Research Findings - Clinical Neuroscience Research
Genetic Variants are Associated with Methadone Doses Required for Effective Treatment of Heroin Dependence
M.J. Kreek and associates at The Rockefeller University determined whether dose differences of methadone in maintained heroin addicts are related to gene variants of ABCB1 (MDR1) gene which encodes the transporter P-glycoprotein of which methadone is a substrate. There is a heterogeneous distribution of genotype allele frequencies between those requiring a higher (>150 mg/day) and lower dose groups for one SNP. Further, individuals with a 3-locus haplotype were 5-fold more likely to need a higher dose; those heterogeneous for this had a 3-fold chance of stabilizing at a lower dose. These data suggest gene variants may be clinically relevant with regard to methadone doses needed for maintenance. Levran O, O'Hara K, Peles E, Li D, Barral S, Ray B, Borg L, Ott J, Adelson M, Kreek MJ. ABCBI (MDR1) genetic variants are associated with methadone doses required for effective treatment of heroin dependence. Hum Mol Genet. 2008; 17(14): 2219-2227.
Genome-wide Association Study Identifies Genes that May Contribute to Risk for Developing Heroin Addiction
M.J. Kreek and associates at The Rockefeller University used an Affymetrix 100k chip to conduct a genome-wide association study in former severe heroin addicts and controls—separately assessing Caucasians and African Americans. Significant associations were found for the vulnerability to develop heroin addiction but they differ between the ethnic groups. In Caucasians, a variant was found in the unannotated region of 1q23.3. In African Americans, another SNP was found in the cytosolic dual specificity phosphatase 27 gene DUSP27. Analysis of the most significant variants in Caucasians yield three loci in the synaptic membrane exocytosis regulating protein 2 gene RIMS2 while those in African-Americans are in cardiomyopathy associated gene CMYA3. Nielsen DA, Fei J, Yuferov V, Ho A, He C, Ott J, Kreek MJ. Genome-wide association study identifies genes that may contribute to risk for developing heroin addiction. Psychiat Genet. 2010 June. [Epub ahead of print].
Individual Differences in Heritability of Risk-Taking
A.P. Anokhin at Washington University studied male and female monozygotic and dizygotic twins to assess the heritability of risk-taking using the BART (an accepted measure of risk-taking). Subjects were assessed twice during early adolescence (ages 12 and 14). Heritability was modest at the early age but later increased to 55% in males but became non-significant in females. It appears, therefore, that this particular test of risk-taking may assess an endophenotype and may only be valid in males. Anokhin AP, Golosheykin S, Grant J, Heath AC. Heritability of risk-taking in adolescence: a longitudinal twin study. Twin Res Hum Genet. 2009 Aug; 12(4): 366-371.
Harsh Corporal Punishment (HCP) is Associated with Decreased Measure of Blood Flow in Dopamine-Rich Regions
M.H. Teicher and associates at Harvard and McLean Hospital recruited college students who reported spanking and such as children to assess neurobiological structures that could have been affected by the punishment. The assessment was accomplished by a specially-developed analysis of T2 relaxometry in steady-state fMRI which is inversely correlated with regional cerebral blood volume. Subjects who had experienced HCP had significantly greater relaxation time in the right caudate and right putamen which to some extent also correlated inversely with measures of short term visual and global memory. While there was no correlation to drug use in these regions, there were correlations between frequency of drug use and relaxation time in bilateral DLPFC and ACC. These data indicate that a relationship between corporal punishment which is less severe than outright physical punishment can influence neurophysiological development which in part increases risk for drug abuse. Sheu Y-S, Polcari A, Anderson CM, Teicher MH. Harsh corporal punishment is associated with increased T2 relaxation time in dopamine-rich regions. NeuroImage. 2010. [doi:10.1016/j.neuroimage.2010.06.043 [Epub ahead of print].
Successful Reversal Learning Recruits Frontocortical Regions Distinct from those of General Response Inhibition
The ability to flexibly respond to changes in the environment is critical for adaptive behavior, and is germane to decisions to refrain from responding to drug cues in drug abuse recovery. Reversal learning (RL) procedures test adaptive response updating when contingencies are altered. David Jentsch and colleagues at UCLA used functional magnetic resonance imaging to examine brain areas that support specific RL components by comparing neural responses to RL and initial learning (acquisition) to isolate reversal-related brain activation independent of cognitive control processes invoked during initial feedback-based learning. Lateral orbitofrontal cortex (OFC) was more activated during reversal than acquisition, suggesting its relevance for reformation of established stimulus-response associations. In addition, the dorsal anterior cingulate (dACC) and right inferior frontal gyrus (rIFG) correlated with change in post-reversal accuracy. These regions and lateral OFC represent distinct neural components that support behavioral flexibility important for adaptive learning. That chronic drug abuse disrupts frontocortical neurocircuitry presents a partial explanation for the difficulty in maintaining abstinence. Ghahremani DG, Monterosso J, Jentsch JD, Bilder RM, Poldrack RA. Neural components underlying behavioral flexibility in human reversal learning. Cereb Cortex. 2010 Aug; 20(8): 1843-1852.
fMRI Study Reveals Brain Circuitry Recruited When We May Need to Say "When"
A. Aron and colleagues at UCSD used trans-cranial magnetic stimulation (TMS) to determine the specific neurocognitive process that underlies the ability to respond with restraint which is an important aspect of cognitive control. The study measured the difference between how much responses slowed (response delay effect) when people respond to "go" stimulus and when they might suddenly need to stop the initiated response compared to when they do not need to stop. They hypothesized that this response delay effect could relate to one or more neurocognitive mechanism(s): partial response suppression (i.e., "active braking"), prolonged decision time, and slower response facilitation. Using TMS, they found that the response delay effect is at least partly explained by active braking, possibly involving a mechanism that is similar to that used to stop responses completely. These results further our understanding of how people respond with restraint by pointing to proactive recruitment of a neurocognitive mechanism heretofore associated with outright stopping. Jahfari S, Stinear CM, Claffey M, Verbruggen F, Aron AR. Responding with restraint: what are the neurocognitive mechanisms? J Cogn Neurosci. 2010 Jul; 22(7): 1479-1492.
Anti-Morphine Antibody: A Novel Target of Medication on the Development of Morphine Tolerance?
J. Mao and colleagues at Massachusetts General Hospital evaluated tolerance to the antinociceptive effect of morphine after a prolonged exposure. After seven consecutive days, development of anti-morphine antibody was evident in rats rendered tolerant to antinociception. The anti-morphine antibody surpressed morphine-induced outward inhibiting current when it was superfused onto animal's spinal cord. Co-administration of morphine with a monoclonal antibody (2.4G(2)) against Fc receptors for seven days significantly attenuated the production of anti-morphine antibody, as well as the behavioral manifestation of morphine tolerance in some rats. These results indicate that anti-morphine antibody produced by chronic morphine exposure may contribute to the development of morphine tolerance possibly through counteracting the inhibitory morphine effect on spinal cord dorsal horn neurons. Kim H, Oh S, Sung B, Tian Y, Yang L, Wang S, Mao J. Anti-morphine antibody contributes to the development of morphine tolerance in rats. Neurosci Lett. 2010 Aug 23;480(3): 196-200.
Sex Differences in Pain and Misuse of Prescription Analgesics among Persons with HIV
J.C. Tsao and colleagues examined sex differences in pain and the use and misuse of prescription analgesics in a representative sample of HIV+ persons in the United States, using a data system that permits a prospective, longitudinal design and structural equation modeling. Women reported more pain than men over a 6-month period regardless of mode of HIV transmission or prior drug use history. Men acknowledged more misuse of prescription analgesics over a 1-year period compared with women, after taking into account pain, use of analgesics specifically for pain, and drug use history. Problem drug use history exerted significant direct and indirect effects on pain, opioid misuse, and pain-specific analgesic use across sex. The findings are consistent with prior evidence indicating female pain predominance as well as the under-treatment of pain among women with HIV. The studies inform the need to improve the assessment and long-term management of pain in HIV+ persons. Tsao JC, Stein JA, Dobalian A. Sex differences in pain and misuse of prescription analgesics among persons with HIV. Pain Med. 2010 Jun;11(6): 815-824.
Overlapping Cognitive Resources Play a Role in Both Pain Processing and Executive Working Memory
T.D. Wager and colleagues evaluated whether pain processing and cognitive function engaged an overlapping set of domain-general, capacity-limited mental resources. A novel paradigm was used in the study to measure concurrent pain and executive working memory in that both task difficulty and the intensity of nociceptive stimulus could be individually calibrated for each participant. Participants reported less pain during the working memory task compared to a visual-matching control condition. Conversely, increasing levels of heat incrementally reduced task performance. Path analyses showed that variations in pain mediated this effect, and that even within a given heat level, trial-by-trial fluctuations in pain predicted decrements in performance. These findings suggested that overlapping cognitive resources play a role in both pain processing and executive working memory. It was proposed that the paradigm could further be used to understand more precisely which components of executive function or other cognitive resources contribute to the experience of pain. Buhle J, Wager TD. Performance-dependent inhibition of pain by an executive working memory task. Pain. 2010 Apr;149(1): 19-26.
Gender Differences in Risk Factors for Aberrant Prescription Opioid Use
A.D. Wasan and colleagues conducted a longitudinal predictive study to examine gender differences in the clinical correlates of risk for opioid misuse among chronic non-cancer pain patients prescribed opioids for pain. Understanding gender differences in substance abuse risk among chronic non-cancer pain patients is important for clinical assessment and treatment. The observational study used a series of patient report outcomes. After 5 months, the subjects were administered a structured prescription drug use interview and submitted a urine sample for toxicology assessment. Their treating physicians also completed a substance misuse behavior checklist. The 5-month follow-up assessment revealed that women tended to score higher on items relating to psychological distress, whereas the male patients tended to report having more legal and behavioral problems. The study suggests that risk factors associated with prescription opioid misuse may differ between men and women. Women are at greater risk to misuse opioids because of emotional issues and affective distress, whereas men tend to misuse opioids because of legal and problematic behavioral issues. Jamison RN, Butler SF, Budman SH, Edwards RR, Wasan AD. Gender differences in risk factors for aberrant prescription opioid use. J Pain. 2010 Apr;11(4): 312-320.
Brain fMRI as Signature of Clinical Trigeminal Neuropathic Pain
D. Borsook, A.D. Wasan and colleagues at McLean Hosptial evaluated the use of brain functional magnetic resonance imaging (fMRI) methods as a signature for clinical pain and pain management. A double-blind 1:1 randomized trial was conducted to evaluate the effects of lamotrigine vs. placebo on patient reported outcome of pain. Lamotrigine decreased pain intensity and achieved an average 63% reduced analgesic effect (from 5.6 to 3.5 on a VAS scale), while it had no effect on other sensory stimuli. Under that condition, the contrast analysis of fMRI results for heat stimuli applied to the affected face for lamotrigine vs. placebo showed an overall decrease in the signal that measures brain blood oxygen dependent level. The pilot study suggested a potential inhibitory effect of the drug on predominantly cortical regions (frontal, parietal, and temporal) that are detectable using fMRI. Scrivani S, Wallin D, Moulton EA, Cole S, Wasan AD, Lockerman L, Bajwa Z, Upadhyay J, Becerra L, Borsook D. An fMRI evaluation of lamotrigine for the treatment of trigeminal neuropathic pain: pilot study. Pain Med. 2010 Jun;11(6): 920-941.
Virtual Reality Hypnosis as an Adjunct Analgesic for Pain Associated with Recovery from Physical Trauma
S.R. Sharar and colleagues assessed the adjunct analgesic effect of virtual reality hypnosis--posthypnotic suggestions administered in combination with standard analgesic care. The posthypnotic suggestions were pain reduction/forgetting about the pain, emotional calm, improved sleep, recalling positive experiences, and looking forward to a better future. Patients under virtual reality hypnosis reported less pain intensity and less pain unpleasantness in comparison to those who experienced virtual reality distraction without hypnosis and standard care alone. Since pain following traumatic injuries often prolongs injury recovery and provides additional challenge in patient management, the study suggests that virtual reality hypnosis could hold promise as an adjunctive analgesic approach. Patterson DR, Jensen MP, Wiechman SA, Sharar SR. Virtual reality hypnosis for pain associated with recovery from physical trauma. Int J Clin Exp Hypn. 2010 Jul;58(3): 288-300.
Genetic x Environmental Mediation in the Association between Conduct Problems and Maltreatment
J.K. Hewitt and colleagues estimated the contribution of gene x environment to the association between maltreatment and conduct problems. Bivariate behavior genetic analyses were conducted on approximately 1,650 twin and sibling pairs drawn from a large longitudinal study of adolescent health. The correlation between maltreatment and conduct problems was found to be small - much of the association between maltreatment and conduct problems was due to a nonpassive gene-environment correlation. Results were more consistent with the hypothesis that parents respond to children's genetically-influenced conduct problems by maltreating them rather than the maltreatment causing conduct problems. Schulz-Heik RJ, Rhee SH, Silvern LE, Haberstick BC, Hopfer C, Lessem JM, Hewitt JK. The association between conduct problems and maltreatment: testing genetic and environmental mediation. Behav Genet. 2010 May;40(3): 338-348.
Monetary Incentives Promote Smoking Abstinence in Adults with ADHD
S.H. Kollins and colleagues explored the effect of monetary incentives to promote abstinence from extended smoking withdrawal. Participants were paid according to an escalating schedule for maintaining abstinence measured as self-report of no smoking and an objective measure of expired air carbon monoxide. About 64% (14/22) of smokers with ADHD and 50% (11/22) of smokers without ADHD maintained complete abstinence for the 2-week duration of the study. About 22% (5/22) and 9% (2/22) of smokers with ADHD and without ADHD, respectively, continued abstinence for up to 10 days following the removal of the contingencies. Though abstinence rates were higher for the smokers with ADHD, the group differences were not statistically significant. Results suggest that monetary incentives may be a useful approach for promoting abstinence in adult smokers with ADHD, perhaps owing to altered reinforcement processes in these individuals. Kollins SH, McClernon FJ, Van Voorhees EE. Monetary incentives promote smoking abstinence in adults with attention deficit hyperactivity disorder (ADHD). Exp Clin Psychopharmacol. 2010 Jun;18(3): 221-228.
Hippocampal and Striatal Gray Matter Volume Associated with a Smoking Cessation Treatment Outcome
F.J. McClernon and colleagues studied associations between the volumes of regional gray matter as measured by voxel-based morphometry and a smoking cessation treatment outcome as measured by point prevalence abstinence at 4 weeks. About 44% (8/18) of smokers achieved abstinence 4 weeks after cessation treatment. After controlling for all covariates, quitters (compared to relapsers) had significantly higher gray matter volume in the left putamen and right occipital lobe and significantly lower gray matter volume in bilateral hippocampus and right cuneus. The results suggest that maintaining smoking abstinence is associated with higher pre-quit brain volume in regions that subserve habit learning and visual processing, and lower brain volume in regions that subserve long-term memory processes and visual information processing. Froeliger B, Kozink RV, Rose JE, Behm FM, Salley AN, McClernon FJ. Hippocampal and striatal gray matter volume are associated with a smoking cessation treatment outcome: results of an exploratory voxel-based morphometric analysis. Psychopharmacology (Berl). 2010 Jul;210(4): 577-583.
Mental Rotation of Hands in HIV Infection: Neuropsychological Evidence of Dysfunction in Fronto-Striato-Parietal Networks
I. Grant and colleagues reported a significant interaction between HIV serostatus and performance on mental rotation tasks, the ability to manipulate three-dimensional objects in space that evaluates neurally complex aspect of spatial cognition. Individuals with HIV committed a greater number of errors than demographically similar seronegative persons on mental rotation tasks, but not on a two-dimensional rotation task. Rotation errors were associated with worse performance on measures of executive functions and working memory, but not with measures of visuoperception. These findings suggest that the observed deficit in the mental rotation may arise from a disrupted fronto-striato-parietal network. Weber E, Woods SP, Cameron MV, Gibson SA, Grant I; HIV Neurobehavioral Research Center Group. Mental rotation of hands in HIV infection: neuropsychological evidence of dysfunction in fronto-striato-parietal networks. J Neuropsychiatry Clin Neurosci. 2010 Winter;22(1): 115-122.
Association of Met/Met Genotype, Executive Dysfunction and their Liabilities for Risky Sexual Behavior
I. Grant and colleagues investigated genetic contributes to executive dysfunction and sexual risk behavior. Catechol-O-methyltransferease (COMT) metabolizes prefrontal cortex dopamine (DA), a neurotransmitter involved in executive behavior. The Val158Met genotype has been linked to executive dysfunction, which might increase sexual risk behaviors favoring HIV transmission. Executive dysfunction, but not COMT, was associated with number of sexual partners. However, there was an interaction between COMT polymorphisms and executive dysfunction; the number of sexual partners and sexual acts was more significant for Met/Met genotypes, intermediate for Val/Met and not significant for Val/Val. The results suggest that in the context of HIV and methamphetamine dependence, dopaminergic overactivity in prefrontal cortex conferred by the Met/Met genotype was liable for executive dysfunction and potentially associated risky sexual behavior. Bousman CA, Cherner M, Atkinson JH, Heaton RK, Grant I, Everall IP, HNRC Group. COMT Val158Met polymorphism, executive dysfunction, and sexual risk behavior in the context of HIV infection and methamphetamine dependence. Interdiscip Perspect Infect Dis. [doi:10.1155/2010/678648].
Longer Term Improvement in Neurocognitive Functioning and Affective Distress among Methamphetamine Users Who Achieve Stable Abstinence
I. Grant and colleagues evaluated the effect of long-term sobriety on neuropsychological and affective evaluations in methamphetamine-dependent individuals. At baseline, methamphetamine-dependent participants performed significantly worse than the healthy subjects on global neuropsychological functioning and were significantly more distressed. About 30% (25/83) of methamphetamine-dependent participants remained abstinent, with identified normalization of function at the one-year follow-up. Both the long-term abstainers and healthy subjects had comparable global neuropsychological performance and affective distress levels, whereas dependants who continued to use methamphetamine had worse performance than the comparison participants. In addition, the abstinent participants demonstrated significantly and disproportionately greater improvement in processing speed and slightly greater improvement in motor abilities than the other participants. These results suggest partial recovery of neuropsychological functioning and improvement in affective distress upon sustained abstinence from methamphetamine that may extend beyond a year or more. Iudicello JE, Woods SP, Vigil O, Cobb Scott J, Cherner M, Heaton RK, Hampton Atkinson J, Grant I. Longer term improvement in neurocognitive functioning and affective distress among methamphetamine users who achieve stable abstinence. J Clin Exp Neuropsychol. 2010 Aug;32(7): 704-718.
White Matter Integrity is Associated with Treatment Outcome Measures in Cocaine Dependence
M. Potenza and colleagues at Yale School of Medicine assessed the correlation of white matter integrity with treatment outcome measures in cocaine dependence. Diffusion tensor imaging (DTI) was used to assess the white matter (WM) of 16 treatment-seeking cocaine-dependent patients before 8 weeks of therapy. Longest self-reported abstinence from cocaine and percent of cocaine-negative urine samples during treatment positively correlated with fractional anisotropy values and negatively correlated with lambda(1), lambda(T), and mean diffusivity values across extensive brain regions including the corpus callosum, frontal, parietal, temporal, and occipital lobes, and cerebellum. The findings of an association between better WM integrity at treatment onset and longer abstinence suggest that strategies for improving WM integrity warrant consideration in developing new interventions for cocaine dependence. Xu J, DeVito EE, Worhunsky PD, Carroll KM, Rounsaville BJ, Potenza MN. White matter integrity is associated with treatment outcome measures in cocaine dependence. Neuropsychopharmacology. 2010 Jun;35(7): 1541-1549.
Striatal Dopamine D2 Receptor Availability Predicts Enduring Thalamic and Medial Prefrontal Responses to Reward
R. Goldstein and colleagues at Brookhaven National Laboratories used PET brain imaging to investigate whether a reduction in dopamine (DA) D2 receptor availability along with the reduced ventral frontal metabolism underlies compromised sensitivity to nondrug reward, a core characteristic of drug addiction. Cocaine abusers who had received PET scans for DA D2 binding shortly after initiating abstinence peformed a monetary reward task using fMRI 3 years later. Initial low DA D2 receptor availability in the dorsal striatum was found to be associated with later decreased thalamic response to monetary reward, whereas low availability in ventral striatum was associated with increased medial prefrontal (Brodmann Area 6/8/32) response to monetary reward. These preliminary results suggest that resting striatal DA D2 receptor availability predicts variability in functional responses to a nondrug reinforcer (money) in prefrontal cortex, implicated in behavioral monitoring, and in thalamus, implicated in conditioned responses and expectation, in cocaine-addicted individuals. Asensio S, Romero MJ, Romero FJ, Wong C, Alia-Klein N, Tomasi D, Wang G, Telang F, Volkow ND, Goldstein RZ. Striatal dopamine D2 receptor availability predicts the thalamic and medial prefrontal responses to reward in cocaine abusers three years later. Synapse. 2010;64(5): 397-402.
Approaching the Bad and Avoiding the Good: Lateral Prefrontal Cortical Asymmetry Distinguishes Between Action and Valence
M. Lieberman and E. Berkman of UCLA used fMRI to determine whether action motivation or stimulus valence is a better descriptor of prefrontal asymmetry. Previous neuroscience investigations have established a left-right prefrontal asymmetry between approaching pleasant and avoiding unpleasant stimuli, but these investigations typically do not untangle the roles of action motivation (approach vs. avoidance) and stimulus valence (pleasant vs. unpleasant) in this asymmetry. Results from this study using fMRI suggest that prefrontal asymmetry is associated with action motivation and not with stimulus valence. Specifically, there was increased left (vs. right) activation in dorsolateral, but not orbitofrontal, prefrontal cortex during approach (vs. avoidance) actions regardless of the stimulus valence, but no such effect was observed for pleasant compared to unpleasant stimuli. Together, these results support the notion that prefrontal asymmetry is associated with action motivation regardless of stimulus valence and, as such, might be linked with goal pursuit processes more broadly. Berkman ET, Lieberman MD. Approaching the bad and avoiding the good: lateral prefrontal cortical asymmetry distinguishes between action and valence. J Cogn Neurosci. 2010 Sep;22(9): 1970-1979.
Individuals with Psychopathic Traits Have Hypersensitive Mesolimbic Dopamine Reward Systems Activity
J. Buckholtz and colleagues at Vanderbilt University combined Positron Emission Tomography and fMRI to examine links between dopamine release, reward sensitivity and personality traits associated with psychopathy. Psychopathy is a personality disorder that is strongly linked to criminal behavior and substance abuse. Impulsive-antisocial psychopathic traits selectively predicted nucleus accumbens dopamine release using [F-18]fallypride and reward anticipation-related neural activity with fMRI in response to pharmacological and monetary reinforcers, respectively. These findings suggest that neurochemical and neurophysiological hyper-reactivity of the dopaminergic reward system may comprise a neural substrate for impulsive-antisocial behavior and substance abuse in psychopathy. Buckholtz JW, Treadway MT, Cowan RL, Woodward ND, Benning SD, Li R, Ansari MS, Baldwin RM, Schwartzman AN, Shelby ES, Smith CE, Cole D, Kessler RM, Zald DH. Mesolimbic dopamine reward system hypersensitivity in individuals with psychopathic traits. Nat Neurosci. 2010;13(4): 419-421.
Effects of Acute Psychosocial Stress on Cigarette Craving and Smoking
E. Childs and H. de Wit at the University of Chicago studied the effects of acute psychosocial stress on cigarette craving, the subjective effects of smoking, and smoking behavior. Stress is thought to influence use of drugs, including cigarette smoking, but the mechanisms by which it does so are not clear. Stress significantly increased cigarette craving but did not increase smoking. When individual differences in nicotine dependence were taken into account, stress influenced CO boost and pleasure from smoking the first cigarette. The results support previous evidence that acute psychosocial stress increases smoking desire. Childs E, de Wit H. Effects of acute psychosocial stress on cigarette craving and smoking. Nicotine Tob Res. 2010 Apr;12(4): 449-453.
Cardiovascular, Hormonal, and Emotional Responses Related to Inhibitory Control in Relation to Sex and Menstrual Cycle Phase
E. Childs and colleagues at the University of Chicago studied how men and women vary in acute stress responses, using the Stop Signal Reaction Time Task as the stressor. Men exhibited greater cortisol responses to stress than women in either the follicular or luteal menstrual phase. Luteal women exhibited the greatest subjective and allopregnanolone responses to stress, whereas follicular women exhibited blunted noradrenaline responses. Partial correlations controlling for group differences revealed that individuals who were most sensitive to the subjective effects of stress exhibited the largest salivary cortisol, noradrenaline, and allopregnanolone responses and the smallest progesterone responses to stress. Childs E, Dlugos A, De Wit H. Cardiovascular, hormonal, and emotional responses to the TSST in relation to sex and menstrual cycle phase. Psychophysiology. 2010 May;47(3): 550-559.
Dopaminergic Prediction Error Responsivity Contributes to Adolescent Reward Seeking
J. Cohen and colleagues at UCLA used fMRI to investigate which aspect of reward processing is responsible for the reward hypersensitivity previously reported in human adolescents. They used a task design that allowed decision value and prediction error signals to be separated. Neural prediction error signals in the striatum peaked in adolescence, whereas neural decision value signals varied depending on how value was modeled. This suggests that heightened dopaminergic prediction error responsivity contributes to adolescent reward seeking. Cohen JR, Asarnow RF, Sabb FW, Bilder RM, Bookheimer SY, Knowlton BJ, Poldrack RA. A unique adolescent response to reward prediction errors. Nat Neurosci. 2010 Jun;13(6): 669-671.
Beta2* Nicotinic Acetylcholine Receptors Modulate Pain Sensitivity in Acutely Abstinent Tobacco Smokers
K. Cosgrove and colleagues at Yale School of Medicine examined the relationship between beta(2)*-nAChR availability and nociception during acute withdrawal in human tobacco smokers using ligand SPECT brain imaging. Nicotine and tobacco smoking administration have demonstrated antinociceptive effects that are mediated by the nicotinic acetylcholine receptor containing the beta2* subunit (beta(2)*-nAChR). Following 7-13 days of tobacco smoking abstinence, increased pain sensitivity, was significantly associated with higher beta(2)*-nAChR availability in the thalamus, parietal, frontal, anterior cingulate, temporal, and occipital cortices. The percent change in pain sensitivity from the first to second cold pressor task was significantly correlated with beta(2)*-nAChR availability in the thalamus, cerebellum, striatum, parietal, anterior cingulate, temporal, and occipital cortices. Similar associations were not observed with pain tolerance. This suggests that beta(2)*-nAChRs play a role in pain sensitivity but not pain tolerance during tobacco smoking withdrawal. Lower beta(2)*- nAChR availability during acute abstinence may be protective for relapse. Cosgrove KP, Esterlis I, McKee S, Bois F, Alagille D, Tamagnan GD, Seibyl JP, Krishnan-Sarin S, Staley JK. Beta2* nicotinic acetylcholine receptors modulate pain sensitivity in acutely abstinent tobacco smokers. Nicotine & Tobacco Res. 2010;12(5): 535-539.
Lesions in the Posterior Ventromedial Prefrontal Cortex Increase the Influence of Recent Events in Decision-Making
A. Bechara and colleagues at University of Southern California assessed brain substrates implicated in two decision making dimensions in a sample of prefrontal cortex patients: (a) the tendency to differently weigh recent compared to past experience; and (b) the tendency to differently weigh gains compared to losses. The results indicated that decisions become influenced by more recent, as opposed to older, events when the damage reaches the posterior sectors of the ventromedial prefrontal cortex (VMPC). Furthermore, the degree of this recency deficit was related to the size of the lesion. These results suggest that the posterior area of the prefrontal cortex directly modulates the capacity to use time-delayed information. Hochman G, Yechiam E, Bechara A. Recency gets larger as lesions move from anterior to posterior locations within the ventromedial prefrontal cortex. Behavioural Brain Res. 2010;213(1): 27-34.
Decreased Cerebral Cortical Serotonin Transporter Binding in Ecstasy Users
S. Kish and colleagues at University of Toronto used PET ligand imaging structural MRI to obtain more precise data regarding changes in serotonin re-uptake sites in recreational users of the drug ecstasy (3,4-methylenedioxymethamphetamine). In particular, the possibility that structural brain differences might account for serotonin transporter binding changes has not been explored. Using PET, results showed that serotonin transporter binding in ecstasy users was significantly decreased throughout all cerebral cortices (range -19 to -46%) and hippocampus (-21%) and related to the extent of drug use (years, maximum dose), but was normal in basal ganglia and midbrain. The serotonin transporter binding loss was not related to structural changes or partial volume effect, use of other stimulant drugs, blood testosterone or estradiol levels, major serotonin transporter gene promoter polymorphisms, gender, psychiatric status, or self-reported hyperthermia or tolerance. The ecstasy group reported subnormal mood and demonstrated generally modest deficits on some tests of attention, executive function and memory, with the latter associated with serotonin transporter decrease. The findings suggest that the typical, low dose (one to two tablets/session) chronic ecstasy-polydrug users might display a highly selective mild to marked loss of serotonin transporter in cerebral cortex/hippocampus, which is not gender-specific or completely accounted for by structural brain changes, recent use of other drugs (as assessed by hair analyses) or other potential confounds that the investigators could address. Kish SJ, Lerch J, Furukawa Y, Tong J, McCluskey T, Wilkins D, Houle S, Meyer J, Mundo E, Wilson AA, Rusjan PM, Saint-Cyr JA, Guttman M, Collins DL, Shapiro C, Warsh JJ, Boileau I. Decreased cerebral cortical serotonin transporter binding in ecstasy users: a positron emission tomography/[(11)C] DASB and structural brain imaging study. Brain. 2010 Jun;133(6): 1779-1797.
Brain CB1 Cannabinoid Receptors in Healthy Subjects and Schizophrenics
D. Wong and colleagues at Johns Hopkins School of Medicine used ligand PET imaging to demonstrate whether schizophrenics exhibit alterations in cannabinoid CB1 receptors using the novel radiotracer, [(11)C]OMAR (JHU75528). CB1 binding (expressed as the distribution volume; V(T)) was highest in the globus pallidus and the cortex in both controls and patients with schizophrenia. Controls showed a correlation with the known distribution of CB1 and decline of [(11)C]OMAR binding with age, most significantly in the globus pallidus. Mean binding in patients with schizophrenia was observed across all regions studied, and this increase was statistically significant in the pons. The results suggest that [(11)C] OMAR can image alterations in human CB1 receptors in normal aging and schizophrenia. In addition, results in subjects with schizophrenia seem to suggest an association of elevated binding specific brain regions and symptoms of the disease. Wong DF, Kuwabara H, Horti AG, Raymont V, Brasic J, Guevara M, Ye W, Dannals RF, Ravert HT, Nandi A, Rahmim A, Ming JE, Grachev I, Roy C, Cascella N. Quantification of cerebral cannabinoid receptors subtype 1 (CB1) in healthy subjects and schizophrenia by the novel PET radioligand [11C]OMAR. NeuroImage. 2010 Oct;52(4): 1505-1513.
Social Cognitive Conflict Resolution: Contributions of Domain-General and Domain-Specific Neural Systems
K. Ochsner and colleagues at Columbia University used fMRI to examine cognitive control mechanisms that allow individuals to resolve conflicts between competing social cues. Healthy subjects were scanned while they drew inferences about the social targets' emotional states based on congruent or incongruent nonverbal and contextual social cues. Conflicts between social cues recruited the anterior cingulate and lateral prefrontal cortex, brain areas associated with domain-general control processes. These data provide evidence about both domain-general and domain-specific mechanisms involved in resolving social cognitive conflicts. Zaki J, Hennigan K, Weber J, Ochsner KN. Social cognitive conflict resolution: contributions of domain-general and domain-specific neural systems. J Neurosci. 2010 Jun;30(25): 8481-8488.
The Interrelationship of Dopamine D2-like Receptor Availability in Striatal and Extrastriatal Brain Regions in Healthy Humans: A Principal Component Analysis of [18F]Fallypride Binding
D. Zald and colleagues at Vanderbilt University used PET ligand imaging to examine individual differences in the levels of dopamine D2-like receptor in one brain region compared to D2 binding in other brain regions. The relationship between D2-like binding potential (D2BP) was examined across striatal and extrastriatal regions in a sample of healthy participants using PET imaging. Individual differences in D2-like D2BP were explained by three distinguishable components. A single component explained almost all of the variance within the striatum, indicating that individual differences in receptor availability vary in a homogenous manner across the caudate, putamen, and ventral striatum. Cortical D2BP was only modestly related to striatal BPND and mostly loaded on a distinct component. After controlling for the general level of cortical D2BP, an inverse relationship emerged between receptor availability in the striatum and the ventral temporal and ventromedial frontal cortices, suggesting possible cross-regulation of D2-like receptors in these regions. The analysis additionally revealed evidence of: (1) a distinct component involving the midbrain and limbic areas; (2) a dissociation between D2BP in the medial and lateral temporal regions; and (3) a dissociation between D2BP in the medial/midline and lateral thalamus. Given that individual differences in D2-like receptor availability reflect several distinct patterns, this study has significant implications for neuropsychiatric models that posit global or regionally specific relationships between dopaminergic tone and behavior. Zald DH, Woodward ND, Cowan RL, Riccardi P, Ansari MS, Baldwin RM, Cowan RL, Smith CE, Hakyemez H, Li R, Kessler RM. The interrelationship of dopamine D2-like receptor availability in striatal and extrastriatal brain regions in healthy humans: A principal component analysis of [18F]fallypride binding. NeuroImage. 2010;51(1): 53-62.
Altered Neural Cholinergic Receptor Systems in Cocaine-Addicted Subjects
B. Adinoff and colleagues at Southwestern Medical Center used SPECT brain imaging to study alterations in cholinergic receptor systems in limbic regions of abstinent cocaine-addicted subjects. Subjects were administered the muscarinic and nicotinic cholinergic agonist physostigmine, the muscarinic antagonist scopolamine, and saline. Both cholinergic probes induced rCBF changes as measured by SPECT in relatively distinct, cholinergic-rich, limbic brain regions. After physostigmine, cocaine-addicted subjects showed altered rCBF, relative to controls, in limbic regions, including the left hippocampus, left amygdala, and right insula. Group differences in the right dorsolateral prefrontal cortex, posterior cingulate, and middle temporal gyrus were also evident. Scopolamine also revealed group differences in the left hippocampus and right insula as well as the posterior cingulate and middle temporal gyrus. The results suggest that cholinergic systems may offer a pharmacologic target for cocaine addiction treatment. Adinoff B, Devous MD, Williams MJ, Best SE, Harris TS, Minhajuddin A, Zielinski T, Cullum M. Altered neural cholinergic receptor systems in cocaine-addicted subjects. Neuropsychopharmacology. 2010 Jun;35(7): 1485-1499.
Component Neural Systems for the Creation of Emotional Memories During Free Viewing of a Complex, Real-World Event
LaBar and colleagues at Duke University used fMRI To investigate the neural systems that contribute to the formation of complex, self-relevant emotional memories. Dedicated fans of rival college basketball teams watched a competitive game while undergoing fMRI scanning. During a subsequent recognition memory task, participants were shown video clips depicting plays of the game, stemming either from previously-viewed game segments (targets) or from non-viewed portions of the same game (foils). After an old-new judgment, participants provided emotional valence and intensity ratings of the clips. The fMRI signal acquired during free viewing of the game was decomposed into spatially independent components. Brain systems that were correlated with emotional intensity ratings included regions implicated in memory and emotional functions, such as the hippocampus and amygdala, as well as a midline fronto-cingulo-parietal network implicated in social cognition and self-relevant processing, including temporal lobe regions. These findings contribute to our understanding of how emotional factors impact distributed neural systems to successfully encode dynamic, personally-relevant event sequences. These findings provide a foundation for understanding the strong emotional memories related to drug use. Botzung A, Labar KS, Kragel P, Miles A, Rubin DC. Component neural systems for the creation of emotional memories during free viewing of a complex, real-world event. Front Hum Neurosci 2010;4: 34.
Cognitive Mechanisms Underlying Risky Decision-Making in Chronic Cannabis Users
Porrino and colleagues at Wake Forest University in collaboration with J. Busmeyer and colleagues at Indiana University used a computational model to determine the cognitive processes underlying poor performance of cannabis users on a test of decision-making, the Iowa Gambling Task (IGT). Two computational models of IGT performance were compared; the Expectancy Valence Learning model (EVL) and the Prospect Valence Learning model (PVL). The results indicated that cannabis abusers tended to be under-influenced by loss magnitude, treating each loss as a constant and minor negative outcome regardless of the size of the loss. In addition, they were more influenced by gains, and made decisions that were less consistent with their expectancies relative to non-using controls. Fridberg DJ, Queller S, Ahn W, Kim W, Bishara AJ, Busemeyer JR, Porrino L, Stout JC. Cognitive mechanisms underlying risky decision-making in chronic cannabis users. J Math Psychol. 2010;54(1): 28-38.
Effect of Methamphetamine Dependence on Everyday Functional Ability
B. Henry and colleagues at the University of California, San Diego examined the effect of the Methamphetamine (METH) on the ability to carry out everyday activities. Chronic METH exposure has been associated with neurotoxic effects, profound neuropsychological deficits, and impaired quality of life. The effect of METH dependence on everyday functioning was assessed using a performance-based measure designed to evaluate real-life skills. METH-dependent participants exhibited significant impairment on several functions, including comprehension, finance, transportation, communication, and medication management compared to drug-free comparison subjects. METH dependence may be associated with decreased everyday functioning ability potentially mediated by frontal cortex dysfunction or the emergence of psychopathology related to chronic drug use. Henry BL, Minassian A, Perry W. Effect of methamphetamine dependence on everyday functional ability. Addict Behav. 2010;35(6): 593-598.
Impaired Insight in Cocaine Addiction: Laboratory Evidence and Effects on Cocaine-Seeking Behavior
R. Goldstein and colleagues at Brookhaven National Laboratories sought to empirically demonstrate whether drug abusers exhibit impaired insight into behavior. Such an insight deficit has been suggested, but never directly tested, in drug addiction. Sixteen cocaine addicted individuals testing positive for cocaine in urine, 26 cocaine addicted individuals testing negative for cocaine in urine, and 23 healthy controls completed a probabilistic choice task that assessed objective preference for viewing four types of pictures (pleasant, unpleasant, neutral and cocaine). Results showed that the urine positive cocaine subjects exhibited impaired insight into their own choice behavior compared with healthy controls; this same study group also selected the most cocaine pictures (and fewest pleasant pictures) for viewing. Importantly, however, it was the urine negative cocaine subjects whose behavior was most influenced by insight, such that impaired insight in this subgroup only was associated with higher cocaine-related choice on the task and more severe actual cocaine use. These findings suggest that interventions to enhance insight may decrease drug-seeking behavior, especially in urine negative cocaine subjects, potentially improving their longer-term clinical outcomes. Moeller SJ, Maloney T, Parvaz MA, Alia-Klein N, Woicik PA, Telang F, Wang GJ, Volkow ND, Goldstein RZ. Impaired insight in cocaine addiction: laboratory evidence and effects on cocaine-seeking behaviour. Brain. 2010;133(5): 1484-1493.
BOLD Responses to Negative Reward Prediction Errors in Human Habenula
R. Salas and PR Montague and colleagues at Baylor School of Medicine used fMRI to determine which brain regions carry information about negative reward prediction errors in humans. Positive reward prediction error (an event that is better than expected) is a key element in reinforced learning that is signaled by dopamine cells, but little is known about brain systems that encode negative reward prediction errors (worse than expected events). Animal studies have indicated that the habenula, an integrative region in the dorsal midbrain, encodes negative reward-related events such as negative reward prediction error signals. In this study, a new method is described to functionally locate and study the habenula in humans using fMRI, based on the expected reward-dependent response phenomenology of habenula and striatum. Conclusive evidence is provided for activation in human habenula to negative reward prediction errors. These data suggest that dysfunctions of habenula may contribute to insensitivity to negative consequences of substance abuse. Salas R, Baldwin P, de Biasi M, Montague PR. BOLD Responses to negative reward prediction errors in human habenula. Front Hum Neurosci. 2010;4: 36.
Overlapping Neural Systems Mediating Extinction, Reversal and Regulation of Fear
M. Delgado and D. Schiller at Rutgers University used fMRI to determine what brain systems regulate the extinction of learned fear. Learned fear is a process allowing quick detection of associations between cues in the environment and prediction of imminent threat. Adaptive function in a changing environment, however, requires organisms to quickly update this learning and have the ability to hinder fear responses when predictions are no longer correct. This study focused on three strategies that can modify conditioned fear, namely extinction, reversal and regulation of fear, and reviews their underlying neural mechanisms. By directly comparing neuroimaging data from separate studies using the three strategies that can modify conditioned fear overlapping brain structures that comprise a general circuitry in the human brain are highlighted. This circuitry potentially enables the flexible control of fear, regardless of the particular task demands. This study raises the question of whether similar circuitry is engaged during extinction and/or regulation of drug-related learned responses. Schiller D, Delgado MR. Overlapping neural systems mediating extinction, reversal and regulation of fear. Trends Cog Sci. 2010;14(6): 268-276.
Striatal and Extrastriatal Dopamine Release Measured with PET and [F-18] Fallypride
A. Abi-Dargham and colleagues at Columbia University used PET ligand brain imaging to determine how dopamine release can differ across brain regions. [F-18] fallypride is a PET radioligand that allows measurement of the effects of amphetamine on D2/D3 ligand binding in striatum and extrastriatal brain regions such as the cerebral cortex. In healthy volunteer subjects, it was found that there was a robust release of dopamine following amphetamine administration in the ventral striatum, globus pallidus, and posterior putamen, with other striatal subregions exhibiting slightly higher variability. Dopamine release was not reliably detected in cortical regions. The results demonstrate that [F-18] fallypride is a suitable ligand for measuring amphetamine effect in striatum and limbic regions, but it is not suitable for measuring the effect in cortical regions and may not provide the most powerful way to measure the effect in striatum. Slifstein M, Kegeles LS, Xu X, Thompson JL, Urban N, Castrillon J, Hackett E, Bae S, Laruelle M, Abi-Dargham A. Striatal and extrastriatal dopamine release measured with PET and [F-18] fallypride. Synapse. 2010;64(5): 350-362.
Disrupted Functional Connectivity in Dopaminergic Midbrain in Cocaine Abusers
D. Tomasi and colleagues at Brookhaven National Laboratories used functional connectivity analysis of BOLD MRI signals to determine how chronic cocaine use affects system-wide brain function. Cocaine addicted subjects performed a sustained attention task during BOLD MRI scans. Cocaine abusers compared to controls, had lower positive functional connectivity of the midbrain region that contains dopamine neurons with other brain regions including the thalamus, cerebellum, and rostral cingulate, and this was associated with decreased activation in thalamus and cerebellum and enhanced deactivation in rostral cingulate. These findings suggest that decreased functional connectivity of the midbrain interferes with the activation and deactivation signals associated with sustained attention in cocaine addicts. Tomasi D, Volkow ND, Wang R, Carrillo JH, Maloney T, Alia-Klein N, Woicik PA, Telang F, Goldstein RZ. Disrupted functional connectivity with dopaminergic midbrain in cocaine abusers. PLoS ONE. 2010;5(5): e10815.
Methylphenidate Attenuates Limbic Brain Inhibition after Cocaine-Cues Exposure in Cocaine Abusers
R. Goldstein and colleagues at Brookhaven National Laboratories used glucose metabolism PET brain imaging to determine the effects of increased tonic dopamine levels (using oral methylphenidate) on brain activation induced by cocaine-cues in cocaine abusers. Methylphenidate administration did not increase self-reported drug craving during a cocaine-cues video any more than placebo; craving increased 68% during the placebo session and 64% after methylphenidate. In contrast, brain activation during viewing of the cocaine video differed between the placebo and methylphenidate sessions. During the placebo session, cocaine-cues decreased glucose metabolism in left limbic regions (insula, orbitofrontal, accumbens) and right parahippocampus, whereas during the methylphenidate session the only reliable changes were decreases in auditory and visual regions, which also occurred with placebo. Decreases in metabolism in these regions were not associated with craving. Significant correlations with craving were found in anterior orbitofrontal cortex (p<0.005), amygdala, striatum and middle insula. These results suggest that methylphenidate's attenuation of brain reactivity to cocaine-cues is distinct from that involved in craving. Volkow ND, Wang G, Tomasi D, Telang F, Fowler JS, Pradhan K, Jayne M, Logan J, Goldstein RZ, Alia-Klein N, Wong C. Methylphenidate attenuates limbic brain inhibition after cocaine-cues exposure in cocaine abusers. PLoS ONE. 2010;5(7): e11509.
Ventromedial Prefrontal Cortex Damage Impairs Judgment of Harmful Intent
A. Bechara and colleagues at the University of Southern California investigated the effects of damage to the orbitofrontal cortex on human's ability to infer intentions. People will often forgive harm if it is unintentional or accidental and will condemn failed attempts to harm. Prior work demonstrated that patients with damage to the ventromedial prefrontal cortex (VMPC) deliver abnormal judgments in response to moral dilemmas and that these patients are especially impaired in triggering emotional responses to inferred or abstract events (e.g., intentions), as opposed to real or actual outcomes. In this study, it was confirmed that VMPC patients judged attempted harms, including attempted murder, as more morally permissible relative to controls. These results highlight the critical role of the VMPC in processing harmful intent for moral judgment. Young L, Bechara A, Tranel D, Damasio H, Hauser M, Damasio A. Damage to ventromedial prefrontal cortex impairs judgment of harmful intent. Neuron. 2010;65(6): 845-851.
Prefrontal-Striatal Pathway Underlies Cognitive Regulation of Craving
K. Ochnsner and colleagues at Columbia University used fMRI to examine neural activity in cigarette smokers related to cognitive strategies to regulate craving. Cognitive down-regulation of craving was associated with (i) activity in regions previously associated with regulating emotion in particular and cognitive control in general, including dorsomedial, dorsolateral, and ventrolateral prefrontal cortices, and (ii) decreased activity in regions previously associated with craving, including the ventral striatum, subgenual cingulate, amygdala, and ventral tegmental area. Decreases in craving correlated with decreases in ventral striatum activity and increases in dorsolateral prefrontal cortex activity, with ventral striatal activity fully mediating the relationship between lateral prefrontal cortex and reported craving. These results provide insight into the mechanisms that enable cognitive strategies to effectively regulate craving, suggesting that it involves neural dynamics parallel to those involved in regulating other emotions. In so doing, this study provides a methodological tool and conceptual foundation for studying this ability across substance using populations and developing more effective treatments for substance use disorders. Kober H, Mende-Siedlecki P, Kross EF, Weber J, Mischel W, Hart CL, Ochsner KN. Prefrontal-striatal pathway underlies cognitive regulation of craving. Proc Natl Acad Sci U S A 2010 Aug; Available from: http://www.ncbi.nlm.nih.gov/pubmed/20679212