Research Findings - Clinical Neuroscience Research
Elevated Cortisol and Learning and Memory Deficits in Cocaine Dependent Individuals
Sinha and colleagues assessed the level of stress in treatment-seeking cocaine dependent individuals and its effect on learning and memory and subsequent relapse. Results demonstrated increased levels of subjective stress, higher morning cortisol levels and selective learning-related deficits compared to healthy controls. Learning deficits included poor immediate verbal recall and recognition as well as selective working memory decrements. Poor verbal learning was associated with more extensive cocaine use (relapse) following discharge from inpatient treatment. The observation that increased perceived stress was associated with learning deficits supports the hypothesis that exposure to increasing levels of glucocorticoids can mediate degeneration of the hippocampus. Of interest, higher cortisol levels in healthy controls was associated with improved recall which seems contradictory but is consistent with the theory that circulating levels of cortisol affect memory in an inverted U-shaped manner. This is the first study to report that a state of high distress may contribute to poor verbal learning and memory in cocaine dependent individuals which, in turn, points to poor treatment outcomes. Fox HC, Jackson ED, Sinha R. Elevated cortisol and learning and memory deficits in cocaine dependent individuals: Relationship to relapse outcomes. Psychoneuroendocrinology. 2009. [Epub ahead of print].
Sleep and Sleep-Dependent Learning Deteriorated in Cocaine Abstinent Men but Not Women
Treatment-seeking cocaine-dependent men and women were assessed for sleep quality and sleep-dependent learning while in an inpatient unit for three weeks. Sleep efficiency (e.g., time asleep while in bed) and total sleep steadily declined in men when assessed approximately two and three weeks from the onset of abstinence; for women there was practically no change. Coincidentally overnight improvement on a motor sequence task deteriorated in men but not women. These findings are the first indication of a sex difference in sleep in persons with substance dependence of any kind. While all women entered the study during their menstrual or early follicular period, hormones were not measured. There is clear indication for follow-up studies addressing the apparent sex differences in cocaine-abstinence effects as these may have important consequences for successful treatment. Morgan PT, Paliwal P, Malison RT, Sinha R. Sex differences in sleep and sleep-dependent learning in abstinent cocaine users. Pharmacol Biochem Behav. 2009. [Epub ahead of print].
Sleep Deprivation Differentially Impairs Cognitive Performance in Abstinent Ecstasy Users
McCann and colleagues at Johns Hopkins School of Medicine examined whether the cognitive deficits reported in MDMA users may be due, in part, to sleep disturbances. In this study, abstinent MDMA (Ecstasy) users were sleep deprived for 40 hours and tested on a computerized battery of cognitive tests. The MDMA users performed less accurately on a task of working memory and more impulsively on several tests and they became increasingly impulsive (and less accurate) on tests of working and short-term memory following deprivation. These findings are the first to demonstrate that memory problems in MDMA users may be related, in part, to sleep disturbance and that such deficits may be exacerbated in situations of sleep deprivation. McCann UD, Wilson MJ, Sgambati FP, Ricaurte GA. Sleep deprivation differentially impairs cognitive performance in abstinent methylenedioxymethamphetamine ("Ecstasy") users. J Neurosci. 2009 Nov 4;29(44):14050-14056.
Increased Sleep Apnea in Young Abstinent Recreational Ecstasy Consumers
McCann and colleagues at Johns Hopkins School of Medicine studied sleep characteristics in two-week abstinent MDMA (Ecstasy) users in a controlled inpatient research setting. There were significantly increased rates of obstructive sleep apnea and hypopnea. The odds ratio of the increase was 8.5, even greater than that associated with obesity. In addition, apnea rates were significantly related to lifetime MDMA exposure. These results point to a greater risk of obstructive sleep apnea in these individuals which suggests a role of brain serotonin neuronal dysfunction as a consequence of MDMA use. McCann UD, Sgambati FP, Schwartz AR, Ricaurte GA. Increased sleep apnea in young abstinent recreational Ecstasy consumers, Neurology. 2009;73(23):2011-2017.
Dopaminergic Response to Drug Words in Cocaine Addiction
Goldstein and colleagues at Brookhaven National Laboratory demonstrated that words related to drug addiction stimulated the mesencephalic regions (as assessed by BOLD fMRI) possibly related to dopaminergic and/or glutamatergic mechanisms in individuals with cocaine use disorders. It has been known for some time that visual and environmental cues stimulate drug craving; this is the first study that demonstrates that cue words alone may have a similar effect. It was also demonstrated that this response correlated with a verbal fluency test, suggesting its use as a biomarker. Goldstein RZ, Tomasi D, Alia-Klein N, Carrillo JH, Maloney T, Woicik PA, Wang R, Telang F, Volkow ND. Dopaminergic response to drug words in cocaine addiction. J Neurosci. 2009 May 6;29(18):6001-6006.
Genetic Variants are Associated with Methadone Doses Required for Effective Treatment of Heroin Dependence
M.J. Kreek and associates divided a sample of methadone-maintained heroin dependent individuals into two groups depending on the effective stabilizing dosage of methadone needed: a"high" dosage group >150 mg/day and a "low" dosage group ≤ 150 mg. Selecting gene variants of the P-glycoprotein encoded by the ABCB1 (MDR1) gene, it was determined that individuals bearing the 3-locus genotype pattern TT-TT-TT have an approximately 5-fold chance of requiring the "high" dose, while individuals heterozygous for these three SNPs have an approximately 3-fold chance of stabilizing at the "low" dose. These data suggest that specific ABCB1 variants may have clinical relevance by influencing the methadone dose required to prevent withdrawal symptoms and relapse. Levran O, O'Hara K, Peles E, Li D, Barral S, Ray B, Borg L, Ott J, Adelson, M, Kreek MJ. ABCB1 (MDR1) genetic variants are associated with methadone doses required for effective treatment of heroin dependence. Hum Mol Genet 2008 April 17;17(14):2219-2227.
Cue Elicited Craving in Marijuana Users Increases BOLD Activations in Several Structures of the Reward Pathway
F.M. Filbey and her colleagues recruited regular marijuana users and, following 3-day abstinence, had them tactually handle marijuana paraphernalia while being scanned. Activations relative to neutral cues were found in the ventral tegmental area, dorsal anterior cingulate cortex, cerebellum, thalamus, pre- and post-central gyri, inferior frontal gyrus/insula, thalamus, amygdala, fusiform gyrus, pre- and post- central gyri, inferior parietal lobe, and superior temporal gyrus. The activated areas were positively correlated with total marijuana problems scale score in both the orbitofrontal cortex and the nucleus accumbens. However, the activation was not correlated with subjective urges. The results demonstrate that cue-induced craving for marijuana elicits the same brain activation as for other drugs of abuse. Filbey FM, Schacht JP, Myers US, Chavez RS, Hutchison, KE. Marijuana craving in the brain. PNAS 2009 August 4;106(31):13016-13021.
Sex Differences in Autonomic and HPA Response to Stress and Drug Cues in Alcohol-Dependent Patients with Cocaine Abuse
R. Sinha and M. J. Kreek and associates assessed physiological measures in alcohol and cocaine co-dependents and healthy controls during stress and drug-associated (compared to neutral) imagery. Substance abusing males showed increased ACTH and epinephrine basal tone but not increase in ACTH and cortisol levels following stress and alcohol cue imagery. Females demonstrated a typically increased stress response in both measures. Also, substance abusing males showed no increase in cardiovascular response to either stress or cue, and no increase in catecholamine response to cue. By contrast, females showed an enhanced ACTH and cortisol response to stress and cue. The results demonstrated that while males showed a generalized suppression of the hypothalamic-pituitary-adrenal and sympathetic adrenal medullary stress systems and cardiovascular markers following stress and cue, women demonstrated a selective sympatho-adrenal suppression to stress only and an enhanced HPA response to both stress and cue. These sex differences may affect both relapse vulnerability and effective treatment strategy and outcome. Fox HC, Hong K-I A, Siedlarz KM, Bergquist K, Anderson G, Kreek MJ, Sinha R. Sex-specific dissociations in autonomic and HPA responses to stress and cues in alcohol-dependent patients with cocaine abuse. Alcohol & Alcoholism. 2009 Sep 30. [Epub ahead of print].
A Functional Haplotype Implicated in Vulnerability to Develop Cocaine Dependence is Associated with Reduced PDYN Expression in Human Brain
Kreek and associates tested six SNPs of the prodynorphin (PDYN) gene for association with cocaine dependence and cocaine/alcohol co-dependence. There were point-wise significant associations of three SNPs which were in high linkage disequilibrium comprising a haplotype block. One haplotype was significantly associated. Using one SNP, allele-specific gene expression of PDYN was assessed in post-mortem brains. One variant was associated with significantly lower expression in the caudate and nucleus accumbens. This study provides evidence that a particular haplotype of the PDYN gene (implicated in cocaine addiction vulnerability) is related to lower mRNA expression in the 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. Neuropsychopharm. 2009;34:1185-1197.
Reduced Prefrontal Cortical Gray Matter Volume in Young Adults Exposed to Harsh Corporal Punishment
M.H. Teicher and colleagues assessed brain volume in young adults who reported having undergone harsh corporal punishment—defined as punishment in childhood by paddling with an object (as opposed to open hand) several times a year for at least three years. Results demonstrated reduced gray matter volume in the right medial frontal gyrus by 19.1%, by 14.5% in the left medial frontal gyrus, and by 16.9% in the right anterior cingulate gyrus. Furthermore, there were significant correlations between brain volume in these regions and performance IQ. It was concluded that harsh corporal punishment may have detrimental effects on trajectories of brain development in areas that are related to vulnerabilities to drug abuse. Tomoda A, Suzuki H, Rabi K, Sheu Y-S, Polcari A, Teicher MH. Reduced prefrontal cortical gray matter volume in young adults exposed to harsh corporal punishment. NeuroImage. 2009 Aug.;47 Suppl2:T66-71.
History of Childhood Abuse is Associated with Cerebellar Size and Alcohol and Drug Use in Young Adults
C.M. Anderson, M.H. Teicher and colleagues collected histories of physical abuse (including harsh corporal punishment) and emotional abuse during childhood plus drug and alcohol use in otherwise healthy young adults. These data were associated with MRI scans with focus on the lobules of the cerebellar vermis. The subjects were divided into three categories depending on the size of the lingula (which may be lobule I [thin] or lobule I+II [thick]). Thicker lobule I of the cerebellar vermis was associated with greater consumption of drugs and hard liquor, particularly in physically maltreated subjects. Physically maltreated subjects consumed more than 2.5 times more alcohol and used drugs 6 times more than comparison groups of individuals who were neither physically nor emotionally maltreated or even those who did experience emotional maltreatment (alone without physical maltreatment). These results indicate that physical maltreatment impacts cerebellar morphology in association with drug and alcohol abuse. Anderson CM, Rabi K, Lukas SE, Teicher MH. Cerebellar lingual size and experiential risk factors associated with high levels of alcohol and drug use in young adults. Cerebellum. 2009 Oct 28. [Epub ahead of print].
Effect of Daily Caffeine Use on Cerebral Blood Flow
Addicott and colleagues, at the Wake Forest University School of Medicine, conducted this study to investigate the effects of caffeine on cerebral blood flow (CBF) as a function of increasing levels of chronic caffeine use. Caffeine is a commonly used neurostimulant that also produces cerebral vasoconstriction by antagonizing adenosine receptors. Chronic caffeine use results in an adaptation of the vascular adenosine receptor system presumably to compensate for the vasoconstrictive effects of caffeine. Low (45 mg/day), moderate (405 mg/day), and high (950 mg/day) caffeine users underwent quantitative perfusion magnetic resonance imaging on four separate occasions: twice in a caffeine abstinent state (abstained state) and twice in a caffeinated state following their normal caffeine use (native state). In each state, there were two drug conditions: participants received either caffeine (250 mg) or placebo. Gray matter CBF was tested with repeated-measures analysis of variance using caffeine use as a between-subjects factor, and correlational analyses were conducted between CBF and caffeine use. Caffeine reduced CBF by an average of 27% across both caffeine states. In the abstained placebo condition, moderate and high users had similarly greater CBF than low users; but in the native placebo condition, the high users had a trend towards less CBF than the low and moderate users. These results suggest that the cerebrovascular adenosine system has a limited ability to compensate for high amounts of daily caffeine use. Addicott MA, Yang LL, Peiffer AM, et al. The effect of daily caffeine use on cerebral blood flow: How much caffeine can we tolerate? Hum Brain Mapp. 2009 Oct;30(10):3102-3114.
Effects of Treatment for Tobacco Dependence on Resting Cerebral Glucose Metabolism
Brody and colleagues at UCLA investigated whether two commonly used treatments for tobacco dependence, bupropion HCl and practical group counseling (PGC), have measurable effects on regional cerebral brain metabolism. 54 tobacco-dependent cigarette smokers underwent resting (18)F-fluorodeoxyglucose-positron emission tomography (FDG-PET) scanning before and after 8 weeks of treatment with bupropion HCl, PGC, or pill placebo. Subjects who received one of the two active treatments (bupropion HCl and PGC) had reduced metabolism in the posterior cingulate gyrus relative to subjects who received placebo. PGC had a greater effect than bupropion HCl on glucose metabolism in this region. There were positive correlations between daily cigarette use and glucose metabolism in the left occipital gyrus and parietal-temporal junction, but no significant negative correlations were found between daily cigarette use and glucose metabolism. These findings suggest that bupropion HCl and PGC reduce neural activity much as the performance of a goal-oriented task does in the default mode network of the brain, including the posterior cingulate gyrus. Thus, this study suggests that active treatments for tobacco dependence increase the brain's ability to engage in a more goal-oriented state. Costello MR, Mandelkern MA, Shoptaw S, et al. Effects of treatment for tobacco dependence on resting cerebral glucose metabolism. Neuropsychopharmacology, 2009 October. [Epub ahead of print].
Rapid Cognitive Screening of Patients with Substance Use Disorders
To date, there has not been a time-efficient and resource-conscious way to identify cognitive impairment in patients with substance use disorders (SUDs). In this study, Marc Copersino and colleagues at Harvard Medical School assessed the validity, accuracy, and clinical utility of a brief (10-min) screening instrument, the Montreal Cognitive Assessment (MoCA), in identifying cognitive impairment among patients with SUDs. The Neuropsychological Assessment Battery-Screening Module, a 45-min battery with known sensitivity to the mild to moderate deficits observed in patients with SUDs, was used as the reference criterion for determining agreement, rates of correct and incorrect decision classifications, and criterion-related validity for the MoCA. Classification accuracy of the MoCA, based on receiver operating characteristic (ROC) analysis, was strong, with an area under the ROC curve of 0.86, 95% confidence interval [0.75, 0.97]. The MoCA also showed acceptable sensitivity (83.3%) and specificity (72.9%) for the identification of cognitive impairment. Using a cutoff of 25 on the MoCA, the overall agreement was 75.0%; chance-corrected agreement (kappa) was 41.9%. These findings indicate that the MoCA provides a time-efficient and resource-conscious way to identify patients with SUDs and neuropsychological impairment, thus addressing a critical need in the addiction treatment research community. Copersino ML, Fals-Stewart W, Fitzmaurice G, Schretlen DJ, Sokoloff J, Weiss RD. Rapid cognitive screening of patients with substance use disorders. Exp Clin Psychopharmacol. 2009 Oct;17(5):337-344.
GABAA-Benzodiazepine Receptor Availability in Smokers and Nonsmokers: Relationship to Subsyndromal Anxiety and Depression
Many smokers experience subsyndromal anxiety symptoms while smoking and during acute abstinence, which may contribute to relapse. Cosgrove and colleagues at Yale University hypothesized that cortical gamma aminobutyric acid(A)-benzodiazepine receptor (GABA(A)-BZR) availability in smokers and nonsmokers might be related to the expression of subsyndromal anxiety, depressive, and pain symptoms. Cortical GABA(A)-BZRs were imaged in 15 smokers (8 men and 7 women), and 15 healthy age and sex-matched nonsmokers, and 4 abstinent tobacco smokers (3 men; 1 woman) using [(123)I]iomazenil and single photon emission computed tomography (SPECT). The relationship between cortical GABA(A)-BZR availability, smoking status, and subsyndromal depression and anxiety symptoms, as well as pain tolerance and sensitivity, were evaluated. There were no statistically significant differences in overall GABA(A)-BZR availability between smokers and nonsmokers or between active and abstinent smokers; however, cortical GABA(A)-BZR availability negatively correlated with subsyndromal state anxiety symptoms in nonsmokers but not in smokers. In nonsmokers, the correlation was seen across many brain areas with state anxiety [parietal, frontal, anterior cingulate, temporal, occipital cortices, and cerebellum], trait anxiety [parietal, frontal, and occipital cortices] and depressive symptoms [parietal, frontal, anterior cingulate, and temporal cortices]. The finding that a similar relationship between GABA(A)-BZR availability and anxiety symptoms was not observed in smokers suggests that there is a difference in GABA(A)-BZR function, but not number, in smokers. Thus, while subsyndromal anxiety and depressive symptoms in nonsmokers may be determined in part by GABA(A)-BZR availability, smoking disrupts this relationship. Aberrant regulation of GABA(A)-BZR function in vulnerable smokers may explain why some smokers experience subsyndromal anxiety and depression. Esterlis I, Cosgrove KP, Batis JC, et al. GABAA-benzodiazepine receptor availability in smokers and nonsmokers: relationship to subsyndromal anxiety and depression. Synapse. 2009 Dec;63(12):1089-1099.
Brain fMRI Reactivity to Smoking-Related Images Before and During Extended Smoking Abstinence
Reactivity to smoking-related cues may play a role in the maintenance of smoking behavior and may change depending on smoking status. Whether smoking cue-related functional MRI (fMRI) reactivity differs between active smoking and extended smoking abstinence states currently is unknown. Jane and colleagues at the Brain Imaging Center of McLean Hospital used fMRI to measure brain reactivity in response to smoking-related versus neutral images in 13 tobacco-dependent subjects before a smoking cessation attempt and again during extended smoking abstinence (52 +/- 11 days) aided by nicotine replacement therapy. Prequit smoking cue induced fMRI activity patterns paralleled those reported in prior smoking cue reactivity fMRI studies. Greater fMRI activity was detected during extended smoking abstinence than during the prequit assessment subcortically in the caudate nucleus and cortically in prefrontal (BA 6, 9, 44, 46), primary somatosensory (BA 1, 2, 3), temporal (BA 22, 41, 42), parietal (BA 7, 40) anterior cingulate (BA 24, 32), and posterior cingulate (BA 31) cortex. These data suggest that during extended smoking abstinence, fMRI reactivity to smoking versus neutral stimuli persists in brain areas involved in attention, somatosensory processing, motor planning, and conditioned cue responding. In some brain regions, fMRI smoking cue reactivity is increased during extended smoking abstinence in comparison to the prequit state, which may contribute to persisting relapse vulnerability. Janes AC, Frederick B, Richardt S, et al. Brain fMRI reactivity to smoking-related images before and during extended smoking abstinence. Exp Clin Psychopharmacol. 2009 Dec;17(6):365-373.
Effects of Sleep Deprivation on Sleep Homeostasis and Restoration During Methadone-Maintenance: A ()P MRS Brain Imaging Study
Insomnia afflicts many individuals, but particularly those in chronic methadone treatment. Studies examining sleep deprivation (SD) have begun to identify sleep restoration processes involving brain bioenergetics. The technique ()P magnetic resonance spectroscopy (MRS) can measure brain changes in the high-energy phosphates: alpha-, beta-, and gamma-nucleoside triphosphate (NTP). In the present study conducted by Lukas and colleagues at McLean Hospital, 21 methadone-maintained (MM) and 16 control participants underwent baseline (BL), SD (40 wakeful hours), recovery1 (RE1), and recovery2 (RE2) study nights. Polysomnographic sleep was recorded each night and ()P MRS brain scanning conducted each morning using a 4T MR scanner (dual-tuned proton/phosphorus head-coil). Increases in total sleep time (TST) and sleep efficiency index (SEI) commonly associated with RE sleep were not apparent in MM participants. Analysis of methadone treatment duration revealed that the lack of RE sleep increases in TST and SEI was primarily exhibited by short-term MM participants (methadone <12 months), while RE sleep in long-term MM (methadone >12 months) participants was more comparable to control participants. Slow wave sleep increased during RE1, but there was no difference between MM and control participants. Spectral power analysis revealed that compared to control participants; MM participants had greater delta, theta, and alpha spectral power during BL and RE sleep. ()P MRS revealed that elevations in brain beta-NTP (a direct measure of ATP) following RE sleep were greater in MM compared to control participants. Results suggest that differences in sleep and brain chemistry during RE in MM participants may be reflective of a disruption in homeostatic sleep function. Trksak GH, Jensen JE, Plante DT, et al. Effects of sleep deprivation on sleep homeostasis and restoration during methadone-maintenance: A ()P MRS brain imaging study. Drug Alcohol Depend. 2009 Sep. [Epub ahead of print].
Transcutaneous Electric Acupoint Stimulation as Adjunctive Treatment for Opioid Detoxification
Lukas and colleagues at McLean Hospital tested the effectiveness of transcutaneous electric acupoint stimulation (TEAS) as an adjunctive treatment for inpatients receiving opioid detoxification with buprenorphine-naloxone at a private psychiatric hospital. Participants (N = 48) were randomly assigned to active or sham TEAS and received three 30-minute treatments daily for 3 to 4 days. In active TEAS, current was set to maximal tolerable intensity (8-15 mA); in sham TEAS, it was set to 1 mA. By 2 weeks postdischarge, participants in active TEAS were less likely to have used any drugs (35% vs. 77%, p < .05). They also reported greater improvements in pain interference (F = 4.52, p < .05) and physical health (F = 4.84, p < .01) over time. TEAS is an acceptable, inexpensive adjunctive treatment that is feasible to implement on an inpatient basis and may be a beneficial adjunct to pharmacological treatments for opioid detoxification. Meade CS, Lukas SE, McDonald LJ, Fitzmaurice GM, Eldridge JA, Merrill N, Weiss RD. A randomized trial of transcutaneous electric acupoint stimulation as adjunctive treatment for opioid detoxification. J Subst Abuse Treat. 2010 Jan;38(1):12-21.
Sensory Gating Impairments in Heavy Cannabis Users are Associated with Altered Neural Oscillations
Central cannabinoid receptors mediate neural oscillations and are localized to networks implicated in auditory P50 sensory gating, including the hippocampus and neocortex. Skosnik and colleagues at Indiana University conducted this study to examine whether neural oscillations evoked by the paired clicks (S1, S2) are associated with abnormal P50 gating reported in cannabis users. Seventeen heavy cannabis users and 16 cannabis naēve controls participated. Analyses included P50 amplitudes, and time-frequency analyses (event-related spectral perturbations, ERSPs; intertrial coherence, ITC). Consistent with prior studies, cannabis users exhibited reduced P50 gating. The ERSP analysis yielded attenuated high frequency activity in the beta range (13-29 Hz) post-S1 and in the gamma range (30-50 Hz) post-S2 in the cannabis group, compared with the control group. Greater levels of cannabis use were positively associated with high P50 ratios and negatively with post-S2 ERSP gamma power. Findings suggest that heavy cannabis use is associated with aberrant beta and gamma activity in the dual-click procedure, which corroborates recent work demonstrating disruption of beta/gamma by cannabinoid receptor (CB1) agonists in a rat analogue of this task and highlights the translational potential of the dual-click procedure. Edwards CR, Skosnik PD, Steinmetz AB, O'Donnell BF, Hetrick WP. Sensory gating impairments in heavy cannabis users are associated with altered neural oscillations. Behav Neurosci. 2009 Aug;123(4):894-904. Erratum in: Behav Neurosci. 2009 Oct;123(5):1065.
A Single Amino Acid Difference in Human APOBEC3H Variants Determines HIV-1 Vif Sensitivity
Several variants of APOBEC3H (A3H) variants have been identified in different human populations. Certain variants of this protein are particularly potent inhibitors of retrotransposons and retroviruses, including HIV-1. It is not clear whether HIV-1 Vif can recognize and suppress the antiviral activity of A3H variants, as it does to other APOBEC3 proteins. Dr. Yu's study found that A3H_Haplotype II (HapII), a potent inhibitor of HIV-1 in the absence of Vif, can indeed be degraded by HIV-1 Vif. Vif-induced degradation of A3H_HapII was blocked by the proteasome inhibitor MG132 and a Cullin5 (Cul5) dominant negative mutant. In addition, Vif mutants that were incapable of assembly with the host E3 ligase complex factors Cul5, ElonginB, and ElonginC were also defective for A3H_HapII suppression. Although Vif hijacks the same E3 ligase to degrade A3H_HapII as it does to inactivate APOBEC3G (A3G) and APOBEC3F (A3F), more Vif motifs were involved in A3H_HapII inactivation than for either A3G or A3F suppression. In contrast to A3H_HapII, A3H_Haplotype I (HapI), which differs in only 3 amino acids from A3H_HapII, was resistant to HIV-1 Vif-mediated degradation. Residue 121 was found to be critical for determining A3H sensitivity and binding to HIV-1 Vif. Zhen A, Wang T, Zhao K, Xiong Y, Yu XF. A single amino acid difference in human APOBEC3H variants determines HIV-1 Vif sensitivity. J Virol. 2009 Nov 25. [Epub ahead of print].
The Loss of APOBEC3B May Increase Host Susceptibility to HIV-1 Acquisition and Progression to AIDS
The human APOBEC3 family of cytidine deaminases provides intrinsic immunity to retroviral infection. A naturally occurring 29.5-kb deletion removes the entire APOBEC3B gene. Dr. Yu examined the impact of the APOBEC3B gene deletion in over 4000 individuals from 5 human immunodeficiency virus type 1 (HIV-1) natural history cohorts. The hemizygous genotype had no effect on either acquisition of HIV-1 infection or progression to AIDS. However, the homozygous deletion was significantly associated with unfavorable outcomes for HIV-1 acquisition, progression to AIDS, and viral set point. These findings suggest that the loss of APOBEC3B may increase host susceptibility to HIV-1 acquisition and progression to AIDS. An P, Johnson R, Phair J, Kirk GD, Yu XF, Donfield S, Buchbinder S, Goedert JJ, Winkler CA. APOBEC3B deletion and risk of HIV-1 acquisition. J Infect Dis. 2009 Oct 1;200(7):1054-1058.
Amino Acids Surrounding HIV-1 Vif Involved in A3G Binding and Inactivation Amino-terminal region of the Vif molecule contains a conserved SLV/Ix4Yx9Y motif in HIV-1, HIV-2, and simian immunodeficiency virus (SIV)
This study found this region is critical for APOBEC3 suppression. In particular, amino acids K22, K26, Y30, and Y40 were important for the Vif-induced degradation and suppression of cellular APOBEC3G (A3G). However, mutation of these residues had little effect on the Vif-mediated suppression of A3F, A3C, or A3DE, suggesting that these four residues are not important for Vif assembly with the Cul5 E3 ubiquitin ligase or protein folding in general. The LV portion of the Vif SLV/Ix4Yx9Y motif was required for optimal suppression of A3F, A3C, or A3DE. Thus, the SLV/Ix4Yx9Y motif and surrounding amino acids represent an important functional domain in the Vif-mediated defense against APOBEC3. In particular, the positively charged K26 of HIV-1 Vif was invariably conserved within the SLV/Ix4Yx9Y motif of HIV/SIV Vif molecules and was the most critical residue for A3G inactivation. A patch of positively charged and hydrophilic residues (K(22)x(3)K(26)x(3)Y(30)x(9)YRHHY(44)) and a cluster of hydrophobic residues (V(55)xIPLx(4-5)LxPhix2YWxL(72)) were both involved in A3G binding and inactivation. These structural motifs in HIV-1 Vif represent attractive targets for the development of lead inhibitors to combat HIV infection. Chen G, He Z, Wang T, Xu R, Yu XF. A patch of positively charged amino acids surrounding the human immunodeficiency virus type 1 Vif SLVx4Yx9Y motif influences its interaction with APOBEC3G. J Virol. 2009 Sep;83(17):8674-8682.
Incorporation of Multi-faceted Approaches for Effective Reduction of Risky Sexual Behavior
Cross-sectional data was collected in this study to elucidate the inconsistent reports regarding contextual influence of methamphetamine dependence (METH), HIV-infection and their combination on mood states and risky sexual behavior (frequency of condom use) among men who have sex with men (MSM). Dr. Grant and colleagues found that METH+ and HIV+ status were both associated with irregular condom use and higher score of negative mood status (depression, tension, anger, fatigue and confusion). Although METH+/HIV+ participants reported significantly less frequent condom use (25% of the time) than reported by METH-/HIV+ participants (51-75% of the time), neither METH nor HIV status showed a moderate (i.e., contextual) effect on the relationships between negative mood and condom use. Since among non-monogamous MSM the METH dependence, HIV+ and negative moods were all associated with reduced condom use without contextual effect, the study suggested that sexual risk reduction interventions for MSM should incorporate multi-faceted approaches, including substance abuse and mental health treatment. Bousman CA, Cherner M, Ake C, Letendre S, Atkinson JH, Patterson TL, Grant I, Everall IP; HNRC Group. Negative mood and sexual behavior among non-monogamous men who have sex with men in the context of methamphetamine and HIV. J Affect Disord. 2009 Dec;119(1-3):84-91.
Antiretroviral Therapy Shifts Cliniconeuropathologic Correlates of HIV from Florid Virus Replication to Diverse Mechanisms
This cross-sectional survey analyzed prospective clinical and neuropathological data collected by the National NeuroAIDS Tissue Consortium (NNTC), comprising 589 brain samples from individuals with advanced HIV disease collected since 1999. It assessed gender, ethnicity/race, mode of transmission, age, year of death, nadir CD4, plasma viral load, last antiretroviral regimen, the presence of parenchymal HIV brain pathology, HIV-associated neurocognitive disorder, and major depressive disorder. The study compared cohort demographic variables with Centers for Disease Control and Prevention US HIV/AIDS statistics and examined associations of parenchymal HIV brain pathology with demographic, clinical, and HIV disease factors. With regard to Centers for Disease Control and Prevention US data, the NNTC cohort had similar age distribution, fewer females and African Americans but more Hispanics and men who have sex with men. Only 22% of the brains examined were neuropathologically normal. Opportunistic infections occurred in 1% to 5% of the cohort. Parenchymal HIV brain pathology was observed in 17.5% of the cohort and was associated with nadir CD4 and plasma viral load. Brains without parenchymal HIV brain pathology often had other noninfectious findings or minimal nondiagnostic abnormalities that were associated with HIV-associated neurocognitive disorder. Clinically, 60% of the cohort reported a lifetime episode of major depressive disorder and 88% had a HIV-associated neurocognitive disorder. No pathological finding correlated with major depressive disorder. Both antiretroviral treatment regimen and elevated plasma HIV viral load were associated with presence of parenchymal HIV brain pathology; however, multivariate analyses suggested a stronger association with plasma viral load. The frequency of HIV brain pathology was lower than previous pre-antiretroviral reports, and was predicted by lower nadir CD4 and higher plasma viral load. Noninfectious pathologies and minimal changes correlated with HIV-associated neurocognitive disorder, suggesting a shift in pathogenesis from florid HIV replication to other, diverse mechanisms. Everall I, Vaida F, Khanlou N, et al. HIV Neurobehavioral Research Center (HNRC). Cliniconeuropathologic correlates of human immunodeficiency virus in the era of antiretroviral therapy. J Neurovirol. 2009 Sep 8:1-11.
The Semantic Relatedness of Cue-intention Pairings Influences Event-based Prospective Memory Failures in Older HIV+ Adults
HIV infection and aging are each independently associated with prospective memory impairment, which increases the risk of poor functional outcomes, including medication non-adherence. The incidence and prevalence of HIV infection among older adults has increased in recent years, thereby raising questions about the combined effects of these risk factors on prospective memory. The present study showed significant additive effects of HIV and aging on event-based prospective memory, with the greatest deficits evident in the older HIV+ group, even after controlling for other demographic factors and potential medical and psychiatric confounds. Event-based prospective memory impairment was particularly apparent in the older HIV+ group on trials for which the retrieval cue and intention were not semantically related. Worse performance on the semantically unrelated cue-intention trials was associated with executive dysfunction, older age, and histories of immunocompromise in the older HIV+ cohort. These data suggest that older HIV-infected adults are significantly less proficient at engaging the strategic encoding and retrieval processes required to execute a future intention when the cue is unrelated to the intended action, perhaps secondary to greater neuropathological burden in the prefrontostriatal systems critical to optimal prospective memory functioning. Woods SP, Dawson MS, Weber E, Grant I. The semantic relatedness of cue-intention pairings influences event-based prospective memory failures in older adults with HIV infection. J Clin Exp Neuropsychol. 2009 Sep 17:1-10.
HIV-Associated Deficits in Action (Verb) Generation May Reflect Astrocytosis
Commensurate with the hypothesized neural dissociation between verb and noun generation, research in HIV infection shows that, relative to noun fluency, action (verb) fluency is disproportionately impaired, more strongly related to executive dysfunction, and more sensitive to declines in everyday functioning. However, whether the neurobiological correlates of HIV-associated deficits in verb and noun generation are separable have not heretofore been investigated. The present study examined the biomarker correlates of action and noun fluency in HIV+ participants. Biomarkers of viral burden, neuroaxonal damage, macrophage activation, neuroprotection, inflammation, and astrocytosis were measured in plasma and cerebrospinal fluid (CSF). Deficits in action, but not noun generation, were significantly associated with higher CSF levels of S100beta, a marker of astrocyte activation, even after controlling for antiretroviral therapy, current immune compromise, and general cognitive impairment. Concurrent validity for the frontal systems hypothesis of verb generation was provided by post hoc analyses demonstrating that S100beta was also associated with measures of executive functions, but not semantic memory or psychomotor speed. Overall, these findings suggest that HIV-associated impairment in action fluency, and executive dysfunction more generally, may reflect astrocytosis (i.e., elevated S100beta). Complementing the literature in HIV and other clinical populations with frontal systems involvement, these data also support the possible neurobiological dissociation of noun and verb generation. Woods SP, Iudicello JE, Dawson MS, Weber E, Grant I, Letendre SL. HIV-associated deficits in action (verb) generation may reflect astrocytosis. J Clin Exp Neuropsychol. 2009 Oct 19:1-6.
Role of Metabolic Syndrome Components in HIV-Associated Sensory Neuropathy
Metabolic syndrome, a cluster of risk factors for atherosclerosis and microvascular disease, is associated with sensory neuropathy. This study assessed whether the syndrome or its components predispose individuals to HIV-associated sensory neuropathy. After controlling for HIV-SN risk factors such as age, CD4 current, length of HIV infection, use of dideoxynucleoside reverse transcriptase inhibitors and protease inhibitors, it found that the risk of HIV-associated sensory neuropathy was increased in HIV+ individuals having diabetes mellitus type 2 and elevated TRG but not those having other components of the Metabolic syndrome. Ances BM, Vaida F, Rosario D, et al. CNS HIV Antiretroviral Therapy Effects Research (CHARTER) Metabolic Study Group. Role of metabolic syndrome components in HIV-associated sensory neuropathy. AIDS. 2009 Nov 13;23(17):2317-2322.
Translating Endogenous Opioid System Activation into Pain Treatment
Dr. Younger's work in this study revealed that a therapeutic effect can be achieved in patients with fibromyalgia symptoms by modulating activity of endogenous opioid system. The opioid antagonist naltrexone at very small doses could stimulate the release of endogenous opioids after an initial short blockage of the receptor activity, inhibit the activity of microglia, and reverse central and peripheral inflammation. Administration of naltrexone reduced diffuse musculoskeletal pain and sensitivity to mechanical stimulation with side effects being infrequent. A greater than 30% reduction of pain symptoms over the placebo effect was evident in the entire cohort. In addition, laboratory testing showed that mechanical and heat pain thresholds were raised after naltrexone treatment. Although it is recognized that drug efficacy needs to be tested in larger samples, the data suggest that low-dose naltrexone might be an effective, highly tolerable, and inexpensive treatment for fibromyalgia. Younger J, Mackey S. Fibromyalgia symptoms are reduced by low-dose naltrexone: A pilot study. Pain Med. 2009 May-Jun 10;(4):663-672.
Turning Quantitative Sensory Testing and Mapping into the Assessment of Neuropathic Pain
To complement the neurologic, musculoskeletal, and general physical examinations, a standard, validated, office evaluation of signs of neuropathic pain is essential to allow for better monitoring of treatment effectiveness and for mechanistic studies of pain. Based upon a comprehensive analysis of available methodologies for quantitative sensory testing and specific tests for the neuropathic pain evaluation, Dr. Wasan and colleagues have proposed a protocol to quantify sensory features of neuropathic pain, including the evaluation of sensory deficits, allodynia and hyperalgesia, which could be evoked by a physiologically representative array of stimuli. Such an examination should include mapping of areas of stimulus-evoked neuropathic pain and standardized, reproducible quantitative sensory testing (QST) of tactile, punctuate, pressure, and thermal modalities. Walk D, Sehgal N, Moeller-Bertram T, Edwards RR, Wasan A, Wallace M, Irving G, Argoff C, Backonja MM. Quantitative sensory testing and mapping: A review of nonautomated quantitative methods for examination of the patient with neuropathic pain. Clin J Pain. 2009 Sep 25;(7):632-640.
Filling-in, Spatial Summation, and Radiation of Pain: Evidence for a Neural Population Code in the Nociceptive System
The receptive field organization of nociceptive neurons suggests that noxious information may be encoded by population-based mechanisms. Although electrophysiological evidence of population coding mechanisms is limited, psychophysical studies examining interactions between multiple noxious stimuli can provide indirect evidence that neuron population recruitment can contribute to both spatial and intensity-related percepts of pain. In this study, Dr. Coghill evaluated pain intensity and perceived spatial attributes of stimuli. Perceived pain spread beyond areas stimulated (radiation of pain), most frequently at 5- and 10-cm distances. Perceived connectivity between two noxious stimuli (filling-in) was influenced by the distance between stimuli, with the greatest connectivity reported at 5- and 10-cm separation distances. Spatial summation of pain occurred over probe separation distances as large as 40 cm and six dermatomes, but was maximal at 5- and 10-cm separation distances. Taken together, all three of these phenomena suggest that interactions between recruited populations of neurons may support both spatial and intensity-related dimensions of the pain experience. Quevedo AS, Coghill RC. Filling-in, spatial summation, and radiation of pain: Evidence for a neural population code in the nociceptive system. J Neurophysiol. 2009 ec102;(6):3544-3553.
Brain Mechanisms Supporting Discrimination of Sensory Features of Pain: A New Model
Pain can be very intense or only mild, and can be well localized or diffuse. Little is known as to how such distinct sensory aspects of noxious stimuli are processed by the human brain. Using functional magnetic resonance imaging and a delayed match-to-sample task, Dr. Coghill's laboratory showed that discrimination of pain intensity, a nonspatial aspect of pain, activated a ventrally directed pathway extending bilaterally from the insular cortex to the prefrontal cortex. This activation was distinct from the dorsally directed activation of the posterior parietal cortex and right dorsolateral prefrontal cortex that occurs during spatial discrimination of pain. Both intensity and spatial discrimination tasks activated highly similar aspects of the anterior cingulate cortex, suggesting that this structure contributes to common elements of the discrimination task such as the monitoring of sensory comparisons and response selection. These results provide the foundation for a new model of pain in which bidirectional dorsal and ventral streams preferentially amplify and process distinct sensory features of noxious stimuli according to top-down task demands. Oshiro Y, Quevedo AS, McHaffie JG, Kraft RA, Coghill RC. Brain mechanisms supporting discrimination of sensory features of pain: A new model. J Neurosci. 2009 Nov 25;29(47):14924-14931.
Cognitive Function May Improve in Individuals with Protracted Drug Abstinence
Chronic methamphetamine (MA) abuse is associated with disruption of frontostriatal function as well as deficits in cognitive control. Dr. Salo found in this study that recently abstinent MA-abusing individuals exhibited greater Stroop reaction time (RT) interference compared with both the control group and the long-term abstinent MA-abusing individuals. There was no difference between long-term abstinent MA-abusing individuals and controls. Stroop RT interference correlated positively with both duration of drug use and drug abstinence. These data suggest that cognitive function may improve with protracted drug abstinence. Salo R, Nordahl TE, Galloway GP, Moore CD, Waters C, Leamon MH. Drug abstinence and cognitive control in methamphetamine-dependent individuals. Subst Abuse Treat. 2009 Oct 37;(3):292-297.
Nicotine Reduced Symptoms and Negative Moods of ADHD Patients
This study tested the effects of nicotine in the everyday lives of smokers and nonsmokers with attention-deficit/hyperactivity disorder (ADHD). The effects of nicotine on ADHD symptoms, moods, and side effects were assessed with electronic diaries. Cardiovascular activity was recorded with ambulatory blood pressure monitors and physical activity was monitored with actigraphs. Nicotine reduced reports of ADHD symptoms by 8% and negative moods by 9%, independent of smoking status. In addition, nicotine increased cardiovascular activity during the first 3 to 6 hours after nicotine patch administration. The results support the self-medication hypothesis for nicotine in adults with ADHD and suggest that smoking cessation and prevention efforts for individuals with ADHD will need to address both the symptom reducing and mood enhancing effects of nicotine. Gehricke JG, Hong N, Whalen CK, Steinhoff K, Wigal TL. Effects of transdermal nicotine on symptoms, moods, and cardiovascular activity in the everyday lives of smokers and nonsmokers with attention-deficit/hyperactivity disorder. Psychol Addict Behav. 2009 Dec 23;(4):644-655.
HIV Nef Inhibited T Cell Migration Involves Multiple Cellular Domains
Lymphocyte trafficking is a multistep, intricate process and involves a number of host factors such as integrins and chemokine receptors on lymphocytes, adhesion molecules on endothelial cells, and chemokines present in the local microenvironment. Previous studies have shown that HIV-1 Nef inhibits T cell chemotaxis in response to the physiological ligand SDF-1alpha. The inhibitory mechanisms and the molecular determinants of HIV-1 Nef for this phenotype were evaluated in this study. It showed that HIV-1 Nef inhibited transwell and transendothelial migration of T cells. HIV-1 Nef protein impaired T cell chemotaxis toward SDF-1alpha without altering CXCR4 expression. HIV-1 Nef protein down-modulated LFA-1 expression on T lymphocytes and diminished adhesion and polarization of T lymphocytes and, as a result, led to decreased migration across the endothelium. The myristoylation site and DeltaSD domain played important roles in Nef-mediated inhibition of transwell and transendothelial migration and polarization of T lymphocytes. However, different sites or domains were needed for Nef-mediated LFA-1 down-modulation and impaired adhesion of T lymphocyte. These results demonstrated that HIV-1 Nef inhibited T lymphocyte migration at multiple steps and suggest that membrane localization and intracellular signaling events likely contribute to the inhibitory effects of Nef on T cell migration and subsequently, the pathobiology of the HIV-1 Nef protein. Park IW, He JJ. HIV-1 Nef-mediated inhibition of T cell migration and its molecular determinants. J Leukoc Biol. 2009 Nov 86;(5):1171-1178.
Sam68 as a Multi-Functional Host RNA-binding Protein
Sam68 has been implicated in a variety of important cellular processes such as RNA metabolism and intracellular signaling. The Sam68 cytoplasmic mutants induced stress granules (SG) and inhibit HIV-1 nef mRNA translation. In this study, Dr. He evaluated the possibility and the underlying mechanisms of the wild-type counterpart Sam68 SG recruitment. Sam68 was significantly recruited into cytoplasmic SG under oxidative stress. Domain aa269-321 and KH domain were both essential for this recruitment while Sam68 knockdown had no effects on SG assembly, indicating that Sam68 is not a constitutive component of the SG. Moreover, Sam68 cytoplasmic mutant-induced SG formation was independent of eIF2alpha phosphorylation. Sam68 was complexed with T-cell intracellular antigen-1 (TIA-1), a core SG component, and that the complex formation was correlated with Sam68 SG recruitment. These results provide direct evidence for the first time that Sam68 is recruited into SG through complexing with TIA-1 in response to oxidative stress and suggest that cytoplasmic SG recruitment of Sam68 and ensuing changes in Sam68 physiological functions are part of the host response to external stressful conditions. Henao-Mejia J, He JJ. Sam68 relocalization into stress granules in response to oxidative stress through complexing with TIA-1. Exp Cell Res. 2009 Nov 5;315(19):3381-3395.
Age-Related Decline in Nicotinic Receptor Availability
Human postmortem studies have reported age-related decreases in brain high affinity nicotine binding. Staley and colleagues at Yale School of Medicine investigated the effect of age on beta(2)-containing nicotinic acetylcholine receptor (beta(2)-nAChR) availability in eight brain regions of living human subjects using the ligand [(123)I]5-IA-85380 ([(123)I]5-IA) and single photon emission computed tomography (SPECT). Healthy, nonsmokers (N=47) ranging in age from 18 to 85 were administered [(123)I]5-IA using a bolus plus constant infusion paradigm and imaged 6-8h later under equilibrium conditions. Age and regional beta(2)-nAChR availability were inversely correlated in seven of the eight brain regions analyzed, with decline ranging from 32% (thalamus) to 18% (occipital cortex) over the adult lifespan, or up to 5% per decade. These results in living human subjects corroborate postmortem reports of decline in high affinity nicotine binding with age and may aid in elucidating the role of beta(2)-nAChRs in cognitive aging. Mitsis EM, Cosgrove KP, Staley JK, et al. Age-related decline in nicotinic receptor availability with [(123)I]5-IA-85380 SPECT. Neurobiol. Aging. 2009 Sep 30;(9):1490-1497.
Altered Affective Response in Marijuana Smokers: An FMRI Study
Gruber and colleagues at McLean Hospital used fMRI to investigate alterations in mood and perception in chronic marijuana users. Endogenous cannabinoids regulate a variety of emotional responses, including anxiety, mood control, and aggression; nevertheless, little is known about smokers' responses to affective stimuli. 15 chronic heavy marijuana smokers were compared to 15 non-marijuana smoking control subjects during the viewing of masked happy and fearful faces. No differences were found on clinical or demographic measures between the groups. Marijuana smokers demonstrated a relative decrease in both anterior cingulate and amygdalar activity during masked affective stimuli; in contrast, control subjects exhibited relative increases in activation within these regions during the viewing of masked faces. That chronic heavy marijuana smokers demonstrate altered activation of frontal and limbic systems while viewing masked faces is consistent with autoradiographic studies reporting high CB-1 receptor density in these regions. These data indicate that marijuana smokers process emotional information differently from those who do not smoke, even when stimuli are presented below the level of conscious processing. Gruber SA, Rogowska J, Yurgelun-Todd DA. Altered affective response in marijuana smokers: An FMRI study. Drug and Alcohol Dependence. 2009 Nov 1;105(1-2):139-153.
Bottom-Up and Top-Down Processes in Emotion Generation: Common and Distinct Neural Mechanisms
Oschner and colleagues at Columbia University used fMRI to investigate the relative contributions of bottom-up and top-down processes on the generation of emotions. 20 female subjects were scanned under two negative emotional conditions: bottom-up perception of aversive images vs. top-down interpretation of neutral images as aversive. Both types of responses activated the amygdala, although bottom-up responses did so more strongly, and bottom-up responses activated systems for attending to and encoding perceptual and affective stimulus properties. On the other hand, top-down responses activated prefrontal regions that represent high-level cognitive interpretations. Self-reported affect correlated with activity in the amygdala during bottom-up responding, but with activity in the medial prefrontal cortex during top-down responding. These findings provide a neural foundation for emotion theories that posit multiple kinds of appraisal processes and help to clarify mechanisms underlying clinically relevant forms of emotion dysregulation. Ochsner KN, Ray RR, Hughes B, McRae K, Cooper JC, Weber J, Gabrieli JD, Gross JJ. Bottom-up and top-down processes in emotion generation: Common and distinct neural mechanisms. Psychological Science. 2009 20;(11):1322-1331.
Cerebral Morphology and Dopamine D2/D3 Receptor Distribution in Humans
Zald and colleagues at Vanderbilt University combined structural MRI and PET receptor ligand imaging to determine the relationship between cerebral morphology and the expression of dopamine receptors in humans. 45 healthy subjects participated in T1-weighted structural MRI as well as PET scanning with the D(2)/D(3) ligand [(18)F]fallypride. Optimized voxel-based morphometry was used to create grey matter volume and density images. Grey matter volume and density images were correlated with D2/D3 receptor binding potential (DaR2-BP) images on a voxel-by-voxel basis. Associations between cerebral morphology and DaR2-BP were also examined for selected regions-of-interest (ROIs) after spatial normalization. Cerebral morphology, particularly grey matter density, correlates with [(18)F]fallypride BP(ND) in a regionally specific manner. Overall, grey matter density appeared more strongly correlated with DaR2-BP than grey matter volume. Voxel-wise analyses indicated that grey matter volume and density positively correlated with DaR2-BP throughout the midbrain, including the substantia nigra. Positive correlations were observed in medial cortical areas, including anterior cingulate and medial prefrontal cortex, and circumscribed regions of the temporal, frontal, and parietal lobes. ROI analyses revealed significant positive correlations between DaR2-BP and cerebral morphology in the caudate, thalamus, and amygdala. Woodward N, Zald D, Ding Z, Riccardi P, Ansari M, Baldwin R, Cowan R, Li R, Kessler R. Cerebral morphology and dopamine D2/D3 receptor distribution in humans: A combined [18F]fallypride and voxel-based morphometry study. Neuroimage. 2009 May 15;46:31-38.
Decoding Cognitive Control in Human Parietal Cortex
Yantis and colleagues at Johns Hopkins University used fMRI to determine how the brain provides efficient execution of perceptual-motor tasks that require rapid voluntary reconfiguration of cognitive task sets as circumstances unfold. Such acts of cognitive control, which are thought to rely on a network of cortical regions in prefrontal and posterior parietal cortex, include voluntary shifts of attention among perceptual inputs or among memory representations, or switches between categorization or stimulus-response mapping rules. A critical unanswered question is whether task set shifts in these different domains are controlled by a common, domain-independent mechanism or by separate, domain-specific mechanisms. Recent studies have implicated a common region of medial superior parietal lobule (mSPL) as a domain-independent source of cognitive control during shifts between perceptual, mnemonic, and rule representations. Using event-related multivoxel pattern classification it was found that spatial patterns of brain activity within mSPL reliably discriminate which of several domains of cognitive control is at play on a moment-by-moment basis. Critically, these spatio-temporal brain patterns are stable over time within subjects tested several months apart and across a variety of tasks, including shifting visuospatial attention, switching categorization rules, and shifting attention in working memory. Esterman M, Chiu Y, Tamber-Rosenau B, Yantis S. Decoding cognitive control in human parietal cortex. Proceedings of the National Academy of Sciences of the United States of America. 2009 Oct 20;106(42): 17974-17979.
Decreased Brain Dopamine Cell Numbers in Human Cocaine Users
Little and colleagues at Baylor University investigated whether cocaine use might cause a loss of dopamine neurons in humans. Although rodent studies have not detected cocaine-induced dopamine cell damage, Cocaine use diminishes striatal and midbrain dopamine neuronal components in both post-mortem and in vivo human experiments. The present experiment involved counting midbrain dopamine neurons utilizing both melanin and tyrosine hydroxylase immunoreactivity in 10 cocaine users and 9 controls. Sections were also examined for signs of acute pathological injury by counting activated macrophages and microglia. Melanized cells at six midbrain levels were significantly reduced in cocaine users by both drug exposures. The estimated total number of melanized dopamine cells in the anterior midbrain was significantly reduced in cocaine users by 16%. Results with tyrosine hydroxylase immunoreactivity were less conclusive because of variability in staining. Both activated macrophages and activated microglia were significantly increased among cocaine users. These results suggest that cocaine exposure may have neurotoxic effects on dopamine neurons in humans. The infiltration of phagocytic cells suggests that the lower number of dopamine cells found in cocaine users was a relatively recent effect. The loss of dopamine cells could contribute to and intensify cocaine dependence, as well as anhedonic and depressive symptoms, in some cocaine users. Further efforts at clarifying the pathophysiological mechanisms involved may help explain treatment refractoriness, and identify targets for therapeutic intervention. Little K, Ramssen E, Welchko R, Volberg V, Roland C, Cassin B. Decreased brain dopamine cell numbers in human cocaine users. Psychiatry Research. 2009 Aug 15;168(3):173-180.
Delayed Extinction Attenuates Conditioned Fear Renewal and Spontaneous Recovery in Humans
LeBar and colleagues at Duke University investigated whether the return of fear after extinction training depends on the retention interval after an aversive learning experience. After fear conditioning, healthy participants underwent extinction training either 5 min or 1 day later and in either the same room (same context) or a different room (context shift). The next day, conditioned fear was tested in the original room. When extinction took place immediately, fear renewal was robust and prolonged for context-shift participants, and spontaneous recovery was observed in the same-context participants. Delayed extinction, by contrast, yielded a brief form of fear renewal that reextinguished within the testing session for context-shift participants, and there was no spontaneous recovery in the same-context participants. The authors conclude that the passage of time allows for memory consolidation processes to promote the formation of distinct yet flexible emotional memory traces that confer an ability to recall extinction, even in an alternate context, and minimize the return of fear. Furthermore, immediate extinction can yield spontaneous recovery and prolong fear renewal. These findings have potential implications for treating responses to conditioned cues, such as drug craving, in substance abuse disorders. Huff N, Hernandez J, Blanding N, LaBar K. Delayed extinction attenuates conditioned fear renewal and spontaneous recovery in humans. Behavioral Neuroscience. 2009 Aug;123(4):834-843.
Dopamine and Serotonin Transporter Availability During Acute Alcohol Withdrawal: Effects of Comorbid Tobacco Smoking
Cosgrove and colleagues at Yale School of Medicine used SPECT receptor imaging to evaluate the effects of alcohol drinking alone from comorbid alcohol drinking and tobacco smoking on dopamine (DAT) and serotonin (SERT) transporter availability. Tobacco smoking is highly comorbid with heavy alcohol drinking, yet the interaction of tobacco smoking and alcohol drinking on brain catecholaminergic synaptic markers is unexplored. A total of 14 heavy alcohol drinking smokers (n=6) and nonsmokers (n=8) and 14 age-matched control smokers (n=6) and nonsmokers (n=8) were imaged with [(123)]beta-CIT which measures both DAT and SERT. Alcohol drinking smokers and nonsmokers consumed 134.3+/-100.3 and 196.5+/-139.9 drinks, respectively, over the previous month and were imaged during acute withdrawal, e.g. within 5 days of their last drink. Striatal DA transporter availability was significantly higher (16%) in alcohol drinkers compared to controls. 5-HT transporter availability was also significantly higher in alcohol drinkers vs. controls in the brainstem (25%) and the diencephalon (8%). This elevation was restricted to alcohol drinking nonsmokers with higher DA transporter availability in the striatum (26%), and higher 5-HT transporter availability in the diencephalon (26%) and brainstem (42%). There was a significant positive correlation between days since last drink and 5-HT transporter availability in the diencephalon (r=0.60) and brainstem (r=0.54), in the total group of alcohol drinkers and in the nonsmokers, but not the smokers. These results demonstrate that during the first week of abstinence, smoking appears to suppress neuroadaptive changes in DA and 5-HT transporters during acute withdrawal from alcohol insofar as DA and 5-HT transporter availability is higher in alcohol drinking nonsmokers but not in alcohol drinking smokers. Cosgrove KP, Krantzler E, Frohlich EB, et al. Dopamine and serotonin transporter availability during acute alcohol withdrawal: effects of comorbid tobacco smoking. Neuropsychopharmacology. 2009 Sep 34;(10):2218-2226.
Effects of Acute 3,4-Methylenedioxymethamphetamine on Sleep and Daytime Sleepiness in MDMA Users
Tancer and colleagues at Wayne State University studied whether acute administration of MDMA (Ecstasy) has an effect on sleep and daytime sleepiness under placebo-controlled conditions. MDMA affects monoamine neurotransmitters that play a critical role in sleep and daytime alertness. 7 recreational MDMA-users and 13 matched control subjects were studied. Participants with a history of MDMA use were studied on 3 sessions of 3 nights (baseline, treatment, and recovery) and 2 days (following night 2 and 3) per session. On treatment nights (night 2), participants received placebo or 2 mg/kg of MDMA or underwent a restricted bed schedule with placebo. Sleep restriction was a positive control to compare sleep loss and consequent sleepiness associated with MDMA use. The scheduled sleep period was 8 hours long on nonrestricted nights, and standard sleep recordings and daytime sleepiness tests were conducted. Age-matched controls received 1 night and day of standard sleep and daytime sleepiness testing. Acute MDMA shortened sleep primarily by increasing sleep latency, and it reduced stage 3/4 sleep and suppressed rapid eye movement (REM) sleep. The MDMA-reduced sleep time was not associated with increased daytime sleepiness the following day, as was seen in the sleep-restriction condition. Compared with control subjects, the MDMA users on the first night in the laboratory had shorter total sleep times and less stage 3/4 sleep. Average daily sleep latency on daytime sleepiness tests the day after nighttime placebo administration was increased in MDMA users compared with the control subjects, and MDMA users had an elevated number of sleep-onset REM periods on these tests, compared with control subjects. Acute MDMA administration disrupts sleep and REM sleep, specifically, without producing daytime sleepiness such as sleep restriction does. Compared with control subjects, recreational MDMA users showed evidence of hyperarousal and impaired REM function. The mechanism behind these effects is likely due to the deleterious effects of MDMA on catecholamines. Randall S, Johanson C, Tancer M, Roehrs T. Effects of acute 3,4-methylenedioxymethamphetamine on sleep and daytime sleepiness in MDMA users: A preliminary study. Sleep. 2009 Nov 1;32(11):1513-1519.
Effects of MDMA on Sociability and Neural Response to Social Threat and Social Reward
de Wit and colleagues at the University of Chicago investigated whether MDMA, (Ecstasy, Ī3,4-Methylenedioxymethamphetamine) produces unique subjective effects, including increased sociability, feelings of closeness with others, and reduced interpersonal defensiveness. Despite their apparent importance in recreational and potential psychotherapeutic use of MDMA, the defining characteristics and neurobiological mechanisms of these interpersonal effects are poorly understood. To address these critical questions, the acute effects of MDMA on self-reported sociability and neuronal activation in response to socially threatening (angry and fearful faces) and socially rewarding (happy faces) stimuli were evaluated in 9 volunteers reporting past ecstasy use. The results of this study provide the first evidence that MDMA may increase sociability in humans both by diminishing responses to threatening stimuli and enhancing responses to rewarding social signals. Bedi G, Phan K, Angstadt M, de Wit H. Effects of MDMA on sociability and neural response to social threat and social reward. Psychopharmacology. 2009 Nov 1;207(1):73-83.
Electrophysiological and Hemodynamic Responses to Reward Prediction Violation
Martin and colleagues at the University of South Florida combined scalp recorded electrical event-related epotentials (ERP) and fMRI to investigate whether anterior cingulate cortex detects outcomes that are worse than expected. ERP and fMRI data were obtained from the same participants in different sessions during a reward prediction violation design. Both the medial frontal negativity (MFN) ERP response and anterior cingulate cortex fMRI activity differentiated between reward delivery and expectation. The largest MFN and anterior cingulate cortex fMRI response occurred when predicted rewards were not delivered. Inverse modeling placed the MFN source near the anterior cingulate cortex hemodynamic activation. The fMRI study also showed increased striatal response to rewards regardless of prediction indicating dissociation of neural processing of reward and reward expectation. Martin L, Potts G, Burton P, Montague P. Electrophysiological and hemodynamic responses to reward prediction violation. NeuroReport. 2009 Aug 26;20(13):1140-1143.
Evaluation of Genetic Variability in the Dopamine Receptor D2 in Relation to Behavioral Inhibition and Impulsivity/Sensation Seeking: An Exploratory Study with D-Amphetamine in Healthy Participants
de Wit and colleagues at the University of Chicago investigated whether inhibition and impulsivity were related to genetic polymorphisms in the DRD2 gene (DRD2) in healthy volunteers (N = 93). The dopamine D2 receptor (DRD2) appears to be involved in impulsive behaviors, and particularly in behavioral inhibition. They therefore investigated the association between 12 single nucleotide polymorphisms (SNPs) and haplotypes in DRD2 and stop task performance in the nondrug (i.e., placebo) session and on the personality measure of impulsivity. Participants received placebo or d-amphetamine in random order. During each session, the participants performed the stop-signal task, measuring behavioral inhibition, rated their mood states, and completed the Zuckerman-Kuhlman Personality Questionnaire, including an Impulsivity subscale. Mood was not related to genotypes in either the drug free condition or in response to drug. However, 2 SNPs, rs4648317 and rs12364283, and a haplotype block consisting of those SNPs, were associated with better performance on the stop-signal task in the drug free condition and lower scores on the Impulsivity subscale. The rs12364283 SNP was associated with effects of d-amphetamine on stop task performance: d-amphetamine decreased stop reaction time (RT) in the A/A group but increased stop RT in the combined A/G + G/G genotype. Of the SNPs evaluated, rs12364283, which has been associated with DRD2 expression, was the most significantly associated with inhibition and impulsivity. The significant relationship between DRD2 genotype and both behavioral inhibition and impulsivity suggests a possible common genetic influence on behavioral and self-report measures of impulsivity. Hamidovic A, Dlugos A, Skol A, Palmer AA, de Wit H. Evaluation of genetic variability in the dopamine receptor D2 in relation to behavioral inhibition and impulsivity/sensation seeking: an exploratory study with d-amphetamine in healthy participants. Exp Clin Psychopharmacol. 2009 Dec 17;(6):374-383.
Evidence for a Common Representation of Decision Values for Dissimilar Goods in Human Ventromedial Prefrontal Cortex
Rangel and colleagues at the University of Southern California used fMRI to determine how the brain computes representations of values in order to make economic choices between goods. It is a matter of controversy whether there exists a region of the brain that commonly encodes decision values for different types of goods, or if, in contrast, the values of different types of goods are represented in distinct brain regions. To address this question, healthy subjects made real purchasing decisions among different categories of goods (food, nonfood consumables, and monetary gambles) during fMRI scans. Activity in the ventromedial prefrontal cortex (vmPFC), a key brain region previously implicated in encoding goal-values, was correlated with the subjects' value for each category of good. Moreover, a single area in vmPFC was correlated with the subjects' valuations for all categories of goods. These results provide evidence that the brain encodes a "common currency" that allows for a shared valuation for different categories of goods. Chib VS, Rangel A, Shimojo S, O'Doherty JP. Evidence for a common representation of decision values for dissimilar goods in human ventromedial prefrontal cortex. J. Neurosci. 2009 Sep 30;29(39):12315-12320.
Executive Control Deficits in Substance-Dependent Individuals: A Comparison of Alcohol, Cocaine, and Methamphetamine and of Men and Women
Bechara and colleagues at the University of Southern California investigated the effect that different drugs and sex have on Executive Function defects. The performance of alcohol- (n = 33; 18 women), cocaine- (n = 27; 14 women), and methamphetamine-dependent individuals (n = 38; 25 women) were compared with sex-matched healthy comparisons (n = 36; 17 women) on complex decision making as measured with the Iowa Gambling Task, working memory, cognitive flexibility, and response inhibition. Cocaine-and methamphetamine-dependent individuals were impaired on complex decision making, working memory, and cognitive flexibility, but not on response inhibition. The deficits in working memory and cognitive flexibility were milder than the decision-making deficits and did not change as a function of memory load or task switching. Interestingly, decision making was significantly more impaired in women addicted to cocaine or methamphetamine than in men addicted to these drugs. Together, these findings suggest that drug of choice and sex have different effects on executive functioning, which, if replicated, may help tailor intervention. van der Plas E, Crone E, van den Wildenberg W, Tranel D, Bechara A. Executive control deficits in substance-dependent individuals: A comparison of alcohol, cocaine, and methamphetamine and of men and women. Journal of Clinical And Experimental Neuropsychology. 2009 31;(6):706-719.
Higher Diffusion in Striatum and Lower Fractional Anisotropy in White Matter of Methamphetamine Users
Chang and colleagues at the University of Hawaii used Diffusion Tensor Imaging (DTI) to investigate microstructural brain changes in METH users. Prior studies have shown that methamphetamine (METH) users have structural and chemical abnormalities on magnetic resonance imaging (MRI) studies, particularly in the frontal and basal ganglia brain regions. In this study, diffusion tensor measures in frontal white matter and basal ganglia were obtained from 30 adult METH users and 30 control subjects. Compared with healthy control subjects, METH users showed lower fractional anisotropy (FA) in right frontal white matter, and higher average diffusion coefficient (ADC) in left caudate and bilateral putamen. Higher left putamen ADC was associated with earlier initiation of METH use, greater daily amounts, and a higher cumulative lifetime dose. Similarly, higher right putamen ADC was associated with greater daily amounts and a higher cumulative lifetime dose. The lower FA in the right frontal white matter suggests axonal injury in these METH users. The higher ADC in the basal ganglia suggests greater inflammation or less myelination in these brain regions of those with younger age of first METH use and greater METH usage. Alicata D, Chang L, Cloak C, Abe K, Ernst T. Higher diffusion in striatum and lower fractional anisotropy in white matter of methamphetamine users. Psychiatry Res. 2009 Oct 30;174(1):1-8.
Hormonal, Cardiovascular, and Subjective Responses to Acute Stress in Smokers
de Wit and colleagues at the University of Chicago investigated how smoking affects physiological and psychological outcomes after stress and how these may interact to motivate smoking. There are complex relationships between stress and smoking; smoking may reduce the emotional discomfort of stress, yet nicotine activates stress systems and may alter responses to acute stress. This study aimed to examine the magnitude and time course of hormonal, cardiovascular, and psychological responses to acute psychosocial stress in smokers and non-smokers to investigate whether responses to acute stress are altered in smokers. Healthy male non-smokers (n = 20) and smokers (n = 15) participated in two experimental sessions involving a standardized public speaking stress procedure and a control non-stressful task. The outcome measures included self-reported mood, cardiovascular measures (heart rate and blood pressure), and plasma hormone levels (noradrenaline, cortisol, progesterone, and allopregnanolone). Smokers exhibited blunted increases in cortisol after the Trier Social Stress Test, and reported greater and more prolonged subjective agitation than non-smokers. Stress-induced changes in progesterone were similar between smokers and non-smokers, although responses overall were smaller among smokers. Stress did not significantly alter levels of allopregnanolone, but smokers exhibited lower plasma concentrations of this neurosteroid. These findings suggest that smoking dampens hormonal responses to stress and prolongs subjective discomfort. Dysregulated stress responses may represent a breakdown in the body's ability to cope efficiently and effectively with stress and may contribute to smokers' susceptibility to acute stress, especially during abstinence. Childs E, de Wit H. Hormonal, cardiovascular, and subjective responses to acute stress in smokers. Psychopharmacology (Berl.). 2009 Mar 203;(1):1-12.
Impaired Error Awareness and Anterior Cingulate Cortex Hypoactivity in Chronic Cannabis Users
Garavan and colleagues at Trinity College used fMRI to investigate whether chronic cannabis use leads to a diminished neural response to errors, particularly in the anterior cingulate cortex (ACC), a brain region thought critical to error processing. A diminished capacity for detecting errors has been linked to clinical symptoms including the loss of insight, delusions, and perseverative behavior. 16 active chronic cannabis users and 16 control participants were administered a Go/No-go response inhibition task during event-related fMRI scans. The task provides measures of inhibitory control and error awareness. Cannabis users' inhibitory control performance was equivalent to that of the control group, but the former showed a significant deficit in awareness of commission errors. Cannabis users showed a diminished capacity for monitoring their behavior that was associated with hypoactivity in the ACC and right insula. In addition, increased levels of hypoactivity in both the ACC and right insula regions were significantly correlated with error-awareness rates in the cannabis group (but not controls). These difficulties are consistent with earlier reports of hypoactivity in the neural systems underlying cognitive control and the monitoring of interoceptive awareness in chronic drug users, and highlight the potential relationship between cognitive dysfunction and behavioral deficits that have the potential to contribute to the maintenance of drug abuse. Hester R, Nestor L, Garavan H. Impaired Error awareness and anterior cingulate cortex hypoactivity in chronic cannabis users. Neuropsychopharmacology. 2009 Oct 34;(11):2450-2458.
Increased Ventral Striatal BOLD Activity During Non-Drug Reward Anticipation in Cannabis Users
Garavan and colleagues at Trinity College used fMRI to investigate whether chronic cannabis use effects reward processing in the brain. Motivational theories regarding long-term drug use posit contrasting predictions with respect to how drug users are likely to process non-drug incentives. The current study examined BOLD responses during reward and loss anticipation and their outcome deliveries in 14 chronic cannabis users and 14 drug-naive controls during a monetary incentive delay (MID) task. Even though there were no significant behavioural differences between the two groups, cannabis users had significantly more right VS BOLD activity during reward anticipation. Correlation analyses demonstrated that this right VS BOLD response was significantly correlated with life-time use and reported life-time cannabis joints consumed. No correlations between cannabis abstinence and BOLD responses were observed. A number of group differences in brain activity were found following outcome deliveries, most notably hypoactivity in the left insula cortex in response to loss and loss avoidance outcome notifications in the cannabis group. These results may suggest hypersensitivity during instrumental response anticipation for non-drug rewards and a hyposensitivity to loss outcomes in chronic cannabis users; the implications of which are discussed with respect to the potentially sensitizing effects of cannabis for other rewards. Nestor L, Hester R, Garavan H. Increased ventral striatal BOLD activity during non-drug reward anticipation in cannabis users. Neuroimage. 2010 Jan 1;49(1):1133-1143.
Kinetic Modeling of the Serotonin 5-HT(1B) Receptor Radioligand [(11)C]P943 in Humans
Ding and colleagues at Yale School of Medicine investigated the properties of [(11)C]P943, a new radioligand recently developed to image and quantify serotonin 5-Hydroxytryptamine (5-HT(1B)) receptors with positron emission tomography (PET). The purpose of this study was to evaluate [(11)C]P943 for this application in humans, and to determine the most suitable quantification method. Positron emission tomography data and arterial input function measurements were acquired in a cohort of 32 human subjects. Using arterial input functions, compartmental modeling, the Logan graphical analysis, and the multilinear method MA1 were tested. Both the two tissue-compartment model and MA1 provided good fits of the PET data and reliable distribution volume estimates. Using the cerebellum as a reference region, BP(ND) binding potential estimates were computed. [(11)C]P943 BP(ND) estimates were significantly correlated with in vitro measurements of the density of 5-HT(1B) receptors, with highest values in the occipital cortex and pallidum. To evaluate noninvasive methods, two- and three-parameter graphical analyses, Simplified Reference Tissue Models (SRTM and SRTM2), and Multilinear Reference Tissue Models (MRTM and MRTM2) were tested. The MRTM2 model provided the best correlation with MA1 binding-potential estimates. Parametric images of the volume of distribution or binding potential of [(11)C]P943 could be computed using both MA1 and MRTM2. The results show that [(11)C]P943 provides quantitative measurements of 5-HT(1B) binding potential. Gallezot J, Nabulsi N, Neumeister A, Planeta-Wilson B, Williams WA, Singhal T, Kim S, Maguire RP, McCarthy T, Frost JJ, Huang Y, Ding Y, Carson RE. Kinetic modeling of the serotonin 5-HT(1B) receptor radioligand [(11)C]P943 in humans. J. Cereb. Blood Flow Metab. 2009 Sep 23;30(1):196-210.
Learning and Memory Deficits in Ecstasy Users and their Neural Correlates during a Face-Learning Task
Garavan and colleagues at Trinity College used fMRI to investigate whether MDMA use leads to neural differences in encoding and recalling face-name associations. It has been consistently shown that ecstasy users display impairments in learning and memory performance. In addition, working memory processing in ecstasy users has been shown to be associated with neural alterations in hippocampal and/or cortical regions as measured by functional magnetic resonance imaging (fMRI). 20 recreational drug users whose predominant drug use was ecstasy and 20 controls participated in an initial study. To address the potential confounding effects of the cannabis use of the ecstasy using group, a second analysis included 14 previously tested cannabis users. Ecstasy users performed significantly worse in learning and memory compared to controls and cannabis users. A conjunction analysis of the encode and recall phases of the task revealed ecstasy-specific hyperactivity in bilateral frontal regions, left temporal, right parietal, bilateral temporal, and bilateral occipital brain regions. Ecstasy-specific hypoactivity was evident in the right dorsal anterior cingulate cortex (ACC) and left posterior cingulate cortex. In both ecstasy and cannabis groups, brain activation was decreased in the right medial frontal gyrus, left parahippocampal gyrus, left dorsal cingulate gyrus, and left caudate. These results elucidated ecstasy-related deficits, only some of which might be attributed to cannabis use. These ecstasy-specific effects may be related to the vulnerability of isocortical and allocortical regions to the neurotoxic effects of ecstasy. Roberts G, Nestor L, Garavan H. Learning and memory deficits in ecstasy users and their neural correlates during a face-learning task. Brain Research. 2009 Oct 6;1292:71-81.
Learning to Attend: Effects of Practice on Information Selection
Yantis and colleagues at Johns Hopkins University investigated how practice affects the deployment of selective attention to filter distracting information. This issue was addressed by examining how performance on a task changed after repeated exposure to distractors. Distraction initially slowed response time during task performance, an effect that diminished with repeated exposure to the distractors. When the distractors were consistent in appearance, the practice effect developed quickly but was stimulus-specific. When the distractors were more variable in appearance, the practice effect developed slowly but transferred more readily to other conditions. These data indicate that practice with overcoming distraction leads to improvements in information filtering mechanisms that generalize beyond the training regimen when variable distractor stimuli are experienced. Kelley T, Yantis S. Learning to attend: Effects of practice on information selection. Journal of Vision. 2009 9;(7):26-32.
Lower Level of Endogenous Dopamine in Patients With Cocaine Dependence: Findings From PET Imaging of D2/D3 Receptors Following Acute Dopamine Depletion
Martinez and colleagues at Columbia University investigated whether the decrease in dopamine type 2 and 3 (D2/D3) receptor binding in cocaine-dependent individuals relative to healthy comparison subjects could be due to an increase in baseline dopamine levels. PET receptor imaging was used to measure D2/D3 receptors following acute dopamine depletion in cocaine-dependent volunteers relative to healthy comparison subjects. Cocaine-dependent volunteers (N=15) and healthy matched comparison subjects (N=15) were scanned using PET, with the dopamine receptor radiotracer [11C]raclopride, at baseline and again following acute depletion of endogenous dopamine via alpha-methyl-para-tyrosine (AMPT) administration. Changes in radiotracer binding were measured in the subdivisions of the striatum (caudate, putamen, and ventral striatum) in addition to the striatum as a whole. Findings revealed that cocaine-dependent volunteers exhibited lower levels of endogenous dopamine relative to comparison subjects, which was measured as an increase in [11C]raclopride binding following AMPT administration. The increase in [11C]raclopride binding in the striatum was 11.1% (SD=4.4%) in healthy comparison subjects and 5.7% (SD=5.9%) in cocaine-dependent volunteers. Similar differences were seen in the subdivisions of the striatum. Thus, the decrease in striatal D2/D3 receptors associated with cocaine dependence cannot be attributed to higher levels of endogenous dopamine. Martinez D, Greene K, Broft A, et al. Lower level of endogenous dopamine in patients with cocaine dependence: Findings from PET imaging of D2/D3 receptors following acute dopamine depletion. Am J Psychiatry. 2009 Oct 1;166(10):1170-1177.
Momentary Reductions of Attention Permit Greater Processing of Irrelevant Stimuli
Weissman and colleagues at the University of Michigan used fMRI to investigate whether increased distraction from irrelevant stimuli can produce momentary reductions of attention which can have extremely adverse outcomes (e.g., during driving). To investigate this hypothesis, trial-by-trial relationships between brain activity and response time were determined in twenty healthy adults while they performed a cross-modal selective attention task. In each trial, participants identified a relevant visual letter while ignoring an irrelevant auditory letter, which was mapped either to the same response as the visual letter (congruent trials) or to a different response (incongruent trials). As predicted, reductions of attention (i.e., increases of response time) were associated not only with decreased activity in sensory regions that processed the relevant visual stimuli, suggesting a failure to enhance the processing of those stimuli, but also with increased activity in sensory regions that processed the irrelevant auditory stimuli, suggesting a failure to suppress the processing of those stimuli. Reductions of attention were also linked to larger increases of activity in incongruent than in congruent trials in anterior cingulate regions that detect response conflict, suggesting that failing to suppress the sensory processing of the irrelevant auditory stimuli during attentional reductions allowed those stimuli to more readily activate conflicting responses in incongruent trials. These findings indicate that heightened levels of distraction during momentary reductions of attention likely stem, at least in part, from increased processing of irrelevant stimuli. Weissman DH, Warner LM, Woldorff MG. Momentary reductions of attention permit greater processing of irrelevant stimuli. Neuroimage. 2009 Nov 15;48(3):609-615.
Risk Prediction and Aversion by Anterior Cingulate Cortex
Brown and Braver used fMRI to test whether the anterior cingulate cortex (ACC) and surrounding areas will become active in proportion to the perceived likelihood of an error (error-likelihood hypothesis). The hypothesis was originally derived from a computational model prediction. The same computational model now makes a further prediction that ACC will be sensitive not only to predicted error likelihood, but also to the predicted magnitude of the consequences, should an error occur. The product of error likelihood and predicted error consequence magnitude collectively defines the general "expected risk" of a given behavior in a manner analogous but orthogonal to subjective expected utility theory. The fMRI results from an incentive change signal task now replicate the error-likelihood effect, validate the further predictions of the computational model, and suggest why some segments of the population may fail to show an error-likelihood effect. In particular, error-likelihood effects and expected risk effects in general indicate greater sensitivity to earlier predictors of errors and are seen in risk-averse but not risk-tolerant individuals. Taken together, the results are consistent with an expected risk model of ACC and suggest that ACC may generally contribute to cognitive control by recruiting brain activity to avoid risk. Brown JW, Braver TS. Risk prediction and aversion by anterior cingulate cortex. Cogn Affect Behav Neurosci. 2007 Dec 7;(4):266-277.
Neural Correlates of Risk Prediction Error During Reinforcement Learning in Humans
Bechara and colleagues at the University of Southern California used fMRI to address how the human brain learns which decisions are risky. Reinforcement learning has never been used to estimate reward variance, a common measure of risk in economics and psychology. It is thus unknown which brain regions are involved in risk learning. To address this question, participants completed a decision-making task during fMRI. They chose repetitively from four decks of cards and each selection was followed by a stochastic payoff. Expected reward and risk differed among the decks. Participants' aim was to maximize payoffs. Risk and reward prediction errors were calculated after each payoff based on a novel reinforcement learning model. For reward prediction error, the strongest correlation was found with the BOLD response in the striatum. For risk prediction error, the strongest correlation was found with the BOLD responses in the insula and inferior frontal gyrus. The results suggest that risk and reward prediction errors are processed by distinct neural circuits during reinforcement learning. Additional analyses revealed that the BOLD response in the inferior frontal gyrus was more pronounced for risk aversive participants, suggesting that this region also serves to inhibit risky choices. d'Acremont M, Lu Z, Li X, Van der Linden M, Bechara A. Neural correlates of risk prediction error during reinforcement learning in humans. Neuroimage. 2009 Oct 1;47(4):1929-1939.
Neural Mechanisms Underlying Drug-Related Cue Distraction in Active Cocaine Users
Garavan and Hester at Trinity College used fMRI to investigate the neuronal basis of the difficulty that human drug abusers have with disengaging attention from drug-related stimuli, a symptom previously shown to be predictive of relapse during treatment. The neural mechanisms underlying this attentional bias in cocaine users was investigated by varying working memory (WM) load to reflect the demands imposed by ruminative craving thoughts. Sixteen active users of cocaine were administered a WM task that manipulated the requirement for selective attention by varying the background contents, cocaine-related or neutral, upon which a recall probe item was shown. Behavioral and fMRI data were collected. Cocaine users had significantly poorer attentional control under high WM demands, suffering both increased response times and reduced recall accuracy, with this effect more pronounced for cocaine stimuli (when compared to neutral stimuli). The presence of background cocaine stimuli was associated with increases in occipital cortex activity, consistent with increased visual processing of the irrelevant stimuli for these trials. In addition, the cocaine stimuli were associated with increased right prefrontal activity with those participants with higher levels of right prefrontal activity having lower levels of attentional bias. Cocaine users under high cognitive demands had difficulty modulating the neural mechanisms underlying cognitive control which appear necessary for restricting the visual processing of task-irrelevant, but salient, drug-related stimuli, a finding that may be relevant to identifying those at most risk of relapse. Hester R, Garavan H. Neural mechanisms underlying drug-related cue distraction in active cocaine users. Pharmacology Biochemistry and Behavior. 2009 Sep 93;(3):270-277.
Neural Responses to Sanction Threats in Two-Party Economic Exchange
Montague and colleagues at Baylor University used fMRI to investigate how sanctions used to enforce obedience to social norms are processed in the brain. Recent studies have demonstrated that cooperation is sometimes reduced when incentives meant to promote prosocial decisions are added to the environment. Although various explanations for this effect have been suggested, the neural foundations of the effect have not been fully explored. Using a modified trust game, it was found that trustees reciprocate relatively less when facing sanction threats, and that the presence of sanctions significantly reduces trustee's brain activity in regions involved in social reward valuation (ventromedial prefrontal cortex (VMPFC), lateral orbitofrontal cortex, and amygdala) while it simultaneously increases brain activity in the parietal cortex, which has been implicated in rational decision making. Moreover, neural activity in a trustee's VMPFC area predicted future level of cooperation under both sanction and no-sanction conditions, and this predictive activity was dynamically modulated by the presence of a sanction threat. Li J, Xiao E, Houser D, Montague P. Neural responses to sanction threats in two-party economic exchange. PNAS USA. 2009 Sep 29;106(39):16835-16840.
PET Imaging of the Effects of Age and Cocaine on the Norepinephrine Transporter in the Human Brain Using (S,S)-[(11)C]O-Methylreboxetine and HRRT
Ding and colleagues at Yale School of Medicine used a novel PET radiotracer to investigate the role of the norepinephrine transporter (NET) in cocaine dependence. This study used the most promising C-11 labeled positron-emission tomography (PET) radioligand for NET developed to date: (S,S)-[(11)C]methylreboxetine ([(11)C]MRB). 10 cocaine abusers (COC) and 12 healthy controls (HC)underwent dynamic (11)C-MRB-PET acquisition using a High Resolution Research Tomograph (HRRT). Binding potential (BP(ND)) parametric images were computed using the simplified reference tissue model (SRTM2) with occipital cortex as reference region. BP(ND) values were compared between the two groups. Locus coeruleus (LC), hypothalamus, and pulvinar showed a significant inverse correlation with age among HC (age range = 25-54 years). The BP(ND) was significantly increased in thalamus (27%) and dorsomedial thalamic nuclei (30%) in COC as compared to HC. Upon age normalization, the upregulation of NET in COC also reached significance in LC (63%) and pulvinar (55%) . These results suggest that (a) brain NET concentration declines with age in HC, and (b) there is a significant upregulation of NET in thalamus and dorsomedial thalamic nucleus in COC as compared to HC. These results demonstrate that [(11)C]MRB and HRRT provide an effective strategy for studying alterations of the NET system in humans. Ding Y, Singhal T, Planeta-Wilson B, et al. PET imaging of the effects of age and cocaine on the norepinephrine transporter in the human brain using (S,S)-[(11)C]O-methylreboxetine and HRRT. Synapse. 2010 Jan 64;(1):30-38.
Striatal Dopamine D2/D3 Receptor Availability Is Reduced in Methamphetamine Dependence and Is Linked to Impulsivity
London and colleagues at the University of California-Los Angeles investigated whether impulsivity is related to striatal dopamine D2/D3 receptor deficits in methamphetamine addicts. Methamphetamine-dependent and healthy control subjects were administered the Barratt Impulsiveness Scale (version 11, BIS-11) and had positron emission tomography scans with [18F]fallypride to measure striatal dopamine D2/D3 receptor availability. The methamphetamine-dependent subjects reported recent use of the drug 3.3 g per week, and a history of using methamphetamine, on average, for 12.5 years. Methamphetamine-dependent subjects had higher scores than healthy control subjects on all BIS-11 impulsiveness subscales. Volume-of-interest analysis found lower striatal D2/D3 receptor availability in methamphetamine-dependent than in healthy control subjects and a negative relationship between impulsiveness and striatal D2/D3 receptor availability in the caudate nucleus and nucleus accumbens that reached statistical significance in methamphetamine-dependent subjects. Combining data from both groups, voxelwise analysis indicated that impulsiveness was related to D2/D3 receptor availability in left caudate nucleus and right lateral putamen/claustrum. The findings suggest that low striatal D2/D3 receptor availability may mediate impulsive temperament and thereby influence addiction. Lee B, London ED, Poldrack RA, et al. Striatal dopamine D2/D3 receptor availability Is reduced in methamphetamine dependence and is linked to impulsivity. J. Neurosci. 2009 Nov 25;29(47):14734-14740.
Relation of Genetic Variability in the Dopamine Receptor D2 and Behavioral Inhibition and Impulsivity/Sensation Seeking
Hamidovic, de Wit and associates assessed the effects of d-amphetamine on healthy volunteers and assessed 12 SNPs and haplotypes in DRD2 in stop task performance and for self-rated impulsivity measures. Variants of two of the SNPs and a haplotype block containing them were associated with better performance on the stop task in the drug free condition and lower scores on an Impulsivity subscale. A variant of one of the SNPs was associated with a decreased stop reaction time with d-amphetamine. This SNP has been associated with DRD2 expression. Therefore it is concluded that genetic variation has an influence on behavioral and self-report measures of impulsivity. Hamidovic A, Dlugos A, Skol A, Palmer AA, de Wit H. Evaluation of genetic variability in the dopamine receptor D2 in relation to behavioral inhibition and impulsivity/sensation seeking: An exploratory study with d-amphetamine in healthy participants. Exptl Clin Psychopharm 2009;17(6):374-383.
High Impulsiveness Associated with Higher μ-Receptor Concentrations and Endogenous Opioid Activation
J-K Zubieta assessed binding potential in healthy men using PET and [11C]carfentanil both at rest and during a (pain) stress challenge. The NEO personality inventory was used determine impulsivity (tendency to act without careful consideration to obtain more immediate gratification) which is believed to be related to problem behaviors such as drug use. Greater binding potential for the μ-receptor was seen for subjects with high impulsivity scores in the right anterior cingulate, right ventral basal ganglia (nucleus accumbens and ventral pallidum), and basolateral area of the right amygdala. When stressed with induced pain, those with the high scores demonstrated significantly greater activation of μ-receptor-mediated neurotransmission. These effects accounted for up to half the variance in trait scores (impulsivity) and provide the first evidence in humans that behavioral facets relevant to motivated behavior—the pursuit of reward, and risk-taking both associated with drug abuse—are related to the individual function of the endogenous opioid system. Love TF, Stohler CS, Zubieta J-K. Positron emission tomography measures of endogenous opioid neurotransmission and impulsiveness traits in humans. Arch Gen Psychiat. 2009 Oct;66(10):1124-1134.
Enhanced Striatal Recruitment by Prospective Immediate Rewards Relative to Equally-Preferred Delayed Rewards
Drug abusers are characterized by severe discounting of delayed rewards. John Monterosso and colleagues at the University of Southern California used fMRI to examine the response of incentive-motivational neurocircuitry to immediate and delayed prospective rewards that were equally preferred by the subject in pre-scan behavioral testing. Anatomical region of interest analysis as well as whole-brain analysis indicated greater response recruited by the immediate rewards (relative to the preference-matched delayed rewards) in regions previously implicated as sensitive to incentive value using the same task (including bilateral putamen, bilateral anterior insula, and midbrain). Reaction time to the target was also faster during the immediate relative to delayed reward trials (p < 0.01), and individual differences in reaction time between immediate versus delayed reward trials correlated positively with variance in magnetic resonance signal in those clusters that responded preferentially to immediate rewards. These findings indicate a discrepancy in incentives associated with the immediate versus the preference-matched delayed rewards. This discrepancy may mark the contribution of self-control processes that are recruited during decision-making but that are absent when rewards are individually anticipated. That this difference in motivational neurocircuitry recruitment was detected in healthy controls suggests that this may contribute to pronounced preference for immediate gratification in drug abusers. Luo S, Ainslie G, Giragosian L, Monterosso JR. Behavioral and neural evidence of incentive bias for immediate rewards relative to preference-matched delayed rewards. J Neurosci. 2009 Nov 25;29(47):14820-14827.
The Neurocircuitry of Impaired Insight in Drug Addiction
More than 80% of addicted individuals fail to seek treatment, which might reflect impairments in recognition of severity of disorder. Considered by some as intentional deception, such 'denial' might instead reflect dysfunction of brain networks subserving insight and self-awareness. This review covers the scant literature on insight in addiction and integrates this perspective with the role of: (i) the insula in interoception, self-awareness and drug craving; (ii) the anterior cingulate in behavioral monitoring and response selection (relevant to disadvantageous choices in addiction); (iii) the dorsal striatum in automatic habit formation; and (iv) drug-related stimuli that predict emotional behavior in addicted individuals, even without conscious awareness. Implications for clinical treatment, including the design of interventions to improve insight into illness severity in addiction are discussed. Goldstein RZ, Craig ADB, Bechara A, Garavan H, Childress AR, Paulus MP, Volkow ND. The neurocircuitry of impaired insight in drug addiction. Trends Cogn. Sci. (Regul. Ed.). 2009 Sep 13;(9):372-380.
The Role of Interoception and Alliesthesia in Addiction
Paulus and colleagues propose a novel conceptualization of addiction, integrating the concepts of interoception (i.e., the CNS representation of visceral feelings) and alliesthesia (i.e., that rewarding properties of stimuli are dependent on the internal state of the individual) with existing theories. It is argued that the body state, as defined by the integration of interoceptive information, is a crucial arbiter of the risk for initiation of and transition to compulsive use of addictive compounds. Overall, individuals at risk for drug dependence are characterized by an altered internal bodily state that leads to a change in hedonic and incentive motivational properties of addictive drugs. Specifically, drug dependent individuals experience alliesthesia of interoceptive processing, leading to increased incentive motivational properties of the drug over time and thereby increasing the probability of subsequent use. This extension of previous theories of addiction to include interoception and alliesthesia is based upon a clearly delineated set of neural substrates mediating interoception, key elements of which also recently have been implicated in drug addiction. The model thereby provides new potential targets for interventions that are aimed at changing the internal state that puts the individual at risk for continued substance use. Paulus MP, Tapert SF, Schulteis G. The role of interoception and alliesthesia in addiction. Pharmacol Biochem Behav. 2009 Nov 94;(1):1-7.
The Role of the Dorsal Anterior Cingulate in Evaluating Behavior for Achieving Gains and Avoiding Losses
Garavan and colleagues at Trinity University investigated how effective goal-directed behavior relies on a network of regions including anterior cingulate cortex and ventral striatum to learn from negative outcomes in order to improve performance. This study also investigated whether this frontal-striatal system is involved in instances of behavior that do not presume negative circumstances. Participants performed a visual target/nontarget search game in which they could optionally abort a trial to avoid errors or receive extra reward for highly confident responses. Anterior cingulate and prefrontal cortex were equally activated for error avoidance and high reward trials but were not active on error trials, demonstrating their primary involvement in self-initiated behavioral adjustment and not error detection or prediction. In contrast, the insula and the ventral striatum were responsive to the high reward trials. Differential activation patterns across conditions for the nucleus accumbens, insula, and prefrontal cortex suggest distinct roles for these structures in the control of reward-related behavior. Magno E, Simões-Franklin C, Robertson IH, Garavan H. The role of the dorsal anterior cingulate in evaluating behavior for achieving gains and avoiding losses. J Cogn Neurosci. 2009 Dec 21;(12):2328-2342.
Worth the ‘EEfRT'? The Effort Expenditure for Rewards Task as an Objective Measure of Motivation and Anhedonia
Zald and colleagues at Vanderbilt University used a novel behavioral paradigm as a means of exploring effort-based decision-making in humans. Drug abuse is generally assumed to reflect aberrant motivation and reward responsivity. However, research has been limited by a lack of objective measures of reward motivation. The Effort-Expenditure for Rewards Task (EEfRT or "effort") was used to test the hypothesis that effort-based decision-making is related to trait anhedonia. 61 subjects completed self-report measures of mood and trait anhedonia, and completed the EEfRT. Across multiple analyses, a significant inverse relationship between anhedonia and willingness to expend effort for rewards was found. These findings suggest that anhedonia is specifically associated with decreased motivation for rewards, and provide initial validation for the EEfRT as a laboratory-based behavioral measure of reward motivation and effort-based decision-making in humans. Treadway MT, Buckholtz JW, Schwartzman AN, Lambert WE, Zald DH. Worth the ‘EEfRT'? The effort expenditure for rewards task as an objective measure of motivation and anhedonia. PLoS ONE. 2009;4(8):e6598.
Traditional Chinese Acupuncture and Placebo (Sham) Acupuncture are Differentiated by their Effects on Mu-Opioid Receptors (MORs)
Zubieta and colleagues at the University of Michigan used PET receptor imaging to investigate whether acupuncture analgesia involves the activation of endogenous opioid antinociceptive systems and mu-opioid receptors (MORs). This is also a neurotransmitter system that mediates the effects of placebo-induced analgesia. This overlap in potential mechanisms may explain the lack of differentiation between traditional acupuncture and either non-traditional or sham acupuncture in multiple controlled clinical trials. The short- and long-term effects of traditional Chinese acupuncture (TA) were compared with sham acupuncture (SA) treatment on in vivo MOR binding availability in chronic pain patients diagnosed with fibromyalgia (FM). Patients were randomized to receive either TA or SA treatment over the course of 4 weeks. Positron emission tomography (PET) with C-11-carfentanil was performed once during the first treatment session and then repeated a month later following the eighth treatment. Acupuncture therapy evoked short-term increases in MOR binding potential in multiple pain and sensory processing regions including the cingulate (dorsal and subgenual), insula, caudate, thalamus, and amygdala. Acupuncture therapy also evoked long-term increases in MOR binding potential in some of the same structures including the cingulate (dorsal and perigenual), caudate, and amygdala. These short- and long-term effects were absent in the sham group where small reductions were observed, an effect more consistent with previous placebo PET studies. Long-term increases in MOR BP following TA were also associated with greater reductions in clinical pain. These findings suggest that divergent MOR processes may mediate clinically relevant analgesic effects for acupuncture and sham acupuncture, Harris R, Zubieta J, Scott D, Napadow V, Gracely R, Clauw D. Traditional Chinese acupuncture and placebo (sham) acupuncture are differentiated by their effects on mu-opioid receptors (MORs). Neuroimage. 2009 Sep 47;(3):1077-1085.