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Director's Report to the National Advisory Council on Drug Abuse - May, 2006

Research Findings - Clinical Neuroscience Research

Cognitive Function and Nigrostrial Markers in Abstinent Methamphetamine Abusers

Johanson and colleagues at Wayne State University in collaboration with investigators at University of Michigan, Haight Ashbury Free Clinics, and Cambridge University used Positron Emission Tomography (PET) to investigate the integrity of dopaminergic terminals and cognitive function in abstinent methamphetamine abusers (MA). Striatal levels of membrane Dopamine transporters (DAT) and vesicular monoamine transporters (VMAT2) were assessed using [11C] methylphenidate and [11C]dihydrotetrabenazine. Tests of motor function, memory, learning, attention, and executive function were also administered to evaluate cognitive function. Mean abstinence from methamphetamine was 3 years and ranged from 3 months to up to 10 years. Both DAT and VMAT2 were lower in MA than controls (-15% DAT, -10% VMAT2) across all striatal regions. MA performed more poorly than controls on 3 of the 12 cognitive tasks, but MA performance was still within normative range. Reductions in VMAT2 in human MA support pre-clinical studies indicating toxic effects of methamphetamine on dopaminergic nerve terminals. Although the failure to find more substantial changes in the PET or cognitive measures may have been due to the length of abstinence, there were no correlations of the PET or cognitive measures with the length of abstinence. The relatively small magnitude of the effects on the integrity of dopaminergic terminals raise questions as to whether clinical signs of dopaminergic deficiency will be evident in former methamphetamine abusers. Johanson, C.E., Frey, K.A., Lundahl, L.H. Keenan, P., Lockhart, N., Roll, J., Galloway, G.P., Koeppe, R.A., Kibourn, M.R., Robbins, T. and Schuster, C.R. Psychopharmacology, 185, pp. 327-338, 2006.

Ambiguity in Groups of Emotional Faces Recruits Ventromedial Prefrontal Cortex

Paulus and colleagues at the University of California, San Diego, used fMRI in a social neuroscience study of affective appraisal of the mood of a group of people. Affective neuroimaging research often uses individual faces as stimuli when exploring the neural circuitry involved in social appraisal, but single face paradigms may not generalize to settings where multiple faces are simultaneously processed. In this study groups of multiple matrices of affective faces were briefly presented during fMRI scans. Subjects were asked to decide whether there were more angry or happy faces (emotional decision) or whether there were more male or female faces (gender decision). In each condition, the array contained either an equal (ambiguous trials) or an unequal (unambiguous trials) distribution of one affect or gender. Ambiguous trials relative to unambiguous trials activated regions implicated in conflict monitoring and cognitive control, including the dorsal anterior cingulate cortex (ACC), dorsolateral PFC, and posterior parietal cortex. The ventromedial PFC (including the ventral ACC) was activated specifically by ambiguous affective decisions compared with ambiguous gender decisions. This supports the dissociation of the ACC into dorsal cognitive and ventral affective divisions, and suggests that the ventromedial PFC may play a critical role in appraising affective tone in a complex display of multiple human faces. This study forms the foundation for investigating whether drug abusers show impairment in brain systems involved in affective appraisal of groups. Since many treatment approaches involve group therapy, such a dysfunction could have substantial implications for treatment development. Simmons, A., Stein, M.B., Matthews, S.C., Feinstein, J.S. and Paulus, M.P. Neuroimage, 29(2), pp. 655-661, 2006.

Prefrontal and Temporal Gray Matter Density Decreases in Opiate Dependence

Renshaw and colleagues at McLean Hospital used structural brain imaging to study gray matter density alteration in opiate-dependent subjects. There have only been a few studies performed to date and these have had varied findings. This method is suitable for studying whole brain-wise structural brain. The current study used voxel-based morphometry (VBM) determination of gray matter density that was made in 63 opiate-dependent subjects and 46 age- and sex-matched healthy comparison subjects. Relative to healthy comparison subjects, opiate-dependent subjects exhibited decreased gray matter density bilaterally in the prefrontal cortex, insula, superior temporal cortex, as well as the left fusiform cortex and right uncus. It remains to be determined whether gray matter density decreases in prefrontal and temporal cortex are associated with behavioral and neuropsychological dysfunction in opiate-dependent subjects. Lyoo, I.K., Pollack, M.H., Silveri, M.M., Ahn, K.H., Diaz, C.I., Hwang, J., Kim, S.J., Yurgelun-Todd, D.A., Kaufman, M.J. and Renshaw, P.F. Psychopharmacology, 184(2), pp. 139-144, 2006.

Increased White Matter Hyperintensities in Male Methamphetamine Abusers

Renshaw and colleagues at McLean Hospital used structural MRI to assess the prevalence, severity, and location of white matter signal hyperintensities (WMH) in methamphetamine (MA) abusers. Axial T-2 weighted images and fluid attenuated inversion recovery axial images were obtained using a 3T MR scanner from 33 MA abusers and 32 age- and gender-matched healthy comparison subjects. The severity of WMH was assessed separately for deep and periventricular WMH. Ordinal logistic regression models were used to assess the odds ratio for WMH. MA abusers had greater severity of WMH than the healthy comparison subjects (odds ratio: 7.06, 8.46, and 4.56 for all, deep, and periventricular WMH, respectively). Severity of deep WMH correlated with total cumulative dose of MA (p = 0.027). These differences were mainly due to increased WMH in male MA abusers. There was greater severity of WMH in male than female MA abusers (odds ratio = 10.00). Male MA abusers had greater severity of WMH than male comparison subjects (odds ratio = 18.86), but there was no significant difference in WMH severity between female MA abusers and female comparison subjects. Increased WMH in MA abusers may be related to MA-induced cerebral perfusion deficits. The lower severity of WMH in female MA abusers may be due to estrogen's protective effect against ischemic or neurotoxic effects of MA. Bae, S.C., Lyoo, I.K., Sung, Y.H., Yoo, J., Chung, A., Yoon, S.J., Kim, D.J., Hwang, J., Kim, S.J. and Renshaw, P.F. Drug And Alcohol Dependence, 81(1), pp. 83-88, 2006.

Grey and White Matter GABA Level Differences in the Human Brain Using Two-Dimensional, J-Resolved Spectroscopic Imaging

Renshaw and colleagues at McLean Hospital used a magnetic resonance spectroscopy (MRS) method to determine brain gamma-aminobutyric acid (GABA) levels. Two-dimensional, J-resolved chemical-shift imaging sequence on a 4T scanner was used to MRS images on a 4 T scanner from six healthy subjects. Using image segmentation and a linear-regression analysis relating brain GABA level to tissue-type, a consistent and significant (n = 6, p < 0.01) elevation of mean GABA levels was measured in the cortical grey matter (0.96 +/- 0.24 mm) compared with white matter (0.44 +/- 0.16 mm) across all six subjects. The results suggest an approximately two-fold elevation of GABA levels in cortical grey matter compared with white matter in vivo. Our findings are consistent with ex vivo studies in the literature of both animal and human brain and demonstrate the significant potential of this technique for detecting and quantifying tissue-specific neurochemical pathology in vivo. Jensen, J.E., Frederick, B.D. and Renshaw, P.F. NMR In Biomedicine, 18(8), pp. 570-576, 2005.

Neural Correlates of Direct and Reflected Self-Knowledge

D'Esposito and colleagues at University of California, Berkeley, in collaboration with investigators at Stanford University, used fMRI to compare brain mechanisms mediating direct appraisals of self (i.e., an individual's own self-beliefs) versus reflected appraisals (i.e., an individual's perception of how others view him or her). One experiment compared the common and distinct neural bases of direct appraisals of the self, close others, and normative judgments of trait desirability. All three judgment types activated medial prefrontal cortex (MPFC) to a similar degree. A second experiment examined the common and distinct neural bases of (1) direct appraisals of self, a close other or a non-close other, and (2) reflected appraisals made from the perspective of a close or a non-close other. Consistent with the first study all judgment types activated MPFC. Direct appraisals of the self as compared to others more strongly recruited MPFC and right rostrolateral PFC. Direct appraisals as compared to reflected appraisals recruited regions associated with a first-person perspective (posterior cingulate), whereas reflected as compared to direct appraisals recruited regions associated with emotion and memory (insula, orbitofrontal, and temporal cortex). These results support models suggesting that MPFC mediates meta-cognitive processes that may be recruited for direct and reflected self appraisals depending upon the demands of a specific task. This type of social neuroscience study forms the foundation of future studies that can assess whether drug abusers have altered brain mechanisms for self-knowledge. Such studies provide insights that can be used to direct new treatment approaches. Ochsner, K.N., Beer, J.S., Robertson, E.R., Cooper, J.C., Gabrieli, J.D.E., Kihsltrom, J.F. and D'Esposito, M. Neuroimage, 28(4), pp. 797-814, 2005.

Neural Responses to Acute Cocaine Administration in the Human Brain Detected by fMRI

Risinger and colleagues at the Medical College of Wisconsin used an improved fMRI method for the reduction of susceptibility artifacts to investigate responses to acute cocaine administration in human cocaine users. Intravenous administration of cocaine (20 mg/70 kg) activated a set of hierarchical brain networks in the anterior prefrontal cortex (aPFC) of Brodmann area 10 (BA10) and orbitofrontal cortex (OFC), regions that had previously been difficult to image using BOLD fMRI. In addition, mesolimbic and mesocortical dopaminergic projection regions exhibited both positive or negative BOLD responses over time. This study provides further evidence that dopaminergic pathways and the hierarchical brain networks participate in mediating cocaine reward, associative learning, motivation, and memory in brains of human cocaine addicts. Kufahl, P.R., Li, Z., Risinger, R.C., Rainey, C.J., Wu, G.H., Bloom, A.S. and Li, S.J. Neuroimage, 28(4), pp. 904-914, 2005.

Cognitive Neuroscience of Emotional Memory

K. LaBar of Duke University reviewed the literature on psychological and neural mechanisms underlying emotional retention advantages in the human brain. A major conclusion was that emotion - memory interactions occur at various stages of information processing, from the initial encoding and consolidation of memory traces to their long-term retrieval. The amygdala is a brain structure that directly mediates aspects of emotional learning and facilitates memory operations in other regions, including the hippocampus and prefrontal cortex. Recent advances are revealing new insights into the reactivation of latent emotional associations and the recollection of personal episodes from the remote past. LaBar, K. Nature Reviews Neuroscience, 7(1), pp. 54-64, 2006.

Prefrontal Grey-Matter Changes In Short-Term and Long-Term Abstinent Methamphetamine Abusers

Renshaw and colleagues at McLean Hospital in collaboration with investigators in South Korea used structural MRI to determine the effect of methamphetamine abuse on grey matter density in methamphetamine abusers. Using voxel-based morphometry, grey-matter density in 29 methamphetamine abusers was compared to 20 healthy comparison subjects. In addition, grey-matter density changes and performance on the Wisconsin Card Sorting test (WCST) was compared between 11 short-term (< 6 months) and 18 long-term (>= 6 months) abstinent methamphetamine abusers. Methamphetamine abusers had lower grey matter density in the right middle frontal cortex (corrected p < 0.05) and more total errors in the WCST (p < 0.01) than healthy comparison subjects. Grey-matter density decreases in the right middle frontal cortex correlated with total errors in the WCST in methamphetamine abusers (r = -0.45). Long-term abstinent abusers had significantly less right middle frontal grey-matter density decreases (p < 0.01) and total errors in the WCST (p < 0.01) than short-term abstinent abusers, but more than the healthy comparison subjects. Thus, methamphetamine abusers have prefrontal grey-matter deficit, which may, in part, recover with long-term abstinence. Kim, S.J., Lyoo, I.K., Hwang, J., Chung, A., Sung, Y.H., Kim, J., Kwon, D.H., Chang, K.H. and Renshaw, P.F International Journal of Neuropsychopharmacology, 9(2), pp. 221-228, 2006.

Nicotine and Cognitive Efficiency In Alcoholics and Illicit Stimulant Abusers: Implications Of Smoking Cessation For Substance Users In Treatment

Nixon and colleagues at the University of Kentucky investigated whether nicotine could have a confounding effect on studies of cognition in detoxified substance users. In the current study of 87 participants, behavioral and electrophysiological indices of cognitive efficiency were measured in tobacco smokers from four groups: alcoholics, illicit stimulant abusers, concurrent abusers, and control subjects. They hypothesized that acute nicotine administration would modify cognitive deficits in alcoholics and illicit stimulant abusing groups. An adaptation of the Rapid Visual Information Processing task was administered after stabilization of nicotine levels via a high- or low-dose transdermal nicotine patch. Across groups, increased nicotine dose was associated with decreased reaction time (p = .03). Increasing doses of nicotine were associated with increased correct responding within the alcoholic group (p = .02). No significant differences in electrophysiology were observed. These results suggest that nicotine may modify cognitive efficiency in alcoholics and illicit stimulant abusers. These results are relevant to both the design of experimental work and the treatment of alcohol and illicit stimulant dependence. Further work is needed to determine whether this effect predominantly reflects facilitation of cognition function or alleviation of nicotine withdrawal. Ceballos, N.A., Tivis, R., Lawton-Craddock, A.and Nixon, S.J. Substance Use & Misuse, 41(3), pp. 265-281, 2006.

Sex, Stress, and Fear: Gender and Individual Differences In Conditioned Learning

LaBar and colleagues at Duke University investigated the relationship among sex, stress hormones, and fear conditioning in humans in order to elucidate factors that contribute to individual variation in emotional learning. Forty-five healthy adults (22 females) underwent differential delay conditioning, using fear-relevant conditioned stimuli and a shock unconditioned stimulus. Salivary cortisol samples were taken at baseline and after acquisition training and a 24-h-delayed retention test. Acquisition of conditioning significantly correlated with postacquisition cortisol levels in males, but not in females. This sex-specific relationship was found despite similar overall levels of conditioning, unconditioned responding, and cortisol. There was no effect of postacquisition cortisol on consolidation of fear learning in either sex. These findings have implications for the understanding of individual differences in fear acquisition and risk factors for stress-elicited relapse in substance abusers. Zorawski, M., Cook, C.A., Kuhn, C.M. and LaBar, K.S. Cognitive Affective & Behavioral Neuroscience, 5(2), pp. 191-201, 2005.

Capacity Differences Predict Working Memory Performance and Prefrontal Activity Following Dopamine Receptor Stimulation

D'Esposito and colleagues at the University of California, Berkeley used fMRI to test the relationships between dopamine, pre-frontal cortical (PFC) function, and individual differences in working memory capacity. Subjects performed a verbal delayed-recognition task after taking either the dopamine receptor agonist bromocriptine or a placebo. Behavioral effects of bromocriptine treatment depended on subjects' working memory spans, with the greatest behavioral benefit for lower span subjects. After bromocriptine, PFC activity was positively correlated with a measure of cognitive efficiency (Reaction Time slope) during the probe period of the task. Less efficient subjects with slower memory retrieval rates had greater PFC activity, whereas more efficient subjects had less activity. After placebo, these measures were uncorrelated. These results support the role of dopamine in verbal working memory and suggest that dopamine may modulate the efficiency of retrieval of items from the contents of working memory. Individual differences in PFC dopamine receptor concentration may thus underlie the behavioral effects of dopamine stimulation on working memory function. These results suggest that the effects of drugs of abuse on working memory may be the result of an interaction between pre-existing cognitive capacity and drug-induced alterations in dopaminergic function. Gibbs, S.E.B. and D'Esposito, M. Cognitive Affective & Behavioral Neuroscience 5(2), pp. 212-221, 2005.

Human Striatal Activation Reflects Degree of Stimulus Saliency

Berns and colleagues at Emory University used fMRI to determine whether the striatum responds in an all-or-none fashion to salient events or instead responds in a graded fashion to the degree of saliency associated with an event. Salient stimuli are characterized by their capability to perturb and seize available cognitive resources. Although the striatum and its dopaminergic inputs respond to a variety of stimuli categorically defined as salient, including rewards, the relationship between striatal activity and saliency is not well understood. Twenty healthy participants performed a visual classification task in which they identified single digits as odd or even numbers. An auditory tone preceded each number, which was occasionally, and unexpectedly, substituted by a novel sound. The novel sounds varied in their ability to interrupt and reallocate cognitive resources (i.e., their saliency) as measured by a delay in reaction time to immediately subsequent numerical task-stimuli. Striatal activity increased proportionally to the degree to which an unexpected novel sound interferes with the current cognitive focus, even in the absence of reward. These results suggest that activity in the human striatum reflects the level of saliency associated with a stimulus, perhaps providing a signal to reallocate limited resources to important events. These results provide a framework to interpret the alterations in striatal function observed in drug addicts. Zink, C.F., Pagnoni, G., Chappelow, J., Martin-Skurski, M. and Berns, G.S. Neuroimage, 29(3), pp. 977-983, 2006.

Perfusion Functional MRI Reveals Cerebral Blood Flow Pattern Under

Detre and colleagues at the University of Pennsylvania used a quantitative and noninvasive neuroimaging technique, arterial spin-labeling perfusion MRI, to measure cerebral blood flow (CBF) changes associated with mild to moderate stress. Mild stress was induced by a mental arithmetic task with performance monitoring, and the degree of stress was verified by self-report of stress and emotional state and measures of heart rate and salivary-cortisol level. Changes in CBF induced by the stress task were positively correlated with subjective stress rating in the ventral right prefrontal cortex (RPFC) and left insula/putamen area. The ventral RPFC along with right insula/putamen and anterior cingulate showed sustained activation after task completion in subjects reporting a high stress level during arithmetic tasks. Variations of baseline CBF in the ventral RPFC and right orbitofrontal cortex were found to correlate with changes in salivary-cortisol level and heart rate caused by undergoing stress tasks. Right prefrontal activation could not be attributed to increased cognitive demand accompanying stress tasks and extended beyond neural pathways associated with negative emotions. These results provide evidence that psychological stress induces negative emotion and vigilance and that the ventral RPFC plays a key role in the central stress response. Wang. J.J., Rao, H.Y., Wetmore, G.S., Furlan, P.M., Korczykowski, M., Dinges, D.F. and Detre, J.A. Proceedings National Academy of Sciences, USA, 102(49), pp. 17804-17809, 2005.

Gender and Functional Asymmetry of Ventromedial Prefrontal Cortex

Bechara and colleagues at the University of Iowa investigated whether gender plays a role in the development of defects in social conduct, emotional functioning and decision-making, following unilateral VMPC damage. A previous lesion study found that the more right-sided sector of the ventromedial prefrontal cortices (VMPCs) was critical for social/emotional functioning and decision-making than the left side. However, all but one of the subjects in that study were men, and the one woman did not fit the pattern very well. The study sample consisted of same-sex pairs of men or women patients who had comparable unilateral VMPC damage in either the left or right hemisphere. Two male pairs and one female pair were formed, and authors included two additional women with unilateral right VMPC damage (8 patients in all). The domains of measurement covered social conduct, emotional processing and personality, and decision-making. A systematic effect of gender was found on the pattern of left-right asymmetry in VMPC. Men had severe function defects following unilateral right VMPC damage, but not following left-sided damage. In contrast, functional defects were only found in women with unilateral left VMPC damage, whereas with right-sided damage the defects were mild or absent. The findings suggest that asymmetric, gender-related differences exist in the neurobiology of left and right VMPC sectors and as a result men and women may use different strategies to solve similar problems that parallel differences in information processing between hemispheres. Such differences could reflect. Tranel, D., Damasio, H., Denburg, N.L. and Bechara, A. Brain 128(12), pp. 2872-2881 2005.

Prefrontal GABA Levels in Cocaine-Dependent (CD) Subjects Increase with Pramipexole and Venlafaxine Treatment

Streeter and colleagues at McLean Hospital used proton (H-1) Magnetic Resonance Spectroscopy (MRS) to measure changes in GABA levels in CD subjects at baseline and after 8 weeks of treatment with pramipexole, venlafaxine, or placebo. There is evidence that prefrontal lobe GABA levels are low in cocaine-dependent (CD) individuals, and treatment with GABA agonists decreases cocaine self-administration. GABA levels in the prefrontal lobe were measured before and after treatment. Only Pramipexole-treated subjects had significantly increased brain GABA levels compared to placebo (p=0.031). Mean percentage changes in GABA levels were as follows: pramipexole +17.0 +/- 28.0%, venlafaxine +13.0 +/- 11.0%, and placebo -2.1 +/- 19.5%. Despite significant changes in GABA levels, there were no significant differences in the number of urine samples positive for cocaine metabolites. This study demonstrates that H-1 MRS can measure changes in GABA levels following pharmacologic treatment. The increase in GABA levels, although significant, is modest compared to other MRS studies of depression or epilepsy, associated with clinical improvements. The failure to see larger increases in GABA levels and an associated reduction in cocaine consumption may reflect the relatively low doses of medication used. Streeter, C.C., Hennen, J., Ke, Y., Jensen, J.E., Sarid-Segal, F., Nassar, L.E., Knapp, C., Meyer, A.A., Kwak, T., Renshaw, P.F. and Ciraulo, D.A. Psychopharmacology, 182(4), pp. 516-526, 2005.

Using Cognitive Models to Map Relations Between Neuropsychological Disorders and Human Decision-Making Deficits

Bechara and collegues used a cognitive model to analyze performance in a complex decision-making task (the Iowa gambling task). This model dissociates performance into three different underlying psychological components: the relative impact of rewards and punishments on evaluations of options; the rate that the contingent payoffs are learned; and the consistency between learning and responding. Findings from 10 studies are organized by distilling the observed decision deficits into the three basic components and locating the neuropsychological disorders in this component space. The results reveal a cluster of populations characterized by making risky choices despite high attention to losses, perhaps because of difficulties in creating emotive representations. These findings demonstrate the potential contribution of cognitive models in building bridges between neuroscience and behavior. Yechiam, E., Busemeyer, J.R., Stout, J.C. and Bechara, A. Psychological Science, 16(12), pp. 973-978, 2005.

Cerebral Metabolic Dysfunction and Impaired Vigilance in Recently Abstinent Methamphetamine Abusers

London and colleagues at the University of California, Los Angeles investigated the relationship between cognitive impairment and cerebral abnormalities in limbic and paralimbic cortices and hippocampus in methamphetamine (MA) abusers. Cerebral glucose metabolism was assessed with [F-18]fluorodeoxyglucose positron emission tomography in 17 abstinent (4 to 7 days) methamphetamine users and 16 control subjects performing an auditory vigilance task and obtained structural magnetic resonance brain scans. Error rates on the task were related to regional radioactivity and hippocampal morphology. Methamphetamine users had higher error rates than control subjects on the vigilance task. The groups showed different relationships between error rates and relative activity in the anterior and middle cingulate gyrus and the insula. Whereas the MA user group showed negative correlations involving these regions, the control group showed positive correlations involving the cingulate cortex. Across groups, hippocampal metabolic and structural measures were negatively correlated with error rates. Dysfunction in the cingulate and insular cortices of recently abstinent MA abusers may contribute to impaired vigilance and other cognitive functions requiring sustained attention. Furthermore, hippocampal structural integrity predicts task performance in methamphetamine users as well as control subjects. London, E.D., Berman, S.M., Voytek, B., Simon, S.L., Mandelkern, M.A., Monterosso, J., Thompson, P.M., Brody, A.L., Geaga, J.A., Hong, M.S., Hayashi, K.M., Rawson, R.A. and Ling, W. Biological Psychiatry, 58(10), pp. 770-778, 2005.

Psychological and Cognitive Effects of Long-Term Peyote Use among Native Americans

Halpern and colleagues at McLean Hospital investigated the long-term, residual psychological and cognitive effects of hallucinogens. The Rand Mental Health Inventory (RMHI), and ten standard neuropsychological tests of memory and attentional/executive functions were administered to three groups of Navajo Native Americans, age 18-45. The groups were: 1) 61 Native American Church members who regularly ingested peyote, a hallucinogen-containing cactus, 2) 36 individual with past alcohol dependence, but currently sober at least 2 months, and 3) 79 individuals reporting minimal use of peyote, alcohol, or other substances. Compared to Navajos with minimal substance use, the peyote group showed no significant deficits on the RMHI or any neuropsychological measures, whereas the former alcoholic group showed significant deficits (p < .05 ) on every scale of the RMHI and on two neuropsychological measures. Within the peyote group, total lifetime peyote use was not significantly associated with neuropsychological performance. Since there is no evidence of psychological or cognitive deficits among Native Americans using peyote regularly in a religious setting, these findings may not generalize to illicit hallucinogen users. Halpern, J.H., Sherwood, A.R., Hudson, J.I., Yurgelun-Todd. D. and Pope, H.G. Biological Psychiatry. 58(8), pp. 624-631, 2005.

Smokers Have Increased fMRI Activation to Smoking-Related Pictorial Cues in the Ventral Striatum/Nucleus Accumbens

Sean David and colleagues recruited smokers and non-smokers to view smoking-related or neutral images while undergoing continuous 3 Tesla fMRI. Three clusters of bilateral activation were observed in smokers for smoking related cues: anterior cingulate/orbitofrontal cortex, superior frontal gyrus, and occipital cortex. Importantly, in secondary analysis (a priori hypothesis) of the ventral striatum/nucleus accumbens region, smokers had significantly greater activation than non-smokers. The authors stipulate that this is the first demonstration of greater activation of this area in addicted smokers than non-smokers presented with smoking-related cues using fMRI. David, S.P., Munaf˜, Johansen-Berg, H., Smith, S.M., Rogers, R.D., Matthews, P.M. and Walton, R.T. Biological Psychiatry, 58, pp. 488-494, 2005.

COMT SNPs and Haplotypes Differentially Associated with European and African American, Male and Female Smokers

Li and colleagues studied 5 SNPs and associated haplotypes in over 600 nuclear families. Results showed the Val/Met polymorphism (rs4680) was associated with three different (but related) measures of smoking. Haplotype analysis revealed one SNP trio was a protective factor for European Americans; another three-SNP haplotype was protective for African Americans while a third was high-risk. However, further analysis showed the protective factors were only for the African American females and the European American males. Both SNPs and haplotypes had different frequencies in the two ethnic groups. These data suggest that COMT variants are related to nicotine dependence but that the effects are both sex and ethnic specific. Other studies have shown the val/met polymorphism to be related to low extraversion and high neuroticism usually in females. Beuten, J., Payne, T.J., Ma, J.Z. and Li, M.D. Neuropsychopharmacology, 31, pp. 675-684, 2006.

Association Between the DOPA Decarboxylase (DDC) Gene and Nicotine Dependence

Based on a suggestive link in previous research, Li and associates studied eight SNPs within the DDC gene in search of an association with nicotine dependence assessed by several measures of smoking severity. It was found in 2037 smokers in 602 nuclear families that one SNP was associated with two of the smoking measures in a European American sample. Haplotype association analysis revealed a risk haplotype. However, a protective haplotype (a different combination of SNPs) was found in the African American sample associated with all smoking measures. These results not only show the involvement of DDC in nicotine dependence but demonstrate a racial specificity. Ma, J.Z., Beuten, J., Payne, T.J., Dupont, R.T., Elson, R.C. and Li, M.D. Human Molecular Genetics, 14(12), pp. 1691-1698, 2005.

Sex Differences in Smoking Initiation and Consumption and in Linkage Analysis

Madden and her colleagues queried their sample of Australian twins with regard to smoking onset and continuation as a "smoker" in both males and females. Results demonstrated the presence of sex differences in the magnitude of genetic and genetic and environmental influences. Heritability was higher for men; shared environment was important only for women in a group where self-described non-smokers were excluded. For smoking initiation, the strongest linkage peak was at 20p13; for cigarette consumption where non-smokers were included, the highest peak was at 11q23 with secondary peaks at4q35 and 6p34. The peaks were similar but not the same when non-smokers were excluded. Also males tended to have the stronger peaks. These results support some recent studies and add to the growing list of possible susceptibility genes for smoking. Morley, K.I., Medland, S.E., Ferreira, M.A.R., Lynsky, M.T., Montgomery, G.W., Heath, A.C., Madden, P.A.F. and Martin, N.G. Behavior Genetics, ONLINE, pp. 1-13, Dec 20, 2005.

Association of the Mu Opioid Receptor Gene (OPRM1) for Drug or Alcohol Dependence

Gelernter and colleagues examined 13 single nucleotide polymorphisms in introns spanning the coding region of the mu opioid receptor gene. In analyses that identified associated haplotypes in European Americans, two blocks were found—one in which a combination of the minor alleles were more common in cases; the other in which they were more common in controls, suggesting a protective factor. These data were repeated in a secondary sample collected in Russia. The association in the first block is close to the much-studied exon (118A/Gˆ asn40 to asp40) gene variant lending support to the affirmative results reported. In summary, the results showed that multiple intronic SNPs in OPRM1 might increase risk for substance dependence. The data are consistent with an interpretation that there are at least two bi-allelic risk variants at the OPRM1 locus mapping to different haplotypes. Zhang, H., Luo, X., Kranzler, H.R., Lappalainen, J., Yang, B.-Z., Krupitsky, E., Zvartau, E. and Gelernter, J. Human Molecular Genetics 15, pp. 807-819, 2006.

Genes Associated with Opioid Dependence Subtypes Determined by Genome-Wide Scan

Gelernter and associates recruited 393 families each with at least one opioid dependent individual and performed a genome-wide scan for phenotypes determined a priori by cluster analysis. Two of the clusters were significantly associated with a location on chromosome 17. There was a LOD score of 3.06 for a "heavy-opioid-use" cluster for all subjects (European American and African American groups combined). A slightly larger LOD score of 3.46 was found for "non-opioid-use" in European Americans only. (These individuals were largely dependent or addicted to other drugs primarily cocaine.) These results are a suggestive step for association to specific subtypes of opioid (or non-opioid) dependent subjects. Gelernter, J., Panhuysen, C., Wilcox, M., Hesselbrock, V., Rounsaville, B., Poling, J., Weiss, R., Sonne, S., Zhao, H., Farrer, L. and Kranzler, H.R. American Journal of Human Genetics, 78, pp. 759-769, May 2006.

Low Socialization Is Correlated with Increased Activity in the Medial Prefrontal Cortex in Cocaine-Dependent Women

Rajita Sinha, T. R. Kosten and C-S. R. Li assessed antisocial personality using the California Psychological Inventory socialization scale and compared it to brain activation during a script-guided induction of stress. Three (right inferior frontal cortex, right anterior cingulate and medial prefrontal cortex (MDFC)) of eight brain regions which showed greater activation during stress imagery than at baseline and which were within the corticolimbic circuitry were correlated with the socialization score separately for males and females. The scores were all correlated but only the MPFC in females was (negatively) significant. A low socialization score means a lower arousal to stress and has been previously related to physiological measurements such as skin conductance and heart rate. In other words, females seemed to be underaroused during stress imagery (a suggestion of antisocial pathology) which is shown to be related to increased brain activity in the MDFC. Li, C-S. R., Kosten, T.R. and Sinha, R. NeuroReport, 17(3), pp. 243-247, 2006.

The Alpha-4 Subunit of the Nicotinic Acetylcholine Receptor Is Ethnically-Specific and Gender-Specific Associated with Nicotine Dependence

M.D. Li and associates assessed over 2,000 European or African American subjects from over 600 families. Two (different) single nucleotide polymorphisms are associated with measures of smoking in each of the two ethnic origin groups. After correction, one SNP and a haplotype remained significant in African American females. There were no associations with the beta-2 subunit of the receptor. These data suggest that there is involvement of the alpha 4 subunit of the nicotinic acetylcholine receptor in nicotine addiction. Li, M.D., Beuten, J, Ma, J.Z., Payne, T.J., Lou, X-Y., Garcia, V., Duenes, A.R., Crews, K.M. and Elston, R.C. Human Molecular Genetics, 14(9), pp. 1211-1219, 2005.

Sleep Quality Deteriorates in Abstinent Cocaine Dependent Individuals

Hobson, Stickgold and associates studied sleep in non-treatment-seeking cocaine dependent individuals on an inpatient basis during a binge-smoking followed by two-week abstinent session. Several measures of sleep quality including duration, efficiency, and onset latency all deteriorated during the abstinent period. By contrast, subjectively the subjects reported no loss of sleep quality. That is, they felt that they were consistently rested across the two-week period while objective measures showed decline. The speculation of this dissociation between objective and subjective sleep quality is a consequence of disruption of the sleep homeostat. How cocaine affects the neurobiology underlying these phenomena and how that relates to relapse is the next stage of this research. Pace-Schott, E.F., Stickgold, R., Muzur, A., Wigren, P.E., Ward, A.S., Hart, C.L., Clarke, D., Morgan, A. and Hobson, J.A. Psychopharmacology, 179, pp. 873-883, 2005.

Methamphetamine Abusers with Low CD4 Lymphocyte Counts Demonstrate an Additive Effect on Neuropsychological Deficits Associated with HIV Infection

Methamphetamine (MA) dependence and HIV infection are independently associated with cerebral dysfunction, especially within frontal-basal ganglia circuits. Recent evidence indicates that MA dependence has an additive effect on neuropsychological (NP) deficits associated with HIV infection. This study by Igor Grant and colleagues extends prior findings by examining the combined effects of MA dependence (MA+) and immuno-suppression (i.e., CD4 lymphocyte count <200) on NP functioning in 284 HIV+ individuals. Prevalence of NP impairment was examined in four demographically comparable groups: (1) MA+/CD4 < 200; (2) MA+/CD4 >/= 200; (3) MA-/CD4 < 200; and (4) MA-/CD4 >/= 200. Results revealed that both MA dependence and immuno-suppression were significant predictors of NP impairment. More importantly, additive effects were evident whereby the MA+/CD4 < 200 group exhibited the highest rate of NP impairment. Findings indicate that MA dependence conveys an additive deleterious impact on NP status in immunosuppressed persons with HIV infection, perhaps reflecting the combined effects of neuropathophysiological mechanisms in fronto-striatal circuits. Carey, C.L., Woods, S.P., Rippeth, J.D., Gonzalez, R., Heaton, R.K. and Grant, I. AIDS Behavior, 10, pp. 1-6, 2006.

Study of Ecstasy in a Naturalistic Environment

Johns Hopkins researcher, Dr. Una McCann, conducted a study in humans to determine whether MDMA (ecstasy), when used in the naturalistic setting of dance parties ("raves"), leads to plasma levels that have been associated with the toxicity to 5-HT neurons seen in animals. A variety of measures were obtained prior to, and hours after, individuals attended a rave where they had taken ecstasy. After the rave, subjects were without clinical complaints, had measurable amounts of residual MDMA in plasma, and nearly half of the subjects also tested positive for methamphetamine, another amphetamine analog that has been shown to have 5-HT neurotoxic potential in animals. Plasma concentrations of MDMA did not correlate with self-reported use of ecstasy and, in some subjects, levels overlapped with those that have been associated with 5-HT neurotoxicity in non-human primates. Others were believed to have had similar concentrations while at the dance party, when one considers the reported time of drug ingestion and the plasma half-life of MDMA in humans. Hematological and biochemical analyses were generally unremarkable. Moderate increases in blood pressure, heart rate and body temperature were observed in the subjects with the highest MDMA plasma concentrations. These findings are consistent with epidemiological findings that most people who use MDMA at dance parties do not develop serious clinical complications. Irvine, R.J., Keane, M., Felgate, P., McCann, U.D., Callaghan, P.D. and White, J.M. Neuropsychopharmacology. 31, pp. 424-430, 2006.

Increased Acoustic Noise During Working Memory May Have A Greater Impact In HIV+ Patients

Linda Chang and colleagues compared HIV- patients to those who were HIV+. HIV+ patients showed reduced acoustic noise (AN) activation and lower neuronal marker N-acetylaspartate in prefrontal and parietal cortices. Competing use of the working memory network between AN and cognitive load showed lower dynamic range of the hemodynamic responses in prefrontal and parietal cortices in HIV patients. These findings suggest that reduced reserve capacity of the working memory network in HIV patients and additional stress (eg, AN) might exhaust the impaired network for more demanding tasks. Tomasi, D., Chang, L., de Castro Caparelli, E., Telang, F. and Ernst, T. The Human Immunodeficiency Virus Reduces Network Capacity: Acoustic Noise Effect. Annals of Neurology, 59, pp. 419 - 423, 2006.

Common Deactivation Patterns During Working Memory And Visual Attention Tasks

Linda Chang and colleagues conducted a parametric functional magnetic resonance imaging (fMRI) study to investigate the balance of negative and positive fMRI signals in the brain. A set of visual attention (VA) and working memory (WM) tasks with graded levels of difficulty was used to deactivate separate but overlapping networks that include the frontal, temporal, occipital, and limbic lobes; regions commonly associated with auditory and emotional processing. Brain activation (% signal change and volume) was larger for VA tasks than for WM tasks, but deactivation was larger for WM tasks. Load-related increases of blood oxygenation level-dependent (BOLD) responses for different levels of task difficulty cross-correlated strongly in the deactivated network during VA but less so during WM. The variability of the deactivated network across different cognitive tasks supports the hypothesis that global cerebral blood flow vary across different tasks, but not between different levels of task difficulty of the same task. The task-dependent balance of activation and deactivation might allow maximization of resources for the activated network. Tomasi, D., Ernst, T., Carpelli, L.C. and Chang, L. Common Deactivation Patterns During Working Memory and Visual Attention Tasks: An Intra-subject fMRI Study at 4 Tesla. Human Brain Mapping, On-Line, January 10, 2006.


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