Research Findings - Clinical Neuroscience Research

Smoking Topography and Mood: Effects of Trauma-Related Recall Versus Recall of Neutral Experiences in Trauma Survivors with PTSD

Researchers at Duke Medical Center measured smoking topography in trauma survivors with and without posttraumatic stress disorder (PTSD) after recalling trauma-related and neutral experiences. Analysis of covariance was performed on puff topography and mood measures using nicotine dependence scores and current major depressive disorder as covariates. Puff volumes were higher in the PTSD group than in the non-PTSD group. The PTSD group exhibited stable puff onset intervals while the non-PTSD group exhibited significantly shorter intervals following trauma recall. These findings support a "ceiling effect" hypothesis in which individuals with PTSD perpetually smoke in such a way as to maximize nicotine delivery, possibly reducing the potentially reinforcing effects of increased smoke delivery in negative affect-inducing situations. McClernon, F.J., Beckham, J.C., Mozley, S.L., Feldman, M.E., Vrana, S.R. and Rose, J.E. Addictive Behaviors, 30, pp. 247-257, 2005.

Additive Effects of HIV and Chronic Methamphetamine Use on Brain Metabolite Abnormalities

Dr. Linda Chang and associates sought to determine whether HIV coupled with a history of chronic methamphetamine (METH) use might have additive or interactive effects on brain metabolite abnormalities. 1H-MRS was performed in 68 HIV-positive subjects (24 with a history of chronic METH use with a lifetime exposure of a mean of 2,167 g and last use a mean of 4.9 months earlier and 44 HIV+ individuals with no history of drug abuse) and compared to 1H-MRS in 75 HIV-negative subjects (36 with a history of chronic METH use with a lifetime exposure of a mean of 8,241 g and last use a mean of 6.3 months earlier; 39 had no history of drug abuse). Results showed decreased N-acetylaspartate and increased myo-inositol in subjects with chronic METH use and in subjects infected with HIV. Chronic METH users who were HIV- showed lower concentrations of N-acetylaspartate in the frontal white matter and basal ganglia and higher concentrations of choline compounds and myo-inositol in the frontal cortex, relative to subjects with no history of drug abuse. HIV+ status was associated with lower concentrations of N-acetylaspartate and creatine in the frontal cortex and higher concentrations of myo-inositol in the white matter, compared with HIV- status. The combined effects of HIV and chronic METH use were consistent with an additive model, suggesting additional neuronal injury and glial activation due to the comorbid conditions. Chang, L., Ernst, T., Speck, O. and Grob, C.S. American Journal of Psychiatry, 162, pp. 361-369, 2005.

Decreased Brain Dopaminergic Transporters in Patients With HIV-Associated Dementia

Since HIV has a propensity to invade subcortical regions of the brain, which may lead to a subcortical dementia termed HIV-cognitive motor complex, NIDA investigators assessed whether dopamine (DA) D2 receptors and transporters (DAT) are affected in the basal ganglia of subjects with HIV, and how these changes relate to dementia status. Fifteen HIV subjects (average age 44.5; mean CD4 185mm) and 13 seronegative controls (average age of 42) were evaluated with PET to assess availability of DAT ([11C]cocaine) and DA D2 receptor ([11C]raclopride). HIV patients with associated dementia (HAD), but not those without dementia (ND) had significantly lower DAT availability in putamen and ventral striatum compared with seronegative controls. Higher plasma viral load in the HIV dementia patients correlated with lower DAT in the caudate and putamen. DA D2 receptor availability, however, showed mild and non-significant decreases in HIV patients. These results provide the first evidence of DA terminal injury in HIV dementia patients, and suggest that decreased DAT may contribute to the pathogenesis of HIV dementia. The greater DAT decrease in the putamen than in the caudate parallels that observed in Parkinson's disease. The inverse relationship between viral burden and DAT availability further supports HIV-mediated neurotoxicity to dopaminergic terminals. Wang, G.J., Chang, L., Volkow, N.D., Telang, F., Logan, J., Ernst, T. and Fowler, J.S. Brain, 127, pp. 2452-2458, 2004.

Neurocognitive Performance of Methamphetamine Users Discordant for History of Marijuana Exposure

Abuse of the stimulant drug methamphetamine (METH) is associated with neural injury and neuropsychological (NP) deficits, while the residual effects of marijuana use remain uncertain. Researchers at UCSD sought to determine if methamphetamine dependent persons who also met criteria for marijuana abuse or dependence evidenced different NP performance than those with dependence for METH alone. Three groups that did not differ significantly on important demographic factors were tested: (1) subjects with a history of METH dependence and history of marijuana (MJ) abuse/dependence (METH+/MJ+, n=27); (2) METH dependent subjects without history of MJ abuse/dependence (METH+/MJ-, n=26); (3) a control group with minimal or no drug use (n=41). A comprehensive NP battery was administered and performance was quantified for five cognitive ability areas. The METH+/MJ- group generally demonstrated the greatest NP impairment, with statistically significant differences observed between the METH+/MJ- and control group in learning, retention/retrieval, and a summary score of global NP performance. The METH+/MJ+ group did not differ significantly from the control or METH+/MJ- group on any NP ability. However, there was a significant linear trend in the global NP score suggesting that the METH+/MJ+ performed intermediate to the control and METH+/MJ- groups. Based on these findings, the authors cannot conclude that there is a protective effect of marijuana use in METH users; however, MJ use clearly did not appear to exacerbate METH neurotoxicity. Further investigations are needed to determine if the emerging literature, suggesting that certain cannabinoids might have neuroprotective actions, is generalizable to community-dwelling substance abusers. Gonzalez, R., Rippeth, J.D., Carey, C.L., Heaton, R.K., Moore, D.J., Schweinsburg, B.C., Cherner, M. and Grant, I.. Drug and Alcohol Dependence, 76, pp. 181-190, 2004.

Route of Administration of Methamphetamine in Men Who Have Sex With Men Uncovers Psychosocial Differences, Risk Behaviors

Dr. Grant and colleagues at UCSD compared injection and non-injection users of METH in terms of background characteristics, drug use patterns, health and social problems, sexual risk behavior, and psychosocial factors. The sample consisted of 194 HIV+Men who have Sex with Men (MSM) who were enrolled in a sexual risk reduction intervention for METH users. Men who injected METH were significantly more likely to be Caucasian, bisexual, homeless, divorced/separated, with lower educational attainment as compared to non-injectors. Injectors also reported more years of METH use, greater frequency and amount of METH, more social and health problems, including higher prevalence of STDs and Hepatitis C, and more sexual risk behaviors. In terms of psychosocial factors, injection users of METH scored significantly higher on measures of impulsivity and experiences of rejection, and lower on a measure of emotional support. A multivariate logistic regression revealed that educational attainment and experiences of rejection were the factors that best discriminated between injection and non-injection users of METH. The unique characteristics of injection METH users are discussed in relation to the development of effective HIV prevention programs for the target population. Semple, S.J., Patterson, T.L. and Grant, I. Drug Alcohol Dependence, 76, pp. 203-212, 2004.

Neurocognitive and Emotional Differences in Abstinent Drug Abusers Compared to Non Users

NIDA researchers undertook a study to compare the performance of abstinent drug abusers (n = 21) and nonuser control participants (n = 20) in neurocognitive and emotional functions by use of the Rogers Decision Making Task, Gambling Task, Emotional Stroop, impulsivity continuous performance task (CPT), and vigilance CPT. Skin conductance (SC) and heart rate (HR) monitoring was synchronized with task performance. Groups showed similar performance for vigilance, impulsivity, and emotional interference; however, drug abusers showed stronger SC responses. Drug abusers performed more poorly on the Gambling and Rogers Decision Making Tasks. When making risky decisions, drug abusers showed significantly less increase in SC activity than controls and exhibited lower HRs throughout performance on all tasks. In conclusion, complex tasks involving decision making, sensitivity to consequences, and emotional regulation discriminated between drug abusers and controls. Fishbein, D., Hyde, C., Eldreth, D., London. E.D., Matochik, J., Ernst, M., Isenberg, N., Steckley, S., Schech, B. and Kimes A. Experimental Clinical Psychopharmacology, 13, pp. 25-40, 2005.

Nicotine Temporarily Normalizes Smooth Pursuit Eye Movement Deficits in Schizophrenia

Dr. Tanabe and colleagues used functional magnetic resonance imaging (fMRI) to examine changes in brain hemodynamic response associated with nicotine administration during a smooth pursuit eye movement task in subjects with schizophrenia. Nine subjects with schizophrenia performed the eye movement task while undergoing fMRI. Subjects were then given nicotine (pilocrilex) or placebo and repeated the task while being scanned. Subjects repeated the procedure the following week, receiving the counterbalanced condition. Compared with placebo, nicotine was associated with greater activity in the anterior and posterior cingulate gyri, precuneus, and area MT/MST and less activity in the hippocampus and parietal eye fields. Changes in area MT/MST and the cingulate gyrus are consistent with an improvement in perception and attention to moving stimuli. The most important observed difference between nicotine and placebo--less activation of the hippocampus after nicotine than after placebo administration--is consistent with nicotinic receptor mediation of inhibitory neuronal dysfunction in schizophrenia. Tregellas J.R., Tanabe J.L., Martin L.F. and Freedman R. American Journal of Psychiatry, 162, pp. 391-393, 2005.

Cognitive Mechanisms Underlying Deficits in Episodic Verbal Memory in Methamphet-amine (METH) Abusers

Dr. Igor Grant and colleagues at UCSD evaluated a component process model of episodic verbal memory in 87 persons with METH dependence (METH+) and 71 demographically similar non-METH-using controls (METH-). Compared with METH- controls, METH+ participants demonstrated deficient overall learning, free recall, and utilization of semantic clustering, as well as higher rates of repetitions and intrusions. No between-groups differences were evident on measures of serial clustering, retention, or recognition discrimination. Taken together, these findings indicate that METH dependence is associated with deficient strategic (i.e., executive) control of verbal encoding and retrieval, which is consistent with the sequelae of METH-related prefronto-striatal circuit neurotoxicity. Woods, S.P., Rippeth, J.D., Conover, E., Gongvatana, A., Gonzalez, R., Carey, C.L., Cherner, M., Heaton, R.K. and Grant, I. Neuropsychology, 19, pp. 35-43, 2005.

Transverse Relaxation Rate Can Compromise fMRI Results

Several modern MRI techniques, such as functional MRI (fMRI), rely on the detection of microscopic changes in magnetic susceptibility. However, differences in magnetic susceptibility between brain tissue, bone, and air also produce local magnetic field gradients that may interfere with the contrast of interest, particularly at high field strengths. Since the magnetic field distribution depends on the orientation of the human head in the MRI scanner, head rotations can change the effective transverse relaxation rate (R(2)*) and confound fMRI studies. The size of the R(2)* changes produced by small head rotations was estimated from a brain-shaped gel-phantom at 4 T, by measuring the signal decay at 96 different echo times. Similar measurements were carried out in a human study. Rotations larger than 2 degrees changed R(2)* more than 1.5 Hz in the phantom, and indicate that even small rotations may compromise fMRI results. Caparelli, E.C., Tomasi, D. and Ernst, T. Neuroimage, 15, pp. 1164-1169, 2005.

Neurotoxic Effects of Prenatal Methamphetamine (METH) Exposure on the Developing Brain and on Cognition

Dr. Linda Chang and associates at the University of Hawaii examined Meth-exposed children (n=13) and unexposed controls (n=15) with MRI in a pilot study to examine neurotoxic effects of prenatal METH exposure. Global brain volumes and regional brain structures were quantified. Ten METH-exposed and nine unexposed children also completed neurocognitive assessments. METH-exposed children scored lower on measures of visual motor integration, attention, verbal memory and long-term spatial memory. There were no differences among the groups in motor skills, short delay spatial memory or measures of non-verbal intelligence. Despite comparable whole brain volumes in each group, the METH-exposed children had smaller putamen bilaterally (-17.7%), smaller globus pallidus (left: -27%, right: 30%), smaller hippocampus volumes (left: -19%, right: -20%) and a trend for a smaller caudate bilaterally (-13%). The reduction in these brain structures correlated with poorer performance on sustained attention and delayed verbal memory. No group differences in volumes were noted in the thalamus, midbrain or the cerebellum. In summary, compared with the control group, children prenatally exposed to METH exhibit smaller subcortical volumes and associated neurocognitive deficits. These preliminary findings suggest that prenatal METH exposure may be neurotoxic to the developing brain. Chang, L., Smith, L.M., LoPresti, C., Yonekura, M.L., Kuo J., Walot, I. and Ernst, T. Psychiatry Research, 132, pp. 95-106, 2004.

New Measures of Corpus Callosum Size Are Related To Drug Abuse and To Childhood Neglect and Abuse

While many neuroimaging studies focus on deficits in cortical gray matter in patients with drug abuse or with cognitive deficits, Dr. Moeller and associates at the University of Texas Health Science Center, Houston, have used recent technology in Diffusion Tensor Imaging (DTI) and found reduced white matter integrity in areas of the corpus callosum in cocaine-dependent subjects. In addition, tests of impulsivity showed significant (negative) correlations with callosal integrity. It should be noted, however, that not the entire callosum showed a difference between cocaine-dependent subjects and controls; differences were found only in the genu and rostral body and are likely related to cross-connecting areas in the prefrontal cortex. Moeller, F.G., Hasan, K.M., Steinberg, J.L., Kramer L.A., Dougherty, D.M., Santos, R.M., Valdes, I., Swann, A.C., Barratt, E.S. and Narayan, P.A. Neuropsychopharmacology, 30, pp. 610-617, 2005.

Childhood Neglect Is Associated With Reduced Corpus Callosum Area

Dr. Teicher and colleagues at McLean Hospital reported reduced corpus callosum area in children who were neglected or abused. This is important because early physical or sexual abuse is likely associated with later drug abuse. However, the affected areas were posterior to those found by Moeller and associates. Nevertheless, these data may help understand the effect of early events in brain development and their impact on drug abuse liability. Teicher, M.H., Dumont, N.L., Ito, Y., Vaituzis, C., Giedd, J.N and Anderson, S.L. Biological Psychiatry, 56, pp. 80-85, 2004.

Specific Brain Regions Are Activated Following Script-Induced Emotions In Cocaine Users and in Non-Using Individuals

Dr. Sinha at Yale University has found limbic and other brain structures to be activated as measured by fMRI in cocaine users and in non-using subjects as they listen personalized scripts designed to induce heightened emotions. In non-using subjects, increases were observed in limbic and midbrain regions such as the striatum, and thalamic regions, caudate, putamen, hippocampus, parahippocampus and posterior cingulate. In some of these areas, left activation was greater. In cocaine users, stress tended to activate temporal areas in addition to medial and superior frontal gyri and anterior cingulate. Of most interest, women seemed to have the greater activation. Sinha, R., Lacadie, C., Skudlarksi, P. and Wexler, B.E., Annals of the New York Academy of Science, 1032, pp. 254-257, 2004; Li, C-S.R., Koston, T.R. and Sinha, R. Biological Psychiatry, 57, pp. 487-494, 2005.

Allelic Variants within the GABAB Receptor Subunit 2 (GABAB2) Gene Significantly Associated with Nicotine Dependence

Dr. Li and colleagues at University of Texas Health Science Center conducted a detailed study on Gamma-aminobutyric acid type B receptor subunit 2 (GABAB2) that is mapped to the linkage area on Chromosome 9. It was investigated with single nucleotide polymorphisms (SNPs) and associated haplotypes in a sample of European Americans (EA) and African Americans (AA). Significant associations to nicotine dependence were found for four of the twelve SNPs in the pooled sample and two SNPs in the AA sample and four in the EA sample. In addition, haplotypes made up of some of these SNPs were also significant, and in two cases, highly significantly associated with nicotine dependence. These results indicate that GABAB2 may be associated with nicotine dependence even though these gene variants themselves were not likely to be responsible for dependence. In addition it is clear there are ethnic differences in the associations. The authors conclude that "the study not only confirms molecular and pharmacological data about the importance of the family of GABA receptor genes in addictive/behavioral trains, but it also provides new information on the genetics of nicotine dependence." Beuten, J., Ma, J.Z., Payne, T.J., Dupont, R.T., Crews, K.M., Somes, G., Williams, N.J., Elson, R.C. and Li, M.D. American Journal of Human Genetics, 76, pp. 859-864, 2005.

Susceptibility Loci and Gene Variants (Including One Within A GABAB2 Subunit) Associated With Nicotine Dependence

Dr. Li and colleagues at the University of Texas Health Science Center, San Antonio, report linkages and suggestive linkages to various chromosome regions and markers from two separate cohorts. One includes permutation linkage analysis of the well-known Framingham Heart Study cohort. Using "cigarettes per day" as the best (highest correlative) measure of nicotine dependence, linkages were found on chromosomes 1,3,4,7,8,9,11,16,17, and 20; the highest significance was for 1 and 4. Most of these have been reported by other nicotine studies and therefore provide good candidate regions for further study. Wang, D., Ma, J.Z. and Li, M.D. The Pharmacogenomics Journal, e-publication, 2005.

Neurophysiology of Motor Function following Cannabis Discontinuation in Chronic Cannabis Smokers: An fMRI Study

Dr. Yurgelun-Todd and her colleagues at McLean Hospital used fMRI to investigate whether attentional areas related to motor function as well as primary and supplementary motor cortices would show diminished activation in chronic cannabis smokers. Nine cannabis smokers and 16 controls were scanned using a 1.5 T scanner during a finger sequencing task. Cannabis users, tested within 4-36 hr of discontinuation, exhibited significantly less activation than controls in the anterior cingulate (BA 24 and 32) and pre-motor cortex (BA 6). There were no statistically significant group differences in BA 4. None of these regional activations correlated with urinary cannabis concentration and verbal IQ for smokers. These results suggest that recently abstinent chronic cannabis smokers produce reduced activation in motor cortical areas in response to finger sequencing compared to controls. Pillay, S.S., Rogowska, J., Kanayama, G., Jon, D.I., Gruber, S., Simpson, N., Cherayil, M., Pope, H.G. and Yurgelun-Todd, D.A. Drug and Alcohol Dependence 76, pp. 261-271, 2004.

Dissociation in Attentional Control in Methamphetamine Dependence

Dr. Ruth Salo and colleagues at the University of California, Davis investigated whether task-shifting, selective inhibition, or both processes were impaired in long-term but currently abstinent methamphetamine-dependent individuals. Methamphetamine-dependent subjects (n=34) and nonsubstance abusing controls (n=20) were tested on an alternating-runs switch task with conflict sequences that required subjects to switch tasks on every second trial (AABBAABB). Methamphetamine-dependent individuals committed more errors on trials that required inhibition of distracting information compared with controls (methamphetamine = 17%, controls = 13%, p =.02). By contrast, error rates did not differ between the groups on switch trials (methamphetamine = 7%, controls = 6%, n.s.). These results indicate that selective inhibition, but not task switching , is selectively compromised by methamphetamine. Salo, R.., Nordahl, T.E., Moore, C., Waters, C., Natsuaki, Y., Galloway, G.P., Kile, S. and Sullivan, E.V. Biological Psychiatry 57, pp. 310-313, 2005.

Role of the Amygdala and the Medial Temporal Lobe Memory System in Retrieving Emotional Memories One Year Later

Dr. Kevin LaBar and colleagues at Duke University used fMRI to investigate the contribution of emotion on memory-enhancing retrieval processes after lengthy retention intervals. In the present study, event related fMRI was used to measure neural activity during the retrieval of emotional and neutral pictures after a retention interval of 1 yr. Retrieval activity for emotional and neutral pictures was separately analyzed for successfully (hits) vs. unsuccessfully (misses) retrieved items and for responses based on recollection vs. familiarity. Recognition performance was better for emotional than for neutral pictures, and this effect was found only for recollection-based responses. Successful retrieval of emotional pictures elicited greater activity than successful retrieval of neutral pictures in the amygdala, entorhinal cortex, and hippocampus. In the amygdala and hippocampus, the emotion effect was greater for recollection than for familiarity, whereas in the entorhinal cortex, it was similar for both forms of retrieval. These findings suggest that the amygdala and the medial temporal lobe memory regions play a role in recollection and familiarity of memories with emotional content after lengthy retention intervals, such as with events associated with drug use. Dolcos, F., LaBar, K.S. and Cabeza, R. Proceedings of the National Academy of Sciences of the United States of America 102, pp. 2626-2631, 2005.

Anger and Depression in Cocaine Addiction: Association with the Orbitofrontal Cortex

Dr. Rita Goldstein and colleagues at Brookhaven National Laboratories investigated whether anger, impulsivity and violence is related to the compromise of higher-order inhibitory control neurocognitive processes mediated by frontal brain regions in cocaine addiction. The Minnesota Multiphasic Personality Inventory-2 (MMPI-2) anger content scale was used as a personality measure of inhibitory control. This scale was examined for correlations with glucose metabolism in the lateral orbitofrontal gyrus (LOFG) at rest as measured by positron emission tomography with 2-deoxy-2[F-18]fluoro-D-glucose (PET (18)FDG) in 17 recently abstinent cocaine-dependent subjects and 16 comparison subjects. Three additional variables-the MMPI-2 depression content scale, metabolism in the medial orbitotrontal gyrus (MOFG) and the anterior cingulate (AC) gyrus were also examined. When level of education was statistically controlled for, the LOFG was significantly associated with anger within the cocaine group. No other region was associated with anger within the cocaine-dependent group. The LOFG did not correlate with depression within any of the study groups. The present study confirms earlier reports in demonstrating a positive association between relative metabolism at rest in the LOFG and cognitive-behavioral and personality measures of inhibitory control in drug addiction: the higher the metabolism, the better the inhibitory control. Goldstein, R.Z., Alia-Klein, N., Leskovjan, A.C., Fowler, J.S., Wang, G.J., Gur, R.C., Hitzemann, R. and Volkow N.D. Psychiatry Research-Neuroimaging 138, p. 13, 2005.

Frontal Networks for Learning and Executing Arbitrary Stimulus - Response Associations

Dr. Mark D'Esposito at the University of California, Berkeley used fMRI to investigate the role of the prefrontal cortex in flexible rule learning, such as the formation of arbitrary stimulus-response (S-R) associations. Since humans learn these rules very quickly, fMRI scans were acquired while normal, healthy subjects learned by trial and error to associate sets of abstract visual stimuli with arbitrary manual responses. Successful learning of this task required discernment of a categorical type of S-R rule in a block design expected to yield sustained rule representation. Our results show that distinct components of the dorsolateral, ventrolateral, and anterior PFC, lateral premotor cortex, supplementary motor area, and the striatum are involved in learning versus executing categorical S-R rules. Boettiger, C.A. and D'Esposito, M. Journal of Neuroscience 25, pp. 2723-2732, 2005.

Brain Metabolite Abnormalities in Methamphetamine Users in Sustained Abstinence

Dr. Thomas Nordahl and colleagues at the University of California, Davis used proton magnetic resonance spectroscopy (MRS) to determine whether methamphetamine abusers (n=8) continue to exhibit abnormalities in brain neurochemistry after 1 year of abstinence compared to recently abstinent methamphetamine abusers (n=16). Absolute levels of creatine (Cr) did not differ between methamphetamine abusers and normal controls. Compared to controls, both recent and long-term abstinent methamphetamine abusers had low levels of n-acetylaspartate-creatine to phosphocreatine ratios (NAA/Cr) in the anterior cingulate cortex. These differences were specific to the frontal cortex in that no differences were seen in NAA/Cr ratios between controls and methamphetamine abusers in the primary visual cortex. On the other hand, choline-creatine to choline-N-acetylaspartate (Cho/NAA) ratios were abnormally elevated in the anterior cingulate of recently abstinent methamphetamine abusers, but were at normal levels in the methamphetamine abusers who had been abstinent for a year. These results indicate that following one year of abstinence from methamphetamine, some, but not all, measures of brain neurochemistry show evidence of recovery. Nordahl, T.E., Salo, R. Natsuaki, Y., Galloway, G.P., Waters, C., Moore, C.D., Kile, S. and Buonocore, M.H. Archives of General Psychiatry 62, pp. 444-452, 2005.