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NIDA Home > Publications > Director's Reports > February, 2008 Index    

Director's Report to the National Advisory Council on Drug Abuse - February, 2008

Research Findings - Clinical Neuroscience Research

Orbitofrontal Cortex Activation to the Words "No" and "Yes"

"No" and "Yes" are involved in conditioning to prohibit or encourage behavior and may therefore activate neuronal circuits involved with valence and emotional control. Functional MRI (fMRI) at 4 Tesla was used to measure regional brain activity while healthy normal participants listened to emphatic vocalizations of the words. "No" and "Yes" were associated with opposite brain-behavior responses. "No" was negatively valenced, produced slower response times, and evoked a negative signal in the right lateral orbitofrontal cortex (OFC). "Yes" was positively valenced, produced faster response times, and evoked a positive signal in a contiguous region of the OFC. Attribution of negative valence to "No" and trait anger control were associated with increased responsivity of the OFC to "No". These results indicate potential neuronal processes that may accompany admonitions to stop using drugs. Alia-Klein, N., Goldstein, R. Z., Tornasi, D., Zhang, L., Fagin-Jones, S., Telang, F., Wang, G-F., Folwer, J.S., and Volkow, N.D. What Is In A Word? No Versus Yes Differentially Engage the Lateral Orbitofrontal Cortex. Emotion, 7(3), pp. 649-659, 2007.

Resisting Craving during Cigarette Cue Exposure Entails Successful Recruitment of Cognitive Conflict-Monitoring Circuitry

In cigarette smokers, the most commonly reported areas of brain activation during visual cigarette cue exposure are the prefrontal, anterior cingulate, and visual cortices. Dr. Arthur Brody and colleagues at UCLA sought to determine changes in brain activity in response to cigarette cues when smokers actively resist craving. Forty-two tobacco-dependent smokers underwent functional magnetic resonance imaging, during which they were presented with videotaped cues. Three cue presentation conditions were tested: cigarette cues with subjects allowing themselves to crave (cigarette cue crave), cigarette cues with the instruction to resist craving (cigarette cue resist), and matched neutral cues. Activation was found in the cigarette cue resist (compared with the cigarette cue crave) condition in the left dorsal anterior cingulate cortex (ACC), posterior cingulate cortex (PCC), and precuneus. Lower magnetic resonance signal for the cigarette cue resist condition was found in the cuneus bilaterally, left lateral occipital gyrus, and right postcentral gyrus. These relative activations and deactivations were more robust when the cigarette cue resist condition was compared with the neutral cue condition. These data provide evidence that suppressing craving during cigarette cue exposure involves activation of limbic (and related) brain regions and deactivation of primary sensory and motor cortices. Brody, A.L., Mandelkern, M.A., Olmstead, R.E., Jou J., Tiongson, E., Allen, V., Scheibal, D., London, E.D., Monterosso J.R., Tiffany S.T., Korb A., Gan, J.J., and Cohen, M.S.. Neural Substrates of Resisting Craving During Cigarette Cue Exposure. Biol. Psychiatry, 62(6), pp. 642-651, 2007.

New Scale-Free Model For Motivation and Decision Making

Marc Potenza, Warren Bickel, and R. Andrew Chambers explored motivated behavior as a scale-free map in building a comprehensive translational theory of addiction. They reframed motivational and behavioral repertoires as link and nodal element sets, respectively, that comprise a scale-free structure. These sets are generated by semi-independent information-processing streams within cortical-striatal circuits that cooperatively provide decision-making and sequential processing functions necessary for traversing maps of motivational links connecting behavioral nodes. Dopamine modulation of cortical-striatal plasticity serves a central-hierarchical mechanism for survival-adaptive sculpting and development of motivational-behavioral repertoires by guiding a scale-free design. Potenza et al proposed that drug-induced dopamine activity promotes drug taking as a highly connected behavioral hub at the expense of natural-adaptive motivational links and behavioral nodes. Conceptualizing addiction as pathological alteration of scale-free motivational-behavioral repertoires unifies neurobiological, neurocomputational and behavioral research while addressing addiction vulnerability in adolescence and psychiatric illness. This model may inform integrative research in defining more effective prevention and treatment strategies for addiction. Chambers, R.A., Bickel, W.K., and Potenza, M.N. A Scale-Free Systems Theory of Motivation and Addiction. Neuroscience Biobehavior Review, 31(7), pp. 1017-1045, 2007.

Assessment of Asymptomatic Neurocognitive Impairment Adds Sensitivity, Specificity and Predictive Power to the Diagnosis of HIV Encephalitis

Asymptomatic neurocognitive impairment can be detectable according to recent developments in neurocognitive tasks. The present study examined whether early signs of neurocognitive dysfunction could be a valuable biomarker of disease progress in asymptomatic HIV+ individuals. Dr. Igor Grant and his group at the HIV Neurobehavioral Research Center (HNRC) compared neuropathological diagnosis of HIV encephalitis made at autopsy to antemortem neurocognitive diagnoses, resulting from HNRC criteria that assess asymptomatic neurocognitive impairment, to the original diagnostic criteria issued in 1991 by the American Academy of Neurology (AAN). Agreement between the two sets of definitional criteria was 79% regarding the classification of cases as either neurocognitively normal or impaired, and 54% with regard to specific neurocognitive diagnoses. When pathological evidence of HIV was taken as the external indicator of HIV-related brain involvement, 64% of cases were correctly classified by AAN criteria, compared to 72% by HNRC criteria. HNRC criteria had better positive predictive power (95% versus 88%), sensitivity (67% versus 56%), and specificity (92% versus 83%). Furthermore, several cases with HIV encephalitis were correctly identified by HNRC criteria for ANI but called normal by AAN criteria. These data suggest that assessment of asymptomatic neurocognitive impairment adds sensitivity, specificity and predictive power to the diagnosis of HIV encephalitis. In addition, it supports the concept that neuropathological changes may develop in individuals with sub-clinical neurocognitive dysfunctions. These results indicate that cognitive disturbances can reliably detect ongoing HIV brain infection without requiring declines in daily functioning, motor, or other behavioral abnormalities. Cherner, M., Cysique, L., Heaton, R., Marcotte, T., Ellis, R., Masliah, E., Grant, I. and HNRC Group. Neuropathologic Confirmation of Definitional Criteria for Human Immuno-deficiency Virus-associated Neurocognitive Disorders. J Neurovirol.,13(1), pp. 23-28, 2007.

PET Study Reveals Minimal Gender Differences or Menstrual Cycle Effects on Nicotinic Acetylcholine Receptors

The effects of sex and hormones on brain chemistry and neurotransmission are not well-characterized, and are of increasing importance as evidence emerges of sex differences in behavioral symptoms and treatment response in neuropsychiatric disorders. The nicotinic acetylcholine receptor (nAChR) system has been implicated in a variety of psychiatric disorders, including tobacco smoking, for which there is strong evidence supporting sex differences in behaviors and response to smoking cessation treatments. Kelly Cosgrove, Julie Staley, and colleagues at Yale examined the availability of nAChR containing the ss2 subunit in healthy men and women nonsmokers, and the influence of menstrual phase among women. Regional brain activity was higher (39%-54%) in women than in men. When regional brain activity was normalized to total plasma parent to correct for individual differences in radiotracer metabolism (VT'), differences of 10%-16% were observed, with women greater than men. In contrast, when regional brain activity was normalized to free plasma parent (VT), there was less than a 4% difference by sex in regional brain ss2-nAChR availability. These sex differences in kBq/cm3 and VT' resulted from significantly higher levels of total plasma parent, free fraction (f1), and free plasma parent in women than in men nonsmokers. No differences in plasma measures or brain ss2-nAChR availability were observed across the menstrual cycle for any outcome measure. Overall, these findings demonstrate no significant difference in brain ss2-nAChR availability between men and women nonsmokers or across the menstrual cycle. Importantly, these findings demonstrate the need to control for sex differences in radiotracer metabolism and plasma protein binding. Cosgrove, K.P., Mitsis, E.M., Bois, F., Frohlich, E., Tamagnan, G.D., Krantzler, E., Perry, E., Maciejewski, P.K., Epperson, C.N., Allen, S., O'Malley S., Mazure, C,M,, Seibyl, J.P., van Dyck, C.H., and Staley, J.K. 123I-5-IA-85380 SPECT Imaging of Nicotinic Acetylcholine Receptor Availability in Nonsmokers: Effects of Sex and Menstrual Phase. J. Nucl. Med., 48(10), pp. 1633-1640, 2007.

No Change in MRS Measures in Moderate MDMA Users

High field strength proton MRS at 4.0 T was used to study absolute concentrations of occipital cortical NAA and MI in a cohort of moderate MDMA users (n = 9) versus non-MDMA using (n = 7) controls in order to resolve ambiguities in previous studies that used MRS at lower field strength. There were no statistical differences in absolute metabolite levels for NAA and MI in occipital cortex of MDMA users and controls. These findings are not supportive of MDMA-induced alterations in NAA or MI levels in this small sample of moderate MDMA users. Cowan, R.L., Bolo, N.R., Dietric, M., Haga, E., Lukas, S.E., and Renshaw, P.F. Psychiatry Research-Neuroimaging, 155(3), pp. 179-188, 2007.

Smoking Abstinence Effects on Selective Attention using the Stroop Task

Difficulty concentrating when abstinent from smoking may contribute to smoking cessation failures. This study compared smokers and nonsmokers on selective attention using the Stroop Test. In addition, the effects in smokers of overnight abstinence from smoking and of acute smoking on selective attention were also determined. Smokers participated after overnight abstinence and also within 1 hour of ad libitum smoking. Smokers each smoked a cigarette between test blocks on each day; nonsmokers did not. Smokers demonstrated longer response latencies for both congruent and incongruent stimuli after overnight when compared with brief abstinence, but no deficit specifically related to selective attention. Whereas nonsmokers showed no changes in performance in the second test block, smoking between blocks reduced the Stroop effect when smokers were abstinent overnight. These data indicate that abstinence from smoking among nicotine-dependent individuals has deleterious effects on cognitive performance, but do not indicate that selective attention is adversely effected. Improvement in selective attention after terminating abstinence with one cigarette may also contribute to smokers' perceived enhanced ability to concentrate after smoking. Domier, C.P., Monterosso, J.R., Brody, A.L., Simon, S.L., Mendrek, A., Olmstead, R., et al. Effects of Cigarette Smoking and Abstinence on Stroop Task Performance. Psychopharmacology, 195(1), pp. 1-9, 2007.

Dissociation of MAO-A Genotype from MAO-A Brain Activity

A functional polymorphism in the promoter region of the monoamine oxidase A (MAO A) gene has two common alleles that are referred to as the high and low MAO A genotypes. The goal of this study was to determine whether there is an association between MAO A genotype and in vivo brain MAO A activity in healthy male subjects using PET ligand imaging. Brain MAO A activity was measured with positron emission tomography and [C-11]clorgyline in adult male nonsmokers genotyped for MAO A polymorphism. There was no significant difference in brain MAO A activity between the high (n = 26) and low (n = 12) MAO A genotypes. The lack of an association between the high and low MAO A genotype and brain MAO A activity suggests that this polymorphism by itself does not contribute to differences in brain MAO A activity in healthy adult male subjects. Fowler, J. S., Alia-Klein, N., Kriplani, A., Logan, J., Williams, B., Zhu, W., Craig, I.W., Telang, F, Goldstein, R., Volkow, N.D. Vaska, P., and Wang, G-J. Evidence that Brain MAO A Activity does not Correspond to MAO A Genotype in Healthy Male Subjects. Biological Psychiatry, 62(4), pp. 355-358, 2007.

Genetic Variants are Associated with Different Roles in Reinforcement Learning

A model that predicts dopamine receptor function differentially affects Go/NoGo performance was tested in healthy humans with different dopamine D1 and D2 gene variants. In particular, individuals with a variant of the DARPP-32 gene associated with the D1 receptor, which has been shown to strongly modulate striatal activity, favored responses in which a choice was made because of the positive reward valuation (as opposed to avoiding a choice because of negative valuation). By contrast, a variant of the DRD2 receptor facilitated avoiding a non-rewarded response. In the model, these striatal areas are hypothesized to be associated with acquisition of reinforced learning. An additional facet of the model involves the prefrontal cortex which hypothesizes that this area is responsible for maintaining reward information in memory for trial-to-trial evaluation. This was tested by variants of the COMT gene which are associated with prefrontal dopamine. It was found that the Val/Val homozygotes that have the lowest prefrontal cortex dopamine were the least responsive to the immediate effects of reward, thus supporting the model. Continued testing and refinement of the model will help establish a picture of cortical functions with regard to decision-making as well as providing a genetic basis for individual differences. Frank, M.J., Moustafa, A.A., Haughey, H.M., Curran, T., and Hutchison, K.E. Genetic Triple Dissociation Reveals Multiple Roles for Dopamine in Reinforcement Learning. Proceedings of the National Academy of Science, 104(41), pp. 16311-16316, 2007.

Cigarette Cues Activate Limbic Brain Regions

This study used arterial spin-labeled (ASL) perfusion fMRI, and newly developed and highly appetitive, explicit smoking stimuli, to examine neural activity to cigarette cue-induced craving that strongly minimized contributions from pharmacological withdrawal. Twenty-one smokers (12 females) completed smoking and nonsmoking cue fMRI sessions. Craving self-reports were collected before and after each session. Blood flow (perfusion) in a priori-selected regions was greater during exposure to smoking stimuli compared to nonsmoking stimuli in ventral striatum, amygdala, orbitofrontal cortex, hippocampus, medial thalamus, and left insula (p < 0.01; corrected). Perfusion positively correlated with intensity of cigarette cue-induced craving in both the dorsolateral prefrontal cortex and posterior cingulate. This pattern of activation that includes the ventral striatum, a critical reward substrate, and the interconnected amygdala, cingulate and OFC, is consistent with decades of neural correlates of cue-induced craving for other drugs of abuse and conditioned drug responses in animals. Franklin, T.R., Wang, Z., Wang, J., Sciortino, N., Harper, D., Li, Y., Ehrman, R, Kampman, K, O'Brien, C.P., Detre, J.A., and Childress, A.R. Limbic Activation to Cigarette Smoking Cues Independent of Nicotine Withdrawal: A Perfusion fMRI Study. Neuropsychopharmacology, 32(11), pp. 2301-2309, 2007.

Cocaine Abuse and Cognitive Control

While hedonic and reward-related processes are central to drug use and dependence, impairment of cognitive processes may also make important contributions to addiction. In particular, attention is drawn to those processes involved in exercising control over behavior as drug dependence is characterized by risky, impulsive behavior. Functional neuroimaging implicates prefrontal deficits in cocaine dependence with an emerging picture of cocaine users having attentional biases towards drug-related stimuli, poor performance in laboratory tests of inhibitory control, and compromised monitoring and evaluation of their behavior. Combined, these deficits may contribute to the continuation of use in dependent individuals and may qualify as important targets for therapeutic interventions. Garavan, H., and Hester, R. The Role of Cognitive Control in Cocaine Dependence. Neuropsychology Review, 17(3), pp. 337-345, 2007.

Frontal-Occipital Interactions in Top-Down Attentional Control

Attention-dependent modulation of neural activity in visual association cortex (VAC) is thought to depend on top-down modulatory control signals emanating from the prefrontal cortex (PFC). Functional connectivity analysis was used to identify possible sources of these modulatory influences by examining how network interactions with VAC are influenced by attentional goals at the time of encoding. The results revealed a network of regions that exhibit strong positive correlations with a VAC seed during all task conditions, including foci in the left middle frontal gyrus (MFG). This PFC region is more correlated with the VAC seed when scenes were remembered and less correlated when scenes were ignored, relative to passive viewing. Moreover, the strength of MFG-VAC coupling correlates with the magnitude of attentional enhancement and suppression of VAC activity. Although these correlation analyses do not permit assessment of directionality, the findings suggest that PFC biases activity levels in VAC by adjusting the strength of functional coupling in accordance with stimulus relevance. These findings provide a basis for interpreting changes in frontal control of attention during presentation of drug-related stimuli that can elicit drug craving. Gazzaley, A., Rissman, J., Cooney, J., Rutman, A., Seibert, T., Clapp, W., D'Esposito, M. Functional Interactions between Prefrontal and Visual Association Cortex Contribute to Top-down Modulation of Visual Processing. Cerebral Cortex, 17, pp I125-I135, 2007.

Neuropsychological Effects of Opioid Use

Neurocognitive effects of acute and chronic opioid use suggest that the use of opiates has both acute and long-term effects on cognitive performance. Neuropsychological data indicate deficits in attention, concentration, recall, visuospatial skills and psychomotor speed with both acute and chronic opioid use. The long-term effects of opiate use appear to have the greatest impact on executive functions, including the ability to shift cognitive set and inhibit inappropriate response tendencies. Factors that contribute to addiction and recovery are discussed, as it is difficult to disentangle the effects of opiate use on cognitive performance from other factors that may affect neurobehavioral measures. Gruber, S.A., Silveri, M.M., and Yurgelun-Todd, D.A. Neuropsychological Consequences of Opiate Use. Neuropsychology Review, 17(3), pp. 299-315, 2007.

Analysis of Correlations of fMRI Activity across Participants

The analysis of correlations of fMRI technique takes advantage of similarities in the patterns of the hemodynamics between participants [i.e., interparticipant correlation (IPC)] to obtain the parsimony of the general linear model (GLM) without assuming a specific fMRI time course. The technique consists of calculating voxel-wise correlations between participants resulting in IPC maps, which indicate the activated regions the participants have in common. IPC analysis was applied to data collected from healthy controls in an auditory oddball task. As expected, the highest inter-participant correlations were detected in auditory cortical regions in the temporal lobes. In addition, areas that appear to be involved in the task were detected using IPC's but not the GLM regression. This technique, designed to have increased sensitivity to inter-subject correlations that are not necessarily task-related, may potentially be useful as a compliment to model-based approaches. Hejnar, M.R., Kiehl, K.A., and Calhoun, V.D. Interparticipant Correlations: A Model Free fMRl Analysis Technique. Human Brain Mapping, 28(9), pp. 860-867, 2007.

Cocaine Abusers Are Not Aware of Making Errors

Active cocaine abusers have a diminished neural response to errors, particularly in the anterior cingulate cortex thought critical to error processing. The inability to detect, or adjust performance following errors, has been linked to clinical symptoms including the loss of insight and perseverative behavior. Twenty-one active cocaine users (six female subjects, mean age 40.3) and 22 non-drug using adults (six female subjects, mean 39.9) participated in a study that used response inhibition tasks that required error awareness and performance adaptation. The results indicated that cocaine users had reduced awareness of committing errors as well as poorer inhibitory control. Cocaine abusers were also poorer at exerting inhibitory control on the trial immediately after failing to inhibit a response. However, post-error reaction times did not differ between groups. Thus, even though cocaine users demonstrated a diminished capacity for monitoring their behavior, they were able to perform post-error adjustment to processes not already suffering an underlying deficit. These difficulties are consistent with previous reports of cocaine-related hypoactivity in the neural system underlying cognitive control, and highlight the potential for cognitive dysfunction to manifest as behavioral deficits that likely contribute to the maintenance of drug dependence. Hester, R., Simoes-Franklin, C., and Garavan, H. Post-Error Behavior in Active Cocaine Users: Poor Awareness of Errors in the Presence of Intact Performance Adjustments. Neuropsychopharmacology, 32(9), pp. 1974-1984, 2007.

Cocaine Dependent Individuals Might Be More Susceptible to Infectious Disease

Irwin and associates at UCLA assessed the immune system in cocaine patients over a 24-hour period. Cocaine-dependent volunteers showed a decreased capacity to express tumor necrosis factor (TNF)-_ and interleukin (IL)-6. The immune response was also blunted in response to a bacterial ligand. These observations were accompanied by sympathetic activity and vagal withdrawal. It was suggested that sympathovagal balance might be a novel strategy for partial amelioration of impairments. Irwin, M.R., Olmos, L., Wang, M., Valladares, E.D., Motivala, S.J., Fong, T., Newton, T., Butch, A., Olmstead, R., and Cole, S.W. Cocaine Dependence and Acute Cocaine Induce Decreases of Monocyte Proinflammatory Cytokine Expression across the Diurnal Period: Autonomic Mechanisms. The Journal of Pharmacology and Experimental Therapeutics, 320(2), pp. 507-515, 2007.

Synthesis of a PET ligand for Alpha 7 Nicotinic Receptors

(3E)-3-[(2,4-dimethoxy- phenyl)methylene]-3,4,5,6-tetrahydro-2,3'-bipyridi ne (GTS-21), is a partial alpha 7 nicotinic acetylcholine receptor agonist drug. GTS-21 was labeled in two different positions with carbon-11 ([2-methoxy-C-11]GTS-21 and [4-C-11]GTS-21) along with two corresponding demethylated metabolites ([2-methoxy-C-11]4-OH-GTS-21 and [4-rnethoxy-C-11]2-OH-GTS-21) for pharmacokinetic studies in baboons and mice with positron emission tomography (PET). The major findings are as follows: (a) extremely rapid uptake and clearance of [2-methoxy-C-11]GTS-21 from the brain, which may need to be considered in developing optimal dosing of GTS-21 for patients, and (b) significant brain uptake of 2-OH-GTS-21, suggesting that it might contribute to the therapeutic effects of GTS-21. This study illustrates the value of comparing different label positions and labeled metabolites to gain insight on the behavior of a central nervous system drug relevant to nicotine addiction and its metabolites in the brain, providing an important perspective on drug pharmacokinetics. Kim, S.W., Ding, Y., Alexoff, D., Patel, V., Logan, J., Lin, K., Shea, C.L., Muench, L., Xua, Y, Carter, P., King, P., Constanzo, J.R., Ciaccio, J.A., and Fowler, J.S. Synthesis and Positron Emission Tomography Studies of C-11-labeled Isotopomers and Metabolites of GTS-21, a Partial alpha-7 Nicotinic Cholinergic Agonist Drug. Nuclear Medicine and Biology, 34(5), pp. 541-551, 2007.

Brain Predictors of Financial Decisions

The balance between expected reward and risk are believed to drive financial decisions. It is now possible to use brain imaging techniques to visualize changes in neural activation before financial decisions are expressed. The results indicate that the ventral striatum plays a role in representation of expected reward, whereas the insula may play a more prominent role in the representation of expected risk. Accumulating evidence also suggests that antecedent neural activation in these regions can be used to predict upcoming financial decisions. These findings have implications for predicting choices and for building a physiologically-constrained theory of decision-making. Knutson, B., and Bossaerts, P. Neural Antecedents of Financial Decisions. Journal of Neuroscience, 27(31), pp. 8174-8177, 2007.

Groups Defined by Statistical Clustering Rather than Diagnosis Have High Heritability: Associated Genes Have the Highest LOD Scores

The H. Kranzler and J. Gelernter team recruited families and sib-pairs who abused one or more illicit drugs. Using an iterative algorithm they empirically formed clusters in an effort to define more homogeneous groups as phenotypes for genome wide analysis. While the clusters were segregated into groups that could be designated with differential names with respect to their drug use, they did not reflect the standard DSM diagnoses. Importantly, gene variants associated with some of the clusters were stronger than for the DSM phenotypes such as Cocaine Dependence. Because psychiatric diagnoses are inclusive of individuals who may have a variety of symptomatology that may not have a similar underlying characteristic associated with a gene, analyses such as these may be helpful in determining genetic variability. Kranzler, H.R., Wilcox, M., Weiss, R.D., Brady, K., Hesselbrock, V., Rounsaville, B., Farrer, L., Gelernter, J. The Validity of Cocaine Dependence Subtypes. Addictive Behaviors, 33, pp. 41-53, 2008.

New Method of Analyzing Cocaine Effects with fMRI

Changes in BOLD fMRI signals in humans before, during and after the administration of a drug often result in a heterogeneous pattern of drug-induced hemodynamic responses in the brain. Exploratory techniques, including blind source separation, can be useful for BOLD data that contain patterns of cross-dependencies. Bayesian source separation (BSS) is a multivariate technique used to calculate the presence of unobserved signal sources in measured fMRI data, as well as the covariance between data voxels and between reference waveforms. Unlike conventional univariate regression analysis, BSS does not assume independence between voxel time series or source components. In this study, BOLD measurement of the acute effect of an intravenous dose of cocaine, a substance shown previously to engage multiple sites within the orbitofrontal cortex, was processed with BSS. The utility of BSS in pharmacological fMRI applications was demonstrated in multiple examples featuring single-ROI, multiple-ROI and whole-slice data. The flexibility of the BSS technique was shown by choosing different modeling strategies to form the prior reference functions, including approximating the pharmacokinetics of cocaine, interpolating simultaneously measured behavioral data and using observed BOLD responses from known subcortical afferents to the cortex of interest. Kufahl, P.R., Rowe, D.B., and Li, S. Processing the Acute Cocaine fMRI Response in Human Brain with Bayesian Source Separation. Digital Signal Processing, 17(5), pp. 965-978, 2007.

Emotional Memory Representation in the Brain

Neurobiological accounts of emotional memory have been derived largely from animal models investigating the encoding and retention of memories for events that signal threat. This literature has implicated the amygdala, a structure in the brain's temporal lobe, in the learning and consolidation of fear memories. Its role in fear conditioning has been confirmed, but the human amygdala also interacts with cortical regions to mediate other aspects of emotional memory. These include the encoding and consolidation of pleasant and unpleasant arousing events into long-term memory, the narrowing of focus on central emotional information, the retrieval of prior emotional events and contexts, and the subjective experience of recollection and emotional intensity during retrieval. Along with other mechanisms that do not involve the amygdala, these functions ensure that significant life events leave a lasting impression in memory. LaBar, K.S. Beyond Fear: Emotional Memory Mechanisms in the Human Brain. Current Directions in Psychological Science, 16(4), pp. 173-177, 2007.

Distinguished Memory Deficits Encourage Systemic Assessment of Neurocognitive Functions in HIV+ Individuals

Effective prevention of transmission of HIV from infected individuals to others relies upon continued preclusion of risk sexual behavior and adherence with medication regimens. It is desirable if the degree of impaired executive control functions mediated by prefrontal cortical systems is assessable in HIV+ individuals and drug abusers. In this study, Dr. Eileen Martin evaluated the possibility of using current available cognitive tasks for different type of episodic memory to predict executive functions among HIV+ substance-dependent individuals and their relevance to "real-world" behaviors, such as future intention of risky decision-making or "remembering what one must do". The study found that compared with HIV-seronegative controls HIV-seropositive participants showed deficits in time-based but not event-based prospective memory. Performance of retrospective memory, but not working memory, correlated significantly with performance of time-based prospective memory. The preliminary study suggested poorer performance on the time-based prospective memory task, a significant predictor of self-reported risky sexual and injection practices. Martin, E.M., Nixon, H., Pitrak, D.L., Weddington, W., Rains, N.A., Nunnally, G., Grbesic, S., Gonzalez, R., Jacobus, J., and Bechara, A. Characteristics of Prospective Memory Deficits in HIV-seropositive Substance-dependent Individuals: Preliminary Observations. J. Clin. Exp. Neuropsychol. 29(5), pp. 496-504, 2007.

Expression of Genes in the Hippocampus that Regulate Extracellular Matrix Remodeling Differ in Cocaine Abusers

Mash and associates assessed gene expression in the hippocampi in postmortem brains of cocaine abusers and controls. The results demonstrated 151 gene transcripts that were up-regulated and 91 that were down-regulated. The gene with the largest up-regulation (two-fold) was RECK (reversion-inducing-cysteine-rich protein with kazal motifs) which is a membrane-anchored matrix metalloproteinase inhibitor that is implicated in the coordinated regulation of extracellular matrix integrity and angiogenesis. It is suggested that modified expression of this gene and others in the hippocampus by cocaine may contribute to the persistent memory of previous "highs" and thus contribute to relapse or prevent abstinence of cocaine use. Mash, D.C., French-Mullen, J., Adi, N., Qin, Y., Buck, A., and Pablo, J. Gene Expression in Human Hippocampus from Cocaine Abusers Identifies Genes which Regulate Extracellular Matrix Remodeling. PLos ONE 2(11), pp. e1187, 2007.

Abstinent Methamphetamine Users Show Reduced Striatal Dopamine Transporter Binding Potentials, Which Relate To Working Memory Deficits

It is not clear whether cognitive deficits and brain DAT reductions fully reverse with sustained abstinence or whether behavioral deficits in METH users are related to persistent dopamine (DA) deficits. Dean Wong and colleagues at Johns Hopkins further investigated potential persistent psychomotor deficits secondary to METH abuse, and their relationship to brain DAT availability, as measured using quantitative PET methods. Twenty-two abstinent METH users and 17 healthy non-METH using controls underwent psychometric testing to test the hypothesis that METH users would demonstrate selective deficits in neuropsychiatric domains known to involve DA neurons (e.g., working memory, executive function, motor function). METH users were found to have modest deficits in short-term memory, executive function, and manual dexterity. Exploratory correlational analyses revealed that deficits in memory, but not those in executive or motor function, were associated with decreases in striatal DAT BP. These results suggest a possible relationship between DAT BP and memory deficits in abstinent METH users, and lend support to the notion that METH produces lasting effects on central DA neurons in humans. McCann, U.D., Kuwabara, H., Kumar A., Palermo, M., Abbey, R., Brasic, J., Ye, W., Alexander, M., Dannals, R.F., Wong, D.F., and Ricaurte, G.A. Persistent Cognitive and Dopamine Transporter Deficits In Abstinent Methamphetamine Users. Synapse 62, pp. 91-100, 2008.

Dopamine DRD4 Receptor Polymorphism Predicts Limbic System Activation in Response to Smoking Cues

A dopamine receptor 4 variable number tandem repeat (DRD4 VNTR) polymorphism has been related to reactivity to smoking cues among smokers, but the effect of this genetic variation on brain responses to smoking cues has not been evaluated. Francis McClernon and colleagues at Duke evaluated the relationship between carrying the DRD4 VNTR 7-repeat allele and transient functional magnetic resonance imaging (fMRI) responses to smoking cues among adult dependent cigarette smokers, who underwent fMRI scanning after a 2 hour abstinence. During scanning, they viewed visual smoking and control cues. A blood sample was assayed for the DRD4 VNTR polymorphism, and participants were categorized based on whether they carried one or two copies of the 7-repeat allele (DRD4 L, n = 7) or not (DRD4 S, n = 8). Smoking cues as compared to control cues elicited transient brain responses in right superior frontal gyrus (BA 8/9/10/32), left anterior cingulate gyrus (BA 32), and right cuneus (BA 19). Exposure to smoking cues resulted in greater activation of right superior frontal gyrus (BA 10) and right insula in DRD4 L compared to DRD4 S individuals. By contrast, exposure to smoking cues among DRD4 S individuals resulted in no significant increases in activation compared to DRD4 L individuals. These brain imaging results suggest that DRD4 VNTR polymorphism is related to transient brain responses to smoking cues in regions subserving executive and somatosensory processes. McClernon, F.J., Hutchison, K.E., Rose, J.E., and Kozink, R.V. DRD4 VNTR Polymorphism Is Associated With Transient fMRI-BOLD Responses To Smoking Cues. Psychopharmacology (Berl), 194(4), pp. 433-41, 2007.

Extinction-Based Treatment For Smoking Cessation Reduces Brain Responses To Smoking Cues in Amygdala

Francis McClernon and colleagues evaluated the effect of an extinction-based smoking cessation treatment on brain responses to smoking cues using functional magnetic resonance imaging (fMRI). Sixteen (n = 16) dependent smokers were scanned using fMRI at baseline, following 2-4 weeks of smoking RNC cigarettes while wearing a 21-mg nicotine patch, and 2-4 weeks following quitting smoking. During scanning, participants viewed smoking-related pictures (e.g. lit cigarette) and pictures of people engaged in everyday activities (e.g., using a stapler). Event-related responses to smoking and control cues were analyzed in regions of interest (ROIs) known to subserve reward, attention, motivation and emotion. The extinction-based treatment simultaneously attenuated responses to smoking cues in amygdala while potentiating responses to control cues. Exploratory analysis indicated that this pattern was also observed in the thalamus of future abstinent but not relapsing smokers. The results of this preliminary study suggest that an extinction-based treatment for smoking cessation alters brain responses to smoking and control cues in amygdala--a region previously associated with drug cue reactivity and extinction. McClernon, F.J., Hiott, F.B., Liu, J., Salley, A.N., Behm, F.M., and Rose, J.E. Selectively Reduced Responses To Smoking Cues In Amygdala Following Extinction-Based Smoking Cessation: Results of a Preliminary Functional Magnetic Resonance Imaging Study. Addiction Biology, 12(3-4), pp. 503-512, 2007.

Positive Arousing Distractors Impair Rapid Target Detection

Emotional stimuli tend to capture and hold attention more than non-emotional stimuli do. Aversive pictures have been found to impair perception of visual targets even after the emotional information has disappeared. The benefits of such interlinked emotion and attention systems have sometimes been discussed within an evolutionary framework, with a survival advantage attributed to early detection of threatening stimuli. However, consistent with recent suggestions that attention is drawn to arousing stimuli regardless of whether they are positive or negative, the current investigation found that erotic distractors, generally rated as both pleasing and arousing, consistently elicited a transient "emotion-induced blindness" similar to that caused by aversive distractors. This effect persisted despite performance-based monetary incentives to ignore the distractors, and following attentional manipulations that reduced interference from aversive images. The findings indicate that positively arousing stimuli can spontaneously cause emotion-induced deficits in visual processing, just as aversive stimuli can. These results form a foundation for interpretation of how drug-related stimuli can capture attention and serve as distractors. Most, S.B., Smith, S.D., Cooter, A.B., Levy, B.N., and Zald, D.H. The Naked Truth: Positive, Arousing Distractors Impair Rapid Target Perception. Cognition and Emotion, 21(5), pp. 964-981, 2007.

Impaired Decision-Making Related to Homeostatic Processing

Decision-making consists of selecting an action from a set of available options. This results in an outcome that changes the state of the decision-maker. Therefore, decision-making is part of a homeostatic process. Individuals with psychiatric disorders show altered decision-making. They select options that are either non-optimal or non-homeostatic. These dysfunctional patterns of decision-making in individuals with psychiatric disorders may fundamentally relate to problems with homeostatic regulation. These may manifest themselves in (i) how the length of time between decisions and their outcomes influences subsequent decision-making, (ii) how gain and loss feedback are integrated to determine the optimal decision, (iii) how individuals adapt their decision strategies to match the specific context, or (iv) how seemingly maladaptive responses result from an attempt to establish an unstable homeostatic balance. Paulus, M.P. Decision-making Dysfunctions in Psychiatry - Altered Homeostatic Processing? Science, 318(5850), pp. 602-606, 2007.

Placebo Effects Are Due To Individual Differences in Reward Processing

Expectancies may contribute to placebo effects by impacting perceptions and biological processes. The role of the nucleus accumbens (NAC), a region centrally involved in the encoding of reward expectation, in the formation of placebo responses was examined using two types of brain imaging in healthy human participants. Increased dopamine (DA) release using PET ligand imaging was observed in the NAC during placebo administration and was related to its anticipated effects, perception-anticipation mismatches, and development of placebo effects. In additional fMRI studies, the expectation of monetary gain increased NAC synaptic activity in a manner proportional to placebo-induced DA release, anticipated effects, perception-anticipation differentials, and actual placebo effects. Individual variations in NAC response to reward expectation accounted for 28% of the variance in the formation of placebo analgesia. Scott, D.J., Stohler, C.S., Egnatuk, C.M., Wang, H., Koeppe, R.A., and Zubieta, J. Individual Differences in Reward Responding Explain Placebo-induced Expectations and Effects. Neuron, 55(2), pp 325-336, 2007.

Temporal Profile of Non-Pharmacological Release of Dopamine and Endogenous Opiates

The time-course of changes in binding potential was measured with [C-11]carfentanil and [C-11]raclopride during moderate levels of sustained pain as a nonpharmacological challenge. It was hypothesized that, contrary to pharmacological probes, the use of a more "physiological" stimulus would be associated with less persistent changes in the BP measures. This challenge induced robust reductions in mu-opioid and DA D2 Binding Potential (BP). The pain challenge was associated with reductions in mu-opioid receptor BP in several cortical and subcortical regions. These did not persist in a subsequent scan. Similar results were obtained for DA D2 receptor BP, where the pain challenge induced significant reductions in the caudate nucleus. These data demonstrate that changes in receptor BP induced by a nonpharmacological challenge did not persist into subsequent scans. They further suggest differences in the effect of pharmacological and nonpharmacological probes on PET BP measures. These may reflect varying levels of change in receptor affinity, receptor internalization, and recycling depending on the type of challenge employed. Scott, D.J., Stohler, C.S., Koeppe, R.A., and Zubieta, J. Time-Course Of Change In [C-11]Carfentanil And [C-11]Raclopride Binding Potential After A Nonpharmacological Challenge. Synapse, 61(9), pp. 707-714, 2007.

Cocaine-Associated Brain Volume Changes in Cerebellum and Other Brain Regions

This study was conducted to explore differences in gray and white matter volume between cocaine-dependent and healthy comparison subjects using optimized voxel-based morphometry (VBM). Brain magnetic resonance imaging (MRI) and neuropsychological function tests were performed for 40 cocaine-dependent subjects (27 men) and 41 healthy age- and sex-matched comparison subjects (26 men). Whole brain MR images were compared between groups with statistical parametric mapping. The cocaine-dependent group had lower gray matter volumes (12%-16%; p<0.05 corrected) in bilateral premotor cortex (Brodmann area (BA) 6, 8), right orbitofrontal cortex (BA 10,), bilateral temporal cortex (BA 20, 38;), left thalamus (and bilateral cerebellum as well as lower right cerebellar white matter volume (10.0%). Duration of cocaine use negatively correlated with right and left cerebellar gray matter volumes (r=-0.37, r=-0.39, respectively). In cocaine-dependent subjects, lower cerebellar hemispheric gray and white matter volumes were correlated with deficits in executive function and decreased motor performance. This study reports that cocaine-dependent subjects have lower gray matter volumes in cerebellar hemispheres as well as in frontal, temporal cortex, and thalamus. The results suggest that the cerebellum may be vulnerable to cocaine-associated brain volume changes, and that cerebellar deficits may contribute to neuropsychological deficits and motor dysfunction frequently observed in cocaine-dependent subjects. Sim, M.E., Lyoo, I.K., Streeter, C.C., Covell, J., Sarid-Segal, O., Ciraulo, D.A., Kim, M.J., Kaufman, M.J., Yurgelun-Todd, D., and Renshaw, P.F. Cerebellar Gray Matter Volume Correlates With Duration Of Cocaine Use In Cocaine-Dependent Subjects. Neuropsychopharmacology, 32(10), pp. 2229-2237, 2007.

Brain Regions Involved in Stress and Cue- Induced Craving

Both stress- and drug-related cues are major factors contributing to drug relapse. Stress and cue-induced craving appear to engage overlapping neural circuits in corticostriatal limbic circuitry underlying both affective and reward processing. Taken as a whole the studies to date suggest medial prefrontal, anterior and posterior cingulate, striatal and posterior insula regions are most associated with relapse outcomes. Altered function in these brain regions is associated with stress-induced and drug cue-induced craving states and an increased susceptibility to relapse. Such alterations can serve as markers to identify relapse propensity and a more severe course of addiction. Efficacy of pharmacological and behavioral treatments that specifically target stress and cue-induced craving and arousal responses may also be assessed via alterations in these brain correlates. Sinha, R., and Li, C.S.R. Imaging Stress- And Cue-Induced Drug And Alcohol Craving: Association With Relapse And Clinical Implications. Drug and Alcohol Dependence, 26(1), 25-31, 2007.

Adults and Adolescents Use Different Brain Regions for Response Inhibition

This study identified age-related differences in the function of neural circuits that are associated with inhibitory behavioral performance across adolescent development. Adolescents differed from adults in the degree of network engagement, regional fronto-striatal-thalamic connectivity, and network dynamics. Functional and effective connectivity analyses of whole brain hemodynamic activity elicited during performance of a Go/No-Go task were used to identify functionally integrated neural networks and characterize their causal interactions. Three response inhibition circuits formed a hierarchical, inter-dependent system wherein thalamic modulation of input to premotor cortex by fronto-striatal regions led to response suppression. Steven, M.C., Kiehl, K. A., Pearlson, G.D., and Calhoun, V.D. Functional Neural Networks Underlying Response Inhibition In Adolescents and Adults. Behavioural Brain Research, 181(1), pp. 12-22, 2007.

Working Memory Neuronal Activity Patterns Are Disrupted in Cocaine Abusers

This study used fMRI to test the hypothesis that cognitive dysfunction during cocaine abstinence reflects in part impairment of cortical and subcortical regions modulated by dopamine. Brain activation during a verbal working memory task was studied in cocaine abusers and healthy controls (n=16). Compared to controls, cocaine abusers showed: (1) hypoactivation in the mesencephalon, where dopamine neurons are located, as well as the thalamus, a brain region involved in arousal; (2) larger deactivation in dopamine projection regions (putamen, anterior cingulate, parahippocampal gyrus, and amygdala); and (3) hyperactivation in cortical regions involved with attention (prefrontal and parietal cortices), which probably reflects increased attention and control processes as compensatory mechanisms. Furthermore, the working memory load activation was lower in the prefrontal and parietal cortices in cocaine abusers when compared with controls, which might reflect limited network capacity. These abnormalities were accentuated in the cocaine abusers with positive urines for cocaine at time of study (as compared to cocaine abusers with negative urines) suggesting that the deficits may reflect in part early cocaine abstinence. These findings provide evidence of impaired function of regions involved with executive control, attention and vigilance in cocaine abusers. This widespread neurofunctional disruption is likely to underlie the cognitive deficits during early cocaine abstinence and to reflect involvement of dopamine as well as other neurotransmitters. Tomasi, D., Goldstein, R. Z., Telang, F., Maloney, T., Alia-Klein, N., Caparelli, E. C., and Volkow, N.D. Widespread Disruption In Brain Activation Patterns To A Working Memory Task During Cocaine Abstinence. Brain Research, 1171, pp. 83-92, 2007.

Cocaine Impairs Attention by Disrupting Thalmo-Cortical Circuits

Functional magnetic resonance imaging (fMRI) and a sustained visuospatial attention task was used to assess the neuronal basis of visual attention network dysfunction in cocaine abusers (n = 14) compared to age-, gender-, and education-matched controls (n= 14). Compared with controls, cocaine abusers showed (1) hypoactivation of the thalamus, which may reflect noradrenergic and/or dopaminergic deficits; (2) hyperactivation in occipital and prefrontal cortices, which may reflect increased visual cortical processing to compensate for inefficient visual thalamic processing; and (3) larger deactivation of parietal and frontal regions possibly to support the larger hemodynamic supply to the hyperactivated brain regions. These findings provide evidence of abnormalities in thalamocortical responses in cocaine abusers that are likely to contribute to the impairments in sensory processing and in attention. The development of therapies that diminish these thalamo-cortical deficits could improve the treatment of cocaine addiction. Tomasi, D., Goldstein, R.Z., Telang, F., Maloney, T., Alia-Klein, N., Caparelli, E.C., and Vokow, N.D. Thalamo-Cortical Dysfunction In Cocaine Abusers: Implications In Attention And Perception. Psychiatry Research-Neuroimaging, 155(3), pp. 189-201, 2007.

Brain Phosphorus Magnetic Resonance Spectroscopy Imaging of Sleep Homeostasis and Restoration in Drug Dependence

Numerous reports have documented a high occurrence of sleep difficulties in drug-dependent populations, prompting researchers to characterize sleep profiles and physiology in drug abusing populations. This mini-review examines studies indicating that drug-dependent populations exhibit alterations in sleep homeostatic and restoration processes in response to sleep deprivation. Sleep deprivation is a principal sleep research tool that results in marked physiological challenge, which provides a means to examine sleep homeostatic processes in response to extended wakefulness. A report from our laboratory demonstrated that following recovery sleep from sleep deprivation, brain high-energy phosphates particularly beta-nucleoside triphosphate (beta-NTP) are markedly increased as measured with phosphorus magnetic resonance spectroscopy (MRS). A more recent study examined the effects of sleep deprivation in opiate-dependent methadone-maintained (MM) subjects. The study demonstrated increases in brain beta-NTP following recovery sleep. Interestingly, these increases were of a markedly greater magnitude in MM subjects compared to control subjects. A similar study examined sleep deprivation in cocaine-dependent subjects demonstrating that cocaine-dependent subjects exhibit greater increases in brain beta-NTP following recovery sleep when compared to control subjects. The studies suggest that sleep deprivation in both MM subjects and cocaine-dependent subjects is characterized by greater changes in brain ATP levels than control subjects. Greater enhancements in brain ATP following recovery sleep may reflect a greater disruption to or impact of sleep deprivation in drug dependent subjects, whereby sleep restoration processes may be unable to properly regulate brain ATP and maintain brain high-energy equilibrium. These studies support the notion of a greater susceptibility to sleep loss in drug dependent populations. Additional sleep studies in drug abusing populations are needed, particularly those that examine potential differential effects of sleep deprivation. Trksak, G., Jensen, J., Renshaw, P., and Lukas, S. Brain Phosphorus Magnetic Resonance Spectroscopy Imaging of Sleep Homeostasis and Restoration in Drug Dependence. Scientific World Journal, 7, pp. 217-222, 2007.

Interaction of Drug Abuse and Anti-Social Personality Disorder on Impulsivity

The purpose of this investigation was to examine the influence of antisociality and extent of multidrug use on cognitive and motor impulsivity among substance-dependent individuals (SDIs) that used primarily cocaine and/or heroin in 100 currently abstinent male SDIs. Extent of multidrug use and degree of antisociality, assessed with the Socialization Scale of the California Psychological Inventory (So-CPI). Participants were classified into one of four groups: high antisocial/low multidrug use, high antisocial/high multidrug use, low antisocial/low multidrug use, and low antisocial/high multidrug use. The Iowa Gambling Task was used assess cognitive impulsivity and the Stroop Task to measure motor impulsivity. Contrary to expectations, antisociality was associated with more advantageous performance on the Iowa Gambling Task, independent of extent of multidrug use. In contrast, greater multidrug use was associated with general psychomotor slowing on the Stroop Task. Results suggest that a subclinical form of antisociality may have a paradoxically facilitating effect on decision-making and cognitive impulsivity among SDIs. Vassileva, J., Gonzalez, R., Bechara, A., and Martin, E. Are All Drug Addicts Impulsive? Effects of Antisociality and Extent of Multidrug Use on Cognitive and Motor Impulsivity. Addict. Behav., 32(12), pp. 3071-3076, 2007.

Placebo Induced Reduction in Pain-Elicited Mu-Opioid Activity

Placebo-induced expectancies have been shown to decrease pain in a manner reversible by opioid antagonists, but little is known about the central brain mechanisms of opioid release during placebo treatment. This study examined placebo effects in pain by using PET with [C-11]carfentanil to assay regional mu-opioid receptor availability. Noxious thermal stimulation was applied at the same temperature for placebo and control conditions. These findings suggest that a mechanism of placebo analgesia is the potentiation of endogenous opioid responses to noxious stimuli. Placebo treatment affected endogenous opioid activity in a number of predicted mu-opioid receptor-rich regions that play central roles in pain and affect, including periaqueductal gray and nearby dorsal raphe and nucleus cuneiformis, amygdala, orbitofrontal cortex, insula, rostral anterior cingulate, and lateral prefrontal cortex. Some regions exhibited placebo-induced opioid activation specific to noxious heat, whereas others showed placebo-induced opioid reduction during warm stimulation in anticipation of pain. Opioid activity in many of these regions was correlated with placebo effects in reported pain. Connectivity analyses on individual differences in endogenous opioid system activity revealed that placebo treatment increased functional connectivity between the periaqueductal gray and rostral anterior cingulate, as hypothesized a priori, and also increased connectivity among a number of limbic and prefrontal regions, suggesting increased functional integration of opioid responses. Overall, the results suggest that endogenous opioid release in core affective brain regions is an integral part of the mechanism whereby expectancies regulate affective and nociceptive circuits. Wager, T., Scott, D., and Zubieta, J. Placebo Effects on Human Mu-Opioid Activity During Pain. PNAS. 104(26), pp. 1056-11061, 2007.

Support Vector fMRI Analysis

Comparisons were made between a machine learning algorithm, the support vector machine (SVM), and the random effect model for arterial spin labeling (ASL) perfusion fMRI analysis. Without any brain response modeling, SVM was used to extract a whole brain spatial discriminance map (SDM), representing the brain response difference between the contrasted experimental conditions. Population inference was then obtained through the random effect analysis (RFX) or permutation testing (PMU) on the individual subjects' SDMs. SDM RFX yielded lower false-positive rates in the null hypothesis test and higher detection sensitivity for synthetic activations with varying cluster size and activation strengths, compared to the univariate general linear model (GLM)-based RFX. For a sensory-motor ASL fMRI study, both SDM RFX and SDM PMU yielded similar activation patterns to GLM RFX and GLM PMU, respectively, but with higher t values and cluster extensions at the same significance level. Capitalizing on the absence of temporal noise correlation in ASL data, this study also incorporated PMU in the individual-level GLM and SVM analyses accompanied by group-level analysis through RFX or group-level PMU. Providing inferences on the probability of being activated or deactivated at each voxel, these individual-level PMU-based group analysis methods can be used to threshold the analysis results of GLM RFX, SDM RFX or SDM PMU. Wang, Z., Childress, A., Wang, J. and Detre, J. Support Vector Machine Learning-Based fMRI Data Group Analysis. Neuroimage, 36(4), pp. 1139-1151, 2007.

Brain Basis of Risky Decision-Making

A new measure of adaptive decision making under risk was used to examine whether damage to neural structures subserving emotion affects an individual's ability to make adaptive decisions differentially for gains and losses. The authors found that individuals with lesions to the amygdala, an area responsible for processing emotional responses, displayed impaired decision making when considering potential gains, but not when considering potential losses. In contrast, patients with damage to the ventromedial prefrontal cortex, an area responsible for integrating cognitive and emotional information, showed deficits in both domains. The authors argue that this dissociation provides evidence that adaptive decision making for risks involving potential losses may be more difficult to disrupt than adaptive decision making, for risks involving potential gains. This research further demonstrates the role of emotion in decision competence. Weller, J.A., Levin, I.P., Shiv, B., and Bechara, A. Neural Correlates of Adaptive Decision Making For Risky Gains and Losses. Psychological Science, 18(11), pp. 958-964, 2007.

Adjustment of Motor Behavior Following Reinforcement Involves Different Neural Systems

Performance of a reward-providing reaction time task during functional magnetic resonance imaging (fMRI) was used to investigate the adaptation of a simple motor response following four different outcomes (delivery versus omission and monetary gain versus loss). Activation in the thalamus and insula predicted adjustments of motor responses due to outcomes that were cued and delivered, whereas activation in the ventral striatum predicted such adjustments when outcomes were cued but omitted. Further, activation of OFC predicted improvement after all punishing outcomes, independent of whether they were omitted rewards or delivered punishments. Finally, activity in anterior cingulate predicted adjustment after delivered punishments and activity in dorsal striatum predicted adaptation after delivered rewards. These results provide evidence that different but somewhat overlapping circuits mediate the same behavioral adaptation when it is driven by different incentive outcomes. These findings form the foundation for investigating altered reinforcement processing by rewards and punishment incurred during substance abuse. Wrase, J., Kahnt, T., Schiagenhauf, F., Beck, A., Cohen, M.X., Knutson, B., and Heinz, A. Different Neural Systems Adjust Motor Behavior In Response To Reward And Punishment. Neuroimage, 36(4), pp. 1253-1262, 2007.


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