Research Findings - Clinical Neuroscience Research

Brain Monoamine Oxidase A (MAO A) Activity Predicts Trait Aggression

A group of scientists at Brookhaven National Laboratory used PET to determine the activity of MAO A in the brain of healthy, male non-smokers. The study was based on reports in the literature that a gene variant resulting in reduced expression of MAO A was associated with increased aggression. The PET method using a radioligand specific for MAO A allowed direct evidence of MAO A activity in the brain. Personality traits were assessed with a questionnaire. Results demonstrated a significant negative correlation between reported aggression tendencies and MAO A activity; greater aggression was associated with lower activity. This was true throughout the brain and only for the aggression trait (and not others) as assessed by the questionnaire. The reduced activity was about 15% for the increased aggression which accounted for more than 30% of the variance. However, the result was found for those who carried the allele for low MAO A expression as was as for high, suggesting there was some other factor--likely environmental influences during development--that was affecting the results in the studies which measured only the genetic differences (coupled with environment). These directly measured results provide a better intermediate (or endo-) phenotype for aggressive tendencies which are also risk factors for drug abuse. Alia-Klein, N., Goldstein, R.Z., Kriplani, A., Logan, J., Tomasi, D., Williams, B., Telang, F., Sumay, E., Biegon, A., Craig, I.W., Henn, F., Wang, G.-J., Volkow, N.D., and Fowler, J.S. Brain Monoamine A Oxidase A Activity Predicts Trait Aggression. J. Neurosci., 28(19), pp. 5099-5104, 2008.

Heritability of Evoked Potential Components during an Action Monitoring Task

Anokhin and colleagues at Washington University used a visually-presented task to assess the heritability of evoked potentials in a task where twin subjects could monitor their success. That is, the task was simple (responding rapidly to a central letter where the distracters that flanked the letter were either the same or different) so that an error of commission was immediately recognized. An error produced a negative-going peak within the first 100 msec and a positivity at about 250 msec. A correct response produced a negative peak after 300 msec. The study was motivated from synthesis of the literature that a reduced error-related negativity is associated with less controlled, disinhibited, and reckless behaviors which are risk factors for drug-taking. If it could be demonstrated that these electrical measures are genetically-determined, the ERPs could provide an endophenotype to associated psychopathologies including drug abuse. By using MZ and DZ twins it was demonstrated that all three responses were 40%-60% heritable and there were correlations among them suggesting some common genetic bases. The authors state that this is the first study to provide evidence for heritable individual differences in the neural substrates of action monitoring suggesting that the three cortical electrical responses could be endophenotypes. Anokhin, A., Golosheykin, S., and Heath, A.C. Heritability of Frontal Brain Function to Action Monitoring. Psychophysiol., 45, pp. 524-534, 2008.

A Risk Allele for Nicotine Dependence in CHRNA5 is a Protective Allele for Cocaine Dependence

In a highly collaborative study led by L. Bierut at Washington University, a gene that codes the alpha-5 subunit of the nicotinic acetylcholine receptor which had shown to be associated with nicotine dependence has now been found to be associated with cocaine dependence but as a protective factor--i.e., the opposite as that found for nicotine dependence. This unexpected conclusion was reached after extensive statistical analysis and replication in an independent sample including smokers/non-smokers and cocaine-dependent/non-dependent users. The postulated explanation involves the effect on specific nicotine receptor function which may act differently for the effects of nicotine as compared to cocaine. Grucza, R.A., Wang, J.C., Stitzel, J.A., Hinrichs, A.L., Saccone, S.F., Saccone, N.L., Bucholz, K.K., Cloninger, C.R., Neuman, R.J., Budde, J.P., Fox, L., Bertelsen, S., Kramer, J., Hesselbrock, V., Tischfield, J., Nurnberger, Jr., J.I., Almasy, L., Goate, A.M., and Bierut, L.J. A Risk Allele for Nicotine Dependence in CHRNA5 is a Protective Allele for Cocaine Dependence. Biol. Psychiat., (doi:10.1016), 2008.

Reduced White Matter Integrity in Smokers as Assessed by Diffusion Tensor Imaging

In a multi-site, international study the integrity of white matter of the corpus callosum was assessed by diffusion tensor imaging. Comparing smokers with non-smokers as well as smokers with low and high (Faegerstrom) smoking scores, the data suggest that smoking reduces the integrity of the white matter in the corpus callosum. Paul, R.H., Grieve, S.M., Niaura, R., David, S.P., Laidlaw, D.H., Cohen, R., Swet, L., Taylor, G., Clark, C.R., Pogun, S., and Gordon, E. Chronic Cigarette Smoking and the Microstructural Integrity of White Matter in Healthy Adults: A Diffusion Tensor Imaging Study. Nicotine & Tobacco Res., 10(1), pp. 137-147, 2008.

The Effect of Sleep Disturbances on Cognitive Function in Abstinent Cocaine Users

Peter Morgan in Robert Malison's laboratory assessed changes in the sleep architecture and sleep-associated learning in the two weeks of abstinence following binge cocaine ingestion. In the first 9 days of abstinence REM sleep significantly increased while REM latency decreased compared to immediate post-drug days and longer abstinence periods. Accordingly, slow-wave sleep was reduced. A visual texture discrimination task has been shown in healthy subjects to be sleep-stage dependent as was shown in this study for cocaine subjects. However, those subjects whose sleep architecture was disrupted showed deficits in this task. These results suggest that disturbances in sleep in cocaine use (and abstinence) could be directly related to some cognitive deficits. Thus treatment strategies should consider the effects on sleep quality. Morgan, P.T., Pace-Schott, E.F., Sahul, Z.H., Coric, V., Stickgold, R., and Malison, R.T. Sleep Architecture, Cocaine, and Visual Learning. Addiction, 103, pp. 1344-1352, 2008.

A Review of the Abuse and Dependence Liability of Benzodiazepine-type Drugs

Stephanie Licata and her colleague at the McLean Hospital/Harvard Medical School have provided this review of the literature on the increasingly important issue of the abuse potential of benzodiazepine-type drugs. Over the past several decades, benzodiazepines and the newer non-benzodiazepines have become the anxiolytic/hypnotics of choice over the more readily abused barbiturates. While all drugs from this class act at the GABA(A) receptor, benzodiazepine-type drugs offer the advantage of being safer and better tolerated. However, there is still potential for these drugs to be abused, and significant evidence exists to suggest that this is a growing problem. This review examines the behavioral determinants of the abuse and dependence liability of benzodiazepine-type drugs. Moreover, the pharmacological and putative biochemical basis of the abuse-related behavior is discussed. Licata, S.C., and Rowlett, J.K. Abuse and Dependence Liability of Benzodiazepine-Type Drugs: GABA(A) Receptor Modulation and Beyond. Pharmacology, Biochemistry and Behavior, 90(1), pp. 74-89, 2008.

A New Approach to Understanding the Impact of Circadian Disruption on Human Health

Mark Rea and colleagues at Rensselaer Polytechnic Institute conducted this study to examine the relationship between circadian disruption and health outcomes. Light and dark patterns are the major synchronizer of circadian rhythms to the 24-hour solar day. Disruption of circadian rhythms has been associated with a variety of maladies. Ecological studies of human exposures to light are very few, making it difficult to determine if light-induced circadian disruption directly affects human health. A newly developed field measurement device recorded circadian light exposures and activity from day-shift and rotating-shift nurses. Circadian disruption also was determined for rats subjected to a consistent 12-hour light/12-hour dark pattern (12L:12D) and ones subjected to a "jet-lagged" schedule. Humans and rats exposed to the consistent light-dark pattern exhibited pronounced similarities in their circular cross-correlation functions and 24-hour phasor representations except for an approximate 12-hour phase difference between species. The phase difference reflects the diurnal versus nocturnal behavior of humans versus rodents. Individuals that worked a rotating shift and rats subjected to the "jet-lagged" schedule exhibited significant reductions in phasor magnitudes compared to the 12L:12D rats and workers on a day shift. The reductions in the 24-hour phasor magnitudes indicate a loss of behavioral entrainment compared to both humans and rats with regular light-dark exposure patterns. This paper provides a quantitative foundation for systematically studying the impact of light-induced circadian disruption in humans and in animal models. Moreover, it should now be possible to bridge ecological studies of circadian disruption in humans to parametric studies of the relationships between circadian disruption and health outcomes using animal models. Rea, M.S., Bierman, A., Figueiro, M.G., and Bullough, J.D. A New Approach to Understanding the Impact of Circadian Disruption on Human Health. Journal of Circadian Rhythms, 6:7, doi:10.1186/1740-3391-6-7, 2008.

Assessment of Forebrain-Dependent Trace Eyeblink Conditioning in Chronic Cannabis Users

Patrick Skosnik and colleagues at the Indiana University used a forebrain-dependent trace eyeblink conditioning procedure in humans to compare results with known results from similar studies in CB1 knockout mice. While CB1 knockout mice exhibit striking impairments on a cerebellar-dependent task called delay eyeblink conditioning (dEBC), these animals demonstrate intact trace EBC (tEBC). Although heavy human cannabis users also show impaired delay EBC, their performance on tEBC is currently unknown. Therefore, 13 heavy cannabis users and 13 cannabis naive controls completed a tEBC procedure. The cannabis group exhibited similar rates of conditioned responding compared to controls in the acquisition and extinction phase. Consistent with reports of overt attentional abnormalities, the cannabis group exhibited decreased N100 ERP amplitudes to the tone CS that were unrelated to mean levels of conditioning across blocks during the acquisition phase. The lack of a significant effect of heavy cannabis use on tEBC reported here, combined with the previous report of impaired dEBC in such users, mirrors the findings observed in CB1 knockout mice, and suggests that the cannabinoid system differentially mediates forebrain- and cerebellar-dependent learning processes in both humans and animals. Edwards, C.R., Skosnik, P.D., Steinmetz, A.B., Vollmer, J.M., O'Donnell, B.F., and Hetrick, W.P. Assessment of Forebrain-Dependent Trace Eyeblink Conditioning in Chronic Cannabis Users. Neuroscience Letters, 439(3), pp. 264-268, 2008.

Evidence for Cannabinoid Modulation of Cerebellar-dependent Learning

Patrick Skosnik and colleagues at the Indiana University examined the effect of chronic cannabis use on classical eyeblink conditioning (EBC), a cerebellar-mediated task which has been shown to be disrupted in CB1 knockout mice. While the cerebellum contains the highest density of cannabinoid receptor (CB1) in the brain, no studies have assessed the effect of exogenous cannabinoids on cerebellar-dependent learning in humans. Chronic cannabis users were evaluated. A delay EBC task was utilized, in which a conditioned stimulus (CS; 400 ms tone) co-terminated with a corneal air puff unconditioned stimulus (US; 50 ms), thus eliciting a conditioned blink response (CR). The cannabis group exhibited markedly fewer, and more poorly timed CRs as compared to drug-naive controls. There were no differences between the groups in either the unconditioned response (UR) or an EEG measure of selective attention to the CS (N100 auditory ERP), indicating that the disruption observed in the cannabis group was specific to CR acquisition. These results suggest that cannabis use is associated with functional deficits in the cerebellar circuitry underlying EBC, a finding that corroborates the recent work in CB1 knockout mice. Skosnik, P.D., Edwards, C.R., O'Donnell, B.F., Steffen, A., Steinmetz, J.E., and Hetrick, W.P. Cannabis Use Disrupts Eyeblink Conditioning: Evidence for Cannabinoid Modulation Of Cerebellar-Dependent Learning. Neuropsychopharmacology. 33(6), pp.1432-1440, 2008.

Quantification of Drug Choice with the Generalized Matching Law in Rhesus Monkeys

Mikhail Koffarnus at the University of Michigan conducted this study to examine rhesus monkeys' drug self-administration choices between identical drug doses, different doses, different drugs (cocaine, remifentanil, and methohexital), and between drug and drug-paired stimuli. The generalized matching law provides precise descriptions of choice, but has not been used to characterize choice between different doses of drugs or different classes of drugs. The bias parameter of the generalized matching law was used to quantify preference for one reinforcer over another. Choice between identical drug doses yielded undermatching. Choice was relatively insensitive to differences in random interval schedule value when one reinforcer was replaced with drug-paired stimulus presentations. These findings suggest the bias parameter may be useful in quantitatively measuring level of preference, which would be an advantage over concurrent FR procedures that often result in exclusive choice. Koffarnus, M.N., and Woods, J.H. Quantification of Drug Choice with the Generalized Matching Law in Rhesus Monkeys. Journal of the Experimental Analysis of Behavior, 89(2), pp. 209-224, 2008.

Antidepressant-Like Effects of Intracerebroventricular FGF2 in Rats

Cortney Turner and her colleagues tested whether administering agents that act on fibroblast growth factor (FGF) receptors would have antidepressant-like effects in rodents. The FGF system is altered in post-mortem brains of individuals with major depressive disorder (MDD), but the functional relevance of this observation remains to be elucidated. They microinjected either FGF2 (200 ng, i.c.v.) or the FG loop (FGL) of neural cell adhesion molecule (NCAM) (5 mug, i.c.v.) into the lateral ventricle of rats and tested them on the forced swim test. Activating FGF receptors acutely had an antidepressant-like effect in the forced swim test. Furthermore, chronic FGF2 decreased depression-like behavior as assessed by two independent tests. Finally, the FGF system itself was altered after FGF2 administration (showing an increase in FGFR1 mRNA in the dentate gyrus 24 h post-FGF2), suggesting the potential for self-amplification of the initial signal. These results support the potential therapeutic use of FGF2 or related molecules in the treatment of MDD and point to alternate mechanisms of neuronal remodeling that may be critical in this treatment. Turner, C.A., Gula, E.L., Taylor, L.P., Watson, S.J., and Akil, H. Antidepressant-Like Effects of Intracerebroventricular FGF2 in Rats. Brain Research, 1224, pp. 63-68, 2008.

Valence and Salience Contribute To Nucleus Accumbens Activation

Knutson and colleagues at Stanford University used fMRI to determine the psychological properties of stimuli that activate the nucleus accumbens. Different accounts of nucleus accumbens (NAcc) function have emphasized its role in representing either valence or salience during incentive anticipation. Using an event-related fMRI paradigm, they independently manipulated valence and salience by cuing participants (healthy subjects) to anticipate certain and uncertain monetary gains and losses. NAcc activation correlated with both valence and salience. On trials with certain outcomes, NAcc activation increased for anticipated gains and decreased for anticipated losses. On trials with uncertain outcomes, NAcc activation increased for both anticipated gains and losses but did not differ between them. These findings suggest that NAcc activation separately represents both valence and salience, consistent with its hypothesized role in appetitive motivation. Knowing what properties of environmental stimuli activate the nucleus accumbens contributes to our understanding of how this brain area is involved in the rewarding properties of drugs of abuse. Cooper, J. C., and Knutson, B. Valence and Salience Contribute To Nucleus Accumbens Activation. Neuroimage 39(1), pp.538-47, 2008.

How Subjective Valuation Contributes to Approach and Avoidance During Decision Making

Bechara and colleagues at the University of Southern California investigated whether approach and avoidance motivations influence decision making through the process of subjective valuation. Studies using the Iowa Gambling Task have revealed individual differences in performance on the task. They examined the implications of a high sensitivity to gains or losses from two perspectives which we labeled scalar multiplication and valuation by feeling. Using two versions of the Iowa Gambling Task, the evidence supported the view that asymmetry in the systems regulating approach and avoidance leads to systematic biases that translate to differences in performance. Specifically, high sensitivity in the Behavioral Activation System (BAS) translated to valuation by feeling and insensitivity to scope in the domain of gains, while high sensitivity in the Behavioral Inhibition System (BIS) translates to valuation by feeling and insensitivity to scope in the domain of losses. These results provide a new perspective in the interpretation of impaired performance on the Iowa Gambling Task exhibited by substance abusers. Desmeules, R., Bechara, A., and Dube, L. Subjective Valuation and Asymmetrical Motivational Systems: Implications of Scope Insensitivity for Decision Making. Journal of Behavioral Decision Making, 21(2), pp. 211-224, 2008.

Effects of Haloperidol on Delta-9-Tetrahydrocannabinol Effects in Humans

D'Souza and colleagues at Yale School of Medicine investigated the extent to which dopaminergic (DA) systems contribute to the effects of Delta-9-tetrahydrocannabinol (Delta-9-THC), by testing how pretreatment with a dopamine receptor antagonist altered the effects of Delta-9-THC in humans. A 2-test-day double-blind study was conducted in both healthy subjects (n=17) and frequent users of cannabis (n=11). The participants were administered active (0.057 mg/kg) or placebo oral haloperidol in random order followed 90 and 215 min later by fixed order intravenous administration of placebo (vehicle) and active (0.0286 mg/kg) Delta-9-THC, respectively. Consistent with previous reports, intravenous Delta-9-THC produced psychotomimetic effects, perceptual alterations, and subjective effects including "high." Delta-9-THC also impaired verbal recall and attention. Contrary to the initial hypothesis, haloperidol pretreatment did not reduce any of the behavioral effects of Delta-9-THC. In fact, haloperidol worsened the immediate free and delayed free and cued recall deficits produced by Delta-9-THC. In addition, Haloperidol and Delta-9-THC worsened distractibility and vigilance. Neither drug impaired performance on a motor screening task, the Stockings of Cambridge task, or the delayed match to sample task. Frequent users had lower baseline plasma prolactin levels and blunted Delta-9-THC induced memory impairments. Although the results are consistent with the preclinical literature in suggesting crosstalk between DA-ergic and cannabinoid systems, the results indicate that DA D-2 receptor mechanisms play a major role in mediating the psychotomimetic and perceptual altering effects of Delta-9-THC. D'Souza, D. Braley, G., Blaise, R., Vendetti, M. Oliver, S., Pittman, B, Ranganathan, M., Bhakta, S., Zimolo, Z., Cooper, T., and Perry E. Effects of Haloperidol on the Behavioral, Subjective, Cognitive, Motor, and Neuroendocrine Effects of Delta-9-Tetrahydrocannabinol in Humans. Psychopharmacology, 198(4), pp. 587-603, 2008.

Error And Post-Error Neural Activity Associated With Adaptive Post-Error Behavior Change

Garavan and colleagues at Trinity College used fMRI to examine how neural activity during and after error commission contributes sustained post-error behavior changes and performance improvements in future trials in healthy participants. Activation of the medial frontal cortex (pMFC) activity during commission of an error has been shown previously to relate to adaptive post-error changes in response behavior on the immediately following trial. In the present study, a modification was made to a standard task that required participants to inhibit a prepotent motor response during infrequent lure trials, which were randomly interspersed among numerous go trials. Post-error behavior was manipulated by introducing a dynamic condition, in which an error on a lure trial ensured that the next lure would appear within two to seven go trials. Behavioral data indicated significantly higher levels of post-error slowing and accuracy during the dynamic condition, as well as fewer consecutive lure errors. Bilateral prefrontal cortex (PFC) and pMFC activity during the post-error period, but not during commission of the error itself, was associated with increased post-error slowing. Activity within two of these regions (right PFC and pMFC) also predicted success on the next lure trial. The findings support a relationship between pMFC/PFC activity and adaptive post-error behavior change, and lay the foundation for investigating neuronal dysfunction that may underlie the failure of drug abusers to correct their behavior after commission errors. Hester, R., Barre, N., Mattingley, J., Foxe, J., and Garavan, H. Avoiding Another Mistake: Error and Post-Error Neural Activity Associated with Adaptive Post-Error Behavior Change. Cognitive Affective & Behavioral Neuroscience, 7(4), pp. 317-326, 2008.

Propranolol Improves Cognitive Flexibility and Memory in Acute Cocaine Withdrawal

Beversdorf and colleagues at Ohio State University determined the effect of beta-adrenergic antagonists on cognitive performance in acute cocaine withdrawal. Their previous work revealed impaired cognitive flexibility in acute cocaine withdrawal, a cognitive domain that appears to be modulated by noradrenergic activity. Eleven subjects acutely withdrawing from cocaine were tested on tasks of cognitive flexibility as well as word fluency, attention, verbal memory, and spatial memory, off and on propranolol in a double-blinded manner. Propranolol significantly benefited certain aspects of cognitive flexibility in acute cocaine withdrawal, and improved some measures of verbal fluency and verbal recall. These results suggest that propranolol or other beta adrenergic agents may help treat cognitive impairment during cocaine withdrawal. Kelley, B., Yeager, K., Pepper, T., Bornstein, R., and Beversdorf, D. The Effect of Propranolol on Cognitive Flexibility and Memory in Acute Cocaine Withdrawal. Neurocase, 13(5-6), pp. 320-327, 2008.

Nucleus Accumbens Mediates Effect of Reward Cues on Financial Risk Taking

Incidental reward cues that activate the nucleus accumbens (NAcc) can influence subsequent financial risk taking. Prior studies have shown that nucleus accumbens (NAcc) activation spontaneously increases before financial risk taking. As predicted, anticipation of viewing rewarding stimuli (erotic pictures in 15 healthy, heterosexual men) increased financial risk taking, and this effect was partially mediated by increases in NAcc activation. These results identify a brain process that may underlie how environmental stimuli associated with drug use not only can lead to subjective craving, but more importantly can lead to increased risk taking. Knutson, B., Wimmer, G., Kuhnen, C., and Winkielman, P. Nucleus Accumbens Activation Mediates the Influence of Reward Cues on Financial Risk Taking. Neuroreport, 19(5), pp. 509-513, 2008.

Brain Mechanisms Leading to Over Valuing Things You Already Own

Knutson and colleagues at Stanford University used fMRI to investigate brain processes that underlie the "endowment effect", which is the tendency to place greater value on items that one owns. The "endowment effect" is of interest because it is an anomaly that violates the reference-independence assumption of rational choice theories. Healthy participants were scanned while considering six products paired with 18 different prices under buying, choosing, or selling conditions. Subjects showed greater nucleus accumbens (NAcc) activation for preferred products across buy and sell conditions combined, but greater medial prefrontal cortex (MPFC) activation in response to low prices when buying versus selling. During selling, right insular activation for preferred products predicted individual differences in susceptibility to the endowment effect. These findings are consistent with a reference-dependent account in which ownership increases value by enhancing the salience of the possible loss of preferred products. In other words, how the brain becomes "attached" to external objects by over estimating the value of those objects. It is notable that these areas of the brain are known to be dysfunctional in substance abusers. These results provide a novel perspective on why drug abusers overvalue drugs and thereby find it difficult to give up drug use. Knutson, B., Wimmer, G., Rick, S., Hollon, N., Prelec, D., and Loewenstein, G. Neural Antecedents of the Endowment Effect. Neuron, 58(5), pp. 814-822, 2008.

Neural Correlates of Impulse Control in Cocaine Abusers

Li and colleagues at Yale University used fMRI to study altered impulse control dysfunction in cocaine abusers. Impulse control was assessed using the stop signal task (SST) which measures the ability to inhibit an action once it has started. Previous studies employing the SST have provided ample evidence indicating the importance of the medial cortical brain regions in conflict/error processing and postconflict/error behavioral adjustment. The SST was modified in order to elicit errors in approximately half of the stop trials despite constant behavioral adjustment of the observers. Prefrontal loci including the ventrolateral prefrontal cortex were found to be involved in post-error slowing in reaction time in a sample of cocaine dependent men. These results add to the accumulating evidence that dysfunction of ventrolateral prefrontal cortex may contribute to impaired inhibitory control in cocaine abusers. Li, C. R., Huang, C., Yan, P., Bhagwagar, Z., Milivojevic, V., and Sinha, R. Neural Correlates of Impulse Control During Stop Signal Inhibition in Cocaine-Dependent Men. Neuropsychopharmacology, 33(8), pp. 1798-806, 2008.

Brain Regions Mediating Post-Error Slowing During A Stop Signal Task

Li and colleagues at Yale University used fMRI to study the neural correlates of behavioral adjustments to impulsive errors in abstinent male patients with cocaine dependence (CD) and healthy controls (HC) subjects. The Stop Signal Task was modified to permit trial-by-trial evaluation of response inhibition co-varying for stop success rate, task-related frustration rating, and post-error slowing, allowing the neural substrates of response inhibition to be isolated independent of attentional monitoring (of the stop signal) and post-response processes including affective responses and error monitoring. No differences were seen in between HC and CD who were matched in stop signal performance in the pre-supplementary motor area (pre-SMA) previously shown to be associated with SSRT. However, compared with HC, CD demonstrated less activation of the rostral anterior cingulate cortex (rACC), an area thought to be involved in the control of stop signal inhibition. The magnitude of rACC activation also correlated negatively with the total score and the impulse control subscore of the Difficulty in Emotion Regulation Scale in PCD. This study thus identified the neural correlates of altered impulse control in CD independent of other cognitive processes that may influence stop signal performance. Relative hypoactivation of the rACC during response inhibition may represent a useful neural marker of difficulties in impulse control in abstinent cocaine-dependent men who are at risk of relapse. Li, C.R., Huang, C., Yan, P., Paliwal, P., Constable, R.T., and Sinha, R. Neural Correlates of Post-Error Slowing During A Stop Signal Task: A Functional Magnetic Resonance Imaging Study. Journal of Cognitive Neuroscience, 20(6), pp. 1021-1029.

Individual Differences in Nicotine Dependence, Withdrawal Symptoms, and Sex Predict Brain Responses to Smoking Cues

McClernon and colleagues at Duke University used fMRI to study the influence of individual difference factors and withdrawal symptoms on brain cue reactivity. Multiple regression analysis was used to evaluate relations between individual difference factors and withdrawal symptoms and event-related fMRI responses to visual smoking cues in a sample of 30 smokers. Predictors were self-report nicotine dependence (Fagerstroem test of nicotine dependence, FTND), prescan withdrawal symptoms (craving and negative affect), and sex. The unique variance of each predictor was examined after controlling for each of the others. Positive associations were observed between FTND and reactivity to cues in right anterior cingulate and orbitofrontal cortex (OFC) whereas negative associations were observed between prescan craving and reactivity in ventral striatum. Higher negative affect or being male was associated with greater reactivity in left hippocampus and left OFC. Women exhibited greater cue reactivity than men in regions including the cuneus and left superior temporal gyrus. Individual difference factors and withdrawal symptoms were uniquely associated with brain reactivity to smoking cues in regions subserving reward, affect, attention, motivation, and memory. These findings provide further evidence that reactivity to conditioned drug cues is multiply determined and suggest that smoking cessation treatments designed to reduce cue reactivity focus on each of these variables. McClernon, F.J., Kozink, R.V., and Rose, J.E. Individual Differences in Nicotine Dependence, Withdrawal Symptoms, and Sex Predict Transient fMRI-BOLD Responses to Smoking Cues. Neuropsychopharmacology, 33(9), pp. 2148-2157, 2008.

Neuronal Basis of Learning and Memory Deficits in Human Cannabis Users

Garavan and colleagues at Trinity College used fMRI to test the hypothesis that impairments in learning and memory in chronic cannabis users is due to alterations in hippocampal functioning. In the first part of the study, 35 current users of cannabis and 38 matched controls were administered a face-name task, which has been shown previously to activate the hippocampal region. Cannabis users were significantly worse on this task with respect to learning, short and long-term memory performance. Based on the behavioral results, a subsequent study used a modified version of the face-name task during fMRI scanning, to examine cortical and (para) hippocampal activity during learning and recall in 14 current users of cannabis and 14 controls. Despite non-significant differences in learning and memory performance, cannabis users had significantly lower levels of BOLD activity in the right superior temporal gyrus, right superior frontal gyrus, right middle frontal gyrus and left superior frontal gyrus compared to controls during learning. In addition, cannabis users had significantly higher BOLD activity in the right parahippocampal gyrus during learning. These results indicate that hypoactivity in frontal and temporal cortices, and relative hyperactivity in the para-hippocampus are involved in functional deficits and compensatory processes in cannabis users. Nestor, L., Roberts, G., Garavan, H., and Hester, R. Deficits in Learning and Memory: Parahippocampal Hyperactivity and Frontocortical Hypoactivity in Cannabis Users. Neuroimage, 40(3), pp. 1328-1339, 2008.

Reduced Behavioral and Neural Activation in Stimulant Users To Different Error Rates During Decision Making

Paulus and colleagues at the University of California, San Diego used fMRI to test the hypothesis that stimulant-using subjects fail to adjust decision-making less as a function of errors, and that this failure is accompanied by reduced neural activation patterns. Twelve young adults who had used stimulants were compared with 12 education-matched, stimulant-naive comparison subjects. Subjects completed the two-choice prediction task with three fixed error-rate conditions (20%, 50%, or 80% errors) during fMRI scanning. Stimulant users relative to comparison subjects showed less strategy adjustment to different error rates. For example, they were less likely to stay with winning responses (win-stay) and to shift away from losing responses (lose-shift). These subjects also showed different activation patterns as a function of error rate in the left insular and bilateral dorsolateral prefrontal cortex but not anterior cingulate. The degree to which individuals adjusted switching rate, or win-stay/lose-shift consistent responses, as a function of errors was correlated with the difference in insular cortex activation differences between high and low error rates. These results indicate that the behavior of stimulant users is less adaptive to the frequency of errors made and fewer brain processing resources are deployed during decision making to anticipate erroneous performance. These findings could be markers for the predisposition of drug taking; however, their relevance for development of drug dependence requires further study. Paulus, M., Lovero, K., Wittmann, M., and Leland, D. Reduced Behavioral and Neural Activation in Stimulant Users to Different Error Rates During Decision Making. Biological Psychiatry, 63(11), pp. 1054-1060, 2008.

A Novel PET Ligand for Imaging Muscarinic M2 Receptors: C-11-Labeled TZTP

Ding and colleagues at Yale University and Brookhaven National Laboratories studied the pharmacokinetics of a novel series of C-11 labeled PET tracers for muscarinic M2 receptors based on an existing F18 labeled ligand: 3-(3-{3-[F-18]fluoropropyl)thio}-1,2,5 -thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine) ([F-18]FP-TZTP). They compared the effect of small structural changes on tracer pharmacokinetics (PK) in brain and peripheral organs for 3 analogs (3, 6, and 10). Values for log D, PPB and affinity constants were similar for the 3 analogs. The fraction of parent radiotracer in the plasma was higher and the AUC lower for the 10 analog than for 3 and 6 analogs. Time Activity Curves for brain regions were similar for 3 and 6, which showed PK similar to the 18F tracer, while 10 showed slower uptake and little clearance over 90 min. Distribution volumes for 3 and 6 were similar to the F-18 tracer but higher for 10. Uptake of the three tracers was significantly reduced by coinjection of unlabeled 3 and 6. These studies indicate that small structural variations on the TZTP structure greatly altered the PK in brain and behavior in blood with little change in the log D, PPB or affinity. The study suggests that C-11-radiolabeled 3 will be a suitable alternative to [F-18]FP-TZTP for translational studies in humans. Reid, A., Ding, Y., Eckelman, W., Logan, J., Alexoff, D., Shea, C., Xu, Y., and Fowler, J. Comparison of the Pharmacokinetics of Different Analogs of C-11-Labeled TZTP for Imaging Muscarinic M2 Receptors With PET. Nuclear Medicine and Biology, 35(3), pp. 287-298, 2008.

Preserved Implicit Attention In Methamphetamine Dependent Subjects

Salo and colleagues at University of California, Davis studied whether methamphetamine abuse leads to deficits in implicit measures of attention, in addition to the known wide range of deficits on explicit tasks of selective attention. A computerized spatial priming task was used to assess implicit attentional processes in 54 methamphetamine (MA) dependent subjects and 32 healthy controls. The MA dependent subjects had been drug-abstinent a minimum of 3 weeks with a mean duration of MA use of 13.27+/-7.75 years. The MA dependent subjects did not differ significantly from controls on either inhibitory priming or facilitory priming. This result is consistent with earlier findings of intact object-based priming in MA dependent individuals and suggests that cortical brain systems typically supporting implicit attentional functioning are relatively intact in long-term MA dependent individuals in contrast to dysfunctions in brain systems supporting explicit attentional processes. Salo, R., Leamon, M. H., Natsuaki, Y., Moore, C., Waters, C., and Nordahl, T. E. Findings of Preserved Implicit Attention in Methamphetamine Dependent Subjects. Prog. Neuropsychopharmacol. Biol. Psychiatry, 32(1), pp. 217-223, 2008.

Behavioral Predictors of Recurrent Methamphetamine-Induced Psychosis

Salo and colleagues at University of California, Davis studied currently drug-abstinent methamphetamine (MA)-dependent subjects (n=39) who experienced psychotic symptoms associated with MA abuse. All participants completed the Wender Utah Rating Scale (WURS), which retrospectively assesses Attention Deficit Hyperactivity Disorder-relevant childhood behaviors. The results suggest the existence of an early cognitive vulnerability to the development of frequent MA-induced psychotic symptoms as well as increased vulnerability associated with a family history of psychiatric illness. Salo, R., Nordahl, T. E., Leamon, M. H., Natsuaki, Y., Moore, C. D., Waters, C., and Carter, C. S. Preliminary Evidence of Behavioral Predictors of Recurrent Drug-Induced Psychosis in Methamphetamine Abuse. Psychiatry Res., 157(1-3), pp. 273-247, 2008.

Individual Differences in Insular Sensitivity During Loss Anticipation Predict Avoidance Learning

Knutson and colleagues at Stanford University used fMRI to study whether individual differences in insular sensitivity would predict learning to avoid aversive stimuli. The anterior insula has been implicated in both the experience and the anticipation of negative outcomes. Insular sensitivity was assessed as participants anticipated monetary losses while undergoing fMRI scanning. Insular responsiveness to anticipated losses predicted participants' ability to learn to avoid losses (but not to approach gains) in a behavioral test several months later. These findings suggest heightened insular sensitivity may promote learning to avoid loss. Dysfunction of the insula may therefore impair the ability of individuals to learn from the adverse consequences of drug use. Samanez-Larkin, G.R., Hollon, N.G., Carstensen, L.L., and Knutson, B. Individual Differences in Insular Sensitivity During Loss Anticipation Predict Avoidance Learning. Psychological Science, 19(4), pp. 320-323, 2008.

Smoking Opportunity Affects Striatal Responses to Monetary Gain and Loss

Delgado and colleagues at Rutgers University and University of Pittsburgh used fMRI to examine the effects of smoking opportunity on neural responses to monetary outcomes in nicotine-deprived cigarette smokers. Participants who were told that they would be able to smoke during the study exhibited smaller responses to monetary gains and losses in the caudate nucleus than did those who anticipated having to wait several hours before having the opportunity to smoke. These findings highlight the importance of investigating the effects of perceived drug use opportunity on motivational processing in addicted populations. Wilson, S., Sayette, M., Delgado, M., and Fiez, J. Effect of Smoking Opportunity on Responses to Monetary Gain and Loss in the Caudate Nucleus. Journal of Abnormal Psychology, 117(2), pp. 428-434, 2008.

Cortical Sources and Targets of Attentional Modulation

Yantis reviewed current findings regarding how the brain implements selective attention. Selective attention is an intrinsic component of perceptual representation in a visual system that is hierarchically organized. Modulatory signals originate in brain regions that represent behavioral goals. These signals specify which perceptual objects are to be represented by sensory neurons that are subject to contextual modulation. Attention can be deployed to spatial locations, features, or objects, and corresponding modulatory signals must be targeted within these domains. Open questions include how nonspatial perceptual domains are modulated by attention and how abstract goals are transformed into targeted modulatory signals. Since drug abuses exhibit a bias to selectively attend to drug-related stimuli, understanding of the brain mechanisms of selective attention will aid in the understanding of cue-related craving and relapse. Yantis, S. The Neural Basis of Selective Attention: Cortical Sources and Targets of Attentional Modulation. Current Directions in Psychological Science, 17(2), pp. 86-90, 2008.

Interpersonal Nature of Empathic Accuracy

Ochsner and colleagues at Columbia University tested the prediction that empathic accuracy may depend on both targets' tendency to express emotion and perceivers' tendency to empathically share that emotion. Although current theories suggest that affective empathy (perceivers' experience of social targets' emotions) should contribute to empathic accuracy (perceivers' ability to accurately assess targets' emotions), extant research has failed to consistently demonstrate a correspondence between them. This group reasoned that prior null findings may be attributable to a failure to account for the fundamentally interpersonal nature of empathy. Using a continuous affect-rating paradigm, they found that perceivers' trait affective empathy was unrelated to empathic accuracy unless targets' trait expressivity was taken into account. Perceivers' trait affective empathy predicted accuracy only for expressive targets. These data suggest that perceivers' self-reported affective empathy can indeed predict their empathic accuracy, but only when targets' expressivity allows their thoughts and feelings to be read. These results may provide a foundation for improving empathic therapeutic relationships in the treatment of substance abusers. Zaki, J., Bolger, N., and Ochsner, K. It Takes Two: The Interpersonal Nature of Empathic Accuracy. Psychological Science, 19(4), pp. 399-404, 2008.

Impaired Visuomotor Performance in Smokers More Related to Addiction Severity as an Individual Difference than to Abstinence/Satiety State

Edythe London and colleagues at UCLA demonstrated that among smokers, performance on the d2 Test of Attention and the Digit Symbol Test Acute did not appreciably differ between overnight abstinence versus ad libitum smoking conditions. Rather, performance under both conditions correlated negatively with measures of addiction severity, where smokers with high nicotine dependence performed more slowly on both tests than less dependent smokers or nonsmokers. The findings suggest that severity of nicotine dependence and slowness in perceptual-motor tasks of attention share an underlying basis. Azizian, A., Monterosso, J.R., Brody, A.L., Simon, S.L., and London, E.D. Severity of Nicotine Dependence Moderates Performance on Perceptual-Motor Tests of Attention. Nicotine and Tobacco Research, 10(4), pp. 599-606, 2008.

Pharmacologic Mechanisms of Methamphetamine

Stephen Kish from the University of Toronto reviewed the pharmacologic mechanisms of crystal methamphetamine. Crystal meth is a form of the stimulant drug methamphetamine that, when smoked, can rapidly achieve high concentrations in the brain. Methamphetamine causes the release of the neurotransmitters dopamine, norepinephrine and serotonin and activates the cardiovascular and central nervous systems. The levels of dopamine are low in the brain of some drug users, but whether this represents neuronal loss is uncertain. The areas of the brain involved in methamphetamine addiction are unknown but probably include the dopamine-rich striatum and regions that interact with the striatum. There is no medication approved for the treatment of relapses of methamphetamine addiction; however, potential therapeutic agents targeted to dopamine and non-dopamine (e.g., opioid) systems are in clinical testing. Kish, S.J. Pharmacologic Mechanisms of Crystal Meth. Canadian Medical Association Journal, 178(13), pp. 167-1682, 2008.

Methamphetamine-Dependent Subjects Show Altered Cortical Recruitment when Evaluating Faces

Predoctoral (F31) fellow Doris Payer and colleagues at UCLA exposed MA-dependent and healthy comparison participants to fearful and angry faces while they performed an affect matching task during fMRI. Although the groups did not differ in task performance, the healthy participants showed more task-related activity than the MA-dependent participants in ventrolateral prefrontal cortex (VLPFC), temporoparietal junction (TPJ), anterior and posterior temporal cortex, and fusiform gyrus in the right hemisphere, and the cuneus in the left hemisphere. In contrast, the MA-dependent participants showed more task-related activity than the healthy participants in the dorsal anterior cingulate cortex (dACC). Dorsal ACC hyperactivity, along with high ratings of hostility in facial stimuli by the MA-dependent group, suggest a hyper-sensitivity to socially threatening cues in the MA-dependent participants, while lower VLPFC activation could point to a deficit in integrating socio-emotional information and/or regulating this limbic hyperactivity. Differences In Cortical Activity Between Methamphetamine-Dependent and Healthy Individuals Performing a Facial Affect Matching Task. Payer, D.E., Lieberman, M.D., Monterosso, J.R., Xu, J., Fong, T.W., and London, E.D. Drug and Alcohol Dependence, 93(1-2), pp. 93-102, 2008.

Cognitive Stress Demands More Brain Reserve Capacity and Uncovers Attention Deficits and is Exacerbated by Antiretroviral Medications in Neuroasymptomatic HIV+ Individuals

Drs. Linda Chang and Thomas Ernest tested whether fMRI could be used as a reasonably sensitive measurement of brain reserve capacity in HIV+ patients . While antiretroviral (ARV) medications successfully lower viral load and improve immune deficit, they may have detrimental effects on brain function in HIV-infected patients. Subtle neuronal dysfunction associated with minor neuronal damage has higher prevalence in otherwise asymptomatic HIV+ individuals. However, no clinical assessment of the minor neurodegenerative damage is currently available. The study was based upon the observation that performance accuracy in response to steps of increasing difficulty of visual attention (cognitive load), and diminished brain function can be detected in HIV+ people who were otherwise neurologically asymptomatic. BOLD signals in frontal regions of normal subjects during visually tracking balls on screen normally decreases across repeated trials even when difficulties in attention level (number of balls) progressively increases. While HIV+ patients also exhibit repetitive adaptation when the requirement of attention level was low, they failed to exhibit adaptation with difficult visual challenges. In contrast to normal subjects, HIV+ patients exhibited load-dependent increases in brain activation. Standard, long-term use of ARV exacerbated the problem, leading to even greater load-dependent BOLD activations in the bilateral superior frontal regions, along with diminished accuracy of visual attention performance. In other words, HIV+ subjects on ARV may demand greater usage of the brain attention network to maintain performance. Since the study controlled for baseline disease stage and medical variables associated with HIV infection, it suggests that the HIV infection could impair plasticity of the brain and lower the compensatory strength of endogenous regulatory system and intrinsic resilience. Therefore, HIV+ARV subjects and HIV+ subjects under stress or influence of drugs may exhibit functional discompensation and declined behavioral performance. Chang, L., Yakupov, R., Nakama, H., Stokes, B., and Ernst, T. Antiretroviral Treatment is Associated with Increased Attentional Load-Dependent Brain Activation in HIV Patients, Journal of Neuroimmunology and Pharmacology, 3, pp. 95-104, 2008.

Individual Differences in Responses to Opioid Analgesic Medications

Dr. James P. Zacny and colleagues investigated how two opioid analgesics containing a common antipyretic agent (cacetaminophen) at typically prescribed doses differed in subjective, psychomotor, and physiological effects within the same healthy individuals. The study was carried out in a randomized, placebo-controlled, double-blind, crossover trial consisting of six sessions. Higher dosage of the drug combinations produced a significant, wider spectrum of subject effects, and impaired psychomotor performance including cognitive abilities in some subjects. Those included substantially increased ratings of "drug high" and "dizzy" and decreased ratings of "in control of body" and "in control of thoughts". Some subjects displayed increased ratings in such measures as "drug liking" and "wanting to take drug again". These results emphasize the need for individualized assessment of subject effects and remediation for chronic pain patients under medications that have addiction potential. Given the diverse individual sensitivity to the drug combination physicians and pharmacists need to discuss safety concerns with their patients on an individualized basis. Zacny, J.P., and Gutierrez, S. Subjective, Psychomotor, and Physiological Effects Profile of Hydrocodone/Acetaminophen and Oxycodone/Acetaminophen Combination Products. Pain Medicine, 9(4), pp. 433-443, 2008.

Capacity of "Remembering to Remember" as a Predictor for Adherence to Antiretroviral Medications

Dr. Igor Grant and colleagues at the University of San Diego investigated whether HIV-associated impairment of prospective memory had predictive value for adherence to antiretroviral medications. Prospective memory represented the ability to encode and execute a future intention, such as remembering to take a medication at a specific time. Optimal adherence to antiretroviral medications is critical to the effective long-term management of HIV+ individuals who often have cognitive deficits and impaired everyday functioning. The results showed a strong association between impaired prospective memory and self-reported medication management in HIV+ persons currently prescribed antiretroviral medications. Specifically, poorer performance in prospective memory tasks correlated well to more frequent complaints on remembering to remember projected events and to poorer self-reported medication management. Analyses revealed that HIV-associated impairment of prospective memory accounted for a significant amount of variance in self-reported medication management, more than that could be explained by other factors known to predict nonadherence, such as mood disorders, psychosocial variables, environmental structure and deficits on a traditional battery of neuropsychological tests. It suggests that an early assessment of the capacity of "remembering to remember" will help medical professionals to better predict their patients' ability in everyday function and their adherence to antiviral medications. It will also be informative for a strategy of individualized remediation. Woods, S.P., Moran, L.M., Carey, C.L., Dawson, M.S., Iudicello, J.E., Gibson, S., Grant, I., Atkinson, J.H., and HIV Neurobehavioral Research Center Group. Prospective memory in HIV infection: is "Remembering to Remember" a Unique Predictor of Self-Reported Medication Management? Archive of Clinical Neuropsychology, 23(3), pp. 257-270, 2008.

Risk Factors Contributing to Major Depressive Episodes in HIV+ Persons

Dr. Igor Grant and colleagues at the University of California, San Diego, carried out a 2-year prospective study to determine risk factors contributing to major depressive episodes in HIV+ persons. When factors like baseline disease stage and medical variables associated with HIV infection were carefully controlled, they found that more severe immune deficit and more rapid progression of HIV infection correlated with higher morbidity of the disease. The two-year cumulative rate of a major depressive episode ranged from 40% in those with stable symptomatic-advanced illness to about 20% in asymptomatic individuals and in controls. Those with symptomatic HIV disease were at significant higher risk by the second year than were people in earlier stage HIV disease and uninfected controls. A history of major depression or of psychiatric comorbidity (two or more psychiatric disorders) strongly predicted subsequent major depressive episode. The rate of first onset and recurrent expression was similar. The likelihood of first onset of depression in symptomatic patients was 50% higher than that in seronegative controls, raising the question of whether HIV infection triggers episodes in individuals previously resistant to mood disorder. This paper also discussed factors that might have an impact on the observation that impaired performance on neuropsychological testing and abnormal neuroimaging did not predict a later depressive episode in this study. Atkinson, J.H., Heaton, R.K., Patterson, T.L., Wolfson, T., Deutsch, R., Brown, S.J., Summers, J., Sciolla, A., Gutierrez, R., Ellis, R.J., Abramson, I., Hesselink, J.R., McCutchan, J.A., Grant, I., and The HNRC Group. Two-year Prospective Study of Major Depressive Disorder in HIV-Infected Men. Journal of Affective Disorders, 108, pp. 225-234, 2008.

Attentional Deficits in Cocaine-Dependent Patients: Converging Behavioral and Electro-physiological Evidence

Boutros and colleagues at Wayne State University used evoked potentials to investigate altered brain activity related to deficits in attention in cocaine abusers. Cocaine-dependent patients (n=14) were examined and compared with healthy control individuals (n=15) on two sustained attention tasks; an auditory oddball event-related task and a Continuous Performance Test (CPT, Identical Pairs version). The cocaine-dependent group displayed P300 amplitude reduction compared to controls, but there were no significant group differences in P300 response latency. On the CPT, the cocaine-dependent patients displayed significantly poorer discriminability and greater errors of commission than the controls. There was a positive correlation between performance on the oddball event-related task and performance on the CPT. This investigation provides converging behavioral and electrophysio-logical evidence of attentional deficits in cocaine-dependent patients. Gooding, D.C., Burroughs, S., and Boutros, N.N. Attentional deficits in Cocaine-Dependent Patients: Converging Behavioral and Electrophysiological Evidence. Psychiatry Research, 160(2), pp. 145-154, 2008.

Tobacco/Nicotine and Endogenous Brain Opioids

Dr. Edward Domino and his colleague at the University of Michigan reviewed the limited knowledge regarding the contribution of the endogenous opioid system to the complex effects of nicotine/tobacco smoking. Standard medications to assist in smoking cessation, such as nicotine replacement therapies and bupropion, are ineffective in many smokers who attempt to quit. Recent developments in the neurobiology of nicotine dependence have identified several neurotransmitter systems that may contribute to the process of smoking maintenance and relapse. These include, especially, dopamine, but also norepinephrine, 5-hydroxytryptamine, acetylcholine, endogenous opioids, gamma-aminobutyric acid (GABA), glutamate, and endocannabinoids. Xue, Y., and Domino, E.F. Tobacco/Nicotine and Endogenous Brain Opioids. Progress in Neuropsychopharmacology & Biological Psychiatry, 32(5), pp. 1131-1138, 2008.

Evidence Against a "Prototypical" Pattern of Neuropsychological Impairment in HIV+ Patients

Dr. Igor Grant and colleagues, at the University of California San Diego, investigated the existence of a "prototypical pattern" of neuropsychological results with HIV infection. Previous studies by others have led to the proposal that HIV infection is characterized by a specific neuropsychological pattern consisting of impaired executive functioning, motor skills, speed of information processing, and learning. On the other hand, memory retention, most language skills, and visuospatial functioning were intact. Using factor analysis of a relatively comprehensive neuropsychological battery from 553 HIV+ adults, 6 component factors were found: verbal memory (VeM), visual memory (ViM), processing speed (PS), attention/working memory (A/WM), executive function (EF), and motor (M). These factor scores were then submitted to a hierarchical cluster analysis followed by a K-means analysis. A 6-cluster solution was found to best fit the data. The definitions of the clusters indicate the relative performance strengths and weaknesses (independent of overall level of performance): Cluster 1: strong EF; Cluster 2: strong M, weak VeM and EF; Cluster 3: strong PS, weak ViM and EF; Cluster 4: strong VeM, weak M; Cluster 5: strong A/WM; Cluster 6: strong VeM, weak EF. Neuropsychological-impairment rates differed across clusters, but all 6 clusters contained substantial numbers of impaired and unimpaired individuals. Cluster membership was not explained by demographic variables or psychiatric or neuromedical confounds. Thus, there does not appear to be a single, prototypical pattern of neuropsychological impairment associated with HIV infection for this battery of representative neuropsychological tests. Dawes, S., Suarez, P., Casey, C.Y., Cherner, M., Marcotte, T.D., Letendre, S., Grant, I., Heaton, R.K.; and HNRC Group. Collaborators (39): Grant, I., Atkinson, J.H., Ellis, R.J., McCutchan, J.A., Marcotte, T.D., Hale, B.R., Ellis, R.J., McCutchan, J.A., Letendre, S., Capparelli, E., Schrier, R., Heaton, R.K., Cherner, M., Woods, S.P., Dawes, S., Jernigan, T., Fennema-Notestine, C., Archibald, S.L., Hesselink, J., Annese, J., Taylor, M.J., Schweinsburg, B., Masliah, E., Everall, I., Langford, T.D., Richman, D., Smith, D.M., McCutchan, J.A., Everall, I., Lipton, S., Atkinson, J.H., von Jaeger, R., Gamst, A.C., Cushman, C., Frybarger, M., Masys, D.R., Abramson, I., Ake, C., and Lazzaretto, D. Variable Patterns of Neuropsychological Performance in HIV-1 Infection. Journal of Clinical and Experimental Neuropsychology, 30(6), pp. 613-626, 2008.

Increased Dynorphin Concentrations in Striatum and Ventral Pallidum in Human Chronic Cocaine Users

Dr. Stephen Kish and colleagues, at the University of Utah examined alterations in neuropeptide levels using radioimmunoassays in post-mortem brains of cocaine abusers. Several brain neuropeptide systems have been proposed as targets for medication development for treatment of cocaine addiction (e.g., kappa opioid agonists) based on animal data showing interactions between the neuropeptides, brain dopamine, and cocaine. Increased dynorphin and other neuropeptides (e.g., metenkephalin, neurotensin and substance P) levels were found in the dopamine-rich caudate, putamen, and nucleus accumbens of human chronic cocaine users (n=12) compared to matched control subjects (n=17). The most marked changes were increased dynorphin immunoreactivity in the ventral pallidum (+346%), caudate (+92%), and decreased neurotensin in the caudate (-49%). There was also a trend for increased dynorphin (+75%) in the putamen. Dynorphin levels were normal in other examined subcortical/cerebral cortical area. In contrast cerebral cortical metenkephalin levels were generally decreased and neurotensin variably changed. The human dynorphin observations parallel well animal findings and suggest that the dynorphin system is upregulated, manifested as elevated neuropeptide levels, after chronic drug exposure in striatum and ventral pallidum. However, the other striatal neuropeptides were not consistent with animal data, but this could be due to differences in patterns between human drug users and the animal models. Nonetheless, the postmortem brain data support the testing of new dynorphin-related therapeutics for the treatment of cocaine addiction. Frankel, P.S., Alburges, M.E., Bush, L., Hanson, G.R., and Kish, S.J. Striatal and Ventral Pallidum Dynorphin Concentrations are Markedly Increased in Human Chronic Cocaine Users. Neuropharmacology, 55(1), pp. 41-46, 2008.

Improved PET Dopamine Receptor Quantification with an Automated Partial Volume Correction

Dr. Dean Wong and colleagues at the Johns Hopkins University tested a new algorithm for partial volume correction (PVC) using an automatized atlas-based analysis to define 3-dimensional regions of interest (ROIs). This new analysis method was evaluated on PET dopamine receptor ligand binding in the normal human brain striatum, without and with PVC. Healthy volunteers received a single injection of (11)C-raclopride, and automatic segmentation of concomitant structural MR images was performed using a maximum-probability atlas in combination with a trained neural network. The results were comparable with those obtained with a manual method currently in use in their laboratory. However, dopamine receptor binding potential appeared less heterogeneous in the normal human striatum after PVC than they did without PVC. Thus, the new algorithm allows for traditional PET data extraction and PVC in an entirely automatic fashion, thus avoiding labor-intensive analyses and potential intra- or interobserver variability. Rousset, O.G., Collins, D.L., Rahmim, A., and Wong, D.F. Design and Implementation of an Automated Partial Volume Correction in PET: Application to Dopamine Receptor Quantification in the Normal Human Striatum. J Nuclear Medicine, 49(7), pp. 1097-1106, 2008.