Research Findings - Clinical Neuroscience Research

"What Might Have Been" Does Not Influence Smoker's Decision, Despite Normative Brain Activation

Read Montague and colleagues at the Baylor College of Medicine hypothesized that anomalies in how the brain responds to "fictive errors" -i.e. notification that better outcomes could have resulted (from choice(s) the subject did not make) contribute to the diminished influence of potential consequences of choices that are made. Using a simple investment game and functional magnetic resonance imaging in chronic cigarette smokers, they measured neural and behavioral responses to error signals derived from actual experience and from fictive outcomes. In nonsmokers, both fictive and experiential error signals predicted subjects' choices and possessed distinct neural correlates. In chronic smokers, choices were not guided by error signals derived from what might have happened, despite ongoing and robust neural correlates of these fictive errors. These data provide human neuroimaging support for computational models of addiction and suggest the addition of fictive learning signals to reinforcement learning accounts of drug dependence. Chiu, P.H., Lohrenz, T.M., and Montague, P.R. Smokers' Brains Compute, But Ignore, A Fictive Error Signal In A Sequential Investment Task. Nature Neurosci., 11(4), pp. 514-520, 2008.

Placebo and Nocebo Effects are Defined by Opposite Opioid and Dopaminergic Responses

Zubieta and colleagues administered a saline solution (placebo) to healthy subjects undergoing a pain challenge and analyzed brain responses (dopamine and opioid receptors) as measured with PET. Most subjects reported a reduction in pain, though some reported an increase. Those that reported analgesic effects showed increases in neurotransmission of the DA D2/D3 receptor system in the ventral basal ganglia and of the endogenous opioid/mu-opioid receptor system in the rostral and subgenual anterior cingulate, orbitofrontal cortex, anterior and posterior insulae, medial thalamus, nucleus accumbens, amygdala and the periaqueductal gray. Those that reported an increase in pain had decreases in these same areas. The circuits involved in these responses are part of reward and motivated behavior which suggests that activation depends, in part, on subject expectations. Scott, D.J., Stohler, C.S., Egnatuk, C.M., Wang, H., Koeppe, R.A., and Zubieta, J. K. Placebo and Nocebo Effects are Defined by Opposite Opioid and Dopaminergic Responses. Archives of General Psychiatry, 65(2), pp. 220-231, 2008.

Significant Association of D1 Dopamine Receptors with Nicotine Dependence

M.D. Li and colleagues studied SNPs within or near the D1 receptor gene (DRD1) for family-based association analyses using smoking phenotypes as assessed by scores on three smoking indices. There were more than 2000 participants from more than 200 families of European and 400 from African ancestry. Significant associations with one SNP (rs686) and one haplotype (which included rs686) were found in the AA sample and the pooled sample. Furthermore, luciferase activity demonstrated that the rs686/A allele had a higher expression level for DRD1 than does the rs686/G allele. These findings demonstrate that the DRD1 is significantly associated with nicotine dependences from both single SNP- and haplotype-based analyses and that the polymorphisms seem to affect the expression level. Huang, W., Ma, J.Z., Payne, T.J., Beuten, J., Dupont, R.T., and Li, M.D. Significant Association of DRD1 with Nicotine Dependence. Human Genetics, 123, pp. 133-140, 2008.

Impaired "Remembering to Remember" in HIV+ Individuals Increases Risk of Social Support in Everyday Functioning and may Jeopardize Adherence to Medication

Igor Grant and colleagues at University of California, San Diego investigated whether HIV infection is associated with impaired ability to carry out an intention in the future, such as remembering to take a medication at a specific time - an aspect of episodic memory referred to as prospective memory. Prospective memory is believed to be a cognitive process that is needed for successful management of the instrumental activities of daily living. In a cohort of 66 HIV-infected individuals, prospective memory accounted for a significant proportion of variance in self-reported dependence on others for carrying out instrumental activities of daily living, over and above that which was explained by retrospective memory and by current affective distress. Analysis of component cognitive processes revealed that the relationship between HIV-associated deficits in prospective memory and dependence in instrumental activities of daily living was driven by impaired cue detection and by deficits in self-initiated intention retrieval. Results were not better explained by demographic factors, HIV disease severity, psychiatric comorbidity, or substance use. Collectively, these data support the potential incremental ecological validity of prospective memory as a predictor of whether an HIV+ individual will become dependent on others for carrying out daily living. Woods, S.P., Iudicello, J.E., Moran, L.M., Carey, C.L., Dawson, M.S., Grant, I., HIV Neurobehavioral Research Center Group. HIV-associated Prospective Memory Impairment Increases Risk of Dependence in Everyday Functioning. Neuropsychology, 22(1), pp. 110-117, 2008.

Individual Differences in Expectation of Pain Relief Associated with Opioid and Dopaminergic Responses

Dr. Zubieta and colleagues at University of Michigan used PET neuroreceptor imaging to investigate individual differences in healthy volunteers' alterations in self-reported physical pain after administration of inert substances and endogenous opioid and dopamine release. In 75% of the subjects, pain (placebo effect) reduction was associated with activation of opioid neurotransmission in the anterior cingulate, orbitofrontal and insular cortices, nucleus accumbens, amygdala, and periaqueductal gray matter (PAG), and dopaminergic (DA) activation in the ventral basal ganglia, including the nucleus accumbens. Regional magnitudes of brain DA and opioid activation correlated with the subjects' perceived efficacy of the inert substances, changes in expectations as a consequence of cognitive-emotional self-assessments of the efficacy, and positive affective state. In addition, greater DA and opioid activity in the nucleus accumbens predicted higher pain relief, and vice versa. It was estimated that nucleus accumbens DA responses accounted for 25% of the variance in inert substances-induced analgesic effects. In contrast, in the remaining 25% of the sample there was enhanced perception of pain after inert substances administration (nocebo response), and these subjects exhibited a corresponding reduction in regional DA and endogenous opioid activity. These studies demonstrate psychophysical responses to the expected therapeutic effect of inert substances administration elicits analgesia or hyperanalgesia, corresponding to dynamic, opposite responses of DA and _-opioid neurotransmission in a distributed yet fully overlapped network of brain regions typically implicated in reward responses and motivated behavior. Scott, D.J., Stohler, C.S., Egnatuk, C.M., Wang, H., Koeppe, R.A., and Zubieta, J.K. Individual Differences in Reward Responding Explain Inert Substances-induced Expectations and Effects. Neuron, 55(2), pp. 325-336, 2007.

Tetrahydrocannabinol Administration Blunts Amygdala Responses to Threatening Stimuli

K. Phan and colleagues at University of Chicago used fMRI to determine the effects of tetrahydrocannabinol (THC) on amygdala responses to social threat signals in healthy, recreational cannabis users. They used a well-validated task to activate the amygdala and a double-blind crossover design for administration of tetrahydrocannabinol (THC) or placebo. They found that THC significantly reduced amygdala reactivity to social signals of threat but did not affect activity in primary visual and motor cortex. These findings fit well with the notion that THC and other cannabinoids may have an anxiolytic role in central mechanisms of fear behaviors and provide a rationale for exploring novel therapeutic strategies that target the cannabinoid system for disorders of anxiety and social fear. Phan, K.L., Angstadt, M., Golden, J., Onyewuenyi, I., Popovska, A., and de Wit, H. Cannabinoid Modulation of Amygdala Reactivity to Social Signals of Threat in Humans. Journal of Neuroscience, 28(10), pp. 2313-2319, 2008.

Alpha Synuclein Protein Levels are Elevated in Recently Abstinent Cocaine Abusers

D. C. Mash and associates analyzed serum levels of alpha synuclein in recently abstinent cocaine abusers and healthy controls. There was an average 8-fold increase (though a wide variation) that was correlated in the abstinent abusers with both intensity of "desire to use" and days of use (in the prior month). The gene for alpha synuclein maps to chromosome 4q21.3-22 which has been associated with drug abuse. While it is not clear how alpha synuclein measured peripherally relates to the levels in the brain, Mash has shown that cocaine abuse leads to state-dependent increases in the post-mortem brain. Because alpha synuclein is involved in the modulation of dopaminergic activity, these preliminary results support a role for alpha gene expression in the intensity of craving for drugs. Mash, D.C., Adi, N., Duque, L., Pablo, J., Kumar, M., and Ervin, F.R. Alpha Synuclein Protein Levels are Increased in Serum from Recently Abstinent Cocaine Abusers. Drug and Alcohol Dependence, 94(1-3), pp. 246-50, 2008.

Efficacy of Bupropion for Smoking Cessation is Influenced by D2 Dopamine Receptors Taq1A Polymorphism

Sean David and colleagues analyzed two comparable randomized placebo-controlled clinical trials of bupropion pharmacotherapy which included 722 smokers and assessed smoking cessation at 10 weeks as well as follow-up after 12 months. Smokers with the A2/A2 genotype of the DRD2 receptor gene were three times as likely (relative to placebo) to be abstinent both at the end of treatment (35% vs. 15%) and at 6-month follow-up (27% vs. 12%) though by 12 months much of the advantage had disappeared (16% vs. 11%). That bupropion therapy may be most beneficial for individuals with a specific genotype provides a strong rationale for examining the characteristics of the gene variant or genes linked with it to determine the cause of this observation. David, S.P., Strong, D.R., Munafo, M.R., Brown, R.A., Lloyd-Richardson, E.E., Wileyto, P.E., Evins, E.A., Shields, P.G., Lerman, C., and Niaura, R. Bupropion Efficacy for Smoking Cessation is Influenced by the DRD2 Taq1A Polymorphism: Analysis of Pooled Data from Two Clinical Trials. Nicotine & Tobacco Research, 9(12), pp. 1251-1257, 2007.

"Suggestive" and "Significant" Susceptibility Genetic Loci for Nicotine Dependence

M. Li at the University of Virginia has provided a comprehensive update of which gene variants are likely candidates lending susceptibility for nicotine dependence. Thirteen regions on 11 chromosomes have been found to be suggestive or significant in at least two independent samples. The strongest support (most replications) is for regions on chromosomes 9, 10, 11, and 17. Others are 3-7, 20, and 22; there were two regions, each, on chromosomes 5 and 9. On chromosome 9 there are three gene variants in one region that have been associated with nicotine dependence: GABA-B receptor unit 2, neurotrophic tyrosine kinase receptor 2 (NTRK2), and Src homology 2 domain-containing transforming protein C3 (SHC3). The region on chromosome 11 contains beta-arrestin 1 which is an important regulator of signal transduction. On chromosome 17, GABA-A receptor-associated protein (GABARAP), Discs, large homolog 4 or post-phosphatase regulatory subunit B1 (PP1R1B) or dopamine- and cAMP-reguated phosphoprotein, 32-KD; DARPP32, and beta-arrestin 2 are associated with nicotine dependence. Finally, within the linkage region on chromosome 12 are ionotropic N-methyl-D-aspartate glutamate receptor 9NMDA) subunit 2B, and neurotrophin 3, GABA-A receptor-associated protein-like protein 1; and on chromosome 22 is beta-adrenergic receptor kinase 2. These findings across studies provide a focus for future work to determine the mechanisms underlying nicotine dependence as well as the individual differences associated with different genotypes. Li, M.D., Identifying Susceptibility Loci for Nicotine Dependence: 2008 Update Based on Recent Genome-wide Linkage Analyses. Human Genetics, 123, pp. 119-131, 2008.

Performance on Stroop Task Predicts Treatment Compliance in Cocaine-Dependence

Chris Streeter and colleagues at the Harvard Medical School used logistic regression analysis to predict therapy completion from psychometric and laboratory cognitive measures. Models using the Stroop task performance as a predictor variable performed better than a model featuring depression scores alone. These findings suggest that the Stroop task can be used to identify cocaine-dependent subjects at risk for treatment dropout. The Stroop task is a widely available, reliable, and valid instrument that can be easily employed to identify and tailor interventions for at-risk individuals with the aim of improving treatment compliance. Streeter, C.C., Terhune, D.B., Whitfield, T.H., Gruber, S., Sarid-Segal, O., Silveri, M.M., et al. Performance on the Stroop Predicts Treatment Compliance in Cocaine-Dependent Individuals. Neuropsychopharmacology, 33(4), pp. 827-836, 2007.

Dopamine Increases in Striatum Elicit Craving in Cocaine Abusers Only When Coupled with Cocaine Cues

Gene-Jack Wang and colleagues at Brookhaven National Laboratory evaluated the extent to which dopamine increases by themselves can induce craving in cocaine abusers. Using PET and [11C]raclopride, they showed that, in cocaine abusers, oral methylphenidate significantly increased dopamine in striatum but did not induce craving unless subjects were concomitantly exposed to video scenes of subjects self-administering cocaine. This suggests that dopamine increases associated with conditioned cues are not primary responses but reflect downstream stimulation of dopamine cells. The fact that methylphenidate induced craving only when given with the cocaine cues highlights the context dependency of methylphenidate's effects and suggests that its use for the treatment of ADHD subjects with comorbid drug abuse should not increase craving. Volkow, N.D., Wang, G., Telang, F., Fowler, J.S., Logan, J., Childress, A., et al. Dopamine Increases In Striatum Do Not Elicit Craving in Cocaine Abusers Unless They are Coupled with Cocaine Cues. NeuroImage, 39(3), pp. 1266-1273, 2008.

Joint Diffusion Tensor Imaging/Volumetric MRI Study Indicates that Structural Brain Abnormalities in Cocaine-Dependent Adults Scale with Duration of Use

Kelvin Lim and colleagues at the University of Minnesota investigated the macrostructural and microstructural correlates of cocaine abuse using structural MRI and diffusion tensor imaging (DTI). Their DTI data revealed that cocaine users had less structured white matter orientation (lower fractional anisotropy; FA) than controls in inferior frontal white matter. FA differences were not seen in other areas. Significant volumetric differences were not seen, but both gray and white matter inferior frontal volumes trended toward smaller in the cocaine group. The data suggested that duration of use was associated with decreased gray and white matter volumes. FA and gray matter volume were correlated in cocaine users suggesting that length of cocaine use was associated with severity of the brain abnormalities. Lim, K.O., Wozniak, J.R., Mueller, B.A., Franc, D.T., Specker, S.M., Rodriguez, C.P., Silverman, A.B., and Rotrosen, J.P. Brain Macrostructural and Microstructural Abnormalities In Cocaine Dependence. Drug and Alcohol Dependence, 92(1-3), pp. 164-172, 2008.

Providing a Cue that Signals Upcoming Cognitive Conflict Enhances Anterior Cingulate Activation and Go/Nogo Task Performance of Methamphetamine Abusers

Martin Paulus and colleagues at the University of California- San Diego used functional MRI to measure anterior cingulate cortex (ACC) activation during performance of a go/nogo response inhibition task in which certain go stimuli (cues) were much more likely than others (noncues) to be followed by nogo trials. Methamphetamine abusers and controls had statistically comparable performance, but only methamphetamine abusers showed an ACC response and lower false alarm rates in trials with warning cues as compared with noncues. Cue-related ACC activity in methamphetamine abusers was positively correlated with this cue-related improvement in inhibitory performance. The ACC, an area associated with error detection and response conflict, may predict the degree to which advanced warning may attenuate MD individuals' difficulty with response inhibition. Leland, D.S., Arce, E., Miller, D.A., and Paulus, M.P. Anterior Cingulate Cortex and Benefit of Predictive Cueing on Response Inhibition in Stimulant Dependent Individuals. Biological Psychiatry, 63(2), pp. 184-190, 2008.

Does Early Onset of Non-Medical Use of Prescription Drugs Predict Subsequent Prescription Drug Abuse and Dependence? Results from a National Study

This study, conducted as part of a training grant (Dr. Margaret Gnegy, PI) by Dr. McCabe and colleagues at the University of Michigan, examined the associations between early onset of non-medical use of prescription drugs (NMUPD; i.e. sedatives, tranquilizers, opioids, stimulants) and the development of prescription drug abuse and dependence in the United States. Data were collected from structured diagnostic interviews. A nationally representative cross-sectional sample of civilian non-institutionalized adults aged 18 years or older in the United States was studied. A higher percentage of individuals who began using prescription drugs non-medically at or before 13 years of age were found to have developed prescription drug abuse and dependence versus those individuals who began using at or after 21 years of age. These odds were reduced by approximately 5% with each year non-medical use was delayed, and were reduced by about 2% with each year onset was delayed when controlling for relevant covariates. The results of this study indicate that early onset of NMUPD was a significant predictor of prescription drug abuse and dependence. These findings reinforce the importance of developing prevention efforts to reduce NMUPD and diversion of prescription drugs among children and adolescents. McCabe, S.E., West, B.T., Morales, M., Cranford, J.A., and Boyd, C.J. Does Early Onset of Non-Medical Use of Prescription Drugs Predict Subsequent Prescription Drug Abuse and Dependence? Results From a National Study. Addiction, 102(12), pp. 1920-1930, 2007.

The Delta-Opioid Receptor Agonist SNC80 [(+)-4-[alpha(R)-alpha-[(2S,5R)-
4-allyl-2,5-dimethyl-1-piperazinyl]-(3-methoxybenzyl)-N,N-diethylbenzamide]
Synergistically Enhances the Locomotor-Activating Effects of Some Psychomotor Stimulants, but not Direct Dopamine Agonists, in Rats

The nonpeptidic delta-opioid agonist SNC80 produces many stimulant-like behavioral effects in rodents and monkeys. This study, conducted as part of a training grant project (Dr. Margaret Gnegy, PI) by Dr. Jutkiewicz and colleagues at the University of Michigan, evaluated acute cross-tolerance between delta-opioid agonists and other locomotor-stimulating drugs. Locomotor activity was measured in male Sprague-Dawley rats implanted with radiotransmitters, and activity levels were recorded in the home cage environment. Three-hour SNC80 pretreatment produced tolerance to further delta-opioid receptor stimulation but also augmented greatly amphetamine-stimulated locomotor activity in a dose-dependent manner. Pretreatments with other delta-opioid agonists and oxymorphindole also modified amphetamine-induced activity levels. SNC80 pretreatment enhanced the stimulatory effects of the dopamine/norepinephrine transporter ligands cocaine and nomifensine, but not the direct dopamine receptor agonists SKF81297 and quinpirole. In conclusion, SNC80 enhanced the locomotor-stimulating effects of monoamine transporter ligands suggesting that delta-opioid receptor activation might alter the functional activity of monoamine transporters or presynaptic monoamine terminals. Jutkiewicz, E.M., Baladi, M.G., Folk, J.E., Rice, K.C., and Woods, J.H. The Delta-Opioid Receptor Agonist SNC80 [(+)-4-[alpha(R)-alpha-[(2S,5R)-4-
allyl-2,5-dimethyl-1-piperazinyl]-(3-methoxybenzyl)-N,N-diethylbenzamide] Synergistically Enhances the Locomotor-Activating Effects of Some Psychomotor Stimulants, but not Direct Dopamine Agonists, in Rats. Journal of Pharmacology and Experimental Therapeutics, 324(2), pp. 714-724, 2008.

A Coalescent Simulation of Marker Selection Strategy for Candidate Gene Association Studies

Recent efforts have focused on the challenges of finding alleles that contribute to health-related phenotypes in genome-wide association studies. However, in candidate gene studies, where the genomic region of interest is small and recombination is limited, factors that affect the ability to detect disease-susceptibility alleles remain poorly understood. In particular, it is unclear how varying the number of markers on a haplotype, the type of marker (e.g., single nucleotide polymorphism (SNP), short tandem repeat (STR)), including the causative site (cs) as a genetic marker, or population demographics influences the power to detect a candidate gene. As part of a training grant project (Dr. Margaret Gnegy, PI) at the University of Michigan, Dr. Cole and her colleagues evaluated the power of association tests using coalescent-modeled computer simulations. Results show that the effective number of markers on a haplotype is dependent on whether the cs is included as a marker. When the analyses include the cs, highest power is achieved with a single-marker association test. However, when the cs is excluded from analyses, the addition of more nonfunctional SNPs on the haplotype increases power to a certain point under most scenarios. Typically, it is found that a rapidly expanding population always has lower power compared to a population of constant size; although utilizing markers with a frequency of at least 5% improves the chance of detecting an association. Comparing the mutational properties of a nonfunctional SNP versus an STR, multi-allelic STRs provide more or comparable power than a bi-allelic SNP unless SNP frequencies are constrained to 10% or more. Similarly, including an STR with SNPs on a haplotype improves power unless SNP frequencies are 5% or more. Cole, S.M. and Long, J.C. A Coalescent Simulation Of Marker Selection Strategy For Candidate Gene Association Studies. American Journal Of Medical Genetics. Part B, Neuropsychiatric Genetics, 147(1), pp. 86-93, 2008.

Acute Effect of Methadone Maintenance Dose on Brain fMRI Response to Heroin-Related Cues

Environmental drug-related cues have been implicated as a cause of illicit heroin use during methadone maintenance treatment of heroin dependence. Dr. Daniel Langleben and colleagues from the University of Pennsylvania sought to identify the functional neuroanatomy of the brain response to visual heroin-related stimuli in methadone maintenance patients. Event-related functional magnetic resonance imaging was used to compare brain responses to heroin-related stimuli and matched neutral stimuli in 25 patients in methadone maintenance treatment. Patients were studied before and after administration of their regular daily methadone dose. The heightened responses to heroin-related stimuli in the insula, amygdala, and hippocampal complex, but not the orbitofrontal and ventral anterior cingulate cortices, were acutely reduced after administration of the daily methadone dose. The medial prefrontal cortex and the extended limbic system in methadone maintenance patients with a history of heroin dependence remains responsive to salient drug cues, which suggests a continued vulnerability to relapse. Vulnerability may be highest at the end of the 24-hour interdose interval. Langleben, D.D., Ruparel, K., Elman, I., Busch-Winokur, S., Pratiwadi, R., Loughead, J., O'Brien, C.P., and Childress, A.R. Acute Effect of Methadone Maintenance Dose on Brain fMRI Response to Heroin-Related Cues. American Journal of Psychiatry, 165(3), pp. 390-394, 2008.

HIV Risk Behavior Among Patients with Co-Occurring Bipolar and Substance Use Disorders: Associations with Mania and Drug Abuse

Bipolar and substance use disorders frequently co-occur, and both are associated with impulsivity, impaired judgment, and risk-taking. In this study, Dr. Meade and colleagues at Harvard Medical School and McLean Hospital, aimed to: (1) describe the rates of HIV sexual and drug risk behaviors among patients with co-occurring bipolar and substance use disorders, (2) test whether acute mania, psychiatric severity, and drug severity independently predict HIV risk, and (3) examine the relationship between specific substance dependencies and sexual risk behaviors. Participants (N=101) were assessed for psychiatric diagnoses, substance abuse, and HIV risk behavior using structured clinical interviews and self-report questionnaires. The majority (75%) were sexually active in the past 6 months and reported high rates of sexual risk behaviors, including unprotected intercourse (69%), multiple partners (39%), sex with prostitutes (24%, men only), and sex trading (10%). In a multivariate linear regression model, recent manic episode, lower psychiatric severity, and greater drug severity were independent predictors of total HIV risk. Cocaine dependence was associated with increased risk of sex trading. Results underscore the importance of HIV prevention for this population. Meade, C.S., Graff, F.S., Griffin, M.L., and Weiss, R.D. HIV Risk Behavior Among Patients with Co-occurring Bipolar and Substance Use Disorders: Associations with Mania and Drug Abuse. Drug and Alcohol Dependence, 92(1-3), pp. 296-300, 2008.

Mesofrontal and Striatal Activation Related to Envisioning of Distal and Proximal Emotional Events

Antoine Bechara and colleagues at University of Southern California used fMRI to investigate whether activation of incentive neurocircuitry is modulated by temporal distance of a variety of envisioned emotional events. Healthy volunteers imagined positive and negative events pertaining to the near future or far future while their brain activity was measured with fMRI. They showed that the anterior part of the ventromedial prefrontal cortex (vmPFC) was more active in envisioning emotional events in the far future than in the near future, whereas the caudate nucleus was engaged in envisioning emotional (especially positive) situations in the near future. This suggests that the anterior part of the vmPFC might assign emotional values to mental representations of future events that pertain to long-term goals, while the caudate might support more concrete simulations of rewarding situations in the near future. Being able to envision emotional events that might happen in the future could be critical in decisions about whether to abstain or relapse to use of an abused drug. D'Argembeau, A., Xue, G., Lu, Z., Van der Linden, M., and Bechara, A. Neural Correlates of Envisioning Emotional Events In The Near and Far Future. NeuroImage, 40(1), pp. 398-407, 2008.

Presence of a Social Stressor Inhibits the Ability to Learn from Bad Choices in a Gambling Task in Men More than in Women

Antoine Bechara and colleagues at University of Southern California used neuropsychological testing to investigate whether decision making during a task is disrupted by an emotional stressor unrelated to the task. Drug-dependent individuals typically encounter a variety of social stressors, some of which are self-initiated. Two groups of healthy volunteers played the Iowa Gambling Task, with one group anticipating having to give a public speech. Those who anticipated having to give a speech took longer to learn to make advantageous choices. In addition, a gender interaction was present later in the game. Stressed female participants exhibited more explicit knowledge and more advantageous performance than stressed males. These results indicate that effects of anticipatory stress on decision making are complex and depend on both the nature of the task and the individual. Preston, S.D., Buchanan, T.W., Stansfield, R.B., and Bechara, A. Effects Of Anticipatory Stress On Decision Making In A Gambling Task. Behavioral Neuroscience, 121(2), pp. 257-263, 2007.

Photic Stimuli of Specific Wavelengths May Provide a Novel Probe of Dopaminergic Tone in Human Subjects

Perry Renshaw and colleagues at McLean Hospital used the functional magnetic resonance imaging (fMRI) BOLD method to measure visual cortical activation in human subjects (N = 6) in response to 8 Hz flashing red and blue light stimuli during placebo conditions and during the oral administration of d-amphetamine. While, there was no effect of D-amphetamine administration on the percent BOLD signal change to red or blue light, there was a specific augmentation of the spatial extent of activation (as measured by the number of activated pixels; p = 0.018) to blue, but not red light following D-amphetamine administration. Thus, blue light function may have utility as an assay of CNS DA tone. Cowan, R.L., Wood, J., Dietrich, M.S., Frederick, B.D., Lukas, S.E., and Renshaw, P.F. Differential Effects of D-Amphetamine on Red and Blue Light-Induced Photic Activation: A Novel Bold fMRI Assay of Human Dopamine Function. Synapse, 62(4), pp. 268-272, 2008.

Right-Left Asymmetry of D2 Receptor Availability in Striatum is Reflective of Individual Differences in Psychometric Scores of Incentive Motivation

Gene-Jack Wang and colleagues at Brookhaven National Laboratory examined the relationship between self-reported degree of incentive motivation and asymmetry of D2 receptor availability in healthy volunteers. Nineteen healthy participants were studied with positron emission tomography (PET) and [11C]raclopride to assess the availability of dopamine D2 receptors in left and right striatum. Incentive motivation was assessed by the Achievement scale of the Multidimensional Personality Questionnaire. The Achievement score was negatively correlated with the Asymmetry Index ([R - L]/[R + L]) of D2 receptor availability (r = -.721, p = .001), suggesting that greater positive incentive motivation is associated with higher receptor availability in the left relative to the right hemisphere. Tomer, R., Goldstein, R.Z., Wang, G., Wong, C., and Volkow, N.D. Incentive Motivation is Associated with Striatal Dopamine Asymmetry. Biological Psychology, 77(1), pp. 98-101, 2008.

Emotional Stimuli and Context Moderate Effects of Nicotine on Specific but Not Global Affects

David Gilbert and colleagues at the University of Southern Illinois investigated how nicotine interacts with the emotional and cognitive modulation of attention. The study involved the presence or absence of emotionally positive and negative stimuli and attentional choice to avoid attending to emotionally negative stimuli. Two groups of habitual smokers (32 per group) performed attentional tasks in which they either had the freedom to look back and forth at 2 simultaneously presented pictures or viewed single pictures without attentional choice. Blocks of pictures contained one of 4 combinations of picture types: a) emotionally negative + neutral, b) negative + positive, c) positive + neutral, or d) neutral + neutral. Participants wore a nicotine patch on one day and a placebo patch on a second day. Nicotine reduced anxiety most when negative pictures were presented in combination with neutral pictures, but it had no effect on anxiety when negative pictures were presented in combination with positive pictures and when negative pictures were not presented. In contrast, nicotine only reduced depressive affect when the participant had attentional choice between positive and negative pictures. Nicotine also enhanced positive affect and reduced negative affect as measured by the Positive and Negative Affect Schedule, but these effects were not moderated by task manipulations. Nicotine tended to enhance eye-gaze orientation to emotional pictures versus neutral pictures in women, but it had no significant effect on eye-gaze in men. Overall, the findings support the view that nicotine's ability to reduce specifically negative affect is moderated by overall emotional context and attentional freedom. Gilbert, D.G., Riise, H., Dillon, A., Huber, J., Rabaanovich, N.E., and Sugai, C. Exp. Clin. Psychopharmacol., 16(1), pp. 33-42, 2008.

Interactions Between Genotype and Retrospective ADHD Symptoms Predict Lifetime Smoking Risk in a Sample of Young Adults

Joseph McClernon and colleagues at Duke University investigated whether ADHD symptoms interact with candidate gene variation to predict smoking risk. Attention-deficit/hyperactivity disorder (ADHD) symptoms are associated with an increased risk of smoking, and genetic studies have identified similar candidate genes associated with both ADHD and smoking phenotypes. Participants were a subsample of individuals from the National Longitudinal Study of Adolescent Health (Add Health), a nationally representative sample of adolescents followed from 1995 to 2002. The sample analyzed included a subset from Add Health of 1,900 unrelated individuals with genotype data. Multiple logistic regression was used to examine relationships between self-reported ADHD symptoms, genotype, and lifetime history of regular smoking. Polymorphisms in the Dopamine D2 receptor gene and, the MAO-A gene (females only) interacted with retrospective reports of ADHD symptoms in contributing to risk for smoking. Trends were observed for interactions between the Dopamine D4 receptor gene and the MAO-A gene (males only) and ADHD symptoms to predict smoking risk. No main effect for any of these polymorphisms was observed. No main effects or interactions with CYP2A6, DAT, and SLC6A4 genes were found. These findings suggest that genotypes associated with catecholamine neurotransmission interact with ADHD symptoms to predict lifetime smoking risk in a sample of young adults. McClernon, F.J., Fuemmeler, B.F., Kollins, S.H., Kail, M.E., and Ashley-Koch, A.E. Nicotine Tob. Res., 10(1), pp. 117-127, 2008.

Persistent Cognitive and Dopamine Transporter Deficits in Abstinent Methamphetamine Users

Una McCann and colleagues at Johns Hopkins School of Medicine investigated potential persistent psychomotor deficits secondary to METH abuse and their relationship to brain dopamine transporter (DAT) availability, as measured using quantitative PET methods with [(11)C]WIN 35428 in abstinent methamphetamine (METH) users. The study sought to determine whether cognitive deficits and brain DAT reductions fully reverse with sustained abstinence, or whether behavioral deficits in METH users are related to dopamine (DA) deficits. 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). A subset of subjects also underwent PET scanning with [(11)C]WIN 35428 to assess DAT availability. 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 executive or motor function deficits, were associated with decreases in striatal DAT binding potential. These results suggest a possible relationship between DAT binding potential and memory deficits in abstinent METH users. One interpretation of these results is that METH produces lasting effects on central DA neurons in humans, but further study is needed to address the potential role of changes in brain serotonin in cognitive deficits in abstinent METH users. 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. Synapse, 62(2), pp. 91-100, 2008.

Increased Activation in the Brain's Visuospatial and Reward Circuitry May Underlie Abstinence-Induced Cravings to Smoke

Ze Wang and colleagues at the University of Pennsylvania used arterial spin labeled (ASL) perfusion magnetic resonance imaging to characterize the neural substrates of abstinence-induced cravings to smoke. Chronic smokers were scanned during a resting state on two separate occasions: (1) smoking satiety and (2) abstinence (after [>=]12 h of smoking deprivation), in counterbalanced order. Smoking abstinence (vs satiety) was associated with increased cerebral blood flow (CBF) in anterior cingulate cortex (ACC)/medial orbitofrontal cortex (OFC) and left OFC. Abstinence-induced cravings to smoke were predicted by CBF increases (abstinence minus satiety) in the right OFC, right dorsolateral prefrontal cortex, occipital cortex, ACC, ventral striatum/nucleus accumbens, thalamus, amygdala, bilateral hippocampus, left caudate, and right insula. These data suggest that increased activation in the brain's visuospatial and reward circuitry underlies abstinence-induced cravings to smoke, and thereby, may be important in relapse. Wang, Z., Faith, M., et al. Neural Substrates of Abstinence-Induced Cigarette Cravings in Chronic Smokers. Journal of Neuroscience, 27(51), pp. 14035-14040, 2007.

Unexpected Versus Expected Cocaine Delivery Elicit Different Patterns of Human Orbitofrontal Cortex Recruitment

Shi-Jiang Li and colleagues at the Medical College of Wisconsin investigated how cocaine expectation modulates human brain responses to acute cocaine administration in non-treatment-seeking cocaine abusers. Distinct regional characteristics in BOLD responses to expected and unexpected cocaine infusions were observed in the medial orbitofrontal gyrus, frontal pole, and anterior cingulate gyrus regions. They reported active engagement in the amygdala and the lateral orbitofrontal cortex by unexpected (but not expected) cocaine infusion. Cocaine expectation did not change BOLD responses to acute cocaine administration in a set of subcortical substrates, however, including the nucleus accumbens, ventral putamen, ventral tegmental area, and thalamus. These results suggest that cocaine expectation modulates the neural-sensitivity adaptation between the expected events and the actual outcomes, but did not modulate the pharmacological characteristics of cocaine. Kufahl, P., Li, Z., Risinger, R., Rainey, C., Piacentine, L., Wu, G., Bloom, A., Yang, Z, and Li S-J. Expectation Modulates Human Brain Responses To Acute Cocaine: A Functional Magnetic Resonance Imaging Study. Biological Psychiatry, 63(2), pp. 222-230, 2008.

Individual Differences in Working Memory Capacity Reflect Dopamine Synthesis Capacity in the Striatum

Mark D'Esposito and colleagues at the University of California at Berkeley demonstrated that working memory capacity as measured by listening span predicts dopamine synthesis capacity in the striatum. They showed that subjects with low working memory capacity have low DA synthesis capacity in the striatum, whereas subjects with high working memory capacity have high DA synthesis capacity in the striatum. Cools, R., Gibbs, S.E., Miyakawa, A., Jagust, W., and D'Esposito, M. Working Memory Capacity Predicts Dopamine Synthesis Capacity in the Human Striatum. Journal of Neuroscience, 28(5), pp. 1208-1212, 2008.

Taq1A DRD2 Genotype Governs Brain Activation Affects of Cabergoline, A D2 Receptor Agonist, During a Reversal Learning Task

NIDA NRSA trainee Michael X. Cohen and colleagues at the University of Bonn used functional MRI and a learning task to show that cabergoline increased neural reward responses in the medial orbitofrontal cortex, cingulate cortex and striatum for Taq1A A1+ subjects but decreased reward responses in these regions for A1- subjects. In contrast, cabergoline decreased task performance and frontostriatal connectivity in A1+ subjects but had the opposite effect in A1- subjects. Further, the drug effect on functional connectivity predicted the drug effect on feedback-guided learning. Thus, individual variability in how dopaminergic drugs affect the brain reflects genetic disposition. These findings may help to explain the link between genetic disposition and risk for addictive disorders. Cohen, M.X., Krohn-Grimberghe, A., Elger, C.E., and Weber, B. Dopamine Gene Predicts the Brain's Response to Dopaminergic Drug. European Journal of Neuroscience, 26(12), pp. 3652-3660, 2007.

Brain Regions Governing "Regret" Identified with fMRI

Greg Berns and colleagues at Emory University used fMRI to investigate the neural correlates of regret and rejoice. They found that activation of medial orbitofrontal cortex, left superior frontal cortex, right angular gyrus, and left thalamus, correlated with the degree of regret. A different network, including the rostral anterior cingulate, left hippocampus, left ventral striatum, and brain stem/midbrain correlated with rejoice. The right inferior orbitofrontal cortex, pre-supplementary motor area, anterior cingulate, and posterior cingulate showed similar patterns of activation with both regret and rejoice, suggesting that these regions may be associated with surprise from the realization of relatively unlikely events. These results suggest that distinct, but overlapping networks are involved in the experiences of regret and rejoice. Chandrasekhar, P.V.S., Capra, C.M., Moore, S., Noussair, C., and Berns, G.S. Neurobiological Regret and Rejoice Functions for Aversive Outcomes. NeuroImage, 39(3), pp. 1472-1484, 2008.

Propranolol Enhances Problem-Solving Skills in the Individuals Who Need the Most Help

David Beversdorf and colleagues at The Ohio State University compared various doses of beta-adrenergic antagonists for their effect on cognitive flexibility in problem solving, and how task difficulty interacts with propranolol benefits. Overall, more anagram problems were solved while on propranolol 40 mg than on placebo. Subjects least able to solve the problems benefited significantly from 40 mg of propranolol. Also, for all subjects the most difficult problems were solved more quickly with propranolol 40 mg than placebo. Benefits were also seen for word fluency and backward digit span. Therefore, noradrenergic modulation of cognitive flexibility is affected by how much difficulty the subject is encountering when searching for the solution, a pattern consistent with what might be expected in an effect on the search of the semantic and associative network. These data may represent a promising avenue for enhancement of decision-making capacity away from relapse. Campbell, H.L., Tivarus, M.E., Hillier, A., and Beversdorf, D.Q. Increased Task Difficulty Results in Greater Impact of Noradrenergic Modulation of Cognitive Flexibility. Pharmacology Biochemistry and Behavior, 88(3), pp. 222-229, 2007.

Ability to Wait for a Larger, Delayed Reward Relates to Both BOLD Signal in the Lateral Orbitofrontal Cortex and COMT Genotype

Mark D'Esposito and colleagues at the University of California at Berkeley used a combination of brain imaging and a candidate genetic analysis to investigate how the brain activations related to reward delay related to polymorphisms in the catechol-O-methyltransferase (COMT) gene. Bias for immediate rewards in healthy volunteers during decision making was found to scale with fMRI BOLD signal magnitude in the posterior parietal cortex (PPC), dorsal prefrontal cortex (dPFC), and rostral parahippocampal gyrus regions. Conversely, the tendency of an individual to wait for a larger, delayed reward was positively correlated with BOLD signal in the lateral orbitofrontal cortex. The Val158Met COMT genotype predicted both impulsive choice behavior and activity levels in the dPFC and PPC during decision making. These genotype effects remained significant after controlling for alcohol abuse history. The results provide evidence that polymorphisms in the COMT gene influences brain activity related to impulsivity and therefore may influence risk or relapse for substance abuse. Boettiger, C.A., Mitchell, J.M., Tavares, V.C., Robertson, M., Joslyn, G., D'Esposito, M., et al. Immediate Reward Bias in Humans: Fronto-Parietal Networks and a Role for the Catechol-O-Methyltransferase 158(Val/Val) Genotype. Journal of Neuroscience 27(52), pp. 14383-14391, 2007.