Research Findings - Clinical Neuroscience Research
Adolescents More Likely to Develop Substance Use Disorder if Preceded by Depression or High Stress
Dr. Uma Rao and her colleagues assessed young adolescents for depression, risk for depression (depressed first degree relatives), and stress (HPA activity as measured by cortisol). Significantly more subjects who were depressed or who were at risk for depression developed substance abuse disorder in one-to-five-year follow-ups. Significantly more of those who had high HPA activity at baseline developed substance abuse disorder compared to those with low HPA activity. However, it was demonstrated that high HPA activity at baseline coupled with later stressful life events increased vulnerability to substance abuse independent of depression. It is speculated that differences in response to antidepressants in treatment of substance abuse (that is, they are ineffective in some individuals) might be related to differences in HPA activity. If so, treatment strategies might be more effective if tailored to differences in stress reactivity. Rao U, Hammen, CL, Poland RE. Mechanisms underlying the comorbidity between depressive and addictive disorders in adolescents: Interactions between stress and HPA activity. Am J Psychiatry. 2009;166:361-9.
Functional Haplotype Implicated in Vulnerability for Cocaine Dependence
Dr. Mary Jean Kreek and associates at Rockefeller University evaluated the influence of polymorphisms of the prodynorphin gene in cocaine and cocaine/alcohol codependent individuals. Three SNPs in the 3' UTR region comprising a haplotype were significantly associated with cocaine dependence in the Caucasian but not African American subgroup. In post-mortem tissue it was found that there were significantly lower levels for the CCT haplotype of prodynorphin in both the caudate and nucleus accumbens. This study provides evidence that a haplotype in the 3' UTR prodynorphin gene is implicated in vulnerability to develop cocaine addiction and/or cocaine/alcohol codependence due to a lower mRNA expression of the gene in human dorsal and ventral striatum. Yuferov V, Ji F Nielsen DA, Levran O, Ho A, Morgello S, Shi R, Ott J, Kreek MJ. A functional haplotype implicated in vulnerability to develop cocaine dependence is associated with reduced PDYN expression in human brain. Neuropsychopharmacology. 2008;34:1185-97.
Ecstasy Use Associated with Reduced Brain Activity in Areas Associated with Semantic Processing
Dr. Ron Cowan and associates at Vanderbilt University used fMRI to investigate dysfunction of brain processes that may contribute to verbal learning deficits in polydrug users who included MDMA as one of their major drugs of abuse. Using a semantic memory task, specific areas were studied that had been shown previously to be associated with this task. Significant results were reported for a correlation between lifetime use of MDMA and (decreased) activation in the left Brodmann Areas 9, 18, and 21/22 for semantic recognition but not accuracy or response time. Since polydrug users were assessed, there was evidence that these results were also due to cannabis and cocaine use. Together with previous evidence that there is reduced gray matter in these same areas, it is concluded that MDMA users' verbal memory impairments are due to neuronal changes due to use. Raj V, Liang HC, Woodward ND, Baurenfeind AL, Lee J, Dietrich MS, Park S, Cowan RL. MDMA (Ecstasy) use is associated with reduced BOLD signal change during semantic recognition in abstinent human polydrug users; a preliminary fMRI study. J Psychopharmacol. 2009; March 20; doi: 10.1177/026988109103203.
The Wake-Promoting Drug Modafinil Blocks Dopamine Transporters
Drs. Joanna Fowler, Nora Volkow and colleagues at Brookhaven National Laboratories used PET to assess the effects of therapeutic doses of Modafinil on extracellular dopamine and on dopamine transporters. The drug is used clinically to treat narcolepsy, but is also used as a cognitive enhancer. Results demonstrated increased extracellular dopamine in the caudate, putamen, and nucleus accumbens as well as blockade of the dopamine transporters. It is concluded that since drugs that increase dopamine in the nucleus accumbens have abuse potential, caution is advised in therapeutic uses. Volkow ND, Fowler JS, Logan J, Alexoff D, Zhu W, Telang F, Wang G-J, Jayne M, Hooker JM, Wong C, Hubbard B, Carter P, Warner D, King P, Shea C, Xu Y, Muench L, Apelskog-Torres K. Effects of Modafinil on dopamine and dopamine transporters in the male human brain. JAMA. 2009;301(11):1148-54.
Ability to Inhibit Responses and Reaction Time Variability of Continuous Attention Served as ADHD Endophenotypes
Dr. Scott Kollins and colleagues at Duke University examined the molecular genetic substrate underlying attention performance in children having attention deficit hyperactivity disorders (ADHD) and in their family members. Haplotype-tagging SNP analyses were conducted to identify SNPs from 10 candidate genes involved in monoaminergic function and their association with quantitatively measurable cognitive performance that requires continuous attention and represents different aspects of executive function. Four different components of performance analyzed in the study were Errors of Omission (not responding to a target stimulus) that indexed sustained attention, Errors of Commission (responding to a non-target stimulus) that indexed the ability to inhibit response, Reaction Time and Reaction Time Variability that indexed attention regulation. After correction for multiple comparisons and controlling for multiple individuals from the same family, it was found that SNPs in dopamine D2 receptor gene were associated with commission errors on the continuous attention task. Polymorphisms in the norepinephrine transporter gene (NET) were related to reaction time variability in ADHD children and their families, supporting the heritability of these processes. These results suggest that commission errors and reaction time variability are related to NE transmission and may serve as ADHD endophenotypes. Kollins SH, Anastopoulos AD, Lachiewicz AM, FitzGerald D, Morrissey-Kane E, Garrett ME, Keatts SL, Ashley-Koch AE. SNPs in dopamine D2 receptor gene (DRD2) and norepinephrine transporter gene (NET) are associated with continuous performance task (CPT) phenotypes in ADHD children and their families. Am J Med Genet B Neuropsychiatr Genet. 2008;147B(8):1580-8.
White Matter Tract Injury and Cognitive Impairment in HIV+ Individuals
Dr. Igor Grant and colleagues at the University of California, San Diego, investigated the relationship of white matter integrity to cognitive impairment and antiretroviral treatment variables using diffusion tensor imaging and a comprehensive neuropsychological evaluation. Approximately half of those infected with the human immunodeficiency virus (HIV+) exhibit cognitive impairment, which has been related to cerebral white matter damage. Despite the effectiveness of antiretroviral treatment, cognitive impairment remains common even in individuals with undetectable viral loads. One explanation for this may be subtherapeutic concentrations of some antiretrovirals in the central nervous system (CNS). Diffusion tensor imaging indices were mapped onto a common whole-brain white matter tract skeleton, allowing between-subject voxel wise comparisons. The total HIV-infected group exhibited abnormal white matter in the internal capsule, inferior longitudinal fasciculus, and optic radiation; whereas those with AIDS exhibited more widespread damage, including in the internal capsule and the corpus callosum. Cognitive impairment in the HIV-infected group was related to white matter injury in the internal capsule, corpus callosum, and superior longitudinal fasciculus. White matter injury was not found to be associated with HIV viral load or estimated CNS penetration of antiretrovirals. Relationships between diffusion alterations in specific white matter tracts and cognitive impairment support the potential utility of diffusion tensor imaging in examining the anatomical underpinnings of HIV-related cognitive impairment, especially in individuals with more advanced HIV infection. The study also confirms that CNS injury is evident in persons infected with HIV despite effective antiretroviral treatment. Gongvatana A, Schweinsburg BC, Taylor MJ, Theilmann RJ, Letendre SL, Alhassoon OM, Jacobus J, Woods SP, Jernigan TL, Ellis RJ, Frank LR, Grant I. White matter tract injury and cognitive impairment in human immunodeficiency virus-infected individuals. J Neurovirol. 2009;22;1-9.
Vulnerability to Pain Persisted Following Opioid Detoxification in Chronic Pain Patients
Dr. Sean Mackey and colleagues at Stanford University investigated how patients receiving opioids to relieve chronic pain may paradoxically experience more pain over time as a result of prolonged administration of opioid analgesic. The need for dose escalation of analgesic can be due to desensitization of antinociceptive mechanisms (tolerance to opioids) or elevated sensitization of pain (opioid-induced hyperalgesia). The outcome of this study suggested that prolonged use of opioids results in a reduced tolerance to pain. The study was conducted in chronic pain patients who voluntarily titrated downward their opioids using an individualized biopsychosocial intervention and who had successfully and completely withdrawn from opioid. The association of tapered dose of opioid with subjective perception and tolerance to cold pain were assessed at admission to and discharge from the inpatient opioid detoxification program. Patients who relied upon a higher dose of opioid analgesic and who had experienced higher reduction in daily opioid use became less tolerant to pain. In these individuals, reduced tolerance threshold, but not perception to cold pain, persisted even though quality of life and daily function were significantly improved after a successful detoxification. In contrast, patients managed under lower dose of opioid analgesic before the detoxification had improved pain tolerance. Therefore, increased sensitivity to pain may sustain following opioids cessation, and greater tapering the dose of opioid strongly correlated with less pain tolerance. The lowered tolerance to pain contributes to the difficulty of tapering opioid medications even when classic withdrawal symptoms appear to be well-managed. Younger J, Barelka P, Carroll I, Kaplan K, Chu L, Prasad R, Gaeta R, Mackey S. Reduced cold pain tolerance in chronic pain patients following opioid detoxification. Pain Med. 2008;9(8):1158-63.
Abnormal Glutamate Metabolism in Neurocognitively Asymptomatic HIV+ Patients
Dr. Pom Sailasuta and colleagues at the California Institute of Technology evaluated the concentration of glutamate, the major excitatory neurotransmitter in the frontal cortex and posterior cingulate gyrus, in HIV-seropositive patients. HIV-seropositive patients taking antiretroviral medication may continue to develop cognitive deficits even if the infection is controlled and immune status is recovered. Biomarkers of neural abnormality at an early stage of HIV progression may predict neurocognitive changes in presymptomatic HIV+ patients. A novel MRS method, TE-averaged MRS, was used to differentiate glutamate from glutamine. Glutamate concentration, but not N-acetyl-aspartate or creatine, was significantly lower in the frontal white matter in HIV+ patients. No reduction was identified in frontal grey matter. In contrast, both glutamate and N-acetyl-aspartate concentrations were increased in the frontal white matter in a control group of abstinent methamphetamine users. Sailasuta N, Shriner K, Ross B. Evidence of reduced glutamate in the frontal lobe of HIV-seropositive patients. NMR Biomed. 2009;22(3):326-31.
Critical Review of Challenges Associated with Treatment of Comorbid Substance Use and Posttraumatic Stress Disorder
Dr. Kathleen Brady and colleagues at the Medical College of South Carolina investigated whether individuals with substance use disorders (SUDs) meet criteria for comorbid posttraumatic stress disorder (PTSD). Co-occurrence of SUD and PSTD may be of increasing importance in veterans of the Iraq and Afghanistan conflicts. Clinicians (N = 423) from four national organizations completed an anonymous questionnaire regarding sources of difficulty and gratification in treatment. Comorbid SUD/PTSD was rated as significantly more difficult to treat than either disorder alone. The most common challenges associated with treating SUD/PTSD patients included knowing how to best prioritize and integrate treatment components, patient self-destructiveness and severe symptomatology, and helping patients abstain from substance use. This comorbidity confers a more complicated clinical presentation that carries with it formidable treatment challenges for practitioners. The findings increase understanding of SUD/PTSD treatment challenges, and may be useful for enhancing therapist training programs, supervision effectiveness, and designing optimal SUD/PTSD interventions. Back SE, Waldrop AE, Brady KT. Treatment challenges associated with comorbid substance use and posttraumatic stress disorder: clinicians' perspectives. Am J Addict. 2009;18(1):15-20.
DAT Genotype Modulates Brain and Behavioral Responses Elicited by Cigarette Cues
Dr. Theresa Franklin and colleagues at the University of Pennsylvania tested whether the variable number of tandem repeats (VNTRs) polymorphism in the DA transporter (DAT) SLC6A3 gene influences DA transport, where brain and behavioral responses may be enhanced in probands carrying the 9-repeat allele. To test this hypothesis, they obtained perfusion fMR images during cue exposure in 19 smokers genotyped for the 40 bp VNTR polymorphism in the SLC6A3 gene. Contrasts between groups revealed that individuals with the 9-repeat polymorphism (9-repeats) had a greater response to smoking (vs nonsmoking) cues than smokers homozygous for the 10-repeat allele (10/10-repeats) in the interconnected ventralstriatal/pallidal/orbitofrontal cortex regions (VS/VP/OFC) of both sides. Activity was increased in 9-repeats and decreased in 10/10-repeats in the VS/VP/OFC (p<0.001 for all analyses). Brain activity and craving was strongly correlated in 10/10-repeats in these regions and others (anterior cingulate, parahippocampal gyrus, and insula; p<0.001 in all regions). There were no significant correlations between brain and behavior in 9-repeats. There were no differences in cigarette dependence, demographics, or resting baseline neural activity between groups. These results provide evidence that genetic variation in the DAT gene contributes to the neural and behavioral responses elicited by smoking cues. Franklin TR, Lohoff FW, Wang Z, Sciortino N, Harper D, Li Y, Jens W, Cruz J, Kampman K, Ehrman R, Berrettini W, Detre JA, O'Brien CP, Childress AR. DAT genotype modulates brain and behavioral responses elicited by cigarette cues. Neuropsychopharmacology. 2009;34(3):717-28.
Social Discounting Demonstrated in a Public Goods Game
Dr. Howard Rachlin and colleagues at the State University of New York, Stony Brook examined the extent to which a human social discount function can measure the value to a person of a reward to another person at a given social distance. Just as delay discounting is a hyperbolic function of delay, and probability discounting is a hyperbolic function of odds-against, social discounting is a hyperbolic function of social distance. Experiment 1 obtained individual social, delay, and probability discount functions for a hypothetical $75 reward; participants also indicated how much of an initial $100 endowment they would contribute to a common investment in a public good. Steepness of discounting correlated, across participants, among all three discount dimensions. However, only social and probability discounting were correlated with the public-good contribution; high public-good contributors were more altruistic and also less risk averse than low contributors. Experiment 2 obtained social discount functions with hypothetical $75 rewards and delay discount functions with hypothetical $1,000 rewards, as well as public-good contributions. The results replicated those of Experiment 1; steepness of the two forms of discounting correlated with each other across participants but only social discounting correlated with the public-good contribution. Most participants in Experiment 2 predicted that the average contribution would be lower than their own contribution. Jones BA, Rachlin H. Delay, probability, and social discounting in a public goods game. Neuropsychopharmacology. J Exp Anal Behav. 2009;91(1):61-73.
Low Prefrontal Perfusion Linked to Depression Symptoms in Methadone-Maintained Opiate-Dependent Patients
Clinically depressed patients without substance use disorders, compared to controls, exhibit significantly lower resting regional cerebral blood flow (rCBF) in the prefrontal cortex (PFC). In this study, Langleben and colleagues, at the University of Pennsylvania, examined the link between resting rCBF in the PFC and current depressive symptoms in methadone-maintained opiate-dependent (MM) patients with or without major depression. The relationship between the Beck Depression Inventory (BDI) score and resting rCBF was examined in a single regression analysis. The BDI scores ranged between 0 and 18 (m=7.0, S.D.=4.8), and 30% of the sample had mild to moderate depression symptoms according to BDI scores. A negative correlation was observed between BDI scores and relative rCBF in the bilateral ventrolateral prefrontal cortex, and middle frontal gyri. The inverse relationship between prefrontal paralimbic rCBF and depression scores suggests a link between reduced fronto-limbic activity and depressive symptoms in MM patients. A significant subgroup of opiate-dependent patients has clinical or sub-clinical depression that is often undetected; these data identify brain substrates of depression symptoms that may also be a potential marker of relapse in this population. Treatment strategies targeting these brain regions may improve outcomes in depressed substance abusers. Suh JJ, Langleben DD, Ehrman RN, Hakun JG, Wang Z, Li Y, Busch SI, O'Brien CP, Childress AR. Drug Alcohol Depend. 2009;99(1-3):11-7.
The Relationship between Recreational Gambling and Substance Abuse/Dependence: Data from a Nationally Representative Sample
Dr. Marc Potenza and colleagues at the Yale University School of Medicine investigated the co-occurrence of substance abuse and recreational gambling. Logistic regression analyses were performed on data from a nationally representative sample from the Gambling Impact and Behavior Study. Substance-abusing recreational gamblers, as compared to non-substance-abusing ones, differed in gambling motivations, began gambling at earlier ages, reported heavier gambling, and preferred and performed strategic forms of gambling. As compared with non-substance-abusing gamblers, substance-abusing gamblers demonstrated different gambling profiles including heavier gambling. These findings suggest the need for additional research on whether and how substance use might promote gambling and vice versa. Liu T, Maciejewski PK, Potenza MN. Drug Alcohol Depend. 2009;100(1-2):164-8.
Ventral Striatal Dopamine Release in Response to Smoking a Regular vs a Denicotinized Cigarette
Prior studies have demonstrated that both nicotine administration and cigarette smoking lead to dopamine (DA) release in the ventral striatum/nucleus accumbens. In tobacco-dependent individuals, smoking denicotinized cigarettes leads to reduced craving, but less pleasure, than smoking regular cigarettes. Using denicotinized cigarettes and (11)C-raclopride positron emission tomography (PET) scanning, Brody and colleagues, at UCLA, sought to determine if nicotine is necessary for smoking-induced DA release. Sixty-two tobacco-dependent smokers underwent (11)C-raclopride PET scanning, during which they smoked either a regular or denicotinized cigarette (double-blind). Change in (11)C-raclopride binding potential (BP) in the ventral striatum from before to after smoking was used as an indirect measure of DA release. Cigarette craving, anxiety, and mood were monitored during scanning. Smoking a regular cigarette resulted in a significantly greater mean reduction in ventral striatal (11)C-raclopride BP than smoking a denicotinized cigarette. Although both groups had reductions in craving and anxiety with smoking, the regular cigarette group had a greater improvement in mood. For the total group, change in BP correlated inversely with change in mood, indicating that greater smoking-induced DA release was associated with more smoking-related mood improvement. Thus, nicotine delivered through cigarette smoking appears to be important for ventral striatal DA release. Study findings also suggest that mood improvement from smoking is specifically related to ventral striatal DA release. Brody AL, Mandelkern MA, Olmstead RE, Allen-Martinez Z, Scheibal D, Abrams AL, Costello MR, Farahi J, Saxena S, Monterosso J, London ED. Neuropsychopharmacology. 2009;34(2):282-9.
Brain Nicotinic Acetylcholine Receptor Occupancy: Effect of Smoking a Denicotinized Cigarette
Brody and colleagues, at UCLA, recently reported that smoking a regular cigarette (1.2-1.4 mg nicotine) resulted in 88% occupancy of brain alpha4beta2* nicotinic acetylcholine receptors (nAChRs). However, this study did not determine whether nicotine inhalation or the many other pharmacological and behavioral factors that occur during smoking resulted in this receptor occupancy. If nicotine is solely responsible for alpha4beta2* nAChR occupancy from smoking, then (as estimated from previous data) smoking a denicotinized (0.05 mg nicotine) or a low-nicotine (0.6 mg nicotine) cigarette (commonly used for research and clinical purposes) would result in substantial 23% and 78% alpha4beta2* nAChR occupancies, respectively, and a plasma nicotine concentration of 0.87 ng/ml would result in 50% alpha4beta2* nAChR occupancy (EC50). Twenty-four positron emission tomography sessions were performed on tobacco-dependent smokers, using 2-[F-18]fluoro-A-85380 (2-FA), a radiotracer that binds to alpha4beta2* nAChRs. 2-FA displacement was determined from before to 3.1 hours after either: no smoking, smoking a denicotinized cigarette, or smoking a low-nicotine cigarette. Analysis of these PET data revealed that smoking a denicotinized and a low-nicotine cigarette resulted in 26% and 79% alpha4beta2* nAChR occupancies, respectively, across three regions of interest. The EC50 determined from this dataset was 0.75 ng/ml. Given the consistency of findings between a previous study with regular cigarettes and the present study, nicotine inhalation during smoking appears to be solely responsible for alpha4beta2* nAChR occupancy, with other factors (if present at all) having either short-lived or very minor effects. Brody AL, Mandelkern MA, Costello MR, Abrams AL, Scheibal D, Farahi J, London ED, Olmstead RE, Rose JE, Mukhin AG. Int J Neuropsychopharmacol. 2009;12;(3):305-16.
MAO-A Genotype Does Not Modulate Resting Brain Metabolism
Dr. Alia-Klein and colleagues at Brookhaven National Laboratory used a combination of brain imaging and genotyping to investigate whether polymorphisms in the MAO-A gene in humans have functional effects on cerebral metabolism. Variation in the monoamine-oxidase-A (MAO-A) gene has been associated with volumetric changes in corticolimbic regions with differences in their response to relevant emotional tasks. However, no differences in baseline regional brain metabolism were observed as a function of genotype. These results suggest that unchallenged, corticolimbic activity is not modulated by the MAO-A genotype. Alia-Klein N, Kriplani A, Pradhan K, Ma J, Logan J, Williams B, Craig I, Telang F, Tomasi D, Goldstein R, Wang G, Volkow N, Fowler J. The MAO-A genotype does not modulate resting brain metabolism in adults. Psychiatry Research-Neuroimaging. 2008;164(1):73-6.
Nonlinear Neurobiological Probability Weighting Functions for Aversive Outcomes
Dr. Greg Berns and colleagues at Emory University used fMRI to investigate what brain processes generate the tendency for people to overestimate the likelihood of improbable events and underestimate the likelihood of probable events. They presented individuals during fMRI with a series of situations that differed with respect to the intensity of a impending (mild) cutaneous electric shock and the probability with which the shock would be received. During the anticipatory phase, prior to the delivery of the shock, activity in a circumscribed network of brain regions including the anterior cingulate, visual, parietal, and temporal cortices was proportional to the probability of the expected outcome. However, the degree of neuronal activity did not scale linearly with the probability of the shock, rather most of these regions displayed responses to probabilities consistent with nonlinear probability weighting. The neural responses to passive situations predicted 79% of subsequent decisions when individuals were offered choices between different situations. More importantly, the prior neuronal activation was a better predictor of later choices than prior behavioral choices near the indifference point. These results indicate that brain activity is a sensitive index of later choices that involve assessment of aversive outcomes. Berns GS, Capra CM, Chappelow J, Moore S, Noussair C. Nonlinear neurobiological probability weighting functions for aversive outcomes. Neuroimage. 2008;39(4):2047-57.
Neurobiological Regret and Rejoice Functions for Aversive Outcomes
Dr. Greg Berns and colleagues at Emory University used fMRI to investigate the neural basis of why winning a bet when winning was unlikely is a more positive experience than when winning was highly probable - even if the absolute amount of the outcome is the same. In this study, "regret" was defined as a choice that results in a more adverse outcome than a different choice would have yielded, whereas "rejoice" when a choice resulted in better outcome than a different choice. Unlike previous studies, non-monetary outcomes were used, consisting of mild electrical shocks to the foot. Subjects were asked to make the choices which allowed for the possibility of avoiding the shocks. It was hypothesized that the neural response to a painful outcome would not only reflect the intensity of the shock, but would also reflect the degree of regret as measured by the likelihood that alternative choices would not have yielded the same adverse outcome. Similarly, when an individual avoided a potential shock, the neuronal response would reflect the degree of rejoicing proportional to the probability he had of receiving the shock. Activation of a cortical network, consisting of the 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. Therefore, distinct, but overlapping networks are involved in the experiences of regret and rejoice. Dysregulation of these networks may contribute to the inability of substance abusers to "regret" adverse outcomes resulting from substance use. Chandrasekhar PVS, Capra CM, Moore S, Noussair C, Berns GS. Neurobiological regret and rejoice functions for aversive outcomes. Neuroimage. 2008;39(3):1472-84.
Abstinence from Chronic Cocaine Self-Administration Alters Striatal Dopamine Systems in Rhesus Monkeys
Dr. Linda Porrino and colleagues at Wake Forest University use ex vivo autoradiography imaging to determine whether changes in dopamine receptors during chronic cocaine self-administration persist after abstinence. Male rhesus monkeys self-administered cocaine (0.3 mg/kg per injection, 30 reinforcers per session) under a fixed-interval 3-min schedule for 100 days. This duration of cocaine self-administration has been previously shown to decrease DA D2-like receptor densities and increase levels of D1-like receptors and DA transporters (DAT). Responding by control monkeys was maintained by food presentation under an identical protocol and the same abstinence periods. Following 30 days of abstinence both D1 receptor binding, indexed by [H-3] SCH 23390, and DAT binding, indexed by [H-3] WIN 35 428, was significantly higher in all portions of the striatum, compared to control animals. In contrast, D2 receptor binding indexed by [H-3] raclopride did not differ between the cocaine and control monkeys. Following 90 days of abstinence, DA D1 receptor and DAT binding were not different from control values. These results indicate that there is eventual recovery of the separate elements of the DA system, but highlight the dynamic nature of these components during the initial phases of abstinence from chronic cocaine self-administration. Beveridge T, Smith H, Nader M, Porrino L. Abstinence from chronic cocaine self-administration alters striatal dopamine systems in rhesus monkeys. Neuropsychopharmacology. 2009;34(5):1162-71.
Transdermal Nicotine Administration and the Electroencephalographic Activity of Substance Abusers in Treatment
Dr. Sara Nixon and colleagues at the University of Florida examined the effects of nicotine on patterns of electroencephalographic (EEG) activity in smokers who concurrently were dependent on other substances. Subjects were regular smokers who were also either alcohol-dependent, stimulant-dependent, or had concurrent alcohol- and stimulant-dependence compared to community controls. After overnight nicotine abstinence, subjects were administered either a high (14 or 21 mg) or low (7 mg) dose transdermal nicotine patch. EEG data were collected during a 2-minute eyes open and 5-minute eyes closed baseline recording session. Results indicated differential pattern of nicotine dose effects by group. There was no difference across nicotine doses in the EEG patterns of controls and concurrent alcohol/stimulant-dependent participants. In contrast nicotine administration in either the alcohol-dependent or stimulant-dependent groups resulted in opposite findings across a range of spectral bands. Although further research is warranted, these data suggest that nicotine-related changes in neurophysiology may be associated with specific drug histories and reinforce the need for caution in generalizing across groups with different drug histories. Ceballos N, Tivis R, Prather R, Nixon S. Transdermal nicotine administration and the electroencephalographic activity of substance abusers in treatment. Journal of Addiction Medicine. 2008;2(4):202-14.
Cognitive Control for Task Sets is the Same for Shifting Spatial Attention and Switching Categorization Rules
Dr. Steven Yantis and colleagues at Johns Hopkins University used fMRI to investigate whether the ability to voluntarily shift in task across different domains of cognitive control (e.g., spatial attention shifts, shifts between categorization rules, or shifts between stimulus-response mapping rules) is associated with separate, domain-specific brain control networks, or whether a common, domain-independent brain source of control initiates shifts in all domains. A rapid event-related fMRI paradigm allowed use of a single paradigm in which subjects were cued to perform both shifts of spatial attention and switches between categorization rules. A conjunction analysis revealed a common transient signal evoked by switch cues in medial superior parietal lobule for both domains of control, revealing a single domain-independent control mechanism. These results suggest that proper functioning of the medial superior partietal lobe may be necessary for drug abusers to be able to shift their attention (and behavior) away from drug-related cues. Chiu Y, Yantis S. A domain-independent source of cognitive control for task sets: shifting spatial attention and switching categorization rules. J Neurosci. 2009;29(12):3930-8.
Striatal Dopamine Predicts Outcome-Specific Reversal Learning and its Sensitivity to Dopaminergic Drug Administration
Dr. Mark D'Esposito and colleagues at the University of California, Berkeley used PET ligand imaging to investigate whether individual variability in reward-based learning is due to quantitative variation in baseline levels of striatal dopamine. Variation in baseline striatal dopamine synthesis capacity measured with 6-[18F]fluoro-L-m-tyrosine (FMT) correlated with reward-based reversal learning. Subjects with high baseline dopamine synthesis in the striatum showed relatively better reversal learning from unexpected rewards than from unexpected punishments, whereas subjects with low baseline dopamine synthesis in the striatum showed the reverse pattern. In addition, baseline dopamine synthesis predicted the direction effects of the D(2) receptor agonist bromocriptine. Bromocriptine improved reward-based relative to punishment-based reversal learning in subjects with low baseline dopamine synthesis capacity, while impairing it in subjects with high baseline dopamine synthesis capacity in the striatum. Finally, this pattern of drug effects was outcome-specific, and driven primarily by drug effects on punishment, but not reward-based reversal learning. These data demonstrate that the effects of D(2) receptor stimulation on reversal learning in humans depend on task demands and baseline striatal dopamine synthesis capacity. Cools R, Frank MJ, Gibbs SE, Miyakawa A, Jagust W, D'Esposito M. Striatal dopamine predicts outcome-specific reversal learning and its sensitivity to dopaminergic drug administration. J Neurosci. 2009;29(5):1538-43.
N-Acetylaspartate (NAA) Correlates Inversely with Cannabis Use in Frontal Cortex of MDMA (Ecstasy) Polydrug Users
Dr. Ron Cowen and colleagues at Vanderbilt University used magnetic resonance spectroscopy (MRS) to investigate the relative contributions of Ecstasy (MDMA) or polydrug exposure to reduced verbal memory. Although, Ecstasy users have reduced gray matter in brain regions mediating verbal memory (BA 18, 21 and 45), MRS studies in Ecstasy users have yielded inconsistent results using N-acetylaspartate (NAA) as a neuronal marker and myoinositol (MI) as a glial marker. Therefore it was hypothesized that Ecstasy combined with other polydrug use would be associated with altered NAA or MI in verbal memory brain regions. No effects were seen for MI in seventeen polydrug Ecstasy users, nor were there any statistically significant associations for lifetime use of Ecstasy, alcohol, or cocaine with NAA. However, lifetime cannabis use was significantly associated with BA45 NAA/Cr (r = -0.687), but not with NAA in BA 18 or 21. These findings suggest that cannabis use may contribute to altered neuronal integrity in Ecstasy polydrug users in a brain region associated with verbal memory processing. Cowan R, Joers J, Dietrich M. N-acetylaspartate (NAA) correlates inversely with cannabis use in a frontal language processing region of neocortex in MDMA (Ecstasy) polydrug users: A 3 T magnetic resonance spectroscopy study. Pharmacology Biochemistry and Behavior. 2009;92(1):105-10.
Cannabinoid Effects on Brain-Derived Neurotrophic Factor (BDNF) Levels in Humans
Dr. Cyril D'Souza and colleagues at Yale School of Medicine investigated whether delta(9)-tetrahydrocannabinol (delta(9)-THC), the principal active component of cannabis, would alter BDNF levels in humans, similar to effects of THC in pre-clinical studies. In a double-blind, fixed order, placebo-controlled, laboratory study light users of cannabis (n = 9) received intravenous administration of delta(9)-THC (0.0286 mg/kg). Serum sampled at baseline, after placebo administration, and after delta(9)-THC administration was assayed for BDNF using ELISA. Delta(9)-THC administration did not increase serum BDNF levels in cannabis users. The doses of delta(9)-THC were pharmacologically active as reflected in produced psychotomimetic effects, perceptual alterations, subjective reports of "high" and spatial memory impairments. The effects of socially relevant doses of cannabinoids on BDNF suggest a possible mechanism underlying the consequences of exposure to cannabis. This may be of particular importance for the developing brain and also in disorders believed to involve altered neurodevelopment such as schizophrenia. However, the effects of cannabinoids on BDNF and other neurotrophins need to be replicated in larger studies. D'Souza D, Pittman B, Perry E, Simen A. Preliminary evidence of cannabinoid effects on brain-derived neurotrophic factor (BDNF) levels in humans. Psychopharmacology. 2009;202(4):569-78.
Impaired Reproduction of Three-Dimensional Objects by Cocaine-Dependent Subjects
Dr. Igor Elman and colleagues at McLean Hospital investigated cognitive impairments in cocaine abusers. Twenty seven cocaine-dependent, 26 marijuana-abusing or dependent, and 33 healthy subjects performed a perceptual-motor task of figure copying. Cocaine-dependent and healthy individuals did not differ in their scores on the copying of a two-dimensional diamond and a cross. In contrast, cocaine-dependent subjects displayed significantly poorer ability to copy a three-dimensional Necker cube, a smoking pipe, a hidden line elimination cube, a pyramid, and a dissected pyramid. Marijuana users' performance on all copied figures was comparable to that of the healthy comparison subjects. Three-dimensional copying ability has been found to be associated with parietal lobe damage, suggesting a role for parietal lobe dysfunction in the pathophysiology of cocaine dependence. Elman I, Chi W, Gurvits T, Ryan E, Lasko N, Lukas S, Pitman R. Impaired reproduction of three-dimensional objects by cocaine-dependent subjects. Journal of Neuropsychiatry and Clinical Neurosciences. 2008;20(4):478-84.
Expert Financial Advice Neurobiologically "Offloads" Financial Decision-Making Under Risk
Dr. Greg Berns and colleagues at Emory University used fMRI to investigate how the brain processes external information, such as advice, during decision-making. The current experiment investigated the neurobiological basis of the influence of expert advice on financial decisions under risk by having participants make a series of financial choices between a certain (100% probability) payment and an uncertain payment (<100% probability) undergoing fMRI scanning. Choices were made in two conditions: 1) advice from a financial expert about which choice to make was displayed (MES condition); and 2) no advice was displayed (NOM condition). Behavioral results showed a significant effect of expert advice. Specifically, probability weighting functions changed in the direction of the expert's advice. This was paralleled by neural activation patterns. Brain activations showing significant correlations with valuation (parametric modulation by value of lottery/sure win) were obtained in the absence of the expert's advice (NOM) in intraparietal sulcus, posterior cingulate cortex, cuneus, precuneus, inferior frontal gyrus and middle temporal gyrus. Notably, no significant correlations with value were obtained in the presence of advice (MES). These findings were corroborated by region of interest analyses. Neural equivalents of probability weighting functions showed significant flattening in the MES compared to the NOM condition in regions associated with probability weighting, including anterior cingulate cortex, dorsolateral PFC, thalamus, medial occipital gyrus and anterior insula. Finally, during the MES condition, significant activations in temporoparietal junction and medial PFC were obtained. These results support the hypothesis that one effect of expert advice is to "offload" the calculation of value of decision options from the individual's brain. Engelmann JB, Capra CM, Noussair C, Berns GS. Expert financial advice neurobiologically "Offloads" financial decision-making under risk. PLoS ONE. 2009;4(3): e4957.
Prefrontal and Midline Interactions Mediating Behavioural Control
Dr. Hugh Garavan and colleagues at Trinity University used fMRI to determine whether frontal and midline brain areas serve to facilitate interaction of top-down control processes with bottom-up stimulus-driven task demands so as to facilitate the smooth execution of behaviour. This study utilized a GO/NO-GO task with cued and uncued inhibitory events to investigate the effect of cue-induced levels of top-down control on NO-GO trial response conflict. Within-subjects on a trial-for-trial basis, high levels of top-down control, as indexed by left dorsolateral prefrontal activation prior to the NO-GO, resulted in lower levels of activation on the NO-GO trial in the pre-supplementary motor area. These results suggest that prefrontal and midline regions work together to implement cognitive control and reveal that intra-subject variability is reflected in these lateral and midline interactions. Since substance abusers have been shown to have structural and functional dysregulation of prefrontal and midline brain regions, these results provide insight into how brain dysfunction may impede the ability to exert behavioral control on drug use. Fassbender C, Hester R, Murphy K, Foxe JJ, Foxe DM, Garavan H. Prefrontal and midline interactions mediating behavioural control. Eur J Neurosci. 2009;29(1):181-7.
Structural Brain Differences in Bipolar Adolescents with and without Cannabis Use Disorders
Dr. Igor Elman and colleagues at McLean Hospital used structural MRI (voxel based morphometry) to determine whether there are differences in brain structure between bipolar adolescents with co-occurring cannabis use disorders (CUD) and bipolar adolescents without any substance use disorder. Whole-brain structural magnetic resonance imaging (MRI) scans were obtained from 14 bipolar adolescents. Seven study participants were diagnosed with CUD before and/or shortly after their MRI scan was obtained, and 7 subjects were free of any substance use disorder at the time of their MRI scan as well as during longitudinal follow up. Bipolar adolescents with CUD demonstrate evidence of greater structural abnormalities than adolescents with bipolar disorder alone in frontal and temporal cortical regions, as well as in subcortical areas linked with emotion and motivational regulation. Specifically, bipolar adolescents with co-occurring CUD demonstrated decreased gray matter volume (GMV) in the left fusiform gyrus and increased GMV in the right caudate and precentral gyrus, as well as increased gray matter density in the right middle occipital and fusiform gyri and cerebellar vermis. Although the limited prescan exposure to marijuana in these adolescents tentatively suggests that these findings may reflect underlying differences, the direct effect of cannabis exposure may also be involved. Jarvis K, DelBello M, Mills N, Elman I, Strakowski S, Adler C. Neuroanatomic comparison of bipolar adolescents with and without cannabis use disorders. Journal of Child and Adolescent Psychopharmacology. 2008;18(6):557-63.
Neural Activity During the Stop Signal Task is Related to Risk Taking and Trait Anxiety
Dr. Chiang Li and colleagues at Yale School of Medicine used the stop signal task (SST) and fMRI to examine the "risk-taking" component of the SST. The current study took advantage of variability of go trial reaction time (RT) and compared the post-go go trials that showed a decrease in RT (risk-taking decision) and those post-go go trials that showed an increase in RT ("risk-aversive" decision) in 33 healthy individuals who underwent fMRI scanning during the SST. This contrast revealed robust activation in bilateral visual cortices as well as left inferior parietal and posterior cingulate cortices, amygdala, and middle frontal gyrus. Furthermore, the magnitude of amygdala activity was positively correlated with trait anxiety of the participants. Li CR, Chao HH, Lee T. Neural correlates of speeded as compared with delayed responses in a stop signal task: An indirect analog of risk taking and association with an anxiety trait. Cereb Cortex. 2009;19(4):839-48.
Improvements in a Nonferrous Smoking Device for Self-Administration of Smoked Drugs with Concurrent fMRI Neuroimaging
Lukas and associates at McLean Hospital improved a previously-developed smoke-delivery device to facilitate investigations of the acute neuronal effects of smoked drugs as the improved device does not interfere with the collection of MRI neuroimaging data. The problem with the previous device was that the amount of nicotine delivered to subjects smoking was reduced by approximately 44% compared to nicotine delivered by cigarettes smoked normally. Improvements were made to the smoke delivery component of this apparatus in an attempt to improve drug delivery, while not interfering with collection of MRI data. The improved device does not interfere with typical drug effects produced by normal smoking. Phantom scans revealed that BOLD signal was not found to be altered by the (in-bore) installation and operation of the improved device. Preliminary data analysis of smoking induced changes in the BOLD response to visual stimulation suggest that this response is not affected by the improved device, the act of smoking, air puffing, nicotine, or other components of cigarette smoke. Lindsey KP, Lukas SE, MacLean RR, Ryan ET, Reed KR, Frederick BD. Design and validation of an improved nonferrous smoking device for self-administration of smoked drugs with concurrent fMRI neuroimaging. Clin EEG Neurosci. 2009;40(1):21-30.
Insular Cortical Activation Reflects both Affective and Sensory Aspects of Touch
Dr. Martin Paulus and colleagues at the University of California, San Diego, used fMRI to examine the contribution of different parts of the insular cortex in the representation of both affective and sensory aspects of touch. Subjects were administered a cued application of touch during functional MRI. Stimulus-related activation occurred in the mid-to-posterior insula, whereas anticipatory related activation was seen mostly in anterior insula. Moreover, the degree of activation in anterior insula during anticipation was correlated with the degree of activation in the posterior insula and caudate during stimulus processing. Finally, the degree of activation in the anterior insula during anticipation was also correlated with experienced intensity of the touch. Taken together, these results are consistent with the hypothesis that the anterior insula is preparing for the sensory and affective impact of touch. This preparatory function has important implications for the understanding of addictive disorders because dysfunctions in anticipatory processing are a fundamental part of the psychopathology. Lovero KL, Simmons AN, Aron JL, Paulus MP. Anterior insular cortex anticipates impending stimulus significance. Neuroimage. 2009;45(3):976-83.
Effect of Impulsivity in Risky Decision-Making
Drs. Laura Martin and Geoffrey Potts at Florida State University used event-related potentials (ERPs) to examine whether sensitivity to reward and punishment modulates impulsivity during risky decision-making in high and low impulsive subjects. The results indicate that the high-risk option appeared to be the default choice of the high impulsives and the low-risk choice the default for the low impulsives since high impulsives had a larger P3 and the low impulsives a smaller P3 when making a low-risk choice. The low, but not the high impulsives, had a larger error-related negativity (ERN) following high-risk choice indicating that the low impulsives evaluated the risky choice as a poor decision. The results indicate that high impulsive individuals are biased towards immediate reward during option evaluation but are less sensitive to the negative consequences of their choices. Since impulsivity is a risk factor for substance abuse as well as a consequence of substance abuse, these results suggest that dysregulation of brain networks in substance abusers bias them to make high risk choices. Martin L, Potts G. Impulsivity in decision-making: An event-related potential investigation. Personality and Individual Differences 2009;46(3):303-8.
Role of the Insula in Compulsive Drug-Taking
Dr. Antoine Bechara at the University of Southern California reviewed the literature indicating that a largely overlooked structure, the insula, plays a crucial part in conscious urges to take drugs. Most prior research on the neurobiology of addiction has focused on the role of subcortical systems, such as the amygdala, the ventral striatum and mesolimbic dopamine system, in promoting the motivation to seek drugs. The insula has been highlighted as a region that integrates interoceptive (i.e. bodily) states into conscious feelings and into decision-making processes that involve uncertain risk and reward. A heuristic model was proposed in which the processing of the interoceptive effects of drug use by the insula contributes to conscious drug urges and to decision-making processes that precipitate relapse. Naqvi NH, Bechara A. The hidden island of addiction: the insula. Trends Neurosci. 2009;32(1):56-67.
Dual Role of Anterior Cingulate Cortex in Navigating Conflict and Increasing Attentional Focus
Dr. Daniel Weissman of the University of Michigan used a novel cross-modal attentional cueing task during fMRI scans in humans to detect regional specialization for processes that detect conflict and processes that increase attention in the cognitive division of the anterior cingulate cortex (ACC(cd)). Activity in a dorsal subregion was associated with increasing attention to relevant stimuli, correlated with behavioral measures of orienting attention to those stimuli, and resembled activity in dorsolateral prefrontal regions that are also thought to bias attention toward relevant stimuli. In contrast, activity in a rostral subregion was associated only with detecting response conflict caused by irrelevant stimuli. These findings support a 2-component model for minimizing distraction and speak to a longstanding debate over how the ACC(cd) contributes to cognitive control. Orr JM, Weissman DH. Anterior cingulate cortex makes 2 contributions to minimizing distraction. Cereb Cortex. 2009;19(3):703-11.
Decision-Makers Resort to Automated Reactions to Risk while under Stress
Dr. Mauricio Delgado of Rutgers University probed the impact of exposure to acute stress on financial decision making and examined the particular influence of stress on decisions with a positive or negative valence. Participants' choices exhibited a stronger reflection effect when participants were under stress than when they were in the no-stress control phase. This suggests that stress modulates risk taking, potentially exacerbating behavioral bias in subsequent decision making (such as responses to drug-predictive cues). Consistent with dual-process approaches, decision makers fall back on automatized reactions to risk under the influence of disruptive stress. This may have significant explanatory power for compulsive drug use in states of negative affect. Porcelli AJ, Delgado MR. Acute stress modulates risk taking in financial decision making. Psychological Science. 2009;20(3):278-83.
Multimodal Evidence for Similar Subjective and Physiological Responses Between Cocaine Craving and Cocaine Reward
Dr. Leslie Prichep and colleagues at New York University studied subjective, physiological and electroencephalographic (EEG) profiles in cocaine dependent subjects in response to cocaine cue exposure or a dose of smoked cocaine. Both stimuli increased subjective ratings of cocaine high and craving, enhanced negative affect, and boosted plasma ACTH and skin conductance levels. However, cocaine dose produced a greater increase in high and a more prolonged increase in plasma ACTH, while cocaine cue produced a decline in skin temperature. Both stimuli produced increases in absolute theta, alpha and beta EEG power over the prefrontal cortex. However, interhemispheric EEG coherence over the prefrontal cortex decreased during cocaine cue exposure but increased following cocaine dose. Moreover, delta and theta activity were associated with negative affect during cocaine cue exposure, but were associated with cocaine craving and reward following cocaine dosing. In both conditions, alpha activity was a marker for anxiousness but not cocaine high. These data demonstrate similar subjective, physiological responding in clinical laboratory states of cocaine craving and reward. However, differences in EEG response profiles, and their relationship to function, indicate distinct neurophysiological mediators of cocaine craving and reward within the prefrontal cortex. Reid MS, Flammino F, Howard B, Nilsen D, Prichep LS. Cocaine cue versus cocaine dosing in humans: evidence for distinct neurophysiological response profiles. Pharmacol Biochem Behav. 2008;91(1):155-64.
Can fMRI Predict Substance Abuse Treatment Response
Dr. Martin Paulus of UCSD reviewed evidence supporting the use of functional neuroimaging as a clinical tool to predict outcomes in substance use disorders. The review focused, in part, on the importance of recognizing the clinical heterogeneity of the substance use disorders population. Empirical and theoretical analyses support the idea that the courses of substance use disorders are relatively independent of the types of substance being used. The review also summarized various approaches to the measurement and characterization of the longitudinal courses of substance use disorders as well as reviewing predictors of outcomes and discussing their limitations. Finally, aspects of their work that focus on using functional magnetic resonance imaging to predict outcomes were described. Reske M, Paulus M. Predicting Treatment Outcome in Stimulant Dependence. Addiction Reviews 2008; 1141270-283.
White Matter Abnormalities in Methamphetamine Abusers Correlate with Impaired Stroop Task Performance
Dr. Ruth Salo and colleagues at the University of California, Davis, used Diffusion Tensor Imaging to investigated whether changes in white matter were related to dysregulated cognitive control in methamphetamine abusers (MA). The study related performance on the Stroop selective attention task with indices of WM microstructure obtained from diffusion tensor imaging (DTI) in the callosal genu and splenium of currently abstinent MA abusers and non-substance abusing control subjects. MA abusers exhibited greater Stroop reaction time interference (i.e., reduced cognitive control) compared with control subjects. After correcting for multiple comparisons, fractional anisotropy, a measure of white matter fiber integrity, within the genu correlated significantly with measures of cognitive control in the MA abusers but not in control subjects. There was a trend for group differences in genu but not splenium. The results indicate that methamphetamine abuse alters anterior callosal WM microstructure, but not posterior callosal WM microstructure. Furthermore, white matter alterations indices within the genu but not splenium correlated with measures of cognitive control in chronic MA abusers. Salo R, Nordahl TE, Buonocore MH, Natsuaki Y, Waters C, Moore CD, Galloway GP, Leamon MH. Cognitive control and white matter callosal microstructure in methamphetamine-dependent subjects: a diffusion tensor imaging study. Biol Psychiatry. 2009;65(2):122-8.
Methamphetamine Abusers Exhibited Blunted Error-Elicited Behavior Change and Reduced Activation in Prefrontal Cortex
Dr. Ruth Salo and colleagues at the University California, Davis, employed a fast-event-related functional magnetic resonance imaging design to examine trial-to-trial reaction time (RT) adjustments in 12 methamphetamine (MA)-dependent subjects and 16 non-substance-abusers. A variant of the Stroop task was used to contrast the groups on error rates, RT conflict, and the level of trial-to-trial adjustments seen after incongruent trials. MA abusers exhibited reduced RT adjustments and reduced activation in the right prefrontal cortex compared to controls on conditions that measured the ability to use exposure to conflict situations (i.e., conflict trials) to regulate behavior. The groups did not differ on accuracy rates or within-trial Stroop conflict effects. The results suggest that deficits in trial-to-trial RT adjustments in methamphetamine abusers may be indicative of an inability of abusers to adapt a behavioral response based on prior experience, which could contribute to further drug-seeking behavior. Salo R, Ursu S, Buonocore MH, Leamon MH, Carter C. Impaired prefrontal cortical function and disrupted adaptive cognitive control in methamphetamine abusers: a functional magnetic resonance imaging study. Biol Psychiatry. 2009;65(8):706-9.
Adolescents have Reduced Brain Activation in Error-Monitoring Neurocircuitry Compared to Adults
Dr. Goeffery Pearlson and colleagues at the Institute of Living, Yale School of Medicine contrasted functional magnetic resonance imaging (fMRI) data collected from 25 adolescent and 25 adult healthy participants (ages 11-37) performing a visual Go/No-Go task. A whole brain functional connectivity analysis was conducted that contrasted correct versus incorrect button presses using independent component analysis (ICA). Previous studies suggest that the anterior cingulate and other prefrontal brain regions might form a functionally-integrated error detection network in the human brain. Correct responses engaged a network comprising left lateral prefrontal cortex, left postcentral gyros/inferior parietal lobule, striatum, and left cerebellum. In contrast, a similar network was uniquely engaged during errors, but this network was not integrated with activity in regions believed to be engaged for higher-order cognitive control over behavior. A medial/dorsolateral prefrontal-parietal neural network responded to all No-Go stimuli, but with significantly greater activity to errors. ICA analyses also identified a third error-related circuit comprised of anterior temporal lobe, limbic, and pregenual cingulate cortices, possibly representing an affective response to errors. Critically, there were developmental differences in error-processing activity within many of these neural circuits, typically reflecting greater hemodynamic activation in adults. These findings characterize the spatial structure of neural networks underlying error commission and identify neurobiological differences between adolescents and adults that may portend developmental vulnerability to persistent risky behaviors such as substance abuse. Stevens M, Kiehl K, Pearlson G, Calhoun V. Brain network dynamics during error commission. Human Brain Mapping. 2009;30(1):24-37.
Implicit Learning Task Reveals that the Anterior Cingulate Encodes Errors made Outside Awareness
Dr. Stefan Ursu and colleagues at the University of California, Davis used fMRI to investigate whether the caudal anterior cingulate cortex (cACC) is involved in performance monitoring and whether these effects may be differentially modulated by awareness. Subjects performed a dual task: 1) a delayed recognition task and 2) a serial response task (SRT) with an implicit probabilistic learning rule (where the stimulus location followed a probabilistic sequence of which the subjects were unaware). Task performance confirmed that the location sequence was learned implicitly. Even though they found no evidence of awareness for the presence of the sequence, increased cACC activity during correct trials which violated the sequence (high-conflict), relative to trials when stimuli followed the sequence (low conflict), was observed using a rapid event-related fMRI paradigm. Errors made with awareness also activated the same brain region. Their results suggest that the performance monitoring function of the cACC extends beyond detection of errors made with or without awareness, and involves detection of multiple responses even when they are outside of awareness. Ursu S, Clark KA, Aizenstein HJ, Stenger VA, Carter CS. Conflict-related activity in the caudal anterior cingulate cortex in the absence of awareness. Biol Psychol. 2009;80(3):279-86.
Inverse Association Between BMI and Prefrontal Metabolic Activity in Healthy Adults
Dr. Nora Volkow and associates at Brookhaven National Laboratory used PET imaging of regional brain glucose metabolism (2-deoxy-2[F-18] fluoro-D-glucose (FDG)) to assess the relationship between brain activity and obesity, assessed by body mass index (BMI). There was significant negative correlation between BMI and resting metabolic activity in prefrontal cortex and cingulate gyrus but not in other regions. Moreover, baseline metabolism in these prefrontal regions was positively associated with performance on tests of memory (California Verbal Learning Test ) and executive function (Stroop Interference and Symbol Digit Modality tests). In contrast, the regional brain changes during performance of the cognitive tasks were not associated with BMI nor with neuropsychological performance. These results further support the concept that obesity and substance abuse involve dysregulation of overlapping neuronal networks. Volkow N, Wang G, Telang F, Fowler J, Goldstein R, Alia-Klein N, Logan J, Wong C, Thanos P, Ma Y, Pradhan K. Inverse association between BMI and prefrontal metabolic activity in healthy adults. Obesity. 2009;17(1):60-5.
Gender Differences in the Ability to Inhibit Brain Activation Elicited by Food Stimulation
Dr. Gene-Jack Wang and associates at Brookhaven National Laboratories assessed the brain activation involved in voluntary inhibition of hunger during food stimulation in 23 fasted men and women. Brain activity was measured using PET assays of regional cerebral glucose metabolism with 2-deoxy-2[(18)F]fluoro-D-glucose ((18)FDG). In men, but not in women, instructions to inhibit responses to food stimulation was associated with significantly decreased activation in regions involved in emotional regulation, conditioning, and motivation, including the amygdala, hippocampus, insula, orbitofrontal cortex, and striatum. The suppressed activation of the orbitofrontal cortex with inhibition in men was associated with decreases in self-reports of hunger, which corroborates the involvement of this region in processing the conscious awareness of the drive to eat. This finding suggests a mechanism by which cognitive inhibition decreases the desire for food and implicates lower ability to suppress hunger in women as a contributing factor to gender differences in obesity. Wang G, Volkow ND, Telang F, Jayne M, Ma Y, Pradhan K, Zhu W, Wong CT, Thanos PK, Geliebter A, Biegon A, Fowler JS. Evidence of gender differences in the ability to inhibit brain activation elicited by food stimulation. Proc Natl Acad Sci U S A. 2009;106(4):1249-54.
Neuropsychology of Cocaine Addiction: Recent Cocaine Use Masks Impairment
Dr. Gene-Jack Wang and colleagues at Brookhaven National Lab examined whether recent cocaine use impairs or improves neuropsychological functions. Drug use was assayed using four measures in subjects with cocaine use disorders (CUD): urine status for cocaine (positive vs negative on study day), cigarette smoking, alcohol consumption, and dysphoria. Compared with healthy control subjects, subjects with CUD exhibited performance deficits on tasks of attention, executive function, and verbal memory (within one standard deviation of controls). Although subjects with CUD with positive urine status, who had higher frequency and more recent cocaine use, reported greater symptoms of dysphoria, these cognitive deficits were most pronounced in the CUD subjects with negative urine status. Cigarette smoking, frequency of alcohol consumption, and dysphoria did not alter these results. These findings suggest that frequent/recent cocaine may mask underlying cognitive (but not mood) disturbances. These results call for development of pharmacological agents targeted to enhance cognition without negatively impacting mood in individuals addicted to cocaine. Woicik PA, Moeller SJ, Alia-Klein N, Maloney T, Lukasik TM, Yeliosof O, Wang G, Volkow ND, Goldstein RZ. The neuropsychology of cocaine addiction: recent cocaine use masks impairment. Neuropsychopharmacology. 2009;34(5):1112-22.
Gender Effects on Mood and Cigarette Craving During Early Abstinence and Resumption of Smoking
Dr. Arthur Brody and colleagues at the University of California, Los Angeles, investigated whether negative mood, cigarette craving, or other symptoms of nicotine withdrawal may contribute to the higher likelihood that women will relapse after initiating abstinence from cigarette smoking compared to men. The study involved 26 female and 38 male smokers who participated in two sessions; one session began within 1 hr after smoking ad libitum and the other followed overnight abstinence. In the first test block, both men and women reported higher scores after >13 hr abstinence than after <1 hr abstinence on the tension-anxiety and anger-hostility subscales of the Profile of Mood States, and for the craving and psychological symptoms of the Shiffman-Jarvik Withdrawal Scale. Moreover, on the tension-anxiety subscale, women also reported a greater reduction than men from smoking one cigarette after overnight abstinence. The findings indicate that overnight abstinence produces more negative mood symptoms and cigarette craving in female smokers than in males, and that resumption of smoking produces greater relief from these symptoms in female smokers. These differences may contribute to the greater likelihood of relapse when women try to quit smoking. Xu J, Azizian A, Monterosso J, Domier CP, Brody AL, London ED, Fong TW. Gender effects on mood and cigarette craving during early abstinence and resumption of smoking. Nicotine Tob Res. 2008;10(11):1653-61.
Adolescent Subgenual Anterior Cingulate Activity is Related to Harm Avoidance
Dr. Martin Paulus and colleagues at the University of California, San Diego, used fMRI to investigate whether the subgenual anterior cingulate cortex (sgACC) is involved in fundamental mental operations such as affective processing and inhibitory control in adolescents as has been found in adults. Seventeen adolescents, 13-17 years of age, underwent functional magnetic resonance imaging while performing a parametric stop-signal task. Greater harm avoidance levels were significantly associated with increased inhibition-related sgACC activity. These results establish, for the first time, a link between personality and differential sgACC activation in adolescents. These findings suggest that individual differences in sgACC function contribute to personality factors that can serve as risk factors for substance. Yang T, Simmons A, Matthews S, Tapert S, Frank G, Bischoff-Grethe A, Lansing A, Wu J, Paulus M, Iusa P. Adolescent subgenual anterior cingulate activity is related to harm avoidance. Neuroreport. 2009;20(1):19-23.
Dynamic Neural Responses to Cue-Reactivity Paradigms in Heroin-Dependent Users
Dr. Shi-Chiang Li at the Medical College of Wisconsin used fMRI to determine the dynamic neural responses to heroin-related cues. Fifteen heroin-dependent and 12 age-matched non-drug using control subjects participated in this study. Overall, the cue-reactivity paradigms significantly activated the dynamic neural activations in the prefrontal system, and the heroin-cue-induced neural responses within the subregions in the PFC system, including the superior frontal, dorsal lateral prefrontal, and orbitofrontal cortices, were significantly intercorrelated. In addition to the prefrontal cortex, other brain regions that were significantly activated included the ventral tegmental area (VTA), the left and right amygdala, the left and right fusiform cortex, and the precuneus in the mesocorticolimbic system. These results suggest that the dynamic response patterns in the PFC system characterize the impaired brain control functions in heroin-dependent subjects. Yang Z, Xie J, Shao Y, Xie C, Fu L, Li D, Fan M, Ma L, Li S. Dynamic neural responses to cue-reactivity paradigms in heroin-dependent users: An fMRI study. Human Brain Mapping. 2009;30(3):766-75.
Midbrain Dopamine Receptor Availability is Inversely Associated with Novelty-Seeking Traits in Humans
Dr. David Zald and colleagues at Vanderbilt University used PET ligand imaging to test whether individual differences in dopamine functioning underlie the personality trait of novelty seeking in humans. Novelty-Seeking personality traits were inversely associated with Dopamine D2-like receptor availability indexed by F-Fallypride in the ventral midbrain regions that includes the substantia nigra/ventral tegmental area. This effect remained significant after controlling for age. The investigators speculate that the lower midbrain autoreceptor availability seen in high novelty seekers leads to accentuated dopaminergic responses to novelty and other conditions that induce dopamine release. These findings provide evidence for a neurobiological explanation for how novelty seeking serves as risk-factor for initiation of substance use. Zald DH, Cowan RL, Riccardi P, Baldwin RM, Ansari MS, Li R, Shelby ES, Smith CE, McHugo M, Kessler RM. Midbrain dopamine receptor availability is inversely associated with novelty-seeking traits in humans. J Neurosci. 2008;28(53):14372-8.
Improved Method for Quantification of Dynamic Radioligand Receptor PET Studies
Dr. Dean Wong and colleagues at Johns Hopkins University developed a new graphical method for PET ligand analysis. This new method is less susceptible to noise-induced negative biases in the estimates of total distribution volume (DV(T)) and binding potential (BP) in the widely used Logan plot. A plasma input function was combined with reference tissue input to estimate DV(T) and BP, followed by an additional condition to ensure that the estimate from the new plot equals DV(T) or BP. It was demonstrated theoretically that 1) the statistical expectations of the estimates from the new plot with given input are independent of the noise of the target tissue concentration measured by PET; and 2) the estimates from the time activity curves of regions of interest are identical to those from the parametric images for the new plot. The computational time for generating DV(T) or BP images in the human studies was reduced by 80% on average by the new plot in contrast to the Logan plot. Overall, the new plot is a consistent and computationally efficient graphical analysis method to improve the quantification of reversible tracer binding in radioligand receptor dynamic PET studies. Zhou Y, Ye W, Brasić JR, Crabb AH, Hilton J, Wong DF. A consistent and efficient graphical analysis method to improve the quantification of reversible tracer binding in radioligand receptor dynamic PET studies. Neuroimage. 2009;44(3):661-70.