Research Findings - Clinical Neuroscience Research

Cortical Recruitment by The Stroop Task at Baseline is Predictive of Abstinence Following Treatment for Cocaine Addiction

Dr. M. Potenza and colleagues at Yale University administered the Stroop task to cocaine-dependent patients during functional magnetic resonance imaging at treatment baseline. During Stroop performance, individuals activated brain regions similar to those reported in nonaddicted individuals, including the anterior cingulate cortex, dorsolateral prefrontal cortex, parietal lobule, insula, and striatum. Longer duration of self-reported abstinence at follow-up correlated with activation of ventromedial prefrontal cortex, left posterior cingulate cortex, and right striatum; percent drug-free urine screens correlated with striatal activation; and treatment retention correlated with diminished activation of dorsolateral prefrontal cortex. A modest correlation between Stroop effect and treatment retention was found. These findings implicate neurocircuitry underlying cognitive control in behavioral treatment outcome and provide insight into the mechanisms of behavioral therapies for cocaine dependence. They also suggest that neural activation patterns during cognitive control tasks are more sensitive predictors of treatment response than behavioral measures. Brewer, J.A., Worhunsky, P.D., Carroll, K.M., Rounsaville, B.J., and Potenza, M.N. Pretreatment Brain Activation During Stroop Task is Associated With Outcomes in Cocaine-Dependent Patients. Biological Psychiatry, 64(11), pp. 998-1004, 2008.

Recovery of Brain Glutamate/Glutamine during Abstinence from Chronic Methamphetamine Use

Dr. Linda Chang and colleagues at the University of Hawaii used proton magnetic resonance spectroscopy (MRS) to asses alterations in the glutamatergic system altered following prolonged methamphetamine (METH) exposure. While overall glutamine concentrations at baseline were similar between METH and control subjects, glutamine concentrations correlated positively with time of abstinence of METH in frontal gray and white matter. Reduced glutamine concentrations in frontal gray matter during early abstinence of METH recovered by the second month and showed a trend of compensatory increase after the fifth month. Subjects with craving symptoms had lower frontal gray matter glutamine than those without craving. These findings suggest dynamic abnormalities in brain glutamine in recently abstinent METH users, with depletion of the glutamatergic system in METH users within the first 2 months of abstinence followed by partial normalization during prolonged abstinence. Ernst, T., and Chang, L. Adaptation of Brain Glutamate Plus Glutamine during Abstinence from Chronic Methamphetamine Use. Journal of Neuroimmune Pharmacology, 3(3), pp. 1157-1890, 2008.

Frontocortical Glucose Metabolism in Methamphetamine Abusers Improves with Abstinence and Correlates with Cognitive Task Improvement

Dr. E. London and colleagues at UCLA used positron emission tomography with [F-18]fluorodeoxyglucose (FDG) to quantify regional cerebral glucose metabolism, an index of brain function, during performance of a vigilance task. A total of 10 methamphetamine-dependent subjects were tested after 5-9 days of abstinence, and after 4 additional weeks of supervised abstinence. A total of 12 healthy control subjects were tested at corresponding times. Global glucose metabolism increased between tests (P=0.01), more in methamphetamine-dependent (10.9%, P=0.02) than in control subjects (1.9%, NS). Glucose metabolism did not change in subcortical regions of methamphetamine-dependent subjects, but increased in neocortex, with maximal increase (>20%) in parietal regions. Changes in reaction time and self-reports of negative affect varied more in methamphetamine-dependent than in control subjects, and correlated both with the increase in parietal glucose metabolism, and decrease in relative activity (after scaling to the global mean) in some regions. Berman, S.M., Voytek, B., Mandelkern, M.A., Hassid, B.D., Isaacson, A., Monterosso, J., Miotto, K., Ling, W., and London, E.D. Changes in Cerebral Glucose Metabolism During Early Abstinence From Chronic Methamphetamine Abuse. Molecular Psychiatry, 13(9), pp. 897-908, 2008.

Changes in Regional Blood Volume During a 28-Day Period of Abstinence in Chronic Cannabis Smokers

Dr. J. Sneider and colleagues at McLean Hospital used dynamic susceptibility contrast MRI (DSCMRI) to determine changes in regional blood volume in the frontal and temporal lobe, and the cerebellum during 28 days of supervised abstinence from cannabis in 15 current, long-term cannabis users. DSCMRI scans were obtained between 6 and 36 h after the subjects' last reported cannabis use (Day 0), and again after 7 and 28 days of abstinence. Resting state CBV images were also acquired on 17 healthy comparison subjects. The present findings demonstrate that at Day 7, cannabis users continued to display increased blood volumes in the right frontal region, the left and right temporal regions, and the cerebellum. However, after 28 days of abstinence, only the left temporal area and cerebellum showed significantly increased CBV values in cannabis users. These findings suggest that while CBV levels begin to normalize with continued abstinence from cannabis, specifically in frontal areas, other temporal and cerebellar brain regions show slower CBV decreases. Sneider, J., Pope, H., Silveri, M., Simpson, N., Gruber, S., and Yurgelun-Todd, D. Differences in Regional Blood Volume During a 28-Day Period of Abstinence in Chronic Cannabis Smokers. European Neuropsychopharmacology, 18(8), pp. 612-619, 2008.

HIV-Associated Deficits in Complex Motor Skills, but not in Procedural Learning Associated with the Performance

Dr. E. Martin and colleagues at the University of. Illinois, Chicago, compared performance across multiple trial blocks of three procedural learning tasks: rotary pursuit, mirror star tracing, and weather prediction. Previous results from this group found HIV+ individuals had a poorer performance on retrospective memory and time-based but not event-based prospective memory. The current study compared HIV seropositive and HIV seronegative participants with history of cocaine and/or heroin dependence who were abstinent from drugs at the time of study and who were well matched on demographic, psychiatric, and substance use parameters. Individuals in the HIV+ group tended to perform worse than those in the HIV- group across all trial blocks of procedural learning tasks with motor demands, especially in the mirror star tracing task. The rate of improvement of the performance however, was not affected across all three procedural learning tasks. These findings support the observation of HIV-associated deficits in complex motor skills, but not in procedural learning. No associations were evident between serostatus and any of the procedural learning tasks. Gonzalez, R., Jacobus, J., Amatya, A.K., Quartana, P.J., Vassileva, J., and Martin, E.M. Deficits in Complex Motor Functions, Despite no Evidence of Procedural Learning Deficits, among HIV+ Individuals with History of Substance Dependence. Neuropsychology, 22(6), pp. 776-786, 2008.

More Pronounced Changes in Brain Metabolite Indices and Correlation with Mild Cognitive Impairment in HIV+ Individuals

Dr. Robert Paul of the University of Missouri along with the HIV MRS consortium and ACTG 700 team examined relationships between cognitive function, magnetic resonance spectroscopy brain metabolite indices in the basal ganglia, and anatomical magnetic resonance imaging of the caudate nucleus and the putamen in the earliest stages of HIV-related cognitive involvement. HIV+ individuals had poorer performance on several cognitive measures, which were associated with significantly higher choline/creatine ratios and significantly lower N-acetyl aspartate/choline ratios. Although caudate and putamen sizes of HIV+ individuals were smaller, there was no statistical difference from the HIV- subjects. Caudate size was significantly correlated with performances on higher-order thinking tests whereas the putamen size was significantly correlated with performances on motor tests. The results suggest that change in the size of basal ganglia is an important contributor to cognitive status in this population, and that changes in MRS measures are more pronounced than alterations in the size of brain region in mild stages of HIV-related cognitive impairment. Paul, R.H., Ernst, T., Brickman, A.M., Yiannoutsos, C.T., Tate, D.F., Cohen, R.A., and Navia, B.A.; ACTG 301 team; ACTG 700 team; and HIV MRS Consortium. Relative Sensitivity of Magnetic Resonance Spectroscopy and Quantitative Magnetic Resonance Imaging to Cognitive Function among Nondemented Individuals Infected with HIV. J. Intern. Neuropsychological Society, 14(5), pp. 725-733, 2008.

Brain Imaging Evidence of Persistent Disease Progression Correlated with Declined Global Deficit Score of HIV Patients at One Year Follow-up

Dr. Linda Chang and colleagues at the University of Hawaii used Diffusion Tensor Imaging (DTI) MRI to investigate whether there are temporal, greater than normal age-related brain inflammatory changes in HIV patients one year after the infection. Post mortem neuropathological data has previously found ongoing neuron inflammation and premature neurodegeneration in HAART treated drug abusers, indicating HAART does not prevent HIV-associated brain damage. In addition, HIV+ patients exhibit an on-going decline in global cognitive deficit scores relative to the initial evaluation compared to stable cognitive performance seen in HIV- subjects. Using DTI, clinically and cognitively stable HIV+ patients exhibited degradation of the microstructure of white matter underlying the frontal and parietal cortex and genu of the corpus collosum, as well as in putamen. DTI is thought to index neuroinflammation associated with ongoing HIV infection since greater increases in mean diffusivity and decreases in fractional anisotropy are associated with elevation of an inflammatory chemokine, macrophage chemoattractant protein-1. These results are similar to studies in patients with multiple sclerosis or with head trauma where correlations existed between cognitive function and diffusion measures. The changes in the brain diffusion within the 1-year follow-up period were observed without accompanying greater changes on the global deficit score. It suggests that DTI can be more sensitive than global cognitive measures and may serve as objective surrogate markers for early detection of disease progression in HIV brain infection. Chang, L., Wong, V., Nakama, H., Watters, M., Ramones, D., Miller, E.N., Cloak, C., and Ernst, T. Greater Than Age-related Changes in Brain Diffusion of HIV Patients After 1 Year. J. Neuroimmune Pharm. 3(4), pp. 265-274, 2008.

Decreased Brain Dopamine Transporters Related to Cognitive Deficits in HIV Patients with or without Cocaine Abuse

Dr. Linda Chang and colleagues at the University of Hawaii combined PET ligand imaging and neuropsychological testing to assess how HIV status affects the relationship between striatal dopamine transporter (DAT) and dopamine D2 receptors (D2R) availability and cognitive performance. Compared to seronegative controls, all HIV subjects had lower DAT in putamen but only HIV+ subjects with a history of cocaine dependence showed lower DAT in caudate. Lower D2R in both regions of all HIV+ subjects was accounted for by the greater nicotine use. Lower DAT, but not D2R, in putamen and caudate were associated with poorer performance on several neuropsychological tests, corrected for the effects of age, education, intelligence, mood, and nicotine use. In addition, lower average dopamine function (both DAT and D2R) was related to poorer overall function on neuropsychological tests. The study suggested that reduced dopaminergic function may contribute to cognitive dysfunction in HIV patients with or without additional cocaine abuse. Chang, L., Wang, G.J., Volkow, N.D., Ernst, T., Telang, F., Logan, J., and Fowler, J.S. Decreased Brain Dopamine Transporters are Related to Cognitive Deficits in HIV Patients with or without Cocaine Abuse. Neuroimage, 42(2), pp. 869-878, 2008.

Sociocultural Specificity in the Neurocognitive Effects of HIV as Evidenced in Hispanics

Susan Morgello of New York University and colleagues, using resources of the NIDA-funded Manhattan HIV Brain Bank, characterized neuropsychological (NP) test performance of HIV+ English-speaking Hispanic participants (n = 51) and investigated the combined roles of sociocultural factors (e.g., ethnicity, socioeconomic status [SES] proxy, and reading level) on NP test performance among HIV+ Hispanic and non-Hispanic White participants (n = 49). Hispanic individuals in the U.S. have been disproportionately impacted by HIV/AIDS, yet little is known regarding the neuropsychological sequelae of HIV within the Hispanic population. The pattern of NP impairment in HIV+ Hispanic participants was consistent with the frontal-striatal pattern observed in HIV-associated CNS sequelae, and the overall prevalence of global NP impairment was high compared to previous reports with more ethnically homogeneous, non-Hispanic White cohorts. Multivariate prediction models that considered both sociocultural factors and CD4 count revealed that reading level was the only unique predictor of global NP functioning, learning, and attention/working memory. In contrast, ethnicity was the only unique predictor of abstraction/ executive functioning. This study provides support for the use of neuropsychological evaluation in detecting HIV-associated NP impairment among HIV+ Hispanic participants and adds to the growing literature regarding the importance of considering sociocultural factors in the interpretation of NP test performance. Mindt, M.R., Byrd, D., Ryan, E.L., Robbins, R., Monzones, J., Arentoft, A., Germano, K.K., Morgello, S., and Henniger, D.E. Characterization and Sociocultural Predictors of Neuropsychological Test Performance in HIV+ Hispanic Individuals. Cultural Diversity & Ethnic Minority Psychology, 14(4), pp. 315-325, 2008.

Genotype Patterns are Shown to Contribute to Increased Risk for, or Protection from, Developing Heroin Addiction

M.J. Kreek and colleagues at Rockefeller University did a genome-wide association study in former severe heroin addicts and matched controls (all of Caucasian ancestry) and found several autosomal variants showing strong association with heroin addiction by genotype frequency analysis. They analyzed gene patterns (rather than haplotypes) and found one pattern using strong risk alleles had an odds ratio of 6.25 that explained 27% of the population attributable risk for heroin addiction in their cohort. Another pattern of the same variants was found to be significantly associated with protection from developing heroin addiction with an odds ratio of 0.13 where lacking this genotype pattern explained 83% of the population attributable risk for developing heroin addiction. This approach has identified several new genes potentially associated with heroin addiction. Nielsen, D.A., Ji, F., Yuferov, V., Ho, A., Chen, A. Levran, O., Ott, J., and Kreek, M.J. Genotype Patterns that Contribute to Increased Risk for or Protection from Developing Heroin Addiction. Mol. Psych., 13, pp. 417-428, 2008.

Genetic Variation in Human NPY Expression Affects Stress Response and Emotion

A collaboration among several NIDA researchers, principally J. K. Zubieta, R. Sinha, and D. Mash, among others and their colleagues, describe convergent evidence that haplotype-driven NPY expression predicts brain response to emotional and stress challenges. Using post-mortem tissue differential expression of mRNA was observed for four haplotypes: two with low expression, one with high expression, and one intermediate; diplotypes (i.e., made up of homozygous or heterozygous alleles) divided into three expression groups. Results demonstrated 1) using fMRI in a threat-related facial expression paradigm, amygdala activation in individuals with low NPY expression diplotype was higher than in those with the high expression; reactivity was predicted in a allele-dosage fashion; 2) using PET to determine the availability of mu-opioid receptors during application of a painful stressor, highly expressed NPY diplotypes predicted significantly higher levels of stress-induced mu-opioid system activation in prefrontal cortex, posterior insula, medial and lateral thalamus, ventral basal ganglia and amygdala; 3) using the TPQ (personality questionnaire), NPY expression was inversely correlated with trait anxiety. These results are consistent with the function of NPY as an anxiolytic peptide and help to explain inter-individual variation in resiliency to stress. Zhou, Z., Zhu, G., Hariri, A.R., Enoch, M.A., Scott, D., Sinha, R., Virkkunen, M., Mash, D.C., Lipsky, R.H., Hu, X.-Z, Hodgkinson, C.A., Ku, K., Buzas, B., Yuan, Q., Shen, P.H., Ferrell, R.E., Manuck, S.B., Brown, S.M., Hauger, R.L., Stohler, C.S., Zubieta, J.Z. and Goldman, D. Genetic Variation in Human NPY Expression Effects Stress Response and Emotion. Nature, 452, pp. 997-1002, 2008.

Brain MAO A Activity but not Genotype Variation Predicts Trait Aggression

Drs. R. Goldstein, N. Alia-Klein and colleagues at Brookhaven National Laboratory investigated whether MAO A activity regardless of genotypes differing the number of tandem repeats is related to personality measures assessed with the MPQ. Using PET, significant correlations were found with aggression for several cortical (temporal, occipital, percuneus, and medial PFC) and subcortical (caudate, putamen, amygdala, and thalamus) brain regions for individuals who had either high or low numbers of tandem repeats upstream of the coding region. No other personality measure assessed with the self-report instrument was correlated. To the extent that this aggression is associated with psychopathology including drug abuse makes MAO A activity a target for treatment. Alia-Klein, N., Goldstein, R.Z., Kriplani, A., Logan, J., Tomasi, D., Williams, B., Teland, F., Shumay, E., Biegon, A. Craig, I.W., Henn, F., Wang, G.-J., Volkow, N.D., and Fowler, J.S. Brain Monoamine Oxidase A Activity Predicts Trait Aggression. Journal of Neuroscience, 28(19), pp. 5099-5104, 2008.

Behavioral and Neurochemical Changes Induced by Oxycodone Differ between Adolescent and Adult Mice

Dr. Y. Zhang in the laboratory of M.J. Kreek at Rockefeller University compared the behavioral and striatal dopamine alterations between adolescent and adult mice after taking oxycodone. Oxycodone is a prescription drug which has seen increased nonmedical use of late. The results demonstrated that pre-exposure to oxycodone during adolescence enhances the ability of oxycodone to increase striatal dopamine levels relative to adult exposure. Assays demonstrated that exposure during adolescence resulted in long-lasting alterations in the nigrostriatal dopamine system, possibly due to over-expression of dopamine receptors and/or enhancement in mu-opioid receptor function. The implication for teenagers is that they may be differentially sensitive to the reinforcing and neurobiological effects thereby encouraging increased use as adults. In other words, teenagers taking the drug for nonprescription use may be at higher risk when becoming adults. Zhang, Y., Picetti, R., Butelman, E.R., Schlussman, S.D., Ho, A., and Kreek, M.J. Behavioral and Neurochemical Changes Induced by Oxycodone Differ between Adolescent and Adult Mice. Neuropsychopharmacology, Sep 10, 2008 [Epub ahead of print; PMID: 18784649; DOI: 10.1038/npp.2008.134].

Limited Abuse-like Effects of Therapeutic Zolpidem in Drug-naive Females: a Pilot Study

Dr. S. Licata and colleagues at the McLean Hospital/Harvard Medical School conducted a double-blind, placebo-controlled, cross over pilot study to investigate the subjective effects of zolpidem (10 mg) in drug-naive females. Over the course of a 5-h period vital signs were monitored and a series of computerized questionnaires was administered. Results indicate that zolpidem engendered subjective effects characteristic of hypnotic drugs, but reduced ratings of drug liking, willing to take again, and willing to pay for, relative to placebo. Thus, a therapeutic dose of zolpidem may have limited potential for misuse among females who have no experience with drugs of abuse. Licata, S.C., Penetar, D.M., Dunlap, S., and Lukas, S.E. A Therapeutic Dose of Zolpidem has Limited Abuse-like Effects in Drug-Naive Females: A Pilot Study. European Journal of Pharmacology, 598(1-3), pp. 64-67, 2008.

Comparison of Methods for Quantification of Self-Reported Caffeine Use

Ms. M. Addicott (a predoctoral candidate) and colleagues, at the Wake Forest University School of Medicine, compared two methods for self-reported caffeine use. The first was a retrospective interview of weekly caffeine use and a 7-day prospective diary. The second was salivary caffeine concentrations in a subset of participants. The estimates of caffeine use (mg/day) from the interview- and diary-based methods correlated with one another (r = 0.77) and with salivary caffeine concentrations (r = 0.61 and 0.68, respectively). However, almost half of the subjects who reported more than 600 mg/day in the interview reported significantly less caffeine use in the diary. Self-report measures of caffeine use are a valid method of predicting actual caffeine levels. Estimates of high caffeine use levels may need to be corroborated by more than one method. Addicott, M.A., Yang, L.L., Peiffer, A.M., and Laurienti, P.J. Methodological Considerations for the Quantification of Self-Reported Caffeine Use. Psychopharmacology (Berl), 2008 Nov 15 [Epub ahead of print; PMID: 19011837; DOI: 10.1007/s00213-008-1403-5].

Brain Mechanisms of Regulation of Reward Expectancy

Dr. M. Delgado and colleagues at Rutgers University and New York University used fMRI to see if emotion regulation strategies can also efficiently regulate expectations of reward arising from conditioned stimuli. Using a monetary reward-conditioning procedure with cognitive strategies in healthy human volunteers, they observed attenuation in both the physiological (skin conductance) and neural correlates (striatum) of reward expectation as participants engaged in emotion regulation. These findings provide a potential brain basis for studying how cognitive and behavioral therapeutic approaches can lead to increased control by drug abusers of craving and other drug-related expectancies. Delgado, M.R., Gillis, M.M., and Phelps, E.A. Regulating the Expectation of Reward Via Cognitive Strategies. Nature Neuroscience, 11(8), pp. 880-881, 2008.

Frequent Users of Cannabis Exhibit Blunted Psychotomimetic and Amnestics Effects During Acute THC Administration

Dr. C. D'Souza and colleagues at Yale School of Medicine sought to determine whether people who frequently use cannabis are either protected from or are tolerant to the effects of Delta-9-THC, the main psychoactive compound in cannabis. 30 frequent users of cannabis and 22 comparison subjects (infrequent cannabis users) were administered Delta-9-THC (0, 2.5, and 5 mg, i.v.) using a double-blind, randomized, placebo-controlled design. THC (1) produced transient psychotomimetic effects and perceptual alterations; (2) impaired memory and attention; (3) increased subjective effects of 'high'; (4) produced tachycardia; and (5) increased serum cortisol in both groups. However, frequent users showed blunted responses to the psychotomimetic, perceptual altering, cognitive impairing, anxiogenic, and cortisol increasing effects of Delta-9-THC but not to its euphoric effects. These data suggest that frequent users of cannabis are either inherently blunted in their response to, and/or develop tolerance to the many effects of cannabinoids. D'Souza, D.C., Ranganathan, M., Braley, G., Gueorguieva, R., Zimolo, Z., Cooper, T., Perry, E., and Krystal, J. Blunted Psychotomimetic and Amnestic Effects of Delta-9-Tetrahydrocannabinol in Frequent Users of Cannabis. Neuropsychopharmacology, 33(10), pp. 2505-2516, 2008.

DAT Genotype Modulation of Brain and Behavioral Responses To Cigarette Cues

Dr. T. Franklin and colleagues at the University of Pennsylvania combined fMRI brain imaging with a candidate gene approach to investigate the basis of the considerable individual variability in brain and subjective responses to cigarette cues observed in previous studies. As dopamine (DA) is critical for reward and its predictive signals, genetically driven variation in DA transmission may account for the observed differences. They hypothesized that brain and behavioral responses may be enhanced in probands carrying the 9-repeat allele of the DA transporter (DAT) SLC6A3 gene. Perfusion fMRI images were acquired during cue exposure in 19 smokers genotyped for the 40 base pair variable tandem repeat number polymorphism in the SLC6A3 gene. Contrasts between groups revealed that 9-repeat (9-repeats) had a greater response to smoking (vs nonsmoking) cues than smokers homozygous for the 10-repeat allele (10/10-repeats) in the interconnected ventral striatal/pallidal/orbitofrontal cortex regions (bilateral VS/VP/OFC). Activity was increased in 9-repeats and decreased in 10/10-repeats in the VS/VP/OFC. Brain activity and craving was strongly correlated (r-squared of 0.79-0.86) in 10/10-repeats in these regions and others (anterior cingulate, parahippocampal gyrus, and insula). Strikingly, there were no significant correlations between brain and behavior in 9-repeats. There were no differences in cigarette dependence, demographics, or resting baseline neural activity between groups. These results provide evidence that genetic variation in the DAT gene contributes to the neural and behavioral responses elicited by smoking cues. Franklin, T.R., Lohoff, F.W., Wang, Z., Sciortino, N., Harper, D., Li, Y., Jens, W., Cruz, J., Kampman, K., Ehrman, R., Berrettini, W., Detre, J.A, O'Brien, C.P., and Childress, A.R. DAT Genotype Modulates Brain and Behavioral Responses Elicited by Cigarette Cues. Neuropsychopharmacology advance online publication, 13 August 2008; doi:10.1038/npp.2008.124].

Compromised Sensitivity to Monetary Reward in Current Cocaine Users: An ERP Study

Dr. R. Goldstein and colleagues at Brookhaven National Laboratories studied modulation of the P300 by monetary reward expected to be received on a sustained attention task in 18 individuals with current cocaine use disorders (CUD) and 18 control subjects. Results in the controls revealed sensitivity to changes in monetary outcomes as indexed by P300 amplitude and speed of behavioral response. Furthermore, these measures were intercorrelated. In contrast, despite generally faster P300 waveforms and higher self-reported interest in the task, individuals with CUD did not display changes in responses to money versus nonreward; at the behavioral level, this impairment correlated with frequency of recent cocaine use. These preliminary results suggest a compromised sensitivity to a secondary reinforcer in CUD. This deficit may underlie the compromised ability to advantageously modify behavior in response to changing inner motivations and environmental contingencies. Goldstein, R., Parvaz, M., Maloney, T., Alia-Klein, N., Woicik, P., Telang, F., Wang, G., and Volkow, N. Compromised Sensitivity to Monetary Reward in Current Cocaine Users: An ERP Study. Psychophysiology, 45(5), pp. 705-713, 2008.

Behavioral and Electrophysiological Evidence for Attentional Deficits in Cocaine Abusers

Dr. N. Boutros and colleagues at Wayne State University used behavioral and evoked potential to study attentional performance of cocaine-dependent patients (n=14) compared to healthy control individuals (n=15). Attention was assessed using an auditory oddball event-related task as well as the Continuous Performance Test (CPT, Identical Pairs version). The cocaine-dependent group displayed P300 amplitude reduction compared to controls, but there were no group differences in P300 response latency. 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 electrophysiological 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.

Heavy Smoking is Not a Potential Confound in the fMRI BOLD Responses

In a multi-site study, Dr. L. Leyba and colleagues investigated whether the vascular effects of heavier long-term cigarette use is a confound in fMRI BOLD signals. The blood oxygen level dependent (BOLD) response to a simple sensorimotor task was compared between schizophrenia patients with a smoking history (mean 17 pack years) and carefully matched patient non-smokers and control non-smokers. Group differences in activation magnitude and spatial extent were non-significant. Therefore, typical smoking histories in schizophrenia patients do not significantly confound fMRI results in simple sensorimotor tasks when patient demographics are carefully controlled. Leyba, L., Mayer, A.R., Gollub, R.L., Andreasen, N.C., and Clark, V.P. Smoking Status as a Potential Confound in the BOLD Response of Patients with Schizophrenia. Schizophrenia Research, 104(1-3), pp. 79-84, 2008.

Gender Related Differences in Subjective Responses and Cardiovascular Effects of Self-Administered Cocaine

Dr. R. Malison and colleagues at Yale School of Medicine examined gender differences in cocaine self-administration and cocaine-induced subjective and cardiovascular measures. Subjects (21 men, 10 women) self-administered cocaine infusions (8, 16 and 32 mg/70 kg) over a 2-hour period under a fixed ratio 1, 5 minute time out schedule in three test sessions. All subjects had a history of either cocaine abuse or dependence and were not currently seeking treatment. Women and men self-administered similar amounts of cocaine. None of the subjective effects measures showed a significant main effect of sex during the cocaine self-administration session. Significant interactions were observed for subjective ratings of 'high' (sex x time) and 'stimulated' (sex x time x dose), with women reporting lower ratings over time/doses than men. Relative to men, cocaine produced dose- and time-dependent increases in feelings of hunger (i.e., reduced appetite suppression) in women. Systolic and diastolic blood pressures showed different patterns of change in men and women, with women showing less robust cocaine-induced increases than men. Taken together, these findings indicate that women and men differ in their subjective and cardiovascular responses to self-administered cocaine. Lynch, W.J., Kalayasiri, R., Sughondhabirom, A., Pittman, B., Coric, V., Morgan, P.T., and Malison, R.T. Subjective Responses and Cardiovascular Effects of Self-Administered Cocaine in Cocaine-Abusing Men and Women. Addiction Biology, 13(3-4), pp. 403-410, 2008.

Error-Specific Medial Cortical and Subcortical Activity During the Stop Signal Task

Dr. R. Li and colleagues at Yale School of Medicine used fMRI in healthy volunteers to investigate how the brain uses error signals specifically to adjust behavior on a moment to moment basis. Subjects performed a version of stop signal task (SST) that was adjusted to elicit errors approximately half of the time in high-conflict trials despite constant behavioral adjustment of the observers. Greater and, sequentially, less activation in the medial cortical regions were observed when observers made an error, compared with when they successfully resolved high-conflict responses. Errors also evoked greater activity in the cuneus, retrosplenial cortex, insula, and subcortical structures including the thalamus and the region of the epithalamus (the habenula). However, error-related medial cortical activities were not correlated with post-error behavioral adjustment, as indexed by post-error slowing (PES) in go trial reaction time. These results delineated an error-specific pattern of brain activation during the SST and suggest that the relationship between error-related activity and post-error behavioral adjustment may be more complicated than proposed in current conceptual frameworks. Li, C.R., Yan, P., Chao, H.H., Sinha, R., Paliwal, P., Constable, R.T., Zhang, S., and Lee, T. Error-Specific Medial Cortical and Subcortical Activity During the Stop Signal Task: A Functional Magnetic Resonance Imaging Study. Neuroscience, 155(4), pp. 1142-1151, 2008.

Different Cortical Thickness Abnormalities in Cocaine Addiction Are Related to Behavioral Performance and Drug Use

Dr. H. Brieiter and colleagues at Massachusetts General Hospital used advanced morphometric methods to compare the thickness of neocortical and paralimbic brain regions between cocaine-dependent and matched control subjects. Four of 18 a priori regions involved with executive regulation of reward and attention were significantly thinner in addicts. Correlations were significant between thinner prefrontal cortex and reduced key-presses during judgment and decision making of relative preference in addicts, suggesting one basis for restricted behavioral repertoires in drug dependence. Reduced effortful attention performance in addicts also correlated with thinner paralimbic cortices. Some thickness differences in addicts were correlated with cocaine use independent of nicotine and alcohol, but addicts also showed diminished thickness heterogeneity and altered hemispheric thickness asymmetry. These observations suggest that brain structure abnormalities in addicts are related in part to drug use and in part to predisposition toward addiction. Makris, N., Gasic, G., Kennedy, D., Hodge, S., Kaiser, J., Lee, M., Kim, Y. Blood, A., Evins, A., Seidman, L., Iosifescu, D., Lee, S., Baxter, C., Perlis, R., Smoller, J., Fava, M., and Breiter, H. Cortical Thickness Abnormalities in Cocaine Addiction-A Reflection of Both Drug Use and a Pre-Existing Disposition to Drug Abuse? Neuron, 60(1), pp. 174-188, 2008.

Abstinent MDMA ("Ecstasy") Users Exhibit Alterations in Serotonin Transporters that are Related to Cognitive Performance but Not to Changes in Dopamine Transporters

Dr. U. McCann and colleagues at Johns Hopkins University used PET ligand binding brain imaging to determine whether MDMA users exhibit reductions in DA transporter (DAT), in addition to previously demonstrated serotonin transporter (SERT) reductions, and whether there is a relationship between transporter binding and cognitive performance. Of particular interest were MDMA users who take closely spaced sequential doses, which engender high plasma MDMA concentrations. Sixteen abstinent MDMA users with a history of using sequential MDMA doses (two or more doses over a 3- to 12-h period) and 16 age-, gender-, and education-matched controls participated. Subjects underwent positron emission tomography with the DAT and SERT radioligands, [11C]WIN 35,428 and [11C]DASB, respectively. Subjects also underwent formal neuropsychiatric testing. MDMA users had reductions in SERT binding in multiple brain regions but no reductions in striatal DAT binding. Memory performance in the aggregate subject population was correlated with SERT binding in the dorsolateral prefrontal cortex, orbitofrontal cortex, and parietal cortex, brain regions implicated in memory function. Prior exposure to MDMA significantly diminished the strength of this relationship. Use of sequential MDMA doses is associated with lasting decreases in brain SERT, but not DAT. Memory performance is associated with SERT binding in brain regions involved in memory function. Prior MDMA exposure appears to disrupt this relationship. These data are the first to directly relate memory performance to brain SERT density. McCann, U., Szabo, Z., Vranesic, M., Palermo, M., Mathews, W., Ravert, H., Dannals, R., and Ricaurte, G. Positron Emission Tomographic Studies of Brain Dopamine and Serotonin Transporters in Abstinent (+/-)3,4-Methylenedioxymeth-amphetamine ("Ecstasy") Users: Relationship to Cognitive Performance. Psychopharmacology, 200(3), pp. 439-450, 2008.

Association of a Polymorphism Near CREB1 with Aversion Processing in the Insula

Dr. H. Breiter and colleagues at Massachusetts General Hospital combined functional brain imaging with a candidate gene analysis in a study of altered brain processing of and behavioral avoidance responses to angry facial expressions. A polymorphism near the cyclic adenosine monophosphate response element binding protein gene (CREB1) has recently been associated with greater self-reported effort at anger control. Changes in CREB expression have also been linked to administration of cocaine and other drugs of abuse A total of 28 healthy caucasian participants (mean age, 29.2 years; 13 women) were genotyped for rs4675690, a single- nucleotide polymorphism near CREB1. Changes in BOLD fMRI signals in the amygdala, insula, anterior cingulate, and orbitofrontal cortex were obtained during passive viewing of photographs of faces with emotional expressions. To measure approach and avoidance responses to anger, an off-line key- press task that traded effort for viewing time assessed valuation of angry faces compared with other expressions. The CREB1- linked single- nucleotide polymorphism was associated with significant differential activation in an extended neural network responding to angry and other facial expressions. The CREB1- associated insular activation was coincident with activation associated with behavioral avoidance of angry faces. These results indicated that A polymorphism near CREB1 is associated with responsiveness to angry faces in a brain network implicated in processing aversion. Coincident activation in the left insula is further associated with behavioral avoidance of these stimuli. Perlis, R., Holt, D., Smoller, J., Blood, A. Lee, S., Kim, B., Lee, M., Sun, M., Makris, N., Kennedy, D., Rooney, K., Dougherty, D., Hoge, R., Rosenbaum, J., Fava, M., Gusella, J., Gasic, G., and Breiter, H. Association of a Polymorphism Near CREB1 with Differential Aversion Processing in the Insula of Healthy Participants. Archives of General Psychiatry, 65(8), pp. 882-892, 2008.

Neural Correlates of Voluntary and Involuntary Risk Taking in the Balloon Analog Risk Task (BART)

Dr. J. Detre and colleagues at the University of Pennsylvania used fMRI to investigate the neuronal basis of voluntary choice on risk taking. A modified version of the Balloon Analog Risk Task (BART) was performed during functional magnetic resonance imaging (fMRI) and administered in both an active choice mode and a passive no-choice mode in order to examine the neural correlates of voluntary and involuntary risk taking in the human brain. Voluntary risk in the active choice task was associated with robust activation in mesolimbic-frontal regions (midbrain, ventral and dorsal striatum, anterior insula, dorsal lateral prefrontal cortex (DLPFC), and anterior cingulate/medial frontal cortex (ACC/MFC)), in addition to activation in visual pathway regions. In contrast, these mesolimbic-frontal activation patterns were not observed for involuntary risk in the passive no-choice task. Decision making was associated with neural activity in the right DLPFC. These findings suggest that recruitment of the brain mesolimbic-frontal pathway during risk-taking is contingent upon the agency of the risk taker. Since the performance of the BART has been shown to be an index of impulsitivity and risk for substance abuse, the present paradigm may be extended to pathological populations to determine the specific neural components of their impaired risk behavior. Rao, H., Korczykowski, M., Pluta, J., Hoang, A., and Detre, J. Neural Correlates of Voluntary and Involuntary Risk Taking in the Human Brain: An fMRI Study of the Balloon Analog Risk Task (BART). Neuroimage, 42(2), pp. 902-910, 2008.

Cognitive Control is Related to White Matter Alterations in the Corpus Collosum of Methamphetamine-Dependent Subjects

Dr. R. Salo and colleagues at the University of California, Davis used Diffusion Tensor Imaging to determine the relationship of cognitive control and indices of white matter (WM) in the callosal genu and splenium in 37 currently abstinent MA abusers and 17 non-substance abusing control subjects. Cognitive control was indexed by performance of a computerized measure of the Stroop selective attention task. Measurements of fractional anisotropy (FA), apparent diffusion coefficient (ADC) of callosal fibers, and diffusion tensor eigenvalues were obtained in all subjects. The MA abusers exhibited greater Stroop reaction time interference (i.e., reduced cognitive control) (p = .04) compared with control subjects. After correcting for multiple comparisons, FA within the genu correlated significantly with measures of cognitive control in the MA abusers (p = .04, Bonferroni corrected) but not in control subjects (p = .26). Group differences in genu but not splenium FA only exhibited a non-significant trend (p = .09). These results demonstrate that methamphet-amine abuse primarily alters anterior callosal WM microstructure compared to posterior callosal WM microstructure. Furthermore, the DTI indices within the genu but not splenium correlated with measures of cognitive control in chronic MA abusers. Salo, R., Nordahl, T.E., Buonocore, M.H., Natsuaki, Y., Waters, C., Moore, C.D., Galloway, G.P., and Leamon, M.H. Cognitive Control and White Matter Callosal Microstructure in Methamphetamine-Dependent Subjects: A Diffusion Tensor Imaging Study. Biological Psychiatry, [Epub ahead of print; PMID: 18814867; DOI:10.1016/j.biopsych.2008.08.004, 2008].

Neural Correlates of the Processing of Another's Mistakes: A Possible Underpinning for Social and Observational Learning

Dr. M. Shane and colleagues at the MIND Institute at University of New Mexico used fMRI to compare and contrast those regions that show sensitivity to the performance, and to the observation, of committed errors. Healthy volunteers performed a speeded go/no-go task and also observed a video of another person performing the same task. Dorsal anterior cingulate, orbitofrontal cortex, and supplementary motor regions were commonly activated to both performed and observed errors, providing evidence for common neural circuitry underlying the processing of one's own and another's mistakes. In addition, several regions, including inferior parietal cortex and anterorostral and ventral cinguli, did not show activation during performed errors, but were instead uniquely activated by the observation of another's mistakes. The unique nature of these 'observer-related' activations suggests that these regions, while of potential import towards recognition of another's errors, are not core to circuitry underlying error monitoring. Rather, the authors suggest that these regions may represent components of a distributed network important for the representation and interpretation of complex social actions. Shane, M.S., Stevens, M., Harenski, C.L., and Kiehl, K.A., Neural Correlates of the Processing of Another's Mistakes: A Possible Underpinning for Social and Observational Learning. NeuroImage, 42(1), pp. 450-459, 2008.

Comparative Distributions of the Monoamine Transporters in the Rodent, Monkey, and Human Amygdala

Drs. L. Porrino and H. Smith from Wake Forest University reviewed the functional relevance of dopamine, serotonin, and norepinephrine transmission in the amygdala, and compared the distributions of the monoamine transporters in the rodent, monkey, and human brain. The transporters were found to be heterogeneously distributed in the amygdala. The dopamine transporter (DAT) is consistently found to be extremely sparsely distributed, however the various accounts of its subregional topography are inconsistent, making any cross-species comparisons difficult. The serotonin transporter (SERT) had the greatest overall degree of labeling of the three markers, and was characterized by substantial inter-species variability in its relative distribution. The norepinephrine transporter (NET) was shown to possess an intermediate level of labeling, and like the SERT, its distribution is not consistent across the three species. The results of these comparisons indicate that caution should be exercised when using animal models to investigate the complex processes modulated by the monoamines in the amygdala, as their relative contributions to these functions may differ across species. Smith, H., and Porrino, L. The Comparative Distributions of the Monoamine Transporters in the Rodent, Monkey, and Human Amygdala. Brain Structure & Function, 213(1-2), pp. 73-91, 2008.

Distinguishing Expected Negative Outcomes from Preparatory Control in the Human Orbitofrontal Cortex

Dr. S. Urus and colleagues at the University of California, Davis used BOLD fMRI to determine if subdivisions of the OFC are specifically engaged when negatively valenced outcomes are expected, and to what extent such areas might be involved in preparatory active control of behavior. In order to dissociate these two processes, healthy human participants performed two tasks during fMRI scanning, which either simultaneously or independently manipulated monetary incentives for correct performance, and demands for active preparation of cognitive control. In both experiments, preparation for performance was associated with lateral PFC activity in response to high incentives, regardless of their valence, as well as in response to increased task demands. In contrast, areas of the OFC centered around the lateral orbital sulcus responded maximally to negatively perceived prospects, even when such prospects were associated with decreases in preparatory cognitive control. These results provide direct support for theoretical models which posit that the OFC contributes to behavioral regulation by representing the value of anticipated outcomes, but does not implement active control aimed at avoiding or pursuing outcomes. Furthermore, they provide additional converging evidence that the lateral OFC is involved in representing specifically the affective impact of anticipated negative outcomes. Ursu, S., Clark, K.A., Stenger, V.A., and Carter, C.S., Distinguishing Expected Negative Outcomes from Preparatory Control in the Human Orbitofrontal Cortex. Brain Research, 1227, pp. 110-119, 2008.

Sleep Deprivation Decreases Binding of [11C]Raclopride to Dopamine D2/D3 Receptors in the Human Brain

Dr. Nora Volkow and colleagues used PET ligand brain imaging to test whether one night of sleep deprivation changes dopamine brain activity in 15 healthy human participants. [11C]raclopride was used to probe dopamine D2/D3 receptor radioligand occupany and [11C]cocaine was used to index dopamine transporter levels. Subjects were tested twice: after one night of rested sleep and after one night of sleep deprivation. The specific binding of [11C]raclopride in the striatum and thalamus were significantly reduced after sleep deprivation and the magnitude of this reduction correlated with increases in fatigue (tiredness and sleepiness) and with deterioration in cognitive performance (visual attention and working memory). In contrast, sleep deprivation did not affect the specific binding of [11C]cocaine in the striatum. Because [11C]raclopride competes with endogenous dopamine for binding to D2/D3 receptors, these data suggest that the decreases in binding reflect dopamine increases with sleep deprivation. However, there is the possibility that decreased [11C]raclopride binding reflects decreases in receptor levels or affinity. Sleep deprivation did not affect dopamine transporters (target for most wake-promoting medications) and thus dopamine increases are likely to reflect increases in dopamine cell firing and/or release rather than decreases in dopamine reuptake. Because dopamine-enhancing drugs increase wakefulness, the authors postulate that dopamine increases after sleep deprivation is a mechanism by which the brain maintains arousal as the drive to sleep increases but one that is insufficient to counteract behavioral and cognitive impairment. Volkow, N.D., Wang, G., Telang, F., Fowler, J.S., Logan, J., Wong, C., Ma, J., Pradhan, K., Tomasi, D., Thanos, P.K., Ferre, S., and Jayne, M. Sleep Deprivation Decreases Binding of [11C]Raclopride to Dopamine D2/D3 Receptors in the Human Brain. J. Neuroscience, 28(34), pp. 8454-8461, 2008.

New Method for Measuring White Matter Conductivity Using Diffusion Tensor MRI

Dr. K. Lim and colleagues at the University of Minnesota developed a new algorithm to derive the anisotropic conductivity of the cerebral white matter (WM) from the diffusion tensor MRI (DT-MRI) data. The new algorithm was applied to the DT-MRI data acquired from two healthy human subjects. The extracted anisotropic conductivity distribution was compared with those obtained by using two existing algorithms, which were based upon a linear conductivity-to-diffusivity relationship and a volume constraint, respectively. The present results suggest that the VF algorithm is capable of incorporating the partial volume effects of the CSF and the intravoxel fiber crossing structure, both of which are not addressed altogether by existing algorithms. Therefore, it holds potential to provide a more accurate estimate of the WM anisotropic conductivity, and may have important applications to clinical neuroscience research. Wang, K., Zhu, S., Mueller, B., Lim, K., Liu, Z., and He, B. A New Method to Derive White Matter Conductivity From Diffusion Tensor MRI. IEEE Transactions on Biomedical Engineering, 55(10), pp. 2481-2486, 2008.

L-Tetrahydropalmatine Reduces Opiate Craving and Increases the Abstinence Rate in Heroin Users

Dr. S. Li and colleagues at Medical College of Wisconsin examined the ability of levotetrahydropalmatine (l-THP) to reduce heroin craving and increase the abstinence rate among heroin-dependent patients (n = 120) using a randomized, double-blinded, and placebo-controlled design. The participants remained in a ward during a 4-week period of l-THP treatment, followed by 4 weeks of observation after treatment. The patients were followed for 3 months after discharge. Outcome measures included the measured severity of the protracted abstinence withdrawal syndrome (PAWS) and the abstinence rate. Four weeks of l-THP treatment significantly ameliorated the severity of PAWS, specifically, somatic syndrome, mood states, insomnia, and drug craving, in comparison to the placebo group. Based on the 3 month follow-up observation, participants who survived the initial 2 weeks of l-THP medication and remained in the trial program had a significantly higher abstinence rate of 47.8% (95% confidence interval [CI]: 33%-67%) than the 15.2% in the placebo group (95% CI: 7%-25%), according to a log-rank test (P < 0.0005). These results support the potential use of l-THP for the treatment of heroin addiction. Yang, Z., Shao, Y., Li, S., Qi, J., Zhang, M., Hao, W., and Jin, G., Medication of L-Tetrahydropalmatine Significantly Ameliorates Opiate Craving and Increases the Abstinence Rate in Heroin Users: A Pilot Study. Acta Pharmacologica Sinica, 29(7), pp. 781-788, 2008.