in relaxometry and functional MRI studies. (c) 2005 Elsevier Inc. All rights reserved.://000230211100003 Times Cited: 1ISI:000230211100003NICHD, STBB, LIMB, NIH, Bethesda, MD 20892 USA. Univ Maryland, Appl Math & Sci Computac Program, College Pk, MD 20742 USA. NIMH, NIH, Bethesda, MD 20892 USA. Rohde, GK, NICHD, STBB, LIMB, NIH, Bldg 13,Room 3w16,13 S Dr, Bethesda, MD 20892 USA. rohdeg@math.umd.edu 8~?u|Kirsch, P. Esslinger, C. Chen, Q. Mier, D. Lis, S. Siddhanti, S. Gruppe, H. Mattay, V. S. Gallhofer, B. Meyer-Lindenberg, A.2005KOxytocin modulates neural circuitry for social cognition and fear in humans 11489-11493Journal of Neuroscience2549DecTIn non-human mammals, the neuropeptide oxytocin is a key mediator of complex emotional and social behaviors, including attachment, social recognition, and aggression. Oxytocin reduces anxiety and impacts on fear conditioning and extinction. Recently, oxytocin administration in humans was shown to increase trust, suggesting involvement of the amygdala, a central component of the neurocircuitry of fear and social cognition that has been linked to trust and highly expresses oxytocin receptors in many mammals. However, no human data on the effects of this peptide on brain function were available. Here, we show that human amygdala function is strongly modulated by oxytocin. We used functional magnetic resonance imaging to image amygdala activation by fear-inducing visual stimuli in 15 healthy males after double-blind crossover intranasal application of placebo or oxytocin. Compared with placebo, oxytocin potently reduced activation of the amygdala and reduced coupling of the amygdala to brainstem regions implicated in autonomic and behavioral manifestations of fear. Our results indicate a neural mechanism for the effects of oxytocin in social cognition in the human brain and provide a methodology and rationale for exploring therapeutic strategies in disorders in which abnormal amygdala function has been implicated, such as social phobia or autism.://000233941900026 Times Cited: 5ISI:000233941900026NIMH, Clin Brain Disorders Branch, Genes Cognit & Psychosis Program, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. Univ Giessen, Ctr Psychiat & Psychotherapy, Cognit Neurosci Grp, D-35385 Giessen, Germany. NIMH, Neuroimaging Core Facil, Genes Cognit & Psychosis Program, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. NIMH, Unit Syst Neurosci Psychiat, Genes Cognit & Psychosis Program, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. Meyer-Lindenberg, A, NIMH, Clin Brain Disorders Branch, Genes Cognit & Psychosis Program, NIH,Dept Hlth & Human Serv, 10-3C103,9000 Rockville Pike, Bethesda, MD 20892 USA. andreasml@nih.gov +~?vMeyer-Lindenberg, A. Mervis, C. B. Sarpal, D. Koch, P. Steele, S. Kohn, P. Marenco, S. Morris, C. A. Das, S. Kippenhan, S. Mattay, V. S. Weinberger, D. R. Berman, K. F.2005eFunctional, structural, and metabolic abnormalities of the hippocampal formation in Williams syndrome 1888-1895!Journal of Clinical Investigation1157JulWilliams syndrome (WS), caused by microdeletion of some 21 genes on chromosome 7q11.23, is characterized by dysmorphic features, mental retardation or learning difficulties, elastin arteriopathy, and striking neurocognitive and social-behavioral abnormalities. Recent studies of murine knockouts of key genes in the microdeleted region, LIM kinase 1 (LIMK1) and cytoplasmatic linker protein 2 (CYLN2), demonstrated significant functional and metabolic abnormalities, but grossly normal structure, in the hippocampal formation (1417). Furthermore, deficits in spatial navigation and long-term memory, major cognitive domains dependent on hippocampal function, have been described in WS. We used multimodal neuroimaging to characterize hippocampal structure, function, and metabolic integrity in 12 participants with WS and 12 age-, sex-, and IQ-matched healthy controls. PET and functional MRI studies showed profound reduction in resting blood flow and absent differential response to visual stimuli in the anterior HF in WS. Spectroscopic measures of N-acetyl aspartate, considered a marker of synaptic activity, were reduced. Hippocampal size was preserved, but subtle alterations in shape were present. These data demonstrate abnormalities in HF in WS in agreement with murine models, implicate LIMK1 and CYLN2 in human hippocampal function, and suggest that hippocampal dysfunction may contribute to neurocognitive abnormalities in WS.://000230292800029 Times Cited: 4ISI:000230292800029NIMH, Sect Integrat Neuroimaging, Bethesda, MD 20892 USA. NIMH, Neuroimaging Core Facil, Bethesda, MD 20892 USA. NIMH, Clin Brain Disorders Branch, Genes Cognit & Psychosis Program, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. Univ Louisville, Dept Psychol & Brain Sci, Neurodev Sci Lab, Louisville, KY 40292 USA. Univ Nevada, Sch Med, Dept Pediat, Las Vegas, NV 89154 USA. Meyer-Lindenberg, A, 10-4C101,9000 Rockville Pike, Bethesda, MD 20892 USA. andreasml@nih.gov|*tical information processing in normal human subjects. 1011-1020Neuropharmacology32P(\?wShaw, P. Gornick, M. Lerch, J. Addington, A. Seal, J. Greenstein, D. Sharp, W. Evans, A. Giedd, J. Castellanos, F. X. Rapoport, J.2007Polymorphisms of the dopamine dF?xrGoldman, A. L. Pezawas, L. Mattay, V. Fischl, B. Verchinski, B. Zoltick, B. Weinberger, D. R. Meyer-Lindenberg, A.in presskHeritability of Brain Morphology Related to Schizophrenia: A Large-Scale Automated MRI Segmentation Study. Biological PsychiatryF?yiStein, J. L. Weidholz, L. M. Bassett, D. S. Weinberger, D. R. Zink, C. F. Mattay, V. Meyer-Lindenberg, A.in press7A validated network of effective amygdala connectivity. Neuroimage~?zlFrank, J. A. Richert, N. Bash, C. Stone, L. Calabresi, P. A. Lewis, B. Stone, R. Howard, T. McFarland, H. F.2004hInterferon-beta-1b slows progression of atrophy in RRMS - Three-year follow-up in NAb- and NAb+ patients719-725 Neurology625MarObjective: To determine the effect of interferon-beta-1b (IFNbeta-1b) treatment on total contrast-enhancing lesions (CEL), white matter lesion load (WMLL), and cerebral atrophy ( CA) in patients with relapsing - remitting multiple sclerosis (RRMS) using serial monthly MRI. Methods: An open-label baseline-vs-treatment crossover trial was conducted with 30 RRMS patients monitored during a 6-month baseline and up to 36 months on treatment with IFNbeta-1b. Monthly MRI exams and neurologic exams using the Expanded Disability Status Scale (EDSS) were performed. Results: The percentage changes from baseline for years 1, 2, and 3 on IFNbeta-1b were as follows: brain volume (BV) = - 1.35, - 1.48, and - 1.68%; CEL = - 76.5, - 60.1, and - 54.7%; WMLL = - 12.2, - 9.8, and - 10.4%. There was no difference in the BV, CEL, or WMLL for between-year comparisons, and the decrease in BV from year 1 to years 2 and 3 was less than the change from baseline to year 1. EDSS did increase ( p < 0.001) when comparing the last 3 months of baseline (2.8 +/- 2.1) and the last 3 months on IFNβ-1b (3.6 +/- 2.1). Eleven patients developed neutralizing antibody (NAb) during the study. The effect of IFNβ-1b on CEL and WMLL was significantly reduced in NAb+ patients compared with NAb- patients ( p < 0.003). Conclusion: IFNbeta-1b decreases contrast-enhancing lesions and white matter lesion load over 3 years on therapy and slows the progression in cerebral atrophy during years 2 and 3.://000220083000009 Times Cited: 18ISI:000220083000009NINDS, Expt Neuroimaging Sect, Lab Diagnost Radiol Res, NIH, Bethesda, MD 20892 USA. NINDS, Neuroimmunol Branch, NIH, Bethesda, MD 20892 USA. Uniformed Serv Univ Hlth Sci, Bethesda, MD 20814 USA. Johns Hopkins Univ, Baltimore, MD USA. Cleveland Clin, Cleveland, OH 44106 USA. Frank, JA, NINDS, Expt Neuroimaging Sect, Lab Diagnost Radiol Res, NIH, 10 Ctr Dr,MSC 1074,Bldg 10,Rm B1N256, Bethesda, MD 20892 USA. jafrank@helix.nih.gov~?{Gupta, S. Solomon, J. M. Tasciyan, T. A. Cao, M. M. Stone, R. D. Ostuni, J. L. Ohayon, J. M. Muraro, P. A. Frank, J. A. Richert, N. D. McFarland, H. F. Bagnato, F.2005VInterferon-beta-Ib effects on re-enhancing lesions in patients with multiple sclerosis658-668Multiple Sclerosis116DecOInterferon-beta (IFN beta) reduces the number and load of new contrast-enhancing lesions (CELs) in patients with multiple sclerosis (MS). However the ability of IFN beta to reduce lesion sizes and re-enhancements of pre-existing CELs has not been examined extensively. Activity of contrast re-enhancing lesions (Re-CELs) and contrast single-enhancing lesions (S-CELs) were monitored in ten patients with relapsing-remitting (RR) MS. These patients underwent monthly post-contrast magnetic resonance imaging (MRIs) for an 18-month natural history phase and an 18-month therapy phase with subcutaneous IFN beta-1b, totaling 37 images per patient. The activity was analysed using the First image as a baseline and registering subsequent active monthly images to the baseline. There was a 76.4% reduction in the number of CELs with IFN beta therapy. The decrease was greater (P = 0.003) for S-CELs (82.3%) than for Re-CELs (57.4%). S-CELs showed no changes in durations of enhancement and maximal lesion sizes with treatment. Exclusively for Re-CELs, IFN beta-1b significantly decreased maximal lesion sizes, total number of enhancement periods and total months of enhancement. Thus, IFN beta appears to be effective in reducing the degree of severity of inflammation among Re-CELs, as reflected by their reduced maximal lesion sizes and durations of enhancement.://000233744100007 Times Cited: 0ISI:000233744100007BNatl Inst Neurol Disorders & Stroke, Neuroimmunol Branch, NIH, Bethesda, MD 20892 USA. New York Med Coll, Valhalla, NY 10595 USA. Med Numer Inc, Sterling, VA USA. NIH, Lab Diagnost Radiol Res, Ctr Clin, Bethesda, MD 20892 USA. Bagnato, F, Bldg 10,Rm 5B16,9000 Rockville Pike, Bethesda, MD 20892 USA. bagnatof@ninds.nih.gov~?|bMorgen, K. Crawford, A. L. T. Stone, R. D. Martin, R. Richert, N. D. Frank, J. A. McFarland, H. F.2005Contrast-enhanced MRI lesions during treatment with interferon beta-1b predict increase in T1 black hole volume in patients with relapsing-remitting multiple sclerosis146-148Multiple Sclerosis112T1 black holes (BH) have been found to represent focal areas of substantial central nervous system tissue damage in multiple sclerosis (MS) patients. We examined the development of T1 BH over a three-year period of treatment with interferon (IFN)beta-1b in a group of 20 patients with relapsing-remitting MS. The number of contrast-enhancing lesions (CEL) after one year of treatment predicted a change in the T1 BH volume in the following two years. In patients without CEL, the T1 BH volume remained stable, whereas it increased in patients with CEL. The occurrence of CEL in patients treated with IFN beta may indicate a heightened risk of accumulating T1 BH.://000227717400004 Times Cited: 1ISI:000227717400004Univ Giessen, Dept Neurol, D-35385 Giessen, Germany. NINDS, NIH, Bethesda, MD 20892 USA. Bender Inst Neuroimaging, Giessen, Germany. Johns Hopkins Univ, Div Hematol Malignancies, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD USA. NIH, Expt Neuroimaging Sect, Lab Diagnost Radiol Res, Bethesda, MD 20892 USA. Morgen, K, Univ Giessen, Dept Neurol, Steg 14, D-35385 Giessen, Germany. Katrin.Morgen@neuro.med.uni-giessen.de C~?}`Richert, N. D. Howard, T. Frank, J. A. Stone, R. Ostuni, J. Ohayon, J. Bash, C. McFarland, H. F.2006TRelationship between inflammatory lesions and cerebral atrophy in multiple sclerosis551-556 Neurology664FebObjective: To investigate the temporal relationship between inflammation and cerebral atrophy in a longitudinal study of 19 patients with relapsing-remitting multiple sclerosis (RRMS) using serial monthly contrast enhanced MRI examinations and monthly measurements of brain fractional volume (BFV) for an average of 4 (range 2.4 to 10) years. Methods: In this retrospective study, all patients had an active MRI scan at entry with a minimum of two new contrast enhancing lesions (CEL) on baseline MRI examinations. Patients were followed for a minimum of 3 months during a baseline (pretreatment) phase and subsequently followed during treatment with recombinant interferon beta (IFN) and various other immunomodulatory agents. Pre- and post contrast axial images were obtained using 3-mm slice thickness and a gadolinium contrast dose of 0.1 mmol/kg. Monthly CEL were sequentially numbered on hardcopy films and monthly BFV was determined on precontrast T1W images using a semiautomated program. For BFV measurements, all T1W scans were registered to the entry examination, which served as a mask image. Cerebral atrophy was measured as percent brain fractional volume change (PBVC) compared to the entry baseline scan. Results: The results demonstrate that cerebral atrophy paralleled that of contrast enhancing lesion accumulation. The correlation between cumulative CEL and PBVC ranged from R-2 = 0.47 to 0.81. Immunomodulatory agents that effectively reduced CEL accumulation also slowed the rate of atrophy. Conclusions: The correlation between contrast enhancing lesions (CEL) and atrophy suggests that patients who are not responding to therapy with a decrease in CEL may also be at risk for developing increased atrophy.://000235645200023 Times Cited: 0ISI:000235645200023CNINDS, Neuroimmunol Branch, NIH, Bethesda, MD 20892 USA. NIH, Expt Neuroimaging Sect, Lab Diagnost Radiol Res, Bethesda, MD 20892 USA. Uniformed Serv Univ Hlth Sci, Dept Radiol, Bethesda, MD 20814 USA. Richert, ND, NINDS, Neuroimmunol Branch, NIH, Bldg 10,Room 5B16,10 Ctr Dr, Bethesda, MD 20892 USA. richertn@helix.nih.gov~?~Chao, L. L. Martin, A.2000CRepresentation of manipulable man-made objects in the dorsal stream478-484 Neuroimage124Oct0We used fMRI to examine the neural response in frontal and parietal cortices associated with viewing and naming pictures of different categories of objects. Because tools are commonly associated with specific hand movements, we predicted that pictures of tools, but not other categories of objects, would elicit activity in regions of the brain that store information about motor-based properties. We found that viewing and naming pictures of tools selectively activated the left ventral premotor cortex (BA 6). Single-unit recording studies in monkeys have shown that neurons in the rostral part of the ventral premotor cortex (canonical F5 neurons) respond to the visual presentation of graspable objects, even in the absence of any subsequent motor activity. Thus, the left ventral premotor region that responded selectively to tools in the current study may be the human homolog of the monkey canonical F5 area. Viewing and naming tools also selectively activated the left posterior parietal cortex (BA 40). This response is similar to the firing of monkey anterior intraparietal neurons to the visual presentation of graspable objects. In humans and monkeys, there appears to be a close link between manipulable objects and information about the actions associated with their use. The selective activation of the left posterior parietal and left ventral premotor cortices by pictures of tools suggests that the ability to recognize and identify at least one category of objects (tools) may depend on activity in specific sites of the ventral and dorsal visual processing streams.://000089737000012 Times Cited: 152ISI:000089737000012mNIMH, Lab Brain & Cognit, Bethesda, MD 20892 USA. Chao, LL, NIMH, Lab Brain & Cognit, Bethesda, MD 20892 USA. ~?(van Turennout, M. Ellmore, T. Martin, A.2000<Long-lasting cortical plasticity in the object naming system 1329-1334Nature Neuroscience312Dec~A single exposure to an object can produce long-lasting behavioral change. Here, using event-related functional magnetic resonance imaging (fMRI), we provide evidence for long-lasting changes in cortical activity associated with perceiving and naming objects. In posterior regions, we observed an immediate (30-second) and long-lasting (3-day) decrease in neural activity after brief (200-ms) exposure to nameable and nonsense objects. In addition, slower-developing decreases in left inferior frontal activity were observed concurrently with increases in left insula activity, only for nameable objects. These time-dependent cortical changes may reflect two distinct learning mechanisms: the formation of sparser, yet more object-form-specific, representations in posterior regions, and experience-induced reorganization of the brain circuitry underlying lexical retrieval in anterior regions.://000167177900020 Times Cited: 68ISI:000167177900020NIMH, Lab Brain & Cognit, Bethesda, MD 20892 USA. van Turennout, M, Max Planck Inst Psycholinguist, Wundtlaan 1, NL-6525 XD Nijmegen, Netherlands.#~?3Beauchamp, M. S. Lee, K. E. Haxby, J. V. Martin, A.2002UParallel visual motion processing streams for manipulable objects and human movements149-159Neuron341MarWe tested the hypothesis that different regions of lateral temporal cortex are specialized for processing different types of visual motion by studying the cortical responses to moving gratings and to humans and manipulable objects (tools and utensils) that were either stationary or moving with natural or artificially generated motions. Segregated responses to human and tool stimuli were observed in both ventral and lateral regions of posterior temporal cortex. Relative to ventral cortex, lateral temporal cortex showed a larger response for moving compared with static humans and tools. Superior temporal cortex preferred human motion, and middle temporal gyrus preferred tool motion. A greater response was observed in STS to articulated compared with unarticulated human motion. Specificity for different types of complex motion (in combination with visual form) may be an organizing principle in lateral temporal cortex.://000174695100017 Times Cited: 79ISI:000174695100017rNIMH, Lab Brain & Cognit, Bethesda, MD 20892 USA. Beauchamp, MS, NIMH, Lab Brain & Cognit, Bethesda, MD 20892 USA.~?#Chao, L. L. Weisberg, J. Martin, A.2002EExperience-dependent modulation of category-related cortical activity545-551Cerebral Cortex125MayQNaming pictures of objects from different categories (e.g. animals or tools) evokes maximal responses in different brain regions. However, these 'category-specific' regions typically respond to other object categories as well. Here we used stimulus familiarity to further investigate category representation. Naming pictures of animals and tools elicited category-related activity in a number of previously identified regions. This activity was reduced for familiar relative to novel stimuli. Reduced activation occurred in all object-responsive areas in the ventral occipito-temporal cortex, regardless of which category initially produced the maximal response. This suggests that object representations in the ventral occipito-temporal cortex are not limited to a discrete area, but rather are widespread and overlapping. In other regions (e.g. the lateral temporal and left premotor cortices), experience-dependent reductions were category specific. Together, these findings suggest that category-related activations reflect the retrieval of information about category-specific features and attributes.://000175159800010 Times Cited: 39ISI:000175159800010Vet Adm Med Ctr, San Francisco, CA 94121 USA. NIMH, Lab Brain & Cognit, Bethesda, MD 20892 USA. Chao, LL, Vet Adm Med Ctr, 4150 Clement St,114Q, San Francisco, CA 94121 USA.+?Beauchamp, M. S.2003)Detection of eye movements from fMRI data376-380Magnetic Resonance in Medicine492]http://www.scopus.com/scopus/inward/record.url?eid=2-s2.0-0037308617&partnerID=40&rel=R6.5.0 CCited By (since 1996): 4 Export Date: 13 August 2007 Source: Scopus~?3Beauchamp, M. S. Lee, K. E. Haxby, J. V. Martin, A.2003YfMRI responses to video and point-light displays of moving humans and manipulable objects991-1001!Journal of Cognitive Neuroscience157OctWe used fMRI to study the organization of brain responses to different types of complex visual motion. In a rapid event-related design, subjects viewed video clips of humans performing different whole-body motions, video clips of manmade manipulable objects ( tools) moving with their characteristic natural motion, point-light displays of human whole-body motion, and point-light displays of manipulable objects. The lateral temporal cortex showed strong responses to both moving videos and moving point-light displays, supporting the hypothesis that the lateral temporal cortex is the cortical locus for processing complex visual motion. Within the lateral temporal cortex, we observed segregated responses to different types of motion. The superior temporal sulcus (STS) responded strongly to human videos and human point-light displays, while the middle temporal gyrus (MTG) and the inferior temporal sulcus responded strongly to tool videos and tool point-light displays. In the ventral temporal cortex, the lateral fusiform responded more to human videos than to any other stimulus category while the medial fusiform preferred tool videos. The relatively weak responses observed to point-light displays in the ventral temporal cortex suggests that form, color, and texture ( present in video but not point-light displays) are the main contributors to ventral temporal activity. In contrast, in the lateral temporal cortex, the MTG responded as strongly to point-light displays as to videos, suggesting that motion is the key determinant of response in the MTG. Whereas the STS responded strongly to point-light displays, it showed an even larger response to video displays, suggesting that the STS integrates form, color, and motion information.://000186004600009 Times Cited: 48ISI:000186004600009{NIMH, LBC, Bethesda, MD 20892 USA. Beauchamp, MS, NIMH, LBC, 10 Ctr Dr MSC 1366,Bldg 10,Room 4C104, Bethesda, MD 20892 USA.?2Beauchamp, M.S. Lee, K. E. Haxby, J. V. Martin, A.2003_Differential response to real and point-light displays of moving humans and manipulable objects991-1001!Journal of Cognitive Neuroscience15~?Martin, A. Weisberg, J.2003CNeural foundations for understanding social and mechanical concepts575-587Cognitive Neuropsychology203-6May-Sep5Motivated by neuropsychological investigations of category-specific impairments, many functional brain imaging studies have found distinct patterns of neural activity associated with different object categories. However, the extent to which these category-related activation patterns reflect differences in conceptual representation remains controversial. To investigate this issue, functional magnetic resonance imaging (fMRI) was used to record changes in neural activity while subjects interpreted animated vignettes composed of simple geometric shapes in motion. Vignettes interpreted as conveying social interactions elicited a distinct and distributed pattern of neural activity, relative to vignettes interpreted as mechanical actions. This neural system included regions in posterior temporal cortex associated with identifying human faces and other biological objects. In contrast, vignettes interpreted as conveying mechanical actions resulted in activity in posterior temporal lobe sites associated with identifying manipulable objects such as tools. Moreover, social, but not mechanical, interpretations elicited activity in regions implicated in the perception and modulation of emotion (right amygdala and ventromedial prefrontal cortex). Perceiving and understanding social and mechanical concepts depends, in part, on activity in distinct neural networks. Within the social domain, the network includes regions involved in processing and storing information about the form and motion of biological objects, and in perceiving, expressing, and regulating affective responses.://000184129000017 Times Cited: 26ISI:000184129000017NIMH, Lab Brain & Cognit, Bethesda, MD 20892 USA. Martin, A, NIMH, Lab Brain & Cognit, Bldg 10,Room 4C-104,10 Ctr Dr MSC 1366, Bethesda, MD 20892 USA.K?Petit, L. Beauchamp, M. S.2003@Neural basis of visually guided head movements studied with fMRI 2516-2527Journal of Neurophysiology895]http://www.scopus.com/scopus/inward/record.url?eid=2-s2.0-0037879576&partnerID=40&rel=R6.5.0 DCited By (since 1996): 16 Export Date: 13 August 2007 Source: ScopusZ~?,van Turennout, M. Bielamowicz, L. Martin, A.2003PModulation of neural activity during object naming: Effects of time and practice381-391Cerebral Cortex134AprRepeated exposure to objects improves our ability to identify and name them, even after a long delay. Previous brain imaging studies have demonstrated that this experience-related. facilitation of object naming is associated with neural changes in distinct brain regions. We used event-related functional magnetic resonance imaging (fMRI) to examine the modulation of neural activity in the object naming system as a function of experience and time. Pictures of common objects were presented repeatedly for naming at different time intervals (1 h, 6 h and 3 days) before scanning, or at 30 s intervals during scanning. The results revealed that as objects became more familiar with experience, activity in occipitotemporal and left inferior frontal regions decreased while activity in the left insula and basal ganglia increased. In posterior regions, reductions in activity as a result of multiple repetitions did not interact with time, whereas in left inferior frontal cortex larger decreases were observed when repetitions were spaced out over time. This differential modulation of activity in distinct brain regions provides support for the idea that long-lasting object priming is mediated by two neural mechanisms. The first mechanism may involve changes in object-specific representations in occipitotemporal cortices, the second may be a form of procedural learning involving a reorganization in brain circuitry that leads to more efficient name retrieval.://000181832200006 Times Cited: 24ISI:000181832200006NIMH, Lab Brain & Cognit, Bethesda, MD 20892 USA. van Turennout, M, FC Donders Ctr Cognit Neuroimaging, POB 9101, NL-6500 HB Nijmegen, Netherlands.i~?ABeauchamp, M. S. Argall, B. D. Bodurka, J. Duyn, J. H. Martin, A.2004]Unraveling multisensory integration: patchy organization within human STS multisensory cortex 1190-1192Nature Neuroscience711NovYAlthough early sensory cortex is organized along dimensions encoded by receptor organs, little is known about the organization of higher areas in which different modalities are integrated. We investigated multisensory integration in human superior temporal sulcus using recent advances in parallel imaging to perform functional magnetic resonance imaging (fMRI) at very high resolution. These studies suggest a functional architecture in which information from different modalities is brought into close proximity via a patchy distribution of inputs, followed by integration in the intervening cortex.://000224749400010 Times Cited: 24ISI:000224749400010NIMH, Lab Brain & Cognit, NIH, Bethesda, MD 20892 USA. NINDS, Sect Adv MRI, Lab Funct & Mol Imaging, NIH, Bethesda, MD 20892 USA. Beauchamp, MS, NIMH, Lab Brain & Cognit, NIH, Bethesda, MD 20892 USA. mbeauchamp@nih.gov~?4Beauchamp, M. S. Lee, K. E. Argall, B. D. Martin, A.2004XIntegration of auditory and visual information about objects in superior temporal sulcus809-823Neuron415MarTwo categories of objects in the environment-animals and man-made manipulable objects (tools)-are easily recognized by either their auditory or visual features. Although these features differ across modalities, the brain integrates them into a coherent percept. In three separate fMRI experiments, posterior superior temporal sulcus and middle temporal gyrus (pSTS/MTG) fulfilled objective criteria for an integration site. pSTS/MTG showed signal increases in response to either auditory or visual stimuli and responded more to auditory or visual objects than to meaningless (but complex) control stimuli. pSTS/MTG showed an enhanced response when auditory and visual object features were presented together, relative to presentation in a single modality. Finally, pSTS/MTG responded more to object identification than to other components of the behavioral task. We suggest that pSTS/MTG is specialized for integrating different types of information both within modalities (e.g., visual form, visual motion) and across modalities (auditory and visual).://000221458200015 Times Cited: 50ISI:000221458200015NIMH, Lab Brain & Cognit, Bethesda, MD 20892 USA. Beauchamp, MS, NIMH, Lab Brain & Cognit, Bethesda, MD 20892 USA. mbeauchamp@nih.gov]?Beauchamp, M. S.2005XSee me, hear me, touch me: Multisensory integration in lateral occipital-temporal cortex145-153Current Opinion in Neurobiology152^http://www.scopus.com/scopus/inward/record.url?eid=2-s2.0-20544448036&partnerID=40&rel=R6.5.0 DCited By (since 1996): 20 Export Date: 13 August 2007 Source: Scopus3?Beauchamp, M. S.2005@Statistical criteria in fMRI studies of multisensory integration93-113Neuroinformatics32^http://www.scopus.com/scopus/inward/record.url?eid=2-s2.0-21344455127&partnerID=40&rel=R6.5.0 CCited By (since 1996): 8 Export Date: 13 August 2007 Source: Scopus?Martin, A. Gotts, S.J.2005FMaking the causal link: frontal cortex activity and repetition priming 1134-1135Nature Neuroscience82005O~?)Simmons, W. K. Martin, A. Barsalou, L. W.2005MPictures of appetizing foods activate gustatory cortices for taste and reward 1602-1608Cerebral Cortex1510OctdIncreasing research indicates that concepts are represented as distributed circuits of property information across the brain's modality-specific areas. The current study examines the distributed representation of an important but under-explored category, foods. Participants viewed pictures of appetizing foods (along with pictures of locations for comparison) during event-related fMRI. Compared to location pictures, food pictures activated the right insula/operculum and the left orbitofrontal cortex, both gustatory processing areas. Food pictures also activated regions of visual cortex that represent object shape. Together these areas contribute to a distributed neural circuit that represents food knowledge. Not only does this circuit become active during the tasting of actual foods, it also becomes active while viewing food pictures. Via the process of pattern completion, food pictures activate gustatory regions of the circuit to produce conceptual inferences about taste. Consistent with theories that ground knowledge in the modalities, these inferences arise as reenactments of modality-specific processing.://000231921600012 Times Cited: 8ISI:000231921600012Emory Univ, Dept Psychol, Atlanta, GA 30322 USA. NIMH, Cognit Neuropsychol Sect, Lab Brain & Cognit, Bethesda, MD 20892 USA. Barsalou, LW, Emory Univ, Dept Psychol, 532 N Kilgo Circle, Atlanta, GA 30322 USA. barsalou@emory.ed~?5Wheatley, T. Weisberg, J. Beauchamp, M. S. Martin, A.2005VAutomatic priming of semantically-related words reduces activity in the fusiform gyrus 1871-1885!Journal of Cognitive Neuroscience1712DecWe used rapid, event-related fMRI to identify, the neural systems underlying object semantics. During scanning, Subjects silently read rapidly presented word pairs (150 msec, SOA = 250 msec) that were either unrelated in meaning (ankle-carrot), semantically related (fork-cup), or identical (crow-crow). Activity in the left posterior region of the fusiform gyrus and left inferior frontal cortex was modulated by word-pair relationship. Semantically related pairs yielded less activity than unrelated pairs, but greater activity than identical pairs, mirroring the pattern of behavioral facilitation as measured by word reading times. These findings provide strong support for the involvement of these areas in the automatic processing of object meaning. In addition, words referring to animate objects produced greater activity in the lateral region of the fusiform gyri, right superior temporal sulcus, and medial region of the occipital lobe relative to manmade, manipulable objects, whereas words referring to manmade, manipulable objects produced greater activity in the left ventral premotor, left anterior cingulate, and bilateral parietal cortices relative to animate objects. These findings are consistent with the dissociation between these areas based on sensory- and motor-related object properties, providing further evidence that conceptual object knowledge is housed, in part, in the same neural systems that subserve perception and action.://000233988600005 Times Cited: 3ISI:000233988600005NIMH, Lab Brain & Cognit, NIH, Bethesda, MD 20892 USA. Wheatley, T, NIMH, Lab Brain & Cognit, NIH, 10 Ctr Dr MSC 1366, Bethesda, MD 20892 USA. wheatley@nih.govT?*Argall, B. D. Saad, Z. S. Beauchamp, M. S.2006DSimplified intersubject averaging on the cortical surface using SUMA14-27Human Brain Mapping271^http://www.scopus.com/scopus/inward/record.url?eid=2-s2.0-32044472524&partnerID=40&rel=R6.5.0 CCited By (since 1996): 5 Export Date: 13 August 2007 Source: Scopusc~?MBellgowan, P. S. F. Bandettini, P. A. van Gelderen, P. Martin, A. Bodurka, J.2006gImproved BOLD detection in the medial temporal region using parallel imaging and voxel volume reduction 1244-1251 Neuroimage294FebUsing gradient-echo EPI, signal dropout due to macroscopic off resonance effects can prevent blood-oxygenation-level-dependent (BOLD) signal change detection. The anterior medial temporal lobe (MTL) is located near these susceptibility gradients and therefore shows considerable signal dropout with GE-EPI. Reducing the volume of the image voxel reduces susceptibility-related signal dropout. However, this is accompanied by a prohibitive reduction in signal-tonoise ratio (SNR). To compensate for SNR loss with smaller voxels, we used a multi-channel MRI receiver with an array of receive-only 16-element surface coils at 3 T. We demonstrate that the reduction of susceptibility artifacts, through use of high resolution images, coupled with the gains in image SNR from the array coil improves the temporal signal-to-noise ratio (TSNR) and enhances the contrast-to-noise ratio (CNR). Furthermore, a comparison of 2 turn with 4-mm-thick axial images both with the same in-plane resolution showed that thinner slices enhanced TSNR and CNR throughout the ventral-medial regions of the temporal lobes, with the greatest improvement in the most anterior regions of the MTL. Further improvements were seen when adjacent 2 mm slices were combined to match overall voxel volume. These results demonstrate that BOLD investigation of anterior MTL function can be enhanced by decreasing voxel size but only in combination with the SNR gained by using the 16-channel head coil system. Published by Elsevier Inc.://000235534400022 Times Cited: 1ISI:000235534400022ENIMH, Sect Cognit Neuropsychol, Bethesda, MD 20892 USA. NIMH, Funct MRI Facil, Bethesda, MD 20892 USA. NIMH, Sect Funct Imaging Methods, Bethesda, MD 20892 USA. NINDS, Adv MRI Sect, Bethesda, MD 20892 USA. Bellgowan, PSF, NIMH, Sect Cognit Neuropsychol, 10 Ctr Dr,Bldg 10,Room 4C104, Bethesda, MD 20892 USA. psfb@mail.nih.gov&~?-Buffalo, E. A. Bellgowan, P. S. F. Martin, A.2006\Distinct roles for medial temporal lobe structures in memory for objects and their locations638-643Learning & Memory135Sep-OctThe ability to learn and retain novel information depends on a system of structures in the medial temporal lobe (MTL) including the hippocampus and the surrounding entorhinal, perirhinal, and parahippocampal cortices. Damage to these structures produces profound memory deficits; however, the unique contribution to memory of each of these structures remains unclear. Here we have used functional magnetic resonance imaging (fMRI) to determine whether the perirhinal and parahippocampal cortices show differential memory-related activity. Based on the distinct patterns of cortical input to these two areas, we reasoned that these structures might show differential activity for spatial and object recognition memory. In each of 11 subjects, we found that the perirhinal cortex was active during both spatial and object memory encoding, while the anterior parahippocampal cortex was active only during spatial encoding. These data support the idea that MTL structures make distinct contributions to recognition memory performance.://000240937000023 Times Cited: 0ISI:000240937000023Emory Univ, Sch Med, Dept Neurol, Atlanta, GA 30329 USA. Yerkes Natl Primate Res Ctr, Atlanta, GA 30329 USA. NIMH, Lab Brain & Cognit, Bethesda, MD 20892 USA. Buffalo, EA, Emory Univ, Sch Med, Dept Neurol, Atlanta, GA 30329 USA. elizabeth.buffalo@emory.edu?ZFurey, M. L. Tanskanen, T. Beauchamp, M. S. Avikainen, S. Uutela, K. Hari, R. Haxby, J. V.2006>Dissociation of face-selective cortical responses by attention 1065-1070OProceedings of the National Academy of Sciences of the United States of America1034^http://www.scopus.com/scopus/inward/record.url?eid=2-s2.0-32244444938&partnerID=40&rel=R6.5.0 CCited By (since 1996): 5 Export Date: 13 August 2007 Source: Scopus?'Grill-Spector, K. Henson, R. Martin, A.2006BRepition and the brain: neural models of stimulus-specific effects14-23Trends in Cognitive Science10? Martin, A.2006XShades of Dejerine - Forging a causal link between the visual word form area and reading173-175Neuron50?-Simmons, W. K. Bellgowan, P. S. F. Martin, A.2007"Measuring selectivity in fMRI data4-5Nature Neuroscience10?)Weisberg, J. van Turennout, M. Martin, A.20072A neural system for learning about object function513-521Cerebral Cortex17?*Wheatley, T. Milleville, S. C. Martin, A.2007ZUnderstanding animate agents: distinct roles for the "social network" and "mirror system."469-474Psychological Science18F?TMahon, B.Z. Milleville, S. C. Negri, G. A. L. Rumiati, R. I. Caramazza A. Martin, A.in pressMAction-related propoerties shape object representations in the ventral streamNeuron?JLoucks, T. M. J. Poletto, C. J. Simonyan, K. Reynolds, C. L. Ludlow, C. L.2007rHuman Brain Activation during Phonation and Exhalation: Common Volitional Control for Two Upper Airway Functions. 131-143 Neuroimage36H~? Ludlow, C. L.2005ACentral nervous system control of the laryngeal muscles in humans205-222%Respiratory Physiology & Neurobiology1472-3JulrLaryngeal muscle control may vary for different functions such as: voice for speech communication, emotional expression during laughter and cry, breathing, swallowing, and cough. This review discusses the control of the human laryngeal muscles for some of these different functions. Sensori-motor aspects of laryngeal control have been studied by eliciting various laryngeal reflexes. The role of audition in learning and monitoring ongoing voice production for speech is well known; while the role of somatosensory feedback is less well understood. Reflexive control systems involving central pattern generators may contribute to swallowing, breathing and cough with greater cortical control during volitional tasks such as voice production for speech. Volitional control is much less well understood for each of these functions and likely involves the integration of cortical and subcortical circuits. The new frontier is the study of the central control of the laryngeal musculature for voice, swallowing and breathing and how volitional and reflexive control systems may interact in humans. (C) 2005 Elsevier B.V. All rights reserved.://000231526800007 Times Cited: 2ISI:000231526800007NINDS, Laryngeal & Speech Sect, Med Neurol Branch, Bethesda, MD 20892 USA. Ludlow, CL, NINDS, Laryngeal & Speech Sect, Med Neurol Branch, Bldg 10,Room 5D 38,10 Ctr Dr MSC 1416, Bethesda, MD 20892 USA. ludlowc@ninds.nih.gov?)Selbie, W. S. Gewalt, S. L. Ludlow, C. L.2002`Developing an anatomical model of the human laryngeal cartilages from magnetic resonance imaging 1077-1090,Journal of the Acoustical Society of America112?FSimonyan, K. Saad, Z. S. Loucks, T. M. J. Poletto, C. J. Ludlow, C. L.2007EFunctional neuroanatomy of human voluntary cough and sniff production401-409 Neuroimage37F?eRich, B. A. Fromm, S. J. Berghorst, L. H. Dickstein, D. P. Brotman, M. A. Pine, D. S. Leibenluft, E.in pressiNeural connectivity in children with bipolar disorder: Impairment in the face emotion processing circuit.*Journal of Child Psychology and Psychiatry)F?Nelson, E. E. Vinton, D. T. Berghorst, L. H. Towbin, K. Hommer, R. E. Dickstein, D. P. Rich, B. A. Brotman, M. A. Pine, D. S. Leibenluft, E.in pressmBrain systems underlying response flexibility in healthy and bipolar adolescents: an event-related fMRI studyBipolar DisordersF?gDickstein, D. P. Rich, B. A. Roberson-Nay, R. Berghorst, L. H. Vinton, D. T. Pine, D. S. Leibenluft, E.in pressRNeural activation during encoding of emotional faces in pediatric bipolar disorderBipolar DisordersT?Leibenluft, E. Rich, B. A. Vinton, D. T. Nelson, E. E. Fromm, S. J. Berghorst, L. H. Joshi, P. Robb, A. Schachar, R. J. Dickstein, D. P. McClure, E. B. Pine, D. S.2007hNeural circuitry engaged during unsuccessful motor inhibition in pediatric bipolar disorder vs controls.309-317American Journal of Psychiatry164~?Rich, B. A. Vinton, D. T. Roberson-Nay, R. Hommer, R. E. Berghorst, L. H. McClure, E. B. Fromm, S. J. Pine, D. S. Leibenluft, E.2006hLimbic hyperactivation during processing of neutral facial expressions in children with bipolar disorder 8900-8905OProceedings of the National Academy of Sciences of the United States of America10323JunReflecting a paradigm shift in clinical neuroscience, many chronic psychiatric illnesses are now hypothesized to result from perturbed neural development. However, most work in this area focuses on schizophrenia. Here, we extend this paradigm to pediatric bipolar disorder (BID), thus demonstrating traction in the developmental psychobiology perspective. To study amygdala dysfunction, we examined neural mechanisms mediating face processing in 22 youths (mean age 14.21 +/- 3.11 yr) with BD and 21 controls of comparable age, gender, and IQ. Event-related functional MRI compared neural activation when attention was directed to emotional aspects of faces (hostility, subjects' fearfulness) vs. nonemotional aspects (nose width). Compared with controls, patients perceived greater hostility in neutral faces and reported more fear when viewing them. Also, compared with controls, patients had greater activation in the left amygdala, accumbens, putamen, and ventral prefrontal cortex when rating face hostility, and greater activation in the left amygdala and bilateral accumbens when rating their fear of the face. There were no between-group behavioral or neural differences in the nonemotional conditions. Results implicate deficient emotion-attention interactions in the pathophysiology of BD in youth and suggest that developmental psychobiology approaches to chronic mental illness have broad applicability.://000238278400057 Times Cited: 1ISI:000238278400057DNIMH, Mood & Anxiety Program, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. Georgia State Univ, Dept Psychol, Atlanta, GA 30302 USA. Virginia Commonwealth Univ, Dept Psychiat, Richmond, VA 23298 USA. Rich, BA, NIMH, Mood & Anxiety Program, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. brendanrich@mail.nih.gov ~?eDickstein, D. P. Milham, M. P. Nugent, A. C. Drevets, W. C. Charney, D. S. Pine, D. S. Leibenluft, E.2005eFrontotemporal alterations in pediatric bipolar disorder - Results of a voxel-based morphometry study734-741Archives of General Psychiatry627Jul0Context: While numerous magnetic resonance imaging (MRI) studies have evaluated adults with bipolar disorder (BPD), few have examined MRI changes in children with BPD. Objective: To determine volume alterations in children with BPD using voxel-based morphometry, an automated MRI analysis method with reduced susceptibility to various biases. A priori regions of interest included amygdala, accumbens, hippocampus, dorsolateral prefrontal cortex (DLPFC), and orbitofrontal cortex. Design: Ongoing study of the pathophysiology of pediatric BPD. Setting: Intramural National Institute of Mental Health; approved by the institutional review board. Patients: Pediatric subjects with BPD (n = 20) with at least I manic or hypomanic episode meeting strict DSM-IV criteria for duration and elevated, expansive mood. Controls (n = 20) and their first-degree relatives lacked psychiatric disorders. Groups were matched for age and sex and did not differ in IQ. Main Outcome Measures: With a 1.5-T MRI machine, we collected 1.2-mm axial sections (124 per subject) with an axial 3-dimensional spoiled gradient recalled echo in the steady state sequence. Image analysis was by optimized voxel-based morphometry. Results: Subjects with BPD had reduced gray matter volume in the left DLPFC. With a less conservative statistical threshold, additional gray matter reductions were found in the left accumbens and left amygdala. No difference was found in the hippocampus or orbitofrontal cortex. Conclusions: Our results are consistent with data implicating the prefrontal cortex in emotion regulation, a process that is perturbed in BPD. Reductions in amygdala and accumbens volumes are consistent with neuropsychological data on pediatric BPD. Further study is required to determine the relationship between these findings in children and adults with BPD.://000230352100006 Times Cited: 11ISI:000230352100006}NIMH, Pediat & Dev Neuropsychiat Branch, Mood & Anxiety Disorders Program, Bethesda, MD 20892 USA. NYU, Sch Med, Dept Psychiat, New York, NY USA. CUNY Mt Sinai Sch Med, Dept Psychiat, New York, NY 10029 USA. Dickstein, DP, NIMH, Pediat & Dev Neuropsychiat Branch, Mood & Anxiety Disorders Program, 10 Ctr Dr,MSC 1255,Bldg10,Room 4N208, Bethesda, MD 20892 USA. Dicksted@mail.nih.gov~?7Leibenluft, E. Gobbini, M. I. Harrison, T. Haxby, J. V.2004WMothers' neural activation in response to pictures of their children and other children225-232Biological Psychiatry564AugBackground. Considerable literature has focused on neural responses evoked by face viewing. We extend that literature and explore the neural correlates of maternal attachment with an fMRI study in which mothers view photographs of their own children. Methods: Seven mothers performed a one-back repetition detection task while viewing photographs of their own child, friends of their child, unfamiliar children, and unfamiliar adults. Results. Viewing one's own child versus a familiar child was associated with activation in the amygdala, insula, anterior paracingulate cortex, and posterior superior temporal sulcus (STS). Viewing familiar versus unfamiliar children elicited increased activation in regions associated with familiarity in adults. Viewing unfamiliar children versus unfamiliar adults was associated with activation in the fusiform gyrus, intraparietal sulcus, precuneus, and posterior STS. Conclusions: The sight of one's own child versus that of a familiar child activates regions that mediate emotional responses (amygdala, insula) and are associated with theory of mind functions (anterior paracingulate cortex, posterior superior temporal sulcus). These activations may reflect the intense attachment, vigilant protectiveness, and empathy that characterize normal maternal attachment. The sight of an unfamiliar child's face compared with that of an unfamiliar adult engages areas associated with attention as well as face perception.://000223327300003 Times Cited: 14ISI:000223327300003NIMH, Pediat & Dev Neuropsychiat Branch, Dept Hlth & Human Serv, NIH, Bethesda, MD 20892 USA. NIMH, Lab Brain & Cognit, Dept Hlth & Human Serv, NIH, Bethesda, MD 20892 USA. Leibenluft, E, 10 Ctr Dr,MSC 1255, Bethesda, MD 20892 USA. Leibs@mail.nih.gov~?xBarbier, E. L. Marrett, S. Danek, A. Vortmeyer, A. van Gelderen, P. Duyn, J. Bandettini, P. Grafman, J. Koretskyk, A. P.2002lImaging cortical anatomy by high-resolution MR at 3.0T: Detection of the stripe of Gennari in visual area 17735-738Magnetic Resonance in Medicine484OctSThe brain can be parcellated into numerous anatomical and functional subunits. The classic work by Brodmann (Vergleichende Lokalisationslehre der Grosshirnrinde in ihren Prinzipien dargestellt auf Grund des Zellenbaues. Leipzig: Barth; 1909) identified areas of the cerebral cortex based on histological differences. An alternative to his cytoarchitectonic approach is the myeloarchitectonic approach. MRI has excellent white/gray matter contrast in the brain due to the presence of myelin, and thus seems uniquely suited for in vivo studies of cortical myeloarchitecture. Here it is demonstrated that the stripe or stria of Gennari can be consistently detected in human occipital cortex. T-1-weighted images obtained at 3T from six of 10 normal volunteers, with resolutions of 350 x 350 x 600 mu, clearly demonstrate this myelin-rich intracortical layer. It is concluded that the striate cortex (area 17 of Brodmann) of the human brain can be delineated in vivo on T-1-weighted images, potentially enabling detection of specific cortical boundaries within individual brains. Published 2002 Wiley-Liss, Inc.://000178361000022 Times Cited: 24ISI:000178361000022NINDS, LFMI, NIH, Bethesda, MD 20892 USA. Univ Grenoble 1, Lab Mixte, INSERM, U438,RMN Bioclin,LRC,CEA,Hop Albert Michallon, Grenoble, France. NIMH, NIH, Tesla Funct Neuroimaging Facil 3, Bethesda, MD 20892 USA. NINDS, NIH, Cognit Neurosci Sect, Bethesda, MD 20892 USA. Univ Munich, Neurol Klin, Munich, Germany. NINDS, Mol Pathologenesis Unit, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. Koretskyk, AP, NINDS, LFMI, NIH, Room 10-B1D118,MSC 1065, Bethesda, MD 20892 USA.~?.Knutson, B. Westdorp, A. Kaiser, E. Hommer, D.2000KFMRI visualization of brain activity during a monetary incentive delay task20-27 Neuroimage121JulComparative studies have implicated striatal and mesial forebrain circuitry in the generation of autonomic, endocrine, and behavioral responses for incentives. Using blood oxygen level-dependent functional magnetic resonance imaging, we sought to visualize functional activation of these regions in 12 normal volunteers as they anticipated and responded for monetary incentives. Both individual and group analyses of time-series data revealed significant activation of striatal and mesial forebrain structures (including insula, caudate, putamen, and mesial prefrontal cortex) during trials involving both monetary rewards and punishments. In addition to these areas, during trials involving punishment, group analysis revealed activation foci in the anterior cingulate and thalamus. These results corroborate comparative studies which implicate striatal and mesial forebrain circuitry in the elaboration of incentive-driven behavior. This report also introduces a new paradigm for probing the functional integrity of this circuitry in humans.://000088317700003 Times Cited: 96ISI:000088317700003NIAAA, Sect Brain Electrophysiol & Imaging, Div Intramural Clin & Biol Res, NIH, Bethesda, MD 20892 USA. Knutson, B, NIAAA, Sect Brain Electrophysiol & Imaging, Div Intramural Clin & Biol Res, NIH, Bethesda, MD 20892 USA.~?4Hommer, D. W. Momenan, R. Kaiser, E. Rawlings, R. R.2001CEvidence for a gender-related effect of alcoholism on brain volumes198-204American Journal of Psychiatry1582FebObjective: The goal of this study was to compare brain volumes of alcoholic and nonalcoholic men and women and determine if the magnitudes of differences in brain volumes between alcoholic women and nonalcoholic women are greater than the magnitudes of the differences between alcoholic men and nonalcoholic men. Method: The study group included 118 subjects: 79 inpatients 30-60 years of age who were alcohol dependent but had no clinically apparent cognitive impairment or medical illness (43 men and 36 women) and 39 healthy comparison subjects of similar age who were not alcoholic (20 men and 19 women). The volume of intracranial contents was segmented into gray matter, white matter, sulcal CSF, and ventricular CSF from a T-1-weighted magnetic resonance image obtained after the alcoholic subjects had attained 3 weeks of sobriety. Results: Alcoholic women had significantly smaller volumes of gray and white matter as well as greater volumes of sulcal and ventricular CSF than nonalcoholic women. The differences in gray and white matter volumes between alcoholic and nonalcoholic men were significant, but the significance of these differences was of a smaller magnitude than the significance of the differences between alcoholic and nonalcoholic women. Direct comparisons of alcoholic men and women showed that the proportion of intracranial contents occupied by gray matter was smaller in alcoholic women than in alcoholic men. The magnitudes of differences in brain volumes adjusted for intracranial size between alcoholic women and nonalcoholic women were greater than the magnitudes of the adjusted differences between alcoholic men and nonalcoholic men. Conclusions: These results are consistent with greater sensitivity to alcohol neurotoxicity among women.://000166761400008 Times Cited: 59ISI:000166761400008NIAAA, Clin Studies Lab, Sect Electrophysiol & Brain Imaging, NIH, Bethesda, MD 20892 USA. Hommer, DW, NIAAA, Clin Studies Lab, Sect Electrophysiol & Brain Imaging, NIH, 10 Ctr Dr,MSC 1256, Bethesda, MD 20892 USA.~?/Knutson, B. Adams, C. M. Fong, G. W. Hommer, D.2001QAnticipation of increasing monetary reward selectively recruits nucleus accumbensart. no.-RC159Journal of Neuroscience2116Aug<Comparative studies have implicated the nucleus accumbens (NAcc) in the anticipation of incentives, but the relative responsiveness of this neural substrate during anticipation of rewards versus punishments remains unclear. Using event-related functional magnetic resonance imaging, we investigated whether the anticipation of increasing monetary rewards and punishments would increase NAcc blood oxygen level-dependent contrast (hereafter, "activation") in eight healthy volunteers. Whereas anticipation of increasing rewards elicited both increasing self-reported happiness and NAcc activation, anticipation of increasing punishment elicited neither. However, anticipation of both rewards and punishments activated a different striatal region (the medial caudate). At the highest reward level ($5.00), NAcc activation was correlated with individual differences in self-reported happiness elicited by the reward cues. These findings suggest that whereas other striatal areas may code for expected incentive magnitude, a region in the NAcc codes for expected positive incentive value.://000170318200001 Times Cited: 71ISI:000170318200001oNIAAA, NIH, Bethesda, MD 20892 USA. Knutson, B, NIAAA, NIH, Bldg 10,Room 6S240,MS 1610, Bethesda, MD 20892 USA.Rc159-~?=Knutson, B. Fong, G. W. Adams, C. M. Varner, J. L. Hommer, D.2001GDissociation of reward anticipation and outcome with event-related fMRI 3683-3687 Neuroreport1217DecReward processing involves both appetitive and consummatory phases. We sought to examine whether reward anticipation vs outcomes would recruit different regions of ventral forebrain circuitry using event-related fMRI. Nine healthy volunteers participated in a monetary incentive delays task in which they either responded to a cued target for monetary reward, responded to a cued target for no reward, or did not respond to a cued target during scanning. Multiple regression analyses indicated that while anticipation of reward Ys non-reward activated foci in the ventral striatum, reward vs non-reward outcomes activated foci in the ventromedial frontal cortex. These findings suggest that reward anticipation band outcomes may differentially recruit distinct regions that lie along the trajectory of ascending dopamine projections. NeuroReport 12:3683-3687 (C) 2001 Lippincott Williams & Wilkins.://000172397000012 Times Cited: 122ISI:000172397000012NIAAA, NIH, Bethesda, MD 20892 USA. Dept Psychol, Stanford, CA 94305 USA. Knutson, B, NIAAA, NIH, 10 Ctr Dr,Bldg 10,Rm 6S240, Bethesda, MD 20892 USA.~?Mann, K. Agartz, I. Harper, C. Shoaf, S. Rawlings, R. R. Momenan, R. Hommer, D. W. Pfefferbaum, A. Sullivan, E. V. Anton, R. F. Drobes, D. J. George, M. S. Bares, R. Machulla, H. J. Mundle, G. Reimold, M. Heinz, A.20014Neuroimaging in alcoholism: Ethanol and brain damage 104S-109S-Alcoholism-Clinical and Experimental Research255MayThis article represents the proceedings of a symposium at the 2000 ISBRA Meeting in Yokohama, Japan. The co-chairs were Karl Mann and Ingrid Agartz. The presentations were (1) Neuropathological changes in alcohol-related brain damage, by Clive Harper; (2) Regional brain volumes including the hippocampus and monoamine metabolites in alcohol dependence, by Ingrid Agartz, Susan Shoal, Robert R, Rawlings, Reza Momenan, and Daniel W Hommer; (3) Diffusion tensor abnormalities in imaging of white matter alcoholism, by Adolf Pfefferbaum and Edith V. Sullivan; (4) Use of functional MRI to evaluate brain activity during alcohol cue exposure in alcoholics: Relationship to craving, by Raymond F. Anton, David J. Drobes, and Mark S. George; and (5) mu -Opiate: receptor availability in alcoholism First results from a positron emission tomography study, by Karl Mann, Roland Bares, Hans-Juergen Machulla, Goetz Mundle, Matthias Reimold, and Andreas Heinz.://000168846000019 Times Cited: 26 Suppl. 1ISI:000168846000019Univ Heidelberg, Dept Addict Behav & Addict Med, Cent Inst Mental Hlth Mannheim, D-68159 Mannheim J5, Germany. Univ Sydney, Dept Pathol, Sydney, NSW 2006, Australia. Royal Prince Alfred Hosp, Camperdown, NSW, Australia. NIAAA, Clin Studies Lab, Sect Electrophysiol & Brain Imaging, NIH, Bethesda, MD 20892 USA. SRI Int, Neuropsychiat Program, Menlo Park, CA 94025 USA. Stanford Univ, Sch Med, Dept Psychiat & Behav Sci, Stanford, CA 94305 USA. Med Univ S Carolina, Alcohol Res Ctr, Charleston, SC 29425 USA. Univ Heidelberg, Cent Inst Mental Hlth, Dept Addict Behav & Addict Med, D-6800 Mannheim, Germany. Univ Tubingen, Dept Nucl Med, D-72074 Tubingen, Germany. Mann, K, Univ Heidelberg, Dept Addict Behav & Addict Med, Cent Inst Mental Hlth Mannheim, D-68159 Mannheim J5, Germany.~?>Agartz, I. Shoaf, S. Rawlings, R. R. Momenan, R. Hommer, D. W.2003ECSF monoamine metabolites and MRI brain volumes in alcohol dependence21-35 Psychiatry Research-Neuroimaging1221JanCorrelations between cerebrospinal fluid (CSF) concentrations of monoamine metabolites (MAM) and brain structure have been described in schizophrenia, but not in alcoholism. To investigate the relationship between monoaminergic transmission and brain structure in alcoholism, the metabolites of dopamine (homovanillic acid, HVA), norepineptirenine (3-methoxy-4-hydroxyphenylethyleneglycol, MHPG) and serotonin (5-hydroxyindoleacetic acid, 5-HIAA) were measured in lumbar CSF in 54 alcohol-dependent patients and 20 healthy subjects. The volumes of the cerebrum, total grey and white matter, total and ventricular CSF, left and right hippocampus, and corpus callosum area were measured with MRI. MHPG and age were positively correlated in alcoholic women. The MAM concentrations were not significantly correlated with the MRI volumes in the subject categories. There were no differences in MAM across subjects defined by diagnosis and gender, age of onset of alcoholism or comorbidity of psychiatric disorders. Total CSF, cerebrum, and white and grey matter tissue volumes differed between patients and healthy subjects. The greatest difference was the white matter reduction in alcoholic women. In alcoholic women and men, monoaminergic neurotransmission measured by the CSF MAM HVA, MHPG, and 5-HIAA is not significantly correlated with the size of different brain structures. (C) 2002 Elsevier Science Ireland Ltd. All rights reserved.://000181443900003 Times Cited: 3ISI:000181443900003(NIAAA, Sect Electrophysiol & Brain Imaging, Clin Studies Lab, NIH, Bethesda, MD 20892 USA. Karolinska Hosp, Dept Clin Neurosci, Clin Alcohol & Drug Addict Res Sect & Human Brain, SE-17176 Stockholm, Sweden. Agartz, I, Karolinska Hosp, Dept Clin Neurosci, Psychiat Sect, S-17176 Stockholm, Sweden.1~?LHommer, D. W. Knutson, B. Fong, G. W. Bennett, S. Adams, C. M. Varner, J. L.2003[Amygdalar recruitment during anticipation of monetary rewards - An event-related fMRI study476-4789Amygdala in Brain Function: Bacic and Clinical Approaches985://000182918800037 *Annals of the New York Academy of SciencesTimes Cited: 7ISI:000182918800037NIAAA, Clin Studies Lab, NIH, Bethesda, MD 20892 USA. Stanford Univ, Dept Psychol, Stanford, CA 94305 USA. Hommer, DW, NIAAA, Clin Studies Lab, NIH, Bethesda, MD 20892 USA. ~?QBjork, J. M. Knutson, B. Fong, G. W. Caggiano, D. M. Bennett, S. M. Hommer, D. W.2004bIncentive-elicited brain activation in adolescents: Similarities and differences from young adults 1793-1802Journal of Neuroscience248FebBrain motivational circuitry in human adolescence is poorly characterized. One theory holds that risky behavior in adolescence results in part from a relatively overactive ventral striatal ( VS) motivational circuit that readily energizes approach toward salient appetitive cues. However, other evidence fosters a theory that this circuit is developmentally underactive, in which adolescents approach more robust incentives ( such as risk taking or drug experimentation) to recruit this circuitry. To help resolve this, we compared brain activation in 12 adolescents (12 - 17 years of age) and 12 young adults (22 - 28 years of age) while they anticipated the opportunity to respond to obtain monetary gains as well as to avoid monetary losses. In both age groups, anticipation of potential gain activated portions of the VS, right insula, dorsal thalamus, and dorsal midbrain, where the magnitude of VS activation was sensitive to gain amount. Notification of gain outcomes ( in contrast with missed gains) activated the mesial frontal cortex (mFC). Across all subjects, signal increase in the right nucleus accumbens during anticipation of responding for large gains independently correlated with both age and self-rated excitement about the high gain cue. In direct comparison, adolescents evidenced less recruitment of the right VS and right-extended amygdala while anticipating responding for gains ( in contrast with anticipation of nongains) compared with young adults. However, brain activation after gain outcomes did not appreciably differ between age groups. These results suggest that adolescents selectively show reduced recruitment of motivational but not consummatory components of reward-directed behavior.://000189210300001 Times Cited: 24ISI:000189210300001NIAAA, Clin Studies Lab, NIH, Bethesda, MD 20892 USA. Stanford Univ, Dept Psychol, Stanford, CA 94305 USA. Catholic Univ Amer, Dept Psychol, Washington, DC 20064 USA. Bjork, JM, NIAAA, Clin Studies Lab, NIH, 10 Ctr Dr,Room 3C-103, Bethesda, MD 20892 USA. jbjork@mail.nih.gov.~?8Momenan, R. Rawlings, R. Fong, G. Knutson, B. Hommer, D.2004sVoxel-based homogeneity probability maps of grapy matter in groups: assessing the reliability of functional effects965-972 Neuroimage213MarA subject of increasing importance in magnetic resonance imaging (MRI) is the analysis of intersubject structural differences, particularly when comparing groups of subjects with different conditions or diagnoses. On the other hand, determining structural homogeneity across subjects using voxel-based morphological (VBM) methods has become even more important to investigators who test for group brain activation using functional magnetic resonance images (fMRI) or positron emission tomography (PET). In the absence of methods that evaluate structural differences, one does not know how much reliability to assign to the functional differences. Here, we describe a voxel-based method for quantitatively assessing the homogeneity of tissues from structural magnetic resonance images of groups. Specifically, this method determines the homogeneity of gray matter for a group of,subjects. Homogeneity probability maps (HPMs) of a given tissue type (e.g., gray matter) are generated by using a confidence interval based on binomial distribution. These maps indicate for each voxel the probability that,, the tissue type is gray for the population being studied. Therefore, HPMs can accompany functional analyses to indicate the confidence one can assign to functional difference at any given voxel. In this paper, examples of HPMs generated for a group of control subjects are shown and discussed. The application of this method to functional analysis is demonstrated. (C) 2004 Elsevier Inc. All rights reserved.://000220148900017 Times Cited: 2ISI:000220148900017NIAAA, Sect Brain Electrophysiol & Imaging, LCS, NIH, Bethesda, MD 20892 USA. Stanford Univ, Dept Psychol, Stanford, CA 94305 USA. Momenan, R, NIAAA, Sect Brain Electrophysiol & Imaging, LCS, NIH, Room 3C114,Bldg 10,10 Ctr Dr,MSC 1256, Bethesda, MD 20892 USA. rezam@nih.gov~?DRio, D. E. Rawlings, R. R. Woltz, L. A. Salloum, J. B. Hommer, D. W.2006Single subject image analysis using the complex general linear model - An application to functional magnetic resonance imaging with multiple inputs10-19,Computer Methods and Programs in Biomedicine821AprDA linear time invariant model is applied to functional fMRI blood flow data. Based on traditional time series analysis, this model assumes that the fMRI stochastic output sequence can be determined by a constant plus a linear filter (hemodynamic response function) of several fixed deterministic inputs and an error term assumed stationary with zero mean. The input function consists of multiple exponential distributed (time delay between images) visual stimuli consisting of negative and erotic images. No a priori assumptions are made about the hemodynamic response function that, in essence, is calculated at each spatial position from the data. The sampling rate for the experiment is 400 ms in order to allow for filtering out higher frequencies associated with the cardiac rate. Since the statistical analysis is carried out in the Fourier domain, temporal correlation problems associated with inference in the time domain are avoided. This formal model easily lends itself to further development based on previously developed statistical techniques. Published by Elsevier Ireland Ltd.://000237046600002 Times Cited: 0ISI:000237046600002NIAAA, Sect Brain Electrophysiol & Imaging, Clin Studies Lab, NIH, Bethesda, MD 20892 USA. Synergy Res Inc, Monrovia, MD 21770 USA. Rio, DE, NIAAA, Sect Brain Electrophysiol & Imaging, Clin Studies Lab, NIH, Bldg 10,CRC,Rm 2-2332,10 Ctr Dr,MSC 1540, Bethesda, MD 20892 USA. drio@nih.gov~?CBeauchamp, M. S. Petit, L. Ellmore, T. M. Ingeholm, J. Haxby, J. V.2001LA parametric fMRI study of overt and covert shifts of visuospatial attention310-321 Neuroimage142AugIt has recently been demonstrated that a cortical network of visuospatial and oculomotor control areas is active for covert shifts of spatial attention (shifts of attention without eye movements) as well as for overt shifts of spatial attention (shifts of attention with saccadic eye movements). Studies examining activity in this visuospatial network during attentional shifts at a single rate have given conflicting reports about how the activity differs for overt and covert shifts. To better understand how the network subserves attentional shifts, we performed a parametric study in which subjects made either overt attentional shifts or covert attentional shifts at three different rates (0.2, 1.0, and 2.0 Hz). At every shift rate, both overt and covert shifts of visuospatial attention induced activations in the precentral sulcus, intraparietal sulcus, and lateral occipital cortex that were of greater amplitude for overt than during covert shifting. As the rate of attentional shifts increased, responses in the visuospatial network increased in both overt and covert conditions but this parametric increase was greater during overt shifts. These results confirm that overt and covert attentional shifts are subserved by the same network of areas. Overt shifts of attention elicit more neural activity than do covert shifts, reflecting additional activity associated with saccade execution. An additional finding concerns the anatomical organization of the visuospatial network. Two distinct activation foci were observed within the precentral sulcus for both overt and covert attentional shifts, corresponding to specific anatomical landmarks. We therefore reappraise the correspondence of these two precentral areas with the frontal eye fields. (C) 2001 Academic Press.://000170253700006 Times Cited: 79ISI:000170253700006NIMH, Lab Brain & Cognit, Bethesda, MD 20892 USA. Univ Caen, Univ Paris 05, CNRS,CEA,UMR 6095, Grp Imagerie Neurofonct, F-14032 Caen, France. Beauchamp, MS, NIMH, Lab Brain & Cognit, Bethesda, MD 20892 USA.v~?(Berardi, A. Parasuraman, R. Haxby, J. V.2001EOverall vigilance and sustained attention decrements in healthy aging19-39Experimental Aging Research271JanAge differences in sustained attention were investigated using a high-event rate digit-discrimination task at 6 levels of stimulus degradation (lasting 8.1 min each). Twenty-one young, 21 middle-aged, and 20 old healthy subjects were studied. Overall sensitivity (d') was equivalent in all groups. Although all subjects showed a sensitivity decrement over blocks, there were no age-related differences in sustained attention capacity. All subjects had larger decrements in d' over blocks at higher degradation levels. However, the performance decrement at higher degradation levels was equivalent in all groups, indicating similar decrement rates in sensitivity with increasing demands on effortful processing. These results indicate that overall levels of vigilance and the ability to sustain attention over time are equivalent in all groups under conditions requiring both automatic (low-degradation) and effortful (high-degradation) stimulus processing.://000165841800002 Times Cited: 7ISI:000165841800002NIA, Neurosci Lab, Bethesda, MD 20892 USA. Catholic Univ Amer, Cognit Sci Lab, Washington, DC 20064 USA. Berardi, A, Univ Metz, Dept Psychol, Ile Saulcy, F-57045 Metz 01, France.~?OHaxby, J. V. Gobbini, M. I. Furey, M. L. Ishai, A. Schouten, J. L. Pietrini, P.2001[Distributed and overlapping representations of faces and objects in ventral temporal cortex 2425-2430Science2935539SepThe functional architecture of the object vision pathway in the human brain was investigated using functional magnetic resonance imaging to measure patterns of response in ventral temporal cortex white subjects viewed faces, cats, five categories of man-made objects, and nonsense pictures. A distinct pattern of response was found for each stimulus category. The distinctiveness of the response to a given category was not due simply to the regions that responded maximally to that category, because the category being viewed also could be identified on the basis of the pattern of response when those regions were excluded from the analysis. Patterns of response that discriminated among A categories were found even within cortical regions that responded maximally to only one category. These results indicate that the representations of faces and objects in ventral temporal cortex are widely distributed and overlapping.://000171237200038 Times Cited: 245ISI:000171237200038NIMH, Lab Brain & Cognit, NIH, Bethesda, MD 20892 USA. Univ Pisa, Dept Human & Environm Sci, I-56126 Pisa, Italy. Univ Pisa, Dept Expt Pathol, Lab Clin Biochem, I-56126 Pisa, Italy. Haxby, JV, NIMH, Lab Brain & Cognit, NIH, Bethesda, MD 20892 USA.~?*Haxby, J. V. Hoffman, E. A. Gobbini, M. I.2002BHuman neural systems for face recognition and social communication59-67Biological Psychiatry511Jan/Face perception is mediated by a distributed neural system in humans that consists of multiple, bilateral regions. The functional organization of this system embodies a distinction between the representation of invariant aspects of faces, which is the basis for recognizing individuals, and the representation of changeable aspects, such as eye gaze, expression, and lip movement, which underlies the perception of information that facilitates social communication. The system also has a hierarchical organization. A core system, consisting of occipitotemporal regions in extrastriate visual cortex, mediates the visual analysis of faces. An extended system consists of regions from neural systems for other cognitive functions that can act in concert with the core system to extract meaning from faces. Of regions in the extended system for face perception, the amygdala plays a central role in processing the social relevance of information gleaned from faces, particularly when that information may signal a potential threat. (C) 2002 Society of Biological Psychiatry.://000173330000007 Times Cited: 131ISI:000173330000007NIMH, Lab Brain & Cognit, Bethesda, MD 20892 USA. Haxby, JV, NIMH, Lab Brain & Cognit, Bldg 10,Room 4C104,10 Ctr Dr,MSC 1366, Bethesda, MD 20892 USA.~?7Gobbini, M. I. Leibenluft, E. Santiago, N. Haxby, J. V.2004ESocial and emotional attachment in the neural representation of faces 1628-1635 Neuroimage224AugTo dissociate the role of visual familiarity from the role of social and emotional factors in recognizing familiar individuals, we measured neural activity using functional magnetic resonance imaging (fMRI) while subjects viewed (1) faces of personally familiar individuals (i.e. friends and family), (2) faces of famous individuals, and (3) faces of strangers. Personally familiar faces evoked a stronger response than did famous familiar faces and unfamiliar faces in areas that have been associated with 'theory of mind', and a weaker response in the amygdala. These response modulations may reflect the spontaneous activation of social knowledge about the personality and attitudes of close friends and relatives and the less guarded attitude one has around these people. These results suggest that familiarity causes changes in neural response that extend beyond a visual memory for a face. (C) 2004 Elsevier Inc. All rights reserved.://000223156000020 Times Cited: 15ISI:000223156000020 Princeton Univ, Dept Psychol, Princeton, NJ 08544 USA. NIMH, Lab Brain & Cognit, NIH, Bethesda, MD 20982 USA. Univ Pisa, Dipartimento Sci Uomo & Ambiente, I-56100 Pisa, Italy. Gobbini, MI, Princeton Univ, Dept Psychol, Princeton, NJ 08544 USA. mgobbini@princeton.edulon is characterized by differential cognitive processes such as control implementation, top down modulation of the response, expectancy, and inhibition of behavioural response, we hypothesized increased al, the dorsal cingulate (dACC), and the parietal cortex (PC). The relative contribution of these regions to these cognitive subprocesses, however, has not been determined. Based on previous findings supporting a role for dACC in the monitoring of conflicting information within a stimulus, we hypothesized greater activity in this cortical region during interference monitoring and suppression relative to response inhibition. On the other hand, as responselon and interference monitoring and suppression 1658-1664 European Journal of Neuroscience236MarMResponse inhibition and interference monitoring and suppression are two important aspects of cognitive control. Previous functional imaging studies have suggested a common network of brain regions underlying these cognitive processes; the dorsolateral prefrontal cortex (DLPFC), the ventrolateral prefrontal corteletti, R. Bertolino, A. Cohen, J. Alce, G. Zoltick, B. Weinberger, D. R. Mattay, V.2007eDifferentiating allocation of resources and conflict detection within attentional control processing.594-602 European Journal of Neuroscience25}Blasi, G. Goldberg, T. E. Weickert, T. Das, S. Kohn, P. Zoltick, B. Bertolino, A. Callicott, J. H. Weinberger, D. R. Mattay, V. S.2006XBrain regions underlying response8?{nBertolino, A. Frye, M. Callicott, J. H. Mattay, V.S. Rakow, R. Shelton-Repella, J. Post, R. Weinberger, D. R. 2003Neuronal pathology in the hippocampal area of patients with bipolar disorder: A study with proton magnetic resonance spectroscopic imaging.906-913Biological Psychiatry534Ǡl|{Blasi, G. Goldberg, T. E.}~?hPietrini, P. Furey, M. L. Ricciardi, E. Gobbini, M. I. Wu, W. H. C. Cohen, L. Guazzelli, M. Haxby, J. V.2004OBeyond sensory images: Object-based representation in the human ventral pathway 5658-5663OProceedings of the National Academy of Sciences of the United States of America10115AprWe investigated whether the topographically organized, category-related patterns of neural response in the ventral visual pathway are a representation of sensory images or a more abstract representation of object form that is not dependent on sensory modality. We used functional MRI to measure patterns of response evoked during visual and tactile recognition of faces and manmade objects in sighted subjects and during tactile recognition in blind subjects. Results showed that visual and tactile recognition evoked category-related patterns of response in a ventral extrastriate visual area in the inferior temporal gyrus that were correlated across modality for manmade objects. Blind subjects also demonstrated category-related patterns of response in this "visual" area, and in more ventral cortical regions in the fusiform gyrus, indicating that these patterns are not due to visual imagery and, furthermore, that visual experience is not necessary for category-related representations to develop in these cortices. These results demonstrate that the representation of objects in the ventral visual pathway is not simply a representation of visual images but, rather, is a representation of more abstract features of object form.://000220861500065 Times Cited: 24ISI:000220861500065Univ Pisa, Sch Med, Dept Expt Pathol, Lab Clin Biochem, I-56126 Pisa, Italy. NIMH, Mood & Anxiety Disorders Program, NIH, Bethesda, MD 20892 USA. NIMH, Lab Brain & Cognit, NIH, Bethesda, MD 20892 USA. Princeton Univ, Dept Psychol, Princeton, NJ 08544 USA. NINDS, Human Cort Physiol Sect, NIH, Bethesda, MD 20892 USA. Univ Pisa, Sch Med, Psychol Branch, Dept Psychiat Neurobiol Pharmacol & Biotechnol, I-56126 Pisa, Italy. Pietrini, P, Univ Pisa, Sch Med, Dept Expt Pathol, Lab Clin Biochem, I-56126 Pisa, Italy. pietro.pietrini@med.unipi.ittconducted an event-related functional magnetic resonance imaging (fMRI) study in 57 healthy volunteers using a task preferentially involving either interference monitoring and suppression or response inhibition. Accuracy for response inhibition was lower than for interference monitoring and suppression. Imaging data showed activation in DLPFC, dACC, VLPFC, PC for both conditions. Comparisons between the two conditions indicated greater activation bilaterally in DLPFC, VLPFC and PC during response inhibition, and greater activation in the dACC during interference monitoring and suppression. These resul?pAgid, Y. Buzsa?ki, G. Diamond, D. M. Frackowiak, R. Giedd, J. Girault, J. A. Grace, A. Lambert, J. J. Manji, H. Mayberg, H. Popoli, M. Prochiantz, A. Richter-Levin, G. Somogyi, P. Spedding, M. Svenningsson, P. Weinberger, D.2007=How can drug discovery for psychiatric disorders be improved?189-201Nature Reviews Drug Discovery63^http://www.scopus.com/scopus/inward/record.url?eid=2-s2.0-33847374225&partnerID=40&rel=R6.5.0 CCited By (since 1996): 2 Export Date: 19 August 2007 Source: Scopus?qGiedd, J. N. Clasen, L. S. Wallace, G. L. Lenroot, R. K. Lerch, J. P. Wells, E. M. Blumenthal, J. D. Nelson, J. E. Tossell, J. W. Stayer, C. Evans, A. C. Samango-Sprouse, C. A.2007hXXY (Klinefelter syndrome): A pediatric quantitative brain magnetic resonance imaging case-control study e232-e240 Pediatrics1191^http://www.scopus.com/scopus/inward/record.url?eid=2-s2.0-33846914971&partnerID=40&rel=R6.5.0 *Export Date: 19 August 2007 Source: Scopus4n the other cortical nodes of the cognitive control network relative to interference monitoring and suppression. To this8~?6Immisch, I. Waldvogel, D. van Gelderen, P. Hallett, M.2001gThe role of the medial wall and its anatomical variations for bimanual antiphase and in-phase movements674-684 Neuroimage143SepNThe medial wall of the frontal cortex is thought to play an important role for bimanual coordination. However, there is uncertainty regarding the exact neuroanatomical regions involved. We compared the activation patterns related to bimanual movements using functional magnetic resonance imaging in 12 healthy right-handed subjects, paying special attention to the anatomical variability of the frontal medial wall. The subjects performed unimanual right and left and bimanual antiphase and in-phase flexion and extension movements of the index finger. Activation of the right supplementary motor area (SMA) proper, right and left caudal cingulate motor area (CMA), and right and left premotor cortices was significantly stronger during bimanual antiphase than bimanual in-phase movements, indicating an important function of these areas with bimanual coordination. A frequent anatomical variation is the presence of the paracingulate sulcus (PCS), which might be an anatomical landmark to determine the location of activated areas. Seven subjects had a bilateral, three a unilateral right, and two a unilateral left PCS. Because the area around the PCS is functionally closer coupled to the CMA than to the SMA, activation found in the area around the PCS should be attributed to the CMA. With anatomical variations such as the presence of a PCS or a vertical branch of the cingulate sulcus, normalization and determination of the activation with the help of stereotaxic coordinates can cause an incorrect shift of CMA activation to the SMA. This might explain some of the discrepancies found in previous studies.://000170722700013 Times Cited: 27ISI:000170722700013NINDS, Human Motor Control Sect, NIH, Bethesda, MD 20892 USA. NINDS, In Vivo NMR Res Ctr, NIH, Bethesda, MD 20892 USA. Immisch, I, NINDS, Human Motor Control Sect, NIH, Bethesda, MD 20892 USA.~?eToma, K. Matsuoka, T. Immisch, I. Mima, T. Waldvogel, D. Koshy, B. Hanakawa, T. Shill, H. Hallett, M.2002_Generators of movement-related cortical potentials: fMRI-constrained EEG dipole source analysis161-173 Neuroimage171SepTo clarify the precise location and timing of the motor cortical activation in voluntary movement, dipole source analysis integrating multiple constraints was conducted for the movement-related cortical potential (AMCP). Six healthy subjects performed single self-paced extensions of the right index finger at about 15-s intervals during EEG and event-related fMRI acquisitions. EEG was recorded from 58 scalp electrodes, and fMRI of the entire brain was obtained every 2.6 s. Coordinates of the two methods were coregistered using anatomical landmarks. During dipole source modeling, a realistic three-layer head model was used as a volume conductor. To identify the number of uncorrelated sources in the MRCP, principal component (PC) analysis was performed, which was consistent with the existence of six sources in the left (Lt SM1) and right (Rt SM1) sensorimotor and medial frontocentral (WC) areas. After dipoles were seeded at the activated spots revealed by fMRI, dipole orientations were fixed based on the interpretation of the topography of distribution of the PC. The strength of the six dipoles (three dipoles in Lt SM1, two in Rt SM1, and one in MFC) was then computed over time. Within the bilateral SM1, activation of the precentral gyrus occurs bilaterally with similar strength from -1.2 s, followed by that of the precentral bank from -0.5 s with contralateral preponderance. Subsequently, the postcentral bank becomes active only on the contralateral side at 0.1 s after movement. Activation of the MFC shows timing similar to that of the bilateral precentral gyri. These deduced patterns of activation are consistent with previous studies of electrocorticography in humans.://000178102000011 Times Cited: 17ISI:000178102000011NINDS, Human Motor Control Sect, Med Neurol Branch, NIH, Bethesda, MD 20892 USA. Toma, K, NINDS, Human Motor Control Sect, Med Neurol Branch, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. ~?LHanakawa, T. Immisch, I. Toma, K. Dimyan, M. A. Van Gelderen, P. Hallett, M.2003PFunctional properties of brain areas associated with motor execution and imagery989-1002Journal of Neurophysiology892Feb^Imagining motor acts is a cognitive task that engages parts of the executive motor system. While motor imagery has been intensively studied using neuroimaging techniques, most studies lack behavioral observations. Here, we used functional MRI to compare the functional neuroanatomy of motor execution and imagery using a task that objectively assesses imagery performance. With surface electromyographic monitoring within a scanner, 10 healthy subjects performed sequential finger-tapping movements according to visually presented number stimuli in either a movement or an imagery mode of performance. We also examined effects of varied and fixed stimulus types that differ in stimulus dependency of the task. Statistical parametric mapping revealed movement-predominant activity, imagery-predominant activity, and activity common to both movement and imagery modes of performance (movement-and-imagery activity). The movement-predominant activity included the primary sensory and motor areas, parietal operculum, and anterior cerebellum that had little imagery-related activity (-0.1 similar to 0.1%), and the caudal premotor areas and area 5 that had mild-to-moderate imagery-related activity (0.2 similar to 0.7%). Many frontoparietal areas and posterior cerebellum demonstrated movement-and-imagery activity. Imagery-predominant areas included the precentral sulcus at the level of middle frontal gyrus and the posterior superior parietal cortex/precuneus. Moreover, activity of the superior precentral sulcus and intraparietal sulcus areas, predominantly on the left, was associated with accuracy of the imagery task performance. Activity of the inferior precentral sulcus (area 6/44) showed stimulus-type effect particularly for the imagery mode. A time-course analysis of activity suggested a functional gradient, which was characterized by a more "executive" or more "imaginative" property in many areas related to movement and/or imagery. The results from the present study provide new insights into the functional neuroanatomy of motor imagery, including the effects of imagery performance and stimulus-dependency on brain activity.://000180827700036 Times Cited: 57ISI:000180827700036NINDS, Human Motor Control Sect, Med Neurol Branch, NIH, Bethesda, MD 20892 USA. NINDS, Lab Funct & Mol Imaging, NIH, Bethesda, MD 20892 USA. Hallett, M, NINDS, Human Motor Control Sect, Med Neurol Branch, NIH, Bldg 10,Room 5N226,10 Ctr Dr, Bethesda, MD 20892 USA.M~?Wu, T. Kansaku, K. Hallett, M.2004OHow self-initiated memorized movements become automatic: A functional MRI study 1690-1698Journal of Neurophysiology914Apr}We used functional magnetic resonance imaging (fMRI) and dual tasks to investigate the physiology of how movements become automatic. Normal subjects were asked to practice some self-initiated, self-paced, memorized sequential finger movements with different complexity until they could perform the tasks automatically. Automaticity was evaluated by having subjects perform a secondary task simultaneously with the sequential movements. Our secondary task was a letter-counting task where subjects were asked to identify the number of times a target letter from the letter sequences was seen. Only the performances that achieved high accuracy in both single and dual tasks were considered automatic. The fMRI results before and after automaticity was achieved were compared. Our data showed that for both conditions, sequential movements activated similar brain regions. No additional activity was observed in the automatic condition. There was less activity in bilateral cerebellum, presupplementary motor area, cingulate cortex, left caudate nucleus, premotor cortex, parietal cortex, and prefrontal cortex during the automatic stage. These findings suggest that most of the motor network participates in executing automatic movements and that it becomes more efficient as movements become more automatic. Our results do not provide evidence for any area to become more activated for automatic movements.://000220086100024 Times Cited: 16ISI:000220086100024NINDS, Human Motor Control Sect, Med Neurol Branch, NIH, Bethesda, MD 20892 USA. Hallett, M, NINDS, Human Motor Control Sect, Med Neurol Branch, NIH, Bethesda, MD 20892 USA. hallettm@ninds.nih.gov @~?'Garraux, G. Hallett, M. Talagala, S. L.2005XCASL fMRI of subcortico-cortical perfusion changes during memory-guided finger sequences122-132 Neuroimage251MarArterial spin labeling (ASL) perfusion functional magnetic resonance imaging (fMRI) is an attractive alternative to BOLD fMRI. Nevertheless, current ASL fMRI techniques are limited by several factors that hamper more routine applications in humans. One of these factors is restricted brain coverage so that whole-brain ASL fMRI studies have never been reported. The present study tested the ability of a multislice continuous ASL (CASL) fMRI approach using a small surface coil placed on the subject's neck to map changes in regional cerebral blood flow (rCBF) throughout the brain while healthy individuals (N = 15) performed memory-guided sequential finger movements at a mean rate of similar to0.5 Hz. As predicted by results from a large number of studies, reliable task-related increases in flow were detected across subjects not only in primary and associative cortical areas but also in subcortical brain regions. When normalized to baseline, rCBF increased 31% in the hand representation area (HRA) of left primary motor cortex (M1) 13% in the left supplementary motor area proper (SMA), 10% in the left dorsolateral prefrontal cortex (DLPFC), 10-18% in the bilateral intraparietal sulci, 6% in the HRA of left putamen, 10% in the left thalamus, and 17% in the right anterior cerebellum. In addition to these increases, 6% and 4% decreases in rCBF were detected in the HRA of the right M1 and the bilateral posterior cingulate sulci, respectively. These results demonstrate that perfusion-based fMRI using CASL with a separate labeling coil can now be used to characterize task-related flow changes in most of the brain volume with adequate accuracy and sensitivity, Published by Elsevier Inc.://000227369600012 Times Cited: 7ISI:000227369600012NINDS, Human Motor Control Sect, NIH, Bethesda, MD 20892 USA. Univ Liege, Cyclotron Res Ctr, B-4000 Cointe Ougree, Belgium. Univ Liege, Dept Neurol, B-4000 Cointe Ougree, Belgium. Natl Inst Neurol Disorders & Stroke, NIH MRI Res Facil, NIH, Bethesda, MD 20892 USA. Garraux, G, NINDS, Human Motor Control Sect, NIH, Bldg 10,Room 5N226,10 Ctr Dr,MSC 1428, Bethesda, MD 20892 USA. hallettm@ninds.nih.gov ~?0Hanakawa, T. Parikh, S. Bruno, M. K. Hallett, M.2005SFinger and face representations in the ipsilateral precentral motor areas in humans 2950-2958Journal of Neurophysiology935MaySeveral human neuroimaging studies have reported activity in the precentral gyrus (PcG) ipsilateral to the side of hand movements. This activity has been interpreted as the part of the primary motor cortex (M1) that controls bilateral or ipsilateral hand movements. To better understand hand ipsilateral-PcG activity, we performed a functional MRI experiment in eight healthy right-handed adults. Behavioral tasks involved hand or lower face movements on each side or motor imagery of the same movements. Consistent with the known M1 organization, the hand contralateral-PcG activity was centered at the "hand-knob" portion of the PcG; face contralateral-PcG activity was localized ventrolateral to it. Hand ipsilateral-PcG activity was identified in most subjects. However, converging results indicated that this ipsilateral PcG activity was situated in Brodmann's area 6 in both hemispheres. The hand ipsilateral-PcG zones were active not only during hand movements but also face movements. Moreover, the hand ipsilateral-PcG zones revealed substantial imagery-related activity, which also failed to differentiate the hand and face. Statistical analyses confirmed poor effector selectivity of the hand ipsilateral PcG activity during both movement and imagery tasks. From these results, we conclude that the hand ipsilateral-PcG activity in healthy adults probably corresponds to a part of the ventral premotor cortex. In contrast, available evidence suggests that M1 contributes to controlling the ipsilateral hand in children and patients after stroke recovery. It appears that within the human PcG, there are two parallel systems potentially capable of controlling ipsilateral hand movements: ventral premotor cortex and M1. These two systems may be differentially influenced by developmental or pathologic changes.://000228575200054 Times Cited: 6ISI:000228575200054NINDS, Human Motor Control Sect, Med Neurol Branch, NIH, Bethesda, MD 20892 USA. Hallett, M, NINDS, Human Motor Control Sect, Med Neurol Branch, NIH, Bldg 10,Rm 5N226,10 Ctr Dr, Bethesda, MD 20892 USA. hallettm@ninds.nih.gov~?Sohn, Y. Kang, S. Hallett, M.2005.Corticospinal disinhibition during dual action95-99Experimental Brain Research1621MarYWhen attempting to perform two tasks simultaneously, the human motor as well as the cognitive system shows interference. Such interference often causes altered activation of the cortical area representing each task compared to the single task condition. We investigated changes in corticospinal inhibition during dual action by transcranial magnetic stimulation (TMS). Single-pulse TMS was applied to the left motor cortex, triggered by right leg movement (tibialis anterior muscle) while the right abductor digiti minimi (ADM) muscle was moderately activated (10-20% of the maximal voluntary contraction). The background electromyography (EMG) activity of ADM was measured before and during the leg movement. The silent period (SP) and amplitude of motor evoked potential (MEP) following magnetic stimulation in active ADM were compared for the conditions with and without leg movement. The mean area of the rectified EMG activity of ADM did not alter, while the SP was significantly shortened during leg movement compared to that without leg movement. MEP amplitude was comparable between the two conditions. These results suggest that corticospinal inhibition tested by the SP duration is reduced during the movement of another body part, presumably in order to help maintain muscle force by compensating interference-related alteration in motor cortical activation.://000227740400011 Times Cited: 0ISI:000227740400011`NINDS, Human Motor Control Sect, NIH, Bethesda, MD 20892 USA. Yonsei Univ, Coll Med, Dept Neurol, Brain Korea 21 Project Med Sci, Seoul, South Korea. Yonsei Univ, Brain Res Inst, Brain Korea 21 Project Med Sci, Seoul, South Korea. Hallett, M, NINDS, Human Motor Control Sect, NIH, Bldg 10-5n226,10 Ctr Dr, Bethesda, MD 20892 USA. hallettm@ninds.nih.gov 7~?Wu, T. Hallett, M.2005RA functional MRI study of automatic movements in patients with Parkinson's disease 2250-2259Brain128Oct5Patients with Parkinson's disease have great difficulty performing learned movements automatically. The neural contribution to the problem has not been identified. In the current study, we used functional magnetic resonance imaging (fMRI) to investigate the underlying neural mechanisms of movement automaticity in Parkinson's disease patients. Fifteen patients with Parkinson's disease were recruited. Three patients were finally excluded because they could not achieve automaticity. The remaining 12 patients were aged from 52 to 67 years, with a mean age of 61.2 years. Controls included 14 age-matched normal subjects. The subjects were asked to practise four tasks, including two self-initiated, self-paced sequences of finger movements with different complexity until they could perform the tasks automatically. Two dual tasks were used to evaluate automaticity. For dual tasks, subjects performed a visual letter-counting task simultaneously with the sequential movements. Twelve normal subjects performed all sequences automatically. All patients performed sequences correctly; 12 patients could perform the simpler sequence automatically; and only 3 patients could perform the more complex sequence automatically. fMRI results showed that for both groups, sequential movements activated similar brain regions before and after automaticity was achieved. No additional activity was observed in the automatic condition. In normal subjects, many areas had reduced activity at the automatic stage, whereas in patients, only the bilateral superior parietal lobes and left insular cortex were less activated. Patients had greater activity in the cerebellum, premotor area, parietal cortex, precuneus and prefrontal cortex compared with normal subjects while performing automatic movements. We conclude that Parkinson's disease patients can achieve automaticity after proper training, but with more difficulty. Our study is the first to demonstrate that patients with Parkinson's disease require more brain activity to compensate for basal ganglia dysfunction in order to perform automatic movements.://000232278600005 Times Cited: 2 Part 10ISI:000232278600005NINDS, Human Motor Control Sect, Med Neurol Branch, NIH, Bethesda, MD 20892 USA. Capital Univ Med Sci, Xuanwu Hosp, Dept Neurol, Beijing Inst Geriatr, Beijing, Peoples R China. Hallett, M, Bldg 10,Rm 5N226,10 Ctr Dr MSC 1428, Bethesda, MD 20892 USA. hallettm@ninds.nih.gov!~?Wu, T. Hallett, M.2005;The influence of normal human ageing on automatic movements605-615Journal of Physiology-London5622JanThere is evidence that aged normal subjects have more difficulty in achieving automaticity than young subjects. The underlying central neural mechanism for this phenomenon is unclear. In the present study, functional magnetic resonance imaging (fMRI) was used to investigate the effect of normal ageing on automaticity. Aged healthy subjects were asked to practice self-initiated, self-paced, memorized sequential finger movements with different complexity until they could perform the tasks automatically. Automaticity was evaluated by having subjects perform a secondary task simultaneously with the sequential movements. Although it took more time, most aged subjects eventually performed the tasks automatically at the same level as the young subjects. Functional MRI results showed that, for both groups, sequential movements activated similar brain regions before and after automaticity was achieved. No additional activity was observed in the automatic condition. While performing automatic movements, aged subjects had greater activity in the bilateral anterior lobe of cerebellum, premotor area, parietal cortex, left prefrontal cortex, anterior cingulate, caudate nucleus and thalamus, and recruited more areas, including the pre-supplementary motor area and the bilateral posterior lobe of cerebellum, compared to young subjects. These results indicate that most healthy aged subjects can perform some complex motor tasks automatically. However, aged subjects appear to require more brain activity to perform automatically at the same level as young subjects. This appears to be the main reason why aged subjects have more difficulty in achieving automaticity.://000226528000022 Times Cited: 4ISI:000226528000022NINCDS, Human Motor Control Sect, Med Neurol Branch, NIH, Bethesda, MD USA. Hallett, M, Bldg 10,Room 5 N226,10 Ctr Dr,MSC 1428, Bethesda, MD 20892 USA. hallettm@ninds.nih.gova~?DYou, S. H. Jang, S. H. Kim, Y. H. Kwon, Y. H. Barrow, I. Hallett, M.2005eCortical reorganization induced by virtual reality therapy in a child with hemiparetic cerebral palsy628-635*Developmental Medicine and Child Neurology479SepQVirtual reality (VR) therapy is a new, neurorehabilitation intervention aimed at enhancing motor performance in children with hemiparetic cerebral palsy (CP). This case report investigated the effects of VR therapy on cortical reorganization and associated motor function in an 8-year-old male with hemiparetic CP. Cortical activation and associated motor development were measured before and after VR therapy using functional magnetic resonance imaging (fMRI) and standardized motor tests. Before VR therapy, the bilateral primary sensorimotor cortices (SMCs) and ipsilateral supplementary motor area (SMA) were predominantly activated during affected elbow movement. After VR therapy, the altered activations disappeared and the contralateral SMC was activated. This neuroplastic change was associated with enhanced functional motor skills including reaching, self-feeding, and dressing. These functions were not possible before the intervention. To our knowledge, this is the first fMRI study in the literature that provides evidence for neuroplasticity after VR therapy in a child with hemiparetic CP.://000231469100011 Times Cited: 1ISI:000231469100011Hampton Univ, Phys Therapy Program, Hampton, VA 23668 USA. Yeungnam Univ, Coll Med, Dept Phys Med & Rehabil, Gyongsan, South Korea. Sungkyunkwan Univ, Coll Med, Dept Phys Med & Rehabil, Seoul, South Korea. Yeungnam Univ, Sch Med, Dept Phys Med & Rehabil, Gyongsan, South Korea. NINDS, Human Motor Control Sect, Bethesda, MD 20892 USA. You, SH, Hampton Univ, Phys Therapy Program, Phoenix Hall 219B, Hampton, VA 23668 USA. sung.you@hamptonu.edu~?eBohlhalter, S. Goldfine, A. Matteson, S. Garraux, G. Hanakawa, T. Kansaku, K. Wurzman, R. Hallett, M.2006_Neural correlates of tic generation in Tourette syndrome: an event-related functional MRI study 2029-2037Brain129AugLittle is known about the neural correlates of tics and associated urges. In the present study, we aimed to explore the neural basis of tics in patients with Tourette syndrome by using event-related functional MRI (fMRI). Ten patients (6 women, 4 men; age: mean +/- SD = 31 +/- 11.2) were studied while spontaneously exhibiting a variety of motor and vocal tics. On the basis of synchronized video/audio recordings, fMRI activities were analysed 2 s before and at tic onset irrespective of the clinical phenomenology. We identified a brain network of paralimbic areas such as anterior cingulate and insular cortex, supplementary motor area (SMA) and parietal operculum (PO) predominantly activated before tic onset (P < 0.05, corrected for multiple comparisons). In contrast, at the beginning of tic action, significant fMRI activities were found in sensorimotor areas including superior parietal lobule bilaterally and cerebellum. The results of this study indicate that paralimbic and sensory association areas are critically implicated in tic generation, similar to movements triggered internally by unpleasant sensations, as has been shown for pain or itching.://000239900600012 Times Cited: 0 Part 8ISI:000239900600012NINDS, Human Motor Control Sect, NIH, Bethesda, MD 20892 USA. Hallett, M, NINDS, Human Motor Control Sect, NIH, Bldg 10,Room 5N226,10 Ctr Dr,MSC-1430, Bethesda, MD 20892 USA. hallettm@ninds.nih.gov~?oFridman, E. A. Immisch, I. Hanakawa, T. Bohlhalter, S. Waldvogel, D. Kansaku, K. Wheaton, L. Wu, T. Hallett, M.20064The role of the dorsal stream for gesture production417-428 Neuroimage292JanSkilled gestures require the integrity of the neural networks involved in storage, retrieval, and execution of motor programs. Premotor cortex and/or parietal cortex lesions frequently produce deficits during performance of gestures, transitive more than intransitive. The dorsal stream links object information with object action, suggesting that mechanical knowledge of tool use is stored focally in the brain. Using event-related fMRI, we explored activity during instructed-delay transitive and intransitive hand gestures. The comparison between planning-preparation and execution of gestures demonstrated a temporal rostral to caudal gradient of activation in the ventral premotor cortex (PMv) and inferior to superior gradient of activation in the posterior parietal cortex (PPc). Comparison between transitive and intransitive gestures established a functional specificity within the dorsal stream for mechanical knowledge. Results demonstrate that not only PPc but also the PMv acts in the processing of sensorimotor information during gestures. This might be the substrate underlying selective deficits in ideomotor apraxia patients. Published by Elsevier Inc.://000234841200007 Times Cited: 3ISI:000234841200007NINDS, Human Motor Control Sect, NIH, Bethesda, MD 20892 USA. Hallett, M, NINDS, Human Motor Control Sect, NIH, Bldg 10,Rm 5N226 10 Ctr Dr,MSC-1438, Bethesda, MD 20892 USA. hallettm@ninds.nih.govx~?KGarraux, G. Goldfine, A. Bohlhalter, S. Lerner, A. Hanakawa, T. Hallett, M.20065Increased midbrain gray matter in Tourette's syndrome381-385Annals of Neurology592Feb8Objective: To investigate cerebral structure in Tourette's syndrome (TS). Methods: Voxel-based morphometry study of high-resolution MRIs in 31 TS patients compared with 31 controls. Results: Increased gray matter mainly in the left mesencephalon in 31 TS patients. Interpretation: This result constitutes strong and direct evidence supporting Devinsky's hypothesis (Devinsky O. Neuroanatomy of Gilles de la Tourette's syndrome. Possible midbrain involvement. Arch Neurol 1983;40:508514) according to which midbrain disturbances play an important pathogenic role in TS.://000235224400021 Times Cited: 3ISI:000235224400021+NINDS, Human Motor Control Sect, NIH, Bethesda, MD 20892 USA. Univ Liege, Cyclotron Res Ctr, B-4000 Liege, Belgium. Univ Liege, Dept Neurol, B-4000 Liege, Belgium. Hallett, M, NINDS, Human Motor Control Sect, NIH, Bldg 10,Room 5N226,10 Ctr Dr,MSC 1428, Bethesda, MD 20892 USA. hallettm@ninds.nih.gov ~?Gerloff, C. Bushara, K. Sailer, A. Wassermann, E. M. Chen, R. Matsuoka, T. Waldvogel, D. Wittenberg, G. F. Ishii, K. Cohen, L. G. Hallett, M.2006Multimodal imaging of brain reorganization in motor areas of the contralesional hemisphere of well recovered patients after capsular stroke791-808Brain129MaraClinical recovery after stroke can be significant and has been attributed to plastic reorganization and recruitment of novel areas previously not engaged in a given task. As equivocal results have been reported in studies using single imaging or electrophysiological methods, here we applied an integrative multimodal approach to a group of well-recovered chronic stroke patients (n = 11; aged 50-81 years) with left capsular lesions. Focal activation during recovered hand movements was assessed with EEG spectral analysis and (H2O)-O-15-PET with EMG monitoring, cortico-cortical connectivity with EEG coherence analysis (cortico-cortical coherence) and corticospinal connectivity with transcranial magnetic stimulation (TMS). As seen from comparisons with age-matched controls, our patients showed enhanced recruitment of the lateral premotor cortex of the lesioned hemisphere [Brodmann area (BA) 6], lateral premotor and to a lesser extent primary sensorimotor and parietal cortex of the contralesional hemisphere (CON-H; BA 4 and superior parietal lobule) and left cerebellum (patients versus controls, Z > 3.09). EEG coherence analysis showed that after stroke cortico-cortical connections were reduced in the stroke hemisphere but relatively increased in the CON-H (ANOVA, contrast analysis, P < 0.05), suggesting a shift of functional connectivity towards the CON-H. Nevertheless, fast conducting corticospinal transmission originated exclusively from the lesioned hemisphere. No direct ipsilateral motor evoked potentials (MEPs) could be elicited with TMS over the contralesional primary motor cortex (iM1) in stroke patients. We conclude that (i) effective recovery is based on enhanced utilization of ipsi- and contralesional resources, (ii) basic corticospinal commands arise from the lesioned hemisphere without recruitment of ('latent') uncrossed corticospinal tract fibres and (iii) increased contralesional activity probably facilitates control of recovered motor function by operating at a higher-order processing level, similar to but not identical with the extended network concerned with complex movements in healthy subjects.://000235433800023 Times Cited: 5 Part 3ISI:000235433800023Univ Tubingen, Sch Med, Dept Neurol, Cort Physiol Res Grp, Tubingen, Germany. NINDS, Human Motor Control Sect, NIH, Bethesda, MD 20892 USA. NINDS, Human Cort Physiol Med Neurol Branch, NIH, Bethesda, MD 20892 USA. NINDS, Brain Simulat Unit, NIH, Bethesda, MD 20892 USA. Gerloff, C, Univ Tubingen, Hertie Inst Clin Brain Res, Dept Gen Neurol, Hoppe Seyler Str 3, D-72076 Tubingen, Germany. christian.gerloff@uni-tuebingen.de hallettm@ninds.nih.govw~?9Hanakawa, T. Honda, M. Zito, G. Dimyan, M. A. Hallett, M.2006xBrain activity during visuomotor behavior triggered by arbitrary and spatially constrained cues: an fMRI study in humans275-282Experimental Brain Research1722Jun Rule-based behavior associating nonspatial visual stimuli with learned responses is called arbitrary visuomotor mapping, an ability that enriches behavioral repertoire. To better understand the underlying neural correlates, the present functional magnetic resonance imaging (fMRI) study explored brain activity during visually informed movement involving two different types of cues and two different effectors. After being trained on the tasks, six healthy subjects performed right or left finger tapping tasks according to either arbitrary cues or spatially constrained cues. An event-related fMRI experiment was conducted on a 3-T MRI. The image data were analyzed with statistical parametric mapping. With the aid of the probabilistic architectonic map in the stereotaxic space, we identified three types of task-related brain activity: cue-selective, effector-selective, and nonselective. The left ventrolateral prefrontal cortex and the rostral part of the right dorsal premotor cortex (PMd) exhibited cue-selective activity, which was greater during the arbitrary condition than the spatially constrained condition. The left ventral prefrontal activity may reflect retrieval of visuomotor association from memory in arbitrary context. The rostral part of the left PMd showed nonselective activity while the caudal part of the PMd on each side showed conspicuous effector-selective activity to the contralateral movement. These findings suggest functional demarcation of the PMd between its rostral and dorsal parts during visuomotor mapping.://000238022900011 Times Cited: 0ISI:000238022900011NINCDS, Human Motor Control Sect, NIH, Bethesda, MD 20892 USA. Natl Ctr Neurol & Psychiat, Dept Cort Funct Disorders, Kodaira, Tokyo 1878502, Japan. Hallett, M, NINCDS, Human Motor Control Sect, NIH, Bldg 10,Room 5N226,10 Ctr Dr,Bldg 10, Bethesda, MD 20892 USA. hallettm@ninds.nih.gov ;~?pPeller, M. Zeuner, K. E. Munchau, A. Quartarone, A. Weiss, M. Knutzen, A. Hallett, M. Deuschl, G. Siebner, H. R.2006`The basal ganglia are hyperactive during the discrimination of tactile stimuli in writer's cramp 2697-2708Brain129Oct:Writer's cramp is a focal hand dystonia that specifically affects handwriting. Though writer's cramp has been attributed to a dysfunction of the basal ganglia, the role of the basal ganglia in the pathogenesis of writer's cramp remains to be determined. Seventeen patients with writer's cramp (nine females; age range: 24-71 years) and 17 healthy individuals (six females; age range: 27-68 years) underwent functional MRI (fMRI) while they discriminated the orientation of gratings delivered to the tip of the right index finger. Statistical parametric mapping was used to analyse the fMRI data. The significance level was set at a corrected P-value of 0.05. Relative to healthy controls, patients with writer's cramp showed a widespread bilateral increase in task-related activity in the putamen, caudate nucleus, internal globus pallidus and lateral thalamus. In these areas, hyperactivity was more pronounced in patients who had recently developed writer's cramp. The enhanced response of the basal ganglia to tactile input from the affected hand is compatible with the concept of impaired centre-surround inhibition within the basal ganglia-thalamic circuit and may lead to an excessive activation of sensorimotor cortical areas during skilled movements affected by dystonia. Outside the basal ganglia, dystonic patients showed task-related overactivity in visual cortical areas, left anterior insula and right intraparietal sulcus, but not in the primary or secondary sensory cortex. In addition, task-related activity in the cerebellar nuclei, posterior vermis, right paramedian cerebellar hemisphere and dorsal pons was inversely related with the severity of hand dystonia. Regional activity in these areas may reflect secondary adaptive reorganization at the systems level to compensate for the dysfunction in the basal ganglia-thalamic loop.://000240925500018 Times Cited: 0 Part 10ISI:000240925500018Univ Kiel, Dept Neurol, D-24105 Kiel, Germany. NeuroImageNord Hamburg Kiel Lubeck, Lubeck, Germany. Univ Hamburg, Dept Neurol, Hamburg, Germany. Univ Messina, Dept Neurosci Psychiat & Anaesthesiol Sci, I-98100 Messina, Italy. NINDS, Human Motor Control Sect, Med Neurol Branch, NIH, Bethesda, MD 20892 USA. Siebner, HR, Univ Kiel, Dept Neurol, Schittenhelmstr 10, D-24105 Kiel, Germany. h.siebner@neurologie.uni-kiel.de~? Slobounov, S. Wu, T. Hallett, M.2006LNeural basis subserving the detection of postural instability: An fMRI study69-89 Motor Control101JanHuman upright posture is a product of a complex dynamic system that relies on integration of input from multimodal sensory sources. Extensive research has explored the role of visual, vestibular, and somatosensory systems in the control of upright posture. However, the role of higher cognitive function in a participant's assessment of postural stability has been less studied. In previous research, we showed specific neural activation patterns in EEG associated with recognition of unstable postures in young healthy participants. Similar EEG patterns have been recently observed in regulation of posture equilibrium in dynamic stances. This article evaluates participants' postural stability in dynamic stances and neural activation patterns underlying visual recognition of unstable postures using event-related functional MRI (fMRI). Our results show that the "stable" participants were successful in recognition of unstable postures of a computer-animated body model and experienced egocentric motion. Successful recognition of unstable postures in these participants induces activation of distinct areas of the brain including bilateral parietal cortex, anterior cingulate cortex, and bilateral cerebellum. In addition, significant activation is observed in basal ganglia (caudate nucleus and putamen) but only during perception of animated postures. Our findings suggest the existence of modality-specific distributed activation of brain areas responsible for detection of postural instability.://000235111200006 Times Cited: 0ISI:000235111200006NINDS, Human Motor Control Sect, NIH, Bethesda, MD 20892 USA. Penn State Univ, Dept Kinesiol, University Pk, PA 16802 USA. Slobounov, S, NINDS, Human Motor Control Sect, NIH, Bethesda, MD 20892 USA.~?GSlobounov, S. Wu, T. Hallett, M. Shibasaki, H. Slobounov, E. Newell, K.2006@Neural underpinning of postural responses to visual field motion188-197Biological Psychology722MayNumerous results emerging from current research strongly implicate the effect of Visual Field Motion on the organization of postural responses. However, this is the first empirical study exploring the neural substrates underlying the subjects' response to Visual Field Motion. Two separate experiments were conducted to investigate the subject responses to Visual Field Motion. In the first experiment, the standing subjects were exposed to Visual Field Motion in the VR environment. In the second experiment, the recumbent subjects viewed the same Visual Field Motion while in a MRI scanner. A virtual reality (VR) prototype of the moving room paradigm [Lee, D.N., Aronson, E., 1974. Visual proprioceptive control of standing in human infants. Perception & Psychophysics 15, 529-532] was developed to simulate various optic flow patterns in a controlled VR environment. Postural responses (center of pressure, body kinematics, vection, egomotion) and brain activation patterns (fMRI signals) were examined. The subjects experienced egomotion and have reported vection in both experiments only when certain attributes of Visual Field Motion were introduced. This was accompanied by significant activation of specific brain structures, including prefrontal, parietal cortices and bilateral cerebellum. We propose the existence of functional interactions between modality specific areas of the brain involved in postural responses to Visual Field Motion (VFM). (c) 2005 Published by Elsevier B.V.://000236564100010 Times Cited: 0ISI:000236564100010NINDS, Motor Control Sect, NIH, Bethesda, MD 20892 USA. Penn State Univ, Dept Kinesiol, University Pk, PA 16802 USA. Slobounov, S, NINDS, Motor Control Sect, NIH, Bldg 10 Room 5N240,10 Ctr Dr,MSC 1428, Bethesda, MD 20892 USA. sms18@psu.eduF?6Krueger, F. Moll, J. Zahn, R. Heinecke, A. Grafman, J.in press`Event frequency modulates the processing of daily life activities in the human prefrontal cortexCerebral CortexF?/Knutson, K. M. Mah, L. Manly, C. F. Grafman, J.in press<Neural correlates of automatic beliefs about gender and raceHuman Brain Mapping?AZahn, R. Moll, J. Krueger, F. Huey, E. D. Garrido, G. Grafman, J.2007HSotial concepts are represented in the superior anterior temporal cortex 6430-6435/Proceedings of the National Academy of Sciences10415?KMoll, J. Krueger, F. Zahn, R. Pardini, M. De Oliveira-Souza, R. Grafman, J.2006JHuman fronto-mesolimbic networks guide decisions about charitable donation 15623-15628/Proceedings of the National Academy of Sciences10342?8Knutson, K. M. Wood, J. N. Spampinato, M. V. Grafman, J.2006,Politics on the brain: an fMRI investigation25-40Social Neuroscience1c~?8Henkel, K. Danek, A. Grafman, J. Butman, J. Kassubek, J.2006hHead of the caudate nucleus is most vulnerable in chorea-acanthocytosis: A voxel-based morphometry study 1728-1731Movement Disorders2110://000241745300025 Times Cited: 1ISI:0002417453000255Univ Ulm, Dept Neurol, D-89081 Ulm, Germany. Univ Munich, Dept Neurol, D-8000 Munich, Germany. Natl Inst Neurol Disorders & Stroke, Cognit Neurosci Sect, Bethesda, MD USA. NIH, Ctr Clin, Bethesda, MD 20892 USA. Henkel, K, Univ Ulm, Dept Neurol, Oberer Eselsberg 45, D-89081 Ulm, Germany. karsten.henkel@gmx.de~?2Wood, J. N. Tierney, M. Bidwell, L. A. Grafman, J.2005cNeural correlates of script event knowledge: A neuropsychological study following prefrontal injury796-804Cortex416Dec://000233894200007 Times Cited: 0ISI:000233894200007NINDS, Cognit Neurosci Sect, NIH, Bethesda, MD 20892 USA. Univ Cardiff Wales, Sch Psychol, Cardiff, Wales. Grafman, J, NINDS, Cognit Neurosci Sect, NIH, Bldg 10,Room 5C205,10 Ctr Dr, Bethesda, MD 20892 USA. grafmanj@ninds.nih.gov~?4Wood, J. N. Romero, S. G. Knutson, K. M. Grafman, J.2005fRepresentation of attitudinal knowledge: role of prefrontal cortex, amygdala and parahippocampal gyrus249-259Neuropsychologia432://000227257600010 Times Cited: 4ISI:000227257600010NINDS, Cognit Neurosci Sect, NIH, Bethesda, MD 20892 USA. Union Coll, Dept Psychol, Schenectady, NY 12308 USA. Grafman, J, NINDS, Cognit Neurosci Sect, NIH, Bldg 10,10 Ctr Dr, Bethesda, MD 20892 USA. grafmanj@ninds.nih.gov~?&Wood, J. N. Knutson, K. M. Grafman, J.2005@Psychological structure and neural correlates of event knowledge 1155-1161Cerebral Cortex158Aug://000230513400007 Times Cited: 1ISI:000230513400007NINDS, Cognit Neurosci Sect, NIH, Bethesda, MD 20892 USA. Grafman, J, NINDS, Cognit Neurosci Sect, NIH, Bldg 10,Room 5C205,10 Ctr Dr, Bethesda, MD 20892 USA. grafmanj@ninds.nih.gov~?)Fiddick, L. Spampinato, M. V. Grafman, J.2005tSocial contracts and precautions activate different neurological systems: An fMRI investigation of deontic reasoning778-786 Neuroimage284Dec://000234015300005 Times Cited: 2ISI:000234015300005NINDS, Cognit Neurosci Sect, Bethesda, MD 20892 USA. Grafman, J, NINDS, Cognit Neurosci Sect, Bldg 10,Room 5C20MSC 1440, Bethesda, MD 20892 USA. grafmanj@ninds.nih.gov~?&Knutson, K. M. Wood, J. N. Grafman, J.2004?Brain activation in processing temporal sequence: an fMRI study 1299-1307 Neuroimage234Dec://000226041800006 Times Cited: 4ISI:000226041800006NINDS, Cognit Neurosci Sect, NIH, Bethesda, MD 20892 USA. Grafman, J, NINDS, Cognit Neurosci Sect, NIH, Room 5C205,Bldg 10,10 Ctr Dr,MSC 1440, Bethesda, MD 20892 USA. grafmanj@ninds.nih.gov~?Goel, V. Makale, M. Grafman, J.2004UThe hippocampal system mediates logical reasoning about familiar spatial environments654-664!Journal of Cognitive Neuroscience164May://000221521200013 Times Cited: 6ISI:000221521200013York Univ, Dept Psychol, Toronto, ON M3J 1P3, Canada. NINDS, Bethesda, MD 20892 USA. Goel, V, York Univ, Dept Psychol, 4700 Keele St, Toronto, ON M3J 1P3, Canada. vgoel@yorku.ca~?0Wood, J. N. Romero, S. G. Makale, M. Grafman, J.2003bCategory-specific representations of social and nonsocial knowledge in the human prefrontal cortex236-248!Journal of Cognitive Neuroscience152Feb://000181452900008 Times Cited: 17ISI:000181452900008NINDS, Cognit Neurosci Sect, NIH, Bethesda, MD 20892 USA. Grafman, J, NINDS, Cognit Neurosci Sect, NIH, Room 5C205,Bldg 10,10 Ctr Dr,MSC 1440, Bethesda, MD 20892 USA.u~?Wood, J. N. Grafman, J.2003EHuman prefrontal cortex: Processing and representational perspectives139-147Nature Reviews Neuroscience42Feb://000180799500018 Times Cited: 58ISI:000180799500018NINDS, Cognit Neurosci Sect, NIH, Bethesda, MD 20892 USA. Grafman, J, NINDS, Cognit Neurosci Sect, NIH, Bethesda, MD 20892 USA.~?Dreher, J. C. Grafman, J.2003Dissociating the roles of the rostral anterior cingulate and the lateral prefrontal cortices in performing two tasks simultaneously or successively329-339Cerebral Cortex134Apr://000181832200001 Times Cited: 32ISI:000181832200001NINDS, Cognit Neurosci Sect, NIH, Bethesda, MD 20892 USA. Grafman, J, NINDS, Cognit Neurosci Sect, NIH, Bldg 10,Room 5C205, Bethesda, MD 20892 USA.~?>Basso, G. Nichelli, P. Wharton, C. M. Peterson, M. Grafman, J.2003JDistributed neural systems for temporal production: A functional MRI study405-411Brain Research Bulletin595Jan://000180428200011 Times Cited: 10ISI:000180428200011Univ Modena, Dipartimento Neurosci TCR, I-41100 Modena, Italy. NINDS, Cognit Neurosci Sect, MNB, NIH, Bethesda, MD 20892 USA. Nichelli, P, Univ Modena, Dipartimento Neurosci TCR, Via Pozzo 71, I-41100 Modena, Italy.~?9Moll, J. de Oliveira-Souza, R. Bramati, I. E. Grafman, J.2002DFunctional networks in emotional moral and nonmoral social judgments696-703 Neuroimage163Jul://000176767800012 Times Cited: 53 Part 1ISI:000176767800012Hosp DOr & LABS, Neuroimaging & Behav Neurol Grp, Rio De Janeiro, RJ, Brazil. Natl Inst Neurol Disorders & Stroke, Cognit Neurosci Sect, Bethesda, MD USA. Moll, J, Hosp DOr & LABS, Neuroimaging & Behav Neurol Grp, Rio De Janeiro, RJ, Brazil.?-Koechlin, E. Danek, A. Burnod, Y. Grafman, J.2002yMedial prefrontal and subcortical mechanisms underlying the acquisition of motor and cognitive action sequences in humans371-381Neuron35~?1Dreher, J. C. Koechlin, E. Ali, S. O. Grafman, J.20028The roles of timing and task order during task switching95-109 Neuroimage171Sep://000178102000007 Times Cited: 40ISI:000178102000007NINDS, Cognit Neurosci Sect, NIH, Bethesda, MD 20892 USA. Univ Paris 06, INSERM, U483, F-75005 Paris, France. NIMH, Biol Psychiat Branch, Bethesda, MD 20892 USA. Dreher, JC, NINDS, Cognit Neurosci Sect, NIH, Bethesda, MD 20892 USA.~?Dreher, J. C. Grafman, J.2002LThe roles of the cerebellum and basal ganglia in timing and error prediction 1609-1619 European Journal of Neuroscience168Oct://000178922900023 Times Cited: 29ISI:000178922900023Natl Inst Neurol Disorder & Stroke, Cognit Neurosci Sect, Bethesda, MD 20892 USA. Grafman, J, Natl Inst Neurol Disorder & Stroke, Cognit Neurosci Sect, Bldg 10,Room 5C205,MSC 1440, Bethesda, MD 20892 USA.?WCassanova, M. F. Christensen, J. D. Giedd, J. Ramsey, J. M. Garver, D. L. Postel, G. C.2005JMagnetic resonance imaging study of brain asymmetries in dyslexic patients842-847Journal of Child Neurology2010^http://www.scopus.com/scopus/inward/record.url?eid=2-s2.0-31144441383&partnerID=40&rel=R6.5.0 CCited By (since 1996): 1 Export Date: 14 August 2007 Source: Scopus?Merke, D. P. Giedd, J. N. Keil, M. F. Mehlinger, S. L. Wiggs, E. A. Holzer, S. Rawson, E. Vaituzis, A. C. Stratakis, C. A. Chrousos, G. P.2005uChildren experience cognitive decline despite reversal of brain atrophy one year after resolution of Cushing syndrome 2531-25360Journal of Clinical Endocrinology and Metabolism905^http://www.scopus.com/scopus/inward/record.url?eid=2-s2.0-21044458995&partnerID=40&rel=R6.5.0 CCited By (since 1996): 6 Export Date: 14 August 2007 Source: Scopus?Thompson, P. M. Sowell, E. R. Gogtay, N. Giedd, J. N. Vidal, C. N. Hayashi, K. M. Leow, A. Nicolson, R. Rapoport, J. L. Toga, A. W.2005$Structural MRI and Brain Development285-323$International Review of Neurobiology67^http://www.scopus.com/scopus/inward/record.url?eid=2-s2.0-33646366688&partnerID=40&rel=R6.5.0 CCited By (since 1996): 4 Export Date: 14 August 2007 Source: Scopus?pBoger-Megiddo, I. Shaw, D. W. W. Friedman, S. D. Sparks, B. F. Artru, A. A. Giedd, J. N. Dawson, G. Dager, S. R.2006MCorpus callosum morphometrics in young children with autism spectrum disorder733-739-Journal of Autism and Developmental Disorders366^http://www.scopus.com/scopus/inward/record.url?eid=2-s2.0-33746639780&partnerID=40&rel=R6.5.0 CCited By (since 1996): 3 Export Date: 14 August 2007 Source: Scopus?Giedd, J. N. Clasen, L. S. Lenroot, R. Greenstein, D. Wallace, G. L. Ordaz, S. Molloy, E. A. Blumenthal, J. D. Tossell, J. W. Stayer, C. Samango-Sprouse, C. A. Shen, D. Davatzikos, C. Merke, D. Chrousos, G. P.2006/Puberty-related influences on brain development154-162$Molecular and Cellular Endocrinology254-255^http://www.scopus.com/scopus/inward/record.url?eid=2-s2.0-33745927160&partnerID=40&rel=R6.5.0 CCited By (since 1996): 2 Export Date: 14 August 2007 Source: Scopus?Gogtay, N. Nugent Iii, T. F. Herman, D. H. Ordonez, A. Greenstein, D. Hayashi, K. M. Clasen, L. Toga, A. W. Giedd, J. N. Rapoport, J. L. Thompson, P. M.20067Dynamic mapping of normal human hippocampal development664-672 Hippocampus168^http://www.scopus.com/scopus/inward/record.url?eid=2-s2.0-33750449331&partnerID=40&rel=R6.5.0 CCited By (since 1996): 5 Export Date: 14 August 2007 Source: Scopus?ZGreenstein, D. Lerch, J. Shaw, P. Clasen, L. Giedd, J. Gochman, P. Rapoport, J. Gogtay, N.2006KChildhood onset schizophrenia: Cortical brain abnormalities as young adults 1003-1012AJournal of Child Psychology and Psychiatry and Allied Disciplines4710^http://www.scopus.com/scopus/inward/record.url?eid=2-s2.0-33750395407&partnerID=40&rel=R6.5.0 CCited By (since 1996): 1 Export Date: 14 August 2007 Source: Scopus3~?Lenroot, R. K. Giedd, J. N.2006bBrain development in children and adolescents: Insights from anatomical magnetic resonance imaging718-729&Neuroscience and Biobehavioral Reviews306UAdvances in neuroimaging have ushered in a new era of developmental neuroscience. Magnetic resonance imaging (MRI) is particularly well suited for pediatric studies because it does not use ionizing radiation which enables safe longitudinal scans of healthy children. Key findings related to brain anatomical changes during childhood and adolescent are increases in white matter volumes throughout the brain and regionally specific inverted U-shaped trajectories of gray matter volumes. Brain morphometric measures are highly variable across individuals and there is considerable overlap amongst groups of boys versus girls, typically developing versus neuropsychiatric populations, and young versus old. Studies are ongoing to explore the influences of genetic and environmental factors on developmental trajectories. (c) 2006 Published by Elsevier Ltd.://000241208800002 Times Cited: 1ISI:000241208800002Natl Inst Mental Hlth, Child Psychiat Branch, Bethesda, MD 20854 USA. Giedd, JN, Natl Inst Mental Hlth, Child Psychiat Branch, Bldg 10,Room 4C110,10 Ctr Dr, Bethesda, MD 20854 USA. jg@nih.gov|4 previous findings by suggesting regional functional specialization within a cortical network supporting cognitive control.://000236176000027 Times Cited: 0ISI:000236176000027@NIMH, CBDB, GCAP, NIH,Dept Hlth & Human Serv, Bethesda, MD 20982 USA. Univ Bari, Psychiat Neurosci Grp, Dept Neurol & Psychiat Sci, Bari, Italy. IRCCS Casa Sollie?\Lerch, J. P. Worsley, K. Shaw, W. P. Greenstein, D. K. Lenroot, R. K. Giedd, J. Evans, A. C.2006aMapping anatomical correlations across cerebral cortex (MACACC) using cortical thickness from MRI993-1003 NeuroImage313^http://www.scopus.com/scopus/inward/record.url?eid=2-s2.0-33744902596&partnerID=40&rel=R6.5.0 CCited By (since 1996): 4 Export Date: 14 August 2007 Source: Scopus4~?dShaw, P. Greenstein, D. Lerch, J. Clasen, L. Lenroot, R. Gogtay, N. Evans, A. Rapoport, J. Giedd, J.2006IIntellectual ability and cortical development in children and adolescents676-679Nature4407084Mar4Children who are adept at any one of the three academic 'R's ( reading, writing and arithmetic) tend to be good at the others, and grow into adults who are similarly skilled at diverse intellectually demanding activities(1-3). Determining the neuroanatomical correlates of this relatively stable individual trait of general intelligence has proved difficult, particularly in the rapidly developing brains of children and adolescents. Here we demonstrate that the trajectory of change in the thickness of the cerebral cortex, rather than cortical thickness itself, is most closely related to level of intelligence. Using a longitudinal design, we find a marked developmental shift from a predominantly negative correlation between intelligence and cortical thickness in early childhood to a positive correlation in late childhood and beyond. Additionally, level of intelligence is associated with the trajectory of cortical development, primarily in frontal regions implicated in the maturation of intelligent activity(4,5). More intelligent children demonstrate a particularly plastic cortex, with an initial accelerated and prolonged phase of cortical increase, which yields to equally vigorous cortical thinning by early adolescence. This study indicates that the neuroanatomical expression of intelligence in children is dynamic.://000236350400045 Times Cited: 11ISI:000236350400045NIMH, Child Psychiat Branch, Bethesda, MD 20182 USA. McGill Univ, Montreal Neurol Inst, Montreal, PQ H3A 2B4, Canada. Shaw, P, NIMH, Child Psychiat Branch, Bethesda, MD 20182 USA. shawp@mail.nih.gov̄an Giovanni Rotondo, Italy. Mattay, VS, NIMH, CBDB, GCAP, NIH,Dept Hlth & Human Serv, Bldg 10,Ctr Dr, Bethesda, MD 20982 USA. vsm@mail.nih.gov~Blasi, G. Mattay, V. S. Bertolino, A. Elvevag, B. Callicott, J. H. Das, S. Kolachana, B. S. Egan, M. F. Goldberg, T. E. Weinberger, D. R.2005REffect of catechol-O-methyltransferase val(158)met ~?jShaw, P. Lerch, J. Greenstein, D. Sharp, W. Clasen, L. Evans, A. Giedd, J. Castellanos, F. X. Rapoport, J.2006Longitudinal mapping of cortical thickness and clinical outcome in children and adolescents with attention-deficit/hyperactivity disorder540-549Archives of General Psychiatry635MayContext: Data from a previous prospective study of lobar volumes in children with attention-deficit/hyperactivity disorder (ADHD) are reexamined using a measure of cortical thickness. Objective: To determine whether regional differences in cortical thickness or cortical changes across time characterize ADHD and predict or reflect its clinical outcome. Design, Setting, and Participants: Longitudinal study of 163 children with ADHD (mean age at entry, 8.9 years) and 166 controls recruited mainly from a local community in Maryland. Participants were assessed with magnetic resonance imaging. Ninety-seven patients with ADHD (60%) had 2 or more images and baseline and follow-up clinical evaluations (mean follow-up, 5.7 years). Main Outcome Measures: Cortical thickness across the cerebrum. Patients with ADHD were divided into better and worse outcome groups on the basis of a mean split in scores on the Children's Global Assessment Scale and persistence/remission of DSM-IV-defined ADHD. Results: Children with ADHD had global thinning of the cortex (mean reduction, -0.09 mm; P = .02), most prominently in the medial and superior prefrontal and precentral regions. Children with worse clinical outcome had a thinner left medial prefrontal cortex at baseline than the better outcome group (-0.38 mm; P = .003) and controls (-0.25 mm; P = .002). Cortical thickness developmental trajectories did not differ significantly between the ADHD and control groups throughout except in the right parietal cortex, where trajectories converged. This normalization of cortical thickness occurred only in the better outcome group. Conclusions: Children with ADHD show relative cortical thinning in regions important for attentional control. Children with a worse outcome have "fixed" thinning of the left medial prefrontal cortex, which may compromise the anterior attentional network and encumber clinical improvement. Right parietal cortex thickness normalization in patients with a better outcome may represent compensatory cortical change.://000237215800008 Times Cited: 0ISI:000237215800008NIMH, Child Psychiat Branch, Bethesda, MD 20892 USA. McGill Univ, Montreal Neurol Inst, Montreal, PQ, Canada. NYU, Child Study Ctr, New York, NY USA. Shaw, P, NIMH, Child Psychiat Branch, Bldg 10,Room 3N202, Bethesda, MD 20892 USA. shawp@mail.nih.gov̄ on attentional control 5038-5045Journal of Neuroscience2520MayThe cingulate cortex is richly innervated by dopaminergic projections and plays a critical role in attentional control ( AC). Evidence indicates that dopamine enhances the neurophysiological signal-to-noise ratio and that dopaminergic tone in the frontal cortex is critically dependent on catechol-O-methyltransferase ( COMT). A functional polymorphism ( val(158)met) in the COMT gene account ?Vidal, C. N. Rapoport, J. L. Hayashi, K. M. Geaga, J. A. Sui, Y. McLemore, L. E. Alaghband, Y. Giedd, J. N. Gochman, P. Blumenthal, J. Gogtay, N. Nicolson, R. Toga, A. W. Thompson, P. M.2006]Dynamically spreading frontal and cingulate deficits mapped in adolescents with schizophrenia25-34Archives of General Psychiatry631^http://www.scopus.com/scopus/inward/record.url?eid=2-s2.0-29844439581&partnerID=40&rel=R6.5.0 DCited By (since 1996): 12 Export Date: 14 August 2007 Source: Scopus~?Wallace, G. L. Schmitt, J. E. Lenroot, R. Viding, E. Ordaz, S. Rosenthal, M. A. Molloy, E. A. Clasen, L. S. Kendler, K. S. Neale, M. C. Giedd, J. N.2006+A pediatric twin study of brain morphometry987-993*Journal of Child Psychology and Psychiatry4710OctBackground: Longitudinal pediatric neuroimaging studies have demonstrated increasing volumes of white matter and regionally-specific inverted U shaped developmental trajectories of gray matter volumes during childhood and adolescence. Studies of monozygotic and dyzygotic twins during this developmental period allow exploration of genetic and non-genetic influences on these developmental trajectories. Method: Magnetic resonance imaging brain scans were acquired on a pediatric sample of 90 monozygotic twin pairs, 38 same-sex dyzygotic twin pairs, and 158 unrelated typically developing singletons. Structural equation modeling was used to estimate the additive genetic, common environment, and unique environment effects, as well as age by heritability interactions, on measures of brain volumes from these images. Results: Consistent with previous adult studies, additive genetic effects accounted for a substantial portion of variability in nearly all brain regions with the notable exception of the cerebellum. Significant age by heritability interactions were observed with gray matter volumes showing a reduction in heritability with increasing age, while white matter volume heritability increased with greater age. Conclusion: Understanding the relative contributions of genetic and nongenetic factors on developmental brain trajectories may have implications for better understanding brain-based disorders and typical cognitive development.://000241625200003 Times Cited: 0ISI:000241625200003NIMH, Child Psychiat Branch, Bethesda, MD 20892 USA. Virginia Commonwealth Univ, Virginia Inst Psychiat & Behav Genet, Richmond, VA 23284 USA. Virginia Commonwealth Univ, Dept Psychiat & Human Genet, Richmond, VA 23284 USA. Inst Psychiat, Social Genet & Dev Psychiat Ctr, London SE5, England. George Washington Univ, Sch Med, Washington, DC 20052 USA. Giedd, JN, NIMH, Child Psychiat Branch, Bethesda, MD 20892 USA. jg@nih.gov|Lpoorer performance than val/methionine ("met") he of the individual variability in executive function mediated by the dorsolateral prefrontal cortex. We explored the effect of this genetic polymorphism on cingulate engagement during a novel AC task. We found that the COMT val(158)met polymorphism also affects the function of the cingulate during AC. Individuals homozygous for the high-activity valine ("val") allele show greater actiN?(Giedd, J. N. Schmitt, J. E. Neale, M. C.2007>Structural brain magnetic resonance imaging of pediatric twins474-481Human Brain Mapping286^http://www.scopus.com/scopus/inward/record.url?eid=2-s2.0-34249795175&partnerID=40&rel=R6.5.0 CCited By (since 1996): 1 Export Date: 14 August 2007 Source: Scopus?Lenroot, R. K. Gogtay, N. Greenstein, D. K. Wells, E. M. Wallace, G. L. Clasen, L. S. Blumenthal, J. D. Lerch, J. Zijdenbos, A. P. Evans, A. C. Thompson, P. M. Giedd, J. N.2007VSexual dimorphism of brain developmental trajectories during childhood and adolescence 1065-1073 NeuroImage364^http://www.scopus.com/scopus/inward/record.url?eid=2-s2.0-34347240342&partnerID=40&rel=R6.5.0 *Export Date: 14 August 2007 Source: Scopus?yMackie, S. Shaw, P. Lenroot, R. Pierson, R. Greenstein, D. K. Nugent Iii, T. F. Sharp, W. S. Giedd, J. N. Rapoport, J. L.2007WCerebellar development and clinical outcome in attention deficit hyperactivity disorder647-655American Journal of Psychiatry1644^http://www.scopus.com/scopus/inward/record.url?eid=2-s2.0-34247535549&partnerID=40&rel=R6.5.0 *Export Date: 14 August 2007 Source: Scopus?Nugent Iii, T. F. Herman, D. H. Ordonez, A. Greenstein, D. Hayashi, K. M. Lenane, M. Clasen, L. Jung, D. Toga, A. W. Giedd, J. N. Rapoport, J. L. Thompson, P. M. Gogtay, N.2007KDynamic mapping of hippocampal development in childhood onset schizophrenia62-70Schizophrenia Research901-3^http://www.scopus.com/scopus/inward/record.url?eid=2-s2.0-33846584937&partnerID=40&rel=R6.5.0 *Export Date: 14 August 2007 Source: Scopus?Schmitt, J. E. Wallace, G. L. Rosenthal, M. A. Molloy, E. A. Ordaz, S. Lenroot, R. Clasen, L. S. Blumenthal, J. D. Kendler, K. S. Neale, M. C. Giedd, J. N.2007dA multivariate analysis of neuroanatomic relationships in a genetically informative pediatric sample70-82 NeuroImage351^http://www.scopus.com/scopus/inward/record.url?eid=2-s2.0-33846946830&partnerID=40&rel=R6.5.0 CCited By (since 1996): 1 Export Date: 14 August 2007 Source: Scopus?Shaw, P. Lerch, J. P. Pruessner, J. C. Taylor, K. N. Rose, A. B. Greenstein, D. Clasen, L. Evans, A. Rapoport, J. L. Giedd, J. N.2007zCortical morphology in children and adolescents with different apolipoprotein E gene polymorphisms: an observational study494-500Lancet Neurology66^http://www.scopus.com/scopus/inward/record.url?eid=2-s2.0-34248324435&partnerID=40&rel=R6.5.0 CCited By (since 1996): 1 Export Date: 14 August 2007 Source: Scopus8~?=Yongbi, M. N. Fera, F. Mattay, V. S. Frank, J. A. Duyn, J. H.2001mSimultaneous BOLD/perfusion measurement using dual-echo FAIR and UNFAIR: sequence comparison at 1.5T and 3.0T 1159-1165Magnetic Resonance Imaging199NovFunctional MRI (fMRI) studies designed for simultaneously measuring Blood Oxygenation Level Dependent (BOLD) and Cerebral Blood Flow (CBF) signal often employ the standard Flow Alternating Inversion Recovery (FAIR) technique. However, some sensitivity is lost in the BOLD data due to inherent T1 relaxation. We sought to minimize the preceding problem by employing a modified UN-inverted FAIR (UNFAIR) technique, which (in theory) should provide identical CBF signal as FAIR with minimal degradation of the BOLD signal. UNFAIR BOLD maps acquired from human subjects (n = 8) showed significantly higher mean z-score of similar to 17% (p < 0.001), and number of activated voxels at 1.5T. On the other hand, the corresponding FAIR perfusion maps were superior to the UNFAIR perfusion maps as reflected in a higher mean z-score of similar to8% (p = 0.013), and number of activated voxels. The reduction in UNFAIR sensitivity for perfusion is attributed to increased motion sensitivity related to its higher background signal, and, T2 related losses from the use of an extra inversion pulse. Data acquired at 3.0T demonstrating similar trends are also presented. (C) 2001 Elsevier Science Inc. All rights reserved.://000172895200002 Times Cited: 2ISI:0001728952000027NINCDS, Lab Funct & Mol Imaging, NIH, Bethesda, MD 20892 USA. NIMH, Clin Brain Disorder Branch, NIH, Bethesda, MD 20892 USA. CNR, Inst Expt Med & Biotechnol, Cosenza, Italy. NIH, Ctr Clin, Lab Diagnost Radiol Res, Bethesda, MD 20892 USA. Yongbi, MN, NINCDS, Lab Funct & Mol Imaging, NIH, Bethesda, MD 20892 USA.A~?8de Zwart, J. A. van Gelderen, P. Kellman, P. Duyn, J. H.2002pApplication of sensitivity-encoded echo-planar imaging for blood oxygen level-dependent functional brain imaging 1011-1020Magnetic Resonance in Medicine486DecThe benefits of sensitivity-encoded (SENSE) echo-planar imaging (EPI) for functional MRI (fMRI) based on blood oxygen level-dependent (BOLD) contrast were quantitatively investigated at 1.5 T. For experiments with 3.4 x 3.4 x 4.0 mm(3) resolution, SENSE allowed the single-shot EPI image acquisition duration to be shortened from 24.1 to 12.4 ms, resulting in a reduced sensitivity to geometric distortions and T-2* blurring. Finger-tapping fMRI experiments, performed on eight normal volunteers, showed an overall 18% loss in t-score in the activated area, which was substantially smaller than expected based on the image signal-to-noise ratio (SNR) and g-factor, but similar to the loss predicted by a model that takes physiologic noise into account.://000179524200013 Times Cited: 29ISI:000179524200013NINDS, Adv MRI, Lab Funct & Mol Imaging, NIH, Bethesda, MD 20892 USA. NHLBI, Cardiac Energet Lab, NIH, Bethesda, MD 20892 USA. de Zwart, JA, NINDS, Adv MRI, Lab Funct & Mol Imaging, NIH, Bldg 10,Rm B1D-118,10 Ctr Dr, Bethesda, MD 20892 USA. Jacco.deZwart@nih.gov~?8de Zwart, J. A. van Gelderen, P. Kellman, P. Duyn, J. H.2002;Reduction of gradient acoustic noise in MRI using SENSE-EPI 1151-1155 Neuroimage164AugA new approach to reduce gradient acoustic noise levels in EPI experiments is presented. Using multichannel RF receive coils, combined. With SENSE data Acquisition and reconstruction, gradient slew-rates in single-shot EPI were reduced fourfold for rate-2 and ninefold for rate-3 SENSE. Multislice EPI experiments Were performed on three different scanner platforms. With 3.4 min in-plane resolution, measuring 6 slices per second (1 slices with 2000 ms TR), this resulted in average sound pressure level reductions of 11.3 dB(A) and 16.5 dB(A) for rate-2 and rate-3 SENSE, respectively. BOLD fMRI experiments, using visually paced finger-tapping paradigms, showed no detrimental effect of the acoustic noise reduction strategy con temporal noise levels and t scores.://000177444900028 Times Cited: 16ISI:000177444900028NINDS, Lab Funct & Mol Imaging, NIH, Bethesda, MD 20892 USA. NHLBI, Cardiac Energet Lab, NIH, Bethesda, MD 20892 USA. de Zwart, JA, NINDS, Lab Funct & Mol Imaging, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA.~?8Kellman, P. van Gelderen, P. de Zwart, J. A. Duyn, J. H.20037Method for functional MRI mapping of nonlinear response190-199 Neuroimage191May1Nonlinear systems analysis combining blood oxygen level dependent (BOLD), functional magnetic resonance imaging (fMRI) and m-sequence stimulation paradigms are proposed as a new method for exploring neuronal responses and interactions. Previous studies of electrical activity in the human visual cortex have observed significant nonlinearities of task-induced activity with temporal dynamics on a timescale of 10-20 Ins. Despite the confounding effect of the seconds-long hemodynamic response, it is demonstrated that BOLD fMRI can be used to probe neuronal interactions on a time scale of tens of ms. Visual activation experiments were performed with various stimuli, and amplitude maps of first and second order kernel coefficients were generated using correlation analysis. Second order nonlinearities in BOLD fMRI were observed and attributed to temporal contrast caused by transitions in the stimulus sequence. In addition, the kernel maps showed significant differences between second order nonlinearities of foveal and peripheral vision. By including a reference experiment with a slightly modified stimulus presentation, a distinction could be made between (fast) neuronal nonlinearities and hemodynamic effects on the time scale of the seconds. The results indicate that BOLD fMRI can probe fast neuronal nonlinearities.://000183236600016 Times Cited: 8ISI:000183236600016NHLBI, Lab Cardiac Energet, NIH, Bethesda, MD 20892 USA. NINDS, Adv MRI, Lab Funct & Mol Imaging, NIH, Bethesda, MD 20892 USA. Kellman, P, NHLBI, Lab Cardiac Energet, NIH, 10B1D416,10 Ctr Dr, Bethesda, MD 20892 USA.7~?\Bodurka, J. Ledden, P. J. van Gelderen, P. Chu, R. X. de Zwart, J. A. Morris, D. Duyn, J. H.20041Scalable multichannel MRI data acquisition system165-171Magnetic Resonance in Medicine511JanA scalable multichannel digital MRI receiver system was designed to achieve high bandwidth echo-planar imaging (EPI) acquisitions for applications such as BOLD-fMRI. The modular system design allows for easy extension to an arbitrary number of channels. A 16-channel receiver was developed and integrated with a General Electric (GE) Signa 3T VH/3 clinical scanner. Receiver performance was evaluated on phantoms and human volunteers using a custom-built 16-element receive-only brain surface coil array. At an output bandwidth of 1 MHz, a 100% acquisition duty cycle was achieved. Overall system noise figure and dynamic range were better than 0.85 dB and 84 dB, respectively. During repetitive EPI scanning on phantoms, the relative temporal standard deviation of the image intensity time-course was below 0.2%. As compared to the product birdcage head coil, 16-channel reception with the custom array yielded a nearly 6-fold SNR gain in the cerebral cortex and a 1.8-fold SNR gain in the center of the brain. The excellent system stability combined with the increased sensitivity and SENSE capabilities of 16-channel coils are expected to significantly benefit and enhance fMRI applications. Published 2003 Wiley-Liss, lnc.(dagger).://000188041500021 Times Cited: 14ISI:0001880415000216NINDS, Adv MRI Sect, LFMI, NIH, Bethesda, MD 20892 USA. NIMH, Funct MRI Facil, NIH, Bethesda, MD 20892 USA. Nova Med Inc, Wakefield, MA USA. NINDS, NMR Facil, NIH, Bethesda, MD 20892 USA. Duyn, JH, NINDS, Adv MRI Sect, LFMI, NIH, Bldg 10,Rm B1d-724-MSC 1065,10 Ctr Dr, Bethesda, MD 20892 USA. jhd@helix.nih.gov~?\Chu, R. N. de Zwart, J. A. van Gelderen, P. Fukunaga, M. Kellman, P. Holroyd, T. Duyn, J. H.2004`Hunting for neuronal currents: absence of rapid MRI signal changes during visual-evoked response 1059-1067 Neuroimage233NovtWhile recent reports have advocated the use of magnetic resonance imaging (MRI) to detect the effects of neuronal currents associated with human brain activity, only preliminary experimental data have been presented so far to demonstrate the feasibility of the method. Furthermore, it has not been adequately demonstrated that (1) MRI can separate neuronal current (NC) effects from other effects such as blood oxygen level-dependent (BOLD) contrast; (2) MRI has adequate sensitivity to detect NCs in vivo. In this work, we introduce a method that can separate slow (e.g., BOLD) processes from potential rapid (e.g., NC) processes and apply this method to investigate whether MRI allows detection of an NC response to a visual stimulus. MRI studies (n = 8) at 3.0 T using a sensitive multichannel detector showed insignificant effects related to NCs (averaged t < 0.05), in the presence of a highly significant BOLD signal Q = 6.15 +/- 0.90). In contrast, magnetoencephalography (MEG) experiments performed under similar conditions on the same subjects showed highly significant electrical activity Q = 7.90 +/- 2.28). It is concluded that, under the conditions used in this study, the sensitivity of MRI to detect evoked responses through NCs is at least an order of magnitude below that of BOLD-based functional MRI (fMRI) or MEG and too low to be practically useful. Published by Elsevier Inc.://000225254100028 Times Cited: 10ISI:000225254100028NINDS, Adv MRI Sect, LFMI, NIH, Bethesda, MD 20892 USA. NHLBI, Cardiac Energet Lab, NIH, Bethesda, MD 20892 USA. NIMH, MEG Facil, NIH, Bethesda, MD 20892 USA. Duyn, JH, NINDS, Adv MRI Sect, LFMI, NIH, Bldg 10,Room B1D-118,9000 Rockville Pike, Bethesda, MD 20892 USA. jhd@helix.nih.gov ~?Qde Zwart, J. A. Ledden, P. J. van Gelderen, P. Bodurka, J. Chu, R. X. Duyn, J. H.2004qSignal-to-noise ratio and parallel Imaging performance of a 16-channel receive-only brain coil array at 3.0 Tesla22-26Magnetic Resonance in Medicine511JanThe performance of a 16-channel receive-only RF coil for brain imaging at 3.0 Tesla was investigated using a custom-built 16-channel receiver. Both the image signal-to-noise ratio (SNR) and the noise amplification (g-factor) in sensitivity-encoding (SENSE) parallel imaging applications were quantitatively evaluated. Furthermore, the performance was compared with that of hypothetical coils with one, two, four, and eight elements (n) by combining channels in software during image reconstruction. As expected, both the g-factor and SNR improved substantially with n. Compared to an equivalent (simulated) single-element coil, the 16-channel coil showed a 1.87-fold average increase in brain SNR. This was mainly due to an increase in SNR in the peripheral brain (an up to threefold SNR increase), whereas the SNR increase in the center of the brain was 4%. The incremental SNR gains became relatively small at large n, with a 9% gain observed when n was increased from 8 to 16. Compared to the (larger) product birdcage head coil, SNR increased by close to a factor of 2 in the center, and by up to a factor of 6 in the periphery of the brain. For low SENSE acceleration (rate-2), g-factors leveled off for n > 4, and improved only slightly (1.4% averaged over brain) going from n = 8 to n = 16. Improvements in g for n > 8 were larger for higher acceleration rates, with the improvement for rate-3 averaging 12.0%. Published 2003 Wiley-Liss, Inc.://000188041500005 Times Cited: 26ISI:000188041500005NINDS, AMRI Sect, LFMI, NIH, Bethesda, MD 20892 USA. Nova Med Inc, Wakefield, MA USA. NIMH, Funct MRI Facil, NIH, Bethesda, MD 20892 USA. de Zwart, JA, NINDS, AMRI Sect, LFMI, NIH, 10 Ctr Dr,Bldg 10,Rm B1D-118, Bethesda, MD 20892 USA. Jacco.deZwart@nih.govB~?NFera, F. Yongbi, M. N. van Gelderen, P. Frank, J. A. Mattay, V. S. Duyn, J. H.2004uEPI-BOLD fMRI of human motor cortex at 1.5 T and 3.0 T: Sensitivity dependence on echo time and acquisition bandwidth19-26%Journal of Magnetic Resonance Imaging191JankPurpose: To investigate the sensitivity dependence of BOLD functional imaging on MRI acquisition parameters in motor stimulation experiments using a finger tapping paradigm. Materials and Methods: Gradient-echo echo-planar fMRI experiments were performed at 1.5 T and 3.0 T with varying acquisition echo time and bandwidth, and with a 4 mm isotropic voxel size. To analyze the BOLD sensitivity, the relative contributions of BOLD signal amplitude and thermal and physiologic noise sources were evaluated, and statistical t-scores were compared in the motor area. Results: At 1.5 T, the number of activated pixels and the average t-score showed a relatively broad optimum over a TE range of 60-160 msec. At 3.0 T, an optimum range was observed between TEs of 30-130 msec. Averaged over nine subjects, maxima in the number of pixels and t-score values were 59% and 18% higher at 3.0 T than at 1.5 T, respectively, an improvement that was lower than the observed 100% to 110% increase in signal-to-noise ratio at 3.0 T. Conclusion: The somewhat disappointing increase in t-scores at 3.0 T was attributed to the increased contribution of physiologic noise at the higher field strength under the given experimental conditions. At both field strengths, reducing the effective image acquisition bandwidth from 35 to 17 Hz per pixel did not affect or only marginally affect the BOLD sensitivity.://000188002000004 Times Cited: 11ISI:000188002000004nNINDS, Lab Funct & Mol Imaging, NIH, Bethesda, MD 20892 USA. NIMH, Clin Brain Disorder Branch, NIH, Bethesda, MD 20892 USA. CNR, Inst Expt Med & Biotechnol, Cosenza, Italy. NIH, Lab Diagnost Radiol Res, Ctr Clin, Bethesda, MD 20892 USA. Duyn, JH, NINDS, Lab Funct & Mol Imaging, NIH, Bldg 10,Room B1D724,9000 Rockville Pike, Bethesda, MD 20892 USA. jhd@helix.nih.gov~?zde Zwart, J. A. Silva, A. C. van Gelderen, P. Kellman, P. Fukunaga, M. Chu, R. X. Koretsky, A. P. Frank, J. A. Duyn, J. H.20053Temporal dynamics of the BOLD fMRI impulse response667-677 Neuroimage243FebUsing computer simulations and high-resolution fMRI experiments in humans (n = 6) and rats (n = 8) we investigated to what extent BOLD fMRI temporal resolution is limited by dispersion in the venous vasculature. For this purpose, time-to-peak (TTP) and full-width at half-maximum (FWHM) of the BOLD impulse response (IR) function were determined. In fMRI experiments, a binary in-sequence probe method was used to obtain high-sensitivity model-free single-pixel estimates of IR. Simulations of posteapillary flow suggested that flow-related dispersion leads to a TTP and FWHM increase, which can amount to several seconds in larger pial veins. fMRI experiments showed substantial spatial variation in IR timing within human visual cortex, together with a correlation between TTP and FWHM. Averaged across the activated regions and across subjects, TTP and FWHM were 4.51 +/- 0.52 and 4.04 +/- 0.42 s, respectively. In regions of interest (ROI) weighted toward the larger venous structures, TTP and FWHM increased to 5.07 +/- 0.64 and 4.32 +/- 0.48 s, respectively. In rat somatosensory cortex, TTP and FWHM were substantially shorter than in humans (2.73 +/- 0.60 and 2.28 +/- 0.63 s, respectively). These results are consistent with a substantial macrovascular dispersive contribution to BOLD IR in humans, and furthermore suggest that neurovascular coupling is a relatively rapid process, with a resolution below 2.3 s FWHM. Published by Elsevier Inc.://000226588500007 Times Cited: 6ISI:0002265885000070NINDS, Adv MRI Sect, LFMI, NIH, Bethesda, MD 20892 USA. NHLBI, Cardiac Energet Lab, NIH, Bethesda, MD 20892 USA. NIH, Lab Diagnost Radiol Res, CC, Bethesda, MD 20892 USA. de Zwart, JA, NINDS, Adv MRI Sect, LFMI, NIH, Bldg 10,Room B1D-728,9000 Rockville Pike, Bethesda, MD 20892 USA. Jacco.deZwart@nih.gov~?FDuyn, J. H. van Gelderen, P. Talagala, L. Koretsky, A. de Zwart, J. A.2005<Technological advances in MRI measurement of brain perfusion751-753%Journal of Magnetic Resonance Imaging226DecMeasurement of brain perfusion using arterial spin labeling (ASL) or dynamic susceptibility contrast (DSC) based MRI has many potential important clinical applications. However, the clinical application of perfusion MRI has been limited by a number of factors, including a relatively poor spatial resolution, limited volume coverage, and low signal-to-noise ratio (SNR). It is difficult to improve any of these aspects because both ASL and DSC methods require rapid image acquisition. In this report, recent methodological developments are discussed that alleviate some of these limitations and make perfusion MRI more Suitable for clinical application. In particular, the availability of high magnetic field strength systems, increased gradient performance, the use of RF coil arrays and parallel imaging, and increasing pulse sequence efficiency allow for increased image acquisition speed and improved SNR. The use of parallel imaging facilitates the trade-off of SNR for increases in spatial resolution. As a demonstration. we obtained DSC and ASL perfusion images at 3.0 T and 7.0 T with multichannel RF coils and parallel imaging, which allowed us to obtain high-quality images with in-plane voxel sizes of 1.5 X 1.5 mm(2).://000233767200014 Times Cited: 0ISI:000233767200014NINDS, Adv MRI Lab, NIH, Bethesda, MD 20892 USA. Duyn, JH, NINDS, Adv MRI Lab, NIH, Bldg 10,Room B1D724,9000 Rockville Pike, Bethesda, MD 20892 USA. jhd@helix.nih.gov?HIkonomidou, V. N. van Gelderen, P. De Zwart, J. A. Fukunaga, M. Duyn, J.2005JOptimizing brain tissue contrast with EPI: a simulated annealing approach.373-385Magnetic Resonance in Medicine542t~?Ovan Gelderen, P. Wu, C. W. H. de Zwart, J. A. Cohen, L. Hallett, M. Duyn, J. H.2005PResolution and reproducibility of BOLD and perfusion functional MRI at 3.0 tesla569-576Magnetic Resonance in Medicine543SepVisual and somatosensory activation studies were performed on normal subjects to compare the spatial discrimination and reproducibility between functional MRI (fMRI) methods based on blood oxygen level-dependent (BOLD) and perfusion contrast. To allow simultaneous measurement of BOLD and perfusion contrast, a dedicated MRI acquisition technique was developed. Repeated experiments of sensory stimulation of single digits of the right hand showed an average variability of activation amplitude of 25% for BOLD data, and a significantly lower variability of 21% for perfusion data. No significant difference in the variability of the locus of activity was observed between the BOLD and perfusion data. In somatotopy experiments, digits II and V were subjected to passive sensory stimulation. Both the BOLD and perfusion data showed substantial overlap in the activation patterns from the two digits. In a retinotopy study, two stimuli were alternated to excite different patches of V1. Again there was substantial overlap between the activation patterns from both stimuli, although the perfusion performed somewhat better than the BOLD method. Particularly for the visual studies, the overlap in activation patterns was more than expected based on the fine-scale retinotopic mapping of cortical activity, suggesting that both BOLD and perfusion contrast mechanisms contribute substantially to the point-spread function(PSF).://000231494000008 Times Cited: 3ISI:000231494000008NINDS, Adv MRI, LFMI, NIH, Bethesda, MD 20892 USA. van Gelderen, P, NINDS, Adv MRI, LFMI, NIH, Rm B1D-725,Bldg 10,10 Ctr Dr, Bethesda, MD 20892 USA. gelderen@nih.govi~?Hde Zwart, J. A. van Gelderen, P. Golay, X. Ikonomidou, V. N. Duyn, J. H.2006FAccelerated parallel imaging for functional imaging of the human brain342-351Nmr in Biomedicine193MayGAccelerated parallel imaging (PI) techniques have recently been applied to functional imaging experiments of the human brain in order to improve the performance of commonly used single-shot techniques like echo-planar imaging (EPI). Potential benefits of PI-fMRI include the reduction of geometrical distortions due to off-resonance signals, the reduction of signal-loss in areas with substantial signal inhomogeneity, increases of the spatial and temporal resolution of the fMR1 experiment and reduction of gradient acoustic noise. Although PI generally leads to a substantial decrease in image signal-to-noise ratio (SNR), its effect on the temporal stability of the signal, which ultimately determines fMRI performance, is only partially determined by image SNR. Therefore, the penalty for using PI is generally not as severe as the SNR reduction. The majority of problems related to single-shot techniques become more severe at an increased magnetic field strength, making PI an important tool in achieving the full potential of fMRI at high field. Copyright (C) 2006 John Wiley & Sons, Ltd.://000238086200006 Times Cited: 0ISI:000238086200006NINDS, Adv MRI Sect, LFMI, NIH, Bethesda, MD 20892 USA. Natl Inst Neurosci, Dept Neuroradiol, Singapore, Singapore. de Zwart, JA, NINDS, Adv MRI Sect, LFMI, NIH, Bldg 10,Rm B1D-726,MSC 1065,9000 Rockville Pike, Bethesda, MD 20892 USA. Jacco.deZwart@nih.gov R~?Deckers, R. H. R. van Gelderen, P. Ries, M. Barret, O. Duyn, J. H. Ikonomidou, V. N. Fukunaga, M. Glover, G. H. de Zwart, J. A.2006[An adaptive filter for suppression of cardiac and respiratory noise in MRI time series data 1072-1081 Neuroimage334DecjThe quality of MRI time series data, which allows the study of dynamic processes, is often affected by confounding sources of signal fluctuation, including the cardiac and respiratory cycle. An adaptive filter is described, reducing these signal fluctuations as long as they are repetitive and their timing is known. The filter, applied in image domain, does not require temporal oversampling of the artifact-related fluctuations. Performance is demonstrated for suppression of cardiac and respiratory artifacts in 10-minute brain scans on 6 normal volunteers. Experimental parameters resemble a typical fMRI experiment (17 slices; 1700 ms TR). A second dataset was acquired at a rate well above the Nyquist frequency for both cardiac and respiratory cycle (single slice; 100 ins TR), allowing identification of artifacts specific to the cardiac and respiratory cycles, aiding assessment of filtering performance. Results show significant reduction in temporal standard deviation (SDt) in all subjects. For an 6 datasets with 1700 ms TR combined, the filtering method resulted in an average reduction in SDt of 9.2% in 2046 voxels substantially affected by respiratory artifacts, and 12.5% for the 864 voxels containing substantial cardiac artifacts. The maximal SDt reduction achieved was 52.7% for respiratory and 55.3% for cardiac filtering. Performance was found to be at least equivalent to the previously published RETROICOR method. Furthermore, the interaction between the filter and fMRI activity detection was investigated using Monte Carlo simulations, demonstrating that filtering algorithms introduce a systematic error in the detected BOLD-related signal change if applied sequentially. It is demonstrated that this can be overcome by combining physiological artifact filtering and detection of BOLD-related signal changes simultaneously. Visual fMRI data from 6 volunteers were analyzed with and without the filter proposed here. Inclusion of the cardio-respiratory regressors in the design matrix yielded a 4.6% t-score increase and 4.0% increase in the number of significantly activated voxels. (c) 2006 Elsevier Inc. All rights reserved.://000242262900006 Times Cited: 0ISI:000242262900006NINDS, LFMI, Adv MRI Sect, NIH, Bethesda, MD 20892 USA. Eindhoven Univ Technol, Dept Biomed Engn, Biomed NMR, NL-5600 MB Eindhoven, Netherlands. Univ Bordeaux 2, CNRS, ERT, F-33076 Bordeaux, France. Stanford Univ, Sch Med, Radiol Sci Lab, Palo Alto, CA 94304 USA. de Zwart, JA, NINDS, LFMI, Adv MRI Sect, NIH, Bldg 10,Rm BID-728,MSC 1065, Bethesda, MD 20892 USA. Jacco.deZwart@nih.gov ~?Fukunaga, M. Horovitz, S. G. van Gelderen, P. de Zwart, J. A. Jansma, J. M. Ikonomidou, V. N. Chu, R. X. Deckers, R. H. R. Leopold, D. A. Duyn, J. H.2006sLarge-amplitude, spatially correlated fluctuations in BOLD fMRI signals during extended rest and early sleep stages979-992Magnetic Resonance Imaging248OctLA number of recent studies of human brain activity using blood-oxygen-level-dependent (BOLD) fMRI and EEG have reported the presence of spatiotemporal patterns of correlated activity in the absence of external stimuli. Although these patterns have been hypothesized to contain important information about brain architecture, little is known about their origin or about their relationship to active cognitive processes such as conscious awareness and monitoring of the environment. In this study, we have investigated the amplitude and spatiotemporal characteristics of resting-state activity patterns and their dependence on the subjects' alertness. For this purpose, BOLD fMRI was performed at 3.0 T on 12 normal subjects using a visual stimulation protocol, followed by a 27 min rest period, during which subjects were allowed to fall asleep. In subjects who were asleep at the end of the scan, we found (a) a higher amplitude of BOLD signal fluctuation during rest compared with subjects who were awake at the end of the scan; (b) spatially independent patterns of correlated activity that involve all of gray matter, including deep brain nuclei; (c) many patterns that were consistent across subjects; (d) that average percentage levels of fluctuation in visual cortex (VC) and whole brain were higher in subjects who were asleep (up to 1.71% and 1.16%, respectively) than in those who were awake (up to 1.15% and 0.96%) at the end of the scan and were comparable with those levels evoked by intense visual stimulation (up to 1.85% and 0.76% for two subject groups); (e) no confirmation of correlation, positive or negative, between thalamus and VC found in earlier studies. These findings suggest that resting-state activity continues during sleep and does not require active cognitive processes or conscious awareness. (C) 2006 Elsevier Inc. All rights reserved.://000241253500001 Times Cited: 0ISI:000241253500001NINDS, ADV MRI, LFMI, NIH, Bethesda, MD 20892 USA. NIMH, Unit Cognit Neurophysiol & Imaging, NIH, Bethesda, MD 20892 USA. Fukunaga, M, NINDS, ADV MRI, LFMI, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. fukunagm@mail.nih.gov?MDuyn, J. van Gelderen, P. Li, T. Q. De Zwart, J. A. Koretsky, A. Fukunaga, M.2007CHigh-field MRI of brain cortical substructure based on signal phase 11796-11801Proc Natl Acad Sci USA10428?EJansma, J. M. Ramsey, N. F. De Zwart, J. A. van Gelderen, P. Duyn, J.2007HfMRI study of effort and information processing in a working memory task431-440Human Brain Mapping285F?cHorovitz, S. G. Fukunaga, M. De Zwart, J. A. van Gelderen, P. Fulton, S. C. Balkin, T. J. Duyn, J.in pressjLow frequency BOLD fluctuations during resting wakefullness and light sleep: a simultaneous EEG-fMRI studyHuman Brain Mapping?Bonne, O. Bain, E. Neumeister, A. Nugent, A. C. Vythilingam, M. Carson, R. E. Luckenbaugh, D. A. Eckelman, W. Herscovitch, P. Drevets, W. C. Charney, D. S.2005^No change in serotonin type 1A receptor binding in patients with posttraumatic stress disorder383-385American Journal of Psychiatry1622^http://www.scopus.com/scopus/inward/record.url?eid=2-s2.0-13444278544&partnerID=40&rel=R6.5.0 CCited By (since 1996): 7 Export Date: 14 August 2007 Source: Scopus?Cannon, D. M. Carson, R. E. Nugent, A. C. Eckelman, W. C. Kiesewetter, D. O. Williams, J. Rollis, D. Drevets, M. Gandhi, S. Solorio, G. Drevets, W. C.2006LReduced muscarinic type 2 receptor binding in subjects with bipolar disorder741-747Archives of General Psychiatry637^http://www.scopus.com/scopus/inward/record.url?eid=2-s2.0-33745712727&partnerID=40&rel=R6.5.0 CCited By (since 1996): 1 Export Date: 14 August 2007 Source: Scopus?Cannon, D. M. Ichise, M. Fromm, S. J. Nugent, A. C. Rollis, D. Gandhi, S. K. Klaver, J. M. Charney, D. S. Manji, H. K. Drevets, W. C.2006kSerotonin Transporter Binding in Bipolar Disorder Assessed using [11C]DASB and Positron Emission Tomography207-217Biological Psychiatry603^http://www.scopus.com/scopus/inward/record.url?eid=2-s2.0-33746218062&partnerID=40&rel=R6.5.0 CCited By (since 1996): 1 Export Date: 14 August 2007 Source: Scopus6? dCannon, D. M. Ichise, M. Rollis, D. Klaver, J. M. Gandhi, S. Charney, D. S. Manji, H. K. Drevets, M.in pressElevated Serotonin Transporter Binding in Major Depressive Disorder Assessed using [11C]DASB and Positron Emission Tomography; Comparison with Bipolar Disorder. Biological Psychiatry? lHasler, G. Neumeister, A. Van Der Veen, J. W. Tumonis, T. Bain, E. E. Shen, J. Drevets, W. C. Charney, D. S.2005Normal prefrontal gamma-aminobutyric acid levels in remitted depressed subjects determined by proton magnetic resonance spectroscopy969-973Biological Psychiatry5812^http://www.scopus.com/scopus/inward/record.url?eid=2-s2.0-29044439012&partnerID=40&rel=R6.5.0 CCited By (since 1996): 8 Export Date: 14 August 2007 Source: Scopus? MHasler, G. Van Der Veen, J. W. Tumonis, T. Meyers, N. Shen, J. Drevets, W. C.2007Reduced prefrontal glutamate/glutamine and ?-aminobutyric acid levels in major depression determined using proton magnetic resonance spectroscopy193-200Archives of General Psychiatry642^http://www.scopus.com/scopus/inward/record.url?eid=2-s2.0-33846877408&partnerID=40&rel=R6.5.0 *Export Date: 14 August 2007 Source: ScopusF? * Neumeister, A. Charney, D. S. Drevets, M.2005Depression and the hippocampusAmerican Journal of Psychiatry16261057? zNeumeister, A. Drevets, W. C. Belfer, I. Luckenbaugh, D. A. Henry, S. Bonne, O. Herscovitch, P. Goldman, D. Charney, D. S.2006nEffects of a alpha-2C-adrenoreceptor gene polymorphism on neural responses to facial expressions in depression 1750-1756Neuropsychopharmacology318^http://www.scopus.com/scopus/inward/record.url?eid=2-s2.0-33746310877&partnerID=40&rel=R6.5.0 CCited By (since 1996): 3 Export Date: 14 August 2007 Source: Scopus?Neumeister, A. Hu, X. Z. Luckenbaugh, D. A. Schwarz, M. Nugent, A. C. Bonne, O. Herscovitch, P. Goldman, D. Drevets, W. C. Charney, D. S.2006Differential effects of 5-HTTLPR genotypes on the behavioral and neural responses to tryptophan depletion in patients with major depression and controls978-986Archives of General Psychiatry639^http://www.scopus.com/scopus/inward/record.url?eid=2-s2.0-33748290041&partnerID=40&rel=R6.5.0 CCited By (since 1996): 1 Export Date: 14 August 2007 Source: Scopus ?Neumeister, A. Nugent, A. C. Waldeck, T. Geraci, M. Schwarz, M. Bonne, O. Bain, E. E. Luckenbaugh, D. A. Herscovitch, P. Charney, D. S. Drevets, W. C.2004Neural and behavioral responses to tryptophan depletion in unmedicated patients with remitted major depressive disorder and controls765-773Archives of General Psychiatry618]http://www.scopus.com/scopus/inward/record.url?eid=2-s2.0-3543136066&partnerID=40&rel=R6.5.0 DCited By (since 1996): 44 Export Date: 14 August 2007 Source: Scopus?vNeumeister, A. Wood, S. Bonne, O. Nugent, A. C. Luckenbaugh, D. A. Young, T. Bain, E. E. Charney, D. S. Drevets, W. C.2005jReduced hippocampal volume in unmedicated, remitted patients with major depression versus control subjects935-937Biological Psychiatry578^http://www.scopus.com/scopus/inward/record.url?eid=2-s2.0-16844385523&partnerID=40&rel=R6.5.0 DCited By (since 1996): 20 Export Date: 14 August 2007 Source: Scopus 7~?Nugent, A. C. Milham, M. P. Bain, E. E. Mah, L. Cannon, D. M. Marrett, S. Zarate, C. A. Pine, D. S. Price, J. L. Drevets, W. C.2006\Cortical abnormalities in bipolar disorder investigated with MRI and voxel-based morphometry485-497 Neuroimage302Apr2Bipolar disorder (BD) has been associated with abnormalities of brain structure. Specifically, in vivo volumetric MRI and/or post mortern studies of BID have reported abnormalities of gray matter (GM) volume in the medial prefrontal cortex (PFC), amygdala, hippocampal subiculum and ventral striatum. These structures share anatomical connections with each other and form part of a "visceromotor" network modulating emotional behavior. Areas of the lateral orbital, superior temporal and posterior cingulate cortices project to this network, but morphometric abnormalities in these areas have not been established in BD. The current study assessed tissue volumes within these areas in 131) using MRI and voxel-based morphometry (VBM). MRI images were obtained from 36 BD subjects and 65 healthy controls. To account for possible neurotrophic and neuroprotective effects of psychotropic medications, BID subjects were divided into medicated and unmedicated groups. Images were segmented into tissue compartments, which were examined on a voxel-wise basis to determine the location and extent of morphometric changes. The GM was reduced in the posterior cingulate/retrosplenial cortex and superior temporal gyrus of unmedicated BD subjects relative to medicated BD subjects and in the lateral orbital cortex of medicated BD subjects relative to controls. White matter (WM) was increased in the orbital and posterior cingulate cortices, which most likely reflected alterations in gyral morphology resulting from the reductions in the associated GM. The morphometric abnormalities in the posterior cingulate, superior temporal and lateral orbital cortices in BD support the hypothesis that the extended network of neuroanatomical structures subserving visceromotor regulation contains structural alterations in BID. Additionally, localization of morphometric abnormalities to areas known to exhibit increased metabolism in depression supports the hypothesis that repeated stress and elevated glucocorticoid secretion may result in neuroplastic changes in BD. (c) 2005 Elsevier Inc. All rights reserved.://000236682200014 Times Cited: 2ISI:000236682200014NIMH, Sect Neuroimaging Mood & Anxiety Disorders Progra, NIH, Bethesda, MD 20892 USA. Univ Illinois, Beckman Inst, Urbana, IL 61810 USA. NIMH, Funct Neuroimaging Facil, NIH, Bethesda, MD 20892 USA. Washington Univ, Sch Med, Dept Anat & Neurobiol, St Louis, MO 63110 USA. Nugent, AC, NIMH, Sect Neuroimaging Mood & Anxiety Disorders Progra, NIH, 1 Ctr Dr,MSC 0135, Bethesda, MD 20892 USA. nugenta@intra.nimh.nih.govstes, who in turn show greater activity and poorer performance than individuals homozygous for the low-activity met allele, and these effects are most evident at the highest demand for AC. These results indicate that met allele load and presumably enhanced dopaminergic tone improve the "efficiency" of local circuit processing within the cingulate cortex and thereby its function during AC.://000229203600016 Ti{~?`Boroojerdi, B. Bushara, K. O. Corwell, B. Immisch, I. Battaglia, F. Muellbacher, W. Cohen, L. G.2000XEnhanced excitability of the human visual cortex induced by short-term light deprivation529-534Cerebral Cortex105MayGLong term deprivation of visual input for several days or weeks leads to marked changes in the excitability and function of the occipital cortex. The time course of these changes is poorly understood. In this study, we addressed the question whether a short period of light deprivation (minutes to a few hours) can elicit such changes in humans. Noninvasive transcranial magnetic stimulation (TMS) of the human occipital cortex can evoke the perception of flashes or spots of light (phosphenes). To assess changes in visual cortex excitability following light deprivation, we measured the minimum intensity of stimulation required to elicit phosphenes (phosphene threshold) and the number of phosphenes elicited by different TMS stimulus intensities (stimulus-response curves). A reduced phosphene threshold was detected 45 min after the onset of light deprivation and persisted for the entire deprivation period (180 min). Following re-exposure to light, phosphene thresholds returned to predeprivation values over 120 min. Stimulus-response curves were significantly enhanced in association with this intervention. In a second experiment, we studied the effects of light deprivation on functional magnetic resonance imaging (fMRI) signals elicited by photic stimulation. fMRI results showed increased visual cortex activation after 60 min of light deprivation that persisted following 30 min of re-exposure to light. Our results demonstrated a substantial increase in visual cortex excitability. These changes may underlie behavioral gains reported in humans and animals associated with light deprivation.://000086802700009 Times Cited: 45ISI:000086802700009NINDS, Human Cort Physiol Sect, NIH, Bethesda, MD 20892 USA. NINDS, Human Motor Control Sect, NIH, Bethesda, MD 20892 USA. Cohen, LG, NINDS, Human Cort Physiol Sect, NIH, Bldg 10,Room 5N 234,10 Ctr Dr,MSC 1428, Bethesda, MD 20892 USA. H~?9Lotze, M. Braun, C. Birbaumer, N. Anders, S. Cohen, L. G.2003*Motor learning elicited by voluntary drive866-872Brain126Apr2Motor training consisting of voluntary movements leads to performance improvements and results in characteristic reorganizational changes in the motor cortex. It has been proposed that repetition of passively elicited movements could also lead to improvements in motor performance. In this study, we compared behavioural gains, changes in functional MRI (fMRI) activation in the contralateral primary motor cortex (cM1) and in motor cortex excitability measured with transcranial magnetic stimulation (TMS) after a 30 min training period of either voluntarily (active) or passively (passive) induced wrist movements, when alertness and kinematic aspects of training were controlled. During active training, subjects were instructed to perform voluntary wrist flexion-extension movements of a specified duration (target window 174-186 ms) in an articulated splint. Passive training consisted of wrist flexion- extension movements elicited by a torque motor, of the same amplitude and duration range as in the active task. fMRI activation and TMS parameters of motor cortex excitability were measured before and after each training type. Motor performance, measured as the number of movements that hit the target window duration, was significantly better after active than after passive training. Both active and passive movements performed during fMRI measurements activated cM1. Active training led to more prominent increases in (i) fMRI activation of cM1; (ii) recruitment curves (TMS); and (iii) intracortical facilitation (TMS) than passive training. Therefore, a short period of active motor training is more effective than passive motor training in eliciting performance improvements and cortical reorganization. This result is consistent with the concept of a pivotal role for voluntary drive in motor learning and neurorehabilitation.://000181545800010 Times Cited: 32 Part 4ISI:000181545800010'Univ Tubingen, Inst Med Psychol & Verhaltensneurobiol, D-72074 Tubingen, Germany. Univ Trent, Ctr Cognit Neurosci, Trent, Italy. NINDS, Human Cort Physiol Sect, NIH, Bethesda, MD 20892 USA. Lotze, M, Univ Tubingen, Inst Med Psychol & Verhaltensneurobiol, Gartenstr 29, D-72074 Tubingen, Germany. ~?BLotze, M. Kaethner, R. J. Erb, M. Cohen, L. G. Grodd, W. Topka, H.2003uComparison of representational maps using functional magnetic resonance imaging and transcranial magnetic stimulation306-312Clinical Neurophysiology1142FebObjective: Comparison of functional magnetic resonance imaging (fMRI) representational maps, that were generated during voluntary thumb abduction, hand dorsiflexion and foot elevation to amplitude maps of motor-evoked potentials (MEPs) elicited by single transcranial magnetic stimulation (TMS) administered to cortical motor representation areas of the muscles of the thenar eminence, extensor carpi radialis and tibialis anterior muscles. Methods: Stimulus locations that produced maximal motor-evoked potential amplitudes were compared to fMRI activation maxima in three-dimensional (3D)-space and in a 2D-projection using a novel technique that allowed fMRI activation sites to be projected onto the surface of the brain. Results and conclusions: When analyzing pooled data from all target muscles, the location of projected fMRI and TMS activation maxima on the cortical surface differed by an average 13.9 mm. The differences in 3D distances were particularly large for representation areas of lower leg muscles. 3D distances between fMRI activation maxima and highest MEP site in TMS correlated significantly with higher TMS thresholds. These observations strongly suggest that higher TMS excitation thresholds and lower MEP amplitudes are largely due to the absolute distance between the stimulation site and the excitable cortical tissue targeting this muscle. After the projection 4 out of 5 representation sites as evaluated by TMS were located anterior to the fMRI activation maxima, an observation which may due to the orientation of the magnetic field induced by the current in the coil. The representation sites as evaluated with both methods were specific for the type of movement: distances between representation maxima of the same movements were significantly smaller than those within different movements. Nevertheless, fMRI and TMS provide complementary information, which is discussed on the basis of the functional map observed with both methods. (C) 2002 Elsevier Science Ireland Ltd. All rights reserved.://000181094000016 Times Cited: 12ISI:000181094000016[Univ Tubingen, Inst Med Psychol & Behav Biol, D-72074 Tubingen, Germany. Univ Tubingen, Dept Neuroradiol, CNS, Sect Expt NMR, Tubingen, Germany. Univ Tubingen, Dept Neurol, Tubingen, Germany. NINDS, Human Cortical Physiol Sect, NIH, Bethesda, MD USA. Lotze, M, Univ Tubingen, Inst Med Psychol & Behav Biol, Gartenstr 29, D-72074 Tubingen, Germany.'~?AWerhahn, K. J. Conforto, A. B. Kadom, N. Hallett, M. Cohen, L. G.2003MContribution of the ipsilateral motor cortex to recovery after chronic stroke464-472Annals of Neurology544OctIt has been proposed that the intact (ipsilateral) motor cortex play a significant role mediating recovery of motor function in the paretic hand of chronic stroke patients, but this hypothesis has not been tested experimentally. Here, we evaluated the effects of transcranial magnetic stimulation (TMS) on motor performance of the paretic hand of chronic stroke patients and healthy controls. We hypothesized that, if activity in the intact hemisphere contributes to functional recovery, TMS should result in abnormal motor behavior in the paretic hand. We found that stimulation of the intact hemisphere resulted in delayed simple reaction times (RTs) in the contralateral healthy but not in the ipsilateral paretic hand, whereas stimulation of the lesioned hemisphere led to a marked delay in RT in the contralateral paretic hand but not in the ipsilateral healthy hand. RT delays in the paretic hand correlated well with functional recovery. Finger tapping in the paretic hand was affected by TMS of the lesioned but not the intact hemisphere. These results are consistent with the idea that recovered motor function in the paretic hand of chronic stroke patients relies predominantly on reorganized activity within motor areas of the affected hemisphere.://000185670600009 Times Cited: 49ISI:000185670600009NINDS, Human Cort Physiol Sect, NIH, Bethesda, MD 20892 USA. NINDS, Neuroimmunol Branch, NIH, Bethesda, MD 20892 USA. NINDS, Human Motor Control Sect, NIH, Bethesda, MD 20892 USA. Cohen, LG, NINDS, Human Cort Physiol Sect, NIH, Bldg 10,Room 5N229,10 Ctr Dr, Bethesda, MD 20892 USA. ~?]Morgen, K. Kadom, N. Tessitore, A. Ohayon, J. McFarland, H. Frank, J. Martin, R. Cohen, L. G.2004ATraining-dependent plasticity in patients with multiple sclerosis 2506-2517Brain127NovCortical reorganization has been demonstrated in the motor network that mediates performance of a motor task in patients with multiple sclerosis. How this network responds to motor training is not known. This study examined functional MRI (fMRI) activation patterns associated with performance of a motor task, consisting of repetition of directionally specific voluntary thumb movements, before and after motor training in a group of multiple sclerosis patients with mild motor impairment of the right upper extremity. Patients and healthy subjects were scanned in one session before, during and after a 30 min training period. fMRI data obtained during rest, thumb flexion (trained movement) and thumb extension (untrained movement) were analysed using random effects analysis (SPM99). Motor kinematics of training motions and EMG from the resting hand were monitored with an accelerometer and surface EMG electrodes. Kinematics of thumb movements before, during and after training were comparable in the absence of mirror EMG activity in the resting hand. Before training, thumb movements elicited more prominent activation of the contralateral dorsal premotor cortex [PMd, Brodmann area (BA) 6] in multiple sclerosis patients than in controls. After training, unlike the control group, multiple sclerosis patients did not exhibit task-specific reductions in activation in the contralateral primary somatosensory (S1), motor (M1) and adjacent parietal association (BA 40) cortices. These results indicate that patients engage the contralateral PMd more than controls in order to perform directionally specific movements before training. The absence of training-dependent reductions in activation in S1, M1 and BA 40 is consistent with a decreased capacity to optimize recruitment of the motor network with practice.://000224703700014 Times Cited: 7 Part 11ISI:000224703700014NINDS, Human Cort Physiol Sect, NIH, Bethesda, MD 20892 USA. NINDS, Neuroimmunol Branch, NIH, Bethesda, MD 20892 USA. NIMH, Clin Brain Disorders Branch, Bethesda, MD 20892 USA. NIH, Lab Radiol Res, Bethesda, MD 20892 USA. Univ Giessen, Dept Neurol, Giessen, Germany. Bender Inst Neuroimaging, Giessen, Germany. Cohen, LG, NINDS, Human Cort Physiol Sect, NIH, Bldg 10,Room 5N226,10 Ctr Dr,MSC-1430, Bethesda, MD 20892 USA. martinr@ninds.nih.gov cohenL@ninds.nih.govd~?Ward, N. S. Cohen, L. G.2004=Mechanisms underlying recovery of motor function after stroke 1844-1848Archives of Neurology6112DeczStroke is the leading cause of long-term disability worldwide and a condition for which there is no universally accepted treatment. The development of new effective therapeutic strategies relies on a better understanding of the mechanisms underlying recovery of function. Noninvasive techniques to study brain function, including functional magnetic resonance imaging, positron emission tomography, transcranial magnetic stimulation, electroencephalography, and magneto encephalography, led to recent studies that identified some of these operating mechanisms, resulting in the formulation of novel approaches to motor rehabilitation.://000225656100003 Times Cited: 21ISI:000225656100003NINDS, Human Cort Phsiol Sect, NIH, Bethesda, MD 20817 USA. Univ Coll London, Inst Neurol, Wellcome Dept Imaging Neurosci, London, England. Cohen, LG, NINDS, Human Cort Phsiol Sect, NIH, Bldg 10,Room 5N226, Bethesda, MD 20817 USA. cohen@ninds.nih.gov Y~?BWu, C. W. H. van Gelderen, P. Hanakawa, T. Yaseen, Z. Cohen, L. G.2005DEnduring representational plasticity after somatosensory stimulation872-884 Neuroimage274OctSomatosensory stimulation (SS), leading to increases in motor cortical excitability, influences motor performance in patients with brain lesions like stroke. The mechanisms by which SS modulates motor function are incompletely understood. Here, we used functional magnetic resonance imaging (fMRI, blood-oxygenation-level-dependent (BOLD), and perfusion imagings simultaneously acquired in a 3 T magnet) to assess the effects of SS on thumb-movement-related activation in three regions of interest (ROI) in the motor network: primary motor cortex (M1), primary somatosensory cortex (SI), and dorsal premotor cortex (PMd) in healthy volunteers. Scans were obtained in different sessions before and after 2-h electrical stimulation applied to the median nerve at the wrist (MNS), to the skin overlying the shoulder deltoid muscle (DMS), and in the absence of stimulation (NOSTIM) in a counterbalanced design. We found that baseline perfusion intensity was comparable within and across sessions. MNS but not DMS nor NOSTIM led to an increase in signal intensity and number of voxels activated by performance of median nerve-innervated thumb movements in M1, S1 and PMd for up to 60 min. Task-related fMRI activation changes were most prominent in M1 followed by S1 and to a lesser extent in PMd. MNS elicited a displacement of the center of gravity for the thumb movement representation towards the other finger representations within S1. These results indicate that MNS leads to an expansion of the thumb representation towards other finger representations within S1, a form of plasticity that may underlie the influence of SS on motor cortical function, possibly supporting beneficial effects on motor control. Published by Elsevier Inc.://000232141200016 Times Cited: 1ISI:000232141200016Natl Inst Neurol Disorders & Stroke, Lab Funct & Mol Imaging, NIH, Bethesda, MD 20892 USA. NINDS, Human Cort Physiol Sect, NIH, Bethesda, MD 20892 USA. Kyoto Univ, Grad Sch Med, Human Brain Res Ctr, Kyoto, Japan. Wu, CWH, Natl Inst Neurol Disorders & Stroke, Lab Funct & Mol Imaging, NIH, 10 Ctr Dr,Bldg 10,Room B1D728, Bethesda, MD 20892 USA. wuwh@ninds.nih.gov cohenl@ninds.nih.gov~?4Hidler, J. Hodics, T. Xu, B. Dobkin, B. Cohen, L. G.2006`MR compatible force sensing system for real-time monitoring of wrist moments during fMRI testing300-307Journal of Neuroscience Methods1552Sep3Functional magnetic resonance imaging (fMRI) of brain function is used in neurorehabilitation to gain insight into the mechanisms of neural recovery following neurological injuries such as stroke. The behavioral paradigms involving the use of force motor tasks utilized in the scanner often lack the ability to control details of motor performance. They are often limited by subjectiveness, lack of repeatability, and complexity that may exclude evaluation of patients with poor function. In this paper we describe a novel MR compatible wrist device that is capable of measuring isometric forces generated at the hand and joint moments along wrist flexion-extension and wrist ulnar-radial deviation axes. Joint moments measured by the system can be visually displayed to the individual and used during target matching block or event related paradigms. Through a small set of pilot testing both inside and outside the MR environment, we have found that the force tracking tasks and performance in the scanner are reproducible, and that high quality force and moment recordings can be made during fMRI studies without compromising the fMRI images. Furthermore, the device recordings are extremely sensitive making it possible for individuals with poor hand and wrist function to be tested. (c) 2006 Elsevier B.V. All rights reserved.://000241217200018 Times Cited: 0ISI:000241217200018^Catholic Univ Amer, Dept Biomed Engn, Washington, DC 20064 USA. Natl Rehabil Hosp, Ctr Appl Biomech & Rehabil Res, Washington, DC 20010 USA. Georgetown Univ Hosp, Dept Neurol, Washington, DC 20007 USA. NINDS, Human Cortical Physiol Sect, NIH, Bethesda, MD 20892 USA. Univ Calif Los Angeles, Reed Neurol Res Ctr, Geffen Sch Med, Neurol Rehabil & Res Program, Los Angeles, CA 90095 USA. Hidler, J, Catholic Univ Amer, Dept Biomed Engn, Pangborn Hall,104b,620 Michigan Ave NE, Washington, DC 20064 USA. hidler@cua.edu tmh33@gunet.georgetown.edu benxu1@mail.nih.gov bdobkin@mednet.ucla.edu cohenl@ninds.nih.gov~?SLotze, M. Grodd, W. Rodden, F. A. Gut, E. Schonle, P. W. Kardatzki, B. Cohen, L. G.2006MNeuroimaging patterns associated with motor control in traumatic brain injury14-23%Neurorehabilitation and Neural Repair201MarObjective. To determine if patients with traumatic brain injury (TBI) and motor deficits show differences in functional activation maps during repetitive hand movements relative to healthy controls. Are there predictors for motor Outcome in the functional maps of these patients? Methods. In an exploratory.. cross-sectional study, functional magnetic resonance imaging (fMRI) was used to study the blood-oxygenation-level-dependent (BOLD) response in cortical motor areas of 34 patients suffering from moderate motor deficits after TBI as they performed unilateral fist-clenching motions. Twelve of these patients with unilateral motor deficits were studied 3 months after TBI and a 2nd time approximately 4 months later. Results. Compared to age-matched, healthy controls performing the same task, TB patients showed diminished fMRI-signal change in the primary sensorimotor cortex contralateral to the moving hand (cSM1), the contralateral dorsal premotor cortex, and bilaterally in the supplementary motor areas (SMAs). Clinical impairment and the magnitude of the fMRI-signal change in cSM1 and SMA were negatively correlated. Patients with poor and good motor recovery showed comparable motor impairment at baseline. Only patients who evolved to "poor clinical outcome's had decreased fMRI-signal change in the cSM1 during baseline. Conclusions. These observations raise the hypothesis that the magnitude of the fMRI-signal change in the cSM1 region could have prognostic value in the evaluation of patients with TBI.://000235280000003 Times Cited: 0ISI:000235280000003Univ Tubingen, Inst Med Psychol & Behav Neurobiol, D-72074 Tubingen, Germany. Univ Tubingen, Dept Neuroradiol, CNS, Sect MR, D-7400 Tubingen, Germany. Univ Konstanz, Kliniken Schmieder, Lurija Inst Rehabil Sci & Hlth Res, Allenbach, Germany. NINDS, Human Cort Physiol Sect, NIH, Bethesda, MD 20892 USA. Lotze, M, Univ Tubingen, Inst Med Psychol & Behav Neurobiol, Gartenstr 29, D-72074 Tubingen, Germany. martin.lotze@uni-tuebingen.de~?;Sevostianov, A. Fromm, S. Nechaev, V. Horwitz, B. Braun, A.2002AEffect of attention on central auditory processing: An fMRI study587-606%International Journal of Neuroscience1125May@Functional magnetic resonance imaging was used to investigate preattentive and attentional processing of auditory stimuli in 18 right-handed normal volunteers. Responses to trains of 1000-Hz pure tones and infrequent (15%) deviant 1300-Hz tones were characterized while subjects ignored all tones; listened for deviants in the left ear; or listened for deviants in the right ear. Preattentive detection of deviants, associated with the mismatch negativity in electrophysiology, was associated with bilateral temporal lobe activation, with a rightward predominance. Processing of deviant stimuli while attending to either ear produced a more robust and widespread activation of these temporal regions, again with a rightward predominance. Thus, preattentive tone processing appears to be linked to asymmetric activation of a core set of temporal regions in which activity is significantly amplified by selective attention. Extratemporal regions activated by attending to targets in either ear included the anterior cingulate cortex, supramarginal gyrus, and dorsolateral prefrontal cortex.://000175943200007 Times Cited: 10ISI:000175943200007pNatl Inst Deafness & Other Commun Disorders, Bethesda, MD USA. Braun, A, NIH, 10-5N118A, Bethesda, MD 20892 USA.~?KSevostianov, A. Horwitz, B. Nechaev, V. Williams, R. Fromm, S. Braun, A. R.20025fMRI study comparing names versus pictures of objects168-175Human Brain Mapping163JulWe performed an fMRI one-back recognition study aimed at distinguishing the semantic versus perceptual aspects of how objects and their written forms are processed. There were three types of visually presented items: pictures (schematic drawings of objects); words identifying these objects; and a mixed condition in which pictures were interleaved with words. A semantic decision about object identity was required when pictures were interleaved with words. This condition, contrasted with the other two, invoked a larger signal in Multiple areas, including frontal cortex, bilateral occipitotemporal cortex, and the right middle temporal gyrus. We propose that the left occipitotemporal and right temporal activations are indicative of the neural substrate mediating picture-word conversions, whereas the frontal activations reflect the coordinating functions of the central executive. Published 2002 Wiley-Liss, Inc.://000176619000004 Times Cited: 9ISI:000176619000004"NIDCD, Language Sect, Voice Speech & Language Branch, NIH, Bethesda, MD 20892 USA. Russian Acad Sci, Inst Human Brain, St Petersburg 196140, Russia. Horwitz, B, NIDCD, Language Sect, Voice Speech & Language Branch, NIH, Bldg 10,Rm 6C420,MSC 1591,9000 Rockville Pike, Bethesda, MD 20892 USA. Q~?Horwitz, B. Braun, A. R.2004HBrain network interactions in auditory, visual and linguistic processing377-384Brain and Language892MayVIn the paper, we discuss the importance of network interactions between brain regions in mediating performance of sensorimotor and cognitive tasks, including those associated with language processing. Functional neuroimaging, especially PET and fMRI, provide data that are obtained essentially simultaneously from much of' the brain, and thus are ideal for enabling one to assess interregional functional interactions. Two ways to use these types of data to assess network interactions are presented. First, using PET, we demonstrate that anterior and posterior perisylvian language areas have stronger functional connectivity during spontaneous narrative production than during other less linguistically demanding production tasks. Second, we show how one can use large-scale neural network modeling to relate neural activity to the hemodynamically-based data generated by fMRI and PET. We review two versions of a model of object processing - one for visual and one for auditory objects. The regions comprising the models include primary and secondary sensory cortex, association cortex in the temporal lobe, and prefrontal cortex. Each model incorporates specific assumptions about how neurons in each of these areas function, and how neurons in the different areas are interconnected with each other. Each model is able to perform a delayed match-to-sample task for simple objects (simple shapes for the Visual model; tonal contours for the auditory model). We find that the simulated electrical activities in each region are similar to those observed in nonhuman primates performing analogous tasks, and the absolute values of the simulated integrated synaptic activity in each brain region match human fMRI/PET data. Thus, this type of' modeling provides a way to understand the neural bases for the sensorimotor and cognitive tasks of interest. Published by Elsevier Inc.://000220944800013 Times Cited: 10ISI:000220944800013Natl Inst Deafness & Other Commun Disorders, Language Branch, NIH, Bethesda, MD 20892 USA. Horwitz, B, Natl Inst Deafness & Other Commun Disorders, Language Branch, NIH, 9000 Rockville Pike,Bldg 10,Rm 6C420,MSC 1591, Bethesda, MD 20892 USA. horwitz@helix.nih.gov ~?LSan Jose-Robertson, L. Corina, D. P. Ackerman, D. Guillemin, A. Braun, A. R.2004}Neural systems for sign language production: Mechanisms supporting lexical selection, phonological encoding, and articulation156-167Human Brain Mapping233NovOvert production of ASL signs was evaluated using (H2O)-O-15 PET to differentiate brain systems that support sign language production at the lexical-selection and phonological-articulatory levels. Subjects were 16 right-handed, congenitally deaf native ASL signers (10 women, six men; age 20 to 29 years). Scans were performed while subjects (1) passively viewed ASL nouns, (2) repeated nouns, (3) generated verbs in response to these nouns, (4) passively viewed videotaped segments depicting transitive actions, and (5) generated a verb to describe these actions. Conjunctions between the two verb-generation tasks revealed left-lateralized activation of perisylvian, frontal, and subcortical regions commonly observed in spoken language generation tasks and implicated in processes of semantic feature binding and lexical selection. Analysis of noun repetition minus viewing condition revealed activation of distinct systems supporting phonological encoding and articulation, including bilateral activation of sensorimotor areas and association cortices in the temporal, parietal, and occipital lobes. In addition, lexical-selection and articulatory processes were associated with activation of different corticostriatal-thalamocortical circuits: articulation with activation of the motor, and lexical-selection with activation of the prefrontal circuits, respectively. The results collectively provide insight into dissociable neural systems underlying these psycholinguistic functions. In addition, activation of regions that are typically associated with the auditory system during sign production suggests that these regions may support modality-independent linguistic processes, or may indicate cross-modal plasticity within the deaf brain. Published 2004 Wiley-Liss, Inc.(dagger)://000224792000003 Times Cited: 1ISI:000224792000003oNatl Inst Deafness & Other Commun Disorders, Language Sect, Voice Speech & Language Branch, NIH, Bethesda, MD 20892 USA. Univ Washington, Dept Psychol, Seattle, WA 98195 USA. Braun, AR, Natl Inst Deafness & Other Commun Disorders, Language Sect, Voice Speech & Language Branch, NIH, Bldg 10,Room 5N118A,10 Ctr Dr,MSC 1407, Bethesda, MD 20892 USA. brauna@nidcd.nih.gov+~? *Boemio, A. Fromm, S. Braun, A. Poeppel, D.2005KHierarchical and asymmetric temporal sensitivity in human auditory cortices389-395Nature Neuroscience83MarLateralization of function in auditory cortex has remained a persistent puzzle. Previous studies using signals with differing spectrotemporal characteristics support a model in which the left hemisphere is more sensitive to temporal and the right more sensitive to spectral stimulus attributes. Here we use single-trial sparse-acquisition fMRI and a stimulus with parametrically varying segmental structure affecting primarily temporal properties. We show that both left and right auditory cortices are remarkably sensitive to temporal structure. Crucially, beyond bilateral sensitivity to timing information, we uncover two functionally significant interactions. First, local spectrotemporal signal structure is differentially processed in the superior temporal gyrus. Second, lateralized responses emerge in the higher-order superior temporal sulcus, where more slowly modulated signals preferentially drive the right hemisphere. The data support a model in which sounds are analyzed on two distinct timescales, 25-50 ms and 200-300 ms.://000227354600025 Times Cited: 15ISI:000227354600025Univ Maryland, Dept Linguist, College Pk, MD 20742 USA. NIMH, Brain & Cognit Lab, NIH, Bethesda, MD 20892 USA. Natl Inst Deafness & Other Commun Disorders, NIH, Bethesda, MD 20892 USA. Poeppel, D, Univ Maryland, Dept Linguist, College Pk, MD 20742 USA. dpoeppel@deans.umd.edu 1~?!*Kemeny, S. Ye, F. Q. Birn, R. Braun, A. R.2005PComparison of continuous overt speech fMRI using BOLD and arterial spin labeling173-183Human Brain Mapping243MarOvert speech production in functional magnetic resonance imaging (fMRI) studies is often associated with imaging artifacts, attributable to both movement and susceptibility. Various image-processing methods have been proposed to remove these artifacts from the data but none of these methods has been shown to work with continuous overt speech, at least over periods greater than 3 s. In this study natural, continuous, overt sentence production was evaluated in normal volunteers using both arterial spin labeling (ASL) and conventional echoplanar blood oxygenation level-dependent (BOLD) imaging sequences on the same 1.5-T scanner. We found a high congruency between activation results obtained with ASL and the de facto gold standard in overt language production imaging, positron emission tomography (PET). No task-related artifacts were found in the ASL study. However, the BOLD data showed artifacts that appeared as large bilateral false-positive temporopolar activations; percent signal change estimated in these regions showed signal increases and temporal dynamics that were incongruent with typical BOLD activations. These artifacts were not distributed uniformly, but were aligned at the frontotemporal base, close to the oropharynx. The calculated head movement parameters for overt speech blocks were within the range of the rest blocks, indicating that head movement is unlikely the reason for the artifact. We conclude that ASL is not influenced by overt speech artifacts, whereas BOLD showed significant susceptibility artifacts, especially in the opercular and insular regions, where activation would be expected. ASL may prove to be the method of choice for fMRI investigations of continuous overt speech. Published 2004 Wiley-Liss, Inc.(dagger).://000227250600003 Times Cited: 5ISI:000227250600003<NIDCD, Language Sect, Voise Speech & Language Branch, NIH,Ckin Ctr, Bethesda, MD 20892 USA. NIMH, Funct Imaging Methods Unit, NIH, Bethesda, MD 20892 USA. Kemeny, S, NIDCD, Language Sect, Voise Speech & Language Branch, NIH,Ckin Ctr, 9000 Rockville Pike Bld 10,Rm 3C716, Bethesda, MD 20892 USA. kemenys@nidcd.nih.gov ~?"1Xu, J. Kemeny, S. Park, G. Frattali, C. Braun, A.2005ULanguage in context: emergent features of word, sentence, and narrative comprehension 1002-1015 Neuroimage253AprContext exerts a powerful effect on cognitive performance and is clearly important for language processing, where lexical, sentential, and narrative contexts should differentially engage neural systems that support lexical, compositional, and discourse level semantics. Equally important, but thus far unexplored, is the role of context within narrative, as cognitive demands evolve and brain activity changes dynamically as subjects process different narrative segments. In this study, we used fMRI to examine the impact of context, comparing responses to a single, linguistically matched set of texts when these were differentially presented as random word lists, unconnected sentences and coherent narratives. We found emergent, context-dependent patterns of brain activity in each condition. Perisylvian language areas were always active, consistent with their supporting core linguistic computations. Sentence processing was associated with expanded activation of the frontal operculum and temporal poles. The same stimuli presented as narrative evoked robust responses in extrasylvian areas within both hemispheres, including precuneus, medial prefrontal, and dorsal temporo-parieto-occipital cortices. The right hemisphere was increasingly active as contextual complexity increased, maximal at the narrative level. Furthermore, brain activity was dynamically modulated as subjects processed different narrative segments: left hemisphere activity was more prominent at the onset, and right hemisphere more prominent at the resolution of a story, at which point, it may support a coherent representation of the narrative as a whole. These results underscore the importance of studying language in an ecologically valid context, suggesting a neural model for the processing of discourse. Published by Elsevier Inc.://000228383500035 Times Cited: 9ISI:000228383500035UNatl Inst Deafness & Other Commun Disorders, Languages Sect, Voice Speech & Language Branch, NIH, Bethesda, MD 20892 USA. NIH, WG Magnuson Clin Ctr, Dept Rehabil Med, Bethesda, MD 20892 USA. Xu, J, Natl Inst Deafness & Other Commun Disorders, Languages Sect, Voice Speech & Language Branch, NIH, Bethesda, MD 20892 USA. xujiang@nidcd.nih.gov F~?#OHusain, F. T. Fromm, S. J. Pursley, R. H. Hosey, L. A. Braun, A. R. Horwitz, B.2006DNeural bases of categorization of simple speech and nonspeech sounds636-651Human Brain Mapping278AugwCategorization is fundamental to our perception and understanding of the environment. However, little is known about the neural bases underlying the categorization of sounds. Using human functional magnetic resonance imaging (fMRI) we compared the brain responses to a category discrimination task with an auditory discrimination task using identical sets of sounds. Our stimuli differed along two dimensions: a speech-nonspeech dimension and a fast-slow temporal dynamics dimension. All stimuli activated regions in the primary and nonprimary auditory cortices in the temporal cortex and in the parietal and frontal cortices for the two tasks. When comparing the activation patterns for the category discrimination task to those for the auditory discrimination task, the results show that a core group of regions beyond the auditory cortices, including inferior and middle frontal gyri, dorsomedial frontal gyrus, and intraparietal sulcus, were preferentially activated for familiar speech categories and for novel nonspeech categories. These regions have been shown to play a role in working memory tasks by a number of studies. Additionally, the categorization of nonspeech sounds activated left middle frontal gyrus and right parietal cortex to a greater extent than did the categorization of speech sounds. Processing the temporal aspects of the stimuli had a greater impact on the left lateralization of the categorization network than did other factors, particularly in the inferior frontal gyrus, suggesting that there is no inherent left hemisphere advantage in the categorical processing of speech stimuli, or for the categorization task itself.://000239316700002 Times Cited: 0ISI:000239316700002Natl Inst Deafness & Other Commun Disorders, NIH, Brain Imaging & Modeling Sect, Bethesda, MD 20892 USA. Natl Inst Deafness & Other Commun Disorders, NIH, Language Sect, Bethesda, MD 20892 USA. NIH, Ctr Informat Technol, Bethesda, MD 20892 USA. Husain, FT, Natl Inst Deafness & Other Commun Disorders, NIH, Brain Imaging & Modeling Sect, Bldg 10,Rm 8S2335E,9000 Rockville Pike, Bethesda, MD 20892 USA. husainf@nidcd.nih.gov~?$EKemeny, S. Xu, J. Park, G. H. Hosey, L. A. Wettig, C. M. Braun, A. R.2006jTemporal dissociation of early lexical access and articulation using a delayed naming task - An fMRI study587-595Cerebral Cortex164AprNeuroimaging studies of overt speech hold an important practical advantage allowing monitoring of subject performance, particularly valuable in disorders like aphasia. However, speech production is not a monotonic process but a complex sequence of stages. Levelt and colleagues have described these as roughly corresponding to two originally independent systems - conceptual and sensorimotor - that are linked in the formulation and expression of spoken language. In the initial stages a word is chosen to match a concept (lexical selection); in the later stages the sound and motor patterns are encoded and the word is uttered (articulation). It has been difficult to discriminate these stages using conventional neuroimaging techniques. We designed a functional magnetic resonance imaging study in an attempt to do this, by introducing a latency into a conventional naming paradigm, delaying the articulated response. Our results showed that left hemisphere perisylvian areas were active throughout, interacting with visual and heteromodal areas during early lexical access and with motor and auditory areas during overt articulation. These results are consistent with the broadest version of the Levelt model and with that derived from Chomsky's minimalist program in which a core language system interacts with conceptual-intentional systems and articulatory-perceptual systems during the early and late stages of lexical access respectively.://000235922200015 Times Cited: 1ISI:000235922200015NIDCD, Language Sect, Voice Speech & Language Branch, NIH, Bethesda, MD 20892 USA. Kemeny, S, NIH, Ctr Clin, 9000 Rockville Pike Bld,10 Rm 3C-716, Bethesda, MD 20892 USA. kemenys@nidcd.nih.gov?%?Limb, C. J. Kemeny, S. Ortigoza, E. B. Rouhani, S. Braun, A. R.2006_Left-Hemispheric Lateralization of Brain Activity During Passive Rhythm Perception in Musicians382-389$Anat Rec A Discov Mol Cell Evol Biol2884?&OMitchell, D. G. V. Nakic, M. Fridberg, D. Kamel, N. Pine, D. C. Blair, R. J. R.2007(The impace of processing load on emotion 1299-1309 Neuroimage34?'CMarsh, A. A. Blair, K. S. Vythilingam, M. Busis, S. Blair, R. J. R.2007Response options and expectations of reward in decision-making: the differential roes of dorsal and rostral anterior cingulate cortex.979-988 Neuroimage35?(4Budhani, S. Marsh, A. A. Pine, D. C. Blair, R. J. R.2007?Neural correlates of response reversal:considering acquisition. 1754-1765 Neuroimage34*?)Blair, K.S. Smith, B.W. Mitchell, D. G. V. Morton, J. Vythilingam, M. Pessoa, L. Fridberg, D. Zametkin, A. Sturman, D. Nelson, E. E. Drevets, W. C. Pine, D. C. Martin, A. Blair, R. J. R.2007;Modulation of emotion by cognition and cognition by emotion430-440 Neuroimage35?*?Nakic, M. Smith, B.W. Busis, S. Vythilingam, M. Blair, R. J. R.2006mThe impace of affect and frequency on lexical decision: the role of the amygdala and inferior frontal cortex. 1752-1761 Neuroimage310~?+HLuo, Q. A. Nakic, M. Wheatley, T. Richell, R. Martin, A. Blair, R. J. R.2006SThe neural basis of implicit moral attitude - An IAT study using event-related fMRI 1449-1457 Neuroimage304MayRecent models of morality have suggested the importance of affect-based automatic moral attitudes in moral reasoning. However, previous investigations of moral reasoning have frequently relied upon explicit measures that are susceptible to voluntary control. To investigate participant's automatic moral attitudes, we used a morality Implicit Association Test (IAT). Participants rated the legality of visually depicted legal and illegal behaviors of two different intensity levels (e.g., high intensity illegal = interpersonal violence; low intensity illegal = vandalism) both when the target concept (e.g., illegal) was behaviorally paired with an associated attribute (e.g., bad; congruent condition) or an unassociated attribute (e.g., good; incongruent condition). Behaviorally, an IAT effect was shown; RTs were faster in the congruent rather than incongruent conditions. At the neural level, implicit moral attitude, as indexed by increased BOLD response as a function of stimulus intensity, was associated with increased activation in the right amygdala and the ventromedial orbitofrontal cortex. In addition, performance on incongruent trials relative to congruent trials was associated with increased activity in the right ventrolateral prefrontal cortex (BA 47), left subgenual cingulate gyrus (BA 25), bilateral premotor cortex (BA 6) and the left caudate. The functional contributions of these regions in moral reasoning are discussed. Published by Elsevier Inc.://000237601500036 Times Cited: 2ISI:000237601500036DNIMH, Unit Affect Cognit Neurosci Mood & Anxiety Progra, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. NIMH, Lab Brain & Cognit, Bethesda, MD 20892 USA. Blair, RJR, NIMH, Unit Affect Cognit Neurosci Mood & Anxiety Progra, Dept Hlth & Human Serv, 15K N Dr,Room 206,MSC 2670, Bethesda, MD 20892 USA. James.Blair@mail.nih.gov~?,dKosson, D. S. Budhani, S. Nakic, M. Chen, G. Saad, Z. S. Vythilingam, M. Pine, D. S. Blair, R. J. R.2006eThe role of the amygdala and rostral anterior cingulate in encoding expected outcomes during learning 1161-1172 Neuroimage294FebSuccessful passive avoidance learning is thought to require the use of learned stimulus-reinforcement associations to guide decision making [Baxter, M.G., Murray, E.A., 2002. The amygdala and reward. Nature Reviews. Neuroscience 3, 563-573]. The current experiment investigated the neural correlates of successful passive avoidance learning in 19 healthy adults. Behaviorally, subjects showed a distinct pattern of performance: early indiscriminate responding to stimuli (pre-criterion performance), followed by relatively rapid learning before a plateau of successful performance (post-criterion performance). Neural responses to post-criterion correct responses were compared with neural responses to both incorrect responses and pre-criterion correct responses. Post-criterion correct responding was associated with increased activation in regions including rostral anterior cingulate, insula, caudate, hippocampal regions, and the amygdala. Published by Elsevier Inc.://000235534400014 Times Cited: 3ISI:000235534400014NIMH, Unit Affect Cognit Neurosci, Mood & Anxiety Disorders Program, NIH, Bethesda, MD 20892 USA. Rosalind Franklin Univ Med & Sci, N Chicago, IL 60064 USA. Univ Coll London, Dept Psychol, London WC1E 6BT, England. NIMH, Sci & Stat Core, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. Blair, RJR, NIMH, Unit Affect Cognit Neurosci, Mood & Anxiety Disorders Program, NIH, 15K North Dr,Room 206,MSC 2670, Bethesda, MD 20892 USA. James.Blair@mail.nih.govm~?-DFinger, E. C. Marsh, A. A. Kamel, N. Mitchell, D. G. V. Blair, J. R.2006oCaught in the act: The impact of audience on the neural response to morally and socially inappropriate behavior414-421 Neuroimage331OctUWe examined the impact of witnesses on the neural response to moral and social transgressions using fMRI. In this study, participants (N = 16) read short vignettes describing moral and social transgressions in the presence or absence of an audience. In line with our hypothesis, ventrolateral (BA 47) and dorsomedial (BA 8) frontal cortex showed increased BOLD responses to moral transgressions regardless of audience and to social transgressions in the presence of an audience relative to neutral situations. These findings are consistent with the suggestion that these regions of prefrontal cortex modify behavioral responses in response to social cues. Greater activity was observed in left temporal-parietal junction, medial prefrontal cortex and temporal poles to moral and to a lesser extent social transgressions relative to neutral stories, regardless of audience. These regions have been implicated in the representation of the mental states of others (Theory of Mind). The presence of an audience was associated with increased left amygdala activity across all conditions. Published by Elsevier Inc.://000241209800041 Times Cited: 0ISI:000241209800041NIMH, Mood & Anxiety Program, Dept Hlth & Human Serv, NIH, Bethesda, MD 20892 USA. Finger, EC, NIMH, Mood & Anxiety Program, Dept Hlth & Human Serv, NIH, 15K N Dr,MSC 2670, Bethesda, MD 20892 USA. fingere@mail.nih.gov ~?.pBlair, K. Marsh, A. A. Morton, J. Vythilingam, M. Jones, M. Mondillo, K. Pine, D. C. Drevets, W. C. Blair, J. R.2006Choosing the lesser of two evils, the better of two goods: specifying the roles of ventromedial prefrontal cortex and dorsal anterior cingulate in object choice 11379-11386Journal of Neuroscience2644Nov-The ventromedial prefrontal cortex (vmPFC) and dorsal anterior cingulate cortices (ACd) are considered important for reward-based decision making. However, work distinguishing their individual functional contributions has only begun. One aspect of decision making that has received little attention is that making the right choice often translates to making the better choice. Thus, response choice often occurs in situations where both options are desirable (e. g., choosing between mousse au chocolat or creme caramel cheesecake from a menu) or, alternatively, in situations where both options are undesirable. Moreover, response choice is easier when the reinforcements associated with the objects are far apart, rather than close together, in value. We used functional magnetic resonance imaging to delineate the functional roles of the vmPFC and ACd by investigating these two aspects of decision making: (1) decision form (i.e., choosing between two objects to gain the greater reward or the lesser punishment), and (2) between-object reinforcement distance (i.e., the difference in reinforcements associated with the two objects). Blood oxygen level-dependent (BOLD) responses within the ACd and vmPFC were both related to decision form but differentially. Whereas ACd showed greater responses when deciding between objects to gain the lesser punishment, vmPFC showed greater responses when deciding between objects to gain the greater reward. Moreover, vmPFC was sensitive to reinforcement expectations associated with both the chosen and the forgone choice. In contrast, BOLD responses within ACd, but not vmPFC, related to between-object reinforcement distance, increasing as the distance between the reinforcements of the two objects decreased. These data are interpreted with reference to models of ACd and vmPFC functioning.://000241727500017 Times Cited: 0ISI:000241727500017NIMH, Mood & Anxiety Disorders Program, NIH, US Dept HHS, Bethesda, MD 20892 USA. Univ Coll London, Inst Cognit Neurosci, London WC1X 8EE, England. Blair, K, NIMH, Mood & Anxiety Disorders Program, NIH, US Dept HHS, 15K North Dr,MSC 2670, Bethesda, MD 20892 USA. blairka@mail.nih.gov~?/5Buchsbaum, B. R. Greer, S. Chang, W. L. Berman, K. F.2005`Meta-analysis of neuroimaging studies of the Wisconsin card-sorting task and component processes35-45Human Brain Mapping251MaywA quantitative meta-analysis using the activation likelihood estimation (ALE) method was used to investigate the brain basis of the Wisconsin Card-Sorting Task (WCST) and two hypothesized component processes, task switching and response suppression. All three meta-analyses revealed distributed frontoparietal activation patterns consistent with the status of the WCST as an attention-demanding executive task. The WCST was associated with extensive bilateral clusters of reliable cross-study activity in the lateral prefrontal cortex, anterior cingulate cortex, and inferior parietal lobule. Task switching revealed a similar, although less robust, frontoparietal pattern with additional clusters of activity in the opercular region of the ventral prefrontal cortex, bilaterally. Response-suppression tasks, represented by studies of the go/no-go paradigm, showed a large and highly right-lateralized region of activity in the right prefrontal cortex. The activation patterns are interpreted as reflecting a neural fractionation of the cognitive components that must be integrated during the performance of the WCST. (c) 2005 Wiley-Liss, Inc.://000228759600004 Times Cited: 8ISI:000228759600004ANIMH, Unit Integrat Neuroimaging, Clin Brain Disorders Branch, NIH,IRP,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. Buchsbaum, BR, NIMH, Unit Integrat Neuroimaging, Clin Brain Disorders Branch, NIH,IRP,Dept Hlth & Human Serv, 9000 Rockville Pike,Bldg 10,Room 4C-101, Bethesda, MD 20892 USA. buchsbab@intra.nimh.nih.gov~?04Buchsbaum, B. R. Olsen, R. K. Koch, P. Berman, K. F.2005tHuman dorsal and ventral auditory streams subserve rehearsal-based and echoic processes during verbal working memory687-697Neuron484NovjTo hear a sequence of words and repeat them requires sensory-motor processing and something more-temporary storage. We investigated neural mechanisms of verbal memory by using fMRI and a task designed to tease apart perceptually based ("echoic") memory from phonological-articulatory memory. Sets of two- or three-word pairs were presented bimodally, followed by a cue indicating from which modality (auditory or visual) items were to be retrieved and rehearsed over a delay. Although delay-period activation in the planum temporale (PT) was insensible to the source modality and showed sustained delay-period activity, the superior temporal gyrus (STG) activated more vigorously when the retrieved items had arrived to the auditory modality and showed transient delay-period activity. Functional connectivity analysis revealed two topographically distinct fronto-temporal circuits, with STG coactivating more strongly with ventrolateral prefrontal cortex and PT coactivating more strongly with dorsolateral prefrontal cortex. These argue for separate contributions of ventral and dorsal auditory streams in verbal working memory.://000233677300020 Times Cited: 1ISI:000233677300020<NIMH, Sect Integrat Neuroimaging, Clin Brain Disorders Branch,Dept Hlth & Human Ser, NIH,Intramural Res Program, Bethesda, MD 20892 USA. Buchsbaum, BR, NIMH, Sect Integrat Neuroimaging, Clin Brain Disorders Branch,Dept Hlth & Human Ser, NIH,Intramural Res Program, Bethesda, MD 20892 USA. buchsbab@intra.nimh.nih.gov~?1QBuchsbaum, B. R. Olsen, R. K. Koch, P. F. Kohn, P. Kippenhan, J. S. Berman, K. F.2005*Reading, hearing, and the planum temporale444-454 Neuroimage242JanNMany neuroimaging studies of single-word reading have been carried out over the last 15 years, and a consensus as to the brain regions relevant to this task has emerged. Surprisingly, the planum temporale (PT) does not appear among the catalog of consistently active regions in these investigations. Recently, however, several studies have offered evidence suggesting that the left posteromedial PT plays a role in both speech production and speech perception. It is not clear, then, why so many neuroimaging studies of single-word reading - a task requiring speech production - have tended not to rind evidence of PT involvement. In the present work, we employed a high-powered rapid event-related fMRI paradigm involving both single pseudoword reading and single pseudoword listening to assess activity related to reading and speech perception in the PT as a function of the degree of spatial smoothing applied to the functional images. We show that the speech area of the PT [Sylvian-parietal-temporal (Spt)] is best identified when only a moderate (5 mm) amount of spatial smoothing is applied to the data before statistical analysis. Moreover, increasing the smoothing window to 10 turn obliterates activation in the PT, suggesting that failure to find PT activation in past studies may relate to this factor. (C) 2004 Elsevier Inc. All rights reserved.://000226454500017 Times Cited: 3ISI:000226454500017.NIMH, NIH, Dept Hlth & Human Serv, Unit Integrat Neuroimaging,Clin Brain Disorders B, Bethesda, MD 20892 USA. Buchsbaum, BR, NIMH, NIH, Dept Hlth & Human Serv, Unit Integrat Neuroimaging,Clin Brain Disorders B, IRP,9000 Rockville Pike,Bldg 10,Room 4C-101, Bethesda, MD 20892 USA. brad.buchsbaum@nih.gov~?2Dreher, J. C. Berman, K. F.2002AFractionating the neural substrate of cognitive control processes 14595-14600OProceedings of the National Academy of Sciences of the United States of America9922OctPsychological and neurobiological theories of cognitive control must account for flexible, seemless transitions among cognitive operations. When subjects switch between tasks, they must both inhibit the previous task and re-engage in a different task. Inhibition of the disengaged task remains active for a period of time and has to be overcome when re-engaging in the same task. Here we used a task-switching paradigm that allows distinction of two control processes: overcoming the inhibition of a previously performed task when re-engaging it and restarting a sequence of tasks after a period of interruption. Behaviorally, these processes were reflected in the facts that: (i) switching to a recently performed task, that is thus unlikely to have fully recovered from inhibition, takes longer than switching to a task less recently performed and (ii) re-engaging in a sequence of tasks after a period of interruption transiently increases response time. Using event-related functional MRI, we found that these two behavioral effects were accompanied by a double dissociation: the right lateral prefrontal cortex was more activated when switching to a task recently performed compared to a task less recently performed, while the anterior cingulate cortex was recruited when a sequence of tasks was initiated. These results provide insights into the functional organization of the frontal lobe in humans and its role in distinct processes involved in cognitive control.://000178967400111 Times Cited: 38ISI:000178967400111NIMH, Clin Brain Disorders Branch, Unit Integrat Neuroimaging, Intramural Res Program,NIH, Bethesda, MD 20892 USA. Dreher, JC, NIMH, Clin Brain Disorders Branch, Unit Integrat Neuroimaging, Intramural Res Program,NIH, Bethesda, MD 20892 USA.~?3$Dreher, J. C. Kohn, P. Berman, K. F.2006PNeural coding of distinct statistical properties of reward information in humans561-573Cerebral Cortex164AprBrain processing of reward information is essential for complex functions such as learning and motivation. Recent primate electrophysiological studies using concepts from information, economic and learning theories indicate that the midbrain may code two statistical parameters of reward information: a transient reward error prediction signal that varies linearly with reward probability and a sustained signal that varies highly non-linearly with reward probability and that is highest with maximal reward uncertainty (reward probability = 0.5). Here, using event-related functional magnetic resonance imaging, we disentangled these two signals in humans using a novel paradigm that systematically varied monetary reward probability, magnitude and expected reward value. The midbrain was activated both transiently with the error prediction signal and in a sustained fashion with reward uncertainty. Moreover, distinct activity dynamics were observed in post-synaptic midbrain projection sites: the prefrontal cortex responded to the transient error prediction signal while the ventral striatum covaried with the sustained reward uncertainty signal. These data suggest that the prefrontal cortex may generate the reward prediction while the ventral striatum may be involved in motivational processes that are useful when an organism needs to obtain more information about its environment. Our results indicate that distinct functional brain networks code different aspects of the statistical properties of reward information in humans.://000235922200013 Times Cited: 2ISI:000235922200013NIMH, Unit Integrat Neuroimaging, Clin Brain Disorders Branch, NIH, Bethesda, MD USA. Dreher, JC, Univ Lyon 1, CNRS, Inst Cognit Sci, 67 Bd Pinel, F-69675 Bron, France. dreher@isc.cnrs.fr?4QDreher, J. C. Schmidt, J.C. Kohn, P. Furman, D. C. Rubinow, D. R. Berman, K. F.2007GMenstrual cycle phase modulates reward-related neural function in women 2465-2470OProceedings of the National Academy of Sciences of the United States of America104 ~?5bKippenhan, J. S. Olsen, R. K. Mervis, C. B. Morris, C. A. Kohn, P. Lindenberg, A. M. Berman, K. F.2005TGenetic contributions to human gyrification: Sulcal morphometry in Williams syndrome 7840-7846Journal of Neuroscience2534AugAlthough gyral and sulcal patterns are highly heritable, and emerge in a tightly controlled sequence during development, very little is known about specific genetic contributions to abnormal gyrification or the resulting functional consequences. Williams syndrome (WS), a genetic disorder caused by hemizygous microdeletion on chromosome 7q11.23 and characterized by abnormal brain structure and striking cognitive ( impairment in visuospatial construction) and behavioral (hypersocial/anxious) phenotypes, offers a unique opportunity to study these issues. We performed a detailed analysis of sulcal depth based on geometric cortical surface representations constructed from high-resolution magnetic resonance imaging scans acquired from participants with WS and from healthy controls who were matched for age, sex, and intelligence quotient, and compared between-group differences with those obtained from a voxel-based morphometry analysis. We found bilateral reductions in sulcal depth in the intraparietal/occipitoparietal sulcus ( PS) in the brains of participants with WS, as well as in the collateral sulcus and the orbitofrontal region in the left hemisphere. The left-hemisphere PS in the WS group averaged 8.5mm shallower than in controls. Sulcal depth findings in the PS corresponded closely to measures of reduced gray matter volume in the same area, providing evidence that the gray matter volume loss and abnormal sulcal geometry may be related. In the context of previous functional neuroimaging findings demonstrating functional alterations in the same cortical regions, our results further define the neural endophenotype underlying visuoconstructive deficits in WS, set the stage for defining the effects of specific genes, and offer insight into genetic mechanisms of cortical gyrification.://000231439300016 Times Cited: 8ISI:000231439300016NIMH, Sect Integrat Neuroimaging, Clin Brain Disorders Branch, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. Univ Louisville, Dept Psychol & Brain Sci, Neurodev Sci Lab, Louisville, KY 40292 USA. Univ Nevada, Sch Med, Dept Pediat, Las Vegas, NV 89102 USA. Kippenhan, JS, NIMH, Sect Integrat Neuroimaging, Clin Brain Disorders Branch, NIH,Dept Hlth & Human Serv, Bldg 10,Room 4C101, Bethesda, MD 20892 USA. shane_kippenhan@nih.govF?6Marenco, S. Siuta, M Kippenhan, J. S. Grodofsy, S. Chang, W. L. Kohn, P. Mervis, C. B. Morris, C. A. Weinberger, D. R. Meyer-Lindenberg, A. Pierpaoli, C. Berman, K. F.2007kGenetic contributions to white matter architecture revealedby diffusion tensor imaging in Williams syndromeOProceedings of the National Academy of Sciences of the United States of Americain press?7fMeyer-Lindenberg, A. Hariri, A. R. Munuz, K.E. Mervis, C. B. Mattay, V. S. Morris, C. A. Berman, K. F.2005NNeural correlates of genetically abnormal socialcognition in Williams syndrome991-993Nature Neuroscience8r~?8eMeyer-Lindenberg, A. Kohn, P. Mervis, C. B. Kippenhan, J. S. Olsen, R. K. Morris, C. A. Berman, K. F.2004]Neural basis of genetically determined visuospatial construction deficit in Williams syndrome623-631Neuron435SepjA unique opportunity to understand genetic determinants of cognition is offered by Williams syndrome (WS), a well-characterized hemideletion on chromosome 7q11.23 that causes extreme, specific weakness in visuospatial construction (the ability to visualize an object as a set of parts or construct a replica). Using multimodal neuroimaging, we identified a neural mechanism underlying the WS visuoconstructive deficit. Hierarchical assessment of visual processing with fMRI showed isolated hypoactivation in WS in the parietal portion of the dorsal stream. In the immediately adjacent parietooccipital/intraparietat sulcus, structural neuroimaging showed a gray matter volume reduction in participants with WS. Path analysis demonstrated that the functional abnormalities could be attributed to impaired input from this structurally altered region. Our observations confirm a longstanding hypothesis about dorsal stream dysfunction in WS, demonstrate effects of a localized abnormality on visual information processing in humans, and define a systems-level phenotype for mapping genetic determinants of visuoconstructive function.://000223691900009 Times Cited: 27ISI:000223691900009NIMH, Unit Integrat Neuroimaging, Clin Brain Disorders Branch, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. Univ Louisville, Neurodev Sci Lab, Dept Psychol & Brain Sci, Louisville, KY 40292 USA. Univ Nevada, Sch Med, Dept Pediat, Las Vegas, NV 89102 USA. Meyer-Lindenberg, A, NIMH, Unit Integrat Neuroimaging, Clin Brain Disorders Branch, NIH,Dept Hlth & Human Serv, 10-4C101,9000 Rockville Pike, Bethesda, MD 20892 USA. andreasml@nih.gov?90Meyer-Lindenberg, A. Mervis, C. B. Berman, K. F.2006gNeural mechanisms of Williams syndrome: a unique window to genetic influences on cognition and behavior561-573Nature Reviews Neuroscience16|Lun Disorders Branch, NIH, Dept Hlth & Human Serv,Gene Cognit & Psychosis Pr, Bethesda, MD 20892 USA. Univ Bari, Dept Neurol & Psychiat Sci, Neurosci Psychiat Grp, I-70124 Bari, Italy. Ist Ricovero & Cura Carattere Sci Casa Sollievo S, Dept Neuroradiol, I-71013 San Giovanni Rotondo, Italy. Weinberger, DR, NIMH, Clin Brain Disorders Branch, NIH, Dept Hlth & Human Serv,Gene Cognit & Psychosis Pr, Bldg 10,Ctr Dr,Room 4S-235, Bethesda, MD 20892 USA. weinberd@mail.nih.govPsw0ckholtz, J. Callicott, J. H. Kolachana, B. Hariri, A. Goldberg, T. E. Genderson, M. Egan, M. Mattay, V. Weinberger, D. R. Meyer-Lindenberg, A.in press{Genetic variation in MAOA modulates ventromedial prefrontal circuitry mediating individual differences in human personalityMolecular Psychiatryluxckholtz, J. Meyer-Lindenberg, A. Honea, R. Straub, R. E. Pezawas, L. Egan, M. Vakkalanka, R. K. Kolachana, B. Verchinksi, B. Sust, S. Mattay, V. Weinberger, D. R. Callicott, J. H.2007]Allelic variation in RGS4 impacts functional and structural connectivity in the human brain. 1584-1593Journal of Neuroscience277w0zckholtz, J. Sust, S. Tan, H. Y. Mattay, V. Straub, R. E. Meyer-Lindenberg, A. Weinberger, D. R. Callicott, J. H.in press<fMRI evidence for functional epistasis between COMT and RGS4Molecular Psychiatry ?sCallicott, J. H. Bertolino, A. Mattay, V. Langheim, F. J. P. Duyn, J. Coppola, R. Goldberg, T. E. Weinberger, D. R.2000[Physiological dysfunction of the dorsolateral prefrontal cortex in schizophrenia revisited. 1078-1092Cerebral Cortex10lxeCallicott, J. H. Egan, M. F. Mattay, V. S. Bertolino, A. Bone, A. D. Verchinksi, B. Weinberger, D. R.2003zAbnormal fMRI response of the dorsolateral prefrontal cortex in cognitively intact siblings of patients with schizophrenia709-719American Journal of Psychiatry1604AprObjective: The identification of neurobiological intermediate phenotypes may hasten the search for susceptibility genes in complex psychiatric disorders such as schizophrenia. Earlier family studies have suggested that deficits in executive cognition0|Ls: 18ISI:000229203600016?;XMeyer-Lindenberg, A. Olsen, R. K. Kohn, P.D. Egan, M. F. Weinberger, D. R. Berman, K. F.2005oRegionally specific disturbance of dorsolateral prefrontal-hippocampal functional connectivity in schizophrenia379-386Archives of General Psychiatry62 ~?<fMeyer-Lindenberg, A. Poline, J. B. Kohn, P. D. Holt, J. L. Egan, M. F. Weinberger, D. R. Berman, K. F.2001]Evidence for abnormal cortical functional connectivity during working memory in schizophrenia 1809-1817American Journal of Psychiatry15811NovObjective: Disturbed neuronal interactions may be involved in schizophrenia because it is without clear regional pathology. Aberrant connectivity is further suggested by theoretical formulations and neurochemical and neuroanatomical data. The authors applied to schizophrenia a recently available functional neuroimaging analytic method that permits characterization of cooperative action on the systems level. Method: Thirteen medication-free patients and 13 matched healthy comparison subjects performed a working memory (n-back) task and sensorimotor baseline task during positron emission tomography. "Functional connectivity" patterns, reflecting distributed correlated activity that differed most between groups, were extracted by a canonical variates analysis. Results: More than half the variance was explained by a single pattern showing inferotemporal, (para-)hippocampal, and cerebellar loadings for patients versus dorsolateral prefrontal and anterior cingulate activity for comparison subjects. Expression of this pattern perfectly separated all patient scans from comparison scans, thus showing promise as a trait marker. This result was validated prospectively by successfully classifying unrelated scans from the same patients and data from a new cohort. An additional 19% of variance corresponded to the pattern activated by the working memory task. Expression of this pattern was more variable in patients during working memory but not the control condition, suggesting inability to sustain a task-adequate neural network, consistent with the disconnection hypothesis. Conclusions: Pronounced disruptions of distributed cooperative activity in schizophrenia were found. A pattern showing disturbed frontotemporal interactions showed promise as a trait marker and may be useful for future investigations.://000171946300007 Times Cited: 104ISI:000171946300007$NIH, Unit Integrat Neuroimaging, Intramural Res Program, Bethesda, MD 20892 USA. CEA, Serv Hosp Frederic Joliot, Dept Rech Med, F-91406 Orsay, France. Meyer-Lindenberg, A, NIH, Unit Integrat Neuroimaging, Intramural Res Program, Bldg 10,Room 4C101,9000 Rockville Pike, Bethesda, MD 20892 USA.~?=MPierpaoli, C. Barnett, A. Pajevic, S. Chen, R. Penix, L. Virta, A. Basser, P.2001cWater diffusion changes in Wallerian degeneration and their dependence on white matter architecture 1174-1185 Neuroimage136JunThis study investigates water diffusion changes in Wallerian degeneration. We measured indices derived from the diffusion tensor (DT) and TB-weighted signal intensities in the descending motor pathways of patients with small chronic lacunar infarcts of the posterior limb of the internal capsule on one side. We compared these measurements in the healthy and lesioned sides at different levels in the brainstem caudal to the primary lesion. We found that secondary white matter degeneration is revealed by a large reduction in diffusion anisotropy only in regions where fibers are arranged in isolated bundles of parallel fibers, such as in the cerebral peduncle. In regions where the degenerated pathway crosses other tracts, such as in the rostral pens, paradoxically there is almost no change in diffusion anisotropy, but a significant change in the measured orientation of fibers. The trace of the diffusion tensor is moderately increased in all affected regions. This allows one to differentiate secondary and primary fiber loss where the increase in trace is considerably higher. We show that DT-MRI is more sensitive than TS-weighted MRI in detecting Wallerian degeneration. Significant diffusion abnormalities are observed over the entire trajectory of the affected pathway in each patient. This finding suggests that mapping degenerated pathways noninvasively with DT-MRI is feasible. However, the interpretation of water diffusion data is complex and requires a priori information about anatomy and architecture of the pathway under investigation. In particular, our study shows that in regions where fibers cross, existing DT-MRI-based fiber tractography algorithms may lead to erroneous conclusion about brain connectivity.://000169056500023 Times Cited: 129 Part 1ISI:000169056500023NICHHD, NIH, Bethesda, MD 20892 USA. NIMH, NIH, Bethesda, MD 20892 USA. NINDS, NIH, Bethesda, MD 20892 USA. NIH, Ctr Informat Technol, Bethesda, MD 20892 USA. Pierpaoli, C, NICHHD, NIH, Bethesda, MD 20892 USA.~?>Basser, P. J. Jones, D. K.2002XDiffusion-tensor MRI: theory, experimental design and data analysis - a technical review456-467Nmr in Biomedicine157-8Nov-DecThis article treats the theoretical underpinnings of diffusion-tensor magnetic resonance imaging (DT-MRI), as well as experimental design and data analysis issues. We review the mathematical model underlying DT-MRI, discuss the quantitative parameters that are derived from the measured effective diffusion tensor, and describe artifacts thet arise in typical DT-MRI acquisitions. We also discuss difficulties in identifying appropriate models to describe water diffusion in heterogeneous tissues, as well as in interpreting experimental data obtained in such issues. Finally, we describe new statistical methods that have been developed to analyse DT-MRI data, and their potential uses in clinical and multi-site studies. Copyright (C) 2002 John Wiley Sons, Ltd.://000180166100003 Times Cited: 76ISI:000180166100003NICHD, Sect Tissue Biophys & Biomimet, NIH, Bethesda, MD 20892 USA. Inst Psychiat, Sect Old Psychiat, London, England. Basser, PJ, NICHD, Sect Tissue Biophys & Biomimet, NIH, Bethesda, MD 20892 USA.~??Pajevic, S. Basser, P. J.2003AParametric and non-parametric statistical analysis of DT-MRI data1-14Journal of Magnetic Resonance1611MarjIn this work parametric and non-parametric statistical methods are proposed to analyze Diffusion Tensor Magnetic Resonance Imaging (DT-MRI) data. A Multivariate Normal Distribution is proposed as a parametric statistical model of diffusion tensor data when magnitude MR images contain no artifacts other than Johnson noise. We test this model using Monte Carlo (MC) simulations of DT-MRI experiments. The non-parametric approach proposed here is an implementation of bootstrap methodology that we call the DT-MRI bootstrap. It is used to estimate an empirical probability distribution of experimental DT-MRI data, and to perform hypothesis tests on them. The DT-MRI bootstrap is also used to obtain various statistics of DT-MRI parameters within a single voxel, and within a region of interest (ROI); we also use the bootstrap to study the intrinsic variability of these parameters in the ROI, independent of background noise. We evaluate the DT-MRI bootstrap using MC simulations and apply it to DT-MRI data acquired on human brain in vivo, and on a phantom with uniform diffusion properties. Published by Elsevier Science (USA).://000182051900001 Times Cited: 22ISI:0001820519000015NICHHD, Sect Tissue Biophys & Biomimet, Lab Integrat & Med Biophys, NIH, Bethesda, MD 20892 USA. NIH, Math & Stat Comp Lab, Ctr Informat Technol, Bethesda, MD 20892 USA. Basser, PJ, NICHHD, Sect Tissue Biophys & Biomimet, Lab Integrat & Med Biophys, NIH, 13 South Dr,Bldg 13,Room 3W16, Bethesda, MD 20892 USA.n~?@Bandettini, P. A. Cox, R. W.2000]Event-related fMRI contrast when using constant interstimulus interval: Theory and experiment540-548Magnetic Resonance in Medicine434AprEvent-related functional magnetic resonance imaging (ER-fMRI) involves the mapping of averaged hemodynamic changes resulting from repeated, brief (<3 sec) brain activation episodes. In this paper, two issues regarding constant-interstimulus interval ER-fMRI were addressed. First, the optimal interstimulus interval (ISI), given a stimulus duration (SD), was determined. Second, the statistical power of ER-fMRI relative to that of a blocked-design paradigm was determined. Experimentally, it was found that with a 2-sec SD, the optimal ISI is 12 to 14 sec. Theoretically, the optimal repetition interval (T-opt = ISI + SD) is 12 to 14 sec for stimuli of 2 sec or less, for longer stimuli, T-opt is 8 + 2 SD. At the optimal ISI for SD = 2 sec, the experimentally determined functional contrast of ER-fMRI was only -35% lower than that of blocked-design fMRI. Simulations that assumed a linear system demonstrated an event-related functional contrast that was -65% lower than that of the blocked design. These differences between simulated and experimental contrast suggest that the ER-fMRI amplitude is greater than that predicted by a linear shift-invariant system. (C) 2000 Wiley-Liss, Inc.://000086214400008 Times Cited: 65ISI:000086214400008Med Coll Wisconsin, Biophys Res Inst, Milwaukee, WI 53226 USA. Bandettini, PA, NIMH, Lab Brain & Cognit, NIH, Bldg 10,Room 4C104,10 Ctr Dr,MSC 1366, Bethesda, MD 20892 USA.,oDrabant, E. M. Hariri, A. Meyer-Lindenberg, A. Munoz, K. E. Mattay, V. Kolachana, B. Egan, M. Weinberger, D. R.2006sCatechol O-methyltran DISC1 affects hippocampal structure and function and increases risk for schizophrenia. 8627-8632OProceedings of the National Academy of Sciences of the United States of America10224et genotype and neural mechanisms related to affective arousal and regulation. 1396-1406Arch Gen Psychiatry63,QyEgan, M. F. Goldberg, T. E. Kolachana, B. S. Callicott, J. H. Mazzanti, C. M. Straub, R. E. Goldman, D. Weinberger, D/?C$Bandettini, P. A. Ungerleider, L. G.2001$From neuron to BOLD: New connections864-866Nature Neuroscience49]http://www.scopus.com/scopus/inward/record.url?eid=2-s2.0-0034873064&partnerID=40&rel=R6.5.0 DCited By (since 1996): 36 Export Date: 14 August 2007 Source: Scopus_~?D)Birn, R. M. Saad, Z. S. Bandettini, P. A.2001ISpatial heterogeneity of the nonlinear dynamics in the FMRI BOLD response817-826 Neuroimage144OctRecent studies of blood oxygenation level dependent (BOLD) signal responses averaged over a region of interest have demonstrated that the response is nonlinear with respect to stimulus duration. Specifically, shorter duration stimuli produce signal changes larger than expected from a linear system. The focus of this study is to characterize the spatial heterogeneity of this nonlinear effect. A series of MR images of the visual and motor cortexes were acquired during visual stimulation and finger tapping, respectively, at five different stimulus durations (SD). The nonlinearity was assessed by fitting ideal linear responses to the responses at each SD. This amplitude, which is constant for different SD in a linear system, was normalized by the amplitude of the response to a blocked design, thus describing the amount by which the stimulus is larger than predicted from a linear extrapolation of the response to the long duration stimulus. The amplitude of the BOLD response showed a nonlinear behavior that varied considerably and consistently over space, ranging from almost linear to 10 times larger than a linear prediction at short SD. In the motor cortex different nonlinear behavior was found in the primary and supplementary motor cortexes.://000171329800003 Times Cited: 39ISI:000171329800003wNIMH, Lab Brain & Cognit, NIH, Bethesda, MD 20892 USA. Birn, RM, NIMH, Lab Brain & Cognit, NIH, Bethesda, MD 20892 USA.p \92 USA. CallP zophrenia are not reducible to simply too much or too little activity but, rather, reflect a compromised neural strategy for handling information mediated by the dorsolateral prefrontal cortex.://000186881900021 Times Cited: 56ISI:000186881900021NIMH, Clin Brain Disorders Branch, NIH, Bethesd?FwBarbier, E. L. Marrett, S. Danek, A. Vortmeyer, A. Van Gelderen, P. Duyn, J. Bandettini, P. Grafman, J. Koretsky, A. P.2002lImaging cortical anatomy by high-resolution MR at 3.0T: Detection of the stripe of Gennari in visual area 17735-738Magnetic Resonance in Medicine484]http://www.scopus.com/scopus/inward/record.url?eid=2-s2.0-0036787435&partnerID=40&rel=R6.5.0 DCited By (since 1996): 28 Export Date: 14 August 2007 Source: Scopus~?G(Birn, R. M. Cox, R. W. Bandettini, P. A.2002WDetection versus estimation in event-related fMRI: Choosing the optimal stimulus timing252-264 Neuroimage151JanWith the advent of event-related paradigms in functional MRI, there has been interest in finding the optimal stimulus timing, especially when the interstimulus interval is varied during the imaging run. Previous works have proposed stimulus timings to optimize either the estimation of the impulse response function (IRF) or the detection of signal changes. The purpose of this paper is to clarify that estimation and detection are fundamentally different goals and to determine the optimal stimulus timing and distribution with respect to both the accuracy of estimating the IRF and the power of detection assuming a particular hemodynamic model. Simulated stimulus distributions are varied systematically, from traditional blocked designs to rapidly varying event related designs. These simulations indicate that estimation of the hemodynamic impulse response function is optimized when stimuli are frequently alternated between task and control states, with shorter interstimulus intervals and stimulus durations, whereas the detection of activated areas is optimized by blocked designs. The stimulus timing for a given experiment should therefore be generated with the required detectability and estimation accuracy. (C) 2002 Elsevier Science.://000173174900025 Times Cited: 27ISI:000173174900025NIMH, 3T Funct Neuroimaging Core, Bethesda, MD 20892 USA. NIMH, Sci & Stat Comp Core, Bethesda, MD 20892 USA. Birn, RM, NIMH, 3T Funct Neuroimaging Core, Bethesda, MD 20892 USA.~?HBodurka, J. Bandettini, P. A.2002iToward direct mapping of neuronal activity: MRI detection of ultraweak, transient magnetic fields changes 1052-1058Magnetic Resonance in Medicine476JunA novel method based on selective detection of rapidly changing DeltaB(o), magnetic fields and suppression of slowly changing DeltaB(o), fields is presented. The ultimate goal of this work is to present a method that may allow detection of transient and subtle changes in B-o in cortical tissue associated with electrical currents produced by neuronal activity. The method involves the detection of NMR phase changes that occur during a single-shot spin-echo (SE) echo-planar sequence (EPI) echo time. SE EPI effectively rephases all changes in B-o that occur on a time scale longer than the echo time (TE) and amplifies all DeltaB(o) changes that occur during TE/2. The method was tested on a phantom that contains wires in which current can be modulated. The sensitivity and flexibility of the technique was demonstrated by modulation of the temporal position and duration of the stimuli-evoked transient magnetic field relative to the 180 RF pulse in the imaging sequence-requiring precise stimulus timing. Currently, with this method magnetic field changes as small as 2 x 10(-10) T (200 pT) and lasting for 40 msec can be detected. Implications for direct mapping of brain neuronal activity with MRI are discussed.://000175935100002 Times Cited: 37ISI:000175935100002 NIMH, Telsa Funct Neuroimaging Facil 3, NIH, Bethesda, MD 20892 USA. NIMH, Lab Brain & Cognit, Unit Funct Imaging Methods, NIH, Bethesda, MD 20892 USA. Bodurka, J, NIMH, Telsa Funct Neuroimaging Facil 3, NIH, Bldg 10,Rm 1D80,10 Ctr Dr,MSC 1148, Bethesda, MD 20892 USA. dies find too little activation and others too much. The authors' goal was to explore this phenomenon. Method: They used the N-back working memory task and functional magnetic resonance imaging at 3 T to examine a group of 14 patients with schizophrenia and a matched comparison group of 14 healthy subjects. Results: Patients' performance was significantly worse |?J8Patterson Ii, J. C. Ungerleider, L. G. Bandettini, P. A.2002cTask-independent functional brain activity correlation with skin conductance changes: An fMRI study 1797-1806 NeuroImage174]http://www.scopus.com/scopus/inward/record.url?eid=2-s2.0-0036939697&partnerID=40&rel=R6.5.0 DCited By (since 1996): 30 Export Date: 14 August 2007 Source: Scopus~?K5Patterson, J. C. Ungerleider, L. G. Bandettini, P. A.2002cTask-independent functional brain activity correlation with skin conductance changes: an fMRI study 1797-1806 Neuroimage174Dec=Lesions of the ventromedial prefrontal cortex cause a loss of skin conductance response (SCR) to stimuli with affective content and an inability to integrate information with social consequences into decisions. Previous behavioral studies using a gambling task were able to differentiate patients with lesions in this region from normal subjects. In the present imaging study, this region, among others, was shown to be "spontaneously" activated during three different cognitive states: a gambling task, a working memory task, and resting state. SCR data were simultaneously collected during the scanning process. Six subjects were scanned at 1.5 T during all three states, and one subject was scanned at 3 T during the resting state only. SCR data were used as a reference function for correlation analysis with the fMRI time series during each of the three tasks. SCR changes were evident during the gambling and two-back tasks as well as during rest. SCR activity was not observed to be specifically related to reward-based decisions in the gambling task. Correlation of the fMRI time series directly with the SCR data revealed a consistent set of activated regions. The activity of these regions showing correlation with the SCR appeared independent of the cognitive state. Further, the subject scanned only at rest (without the possible confound of task-related carryover activity) replicated the findings in the original six subjects. From these data, SCR appears to be a marker of a network that is active during, but independent of, the task being studied. (C) 2002 Elsevier Science (USA).://000179969800013 Times Cited: 19ISI:000179969800013NIMH, Lab Brain & Cognit, Bethesda, MD 20892 USA. Patterson, JC, Louisiana State Univ, Ctr Hlth Sci, Inst Biomed Res, PET Imaging Ctr, 1505 Kings Highway, Shreveport, LA 71130 USA.f?L7Pessoa, L. Gutierrez, E. Bandettini, P. Ungerleider, L.2002TNeural correlates of visual working memory: fMRI amplitude predicts task performance975-987Neuron355]http://www.scopus.com/scopus/inward/record.url?eid=2-s2.0-0037194739&partnerID=40&rel=R6.5.0 DCited By (since 1996): 58 Export Date: 14 August 2007 Source: Scopusx Clin Brain Disorders Branch, NIH, Bldg 10,Rm 4D-20,MSC 1389, Bethesda, MD 20892 USA.\Callicott, J. H. Straub, R. E. Pezawas, L. Egan, M. Mattay, V. Hariri, A. Verchinksi, B. Meyer-Lindenberg, A. Balkissoon, R. Kolachana, B. Goldberg, T. E. Weinberger, D. R.20~?N1Bellgowan, P. S. F. Saad, Z. S. Bandettini, P. A.2003|Understanding neural system dynamics through task modulation and measurement of functional MRI amplitude, latency, and width 1415-1419OProceedings of the National Academy of Sciences of the United States of America1003FebEstimates of hemodynamic amplitude, delay, and width were combined to investigate system dynamics involved in lexical decision making. Subjects performed a lexical decision task using word and nonword stimuli rotated 0degrees, 60degrees, or 120degrees. Averaged hemodynamic responses to repeated stimulation were fit to a Gamma-variate function convolved with a heavyside function of varying onset and duration to estimate each voxel's activation delay and width. Consistent with prolonged reaction times for the rotated stimuli and nonwords, the motor cortex showed delayed hemodynamic onset for both conditions. Language areas such as the lingual gyrus, middle temporal gyrus, fusiform gyrus, and precuneus all showed delayed hemodynamic onsets to rotated stimuli but not to nonword stimuli. The inferior frontal gyrus showed both increased onset latency for rotated stimuli and a wider hemodynamic response to nonwords, consistent with prolonged processing in this area during the lexical decision task. Phonological processing areas such as superior temporal and angular gyrus showed no delay or width difference for rotated stimuli. These results suggest that phonological routes but not semantic routes to the lexicon can proceed regardless of stimulus orientation. This study demonstrates the utility of estimating hemodynamic delay and width in addition to amplitude allowing for more quantitative measures of brain function such as mental chronometry.://000180838100115 Times Cited: 18ISI:000180838100115NIMH, Lab Brain & Cognit, Bethesda, MD 20892 USA. NIMH, Sci & Stat Comp Core, Bethesda, MD 20892 USA. Bellgowan, PSF, NIMH, Lab Brain & Cognit, Bethesda, MD 20892 USA.~?O-Knight, D. C. Nguyen, H. T. Bandettini, P. A.20039Expression of conditional fear with and without awareness 15280-15283OProceedings of the National Academy of Sciences of the United States of America10025DecConditional responding during simple Pavlovian conditioning is often characterized as a form of implicit memory. The extent to which this type of associative learning is independent of awareness is an issue of continuing debate. Previous studies have demonstrated conditioning in the absence of awareness. However, their results have been questioned based on methodological concerns with postexperimental questionnaires. In the present study, skin conductance response (SCR) and unconditioned stimulus (UCS) expectancy were measured concurrently as participants were exposed to a differential delay fear conditioning procedure in which one tone (CS+) predicted a loud white noise, whereas a second tone (CS-) was presented alone. UCS predictability was varied on a trial-by-trial basis by presenting conditioned stimuli (CSs) at volumes just above or below the perceptual threshold. Differential UCS expectancy (awareness) was observed only on perceived trials, whereas differential SCR developed on both perceived and unperceived trials. Although perceived stimuli elicited larger SCRs, the magnitude of conditioning, indexed by differential conditioned response expression (conditioned SCR to CS+ minus the SCR to CS-), was not influenced by stimulus perception. These data indicate that conditional fear can be expressed when individuals are unaware of fear-eliciting stimuli and suggest that the degree of conditioning is independent of awareness during differential Pavlovian fear conditioning.://000187227200120 Times Cited: 10ISI:000187227200120oNIMH, Lab Brain & Cognit, Bethesda, MD 20892 USA. Knight, DC, NIMH, Lab Brain & Cognit, Bethesda, MD 20892 USA. S~?P9Saad, Z. S. Ropella, K. M. DeYoe, E. A. Bandettini, P. A.2003'The spatial extent of the BOLD response132-144 Neuroimage191May%Functional magnetic resonance imaging is routinely used to localize brain function, with multiple brain scans averaged together to reveal activation volumes. In this study, we examine the seldom-studied effect of multiple scan averaging on the extent of activation volume. Using restricted visual field stimulation, we obtained a large number of scan repetitions and analyzed changes in activation volume with progressively increased averaging and across single scans. Activation volume increased monotonically with averaging and failed to asymptote when as many as 22 scans were averaged together. Expansions in the spatial extent of activation were not random; rather, they were centered about activation loci that appear with little or no averaging. Using empirical and simulated data, changes with averaging in activation volumes and cross correlation coefficient distributions revealed the presence of considerably more activated voxels than commonly surmised. Many voxels have low SNR and remain undetected without extensive averaging. The primary source of such voxels was not downstream venous drainage since there was no significant and consistent delay difference between voxels activated at different averaging levels. Voxels with low SNR may reflect a diffuse subthreshold activity centered about spiking neurons, dephasing gradients from distal veins, or simply a blood flow response extending beyond the locus of neuronal firing. Across single scans, as much as twofold changes in activation volume were observed. These changes were not correlated with the order of scan acquisition, subject task performance, or signal and noise properties of activated voxels. Instead, they may reflect subtle changes between overlapping noise and signal frequency components. (C) 2003 Elsevier Science (USA). All rights reserved.://000183236600011 Times Cited: 15ISI:000183236600011ANIMH, Stat & Sci Comp Core, Lab Brain & Cognit, NIH, Bethesda, MD 20892 USA. Marquette Univ, Dept Biomed Engn, Milwaukee, WI 53233 USA. Med Coll Wisconsin, Dept Cell Biol Neurobiol & Anat, Milwaukee, WI 53226 USA. Saad, ZS, NIMH, Stat & Sci Comp Core, Lab Brain & Cognit, NIH, 10 Ctr Dr,room 1D80, Bethesda, MD 20892 USA.~?Q(Birn, R. M. Cox, R. W. Bandettini, P. A.2004`Experimental designs and processing strategies for fMRI studies involving overt verbal responses 1046-1058 Neuroimage233NovEvent-related paradigms have been used increasingly in the past few years for the localization of function in tasks involving overt speech. These designs exploit the differences in the temporal characteristics between the rapid motion-induced and the slower hemodynamic signal changes. The optimization of these designs and the best way to analyze the acquired data has not yet been fully explored. The purpose of this study is to investigate various design and analysis strategies for maximizing the detection of function while minimizing task-induced motion artifacts. Both event-related and blocked paradigms can be specifically designed to meet these goals. Various event-related and blocked designs were compared both in simulation and in experiments involving overt word reading in their ability to detect function and to avoid speech-induced motion artifact. A blocked design with task and control durations of 10 s and an event-related design with a minimum stimulus duration (SD) of 5 s and an average interstimulus interval (ISI) of 10 s were found to optimally detect blood oxygenation leveldependent signal changes without significant motion artifact. Ignoring images acquired during the speech can help recover function in areas particularly affected by motion but substantially reduces the detection power in other regions. Using the stimulus timing as an additional regressor to model the motion offers little benefit in practice due to the variability of the motion-induced signal change. Published by Elsevier Inc.://000225254100027 Times Cited: 7ISI:000225254100027NIMH, Lab Brain & Cognit, Bethesda, MD 20892 USA. Birn, RM, NIMH, Lab Brain & Cognit, 10 Ctr Dr Bldg 10,Room 1D80, Bethesda, MD 20892 USA. rbim@nih.govhzLing memory may be related to genetic susceptibility for schizophrenia, but the biological basis for this behavioral phenotype has not been identified. Method: The authors used functional magnetic resonance imaging (fMRI) during performance of the N-back working memory task to assess working memory-related cortical physiology in nonschizop $~?S*Bandettini, P. A. Petridou, N. Bodurka, J.2005QDirect detection of neuronal activity with MRI: Fantasy, possibility, or reality?65-88Applied Magnetic Resonance291Hemodynamic-based functional magnetic resonance imaging (fMRI) techniques have proven to be extremely robust and sensitive methods for noninvasive detection and mapping of human brain activation. Nevertheless, limitations in temporal and spatial resolution as well as interpretation remain because hemodynamic changes accompanying brain activation are relatively sluggish and variable and therefore imprecise measures of neuronal activity. A hope among brain imagers would be to possess a technique that would allow direct mapping of brain activity with spatial resolution on the order of a cortical column and temporal resolution on the order of an action potential or at least a postsynaptic potential. Recent efforts in understanding the direct effects of neuronal activity on MRI signal have provided some degree of hope for those who want a more precise noninvasive brain activation mapping technique than fMRI as we know it now. While the manner in which electrical currents influence MRI signal is well understood, the manner in which neuronal firing spatially and temporally integrates on the spatial scale of an MRI voxel to pro duce a magnetic field shift and subsequently an NMR phase and/or magnitude change is not well understood. It is also not established that this field shift would be large or long enough in duration to be detected. The objective of this paper is to provide a perspective of the work that has been performed towards the direction of achieving direct neuronal current imaging with MRI. A specific goal is to further clarify what is understood about the theoretical and practical possibilities of neuronal current imaging. Specifically discussed are modeling efforts, phantom studies, in vitro studies, and human studies.://000232323600005 Times Cited: 2ISI:000232323600005;NIMH, Unit Funct Imaging Methods, Funct MRI Facil, NIH, Bethesda, MD 20892 USA. NIMH, Unit Funct Imaging Methods, Lab Brain & Cognit, NIH, Bethesda, MD 20892 USA. Bandettini, PA, NIMH, Unit Funct Imaging Methods, Funct MRI Facil, NIH, Bldg 10,Room 1D80,10 Ctr Dr,MSC 1148, Bethesda, MD 20892 USA. bandettini@nih.gova~?TBirn, R. M. Bandettini, P. A.2005OThe effect of stimulus duty cycle and "off" duration on BOLD response linearity70-82 Neuroimage271AugAn ongoing question in functional MRI is precisely how measured signal changes relate to neuronal activity. While this question has been probed using animal models and electrophysiologic measures of neuronal activity, it has also been probed by examining, in humans, the spatial location, magnitude, and temporal dynamics of signal changes to well understood stimuli. With regard to dynamics, several earlier studies have revealed a larger than expected response to brief stimuli, hypothesized to result from nonlinearities in either the hemodynamics or the neuronal activity. In this study, we investigate the linearity of the increase in blood oxygenation level dependent (BOLD) contrast as a function of stimulus duty cycle, as well as the linearity of the decrease in BOLD as a function stimulus "off" duration. These findings not only shed further light on the mechanisms behind BOLD contrast but also give practical information as to what to keep in mind when performing and interpreting event related fMRI experiments. These experiments demonstrated: a) the BOLD signal decrease, on stimulus cessation, was smaller than predicted by a linear system-opposite to what has been reported in the literature associated with a signal increase, and b) the deconvolved event-related BOLD signal is highly dependent on duty cycle (the fraction of time activated vs. non-activated), Several potential mechanisms explaining these dynamics are discussed and modeled. We find that the experimental results are most consistent with a nonlinear neuronal response, but do not rule out significant effects of nonlinear hemodynamic factors, in particular the nonlinear relationship between oxygen extraction fraction and blood flow. Published by Elsevier Inc.://000230701200007 Times Cited: 1ISI:000230701200007NIMH, Lab Brain & Cognit, Bethesda, MD 20892 USA. Birn, RM, NIMH, Lab Brain & Cognit, 10 Ctr Dr,Bldg 10,Room 1D80, Bethesda, MD 20892 USA. rbirn@nih.govD~?U-Knight, D. C. Nguyen, H. T. Bandettini, P. A.2005NThe role of the human amygdala in the production of conditioned fear responses 1193-1200 Neuroimage264JullThe amygdala plays a central role in the acquisition and expression of fear memories. Laboratory animal studies indicate that the amygdala both receives sensory information and produces learned behavioral and autonomic fear responses. However, prior functional imaging research in humans has largely focused on amygdala activity elicited by fearful stimuli giving less attention to this region's role in the production of fear responses. In contrast, the present study used functional magnetic resonance imaging to investigate the amygdala's influence on the generation of conditional fear responses. Significant increases in amygdala activity were observed during the production of conditioned (learning-related), but not orienting, nonspecific, and unconditioned (nonlearning-related) skin conductance responses. Further, greater amygdala activity was demonstrated during conditioned response production than during conditioned stimulus presentation. These results suggest the amygdala not only responds to fearful stimuli, but also generates learning-related changes in human autonomic fear expression. Published by Elsevier Inc.://000230071300023 Times Cited: 5ISI:000230071300023NIMH, Unit Funct Imaging Methods, Lab Brain & Cognit, Bethesda, MD 20892 USA. Knight, DC, NIMH, Unit Funct Imaging Methods, Lab Brain & Cognit, Bldg 10,Room 1D80, Bethesda, MD 20892 USA. knightd@mail.nih.govicient prefrontal information processing will increase risk for schizophrenia.://000182096300019 Times Cited: 57ISI:000182096300019NIMH, Clin Brain Disorders Branch, IRP, NIH, Bethesda, MD 20892 USA. Callicott, JH, NIMH, Clin Brain Disorders Branch, IRP, NIH, Bldg 10,Ctr Dr,Rm 4D-20 MSC1389, BethHLognitively intact siblings of patients with schizophrenia. They compared 23 unaffected siblings of schizophrenic patients to 18 matched comparison subjects. As a planned replication, they studied another 25 unaffected siblings and 15 comparison subjects. Results: In both cohorts, there were no group differences in working memory performance. Nevertheless, both groups of siblings showed an exaggerated physiological response in the right dorsolateral prefrontal cortex that was qualitatively similar to results of earlier fMRI studies of patients with schizophrenia. Conclusions: These fMRI data provide direct evidence of a primary physiological abnormality in dorsolateral prefrontal cortex function in individuals at greater genetic risk for schizophrenia, even in the absence of a manifest cognitive abnormality. This exaggerated fMRI response implicates inefficient processing of memory information at the level of intrinsic prefrontal circuitry, similar to earlier findings in patients with schizophrenia. These data predict that inheritance of alleles that contributePnce on the N-back working memory task is similar to that of healthy comparison subjects use greater prefrontal resources but achieve lower accuracy (i.e., inefficiency) and that other patients with schizophrenia fail to sustain the prefrontal network that processes the information, achieving even lower accuracy as a result. These findings add to other evidence that abnormalities of prefrontal cortical functio o-back working memory task than that of healthy subjects. However, there were areas within the dorsolateral prefrontal cortex of the patients that were more active and areas that were less active than those of the healthy subjects. When the groups were subdivided on the basis of performance on the working memory task into healthy subjects and patients with high or low performance, locales of greater prefrontal activation and locales of less activation were found in the high-performing patients but only locales of underactivation were found in the low-performing patients. Conclusions: These findings suggest that patients with schizophrenia whose?X9Birn, R. M. Diamond, J. B. Smith, M. A. Bandettini, P. A.2006iSeparating respiratory-variation-related fluctuations from neuronal-activity-related fluctuations in fMRI 1536-1548 NeuroImage314^http://www.scopus.com/scopus/inward/record.url?eid=2-s2.0-33746852686&partnerID=40&rel=R6.5.0 CCited By (since 1996): 9 Export Date: 14 August 2007 Source: Scopus$LSA.ԄZCallicott, J. H. Mattay, V. S. Verchinski, B. A. Marenco, S. Egan, M. F. Weinberger, D. R.2003TComplexity of prefrontal cortical dysfunction in schizophrenia: More than up or down 2209-2215American Journal of Psychiatry16012Dec5Objective: Numerous neuroimaging studies have examined the function of the dorsolateral prefrontal cortex in schizophrenia; although abnormalities usually are identified, it is unclear why?ZIlles, J. Kirschen, M. P. Edwards, E. Stanford, L. R. Bandettini, P. Cho, M. K. Ford, P. J. Glover, G. H. Kulynych, J. Macklin, R. Michael, D. B. Wolf, S. M.2006-Incidental findings in brain imaging research783-784Science3115762^http://www.scopus.com/scopus/inward/record.url?eid=2-s2.0-32444440079&partnerID=40&rel=R6.5.0 DCited By (since 1996): 11 Export Date: 14 August 2007 Source: Scopus\?[-Knight, D. C. Nguyen, H. T. Bandettini, P. A.2006DThe role of awareness in delay and trace fear conditioning in humans157-1620Cognitive, Affective and Behavioral Neuroscience62^http://www.scopus.com/scopus/inward/record.url?eid=2-s2.0-33748451366&partnerID=40&rel=R6.5.0 *Export Date: 14 August 2007 Source: Scopus~?\*Kriegeskorte, N. Goebel, R. Bandettini, P.2006*Information-based functional brain mapping 3863-3868OProceedings of the National Academy of Sciences of the United States of America10310MarYThe development of high-resolution neuroimaging and multielectrode electrophysiological recording provides neuroscientists with huge amounts of multivariate data. The complexity of the data creates a need for statistical summary, but the local averaging standardly applied to this end may obscure the effects of greatest neuroscientific interest. In neuroimaging, for example, brain mapping analysis has focused on the discovery of activation, i.e., of extended brain regions whose average activity changes across experimental conditions. Here we propose to ask a more general question of the data: Where in the brain does the activity pattern contain information about the experimental condition? To address this question, we propose scanning the imaged volume with a "searchlight," whose contents are analyzed multivariately at each location in the brain.://000236225300065 Times Cited: 3ISI:0002362253000658NIMH, Sect Funct Imaging Methods, Lab Brain & Cognit, Bethesda, MD 20892 USA. Univ Maastricht, Fac Psychol, Dept Cognit Neurosci, NL-6229 ER Maastricht, Netherlands. Kriegeskorte, N, NIMH, Sect Funct Imaging Methods, Lab Brain & Cognit, Bldg 10,Room 1D80B,10 Ctr Dr MSC 1148, Bethesda, MD 20892 USA. niko@nih.govD~?]JPetridou, N. Plenz, D. Silva, A. C. Loew, M. Bodurka, J. Bandettini, P. A.2006CDirect magnetic resonance detection of neuronal electrical activity 16015-16020OProceedings of the National Academy of Sciences of the United States of America10343OctPresent noninvasive neuroimaging methods measure neuronal activity indirectly, via either cerebrovascular changes or extracranial measurements of electrical/magnetic signals. Recent studies have shown evidence that MRI may be used to directly and noninvasively map electrical activity associated with human brain activation, but results are inconclusive. Here, we show that MRI can detect cortical electrical activity directly. We use organotypic rat-brain cultures in vitro that are spontaneously active in the absence of a cerebrovascular system. Single-voxel magnetic resonance (MR) measurements obtained at 7 T were highly correlated with multi-site extracellular local field potential recordings of the same cultures before and after blockade of neuronal activity with tetrodotoxin. Similarly, for MR images obtained at 3 T, the MR signal changed solely in voxels containing the culture, thus allowing the spatial localization of the active neuronal tissue.://000241568500052 Times Cited: 0ISI:000241568500052Sect Funct Imaging Methods, Lab Brain & Cognit, NIH, Bethesda, MD 20892 USA. Lab Syst Neurosci, Neural Network Physiol Unit, NIH, Bethesda, MD 20892 USA. NIMH, Funct MRI Facil, NIH, Bethesda, MD 20892 USA. Natl Inst Neurol Disorders & Stroke, Cerebral Microcirculat Unit, Lab Funct & Mol Imaging, NIH, Bethesda, MD 20892 USA. George Washington Univ, Dept Elect & Comp Engn, Inst Med Imaging & Image Anal, Washington, DC 20052 USA. Bandettini, PA, Sect Funct Imaging Methods, Lab Brain & Cognit, NIH, Bethesda, MD 20892 USA. bandettini@nih.gov ?^Bandettini, P.2007Functional MRI today138-145)International Journal of Psychophysiology632^http://www.scopus.com/scopus/inward/record.url?eid=2-s2.0-33846250878&partnerID=40&rel=R6.5.0 CCited By (since 1996): 1 Export Date: 14 August 2007 Source: Scopusg?_<Bodurka, J. Ye, F. Petridou, N. Murphy, K. Bandettini, P. A.2007eMapping the MRI voxel volume in which thermal noise matches physiological noise-Implications for fMRI542-549 NeuroImage342^http://www.scopus.com/scopus/inward/record.url?eid=2-s2.0-33751459532&partnerID=40&rel=R6.5.0 *Export Date: 14 August 2007 Source: Scopus?`QMaieron, M. Iannetti, G. D. Bodurka, J. Tracey, I. Bandettini, P. A. Porro, C. A.2007yFunctional responses in the human spinal cord during willed motor actions: Evidence for side- and rate-dependent activity 4182-4190Journal of Neuroscience2715^http://www.scopus.com/scopus/inward/record.url?eid=2-s2.0-34247099877&partnerID=40&rel=R6.5.0 *Export Date: 14 August 2007 Source: ScopusX?a(Murphy, K. Bodurka, J. Bandettini, P. A.2007jHow long to scan? The relationship between fMRI temporal signal to noise ratio and necessary scan duration565-574 NeuroImage342^http://www.scopus.com/scopus/inward/record.url?eid=2-s2.0-33751497550&partnerID=40&rel=R6.5.0 *Export Date: 14 August 2007 Source: Scopus4 receptor, clinical outcome, and cortical structure in attention-deficit/hyperactivity disorder.921-931Archives of General Psychiatry648*tamura, M. Elvevag, B. Blasi, G. Bertolino, A. Callicott, J. H. Weinberger, D. R. Mattay, V. Goldberg, T. E.2007SDissociating the effects of Sternberg working memory demands in prefrontal cortex. 103-114Psychiatry Research1542(ǠzApud, J.A. Mattay, V. Chen, J. Kolachana, B. Callicott, J. H. Rasetti, R. Alce, G. Iudicello, J.E. Akbar, N. Egan, M. Goldberg, T. E. Weinberger, D. R.2007ZTolcapone improves cpN+H98 USA. Egan, MF, NIMH, Clin Brain Disorders Branch, Bldg 10,Ctr Dr, Bethesda, MD 20892 USA.$*1lan, M. F. Kojima, M. Callicott, J. H. Goldberg, T. E. Kolachana, B. S. Bertolino, A. Zaitsev, E. Gold, B. Goldman, D. Dean, M. Lu, B. Weinberger, D. R.2003uThe BDNF val66met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function257-269Cell1122JanBrain-derived neurotrophic factor (BDNF) modulates hippocampal plasticity and hippocampal-dependent memory in cell models and in animals. We examined the effects of a valine (val) to methionine (met) substitution in the 5' pro-region of the human BDNF protein. In human subjects, the met allele was associated with poorer episodic memory, abnormal hippocampal activation assayed with fMRI, and lower hippocampal n-acetyl aspartate (NAA), assayed with MRI spectroscopy. Neurons transfected with met-BDNF-GFP showed lower depolarization-induced secretion, while constitutive secretion was unchanged. Furthermore, met-BDNF-GFP failed to localize to secretory granules or synapses. These results demonstrate a role for BDNF://000181191600014 Times Cited: 284ISI:000181191600014NICHHD, Sect Neural Dev & Plast, NIH, DHHS, Bethesda, MD 20892 USA. NIMH, Clin Brain Disorders Branch, Bethesda, MD 20892 USA. NIAAA, Neurogenet Lab, Rockville, MD 20857 USA. NCI, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. Natl Inst AIST, Cell Dynam Res Grp, Osaka 5638577, Japan. Japan Sci & Technol Corp, CREST, Kawaguchi 3320012, Japan. Lu, B, NICHHD, Sect Neural Dev & Plast, NIH, DHHS, Bldg 49-6A67, Bethesda, MD 20892 USA. +H://000223596200039 Times Cited: 34ISI:000223596200039NIMH, Clin Brain Disorders Branch, Intramural Res Program, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. Baylor Coll Med, Dept Mol & Human Genet, Human Genome Sequencing Ctr, Houston, TX 77030 USA. Univ Bari, Clin Psichiatr 2, I-70121 Bari, Italy. ES Cell Int Pte Ltd, Melbourne, Vic 8008, Australia. Weinberger, DR, NIMH, Clin Brain Disorders Branch, Intramural Res Program, NIH,Dept Hlth & Human Serv, Bldg 10,Ctr Dr,Room 45-227,MSC 1384, Bethesda, MD 20892 USA. weinberd@intra.nimh.nih.gov81l=ra, F. Weickert, T. Goldberg, T. E. Tessitore, A. Hariri, A. Das, S. Lee, S. Zoltick, B. Meeter, M. Myers, C. E. Gluck, M. A. Weinberger, D. R. Mattay, V.2005MNeural mechanisms underlying probabilistic category learning in normal aging. 11340-11348Journal of Neuroscience2549 ://000239920400019 Times Cited: 0ISI:000239920400019NIMH, Clin Brain Disorders Branch, IRP, NIH, Bethesda, MD USA. Goldberg, TE, Hillside Hosp, Div Psychiat Res, 75 59 263rd St, Glen Oaks, NY 11004 USA. tgoldber@nshs.edu=Hriri, A. Drabant, E. M. Munoz, K. E. Kolachana, B. Mattay, V. Egan, M. Weinberger, D. R.2005WA susceptibility gene for affective disorders and the response of the human amygdala. 142-152Arch Gen Psychiatry622GIxriri, A. Mattay, V. Tessitore, A. Kolachana, B. Fera, F. Goldman, D. Egan, M. Weinberger, D. R.2002OSerotonin transporter genetic variation and the response of the human amygdala.400-403Science297,HQriri, A. R. Goldberg, T. E. Mattay, V. S. Kolachana, B. S. Callicott, J. H. Egan, M. F. Weinberger, D. R.2003Brain-derived neurotrophic factor val(66)met polymorphism affects human memory-related hippocampal activity and predicts memory performance 6690-6694Journal of Neuroscience2317JulBDNF plays a critical role in activity-dependent neuroplasticity underlying learning and memory in the hippocampus. A frequent single nucleotide polymorphism in the targeting region of the human BDNF gene (val (66)met) has been associated with abnormal intracellular trafficking and regulated secretion of BDNF in cultured hippocampal neurons transfected with the met allele. In addition, the met allele has been associated with abnormal hippocampal neuronal function as well as impaired episodic memory in human subjects, but a direct effect of BDNF alleles on hippocampal processing of memory has not been demonstrated. We studied the relationship of the BDNF val (66)met genotype and hippocampal activity during episodic memory processing using blood oxygenation level-dependent functional magnetic resonance imaging and a declarative memory task in healthy individuals. Met carriers exhibited relatively diminished hippocampal engagement in comparison with val homozygotes during both encoding and retrieval processes. Remarkably, the interaction between the BDNF val (66)met genotype and the hippocampal response during encoding accounted for 25% of the total variation in recognition memory performance. These data implicate a specific genetic mechanism for substantial normal variation in human declarative memory and suggest that the basic effects of BDNF signaling on hippocampal function in experimental animals are important in humans.://000184469200003 Times Cited: 90ISI:000184469200003NIMH, Clin Brain Disorders Branch, Intramural Res Program, NIH,US Dept HHS, Bethesda, MD 20892 USA. Weinberger, DR, NIMH, Clin Brain Disorders Branch, Intramural Res Program, NIH,US Dept HHS, 10 Ctr Dr,Room 4S235, Bethesda, MD 20892 USA.(IxWriri, A. R. Mattay, V. S. Tessitore, A. Fera, F. Smith, W. G. Weinberger, D. R.2002>Dextroamphetamine modulates the response of the human amygdala 1036-1040Neuropsychopharmacology276Dec(Amphetamine, a potent monoaminergic agonist, has pronounced effects on emotional behavior in humans, including the generation of fear and anxiety. Recent animal studies have demonstrated the importance of monoamines, especially dopamine, in modulating the response of the amygdala, a key brain region involved in the perception of fearful and threatening stimuli, and the generation of appropriate physiological and behavioral responses. We have explored the possibility that the anxiogenic effect of amphetamine in humans reflects the drug's influence on the activity of the amygdala. In a double-blind placebo controlled study, fMRI revealed that dextroamphetamine potentiated the response of the amygdala during the perceptual processing of angry and fearful facial expressions. Our results provide the first evidence of a specific neural substrate for the anxiogenic effects of amphetamine and are consistent with animal models of dopaminergic activation of the amygdala. (C) 2002 American College of Neuropsychopharmacology. Published by Elsevier Science Inc.://000179156900015 Times Cited: 23ISI:000179156900015NIMH, Clin Brain Disorders Branch, Intramural Res Program, NIH, Bethesda, MD 20892 USA. Hariri, AR, NIMH, Clin Brain Disorders Branch, Intramural Res Program, NIH, 10 Ctr Dr,Room 3C108, Bethesda, MD 20892 USA.Q`hriri, A. R. Mattay, V. S. Tessitore, A. Fera, F. Weinberger, D. R.2003BNeocortical modulation of the amygdala response to fearful stimuli494-501Biological Psychiatry536Mar{Background: The cortical circuitry involved in conscious cognitive processes and the subcortical circuitry involved in fear responses have been extensively studied with neuroimaging, but their interactions remain largely unexplored. A recent functional magnetic resonance imaging (fMRI) study demonstrated that the engagement of the right prefrontal cortex during the cognitive evaluation of angry and fearful facial expressions is associated with an attenuation of the response of the amygdala to these same stimuli, providing evidence for a functional neural network for emotional regulation. Methods: In the current study, we have explored the generalizability of this functional network by using threatening and fearful non-face stimuli derived from the International Affective Picture System (IAPS), as well as the influence of this network on peripheral autonomic responses. Results: Similar to the earlier findings with facial expressions, blood oxygen level dependent fMRI revealed that whereas perceptual processing of IAPS stimuli was associated with a bilateral amygdala response, cognitive evaluation of these same stimuli was associated with attenuation of this amygdala response and a correlated increase in response of the right prefrontal cortex and the anterior cingulate cortex. Moreover, this pattern was reflected in changes in skin conductance. Conclusions: The current results further implicate the importance of neocortical regions, including the prefrontal and anterior cingulate cortices, in regulating emotional responses mediated by the amygdala through conscious evaluation and appraisal. (C) 2003 Society of Biological Psychiatry.://000181569900004 Times Cited: 90ISI:000181569900004NIMH, Clin Brain Disorders Branch, Intramural Res Program, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. Hariri, AR, NIMH, Clin Brain Disorders Branch, Intramural Res Program, NIH,Dept Hlth & Human Serv, 10 Ctr Dr,Rm 3C108, Bethesda, MD 20892 USA.,Wgriri, A. R. Tessitore, A. Mattay, V. S. Fera, F. Weinberger, D. R.2002LThe amygdala response to emotional stimuli: A comparison of faces and scenes317-323 Neuroimage171SepPAs a central fear processor of the brain, the amygdala initiates a cascade of critical physiological and behavioral responses. Neuroimaging studies have shown that the human amygdala responds not only to fearful and angry facial expressions but also to fearful and threatening scenes such as attacks, explosions, and mutilations. Given the relative importance of facial expressions in adaptive social behavior, we hypothesized that the human amygdala would exhibit a stronger response to angry and fearful facial expressions in comparison to other fearful and threatening stimuli. Twelve subjects completed two tasks while undergoing fMRI: matching angry or fearful facial expressions, and matching scenes depicting fearful or threatening situations derived from the International Affective Picture System (IAPS). While there was an amygdala response to both facial expressions and IAPS stimuli, direct comparison revealed that the amygdala response to facial expressions was significantly greater than that to IAPS stimuli. Autonomic reactivity, measured by skin conductance responses, was also greater to facial expressions. These results suggest that the human amygdala shows a stronger response to affective facial expressions than to scenes, a bias that should be considered in the design of experimental paradigms interested in probing amygdala function.://000178102000023 Times Cited: 63ISI:000178102000023NIMH, Clin Brain Disorders Branch, Intramural Res Program, NIH, Bethesda, MD 20892 USA. Hariri, AR, NIMH, Clin Brain Disorders Branch, Intramural Res Program, NIH, Bethesda, MD 20892 USA.`hmhriri, A. R. Weinberger, D. R.2003Imaging genomics259-270British Medical Bulletin65;The recent completion of a working draft of the human genome sequence promises to provide unprecedented opportunities to explore the genetic basis of individual differences in complex behaviours and vulnerability to neuropsychiatric illness. Functional neuroimaging, because of its unique ability to assay information processing at the level of brain within individuals, provides a powerful approach to such functional genomics. Recent fMRI studies have established important physiological links between functional genetic polymorphisms and robust differences in information processing within distinct brain regions and circuits that have been linked to the manifestation of various disease states such as Alzheimer's disease, schizophrenia and anxiety disorders. Importantly, all of these biological relationships have been revealed in relatively small samples of healthy volunteers and in the absence of observable differences at the level of behaviour, underscoring the power of a direct assay of brain physiology like fMRI in exploring the functional impact of genetic variation.://000182080300019 Times Cited: 47ISI:000182080300019NIMH, Clin Brain Disorders Branch, Intramural Res Program, NIH, Bethesda, MD 20892 USA. Weinberger, DR, NIMH, Clin Brain Disorders Branch, Intramural Res Program, NIH, 10 Ctr Dr,Room 4S235, Bethesda, MD 20892 USA.guinz, A. Romero, B. Gallinat, J. Juckel, G. Weinberger, D. R.2003JMolecular brain imaging and the neurobiology and genetics of schizophrenia S152-S157Pharmacopsychiatry36NovIt has been hypothesized that schizophrenia is related to dysfunction in temporolimbic-prefrontal neuronal networks, which is acquired early in an individual's development. After puberty, relatively reduced prefrontal control of striatal dopaminergic neurotransmission may lead to unmodulated striatal dopamine (DA) activity, and the positive symptoms of acute psychosis. Brain imaging studies support the notion of prefrontal dysfunction in schizophrenia and correlated upregulation of presynaptic striatal DA activity. Recent molecular brain imaging studies have combined genetic assessments with a multimodal neuroimaging approach to further refine our understanding of the pathophysiologic architecture of the disorder. We review the literature on functional brain imaging in schizophrenia and discuss genotype effects on core psychotic symptoms. A promising research strategy is the identification of genetic and environmental factors that contribute to intermediate phenotypes such as working memory deficits in schizophrenia. Molecular brain imaging can help to unravel the complex interactions between genes and environment and its association with neuronal network dysfunction in schizophrenia.://000188081200002 Times Cited: 6 Suppl. 3ISI:000188081200002Charite Univ Med Berlin, Dept Psychiat & Psychotherapy, D-10117 Berlin, Germany. NIMH, Clin Brain Disorders Branch, NIH, Bethesda, MD 20892 USA. Heinz, A, Charite Univ Med Berlin, Dept Psychiat & Psychotherapy, CCM, Schumannstr 20-21, D-10117 Berlin, Germany. andreas.heinz@charite.de/?Heinz, A. Smolka, M. N. Braus, D. F. Wrase, J. Beck, A. Flor, H. Mann, K. Schumann, G. Buchel, C. Hariri, A. Weinberger, D. R.2007nSerotonin transporter genotype (5-HTTLPR): Effects of neutral and undefined conditions on amygdala activation. 1011-1014Biological Psychiatry61Pmhvea, R. Meyer-Lindenberg, A. Hobbs, K. B. Pezawas, L. Mattay, V. Egan, M. Verchinksi, B. Passingham, R. E. Weinberger, D. R. Callicott, J. H.in pressIs gray matter volume an intermediate phenotype for schizophrenia? A VBM study of patients with schizophrenia and their healthy siblings.Biological Psychiatryu|utson, B. Bjork, J. M. Fong, G. W. Hommer, D. Mattay, V. S. Weinberger, D. R.20040Amphetamine modulates human incentive processing261-269Neuron432JulResearch suggests that psychostimulants can physiologically alter dopamine kinetics in the ventral striatum (VS) and psychologically enhance mood and attention. Using event-related functional magnetic resonance imaging (fMRI), we conducted a within-subject, double-blind, placebo (PLAC)-controlled study of the effects of oral dextroamphetamine (AMPH, 0.25 mg/kg) treatment on brain activity and affect during incentive processing. In two counterbalanced scanning sessions 60-180 min after ingesting AMPH or PLAC, 8 healthy volunteers played a game involving anticipation and receipt of monetary gains and losses. Group and volume of interest analyses suggested that by enhancing tonic over phasic activation, AMPH treatment "equalized" levels of VS activity and positive arousal during anticipation of both gain and loss. These findings suggest that therapeutic effects of amphetamine on incentive processing may involve reducing the difference between anticipation of gains and losses.://000222905400014 Times Cited: 11ISI:000222905400014Stanford Univ, Dept Psychol, Stanford, CA 94305 USA. NIAAA, Clin Studies Lab, Bethesda, MD 20892 USA. NIMH, Clin Brain Disorders Branch, Bethesda, MD 20892 USA. Knutson, B, Stanford Univ, Dept Psychol, Stanford, CA 94305 USA. knutson@psych.stanford.eduv@gheim, F. J. P. Callicott, J. H. Mattay, V. S. Duyn, J. H. Weinberger, D. R.20027Cortical systems associated with covert music rehearsal901-908 Neuroimage164AugMusical representation and overt music production are necessarily complex cognitive phenomena. While overt musical performance may be observed and studied, the act of performance itself necessarily skews results toward the importance of primary sensorimotor and auditory cortices. However, imagined musical performance (IMP) represents a complex behavioral task involving components suited to exploring the physiological underpinnings of musical cognition in music performance without the sensorimotor and auditory confounds of overt performance. We mapped the blood oxygenation level-dependent fMRI activation response associated with IMP in experienced musicians independent of the piece imagined. IMP consistently activated supplementary motor and premotor areas, right superior parietal lobule, right inferior frontal gyrus, bilateral mid-frontal gyri, and bilateral lateral cerebellum in contrast with rest, in a manner distinct from fingertapping versus rest and passive listening to the same piece versus rest. These data implicate an associative network independent of primary sensorimotor and auditory activity, likely representing the cortical elements most intimately linked to music production.://000177444900005 Times Cited: 13ISI:000177444900005NIMH, Intramural Res Program, Clin Brain Disorders Branch, NIH, Bethesda, MD 20892 USA. NINDS, Lab Funct & Mol Imaging, IRP, NIH, Bethesda, MD 20892 USA. Callicott, JH, NIMH, Intramural Res Program, Clin Brain Disorders Branch, NIH, Bethesda, MD 20892 USA.?+Marenco, S. Bertolino, A. Weinberger, D. R.2006BIn vivo NMR measures of NAA and the neurobiology of schizophrenia.227-240Adv Exp Med Biol576|renco, S. Rawlings, R. Rohde, G. K. Barnett, A. S. Hone, R. A. Pierpaoli, C. Weinberger, D. R.2006FRegional distribution of measurement error in diffusion tensor imaging69-78 Psychiatry Research-Neuroimaging1471JunnThe characterization of measurement error is critical in assessing the significance of diffusion tensor imaging (DTI) findings in longitudinal and cohort studies of psychiatric disorders. We studied 20 healthy volunteers, each one scanned twice (average interval between scans of 51 +/- 46.8 days) with a single shot echo planar DTI technique. Intersession variability for fractional anisotropy (FA) and Trace (D) was represented as absolute variation (standard deviation within subjects: SDw), percent coefficient of variation (CV) and intraclass correlation coefficient (ICC). The values from the two sessions were compared for statistical significance with repeated measures analysis of variance or a non-parametric equivalent of a paired t-test. The results showed good reproducibility for both FA and Trace (CVs below 10% and ICCs at or above 0.70 in most regions of interest) and evidence of systematic global changes in Trace between scans. The regional distribution of reproducibility described here has implications for the interpretation of regional findings and for rigorous preprocessing. The regional distribution of reproducibility measures was different for SDw, CV and ICC. Each one of these measures reveals complementary information that needs to be taken into consideration when performing statistical operations on groups of DT images. Published by Elsevier Ireland Ltd.://000239973800006 Times Cited: 0ISI:000239973800006aNIMH, CBDB, Genes Cognit & Psychosis Program, IRP, Bethesda, MD 20892 USA. NIAAA, Sect Brain Electrophysiol & Imaging, LCS, IRP, Bethesda, MD USA. NICHD, Sect Tissue Biophys & Biomimet, LIMB, IRP, Bethesda, MD USA. Marenco, S, NIMH, CBDB, Genes Cognit & Psychosis Program, IRP, 10 Ctr Dr,Bldg 10,Room 4S235, Bethesda, MD 20892 USA. marencos@mail.nih.gov ?_Marenco, S. Steele, S. Egan, M. Goldberg, T. E. Straub, R. E. Sharrief, A. Z. Weinberger, D. R.2006xEffect of metabotropic glutamate receptor 3 genotype on N-acetylaspartate measures in the dorsolateral prefrontal cortex740-742American Journal of Psychiatry163?}Mattay, V. Callicott, J. H. Bertolino, A. Heaton, I. Frank, J. A. Coppola, R. Berman, K. F. Goldberg, T. E. Weinberger, D. R.2000OEffects of dextroamphetamine on cognitive performance and cortical activation. 268-275 Neuroimage12@tay, V. Tessitore, A. Callicott, J. H. Bertolino, A. Goldberg, T. E. Chase, T. N. Hyde, T. M. Weinberger, D. R.2002S Dopaminergic modulation of cortical function in patients with Parkinson's disease.156-164 Ann Neurol512 Lttay, V. S. Fera, F. Tessitore, A. Hariri, A. R. Berman, K. F. Das, S. Meyer-Lindenberg, A. Goldberg, T. E. Callicott, J. H. Weinberger, D. R.2006ONeurophysiological correlates of age-related changes in working memory capacity32-37Neuroscience Letters3921-2JanCognitive abilities such as working memory (WM) capacity decrease with age. To determine the neurophysiological, correlates of age-related reduction in working memory capacity, we studied 10 young subjects (<35 years of age; mean age = 29) and twelve older subjects (>55 years of age; mean age = 59) with whole brain blood oxygenation-level dependent (BOLD) fMRI on a 1.5 T GE MR scanner using a SPIRAL FLASH pulse sequence (TE = 24 ms, TR = 56 ms, FA = 60 degrees, voxel dimensions = 3.75 mm(3)). Subjects performed a modified version of the "n" back working memory task at different levels of increasing working memory load (I-Back, 2-Back and 3-Back). Older subjects performed as well as the younger subjects at 1-Back (p = 0.4), but performed worse than the younger subjects at 2-Back (p < 0.01) and 3-Back (p = 0.06). Older subjects had significantly longer reaction time (RT) than younger subjects (p < 0.04) at all levels of task difficulty. Image analysis using SPM 99 revealed a similar distribution of cortical activity between younger and older subjects at all task levels. However, an analysis of variance revealed a significant group x task interaction in the prefrontal cortex bilaterally; within working memory capacity, as in I-Back when the older subjects performed as well as the younger subjects, they showed greater prefrontal cortical (BA 9) activity bilaterally. At higher working memory loads, however, when they performed worse then the younger subjects, the older subjects showed relatively reduced activity in these prefrontal regions. These data suggest that, within capacity, compensatory mechanisms such as additional prefrontal cortical activity are called upon to maintain proficiency in task performance. As cognitive demand increases, however, they are pushed past a threshold beyond which physiological compensation cannot be made and, a decline in performance occurs. (C) 2005 Elsevier Ireland Ltd. All rights reserved.://000234268400007 Times Cited: 3ISI:000234268400007NIMH, Clin Brain Disorders Branch, Cognit & Psychosis Program, NIH, Bethesda, MD 20892 USA. Mattay, VS, Bldg 10,Ctr Dr,Rm 3C-108, Bethesda, MD 20982 USA. vsm@mail.nih.govttay, V. S. Fera, F. Tessitore, A. Hariri, A. R. Das, S. Callicott, J. H. Weinberger, D. R.2002LNeurophysiological correlates of age-related changes in human motor function630-635 Neurology584FebBackground: There are well-defined and characteristic age-related deficits in motor abilities that may reflect structural and chemical changes in the aging brain. Objective: To delineate age-related changes in the physiology of brain systems subserving simple motor behavior. Methods: Ten strongly right-handed young (<35 years of age) and 12 strongly right-handed elderly (>50 years of age) subjects with no evidence of cognitive or motor deficits participated in the study. Whole-brain functional imaging was performed on a 1.5-T MRI scanner using a spiral pulse sequence while the subjects performed a visually paced "button-press" motor task with their dominant right hand alternating with a rest state. Results: Although the groups did not differ in accuracy, there was an increase in reaction time in the elderly subjects (mean score +/- SD, young subjects = 547 +/- 97 ins, elderly subjects = 794 280 ms, p < 0.03). There was a greater extent of activation in the contralateral sensorimotor cortex, lateral premotor area, supplementary motor area, and ipsilateral cerebellum in the elderly subjects relative to the young subjects (p < 0.001). Additional areas of activation, absent in the young subjects, were seen in the ipsilateral sensorimotor cortex, putamen (left > right), and contralateral cerebellum of the elderly subjects. Conclusions: The results of this study show that elderly subjects recruit additional cortical and subcortical areas even for the performance of a simple motor task. These changes may represent compensatory mechanisms invoked by the aging brain, such as reorganization and redistribution of functional networks to compensate for age-related structural and neurochemical changes.://000174012600022 Times Cited: 46ISI:000174012600022NIMH, Clin Brain Disorders Branch, Intramural Res Program, NIH, Bethesda, MD 20892 USA. Mattay, VS, Bldg 10,Ctr Dr,Rm 4S-235, Bethesda, MD 20982 USA. Ltay, V. S. Goldberg, T. E. Fera, F. Hariri, A. R. Tessitore, A. Egan, M. F. Kolachana, B. Callicott, J. H. Weinberger, D. R.2003pCatechol O-methyltransferase val(158)-met genotype and individual variation in the brain response to amphetamine 6186-6191OProceedings of the National Academy of Sciences of the United States of America10010May\Monamines subserve many critical roles in the brain, and monoaminergic drugs such as amphetamine have a long history in the treatment of neuropsychiatric disorders and also as a substance of abuse. The clinical effects of amphetamine are quite variable, from positive effects on mood and cognition in some individuals, to negative responses in others, perhaps related to individual variations in monaminergic function and monoamine system genes. We explored the effect of a functional polymorphism (val(158)-Met) in the catechol O-methyltransferase gene, which has been shown to modulate prefrontal dopamine animals and prefrontal cortical function in humans, on the modulatory actions of amphetamine on the prefrontal cortex. Amphetamine enhanced the efficiency of prefrontal cortex function assayed with functional MRI during a working memory task in subjects with the high enzyme activity val/val genotype, who presumably have relatively less prefrontal synaptic dopamine, at all levels of task difficulty. In contrast, in subjects with the low activity met/met genotype who tend to have superior baseline prefrontal function, the drug had no effect on cortical efficiency at low-to-moderate working memory load and caused deterioration at high working memory load. These data illustrate an application of functional neuroimaging in pharmacogenomics and extend basic evidence of an inverted-"U" functional-response curve to increasing dopamine signaling in the prefrontal cortex. Further, individuals with the met/met catechol O-methyltransferase genotype appear to beat increased risk for an adverse response to amphetamine.://000182939400110 Times Cited: 125ISI:000182939400110NIMH, Clin Brain Disorders Branch, NIH, Dept Hlth & Human Serv, Bethesda, MD 20982 USA. Weinberger, DR, NIMH, Clin Brain Disorders Branch, NIH, Dept Hlth & Human Serv, Bldg 10,Ctr Dr,Room 4S-235, Bethesda, MD 20982 USA.Clure, R. K. Phillips, I. Jazayerli, R. Barnett, A. S. Coppola, R. Weinberger, D. R.2006^Regional change in brain morphometry in schizophrenia associated with antipsychotic treatment.121-132Biological Research148\$yer-Lindenberg, A. Buckholtz, J. W. Kolachana, B. Hariri, A. R. Pezawas, L. Blasi, G. Wabnitz, A. Honea, R. Verchinski, B. Callicott, J. H. Egan, M. Mattay, V. Weinberger, D. R.2006HNeural mechanisms of genetic risk for impulsivity and violence in humans 6269-6274OProceedings of the National Academy of Sciences of the United States of America10316AprNeurobiological factors contributing to violence in humans remain poorly understood. One approach to this question is examining allelic variation in the X-linked monoamine oxidase A (MAOA) gene, previously associated with impulsive aggression in animals and humans. Here, we have studied the impact of a common functional polymorphism in MAOA on brain structure and function assessed with MRI in a large sample of healthy human volunteers. We show that the low expression variant, associated with increased risk of violent behavior, predicted pronounced limbic volume reductions and hyperresponsive amygdala during emotional arousal, with diminished reactivity of regulatory prefrontal regions, compared with the high expression allele. In men, the low expression allele is also associated with changes in orbitofrontal volume, amygdala and hippocampus hyperreactivity during aversive recall, and impaired cingulate activation during cognitive inhibition. Our data identify differences in limbic circuitry for emotion regulation and cognitive control that may be involved in the association of MAOA with impulsive aggression, suggest neural systems-level effects of X-inactivation in human brain, and point toward potential targets for a biological approach toward violence.://000236999000039 Times Cited: 6ISI:000236999000039US Dept HHS, Unit Syst Neurosci Psychiat, NIMH, NIH, Bethesda, MD 20892 USA. US Dept HHS, Neuroimaging Core Facil, NIMH, NIH, Bethesda, MD 20892 USA. US Dept HHS, Clin Brain Disorders Branch, NIMH, Genes Cognit & Psychosis Program,NIH, Bethesda, MD 20892 USA. Meyer-Lindenberg, A, US Dept HHS, Unit Syst Neurosci Psychiat, NIMH, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. andreasml@nih.gov<`yer-Lindenberg, A. Nichols, T. Callicott, J. H. Ding, J. Kolachana, B. Buckholtz, J. Mattay, V. S. Egan, M. Weinberger, D. R.2006CImpact of complex genetic variation in COMT on human brain function867-877Molecular Psychiatry119Sep:Catechol-O-methyltransferase (COMT) has been shown to be critical for prefrontal dopamine flux, prefrontal cortex-dependent cognition and activation. Several potentially functional variants in the gene have been identified, but considerable controversy exists regarding the contribution of individual alleles and haplotypes to risk for schizophrenia, partly because clinical phenotypes are ill-defined and preclinical studies are limited by lack of adequate models. Here, we propose a neuroimaging approach to overcome these limitations by characterizing the functional impact of ambiguous haplotypes on a neural system-level intermediate phenotype in humans. Studying 126 healthy control subjects during a workingmemory paradigm, we find that a previously described risk variant in a functional Val158Met (rs4680) polymorphism interacts with a P2 promoter region SNP (rs2097603) and an SNP in the 30 region (rs165599) in predicting inefficient prefrontal working memory response. We report evidence that the nonlinear response of prefrontal neurons to dopaminergic stimulation is a neural mechanism underlying these nonadditive genetic effects. This work provides an in vivo approach to functional validation in brain of the biological impact of complex genetic variations within a gene that may be critical for its clinical association.://000240043100010 Times Cited: 3ISI:000240043100010NIMH, Neuroimaging Core Facil, NIH, DHHS, Bethesda, MD 20892 USA. NIMH, Unit Syst Neurosci Psychiat, NIH, DHHS, Bethesda, MD 20892 USA. NIMH, Clin Brain Disorders Branch, NIH, DHHS,Cognit & Psychosis Program, Bethesda, MD 20892 USA. Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA. Meyer-Lindenberg, A, NIMH, Neuroimaging Core Facil, NIH, DHHS, 10-3C103,9000 Rockville Pike, Bethesda, MD 20892 USA. andreasml@nih.govH$zawas, L. Meyer-Lindenberg, A. Drabant, E. M. Verchinksi, B. Munoz, K. E. Kolachana, B. Egan, M. Mattay, V. Hariri, A. Weinberger, D. R.2005y 5-HTTLPR polymorphism impacts human cingulate-amygdala interactions: a genetic susceptibility mechanism for depression. 828-834Nature Neuroscience868`awas, L. Verchinksi, B. Mattay, V. Callicott, J. H. Kolachana, B. Straub, R. E. Egan, M. Meyer-Lindenberg, A. Weinberger, D. R.2004i The brain-derived neurotrophic factor val66met polymorphism and variation in human cortical morphology. 10099-10102Journal of Neuroscience2545amvougeras, A. Kigar, D. L. Jones, D. Weinberger, D. R. Witelson, S. F.2003eSize of the human corpus callosum is genetically determined: an MRI study in mono and dizygotic twins91-94Neuroscience Letters3382FebThe factors determining the large variation seen in human corpus callosum (CC) morphology are as yet unknown. In this study heritability of CC size was assessed by comparing the concordance of CC midsagittal area in 14 monozygotic and 12 dizygotic twin pairs with a mean age of 27 years, using magnetic resonance imaging and various methods of calculating trait heritability. Heritability was high regardless of method of assessment. The application of a structural equation model resulted in the estimate that 94% of the variance in CC midsagittal size is attributable to the genome. This indicates that under normal conditions and before the effects of normal aging, there is very modest influence of the environment on CC morphology. The results suggest that correlates of CC size, such as the pattern of cerebral lateralization, cognitive abilities and neuropsychiatric dysfunction may be associated with the genetic determinants of CC morphology. (C) 2002 Published by Elsevier Science Ireland Ltd.://000181014300001 Times Cited: 6ISI:000181014300001McMaster Univ, Albert Einstein Irving Zucker Chair Neurosci, Dept Psychiat & Behav Neurosci, Hamilton, ON L8N 3Z5, Canada. Univ British Columbia, Dept Psychiat, Neuropsychiat Unit, Vancouver, BC, Canada. NIMH, Clin Brain Disorders Branch, Intramural Res Program, NIH, Bethesda, MD 20892 USA. Witelson, SF, McMaster Univ, Albert Einstein Irving Zucker Chair Neurosci, Dept Psychiat & Behav Neurosci, 1200 Main St W, Hamilton, ON L8N 3Z5, Canada. Lawrence, K. S. Ye, F. Q. Lewis, B. K. Weinberger, D. R. Frank, J. A. McLaughlin, A. C.2002wEffects of indomethacin on cerebral blood flow at rest and during hypercapnia: An arterial spin tagging study in humans628-635%Journal of Magnetic Resonance Imaging156JunPurpose: To investigate using an arterial spin tagging (AST) approach the effect of indomethacin on the cerebral blood flow (CBF) response to hypercapnia. Materials and Methods: Subjects inhaled a gas mixture containing 6% CO2 for two 5-minute periods, which were separated by a 10-minute interval, in which subjects inhaled room air. In six subjects, indomethacin (i.v., 0.2 mg/ kg) was infused in the normocapnic interval between the two hypercapnic periods. Results: Indomethacin reduced normocapnic gray matter CBF by 36 +/- 5% and reduced the CBF increase during hypercapnia from 43 +/- 9% to 16 +/- 5% in gray matter (P < 0.001) and from 48 +/- 11% to 35 +/- 9% in white matter (P < 0.025). Conclusion: The results demonstrate that an AST approach can measure the effects of indomethacin on global CBF increases during hypercapnia and suggest that an AST approach could be used to investigate pharmacological effects on focal CBF increases during functional activation.://000175918300002 Times Cited: 4ISI:000175918300002NIH, Lab Diagnost Radiol Res, Clin Ctr, Bethesda, MD 20892 USA. St Lawrence, KS, NIH, Lab Diagnost Radiol Res, Clin Ctr, Bldg 10 Rm B1N 256 10 Ctr Dr MSC 1074, Bethesda, MD 20892 USA.D4raub, R. E. Lipksa, B. K. Egan, M. Goldberg, T. E. Callicott, J. H. Mayhew, M. B. Vakkalanka, R. K. Kolachana, B. Kleinman, J. E. Weinberger, D. R.in presswAllelic variation in GAD1 (GAD67) is associated with schizophrenia and influences cortical function and gene expressionMolecular Psychiatry?AStyner, M. Gerig, G. Lieberman, J. A. Jones, D. Weinberger, D. R.2003OStatistical shape analysis of neuroanatomical structures based on medial models207-220Med Image Anal7M?PStyner, M. Lieberman, J. A. McClure, R. K. Weinberger, D. R. Jones, D. Gerig, G.2005Morphometric analysis of lateral ventricles in schizophrenia and healthy controls regarding genetic and disease specific factors. 4872-4877OProceedings of the National Academy of Sciences of the United States of America102PЄ, H. Y. Chen, Q. Sust, S. Buckholtz, J. Egan, M. Mattay, V. Meyer-Lindenberg, A. Weinberger, D. R. Callicott, J. H.in pressiEvidence of biologic epistasis between COMT and GRM3 on human prefrontal function during working memory. OProceedings of the National Academy of Sciences of the United States of America $4ڨ, H. Y. Sust, S. Buckholtz, J. W. Mattay, V. S. Meyer-Lindenberg, A. Egan, M. F. Weinberger, D. R. Callicott, J. H.2006RDysfunctional prefrontal regional specialization and compensation in schizophrenia 1969-1977American Journal of Psychiatry16311NovObjective: It has been suggested that in healthy persons higher-order cognitive processing engaged by incremental working memory load hierarchically employs more dorsal than ventral prefrontal resources in healthy individuals. Given that working memory performance is impaired in schizophrenia, especially at higher executive loads, the authors investigated how this prefrontal functional organization might be altered in disease, independent of performance deficits. Method: Using N-back working memory functional magnetic resonance imaging (fMRI) data, the authors studied 15 patients with schizophrenia and 26 healthy comparison subjects. Subgroups based on median performance accuracy at 2-back were analyzed; high performers included eight schizophrenia patients and 14 comparison subjects, and low performers included seven patients and 12 comparison subjects. Results: High-performing but not low-performing comparison subjects responded to incremental working memory executive load with disproportionately greater dorsal but not ventral prefrontal cortex activation, which also predicted performance accuracy. In the high-and low-performing patient groups, incremental working memory load caused a disproportionate increase in ventral but not dorsal prefrontal cortex activation relative to the respective comparison group, which also correlated with accuracy. Functional connectivity between the ventral prefrontal cortex and posterior parietal cortex was relatively greater in patients, whereas comparison subjects had greater functional connectivity between the dorsal prefrontal cortex and posterior parietal cortex. Conclusions: The hierarchical organization of the prefrontal cortex may be compromised in schizophrenia, resulting in loss of functional specialization and integration at the dorsal prefrontal cortex and in compensatory activation from the ventral prefrontal cortex, which may ultimately affect working memory and executive cognition.://000241669900021 Times Cited: 0ISI:000241669900021 NIMH, Unit Funct MRI, Clin Brain Disorders Branch, Intramural Res Program, Bethesda, MD 20892 USA. Callicott, JH, NIMH, Unit Funct MRI, Clin Brain Disorders Branch, Intramural Res Program, 10 Ctr Dr,Rm 4C-216,MSC 1364, Bethesda, MD 20892 USA. callicottj@mail.nih.govЄ://000178686600035 Times Cited: 28ISI:000178686600035NIMH, Clin Brain Disorders Branch, NIH, Bethesda, MD 20892 USA. NINDS, Expt Therapeut Branch, NIH, Bethesda, MD 20892 USA. Mattay, VS, NIMH, Clin Brain Disorders Branch, NIH, 10 Ctr Dr,Room 3C108, Bethesda, MD 20892 USA. ڨ0ssitore, A. Hariri, A. R. Fera, F. Smith, W. G. Das, S. Weinberger, D. R. Mattay, V. S.2005`Functional changes in the activity of brain regions underlying emotion processing in the elderly9-18 Psychiatry Research-Neuroimaging1391MayAging is associated with a decline in both cognitive and motor abilities that reflects deterioration of underlying brain circuitry. While age-related alterations have also been described in brain regions underlying emotional behavior (e.g., the amygdala), the functional consequence of such changes is less clear. To this end, we used blood oxygenation-level dependent (BOLD) functional magnetic resonance imaging (fMRI) to explore age-related changes in brain regions underlying emotion processing. Twelve young (age < 30 years) and 14 elderly subjects (age > 60 years) were studied with BOLD fMRI during a paradigm that involved perceptual processing of fearful and threatening stimuli. Consistent with previous reports, direct group comparisons revealed relatively increased BOLD fMRI responses in prefrontal cortical regions, including Broca's area, and relatively decreased responses in the amygdala and posterior fusiform gyri in elderly subjects. Importantly, additional analyses using an elderly-specific brain template for spatial normalization of the elderly BOLD fMRI data confirmed these divergent regional response patterns. While there was no difference between groups in accuracy on the task, elderly subjects were significantly slower (delayed reaction times) in performing the task. Our current data suggest that elderly subjects engage a more distributed neocortical network during the perceptual processing of emotional facial expressions. In light of recent converging data froth two other studies, our observed effects may reflect age-related compensatory responses and/or alternative strategies in processing emotions, as the elderly appear to engage cognitive/linguistic systems in the context of reduced sensory and/or limbic responses. (c) Published by Elsevier Ireland Ltd.://000230603600002 Times Cited: 2ISI:000230603600002NIMH, Clin Brain Disorders Branch, Genes Cognit & Psychosis Program, NIH, Bethesda, MD 20892 USA. Univ Naples 2, Dept Neurosci, Div Neurol 2, I-80138 Naples, Italy. Univ Pittsburgh, Sch Med, Dept Psychiat, Pittsburgh, PA 15213 USA. CNR, Inst Neurol Sci, Lab Neuroimaging, I-87050 Cosenza, Italy. Mattay, VS, NIMH, Clin Brain Disorders Branch, Genes Cognit & Psychosis Program, NIH, Bethesda, MD 20892 USA. vsm@helix.nih.gov?pWeinberger, D. R. Egan, M. Bertolino, A. Callicott, J. H. Mattay, V. Lipksa, B. K. Berman, K. F. Goldberg, T. E.20015Prefrontal neurons and the genetics of schizophrenia.825-844Biological Psychiatry50 <@inberger, D. R. McClure, R. K.2002zNeurotoxicity, neuroplasticity, and magnetic resonance imaging morphometry - What is happening in the schizophrenic brain?553-558Archives of General Psychiatry596JunIn an era of dramatic discoveries in neuroscience and genetics, it is likely that many popular theories and formulations about mental illness will need to be revised, if not discarded. The "neurodevelopmental hypothesis" is one of the popular theories about the origins of schizophrenia, which posits that abnormalities of early brain development increase risk for the subsequent emergence of the clinical syndrome.(1-3) An early piece of evidence in support of this hypothesis was the apparent lack of progression of cerebral ventricular enlargement observed with computed tomography during illness.(4-9) An important assumption of the neuro developmental hypothesis is that the putative primary pathologic condition of the brain is a reflection of abnormalities of early development. The neuro developmental hypothesis thus assumes that developmental neuropathologic conditions should arrest early in life and not continue to progress. The computed tomography results showing no apparent progression seemed consistent with this assumption. However, a recent series of magnetic resonance imaging (MRI) studies has called into question this assumption, by revealing changes in measurements of brain structures over short periods in patients who have been ill for varying durations and at various stages of life. These recent studies'(10-14) have generated enthusiasm for a "neurodegenerative hypothesis," harkening back to proposals of Kraepelin and other neuropathologists during the first quarter of the 20th century that there is destruction of neural tissue associated with psychosis. In fact, results of MRI measurements have been cited as support for a much broader conceptual revolution in psychiatry, a "neurotoxicity hypothesis" for many psychiatric illnesses, including affective disorders(15,16) and anxiety and stress disorders(17-19) and even jet lag.(20) This recent trend has been bolstered by basic discoveries about the adaptability of neuronal connections(21) and the viability and reproducibility of neurons in the adult brain (eg, apoptosis and neurogenesis).(22,23) These developments have led some to opine that the neurodegenerative hypothesis of schizophrenia may have been unjustly overshadowed by the ascendancy of the neuro developmental hypothesis.(24)://000176055400010 Times Cited: 62ISI:000176055400010NIMH, Clin Brain Disorders Branch, Intramural Res Program, NIH, Bethesda, MD 20892 USA. Weinberger, DR, NIMH, Clin Brain Disorders Branch, Intramural Res Program, NIH, 10 Ctr Dr,Bldg 10,Room 3C-101,MSc 1255, Bethesda, MD 20892 USA.00terer, G. Carver, F. W. Musso, F. Mattay, V. Weinberger, D. R. Coppola, R.in pressnComplex relationship between BOLD signal and synchronization/desynchronization of human brain MEG oscillationsHuman Brain Mappingh@nterer, G. Coppola, R. Egan, M. F. Goldberg, T. E. Weinberger, D. R.2003WFunctional and effective frontotemporal connectivity and genetic risk for schizophrenia 1181-1192Biological Psychiatry5411DecBackground: Functional neuroimaging and electrophysiologic studies have found disturbed frontotemporal interaction in schizophrenia. We sought to determine whether abnormalities of frontotemporal connectivity are trait markers of genetic risk for schizophrenia. Methods: We investigated 64 schizophrenia patients, 79 of their clinically unaffected siblings, and 88 unrelated normal controls with an auditory oddball electroencephalogram (EEG) evoked potential paradigm. We measured: 1) frontotemporal event-related EEG-coherence (i.e. a measure of functional connectivity); and 2) we performed structural equation modeling of the effective connectivity between the frontal P300 and temporoparietal P300-amplitude. Results: Schizophrenic patients and their siblings showed a reduction of frontotemporal coherence. At peak activation during the P300 time-window, a negative ("inhibitory") frontotemporal path coefficient was found in normal controls, whereas a positive coefficient was seen in schizophrenic patients with siblings being intermediate. Intra-class correlations between sib-pairs and relative risk estimates of the applied connectivity measures were non-significant. Topographic correlation matrix analyses suggested that the altered functional and effective frontotemporal connectivity indirectly reflect regional abnormalities of increased activation variance. Conclusions: Impaired interaction of the frontotemporal macro-circuit indirectly reflects genetically determined abnormalities of frontal and temporoparietal microcircuits. The reasons why frontotemporal connectivity appears to be a poor predictor of genetic risk for schizophrenia are discussed.://000186792300007 Times Cited: 23ISI:000186792300007NIMH, Clin Brain Disorders Branch, NIH, Bethesda, MD 20892 USA. Winterer, G, Univ Mainz, Psychiat Klin & Poliklin, Untere Zahlbacher Str 8, D-55131 Mainz, Germany.0 `terer, G. Musso, F. Beckmann, C. Mattay, V. Egan, M. F. Jones, D. W. Callicott, J. H. Coppola, R. Weinberger, D. R.2006<Instability of prefrontal signal processing in schizophrenia 1960-1968American Journal of Psychiatry16311Nov Objective: Prefrontal dysfunction is considered a fundamental characteristic of schizophrenia. Recent electrophysiological evidence points to a major instability of signal processing in prefrontal cortical microcircuits because of reduced phase-synchronization (i.e., an increased stimulusrelated variability [noise] of single-trial responses in the spatial and time domain). The authors used functional magnetic resonance imaging (fMRI) during a visual two-choice reaction task in order to measure, with higher topographic accuracy, signal stability in patients with schizophrenia and its relationship to more traditional measures of activation. Method: Twelve clinically stable inpatients with schizophrenia and 16 matched comparison subjects were evaluated. Event-related blood-oxygen-level-dependent responses were subjected to an analysis of residual noise variance and to independent data dimension independent component analysis in the medial prefrontal cortex. Results: In patients with schizophrenia, the authors found increased residual noise variance of the blood-oxygen-level-dependent response that predicted the level of prefrontal activation in these subjects. In the left hemisphere, residual noise variance strongly correlated with psychotic symptoms. Independent component analysis revealed a "fractionized" and unfocussed pattern of activation in patients. Conclusions: These findings suggest that unstable cortical signal processing underlies classic abnormal cortical activation patterns as well as psychosis in schizophrenia.://000241669900020 Times Cited: 0ISI:000241669900020dNIH, Genes Cognit & Psychosis Program, NIMH, Bethesda, MD 20892 USA. Univ Mainz, Dept Psychiat, Lab Mol Neuroimaging & Electrophysiol, D-6500 Mainz, Germany. Oxford Ctr Funct Magnet Resonance Imaging Brain, Oxford, England. Weinberger, DR, NIH, Genes Cognit & Psychosis Program, NIMH, 10 Ctr Dr,MSC 1379, Bethesda, MD 20892 USA. weinberd@intra.nimh.nih.gov dnterer, G. Musso, F. Vucurevic, G. Stoeter, P. Konrad, A. Seker, B. Gallinat, J. Dahmen, N. Weinberger, D. R.2006SCOMT genotype predicts BOLD signal and noise characteristics in prefrontal circuits 1722-1732 Neuroimage324OctObjective: Prefrontal dopamine (DA) is catabolized by the COMT (catechol-O-methyltransferase) enzyme. Literature suggests that the Val/Met single nucleotide polymorphism (SNP) in the COMT gene predicts executive cognition in humans with Val carriers showing poorer performance due to less available synaptic DA. Recent fMRI studies are thought to agree with these studies having demonstrated prefrontal hyperactivation during n-back and attention-requiring tasks. This was interpreted as "less efficient" processing due to impaired signal-to-noise ratio (SNR) of neuronal activity. However, electrophysiological studies of neuronal SNR in primates and humans imply that prefrontal cortex should show a diminished prefrontal BOLD response in Val carriers. In the present study, we addressed the question of whether the prefrontal SNR of the BOLD response is decreased in Val carriers using a visual oddball task and an approach to analysis of fMRI data that maximizes noise characterization. Methods: We investigated N=17 homozygous Met carriers compared with N=24 Val carriers matched for age, sex, education, IQ, reaction time (variability) and head motion. Event-related fMRI was conducted presenting 160 visual stimuli (40 targets, checkerboard reversal). Subjects had to respond as quickly as possible to targets by button press. In the fMRI GLM [y(t)=beta* x(t)+c+e(t)] analysis, voxel-by-voxel 'activation' [y(t)] as well as residual noise variance [e(t)=sigma(2)] were calculated using a conservative full-width half maximum (FWHM=6 mm). Results: As compared to Val carriers, we observed a stronger and more extended BOLD responses in homozygous Met carriers in left supplementary motor area (SMA) extending to ACC and dorsolateral prefrontal cortex. Vice versa, increased levels of noise were seen in Val carriers surrounding the peak activation maximum. Discussion: In line with our expectations from prior electrophysiological studies, we observed a diminished BOLD response and increased noise in Val carriers. This suggests that the DA stabilizes cortical microcircuits by sharpening the signal and suppressing surrounding noise. (c) 2006 Elsevier Inc. All rights reserved.://000240969200018 Times Cited: 0ISI:000240969200018Univ Dusseldorf, Dept Psychiat, D-40629 Dusseldorf, Germany. Univ Mainz, Inst Neuroradiol, D-6500 Mainz, Germany. Univ Mainz, Dept Psychiat, D-6500 Mainz, Germany. Charite Berlin, Berlin, Germany. NIMH, Genes Cognit & Psychosis Program, Bethesda, MD 20892 USA. Winterer, G, Univ Dusseldorf, Dept Psychiat, Bergische Landstr 2, D-40629 Dusseldorf, Germany. georg.winterer@uni-duesseldorf.dePK17I/**refs.FRM 0B< !// !HPRIMARYyearIndex 6ByP/) idreference_type text_stylesauthoryear title pages secondary_title volume numbernumber_of_volumessecondary_authorplace_published publishersubsidiary_authoredition keywords type_of_workdate2)  abstractlabelurltertiary_titletertiary_author notes isbn custom_1 custom_2 custom_3 custom_4alternate_titleaccession_number call_number short_title custom_5 custom_6sectionoriginal_publicationH) reprint_editionreviewed_itemauthor_addressimagecaption custom_7 electronic_resource_number link_to_pdf translated_author translated_titlename_of_databasedatabase_providerresearch_notes language access_datelast_modified_date !! H!H!H! (H! 3H! >H! IH! TH!_H!jH!uH! H!H!H! H! H!H! H!H!H!H!H! H! H! H! H! %H! 0H!;H!FH! QH! \H! gH! rH!}H!H!H!H!H!H!H! H! H! H! H! H!H! H!H! 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