Research Findings - Clinical Neuroscience Research

Is Decreased Prefrontal Cortical Sensitivity to Monetary Reward Associated with Impaired Motivation and Self-Control in Cocaine Addiction?

Dr. Rita Goldstein and colleagues at Brookhaven National Laboratory used fMRI to investigate alterations in the brain's sensitivity to monetary rewards of different magnitudes in cocaine abusers and to study its association with motivation and self-control. Sixteen cocaine abusers and 13 matched healthy comparison subjects performed a forced-choice task under three monetary value conditions while brain activation was measured with functional magnetic resonance imaging. Objective measures of state motivation were assessed by reaction time and accuracy, and subjective measures were assessed by self-reports of task engagement. Measures of trait motivation and self-control were assessed with the Multidimensional Personality Questionnaire. The cocaine abusers demonstrated an overall reduced regional brain responsivity to differences between the monetary value conditions. Also, in comparison subjects but not in cocaine abusers, reward-induced improvements in performance were associated with self-reports of task engagement, and money-induced activations in the lateral prefrontal cortex were associated with parallel activations in the orbitofrontal cortex. For cocaine abusers, prefrontal cortex sensitivity to money was instead associated with motivation and self-control. These findings suggest that in cocaine addiction 1) activation of the corticolimbic reward circuit to gradations of money is altered; 2) the lack of a correlation between objective and subjective measures of state motivation may be indicative of disrupted perception of motivational drive, which could contribute to impairments in self-control; and 3) the lateral prefrontal cortex modulates trait motivation and deficits in self-control, and a possible underlying mechanism may encompass a breakdown in prefrontal-orbitofrontal cortical communication. Goldstein, R.Z., Alia-Klein, N., Tomasi, D., Zhang, L., Cottone, L.A., Maloney, T., Telang, F., Caparelli, E.C., Chang, L., Ernst, T., Samaras, D., Squires, N.K., and Volkow, N.D. American Journal of Psychiatry, 164(1), pp. 43-51, 2007.

Smoking Modulation of Mu-opioid and Dopamine D2 Receptor-Mediated Neurotransmission in Humans

Dr. Edward Domino and colleagues at University of Michigan used PET ligand imaging to test the hypothesis that some of the effects of smoking cigarettes in humans are mediated through nicotine activation of opioid and dopamine (DA) neurotransmission. Neuroimaging was performed using positron emission tomography and the radiotracers [C-11] carfentanil and [C-11] raclopride, labeling mu-opioid and DA D2 receptors, respectively. Six healthy male smokers were abstinent overnight. After radiotracer administration, subjects smoked two denicotinized cigarettes, followed 45 min later by two average nicotine cigarettes. Dynamic data were acquired over 90 min, and transformed into parametric maps of receptor availability in vivo (binding potential, BP), corresponding to low and high nicotine smoking periods and analyzed on a voxel-by-voxel basis using SPM'99 and correction for multiple comparisons. Significant activation of m-opioid receptor-mediated neurotransmission from denicotinized to average nicotine conditions was observed in the right anterior cingulate cortex. DA D2 neurotransmission was activated in the ventral basal ganglia, correlating with Fagerstrom scale nicotine dependence scores. Lower m-opioid receptor BP was also detected during the denicotinized smoking condition in the smoker group, compared to baseline scans in non-smokers, in the cingulate cortex, thalamus, ventral basal ganglia, and amygdala. These reductions were reversed during the average nicotine condition in the thalamus, ventral basal ganglia and amygdala. These data point to both the feasibility of simultaneously examining opioid and DA neurotransmission responses to smoking in humans, as well as to the need to examine non-nicotine aspects of smoking to more fully understand the behavioral effects of this drug. Scott, D.J., Domino, E.F., Heitzeg, M.M., Koeppe, R.A., Ni, L.S., Guthrie, S., and Zubieta, J.K. Neuropsychopharmacology, 32(2), pp. 450-457, 2007.

Role of the Anterior Cingulate and Medial Orbitofrontal Cortex in Processing Drug Cues in Cocaine Addiction

Dr. Rita Goldstein and colleagues at Brookhaven National Laboratory used fMRI to probe the role of the anterior cingulate cortex (ACC) and orbitofrontal cortex (OFC) in processing of salient symptom-related cues during the simultaneous performance of an unrelated task in drug-addicted persons. They used a novel fMRI color-word drug Stroop task in 14 individuals with cocaine use disorders; subjects had to press for color of drug vs. matched neutral words. Although there were no accuracy or speed differences between the drug and neutral conditions in the current sample of subjects, drug words were more negatively valenced than the matched neutral words. Further, consistent with prior reports in individuals with other psychopathologies using different Stroop fMRI paradigms, this more classical color-word Stroop design revealed bilateral activations in the caudal-dorsal anterior cingulate cortex (cdACC) and hypoactivations in the rostro- ventral anterior cingulate cortex/medial orbitofrontal cortex (rACC/mOFC). A trend for larger rACC/mOFC hypoactivations to the drug than neutral words did not survive whole-brain corrections. Nevertheless, correlation analyses indicated that (1) the more the cdACC drug-related activation, the more negative the valence attributed to the drug words (r=-0.86, P < 0.0001) but not neutral words; and (2) the more the rACC/mOFC hypoactivation to drug minus neutral words, the more the errors committed specifically to the drug minus neutral words (r=0.85, P < 0.0001). Taken together, results suggest that this newly developed drug Stroop fMRI task may be a sensitive biobehavioral assay of the functions recruited for the regulation of responses to salient symptom-related stimuli in drug-addicted individuals. Goldstein, R.Z., Tomasi, D., Rajaram, S., Cottone, L.A., Zhang, L., Maloney, T., Telang, F., Alia-Klein, N., and Volkow, N.D. Neuroscience, 144(4), pp. 1153-1159, 2007.

Reinforcement Learning Signals Predict Future Decisions

Dr. Michael Cohen and colleagues at University of California, Davis used event-related brain potentials (ERPs) to investigate how flexibility to adapt decision strategies based on recent outcomes emerges through a reinforcement learning process, in which reward prediction errors are used dynamically to adjust representations of decision options. Authors recorded event-related brain potentials (ERPs) while subjects played a strategic economic game against a computer opponent to evaluate how neural responses to outcomes related to subsequent decision-making. Analyses of ERP data focused on the feedback-related negativity (FRN), an outcome-locked potential thought to reflect a neural prediction error signal. Consistent with predictions of a computational reinforcement learning model, the authors found that the magnitude of ERPs after losing to the computer opponent predicted whether subjects would change decision behavior on the subsequent trial. Furthermore, FRNs to decision outcomes were disproportionately larger over the motor cortex contralateral to the response hand that was used to make the decision. These findings provide novel evidence that humans engage a reinforcement learning process to adjust representations of competing decision options. These findings form a foundation for understanding how drugs of abuse that act on reinforcement learning sytems could lead to dysfunctional decision-making. Cohen, M.X., and Ranganath, C. Journal of Neuroscience, 27(2), pp. 371-378, 2007.

Impaired Decision-making in Psychopathic Heroin Addicts

Dr. Jasmin Vassileva at University of Illinois, Chicago, investigated neurocognitive deficits in decision-making in a sample of pure heroin users to avoid two significant methodological challenges present in previous studies: polysubstance dependence and comorbid conditions, which are independently associated with neurocognitive impairments. Heroin addiction is highly prevalent in Bulgaria but polysubstance dependence is rare. The goal of the current study was to evaluate the potential contribution of psychopathogy to decision-making processes among this group of Bulgarian heroin addicts. They tested 78 male currently abstaining heroin addicts, classified as psychopathic or non-psychopathic using the Hare Psychopathy Checklist, Revised (PCL-R). Psychopathic heroin addicts showed notable deficits in decision-making in that they made significantly more disadvantageous decisions relative to non-psychopathic heroin addicts. Results indicate that the presence of psychopathy may exacerbate decision-making deficits in heroin addicts. Vassileva, J., Petkova, P., Georgiev, S., Martin, E.M., Tersiyski, R., Raycheva, M., Velinov, V., and Marinov, P. Drug and Alcohol Dependence, 86(2-3), pp. 287-289, 2007.

Early Sign of Cognitive Declination in Asymptomatic HIV+ individuals - Detectable upon Additional Stresses that Uncover Diminished Brain Reserve Network Capacity

Dr. Linda Chang and colleagues used fMRI to investigate how AIDS-associated dementia impairs cognitive systems, particularly working memory. Their results indicate that at the late stage of disease progression where neurodegeneration and related cognitive impairment had already developed, no therapeutic approaches can effectively intervene with the complication. Their findings suggest that new strategies are needed, such as aiming at the early stages of the disease prior to the emergence of clinical signs and symptoms of dementia become apparent, to prevent the recoverable subtle dysfunction from irreversible permanent neurodegeneration and to prevent development of risk-taking behavior due to cognitive impairment. Several recent fMRI studies carried out by Dr. Linda Chang and colleagues reveal that HIV-induced subtle brain dysfunction was detectable at early onset of the disease, which preceded clinical signs or deficits on cognitive tests, and which suggests BOLD fMRI to be more sensitive than clinical and neuropsychological evaluations in detecting early HIV-associated brain injury. Their work detected increased brain activation (elevated signal intensity of blood oxygenation) during working memory tasks in HIV patients with mild dementia, presumably because the brain injury required additional activation of the frontal lobes, greater modulation of the neural circuits, and increased usage of brain reserve to maintain normal cognitive function. The increased brain activation was also demonstrated in asymptomatic HIV+ individuals to challenges of more difficult cognitive tasks that required heavier load of attention for working memory. Compared with control subjects, the asymptomatic HIV+ individuals showed greater magnitude of brain activation in the lateral prefrontal cortex during fMRI, yet normal on a battery of neuropsychological tests until the degree of difficulty in the task was increased. The patients with HIV also showed increased brain volume in the lateral prefrontal cortex but not in other activated regions, including the posterior parietal cortex, supplementary motor area, thalamus, caudate, and occipital cortex. The increase in activated brain volume was independent of task difficulty. Authors also observed abnormal fMRI activation and lower neuronal marker N-acetylaspartate in prefrontal and parietal cortices in another study where acoustic noise was the additional stressor, which presumably exhausted the already impaired network for more demanding working memory tasks. These studies demonstrate that fMRI can detect changes due to HIV brain injury even during the asymptomatic stage of the disease and suggest an increased usage of brain reserve to maintain cognitive performance as a compensatory response. Understanding how can brain function be strengthened to enhance compensation for HIV-associated, early stage perturbation and to preserve normal function may inform interventions to ameliorate cognitive impairment, such as facilitate neuronal processes of neuroresiliance and neuroplasticity. Tomasi, D., Chang, L., de Castro Caparelli, E., Telang, F., and Ernst, T., The Human Immunodeficiency Virus Reduces Network Capacity: Acoustic Noise Effect. Ann Neurol, 59(2), pp. 419-23, 2006.; Chang, L., Speck, O., Miller, E.N., Braun, J., Jovicich, J., Koch, C., Itti, L., and Ernst, T. Neural Correlates of Attention and Working Memory Deficits in HIV Patients. Neurology, 57(6), pp.1001-7, 2001; Ernst, T., Chang, L., Jovicich, J., Ames, N., and Arnold, S. Abnormal Brain Activation on Functional MRI in Cognitively Asymptomatic HIV Patients. Neurology, 59(9), pp. 1343-1349, 2002; Chang, L., Tomasi, D., Yakupov, R., et al. Adaptation of the Attention Network in Human Immunodeficiency Virus Brain Injury. Ann Neurol, 56, pp. 259 -272, 2004.

Altered Regional Blood Volume in Chronic Cannabis Smokers

Dr. Yurgelun-Todd and colleagues at McLean Hospital used dynamic susceptibility contrast MRI to study cerebral blood volume (CBV) alterations in long-term daily cannabis users. The objective of the present study was to examine differences in relative regional blood volume in focal regions of interest-including the frontal lobe, the temporal lobe, and the cerebellum-during a period of supervised abstinence from cannabis. Resting state CBV images were collected following a bolus of gadolinium contrast agent on 12 current, long-term daily cannabis users between 6 and 36 hr after the subjects' last reported cannabis use and 17 healthy comparison subjects. Cannabis users had significantly increased blood volumes in the right frontal area, in the left temporal area, and in the cerebellum relative to comparison subjects. Among the cannabis users, there were no significant correlations between regional blood volumes and either total lifetime episodes of smoking or urinary tetrahydrocannabinol concentrations. These findings have important implications for understanding the effects of chronic heavy cannabis use on brain function. It would be of interest to extend the investigation beyond 6-36 hr of abstinence from cannabis to determine whether increased CBV values persist for several weeks or eventually normalize. Sneider, J.T., Pope, H.G., Silveri, M.M., Simpson, N.S., Gruber, S.A., and Yurgelun-Todd, D.A. Experimental and Clinical Psychopharmacology,14(4), pp. 422-428, 2006.

Using Functional Magnetic Resonance Imaging to Pinpoint Brain Differences Relevant to Stimulant Use

Dr. Martin Paulus at University of California, San Diego, reviewed the neural substrate dysfunctions and disrupted cognitive, affective and experiential processes observed in methamphetamine and cocaine- dependent individuals. They reviewed all publications in PubMed that conducted comparison studies between healthy volunteers and cocaine-, amphetamine- or methamphetamine- dependent individuals using functional magnetic resonance imaging. They found that stimulant dependence was characterized by a distributed alteration of functional activation to a number of experimental paradigms. Attenuated anterior and posterior cingulate activation, reduced inferior frontal and dorsolateral prefrontal cortex activation and altered posterior parietal activation point towards an inadequate demand-specific processing of information. Processes reported most consistently to be deficient in these functional neuroimaging studies include inhibitory control, executive functioning and decision-making. One emerging theme arising from this research is that stimulant-dependent individuals show specific, rather than generic, brain activation differences, i.e. instead of showing more or less brain activation regardless of task, they exhibit process-related brain activation differences that are consistent with a shift from context-specific, effortful processing to more stereotyped, habitual response generation. Aron, J.L., and Paulus, M.P. Addiction 102, pp. 33-43 Suppl. 1, 2007.

Linking Nucleus Accumbens Dopamine and Blood Oxygenation

Dr. Brian Knutson at Stanford University reviewed the literature concerning the physiological relationship between dopamine release and BOLD signal increases in the Nucleus Accumbens (NAcc). Animal research suggests that anticipation of reward can elicit dopamine release in the NAcc. Human functional magnetic resonance imaging (fMRI) research further suggests that reward anticipation can increase local blood oxygen level dependent (BOLD) signal in the NAcc. However, it is not clear whether pharmacological MRI (phMRI) evidence exists for a directional relationship between NAcc dopamine release and BOLD signal. Accumulating phMRI evidence supports a simple model in which NAcc dopamine release activates postsynaptic D1 receptors, which changes postsynaptic membrane potential, eventually increasing local BOLD signal. This continuing influence can change on a second-to-second basis. Dopamine release in the NAcc appears to increase local BOLD signal via agonism of postsynaptic D1 receptors. Such a physiological mechanism implies that fMRI may be used to track symptoms related to NAcc dopaminergic dysregulation in substance abuse and other disorders. Knutson, B., and Gibbs, S.E.B. Psychopharmacology, 191(3), pp. 813-822, 2007.

Mood Alters Amygdala Activation to Sad Distractors During an Attentional Task

Dr. Kevin Labar and colleagues at Duke University used fMRI in healthy subjects to determine whether the amygdala's response to sad sensory stimuli is functionally modulated by mood state. Healthy adults underwent functional magnetic resonance imaging during task runs that were preceded by sad or happy movie clips. Amygdala activation was subsequently evoked by sad and neutral pictures presented as distractors during an attentional oddball task. Happy and sad mood induction was conducted within-subjects on consecutive days in counterbalanced order. Amygdala activation to sad distractors was enhanced after viewing sad movies relative to happy ones and was correlated with reaction time costs to detect attentional targets. The anterior cingulate, ventromedial and orbital prefrontal conex, insula, and other posterior regions also showed enhanced responses to sad distractors during sad mood. The activation was higher in female subjects in the right hemisphere. These findings reveal brain mechanisms that integrate emotional input and current mood state, with implications for understanding cognitive distractibility in mood alterations in substance abusers. Wang, L.H., Labar, K.S., and McCarthy, G. Biological Psychiatry, 60(10), pp. 1139-1146, 2006.

The Neural Effect of Stimulus-response Modality Compatibility on Dual-task Performance: an fMRI Study

Dr. Mark D'Esposito and colleagues at University of California Berkeley used fMRI to investigate whether inferior frontal sulcus (IFS) is involved in the coordination of interfering processes in dual-task situations in healthy subjects. The present study was specifically concerned with whether the compatibility between stimulus and response modalities modulates dual-task-related activity along the IFS. It has been shown behaviorally that the degree of interference, as measured by dual-task costs, increases in modality-incompatible conditions (e.g. visual-vocal tasks combined with auditory-manual tasks) as compared to modality-compatible conditions (e.g. visual-manual tasks combined with auditory-vocal tasks). Using fMRI, authors measured IFS activity when participants performed modality-compatible and modality-incompatible single and dual tasks. Behaviorally, authors replicated the finding of higher dual-task costs for modality-incompatible tasks compared to modality-compatible tasks. The fMRI data revealed higher activity along the IFS in modality-incompatible dual tasks compared with modality-compatible dual tasks when inter-individual variability in functional brain organization is taken into account. These data suggest that the IFS is involved in the coordination of cognitive processes associated with the concurrent mapping of sensory information onto corresponding motor responses in dual-task situations. Stelzel, C., Schumacher, E.H., Schubert, T., and D'Esposito, M. Psychological Research, 70(6), pp. 514-525, 2006.

Reward-Aversion Circuitry in Analgesia and Pain: Implications for Psychiatric Disorders

Drs. Perry Renshaw, Igor Elman and colleagues at McLean Hospital reviewed how interaction between sensory and emotional systems are altered in chronic pain patients. Pain and analgesia are interpreted by the nervous system as aversive and rewarding processes that trigger specific behavioral responses. Under normal physiological conditions these processes are adaptive. However, under chronic pain conditions, functional alterations of the central nervous system frequently result in maladaptive behaviors. In this review the authors examine (a) the interactions between sensory and emotional systems involved in processing pain and analgesia in the physiological state; (b) the role of reward/aversion circuitry in pain and analgesia; and (c) the role of alterations in reward/aversion circuitry in the development of chronic pain and co-morbid psychiatric disorders. These underlying features have implications for understanding the neurobiology of substance abuse in chronic pain patients and for the development and evaluation of novel therapeutic interventions. Borsook, D., Becerra, L., Carlezon, W.A., Show, M., Renshaw, P., Elman, I., and Levine, J. European Journal of Pain, 11(1), pp. 7-20, 2007.

The Role of Emotion in Decision Making: A Cognitive Neuroscience Perspective

Dr. Antoine Bechara and colleagues reviewed how decision making is altered in the face of uncertainty about whether one's choices will lead to benefit or harm. The somatic-marker hypothesis is a neurobiological theory of how decisions are made in the face of uncertain outcome. This theory holds that such decisions are aided by emotions, in the form of bodily states, that are elicited during the deliberation of future consequences and that mark different options for behavior as being advantageous or disadvantageous. This process involves an interplay between neural systems that elicit emotional/bodily states and neural systems that map these emotional/bodily states. Naqvi, N., Shiv, B., and Bechara, A. Current Direction in Psychological Science, 15(5), pp. 260-264, 2006.

Effects of Acute Smoking on Brain Activity Vary with Abstinence in Smokers Performing the N-Back Task: A Preliminary Study

Dr. Edythe London and colleagues at University of California, Los Angeles used fMRI to determine whether recent smoking (overnight abstinence vs. smoking ad libitum) influenced the effect of smoking a cigarette on brain activity related to a working memory challenge. Six smokers performed the N-Back working memory task during functional magnetic resonance imaging (fMRI) both before and after smoking a cigarette in each of two test sessions: one following overnight abstinence from smoking (similar to 13 h) and the other following ad libitum smoking. Task-related activity in L-DLPFC showed a significant interaction between the effects of acute smoking, test session, and task load. After overnight abstinence, post-smoking brain activity in L-DLPFC was lower than before smoking at low task load and higher at high task load; corresponding activity on a day of ad libitum smoking was higher at low load and lower at high task load after smoking during the session. These data suggest that the effect of acute smoking on working memory processing depends on recent prior smoking and task load. In particular, they provide preliminary evidence that functional efficiency of working memory is improved by smoking a cigarette during abstinence, while the effect of a cigarette in a non-deprived state varies with the nature and difficulty of the working memory challenge. This interaction merits further examination in larger studies specifically designed to consider this issue. Xu, J.S., Mendrek, A., Cohen, M.S., Monterosso, J., Simon, S., Brody, A.L., Jarvik, M., Rodriguez, P., Ernst, M., and London, E.D. Psychiatry Research-Neuroimaging, 148(2-3), pp. 103-109, 2006.

Spatially Selective Representations of Voluntary and Stimulus-driven Attentional Priority in Human Occipital, Parietal, and Frontal Cortex

Dr. Steven Yantis and colleagues at Johns Hopkins University used fMRI in healthy subjects to determine the neuronal systems engaged in mediating attentional priority when competing factors are present. When multiple objects are present in a visual scene, they compete for cortical processing in the visual system; selective attention biases this competition so that representations of behaviorally relevant objects enter awareness and irrelevant objects do not. Deployments of selective attention can be voluntary (e.g., shift or attention to a target's expected spatial location) or stimulus driven (e.g., capture of attention by a target-defining feature such as color). Here authors used functional magnetic resonance imaging to show that both of these factors induce spatially selective attentional modulations within regions of human occipital, parietal, and frontal cortex. In addition, the voluntary attentional modulations are temporally sustained, indicating that activity in these regions dynamically tracks the locus of attention. These data show that a convolution of factors, including prior knowledge of location and target-defining features, determines the relative competitive advantage of visual stimuli within multiple stages of the visual system. Serences, J.T., and Yantis, S., Cerebral Cortex, 17(2). pp, 284-293, 2007.

Neuroimaging Research in Human MDMA Users: A Review

Dr. Ronald Cowan of Vanderbilt University reviewed the literature to determine under what circumstances, and to what extent 3,4-methylenedioxymethamphetamine (MDMA) exposure produces chronic changes in human brain function is a critical public health issue. MDMA is a widely used recreational drug commonly sold as "Ecstasy". Because findings from the animal literature have indicated that specific dosage regimens of MDMA can produce long-lasting alterations in serotonergic function, existing studies of MDMA effects in humans have examined brain serotonin (5-HT) transporters (5-HTT) and receptors or have examined brain structures or functions potentially affected by MDMA. The objectives of this review were to provide a background for interpreting human MDMA neuroimaging research; to examine existing neuroimaging data regarding the rationale for and limitations to human MDMA research; and to provide suggestions for improving the design and interpretation of future neuroimaging approaches. Results showed that of the existing neuroimaging studies in human MDMA users, few experimental designs have been replicated across different research groups. Only investigations employing nuclear imaging methods to assay brain 5-HTT levels have been replicated across methods and research laboratories. These studies have found reduced levels of the 5-HTT in recently abstinent MDMA users with some evidence for normalization of 5-HTT levels with prolonged abstinence. However, the sensitivity of these methods is unknown. The current state of neuroimaging in human MDMA users does not permit conclusions regarding the long-term effects of MDMA exposure. Future study designs might benefit from improved sample homogeneity, increased length of MDMA abstinence, longitudinal study design, test-retest measures, serotonergic specificity, and multimodal approaches. Cowan, R.L. Psychopharmacology, 189(4), pp. 539-556, 2007.

The Vulnerability to Alcohol and Substance Abuse in Individuals Diagnosed with Schizophrenia

Dr. Cyril D'Souza and colleagues at Yale University reviewed the literature on how individuals with schizophrenia are at increased risk for developing substance abuse disorders. The authors considered several factors that might elevate their risk for substance abuse. The tendency among schizophrenic individuals to overvalue drug-like rewards and to devalue the potential negative consequences of substance abuse may be a contributing factor to their substance abuse risk. This bias, which may partly reflect the convergence of glutamatergic and dopaminergic input to the limbic striatum, also may contribute to disadvantageous decision-making and other impulsive behavior. This propensity to seek drug-like rewards is augmented by alterations in nicotinic cholinergic, GABAergic, glutamatergic, and cannabinnoid receptor function associated with schizophrenia that increase the abuse liability of low doses of nicotine, ethanol, and perhaps cannabis, and augment the dysphoric effects of higher doses of ethanol and cannabis. The distortions in reward processing and altered response to substances of abuse also increase the likelihood that individuals with schizophrenia will self-medicate their subjective distress with abused substances. The focus on distinctions between motivation and reward with respect to substance abuse risk by schizophrenic patients suggests a need for a reconsideration of the construct of "negative symptoms" for this dually-diagnosed patient group. Krystal, J.H., D'Souza, D.C., Gallinat, J., Driesen, N., Abi-Dargham, A., Petrakis, I., Heinz, A., and Pearlson, G. Neurotoxicity Research, 10(3-4), pp. 235-252, 2006.

Altruism is Associated with an Increased Neural Response to Agency

Dr. Scott Huettel and colleagues at Duke University used fMRI to investigate the neural mechanisms underlying altruism in healthy subjects. Empathy and its component abilities, such as the perception of the actions and intentions of others have been proposed as key contributors. Tasks requiring the perception of agency activate the posterior superior temporal cortex (pSTC), particularly in the right hemisphere. Here, the authors demonstrate that differential activation of the human pSTC during action perception versus action performance predicts self-reported altruism. These studies form the foundation for understanding how substance abuse may lead to dysfunctional social abilities. Tankersley, D., Stowe, C.J., and Huettel, S.A. Nature Neuroscience, 10(2), pp. 150-151, 2007.

Neuroimaging Attentional Impairment

Dr. David Gilbert and colleagues at Southern Illinois University used evoked response potential (ERP) to investigate how aversive and smoking-related stimuli during abstinence are related to smoking urges and relapse, and whether such stimuli can be potent distractors of selective attention. It has been suggested that the beneficial effect of nicotine replacement therapy (NRT) may be mediated partly by the ability of nicotine to reduce distraction by such stimuli and thereby to facilitate attention to task-relevant stimuli. The present study tested the hypothesis that nicotine reduces distraction by aversive and smoking-related stimuli as indexed by the parietal P3b brain response to a task-relevant target digit. The effect of nicotine on distraction by emotionally negative, positive, neutral, and smoking-related pictures immediately preceding target digits during a rapid visual information processing task in smokers was assessed. Nicotine enhanced P3b responses associated with target digits immediately subsequent to negative emotional pictures bilaterally and subsequent to smoking-related pictures only in the right hemisphere. No effects of nicotine were observed for P3bs subsequent to positive and neutral distractor pictures. Another measure of attention, contingent negative variation amplitude in anticipation of the target digits also was increased by nicotine, especially in the left hemisphere and at posterior sites. Together, these findings suggest that nicotine reduces the distraction by emotionally negative and smoking-related stimuli and promotes attention to task-related stimuli by modulating somewhat lateralized and task specific neural networks. Gilbert, D.G., Sugai, C., Zuo, Y., Rabinovich, N.E., McClernon, F.J., and Froeliger, B. Brain Indices of Nicotine's Effects on Attentional Bias to Smoking and Emotional Pictures and to Task-Relevant Targets Nicotine Tob Res. 9(3), pp. 351-363, 2007.

Several Genes are Associated with Nicotine Dependence

Dr. Li and associates continue to report discoveries from their first round of funding of genes associated with nicotine dependence. European- (EA) and African-American (AA) smokers and families were recruited over five years from regions of the mid-South. Nicotine dependence was ascertained by three commonly-used, highly-correlated measures. In linkage, association and fine-mapping methodologies the following have been reported: 1) Following replication of linkage of chromosome 9q22-q23, haplotypes of the gene encoding src homology 2 domain-containing transforming protein Cs (SHC3) within this region were found to be negatively-correlated, suggesting a protective factor in both EA and AA subjects. Li, M.D., Sun, D., Lou, X-Y., Beuten, J., and Ma, J.Z., Molecular Psychiatry 2006; 2) Neurotrophic tyrosine kinase receptor 2 gene also found in this region was also investigated with the result that some SNPs and haplotypes were significantly associated in EA and one haplotype was associated in AA. Beuten, J., Ma, J.Z., Payne, T.J., Dupont, R.T., Lou, X-Y., Crews, K.M., Elson, R.C., and Li, M.D., Biological Psychiatry 61, pp. 48-55, 2007; 3) fine-mapping of a linkage region on chromosome 17p13 (from a previous study) demonstrated associations of both the GABARAP and DLG4 genes within this region to be associated only in the EA with marginal, if any, association in AA. Lou, X.Y., Ma, J.Z., Sun, D., Payne, T.J., and Li, M.D. Human Molecular Genetics, 16(2), pp. 142-153, 2006.

Resting Motor Threshold (RMT) Was Elevated in Cocaine-Dependent Patients as Assessed by Transcranial Magnetic Stimulation (TMC)

Boutros and colleagues sought to explore differences in cortical excitability in abstinent cocaine patients compared to non-drug users. First, they replicated a previous finding of elevated RMT using a single pulse applied to an area above the left parietal cortex in right-handers. They then investigated facilitation (or inhibition) of cortical responses with a two-pulse methodology at various interstimulus intervals (ISI) believed to indicate exaggerated motor cortical excitability. At an ISI, they found a three-fold increase (and no effect on inhibitory systems) which they hypothesized was due to enhanced glutamatergic excitability through NMDA and/or non-NMDA receptors in cocaine dependent individuals. They also suggested that the elevated resting potential might be a protective mechanism. Sundaresan, K., Ziemann, U., Stanley, J., and Boutros, N. Neuro Report, 18(3), pp. 289-292, 2007.

Increased Risk of Infection in Cocaine Patients due to Decreased Cytokine Expression

Irwin and colleagues assessed the expression of monocytes expression of tumor necrosis factor-alpha and interleukin-6 in cocaine patients a) following acute abstinence, b) in response to single-dose cocaine administration, and c) in response to bacterial ligand lipopolysaccharide. In all cases, there was decreased cytokine expression either at "rest" or in response to the bacterial ligand. Moreover, the effect persisted over a two-day period, long after cocaine had cleared metabolically from the blood. These data imply there is an increased risk of bacterial infectious diseases both in subjects with sustained use and among those who use a single dose of cocaine. Irwin, M.R., Olmos, L., Wang, M., Valladares, E.M., Motivala, S.J., Fong, T., Newton, T., Butch, A., Olmstead, R. and Cole, S.W. Journal of Pharmacology and Experimental Therapies, 320, pp. 507-515, 2007.

Alcohol Dehydrogenase Gene Variants Modulate Risk for Drug Dependence Together with or Separate from Risk Conferred to Patients with Alcohol Dependence

Following up on a previous finding that certain gene variants conferred risk in individuals with alcohol dependence, Gelernter and colleagues assessed the effect of gene variants among the ADH genotypes on drug dependence (either opioid or cocaine dependence). Using diplotype trend regression analyses, it was found that some variants of ADH5 and ADH6 were observed both in both European- and African-American drug dependent populations while others were associated in one population but not another or had opposite effects. Part of this observation is explained by differential frequencies of the rare allele in one or the other population. These data suggest that a common etiology, in part, underlies both alcohol dependence and drug dependence thereby explaining the high rate of comorbidity. Luo, X., Kranzler, H.R., Zuo, L., Wang, S., Schork, N.J., and Gelernter, J. Human Molecular Genetics, 16(4), pp. 380-390, 2007.

Prefrontal Cortex Activity is Reduced in Gambling and Non-Gambling Substance Users During Decision-Making

Poor decision-making is a hallmark of addiction, whether to substances or activities. Performance on a widely used test of decision-making, the Iowa Gambling Task (IGT), can discriminate controls from persons with ventral medial frontal lesions, substance-dependence, and pathological gambling. Positron emission tomography (PET) studies indicate that substance-dependent individuals show altered prefrontal activity on the task. Here authors adapted the IGT to an fMRI setting to test the hypothesis that defects in ventral medial and prefrontal processing are associated with impaired decisions that involve risk but may differ depending on whether substance dependence is comorbid with gambling problems. Eighteen controls, 14 substance-dependent individuals (SD), and 16 SD with gambling problems (SDPG) underwent fMRI while performing a modified version of the IGT. Group differences were observed in ventral medial frontal, right frontopolar, and superior frontal cortex during decision-making. Controls showed the greatest activity, followed by SDPG, followed by SD. Results of this work support a hypothesis that defects in ventral medial frontal processing lead to impaired decisions that involve risk. Reductions in right prefrontal activity during decision-making appear to be modulated by the presence of gambling problems and may reflect impaired working memory, stimulus reward valuation, or cue reactivity in substance-dependent individuals. Tanabe, J., Thompson, L., Claus, E., Dalwani, M., Hutchison, K., and Banich, M.T. Hum Brain Mapp, February 1, 2007 [Epub ahead of print].