Research Findings - Clinical Neuroscience Research

Cocaine Cues and Dopamine In Dorsal Striatum: Mechanism of Craving In Cocaine Addiction

Nora Volkow and colleagues at Brookhaven National Laboratory and the University of Pennsylvania used Positron Emission Tomography ligand imaging to test whether dopamine increases occur to drug-related stimuli in cocaine addicts and whether the dopamine increases are associated with drug craving. The ability of drugs of abuse to increase dopamine in nucleus accumbens underlies their reinforcing effects. However, preclinical studies have shown that with repeated drug exposure neutral stimuli paired with the drug (conditioned stimuli) start to increase dopamine by themselves, which is an effect that could underlie drug-seeking behavior. Positron emission tomography studies using [C-11] raclopride, a dopamine D-2 receptor radioligand sensitive to competition with endogenous dopamine, were conducted in eighteen cocaine-addicted subjects. Changes in dopamine were measured by comparing the specific binding of [C-11] raclopride when subjects watched a neutral video (nature scenes) versus when they watched a cocaine-cue video (scenes of subjects smoking cocaine). The specific binding of [C-11] raclopride in dorsal (caudate and putamen) but not in ventral striatum (in which nucleus accumbens is located) was significantly reduced in the cocaine-cue condition. The magnitude of this reduction correlated with self-reports of craving. Moreover, subjects with the highest scores on measures of withdrawal symptoms and of addiction severity (shown to predict treatment outcomes), had the largest dopamine changes in dorsal striatum. This provides evidence that dopamine in the dorsal striatum (region implicated in habit learning and in action initiation) is involved with craving and is a fundamental component of addiction. Because craving is a key contributor to relapse, strategies aimed at inhibiting dopamine increases from conditioned responses are likely to be therapeutically beneficial in cocaine addiction. Volkow, N.D., Wang, G.J., Telang, F., Fowler, J.S., Logan, J., Childress, A.R., Jayne, M., Ma, Y.M., and Wong, C. Journal of Neuroscience, 26, pp. 6583-6588, 2006.

Very Little Cigarette Smoking Results in Substantial Levels of Nicotinic Acetylcholine Receptor Occupancy

Arthur Brody and colleagues at University of California, Los Angeles and the PET Center at the NIDA Intramural Research Program used PET ligand imaging to determine the effect of cigarette smoking on nicotinic acetylcholine receptor (nAChR) availability in tobacco dependent smokers during early abstinence. nAChR occupancy was measured with 2-[18F] fluoro-3-(2(S)azetidinylmethoxy) pyridine. The effective dose required to displace 50% of the radiotracer (ED50) in the nAChR-rich thalamus was 1-3 puffs (15%) of a cigarette, or a peak plasma nicotine concentration of 0.83 ng/ml. Thus, very little cigarette smoking results in substantial brain nAChR occupancy during smokers' high risk period for relapse. Findings from the present study have implications for the treatment of tobacco dependence. Attempts to block the addicting properties of tobacco, including the use of nAChR antagonists, and nicotine vaccines, are currently being used or evaluated for their potential to treat tobacco dependence. The present study points to nicotine replacement therapies (e.g., nicotine patch, gum, and lozenges, or vaccines) to produce high levels of nicotine in the in blood in order to produce substantial nAChR occupancy or blockade, to overcome the high levels of receptor occupancy produced by nicotine in tobacco. The methodology in this study also may prove useful for evaluating the pharmacological effects of such treatments and guiding efforts to enhance their efficacy. Brody, A.L., Mandelkern, M.A., London, E.D., Olmstead, R.E., Farahi, J., Scheibal, D., Jou, J., Allen, V., Tiongson, N., Chefer, S.I., Koren, A., and Mukhin, A.G. Archives General Psychiatry, 63, pp. 907-914, 2006.

Changes in Nicotine Receptor Levels During Smoking Cessation

Julie Staley and colleages at Yale School of Medicine used SPECT ligang imaging to monitor changes in the number of nicotine receptors after individuals quite smoking. It was hypothesized that abnormal numbers of these receptors during early abstinence may contribute to a smoker's urge to smoke and impact their ability to remain abstinent. Using molecular imaging in nonhuman primates, the time interval necessary for smokers to abstain in order to be free of residual nicotine was established. Human smokers were then imaged after an average of 6.8 days of abstinence. Results indicated the nicotine receptor subtypes were higher throughout the cerebral cortex (26-36%) and in the striatum (27%) than in nonsmokers, suggesting higher levels of these receptors in recently abstinent smokers. Greater availability in recently abstinent smokers correlated with the days since last cigarette and the urge to smoke to relieve withdrawal symptoms but not the severity of nicotine dependence, severity of nicotine withdrawal, or the desire to smoke. These findings indicate that, when smokers quit smoking, they do so in the face of a significant increase in the receptors normally activated by nicotine and this increased availability impact the ability of smokers to maintain abstinence. Staley, J.K., Krishnan-Sarin, S., Cosgrove, K.P., Krantzler, E., Frohlich, E., Perry, E., Dubin, J.A., Estok, K., Brenner, E., Baldwin, R.M., Ttamagnan, E.G., Seibyl, J.P., Jatlow, P., Picciotto, M.R., London, E.D., O'Malley, S., van Dyke, C.H. Journal of Neuroscience, 26, pp. 8653-8657, 2006.

Neurobiological Substrates of Dread

Greg Berns and colleagues at Emory University used BOLD fMRI to examine the neuronal systems involved in dread, i.e. emotions associated with waiting for an adverse outcome. Given the choice of waiting for an adverse outcome or getting it over with quickly, many people choose the latter. Theoretical models of decision-making have assumed that this occurs because there is a cost to waiting - i.e., dread. Using functional magnetic resonance imaging, authors measured the neural responses to waiting for a cutaneous electric shock in healthy individuals. Some individuals dreaded the outcome so much that, when given a choice, they preferred to receive more voltage rather than wait. Even when no decision was required, these extreme dreaders were distinguishable from those who dreaded mildly by the rate of increase of neural activity in the posterior elements of the cortical regions associated with pain responsivity (e.g. posterior cingulate). This suggests that dread derives, in part, from the attention devoted to the expected physical response and not simply from fear or anxiety. Although these differences were observed during a passive waiting procedure, they correlated with individual behavior in a subsequent choice paradigm, providing evidence for a neurobiological link between the experienced disutility of dread and subsequent decisions about unpleasant outcomes. Berns, G.S., Chappelow, J., Cekic, M., Zink, C.F., Pagnoni, G., Martin-Skurski, M.E. Science, 312, pp. 754-758, 2006.

Reduced Punishment Sensitivity in Neural Systems of Behavior Monitoring in Impulsive Individuals

Geoffery Potts and colleagues at Rice University used event-related potential recordings of the error-related negativity (ERN) to determine whether impulsive individuals show reduced brain responses during punishment. The ERN was recorded during a flanker task with performance-based monetarily rewarding and punishing trials in 37 undergraduate students separated into high- and low-impulsive groups based on a median split on self-reported Barrett Impulsiveness Scale. The high-impulsive group had a smaller medial frontal error-related negativity (ERN) on punishment trials than the low-impulsive group. The medial prefrontal neural system of behavior monitoring, indexed by the ERN, appears less sensitive to punishment signals in normal impulsivity. This reduced punishment sensitivity in impulsivity; a personality variation associated substance abuse may be related to the tendency to select short-term rewards despite potential long-term negative consequences in these individuals. Potts, G.F., George, M.R.M., Martin L.E., and Barratt, E.S. Neuroscience Letters, 397, pp. 130-134, 2006.

Controlling the Integration of Emotion and Cognition - The Role of Frontal Cortex in Distinguishing Helpful from Hurtful Emotional Information

Jennifer Beer and colleagues at the University of California, Berkeley examined the role of orbitofrontal cortex when it was appropriate to control (i.e., prevent) the influence of emotion in decision-making and to incorporate the influence of emotion in decision making. The orbitofrontal cortex has been identified as a neural area involved in incorporating emotion into decision-making. However, it is unclear whether this area's function specific to the integration of emotion and cognition, or does it more broadly govern whether emotional information should be integrated into cognition? The results suggest that activity in lateral orbitofrontal cortex is associated with evaluating the contextual relevance of emotional information for decision making. These findings provide a framework for interpreting the abnormalities in the orbitofrontal cortex that have been repeatedly observed in substance abusers, Beer, J.S., Knight, R.T., and D'Esposito, M. Psychological Science, 17, pp. 448-453, 2006.

Executive Dysfunction in Substance Dependent Individuals During Drug Use and Abstinence

Antoine Bechara and colleagues at the University of Southern California used neuropsychological testing to compare impairments in substance abusers on executive control tasks relying on different systems within the prefrontal cortex (PFC). Three different functional systems have been described: the dorsolateral prefrontal cortex (DLPC), orbitofrontal cortex (OFC), and anterior cingulate Cortex (ACC) circuits. Dysfunction within each PFC system is associated with different behavioral, cognitive, and emotional abnormalities. Substance abusers (including alcohol, cocaine, and methamphetamine polysubstance users, n=35) were compared with healthy controls (n = 36) on a series of behavioral (Frontal Systems Behavior Scale), cognitive (N-back. Go-No Go, and Wisconsin Card Sorting Tasks), and emotional (International Affective Picture System (IAPS)) tasks each of which was thought to tax a different component of these PFC functional systems. Substance Abusers exhibited greater behavioral problems in the apathy, disinhibition, and executive dysfunction subscales of the Frontal Systems Behavioral Scale. Behavioral deficits were significantly associated with several real-life domains in which SDI typically have problems. SDI also showed poorer performance on cognitive tests of working memory, response inhibition and mental flexibility and abnormal processing of affective images from the IAPS. These cognitive, behavioral, and emotional measures were moderately correlated. Verdejo-Garcia, A., Bechara, A., Recknor, E.C., and Perez-Garcia, M. Journal of The International Neuropsychological Society, 12, pp. 405-415, 2006.

Neural Signatures of Economic Preferences for Risk and Ambiguity

Scott Huettel and colleagues at Duke University used functional magnetic resonance imaging (fMRI) to compare brain response associated with risk (uncertainty with known probabilities) versus ambiguity (uncertainty with unknown probabilities). People often prefer the known over the unknown, sometimes sacrificing potential rewards for the sake of surety. Overcoming impulsive preferences for certainty in order to exploit uncertain but potentially lucrative options may require specialized neural mechanisms. Individuals' preferences for risk (uncertainty with known probabilities) and ambiguity (uncertainty with unknown probabilities) were found to predict brain activation associated with decision making. Activation within the lateral prefrontal cortex was predicted by ambiguity preference and was also negatively correlated with an independent clinical measure of behavioral impulsiveness, suggesting that this region implements contextual analysis and inhibits impulsive responses. In contrast, activation of the posterior parietal cortex was predicted by risk preference. Together, this novel double dissociation indicates that decision making under ambiguity does not represent a special, more complex case of risky decision making, instead, these two forms of uncertainty are supported by distinct mechanisms. These findings may help clarify the mechanisms underlying increased impulsiveness in drug abusers. Huettel, S.A., Stowe, C.J., Gordon, E.M., Warner, B.T., and Platt, M.L., Neuron 49, pp. 765-775, 2006.

Anterior Cingulate Activity Modulates Nonlinear Decision Weight Function of Uncertain Prospects

Martin Paulus and colleagues at the University of Califonia, San Diego used fMRI to examine how healthy individuals used information about probabilities to guide decisions. The study was based on Prospect theory developed by Kahneman and Tversky, which has been among the most influential psychological models and explains many nonnormative decision-making phenomena, e.g. why people play the lottery or bet on long-shots. A Certainty Equivalent procedure was used during fMRI to identify the neural substrates that are important for nonlinear transformation of probabilities to decision weights. Differential activation in the anterior cingulate cortex during high versus low probability prospects correlated highly (r = 0.84) with the degree of the nonlinearity of the transformation of probabilities to decision weights, which indicates that risk-seeking behavior for low probability prospects and risk-averse decision-making for mid to high probability prospects may be due to a lack of controlled processing by the anterior cingulate cortex. Since dysfunctional activity in the anterior cingulate has been observed in substance abusers under a number of conditions, these results may provide a basis for understanding impaired decision-making in substance abusers. Paulus, M.P., Frank, L.R. Neuroimage, 30, pp. 668-677, 2006.

The Medial Frontal Cortex Processes Events That Are Both Better or Worse Than Expected

Geoffery Potts and colleagues at Rice University investigated whether two event-related potential (ERP) components, the anterior positivity (P2a) and the medial frontal negativity (MFN) reflect neural activity from the same region of the medial frontal cortex. A prominent theoretical model proposes that the dopamine (DA) system, via its reward prediction properties, provides a "gate" through which information gains access to limited-capacity frontal attentional control systems. The medial frontal event-related potential (ERP) index of attention selection, the anterior positivity (P2a), is thought to be associated with DA reward system input to the MFC for the identification of task-relevant perceptual representations. However, the P2a has a similar spatio-temporal distribution as the medial frontal negativity (MFN), elicited to error responses or choices resulting in monetary loss. The MFN has also been linked to DA projections to the MFC but for action monitoring rather than attention selection. This study used a passive reward prediction design containing neither instructed attention nor response to demonstrate that the ERP over medial frontal leads at the P2a/MFN latency probably reflects the same neurophysiological responses but is positive to unpredicted rewards and negative when a predicted reward is withheld. This result suggests that MFC activity is regulated by DA reward system input and may function to identify items or actions that exceed or fail to meet motivational prediction. Potts, G.F, Martin, L., Burton, P., and Montague, P.R. Journal of Cognitive Neuroscience 18, pp. 1112-1119, 2006.

Chronic Cocaine Self-Administration Is Associated with Altered Functional Activity in the Temporal Lobes of Non Human Primates

Porrino and colleagues at Wake Forest University characterize the effects of reinforcing doses of cocaine on cerebral metabolism in a nonhuman primate model of cocaine self-administration, following an extended history of cocaine exposure, using the quantitative 2-[C-14]deoxyglucose (2-DG) method. Previous studies utilizing a nonhuman primate model have shown that cocaine self-administration in its initial stages is accompanied by alterations in functional activity largely within the prefrontal cortex and ventral striatum. However, continued cocaine exposure may considerably change this response. Rhesus monkeys were trained to self-administer 0.03 mg/kg/injection (n = 4) or 0.3 mg/kg/injection (n = 4) cocaine and compared to monkeys trained to respond under an identical schedule of food reinforcement (n =6). Monkeys received 30 reinforcers per session for a total of 100 sessions. Metabolic mapping was conducted at the end of the final session. After this extended history, cocaine self-administration dose-dependently reduced glucose utilization throughout the striatum and prefrontal cortex similarly to the initial stages of self-administration. However, glucose utilization was also decreased in a dose-independent manner in large portions of the temporal lobe including the amygdala, hippocampus and surrounding neocortex. The recruitment of temporal structures indicates that the pattern of changes in functional activity has undergone significant expansion beyond limbic regions into association areas that mediate higher order cognitive and emotional processing. These data strongly contribute to converging evidence from human studies demonstrating structural and functional abnormalities in temporal and prefrontal areas of cocaine abusers, and suggest that substance abusers may undergo progressive cognitive decline with continued exposure to cocaine. Beveridge, T.J.R., Smith, H.R., Daunais, J.B., Nader, M.A., and Porrino, L.J. European Journal of Neuroscience, 23, pp. 3109-3118, 2006.

Cognitive Function and Mood in MDMA/THC Users, THC Users and Non-Drug Using Controls

Antoine Bechara and colleagues at University of Southern California tested the hypothesis that reported feelings of depression and anxiety and cognitive impairment (memory, executive function and decision making) are more severe in MDMA/THC users than in THC users. Repeated ecstasy (MDMA) use is reported to impair cognition and cause increased feelings of depression and anxiety. Yet, many relevant studies have failed to control for use of drugs other than MDMA, especially marijuana (THC). The behavioral performance of 11 MDMA/THC users was compared to 15 THC users and 15 non-drug users matched for age and intellect. MDMA/THC users reported more intense feelings of depression and anxiety than THC users and non-drug users. Memory function was impaired in both groups of drug users. MDMA/THC users showed slower psychomotor speed and less mental flexibility than non-drug users. THC users exhibited less mental flexibility and performed worse on the decision making task compared to non-drug user s but these functions were similar to those in MDMA/THC users. It was concluded that MDMA use is associated with increased feelings of depression and anxiety compared to THC users and non-drug users. THC users were impaired in some cognitive abilities to the same degree as MDMA/THC users, suggesting that some cognitive impairment attributed to MDMA is more likely due to concurrent THC use. Lamers, C.T.J., Bechara, A., Rizzo, M., and Ramaekers, J.G. Journal of Psychopharmacology, 20, pp. 302-311, 2006.

Cerebellar Vermis Involvement in Cocaine-Related Behaviors

Carl Anderson and colleagres at McLean Hospital used a combination of fMRI and PET ligand imaging to test the hypothesis that the vermis areas of the cerebellum would be activated in cocaine abusers by cocaine-related cues and, in healthy humans, would accumulate DAT-selective ligands. Although the cerebellum is increasingly being viewed as a brain area involved in cognition, it typically is excluded from circuitry considered to mediate stimulant-associated behaviors since it is low in dopamine. In the fMRI study, cocaine-related cues selectively induced neural activation in lobules II-III and VIII-IX in cocaine users. Studies in primates have shown that cerebellar vermis (lobules II-III and VIII-IX) contains dopamine transporter immunoreactivity (DAT-IR). A positron emission tomography imaging study of healthy humans using the DAT-selective ligand using [C-11] altropane found appreciable ligand accumulation in vermis regions (lobules VIII-IX), suggestive of DAT presence in this region. These data suggest that parts of cerebellar vermis could mediate some of cocaine's persisting and acute effects. In light of prior findings illustrating vermis connections to midbrain dopamine cell body regions, established roles for the vermis as a locus of sensorimotor integration and motor planning, and findings of increased vermis activation in substance abusers during reward-related and other cognitive tasks, the vermis could be considered one of the structures involved in cocaine- and other incentive-related behaviors. Anderson, C.M., Maas, L.C., Frederick, B.D., Bendor, J.T., Spencer, T.J., Livni, E., Lukas, S.E., Fischman, A.J., Madras, B.K., Renshaw, P.F., and Kaufman, M.J. Neuropsychopharmacology, 31, pp. 1318-1326, 2006.

Distribution of Norepinephrine Transporters in the Non-Human Primate Brain

Linda Porrino and colleagues at Wake Forest University used the selective ligand [H-3]nisoxetine to describe autoradiographically the normal regional distribution of the norepinephrine transporter (NET) in the non-human primate central nervous system. Noradrenergic terminals in the central nervous system are widespread, as such this system plays a role in varying functions such as stress responses, sympathetic regulation, attention, and memory processing, and its dysregulation has been linked to several pathologies. In particular, the NET transporter is a target in the brain of many therapeutic and abused drugs. The NET transporter in the monkey brain was distributed heterogeneously, with highest levels occurring in the locus coeruleus complex and raphe nuclei, and moderate binding density in the hypothalamus, midline thalamic nuclei, bed nucleus of the stria terminalis, central nucleus of the amygdala, and brainstem nuclei such as the dorsal motor nucleus of the vagus and nucleus of the solitary tract. Low levels of binding to the norepinephrine transporter were measured in basolateral amygdala and cortical, hippocampal, and striatal regions. The distribution of the NET in the non-human primate brain was comparable overall to that described in other species, however disparities exist between the rodent and the monkey in brain regions that play a role in such critical processes as memory and learning. The differences in such areas point to the possibility of important functional differences in noradrenergic information processing across species, and suggest the use of caution in applying findings made in the rodent to the human condition. Smith, H.R., Beveridge, T.J.R., and Porrino, L.J. Neuroscience 138, pp. 703-714, 2006.

Methadone Maintenance Improves Cognitive Performance After Two Months Of Treatment

Stacy Gruber and colleagues at McLean Hospital examined neurocognitive effects associated with Methadone maintenance (MM). The present study examined cognitive function in 17 opiate-dependent subjects at baseline and after 2 months of MM treatment. Subjects demonstrated significant improvements from baseline on measures of verbal learning and memory, visuospatial memory, and psychomotor speed and reduced frequency of drug use (Addiction Severity Index) relative to baseline, although the total percentage of urine samples positive for additional illicit substances was slightly increased. No effect of illicit drug use was observed when the sample was stratified by urine toxicology results, suggesting that improvements in cognition were not associated with additional illicit drug use. Results suggest that opiate-dependent subjects exhibit significant improvement in cognitive function after MM treatment. Gruber, S.A., Silveri, M.M., Renshaw, P.F., Tzilos, G.K., Pollack, M., Kaufman, M.J., and Yurgelun-Todd, D.A. Experimental and Clinical Psychopharmacology 14, pp. 157-164, 2006.

Affect Modulates Appetite-Related Brain Activity To Images Of Food

Deborah Yugelun-Todd and colleagues used fMRI to determine whether affect ratings predicted regional brain responses to high and low-calorie foods in healthy individuals. Thirteen normal-weight adult women viewed photographs of high and low-calorie foods during BOLD functional magnetic resonance imaging (fMRI). Positive and negative affect had different effects on several important appetite-related regions depending on the calorie content of the food images. When viewing high-calorie foods, positive affect was associated with increased activity in satiety-related regions of the lateral orbitofrontal cortex, but when viewing low calorie foods, positive affect was associated with increased activity in hunger-related regions including the medial orbitofrontal and insular cortex. The opposite pattern of activity was observed for negative affect. These findings describe the neurobiologic substrates involved in the commonly reported increase in cravings for calorie-dense foods during heightened negative emotions. Killgore, W.D.S., and Yurgelun-Todd, D.A. International Journal Of Eating Disorders, 39, pp. 357-363, 2006.

Caudate Blood Flow and Volume Are Reduced in HIV+ Neurocognitively Impaired Patients

John Detre and colleagues at the University of Pennsylvania used continuous arterial spin labeled MRI (ASL) to evaluate the effects of HIV-associated neurocognitive impairment on caudate blood flow and volume. Caudate blood flow and volume of 42 HIV+ patients (23 subsyndromic and 19 HIV neurosymptomatic) on highly active antiretroviral therapy was compared to 17 seronegative controls. Decreased caudate blood flow and volume was associated with increased HIV-associated neurocognitive impairment. Compared with seronegative controls, baseline caudate blood flow was reduced in HIV+ neurosymptomatic patients with a similar decreasing trend for subsyndromic HIV+ patients. Differences in caudate volume were observed only for neurosymptomatic HIV+ patients compared with controls. There was no significant correlation between caudate blood flow and volume for each group. These results demonstrate that decreasing levels in caudate blood flow and volume were associated with significantly increasing HIV-associated neurocognitive impairment, with the greatest decreases observed for more severely impaired patients. However, reductions in caudate blood flow and volume were poorly correlated. Changes in residual caudate blood flow may act as a surrogate biomarker for classifying the degree of HNCI HIV-associated neurocognitive impairment. Ances, B.M., Roc, A.C., Wang, J., Korczykowski, M., Okawa, J., Stern, J., Kim, J., Wolf, R., Lawler, K., Kolson, D.L., and Detre, J.A. Neurology, 66, pp. 862-866, 2006.

Prospective Memory in HIV-1 Infection

Dr. Igor Grant and colleagues at the University of California, San Diego investigated whether prospective memory (ProM) is one of the cognitive deficits associated with HIV-1 infection. ProM is a form of episodic memory that involves the complex processes of forming, monitoring, and executing future intentions vis-a-vis ongoing distractions. Although ProM is thought to be largely dependent on prefronto-striatal circuits, which is known to be altered with HIV infection, ProM has not previously been examined in an HIV-1 sample. In the current study ProM was compared in 42 participants with HIV-1 infection and 29 demographically similar seronegative healthy comparison (HC) subjects. The HIV-1 sample demonstrated deficits in time- and event-based ProM, as well as more frequent 24-hour delay ProM failures and task substitution errors relative to the HC group. In contrast, there were no significant differences in recognition memory performance, indicating that the HIV-1 group was able to accurately retain and recognize the ProM intention when retrieval demands were minimized. Secondary analyses revealed that ProM performance correlated with validated clinical measures of executive functions, episodic memory (free recall), and verbal working memory, but not with tests of semantic memory, retention, or recognition discrimination. Taken together, these findings indicate that HIV-1 infection is associated with ProM impairment that is primarily driven by a breakdown in the strategic (i.e., executive) aspects of retrieving future intentions, which is consistent with existing evidence of prefronto-striatal circuit neuropathogenesis associated with HIV infection. Carey, C.L., Woods, S.P., Rippeth, J.D., Heaton, R.K., Grant, I., and Neurobehavioral Research Center (HNRC) Group. J Clin Exp Neuropsychol, 28, pp. 536-548, 2006.

Additive Deleterious Effects of Methamphetamine Dependence and Immunosuppression on Neuropsychological Functioning in HIV Infection

Igor Grant and colleagues at the University of California, San Diego investigated the combined effects of MA dependence (MA) and immunosuppression (i.e., CD4 lymphocyte count <200) on neuropsychological (NP) functioning in 284 HIV+ individuals. Prevalence of NP impairment was examined in four demographically comparable groups: MA+/CD4 < 200; MA+/CD4 > or = 200; MA-/CD4 < 200; and MA-/CD4 > or = 200. Results revealed that both MA dependence and immunosuppression were significant predictors of NP impairment. More importantly, additive effects were evident whereby the MA+/CD4 < 200 group exhibited the highest rate of NP impairment. These findings demonstrate that MA dependence conveys an additive deleterious impact on NP status in immunosuppressed persons with HIV infection, which perhaps reflects the combined effects of neuropatho- physiological mechanisms in fronto-striatal circuits. Carey, C.L., Woods, S.P., Rippeth, J.D., Gonzalez, R., Heaton, R.K., and Grant. I. AIDS Behavior, 10, pp. 185-90, 2006.

Cortical and Subcortical Neurodegeneration is Associated with HIV Neurocognitive Impairment

Igor Grant and colleagues from University of California, San Diego, investigated the association between markers of regional neurodegeneration (ND) in post-mortem tissue and degree of neuro-cognitive impairment in persons with HIV. In a prospectively followed cohort of HIV+ individuals, they examined the relationship between antemortem neuropsychological (NP) abilities and postmortem neuropathological data. Twenty-seven HIV+ individuals with both NP and neuropathological data were identified. Laser confocal scanning microscopy was used to determine the degree of ND based on microtubule-associated protein (MAP2; reflecting neuronal cell bodies and dendrites) and synaptophysin (SYN; a measure of presynaptic terminals). A regional combined score, based on the distribution of percentage neuropil occupied by MAP2 and SYN and emphasizing severity of ND, was created for each brain ROI: MFC, hippocampus, and putamen. The regional combined scores from each brain region studied were better correlated with level of global NP impairment than measures of SYN and MAP2 individually. Hippocampal and putamen regional combined scores were independent predictors of degree of antemortem NP impairment The correlations among regional ND measures demonstrated that there is an uneven distribution across multiple brain regions. As the anatomic distribution and temporal progression of neuropathologic changes appears to differ across individuals, it is important to consider both cortical and subcortical brain regions in studies of neuropathogenesis and treatment of HIV-related brain disease. Furthermore, combining information from several markers of neural injury provided the strongest association with degree of neurocognitive impairment during life. Moore, D.J., Masliah, E., Rippeth, J.D., Gonzalez, R., Carey, C.L., Cherner, M., Ellis, R.J., Achim, C.L., Marcotte, T.D., Heaton, R.K., Grant, I., and HNRC Group. AIDS, pp. 879-887, April 4, 2006.

A Battery Approach for Measuring Neuropsychological Change

Igor Grant and colleagues from the University of California, San Diego, investigated the specificity of a modified Reliable Change Index (RCI) methodology applied across a focused battery of commonly used neuropsychological tests. Fifty-seven healthy controls underwent NP assessment at two time points separated by approximately 1 year. Test-retest reliability coefficients and standard RCI confidence intervals for the individual tests were broadly comparable with prior research in healthy populations. Battery change scores were generated by calculating z-scores of change for each individual test, which were summed across the entire test battery. The RCI methodology was applied to the summed z-score to provide a 90% confidence interval as an indicator of overall cognitive stability. These battery RCI normative standards demonstrated adequate specificity when applied to 29 persons with HIV-1 infection who were classified as medically and neurologically stable. Findings from this study represent the first steps towards establishing normative standards for determining reliable changes in performance across a commonly used battery of NP tests. Woods, S.P., Childers, M., Ellis, R.J., Guaman, S., Grant, I., Heaton, R.K., and The HIV Neuro-behavioral Research Center (HNRC) Group. Archives of Clinical Neuropsychology, 21, pp. 83-89, 2006.

Action (Verb) Fluency Predicts Dependence in Instrumental ADL's in Persons Infected with HIV-1

Igor Grant and colleagues from the University of California, San Diego, evaluated the ecological validity of Action Fluency as a predictor of instrumental activities of daily living (IADL) among persons with HIV-1 infection. Based on hypothesized neural dissociation between the retrieval of nouns and verbs, several studies now support the construct validity of Action (verb) Fluency as a measure of frontostriatal systems function. Relative to traditional noun- and letter-cued verbal fluency tests, Action Fluency is more sensitive to HIV-1-associated neuropsychological impairment, which may reflect inefficiencies engaging motor representations during action retrieval in this population. Accordingly, impaired Action Fluency might adversely impact IADL by disrupting the production and organization of script-based action schemas upon which successful IADL performance depends. Action, Letter (FAS), and Noun (animal) fluency were compared in 21 HIV-1-infected participants with self-reported IADL decline relative to 76 demographically comparable HIV-1-infected participants who reported no IADL declines. Results revealed significant between-group differences in Action and Letter Fluency, but not Noun Fluency. Action Fluency achieved an overall hit rate of 76% and was more sensitive than Letter Fluency in classifying IADL dependent participants. Individuals with impaired Action Fluency performance had a fivefold risk of concurrent IADL decline as compared to those who performed within normal limits, suggesting that Action Fluency may possess incremental ecological validity. Woods, S.P., Morgan, E.E., Dawson, M., Scott, J.C., Grant, I., and The HNRC Group. Journal of Clinical and Experimental Neuropsychology, 28, pp. 1030-1042, 2006.

Brain Dopamine Gene Variants Influence Smoking-Induced Dopamine Release

Arthur Brody and colleagues at University California, Los Angeles used PET ligand imaging to investigate whether common gene variants of the brain DA pathway could account for the considerable inter-individual variability that has been observed in the extent of smoking-induced DA release in the ventral striatum in humans. Positron emission tomography (PET) scanning with the radiotracer 11C-raclopride was performed to measure dopamine release, and genotyping was perfomed using blood samples. Thirty five subjects smoked during the scanning and 10 did not. Those smokers who had a specific combination of Dopamine-relating gene polymorphines (at least one 9 allele of the DA transporter variable nucleotide tandem repeat, fewer than 7 repeats of the D4 variable nucleotide tandem repeat, and the val/val catechol-O-methyltrans-ferase genotype) had greater decreases in binding potential (an indirect measure of DA release) with smoking than those with the alternate genotypes. When compared to those who did not smoke during scanning, an overall decrease in the smokers' ventral striatal binding potential was noted; albeit, smaller in magnitude than previously reported. These results may have future implications for subtyping smokers based on clinical characteristics and possibly in identifying smokers who would be more likely to respond to DA pharmacotherapies or therapies that affect the brain DA system. Brody, A.L., Mandelkern, M.A., Olmstead, R.E., Scheibal, D., Hahn, E., Shiraga, S., Zamora-Paja, E., Farahi, J., Saxena, S., London, E.D., and McCracken, J.T. Archives General Psychiatry, 63, pp. 808-816, 2006.

Functional Imaging of Tobacco Use

Based on a review of the literature on functional brain imaging studies of tobacco use and dependence, Arthur Brody of the University California, Los Angeles proposed a model of brain function in smokers. Many research groups have examined the effects of acute and chronic nicotine/ cigarette exposure on brain activity using functional imaging. Responses to acute administration of nicotine/smoking include: a reduction in global brain activity; activation of the prefrontal cortex, thalamus, and visual system; activation of the thalamus and visual cortex during visual cognitive tasks; and increased dopamine (DA) concentration in the ventral striatum/nucleus accumbens. Responses to chronic nicotine/cigarette exposure include decreased monoamine oxidase (MAO) A and B activity in the basal ganglia and a reduction in _4_2 nicotinic acetylcholine receptor (nAChR) availability in the thalamus and putamen. Taken together, these findings indicate that smoking enhances neurotransmission through cortico-basal ganglia-thalamic circuits either by direct stimulation of nAChRs, indirect stimulation via DA release or MAO inhibition, or a combination of these factors. Activation of this circuitry may be responsible for the effects of smoking seen in tobacco dependent subjects, such as improvements in attentional performance, mood, anxiety, and irritability. Brody, A.L. Journal of Psychiatric Research, 40, pp. 404-418, 2006.

Working Memory in Cigarette Smokers During Abstinence

Edythe London and colleagues at University California, Los Angeles examined the effect of cigarette smoking and withdrawal on working memory as measured by the N-Back task. Participants included 15 smokers and 22 matched non-smokers. The N-Back Task was administered in two test blocks on each of two days. Smokers were tested in separate sessions after 13 or more hours of abstinence or one hour after smoking. Smokers inhaled one cigarette between the blocks on each test day. Results indicated that performance of smokers after 13 hours but not 1 hour of abstinence was significantly less accurate than that of non-smokers. A within-subject comparison revealed that in the abstinence session, smokers had significantly longer response latencies (in the 2-back condition) and made more overall errors compared to the satiety session. Smoking between test blocks in the abstinence session did not significantly affect performance although it significantly reduced craving. These findings provide further evidence for a deficit in working memory associated with acute abstinence from smoking, which may contribute to the difficulty of smoking cessation. Mendrek, A., Monterosso, J., Simon, S.L., Jarvik, M., Brody, A., Olmstead, R., Domier, C.P., Cohen, M.S., Ernst. M., and London, E.D. Addictive Behaviors, 31, pp. 833-844, 2006.

Ethnic Differences in Enhanced Cue-Elicited Brain Activation

Okuyemi and colleagues used fMRI imaging to investigate differences in brain reactivity to smoking cues between ethnic groups. African-Americans exhibit a different pattern of reactivity to smoking related cues than Caucasians (CC). Although African Americans (AA) are more likely to attempt to quit smoking than Caucasians (CC) in any given year, recent evidence suggests success rates are lower for AA. However, factors contributing to these differences are not well known. Seventeen smokers (8 AA, 9 CC) were studied after 12-hour abstinence as were 17 non-smokers (8 AA, 9 CC) matched by age, gender, years of education, and handedness. The AA and CC smoking groups were also matched for number of cigarettes smoked per day. Participants underwent morning fMRI scanning while viewing images of AA models and CC models who were either smoking (smoking cues) or engaging in everyday activities (neutral cues), interspersed with a fixation baseline period. There was a strong ethnicity X condition interaction among smokers in several brain regions identified a priori on the basis of prior cue-reactivity brain imaging studies.. AA smokers showed a greater increase in response to smoking (versus neutral) cues than CC smokers in the medial pre-frontal cortex, right lateral orbitofrontal cortex, and bilateral ventrolateral pre-frontal cortex. In smoking versus baseline contrasts, additional areas of greater activation were found in AA, including the right amygdala and left caudate nucleus. No significant differences in cue-elicited brain activation were found between AA and CC non-smokers. Although preliminary, these findings suggest that variation in brain activation in response to smoking cues smokers in may reflect fundamental differences in attention to smoking cues between AA and CC, which may in turn contribute to differences in effectiveness of nicotine dependence treatments among ethnic populations. Okuyemi, S.K., Powell, J.N., Savage, C.R., Hall, S.B., Nolan, N., Holsen, L.M., McClernon, F.J., and Ahluwalia, J.S. Addiction Biology, 11, pp. 97-106, 2006.

Gender Differences Among Recreational Gamblers: Association With the Frequency of Alcohol Use

Marc Potenza and colleagues at Yale School of Medicine investigated the interactive effects of alcohol use and gender on health and gambling attitudes and behaviors in recreational gamblers. The Gambling Impact and Behavior Study surveyed by telephone 2,417 adults targeted to be representative of the U.S. adult population. Male and female recreational gamblers (n = 1,471) were stratified by frequency of alcohol use on measures of health and gambling. Significant Gender x Alcohol Use group interactions were observed such that moderate-to-high frequency alcohol consumption correlated with heavier gambling in men than in women, whereas such an association did not exist among abstinent or low frequency drinkers. There were few gender differences in the correlations between alcohol consumption and health. Future research should consider gender-related influences when examining alcohol use and gambling behaviors. Desai, R.A., Maciejewski, P.K., Pantalon, M.V., and Potenza, M.N. Psychology of Addictive Behaviors, 20, pp. 145-153, 2006.

Cue-Induced Stress Reduced Time To Relapse In Cocaine Dependent Patients

Rajita Sinha and associates at Yale School of Medicine presented patient specific image-provoking scripts to patients seeking treatment for cocaine dependence. Stress-inducing imagery was associated with earlier relapse compared to neutral imagery. The amount of cocaine used prior to treatment was also associated with time to relapse. While corticotropin and cortisol responses were induced by the stress imagery, they were not associated with time to relapse, but were associated with the amount of cocaine used when relapse did occur. By contrast, drug-cue-inducing imagery was not associated with either the relapse rate or the amount of cocaine used even though the craving it induced was correlated with craving induced by stress. Furthermore, corticotropin increases induced by stress cues was correlated with increases induced by drug cues. The same was true of cortisol. These data indicate that stress acts in different ways—directly to hasten relapse or indirectly on the HVA axis to influence drug-taking amounts. To some extent these results suggest that some parameters in treatment may be predictable by an individual's responses to stressors. Sinha, R., Garcia, M., Palikwal, P., Kreek, M.J., and Rounsaville, B.J. Archives of General Psychiatry, 63, pp. 324-331, 2006.

Physiological Responses To Psychological Stress During Early Abstinence From Smoking Predicts Early Relapse

While it is known that stress is associated with relapse, al 'Absi and colleagues at the University of Minnesota tried to define the effect by challenging treatment-seeking smokers 24 hours after abstinence with a "standard" public speaking test and psychological tasks and then measuring ACTH, (plasma) cortisol, blood pressure, affect, and withdrawal symptoms. Those who relapsed within a 4-week follow-up showed attenuated hormonal and cardiovascular responses to these stressors and had exaggerated withdrawal symptoms. These factors remained significant in stepwise regression analyses as well as analyses that included baseline smoking and psychological measures as co-variates. By understanding the physiological and psychological factors underlying relapse, better treatment strategies can be developed. al 'Absi, M., Hatsukami, D., and Davis, G.L. Psychopharmacology, 181, pp. 107-117, 2006.

Cognitive Deficits Were Found In Non-Clinically-Referred College Women Who Were Sexually Abused Prior To Age 18

Clinically-reported sexual abuse is associated with several disorders appearing in adutlthood including drug abuse. Teicher and colleagues at Mclean Hospital assessed cognitive effects in community-based subjects recruited by advertisement and assessed college women who endorsed at least three episodes of "forced contact sexual abuse" and were physically healthy on a number of cognitive tests. Some of the subjects had either current or past diagnoses of Major Depressive Disorder, Post-Traumatic Stress Disorder, or General Anxiety Disorder. Results showed that there were a constellation of deficits in some but not all tests. In particular, the abused group had a diminished capacity on a test requiring response inhibition, performed less well on the Math SAT tests (in spite of normal level verbal scores), and demonstrated memory deficits as a function of abuse duration. Navalta, C.P., Polcari, A., Webster, D.M., Boghossian, A., and Teicher, M.H. Journal of Neuropsychiatry and Clinical Neuroscience, 18(1), pp. 45-53, 2006.

P300, An Endophenotype Related Externalizing As A Possible Factor Underlying Several Disorders Including Substance Abuse

Iacono, McGue, and associates at the University of Minnesota determined, by principal components analysis of symptom counts from several assessments of their subjects, that "externalizing" was a strong common factor. They then assessed the P300 evoked potential from an oddball visual task that has been shown to be attenuated in subjects of alcohol-risk studies. The results showed that higher scores on the externalizing factor, reflecting greater severity and breadth of externalizing symptoms, were associated with smaller P300 amplitude. There was no higher loading on variables defining individual diagnostic variables supporting that the P300 endophenotype was related to a common neurobiological of all the disorders. The current belief based on the broad literature is that the attenuated evoked potential is related to a diminished capacity for neuronal inhibition which is associated with these disorders. It is suggested in light of these findings that this endophenotype be the target of future research as, for example, the associated genotype. Patrick, C.J., Bernt, E.M., Malone, S.M., Iacono, W.G., Krueger, R.F., and McGue, M. Psychophysiology, 43, pp. 84-92, 2006.

Neuropsychology and Neuropharmacology Of P3a And P3b

John Polich and James Criado of Scripps Institute reviewed literature supporting a distinction between the P3a and P3b subcomponents of the P300 evoked response potential (ERP). Abnormalities in the P300 have been suggested as biomarkers of the risk for substance abuse, and the P3a component has been suggested as a biomarker for relapse. The critical factor for eliciting P3a is how target/standard discrimination difficulty rather than novelty modulates task processing. The neural loci of P3a and P3b generation were sketched and a theoretical model was developed. P3a originates from stimulus-driven disruption of frontal attention engagement during task processing. P3b originates when temporal-parietal mechanisms process the stimulus information for memory storage. The neuropharmacological implications of this view are then outlined by evaluating how acute and chronic use of ethanol, marijuana, and nicotine affect P3a and P3b. The findings suggest that the circuit underlying ERP generation is influenced in different ways for acute intake and varies between chronic use levels across drugs. Theoretical implications are assessed. Polich J., and Criado J.R. International Journal of Psychophysiology 60, pp. 172-185, 2006.

Genes Contributed To The Covariance Between Conduct Disorder And Dependence Vulnerability

Stallings and Hewitt in Crowley's group at Boulder's Institute for Behavioral Genetics examined the genetic, shared and non-shared environmental factors contributing to both conduct disorders and dependence vulnerability or to dependence vulnerability alone. The subjects were nearly 900 twin pairs encompassing all five groups—monozygotic males and females, dizygotic males and female, and dizygotic male/female pairs. Symptoms of both disorders were significantly heritable and all three factors contributed to the co-variation: genes contributed 35% of the phenotypic covariance, shared environment contributed 46%, and non-shared environment contributed the remaining 19%. Finally, it was noted that the etiology of the comorbidity was similar in males and females. Button, T.M.M., Hewitt, J.K., Rhee, S.H., Young, S.E., Corley, R.P., Stallings, M.C. Twin Research and Human Genetics, 9(1), pp. 38-45, 2006.

Abstinence From Cocaine Affects Sleep Suggestive of Insomnia

R. Malison, P. Morgan, and colleagues at Yale in collaboration with R. Stickgold and colleagues at Harvard assessed sleep, vigilance, and procedural learning in a 23-day inpatient study of self-administered cocaine and abstinence. The protocol provided for a test day of cocaine use followed in 4 or 17 days with three days of cocaine bingeing (or placebo). Polysomnography, EEG spectral analysis, and subjective measures were obtained throughout. Simple and vigilant response times were measured daily; procedural learning of a motor sequence was assessed on study days preceding or following cocaine binges. Results demonstrated that with sustained abstinence, chronic cocaine users exhibited decreased sleep, impaired vigilance and sleep-dependent procedural learning, and abnormal spectral activity, all of which were suggestive of chronic insomnia. By contrast, these same subjects reported improving sleep efficiency, apparently unaware of their dysregulated sleep in what the authors are calling "occult" insomnia. Morgan, P.T., Pace-Schott, E.F., Sahul, Z.H., Coric, V., Stickgold, R., and Malison, R.T. Drug and Alcohol Dependence, 82, pp. 238-249, 2006.

Gene Variants of the Dopa Decarboxylase (DDC) Gene Are Associated With Smoking Behavior

J.Gelernter and collaborators genotyped 18 SNPs in a region that included the DDC and flanking genes from families of either European or African American heritage in search of variants associated with measures of smoking. Several SNPs were significantly related in both EA and AA samples suggesting a link to nicotine dependence. The SNP with the most significant association is in the same intron as the splice site for a neuronal isoform of DDC. Whether this means that an alternatively spliced form of the gene is the link between DDC and nicotine dependence requires additional studies. This study confirms an earlier study by others linking this gene to nicotine dependence. Yu, Y., Panhuysen, C., Kranzler, H.R., Hesselbrock, V., Rounsaville, B., Weiss, R., Brady, K., Farrer, L.A., and Gelernter, J. Human Molecular Genetics, 15, pp. 2192-2199, 2006.

Haplotypes of the Neurotrophic Tyrosine Kinase Receptor 2 Gene (NTRK2) Are Significantly Associated With Nicotine Dependence

Li and associates selected NTRK2 for further study in association with smoking because it lies in a suggestive linkage region on chromosome 9 that they and others had found. European and African American samples were analyzed separately. Three SNPs showed significant association with measures of nicotine dependence in the European American group; only one was suggestive in the African American group. Haplotype analyses with combinations of these SNPs were also significant in the EA sample. This study is believed to be the first to demonstrate the association of NTRK2 on nicotine dependence and suggest it is a biological candidate in its determination. Beuten, J., Ma, J.Z., Payne, T.J., Dupont, R.T., Lou, X.-Y., Crews, K.M., Elston, R.C., and Li, M.D. Biological Psychiatry, Epub ahead of print, doi:10.1016, 2006.

A Cognitive Neuroscience Perspective on Psychopathy: Evidence For Paralimbic System Dysfunction

Kent Kiehl of the Institute of Living reviewed studies of behavioral and cognitive changes associated with focal brain lesions or insults and results from psychophysiology, cognitive psychology and cognitive and affective neuroscience in health and psychopathy to formulate hypotheses regarding the brain regions implicated in psychopathy. There is a high degree of co-occurrence between psychopathy and substance abuse. Psychopathy is a complex personality disorder that includes interpersonal and affective traits such as glibness, lack of empathy, guilt or remorse, shallow affect, and irresponsibility, and behavioral characteristics such as impulsivity, poor behavioral control, and promiscuity. Much is known about the assessment of psychopathy, however, relatively little is understood about the relevant brain disturbances. The review illustrates that the brain regions implicated in psychopathy include the orbital frontal cortex, insula, anterior and posterior cingulate, amygdala, parahippocampal gyrus, and anterior superior temporal gyrus. The relevant functional neuroanatomy of psychopathy thus includes limbic and paralimbic structures that may be collectively termed 'the paralimbic system'. The paralimbic system dysfunction model of psychopathy is discussed as it relates to the extant literature on psychopathy. Kiehl, K.A. Psychiatry Research 142, pp. 107-128, 2006.

Perfusion fMRI For Measurement of Continuous Changes In Neural Activity With Learning

John Detre and colleagues at the University of Pennsylvania examined whether arterial spin labeled (ASL) perfusion MRI can be used to detect continuous, gradual changes in neural activity. Unlike BOLD imaging, the perfusion signal is stable over long time-scales, allowing for accurate assessment of continuous performance. In addition, perfusion fMRI provides an absolute measure of blood flow so signal changes can be interpreted without reference to a baseline. The task we used was the serial response time task, a sequence-learning task. There were reliable correlations between performance improvements and decreases in blood flow in premotor cortex and the inferior parietal lobe, supporting the model that learning procedures that increase efficiency of processing will be reflected in lower metabolic needs in tissues that support such processes. More generally, the results show that perfusion fMRI may be applied to the study of mental operations that produce gradual changes in neural activity, such as cue-elicited craving. Olson, I.R., Rao, H.Y., Moore, K.S., Wang, J.J., Detre, J.A., and Aguirre, G.K. Brain and Cognition, 60, pp. 262-271, 2006.

Functional Reintegration of Prefrontal Neural Networks For Enhancing Recovery After Brain Injury

Mark D'Esposito and colleagues at the University of California, Berkeley describe approaches to cognitive training that are hypothesized to specifically enhance PFC function. The training was based on a theoretical framework regarding the effects of training on the functional integration of processes across distributed networks of brain regions. Functions of the prefrontal cortex (PFC) are fundamental to learning and rehabilitation after brain injuries, but the PFC is particularly vulnerable to trauma and has been suggested to be dysfunctional in substance abusers. Specific outcome measurements that may be used to test these hypotheses in clinical trials are proposed. This neural network-level approach may guide cognitive rehabilitation and facilitate development of adjunctive biologic treatments to enhance the effects of training. Chen, A.J.W., Abrams, G.M., and D'Esposito, M. Journal of Head Trauma Rehabilitation, 21, pp. 107-118, 2006.

A Functional Magnetic Resonance Imaging Study of the Effects of Pergolide, A Dopamine Receptor Agonist, on Component Processes of Working Memory

Mark D'Esposito and colleagues at the University of California, Berkeley tested the effects of the mixed D1-D2 dopamine receptor agonist pergolide on component processes of human working memory using functional magnetic resonance imaging (fMRI). Working memory is dependent on a network of prefrontal and posterior cortical regions. An event-related trial design allowed separation of the effects on encoding, maintenance, and retrieval processes. Subjects were tested with spatial and object memoranda to investigate modality-specific effects of dopaminergic stimulation. Baseline working memory capacity was also measured as previous studies have shown that effects of dopamine agonists vary with working memory span. Pergolide improved reaction time for high-span subjects and impaired reaction time for low-span subjects. This span-dependent change in behavior was accompanied by span-dependent changes in delay-related activity in the premotor cortex. Modality-specific effects of pergolide were only found only during the response period. Pergolide increased activity for spatial memoranda and decreased activity for object memoranda in task-related regions including the prefrontal and parietal cortices. These findings may provide a framework to investigate dopamine related alternation in working memory function associated with use of illicit drugs that act through the dopaminergic system. Gibbs, S.E.B., D'Esposito, M. Neuroscience, 139, pp. 359-371, 2006.

Peripheral Blood Pressure Changes Induced By Dobutamine Do Not Alter BOLD

Si-Jiang Li and colleagues at the Medical College of Wisconsin investigated whether peripheral blood pressure changes induced by pharmacological agents could independently produce a change in the blood oxygenation level-dependent (BOLD) fMRI signal, resulting in difficulties distinguishing or interpreting drug-induced neural activations. Cocaine-dependent subjects were administered intravenous dobutamine, a beta-adrenergic receptor agonist that does not cross the blood-brain barrier, to increase the mean arterial blood pressure (MABP), while examining the effects of MABP changes on the BOLD fMRI signal. Dobutamine infusion significantly increased the MABP from 93.8 mm Hg to 106 +/- 12 mm Hg, but did not produce a significant change in the global BOLD signal. However, a few voxels in the anterior cingulate did exhibit BOLD signal changes that paralleled the changes in blood pressure (BP). Our observations support the conclusion that following the infusion of psychoactive agents, brain BOLD signals accurately reflect neuronal activity, even in the face of relatively large peripheral cardiovascular effects that transiently increase systemic BP. Liu, H., Rainey, C., Lauer, K.K., Piacentine, L., Bloom, A., Risinger, R., Ward, B.D., Stein, E., and Li, S.J. Neuroimage, 30, pp. 745-752, 2006.