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Director's Report to the National Advisory Council on Drug Abuse - February, 2005

Research Findings - Clinical Neuroscience Research

Executive Dysfunction in Cocaine Addiction: Evidence for Discordant Frontal, Cingulate, and Cerebellar Activity

Dr. Hugh Garavan and colleagues at Trinity University used event-related fMRI to investigate neuronal activity associated with compromised abilities of cocaine users to exert control over strong prepotent behaviors as demands on working memory increase. Increasing working memory load was found to further degrade performance of cocaine abusers on a GO-NOGO response inhibition task and increase the hypoactivity in the anterior cingulate and right prefrontal cortices previously found in cocaine abusers. Furthermore, unlike drug-naive controls, and opposite to the anterior cingulate pattern, cocaine users showed an over-reliance on the left cerebellum, a compensatory pattern previously seen in alcohol addiction. The results indicate that cocaine users find it difficult to inhibit their own actions, particularly when working memory demands, which have been shown previously to increase during cue-induced craving for the drug, are increased. The results reveal a neuroanatomical basis for this dysexecutive component to addiction, supporting the suggested importance cognitive functions may play in prolonging abuse or predisposing users toward relapse. Hester, R., Garavan, H. J. Neuroscience, 24(49), pp. 11017-11022, 2004.

PFC Dysfunction in Abstinent Cocaine Abusers

The anterior cingulate cortex (ACC) and lateral prefrontal cortex (LPFC) are brain regions important to executive cognitive functions (ECF). The aim of this study was to determine if cocaine abusers have impaired function of these ROI's. Dr. Bolla from Johns Hopkins and colleagues used (PET 15O-H2O) imaging during performance of a modified version of the Stroop Task to determine ACC and LPFC function in 23-day abstinent chronic cocaine users. Overall, the cocaine abusers showed less activation than non-drug using controls in the left ACC and the right LPFC and greater activation in the right ACC. The average use of weekly cocaine was negatively correlated with activity in the rostral ACC and right LPFC. It is possible that the disruption of ECF in substance abusers could interfere with attempts to stop drug use and undermine treatment efforts. Since impairment in ECF may be a common feature of various neuropsychiatric disorders, these findings have applicability beyond the neurobiology of addiction. Bolla, K., Ernst, M., Kiehl, K., Mouratidis, M., Eldreth, D., Contoreggi, C., Matochik, J., Kurian, V., Cadet, J. and London, E. J Neuropsychiatry Clinical Neurosciences, 16(4), pp. 456-464, 2004.

Residual Neuropsychological Effects of MDMA in Individuals with Minimal Exposure to Other Drugs

Dr. John Halpern and colleagues at McLean Hospital investigated whether residual cognitive deficits reported in users of illicit 3,4-methylenedioxymethamphetamine (MDMA or "ecstasy") are due to MDMA, as opposed to other drug use or additional confounding factors. They administered a battery of neuropsychological tests to 23 young MDMA users who reported minimal exposure to any other drugs, including alcohol, and to 16 comparison individuals equally involved with the rave subculture, but reporting no MDMA use. MDMA users as a whole performed worse than non-users on most test measures, but these differences only reached statistical significance on two measures. Heavy users (> 60 lifetime doses) displayed significant deficits on many measures, particularly those associated with mental processing speed and impulsivity, but moderate users displayed virtually no differences from non-users on any measures. These differences did not appear explainable by differences in family-of-origin variables, verbal IQ, levels of depression, or time since last MDMA use. These data from unusually "pure" frequent users of illicit MDMA provides direct evidence that residual cognitive deficits in heavy MDMA users are not simply due to the use of other drugs. Halpern, J.H., Pope, H.G., Sherwood, A.R., Barry, S., Hudson, J.I., Yurgelun-Todd, D. Drug and Alcohol Dependence, 75, pp. 135-147, 2004.

Decreased Absolute Amygdala Volume in Cocaine Addicts

Dr. Hans Brieter and colleagues at Massachusetts General Hospital used structural MRI to examine the volumes of the amygdala and hippocampus in cocaine-addicted subjects. Compared to matched healthy controls, the amygdala but not the hippocampus was significantly reduced in volume in cocaine abusers, and the right-left amygdala asymmetry in control subjects was absent in the cocaine addicts. Topological analysis of amygdala suggested the volume difference were due alterations in the corticomedial and basolateral nuclei. Since amygdala volume did not correlate with any measure of cocaine use, these findings suggest that reduced amygdala volume predisposes the individual to cocaine dependence. Makris, N., Gasic, G.P., Seidman, L.J., Goldstein, J.M., Gastfriend, D.R., Elman, I., Albaugh, M.D., Hodge, S.M., Ziegler, D.A., Sheahan, F.S., Caviness, V.S., Tsuang, M.T., Kennedy, D.N., Hyman, S.E., Rosen, B.R. and Breiter, H.C. Neuron 44(4), pp. 729-740, 2004.

Adaptation of the Attention Network in HIV Brain Injury

Human immunodeficiency virus (HIV)-positive patients commonly have attention and concentration problems. However, it remains unclear how HIV infection affects the attention network. Therefore, blood oxygenation level dependent functional magnetic resonance imaging (BOLD-fMRI) was performed in 36 subjects (18 HIV and 18 seronegative [SN] controls) during a set of visual attention tasks with increasing levels of attentional load. Compared with SN controls, HIV subjects showed similar task performance (accuracies and reaction times) but decreased activation in the normal visual attention network (dorsal parietal, bilateral prefrontal, and cerebellar regions) and increased activation in adjacent or contralateral brain regions. Cognitive performance (assessed with NPZ-8), CD4, and viral load all correlated with activated BOLD signals in brain regions that activated more in HIV subjects. Furthermore, HIV subjects activated more than SN controls in brain regions that showed load-dependent increases in activation (right prefrontal and right parietal regions) but less in regions that showed a saturation effect with increasing load. These findings suggest that HIV-associated brain injury leads to reduced efficiency in the normal attention network, thus requiring reorganization and increased usage of neural reserves to maintain performance. Chang, L., Tomasi, D., Yakupov, R., Lozar, C., Arnold, S., Caparelli, E. and Ernst, T. Annals Neurology, 56(2), pp. 259-272, 2004.

White Matter Hyperintensities in Subjects with Cocaine and Opiate Dependence and Healthy Comparison Subjects

Dr. Marc Kaufman and colleagues at McLean Hospital used structural MRI to investigate white matter signal hyperintensities (WMH), a marker of white matter damage, in patients with cocaine or opiate dependence. The severity of WMH was assessed separately for deep (and insular) and periventricular WMH, using a modified composite version of the rating scales of Fazekas and Coffey. The cocaine-dependent group (n=32) had greater severity of WMH than the opiate-dependent group (n=32), which in turn had greater severity of WMH than the age- and sex-matched healthy comparison group (n= 32). The cocaine-dependent group had greater lesion severity of deep and insular WMH than the opiate-dependent group and the healthy comparison group (odds ratio > 3.25 for deep WMH; odds ratio > 4.38 for insular WMH). For periventricular WMH, there were no significant differences between the three groups. The frontal lobes were the predominant locations of WMH in both substance-dependent groups. The greater prevalence and severity of WMH in cocaine-dependent subjects than in opiate-dependent subjects may reflect the fact that cocaine induces more ischemia via vasoconstriction than opiates. Lyoo, I.K., Streeter, C.C., Ahn, KH., Lee, H.K., Pollack, M.H., Silveri, M.M., Nassar, L., Levin, M., Sarid-Segal, O., Ciraulo, D.A., Renshaw, P.F., Kaufman, M.J. Psychiatry Research-Neuroimaging 131(2), pp. 135-145, 2004.

Motivation-Dependent Responses in the Human Caudate Nucleus

Dr. Julie Fiez and colleagues at the University of Pittsburg used event-related fMRI to determine how the dorsal striatum, particularly the caudate nucleus, responds to changes in the motivational context of a task. Normal subjects were given positive and negative feedback upon guessing the value of an unknown card. The motivational context of the task was manipulated by dividing trials into periods of high incentive (where visual feedback indicated monetary rewards and punishments) and low incentive (where visual feedback indicated only accuracy). Activity in the caudate nucleus was strongly influenced by the different incentive periods. Larger differences between positive and negative feedback were observed during periods of high incentive. These results suggest that changes in motivation are capable of modulating basal ganglia activity, and further support an important role for the caudate nucleus in affective processing. Delgado, M.R., Stenger, V.A. and Fiez, J.A. Cerebral Cortex 14(9), pp. 1022-1030. 2004.

Dissociable Effects of Arousal and Valence on Prefrontal Activity

Dr. Kevin LaBar and colleagues at Duke University investigated the role of the prefrontal cortex (PFC) activity in emotional evaluation and subsequent memory using with event-related functional MRI (fMRI) in normal subjects. Consistent with the valence hypothesis, specific regions in left dorsolateral PFC were more activated for positive than for negative picture evaluation, whereas regions in right ventrolateral PFC showed the converse pattern. Dorsomedial PFC activity was sensitive to emotional arousal, whereas ventromedial PFC activity was sensitive to positive valence, consistent with evidence linking these regions, respectively, to emotional processing and self-awareness or appetitive behavior. Finally, successful encoding (Dm) activity in left ventrolateral and dorsolateral PFC was greater for arousing than for neutral pictures. This finding suggests that the enhancing effect of emotion on memory formation is partly due to an augmentation of PFC-mediated strategic, semantic, and working memory operations. These results underscore the critical role of PFC in emotional evaluation and memory, and disentangle the effects of arousal and valence across PFC regions associated with different cognitive functions. These results provide insight into how the PFC may process stimuli that can evoke cue-elicited drug craving. Dolcos, F., LaBar, K.S., Cabeza, R. Neuroimage 23(1), pp. 64-74, 2004.

An ERP Index of Task Relevance Evaluation of Visual Stimuli

Dr. Geoffery Potts of Rice University investigated whether the anterior P2 (P2a) evoked potential component (also known as the frontal selection positivity FSP, or the frontal P3) reflects the neural processes involved in feature selection, stimulus evaluation, or response production. The present study employed a visual target detection (oddball) design with different response conditions: passive (no response), overt (keypress), and covert (silent count), to examine the impact of task relevance and response production on the frontal P2a in normal subjects. The results suggest that the P2a is an index of stimulus evaluation, rather than response production in that he P2a was present to task-relevant stimuli but had the same scalp topography and estimated source-dipole locations in both overt and covert responding. These results suggest that the P2a may be useful in clinical studies involving the saliency of drug-related stimuli. Potts, G. Brain and Cognition. 56(1), pp. 5-13, 2004.

Cerebral Phosphorus Metabolite Abnormalities in Heroin-Dependent Subjects

Dr. Perry Renshaw and colleagues at McLean hospital used Phosphorous Magnetic Resonance Spectroscopy (P-31MRS) to investigate cerebral bioenergetic and phospholipid abnormalities in heroin-dependent subjects. Compared with healthy comparison subjects (n=15), heroin abusers during the first month of methadone maintenance (MM) exhibited reduced phosphocreatine (PCr) levels (-15.3%) and elevated phosphodiesters (+ 12.9%, PDE) in an axial slice prescribed through the orbitofrontal and occipital cortices, which included the basal ganglia and frontal cortex. A treatment duration effect on metabolite values was found when MM subjects were stratified into subgroups based on treatment duration. Reduced PCr was observed only after 8+ days of MM, and phosphomonoesters (PME) were elevated in the 15-28 day MM group. Taken together, these cross-sectional data suggest that the first month of MM treatment may be associated with altered cerebral bioenergetics and phospholipid metabolite levels. Silveri, M.M., Pollack, M.H., Diaz, C.I., Nassar, L.E., Mendelson, J.H., Yurgelun-Todd, D.A., Renshaw, P.F.and Kaufman, M.J. Psychiatry Research-Neuroimaging 131(3), pp. 217-226, 2004.

The Effects of Vagus Nerve Stimulation on Decision-Making

Dr. Antoine Bechara and colleagues at the University of Iowa investigated whether the vagus nerve may be a possible conduit for somatic afferent signals pertinent to decision-making. The somatic marker hypothesis (SMH) views the participation in decision-making by the body proper as integral to emotional biasing and hence key to choosing in an advantageous manner. Eight epileptic patients with implanted left vagus nerve stimulators were tested on the Iowa Gambling Task. Using a counterbalanced design, each participant performed the gambling task under a condition in which low-level vagus nerve stimulation (VNS) was covertly delivered, and another condition in which no VNS was delivered. Participants showed improved performance, that is, made more advantageous choices, in the stimulated relative to the unstimulated condition. Although these results should be viewed as preliminary, they suggest that the vagus nerve is a conduit for afferent somatic signals that can influence decision-making. Martin, C.O., Denburg, N.L., Tranel, D., Granner, M.A. and Bechara, A. Cortex 40(4-5), pp. 605-612, 2004.

Regional Cerebral Blood Flow and Plasma Nicotine after Smoking Tobacco Cigarettes

Dr. Edward Domino and colleagues at the University of Michigan used PET imaging with [15O] water to determine whether regional cerebral blood flow (rCBF) in specific brain areas is correlated with arterial plasma nicotine concentrations after tobacco smoking. Twenty-one healthy adult tobacco smokers of both genders were studied after overnight tobacco abstinence. Subjects smoked tobacco cigarettes that were either of average (1.0 mg) or low (0.08 mg) nicotine. Six separate scans were taken about 12 min apart with the subjects' eyes closed and relaxed. Increases in normalized rCBF were obtained in the occipital cortex, cerebellum, and thalamus, and decreases in the anterior cingulate, nucleus accumbens, amygdala, and hippocampus immediately after smoking the first average nicotine yield cigarette of the morning. After smoking the second average nicotine yield cigarette, the effects were less than smoking the first. Low-nicotine cigarettes produced fewer changes in rCBF than those after the first average cigarette. Correlations with arterial nicotine on rCBF were statistically significant in brain areas with the greatest changes in relative blood flow such as the cerebellum and occipital cortex. These studies suggest that nicotine delivery by tobacco smoking is only one of the factors which contribute to changes in rCBF. Domino, E.F., Ni, L.S., Xu Y.J., Koeppe R.A., Guthrie, S. and Zubieta J.K., Progress In Neuropsychopharmacology & Biological Psychiatry 28(2), pp. 319-327, 2004.


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