Research Findings - Clinical Neuroscience Research

Cue-Induced Stress Increases Craving and HPA Responses in More Frequent Users of Cocaine and Alcohol Relative to Less Frequent Users

Rajita Sinha and colleagues provided stressful or drug-related (and neutral) scripts of personal relevance to treatment-seeking cocaine dependent patients followed by self-report assessment of craving and anxiety as well as physiological measures including those associated with the HPA axis (e.g., heart rate, blood pressure, cortisol, ACTH). Results demonstrated that the more frequent users had enhanced drug craving and subjective anxiety plus a hypersensitivity to the HPA axis measured by increases in ACTH, cortisol, and prolactin (compared to a neutral condition). These findings suggest a facilitation of neuroendocrine response and may indicate an increased vulnerability whereby induced stress may enhance drug-taking in the first place and hasten relapse in those seeking treatment. Fox, H.C., Talih, M., Malison, R., Anderson, G.M., Kreek, M.J. and Sinha, R. Psychoneuroendocrinology, 30, pp. 880-891, 2005.

Treatment-Engaged Cocaine Patients Different in Brain Areas Activated in a Cue-Induced Stress Paradigm

Sinha and colleagues used fMRI BOLD to assess activation in cocaine patients in treatment while they listened to a personalized script description of a stressful event in their lives. Compared to controls, there was less activation in the anterior cingulate region, left hippocampal/parahippocampal region right fusiform gyrus, and the right postcentral gyrus. The patients had increased activity in the caudate and dorsal striatum; these activations were significantly associated with stress-induced craving ratings. The results are interpreted as patients having reduced control of emotion and distress during stress but increased reward circuitry which may be related to craving. Sinha, R., Lacadie, C., Skudlarski, P., Fulbright, R.K., Rounsaville, B.J., Koston, T.R., and Wexler, B.E. Psychopharmacology, Online: DOI 10.1007/s00213-005-0147-8, September 15, 2005.

Evidence for a Molecular Genetic Basis for Comorbidity between Dependence Vulnerability and Antisocial Behavior

Stallings and colleagues in Crowley's group used symptom counts in a Quantitative Trait Locus analysis in clinic-referred adolescents to search for a common gene or genes underlying both dependence vulnerability and conduct disorder symptoms. In single and multiple point analysis, the strongest peak was observed on chromosome 9q34 (near markers D9S1826 and D9S1838) with a LOD score of 2.65. Another peak for comorbidity was found on chromosome 3 though the larger contribution came from dependence vulnerability alone. A third peak for conduct disorder symptoms was found on chromosome 17. These data demonstrate a possible underlying etiology for these comorbid conditions. Stallings, M.C., Corley, R.P., Dennehey, B., Hewitt, J.K., Krauter, K.S., Lessem J.M., Mikulich-Gilbertson, S.K., Rhee, S.H., Smolen, A., Young, S.E., and Crowley, T.J. Archives of General Psychiatry, 62, pp. 1042-1051, 2005.

ADH4 Gene Variation is Associated With Alcohol and Drug Dependence

In a follow-up study Gelernter and associates confirmed a previously reported association between alcohol and drug dependence and the ADH4 gene after controlling for population stratification and admixture effects. In addition, seven SNPs at the ADH4 locus were genotyped; those at SNP2 (rs1042363) were significantly associated with drug (mainly cocaine) dependence as well as alcohol dependence. Also, one seven-variant haplotype and one diplotype were significantly associated with alcohol dependence and other seven-variant diplotypes were significantly associated with drug dependence-both opiate and cocaine. It is concluded that variation at ADH4 predisposes to alcohol and drug dependence. Luo, X., Kranzler, H.R., Lingjun, Z., Yan, B., Lappalainen, J. and Gelernter, J. Pharmacogenetics and Genomics, 15, pp. 755-768, 2005.

Sleep Quality Deteriorates During Abstinence From Binge Cocaine

In a collaboration between J. Allan Hobson of Harvard and the late Marian Fischman of Columbia, several aspects of sleep and sleep architecture were investigated in a 3-week, inpatient protocol where chronic cocaine users were given binge doses of cocaine followed by 2 weeks abstinence. Sleep monitors demonstrated deterioration in several aspects of sleep including, total sleep time, sleep efficiency, and sleep onset time. However, in spite of these objective measures of deteriorating sleep, the subjects did not report them subjectively. This was true even though some of the measures fell within the range of insomnia patients. Also shortened REM latency was in the range reported for patients with major depression. These data cannot distinguish whether these sleep disturbances preceded chronic cocaine use or were consequences of it. However, since similar neurotransmitter systems are involved (e.g., the dopamine system), further studies are encouraged of sleep disturbances in relation to drug-taking. Pace-Schott, E.F., Stickgold, R., Muzur, A., Wigren, P.E., Ward, A.S., Hart, C.L., Clarke, D., Morgan, A. and Hobson, J.A. Psychopharmacology, 179, pp. 873-883, 2005.

Further Evidence Where Brain Activation in Cannabis Abusers is Adversely Affected

Sinha and colleagues assessed cerebral activation using BOLD during a script-guided stress-inducing script in cocaine dependent individuals. When the group was divided into those who also were or were not concurrent cannabis abusers, it was demonstrated that the cannabis users had hypo-activation in frontal areas in the perigenual anterior cingulate during increased emotional stress. These results were found despite similar changes in physiological and behavioral anxiety measures during the script-induced emotional stress imagery. It is concluded that cannabis has a specific effect when taken together with cocaine in cocaine abusers. Li, C-s., R. Milivojenic, V., Constable, R.T. and Sinha, R. Psychiatry Research: Neuroimaging, 140, pp. 271-280, 2005.

fMRI-Acoustic Noise Alters Brain Activation During Working Memory Tasks

Chang and colleagues at University of Hawaii studied the effects of scanner noise during functional magnetic resonance imaging (fMRI) to determine level of interference with brain function and change blood oxygenation level dependent (BOLD) signals. The effect of increased acoustic noise on fMRI during verbal working memory (WM) processing was studied with the sound pressure level of scanner noise increasing from ''Quiet'' to ''Loud'' echo planar imaging (EPI) scans. A WM paradigm with graded levels of task difficulty was used to further access WM load. Increased scanner noise produced increased BOLD responses (percent signal change) bilaterally in the cerebellum, inferior (IFG), medial (medFG), and superior (SFG) frontal, fusiform (FusG), and the lingual (LG) gyri, and decreased BOLD responses bilaterally in the anterior cingulate gyrus (ACG) and the putamen. This finding suggests greater recruitment of attention resources in these brain regions, probably to compensate for interference due to louder scanner noise. Increased working memory load increased the BOLD signals in IFG and the cerebellum, but decreased the BOLD signals in the putamen and the LG. These findings also support the idea that brain function requires additional attention resources under noisier conditions. Load- and acoustic-noise-related changes in BOLD responses correlated negatively in the WM network. This study demonstrates that MR noise affects brain activation pattern. Future comparisons between studies performed under different acoustic conditions (due to differing magnetic field strengths, pulse sequences, or scanner manufacturers) might require knowledge of the sound pressure level of acoustic noise during fMRI. Tomasi, D., Carperelli, E.C., Chang, L., Ernst, T. Neuroimage, 27, pp. 377- 386, 2005.

Cerebral Metabolic Dysfunction and Impaired Vigilance in Recently Abstinent Methamphetamine Abusers

London and colleagues at UCLA assessed cerebral glucose metabolism (rCMRglc) with [F-18]fluorodeoxyglucose positron emission tomography in 17 abstinent (4 to 7 days) methamphetamine (MA) users and 16 control subjects performing an auditory vigilance task and obtained structural magnetic resonance brain scans. Error rates on the task were related to rCMRglc and hippocampal morphology. MA abusers had higher error rates than control subjects on the vigilance task. The groups showed different relationships between error rates and relative activity in the anterior and middle cingulate gyrus and the insula. Whereas the MA user group showed negative correlations involving these regions, the control group showed positive correlations involving the cingulate cortex. Across groups, hippocampal metabolic and structural measures were negatively correlated with error rates. Dysfunction in the cingulate and insular cortices of recently abstinent MA abusers contribute to impaired vigilance and other cognitive functions requiring sustained attention. Hippocampal integrity predicts task performance in methamphetamine users as well as control subjects. London, E.D., Berman, S.M., Voytek, B., Simon, S., Mandelkern, M.A., Monterrosa, J., Thompson, P.M.., Brody, A.L., Geagas, J.A., Hong, M.S., Hayashi, K.M., Rawson, R.A., Ling, W. Biological Psychiatry, 58(10), pp. 770-778, 2005.

Neurocognitive Features of HCV Infection in Drug Users: Potential Challenges and Lessons Learned

Gonzalez and colleagues at the University of Illinois, Chicago, conducted a review of the literature on similarities between human immunodeficiency virus (HIV) and HCV infection in their neurocognitive features. Injection drug users are at high risk of acquiring HCV infection, and the majority of HCV-infected persons are substance dependent. Examining neurocognitive functions among HCV positive substance-dependent persons is a challenging, but by no means impossible, endeavor. Experiences from investigations of HIV infection and neurocognition, which have a relatively long scientific history, may help in providing direction for future investigations of HCV infection. They discuss challenges associated with research among drug users, advocate that the HIV literature can usefully inform studies of HCV, and review their own findings on neurocognition among substance users with HIV and/or HCV infection. Gonzalez, R., Jacobus, J., Martin. E.M. Clinical Infectious Disease; 41 Suppl. 1, pp. S45-S49, 2005.

Association Between Smoking and ADHD in Young Adults

Scott and colleagues at Duke University evaluated the relation between smoking-related variables and the number of retrospectively reported ADHD inattentive and hyperactive/ impulsive symptoms in a sample of young adults. The study population consists of 15,197 eligible participants from wave III of the National Longitudinal Study of Adolescent Health, a nationally representative sample of adolescents followed from 1995 to 2002. Logistic regression was used to examine the relation between self-reported ADHD symptoms and the lifetime likelihood of being a regular smoker, defined by having smoked at least 1 cigarette a day for 30 days. For individuals reporting regular smoking, the extent to which ADHD symptoms predicted age at onset of regular smoking was related to the number of cigarettes smoked: A linear relation was identified between the number of self-reported inattentive and hyperactive/impulsive symptoms and smoking outcome measures. Controlling for demographic and conduct disorder symptoms, each reported inattention and hyperactivity/impulsivity symptom significantly increased the likelihood of regular smoking. For those reporting lifetime regular smoking, reported symptoms decreased the estimated age at onset and increased the number of cigarettes smoked: Self-reported ADHD symptoms were found to be associated with adult smoking outcome variables in this nationally representative sample, providing further evidence of a likely link between ADHD symptoms and risk for tobacco use. Scott H., Kollins, S.H., McClernon, F.J. and Fuemmeler, B.F. Archives General Psychiatry. 62, pp. 1142-1147, 2005.

Frontal Glucose Hypometabolism in Abstinent Methamphetamine Users

Renshaw and colleagues at McLean Hospital and in Korea examined changes in relative regional cerebral glucose metabolism (rCMRglc) and potential gender differences in abstinent methamphetamine (METH) users. Relative rCMRglc was measured by 18F-fluorodeoxyglucose PET. Frontal executive functions, as assessed by Wisconsin card sorting test (WCST), were compared between 35 abstinent METH users and 21 healthy comparison subjects. In addition, male and female METH users and their gender-matched comparison subjects were compared to investigate potential gender differences. METH users had lower rCMRglc levels in the right superior frontal white matter and more perseveration and nonperseveration errors in the WCST, relative to healthy comparison subjects. Relative rCMRglc in the frontal white matter correlated with number of errors in the WCST in METH users. In the subanalysis for gender differences, lower rCMRglc in the frontal white matter and more errors in the WCST were found only in male METH users, not in female METH users, relative to their gender-matched comparison subjects. The current findings suggest that METH use causes persistent hypometabolism in the frontal white matter and impairment in frontal executive function. These findings also suggest that the neurotoxic effect of METH on frontal lobes of the brain might be more prominent in men than in women. Kim, S.J., Lyoo, I.K, Hwang, J., Young, H.S., Lee, H.L, Lee, D.S., Jeong, D. and Renshaw P. Neuropsychopharmacology, 30, pp. 1383-1391, 2005.

Prefrontal GABA Levels in Cocaine-Dependent Subjects Increase with Pramipexole and Venlafaxine Treatment

Streeter and colleagues at McLean Hospital measured changes in GABA levels in cocaine dependent (CD) subjects at baseline and after 8 weeks of treatment with pramipexole, venlafaxine, or placebo using proton (1H) magnetic resonance spectroscopy (MRS). CD subjects enrolled in a treatment trial for cocaine dependence were recruited for this study. GABA levels in the prefrontal lobe were measured before and after treatment. Mean percentage changes in GABA levels were as follows: Pramipexole +17.0±28.0%, venlafaxine +13.0±11.0%, and placebo _2.1±19.5%. Pramipexole-treated subjects had significantly increased brain GABA levels compared to placebo (p=0.031). Venlafaxine treatment was not significantly associated with increased GABA levels compared to placebo. The overall effect of drug treatment vs. placebo on brain GABA levels, including adjustment for baseline levels, was highly significant. Despite significant changes in GABA levels, there were no significant differences in the number of urine samples positive for cocaine metabolites. This study demonstrates that 1H MRS can measure changes in GABA levels following pharmacologic treatment. The increase in GABA levels, although significant, is modest compared to other MRS studies of depression or epilepsy associated with clinical improvements. The failure to see larger increases in GABA levels and an associated reduction in cocaine consumption may reflect the relatively low doses of medication used. Streeter, C.C., Hennen, J., Ke. Y., Jensen, J.E., Sarid-Segal O., Nassar, L.E., Knapp, C., Meyer, A.A., Twak, T., Renshaw, P. and Ciraulo, D.A. Psychopharmacology, 182, pp. 516-526, 2005.

Increased White Matter Hyperintensities in Male Methamphetamine Abusers

Renshaw and colleagues at McLean Hospital and in Korea used structural MRI to compare the prevalence, severity, and location of white matter signal hyperintensities (WMH) in methamphetamine (METH) abusers. Thirty-three METH abusers and 32 age- and gender-matched healthy comparison subjects were studied. Axial T-2 weighted images and fluid attenuated inversion recovery axial images were obtained using a 3.0 T MR scanner. The severity of WMH was assessed separately for deep and periventricular WMH. Ordinal logistic regression models were used to assess the odds ratio for WMH. The METH abusers had greater severity of WMH than the healthy comparison subjects (odds ratio: 7.06, 8.46, and 4.56 for all, deep, and periventricular WMH, respectively). Severity of deep WMH correlated with total cumulative dose of METH. Male METH abusers had greater severity of WMH than female METH abusers. Although male METH abusers had greater severity of WMH than male comparison subjects, there was no significant difference in WMH severity between female METH abusers and female comparison subjects. The current study reports increased WMH in METH abusers, which may be related to METH-induced cerebral perfusion deficits. In addition, female METH abusers had less severe WMH than male METH abusers, possibly due to estrogen's protective effect against ischemic or neurotoxic effects of METH. Bae, C.S, Lyoo, I.K., Sung, Y.H., Yoo, J., Yoon, C.S.J., Kimd, D-J., Hwang, D.W., Kime, S.J. and Renshaw, P. Drug and Alcohol Dependence, 81, pp. 83-88, 2006.

Functional Neuroanatomical Substrates of Altered Reward Processing in Major Depressive Disorder

Trembly and colleagues at the University of Toronto used fMRI to determine the brain mechanisms of anhedonia in major depressions. The hypothesis that a hypersensitive response to increased dopaminergic function in major depression involves the prefrontal cortex and the striatum was tested by administration of dextroamphetamine sulfate. FMRI scans were acquired in a single session while the subject performed a simple attention task before and after single-blind administration of a 30-mg dose of oral dextroamphetamine. Twelve depressed subjects (mean age, 34.8 years, male-female ratio, 6), who met criteria for major depressive disorder (MDD) according to the DSM-IV, were not taking antidepressants, and had no comorbid Axis I disorders were compared to twelve healthy control subjects (mean age, 29.3 years, male-female ratio, 5). Dextroamphetamine-induced subjective effects were assessed using the Addiction Research Center Inventory. Subjects with major depression had a 2 fold larger subjective rewarding effects of dextroamphetamine compared to controls. Depressed subjects also had altered brain activation in response to amphetamine in the ventrolateral prefrontal cortex and the orbitofrontal cortex and the caudate and putamen. Theses results demonstrate that dopamine-related neuroanatomical substrates are involved in altered reward processing in MDD, suggesting that self-medication efforts may drive stimulant abuse in subjects with depression. Tremblay, L.K., Naranjo, C.A., Graham, S.J., Herrmann, N., Mayberg, H.S., Hevenor, S. and Busto, U.E. Arch Gen Psychiatry 62(11), pp. 1228-1236, 2005.

The Airway Sensory Impact of Nicotine Contributes to the Conditioned Reinforcing Effects of Individual Puffs from Cigarettes

Naqvi and Bechara at the University of Iowa examined the extent to which reward from cigarette smoking can be derived from the airway sensory effect of nicotine, in the absence of a direct central nervous system effect of nicotine. They measured self-reported increases in reward in response to individual puffs from nicotinized, denicotinized and unlit cigarettes within 7 s of inhalation, which is before nicotine had an opportunity to reach the brain. In addition, self-reported strength of airway sensations elicited by the puffs were obtained. Nicotinized puffs were rated as both stronger and more rewarding than denicotinized and unlit puffs, and the extent to which nicotine elicited reward was directly correlated with the extent to which nicotine elicited airway sensations. These results indicate that the airway sensory effects of nicotine contribute to the reward from puffs, above and beyond the reward derived from the airway sensory effects of non-nicotine constituents. These findings have implications for the interpretation of studies that use puffs as experimental units to examine nicotine reward. They also have implications for the use of denicotinized and low nicotine cigarettes as aids to smoking cessation. Naqvi, N.H. and Bechara, A. Pharmacology Biochemistry and Behavior, 81(4), pp. 821-829, 2005.

Smoking Expectancy Modulates Cue-Elicited Neural Activity

Wilson and colleagues at the University of Pittsburgh used fMRI to identify how brain activity during cue-induced drug craving is modulated by expectations regarding the opportunity to use a drug.. Male cigarette smokers deprived of nicotine for 8 hr were scanned during exposure to neutral (e.g., roll of tape) and smoking-related (a cigarette) stimuli after being instructed that they would or would not be able to smoke after the scans. As predicted, several brain regions (e.g., the anterior cingulate cortex) exhibited differential activation during cigarette versus neutral cue exposure. Moreover, they found that subregions of the prefrontal cortex (i.e., ventromedial, ventrolateral, and dorsolateral prefrontal cortices) showed cue-elicited activation that was modulated by smoking expectancy. These results highlight the importance of perceived drug use opportunity in the neurobiological response to drug cues. Wilson, S.J., Sayette, M.A., Delgado, M.R. and Fiez, J.A. Nicotine Tob Res., 7(4), pp. 637-645, 2005.

Abstinence-Induced Changes In Self-Report Craving Correlate With Event-Related fMRI Responses to Smoking Cues

McClernon and colleagues at Duke University used event-related fMRI to evaluate the stability of event-related responses to visual drug cues following smoking-as-usual and following overnight abstinence. In addition, self-reported craving measures were obtained before, during, and after scanning. Thirteen regions of interest were selected for analysis in a cohort of 13 dependent smokers. Responses to smoking cues were larger than to control cues in ventral anterior cingulate gyrus (vACG) and superior frontal gyrus. Responses to smoking cues in these and all other regions revealed no effects of abstinence/satiety, thus supporting the notion that cue-elicited brain responses are relatively stable. However, while the abstinence manipulation did not alter group-level responses to smoking cues, at the individual level, abstinence-induced changes in craving (abstinence minus satiety) were positively correlated with changes in fMRI response amplitude to smoking cues in frontal regions including left inferior frontal gyrus, left vACG, and bilateral middle frontal gyrus. These results suggest that brain responses to smoking cues, while relatively stable at the group level following short-term abstinence, may be modulated by individual differences in craving in response to abstinence-particularly in regions subserving attention and motivation. McClernon, F.J., Hiott, F.B., Huettel, S.A. and Rose, J.E. Neuropsychopharmacology, 30(10), pp. 1940-1947, 2005.

Decision Making, Impulse Control and Loss of Willpower to Resist Drugs: A Neurocognitive Perspective

Based on a review of the literature, Bechara at the University of Iowa concludes that that addicted people become unable to make drug-use choices on the basis of long-term outcome, and proposes a neural framework that explains this myopia for future consequences. He suggests that addiction is the product of an imbalance between two separate, but interacting, neural systems that control decision making, i.e., an impulsive, amygdala system for signaling pain or pleasure of immediate prospects, and a reflective, prefrontal cortex system for signaling pain or pleasure of future prospects. After an individual learns social rules, the reflective system controls the impulsive system via several mechanisms. However, this control is not absolute, because hyperactivity within the impulsive system can override the reflective system. He proposes that drugs can trigger bottom-up, involuntary signals originating from the amygdala that modulate, bias or even hijack the goal-driven cognitive resources that are needed for the normal operation of the reflective system and for exercising the willpower to resist drugs. Bechara, A. Nature Neuroscience 8(11), pp. 1458-1463, 2005.

Modulation of Prefrontal Cortex Activity by Information Toward a Decision Rule

Huettel and Misiurek at the Duke University used fMRI to investigate how the information content of a stimulus influences activity in brain systems that support decision making in healthy subjects. Subjects learned decision rules based upon the color, shape, or fill pattern of a series of stimuli. Each stimulus was classified by its information content, defined formally by the decision rules it excluded. While activity in dorsolateral prefrontal cortex (DLPFC) increased with increasing stimulus information, activity in the striatum did not. In contrast, within both the striatum and DLPFC, stimuli consistent with the rule evoked greater activity than stimuli inconsistent with the rule. This dissociation indicates that DLPFC supports modification of sets of stimulus-response contingencies while the striatum supports stimulus-specific learning. These results provide a foundation to examine how impaired frontal function may alter specific aspects of decision-making in substance abusers. Huettel S.A. and Misiurek, J. Neuroreport, 15(12), pp. 1883-1886, 2004.

Selective Activation of the Nucleus Accumbens during Risk-Taking Decision Making

Paulus and colleagues at the University of California, San Diego used fMRI to probe the brain circuitry involved in risk-taking decision-making in 12 healthy control subjects. Deliberation prior to selection of safe relative to risky responses generated greater activation in the inferior frontal cortex, superior temporal gyrus, and middle temporal gyrus. In contrast, deliberation prior to selection of risky relative to safe responses generated greater activation in medial frontal cortex, occipital cortex, nucleus accumbens and caudate. Additionally, nucleus accumbens activation correlated positively with the harm avoidance subscale of the Temperament and Character Inventory (TCI) 125. These findings may provide target neural systems to study in substance abusing subjects who exhibit problematic risk-taking behaviors. Matthews S.C, Simmons A.N., Lane, S.D., Paulus, M.P. Neuroreport, 15(13), pp. 2123-2127, 2004.

Reward Sensitivity in Impulsivity

Potts and Martin at Rice University used even-related potentials to investigate the neural basis of impulsivity as expressed as choosing immediate small over delayed larger rewards. The anterior P2a event-related potential component was used as an index of reward-related orbitofrontal activity. In subjects higher on self-reported impulsiveness, the P2a was largest to non-predicted rewards and smallest in the absence of predicted rewards, consistent with the hypothesis of reward hypersensitivity in impulsivity. Martin L.E. and Potts, G.F. Neuroreport ,15(9), pp. 1519-1522, 2004.

MDMA Affects Both Error-Rate Dependent and Independent Aspects of Decision-Making in a Two-Choice Prediction Task

Paulus and colleagues examined whether MDMA alters decision-making in a way that depends on the manipulations of error rate, i.e., the degree of success and outcome. Forty-two normal, healthy volunteers were given placebo or 1.5 mg/kg p.o. MDMA in a randomized crossover design. Subjects completed the two-choice prediction task 120 min after administration of the drug. Decision-making characteristics were obtained at 20% error rate, 50% error rate or 80% error rate. MDMA did not significantly alter basic response characteristics such as response latency or switching. Rather, MDMA effects on decision-making were dependent on the error rate. MDMA increased the degree to which the previous stimulus influenced the selection of the current response at 20%, 50% or 80% error rate. At low error rates (i.e., high success rates), administration of MDMA increased the degree to which the previous response predicted the current response and the average response sequence predictability. Self-assessment of the psychological state induced by MDMA did not predict the MDMA induced decision-making patterns. These results support the hypothesis that acute administration of MDMA affects success-related response selection during decision-making. These results suggest that MDMA abuse may increase the likelihood of engaging in risky behavior mainly under conditions of initial success. Vollenweider, F.X., Liechti, M.E. and Paulus, M.P. Journal of Psychopharmacology, 19(4), pp. 366-374, 2005.

Probing Reward Function in Post-Traumatic Stress Disorder with Beautiful Facial Images

Elman and colleagues at McLean Hospital investigated dysfunction of reward processing in post-traumatic stress disorder (PTSD). Male heterosexual Vietnam veterans with (n = 12) or without (n = 11) current PTSD were administered two tasks: (a) key pressing to change the viewing time of average or beautiful female or male facial images, and (b) rating the attractiveness of these images. There were no significant group differences in the attractiveness ratings. However, PTSD patients expended less effort to extend the viewing time of the beautiful female faces. These findings suggest a reward deficit in PTSD, and may contribute to the high incidence of substance abuse in patients with PTSD. Elman, I., Ariely, D., Mazar, N., Aharon, I., Lasko, N.B., Macklin, M., Orr, S.P., Lukas, S.E. and Pitman, R.K. Psychiatry Research, 135(3), pp. 179-183, 2005.

Quantitative PET Studies of the Serotonin Transporter in MDMA Users and Controls Using [C-11]Mcn5652 and [C-11]DASB

McCann and colleagues at Johns Hopkins Medical School used a novel PET ligand to follow-up on their initial report of loss of serotonergic makers in humans MDMA abusers. In the present study, 23 abstinent MDMA users and 19 non-MDMA controls underwent quantitative positron emission tomography (PET) studies using [C-11]McN5652 and [C-11]DASB, first- and second-generation serotonin transporter (SERT) ligands previously validated in baboons for detecting MDMA-induced brain serotonin neurotoxicity. Global and regional distribution volumes and two additional SERT-binding parameters were compared in the two subject populations using parametric statistical analyses. Strong correlations existed between the various binding parameters of [C-11] McN5652 and [C-11]DASB, both in individual brain regions and individual subjects. Global SERT reductions were found in MDMA users with both PET ligands, using all three of the above-mentioned SERT-binding parameters. Preplanned comparisons in 15 regions of interest demonstrated reductions in selected cortical and subcortical structures. Exploratory correlational analyses suggested that SERT measures recover with time, and that loss of the SERT is directly associated with MDMA use intensity. These quantitative PET data, obtained using validated first- and second-generation SERT PET ligands, provide strong evidence of reduced SERT density in some recreational MDMA users. McCann, U.D., Szabo, Z., Seckin, E., Rosenblatt, P., Mathews, W.B., Ravert, H.T., Dannals, R.F. and Ricaurte G.A. Neuropsychopharmacology, 30(9), pp. 1741-1750, 2005.

Regional Activation in the Striatum Is Related to Successful Learning in an Implicit Cognitive Task

Paulus and colleagues at the University of California, San Diego used fMRI to test whether striatal involvement in implicit learning depends on successful learning. Fifteen healthy normal subjects performed an implicit learning task, i.e., a task where subjects acquire a behavior without being necessarily aware of the rules governing the behavior. Dorsal and ventral striatum activation was observed in the eight participants who demonstrated implicit learning. Ventral striatum activations occurred to a greater extent in implicit learning versus non-implicit learning participants, and were correlated with the degree of reaction time advantage in implicit learning participants, even after controlling for general decreases in reaction time over time. These findings strengthen the specificity of the striatum in implicit learning and are suggestive of a dissociation of striatal regions relative to elements of implicit learning performance. These results provide a foundation for testing for the cognitive consequences of striatal dysfunction in substance abusers. Reiss J.P., Campbell, D.W., Leslie, W.D., Paulus, M.P., Stroman, P.W., Polimeni J.O., Malcolmson K.A. and Sareen, J. Neuroreport, 16(12), pp. 1291-1295, 2005.

Mapping Dopamine D2/D3 Receptor Function Using Pharmacological Magnetic Resonance Imaging

Jenkins and colleagues at Massacheusetts General Hospital used pharmacological magnetic resonance imaging (phMRI) to determine whether regulation of dopamine release and. synthesis occurs via pre-synaptic dopamine (DA) D2/D3 autoreceptors (DARs). They hypothesized that relative cerebral blood volume (rCBV) changes induced by amphetamine could be modulated by DA D2 receptor antagonists and agonists in a manner consistent with modulation of DAR function. The MRI results were then compared to microdialysis under similar conditions. Iron oxide contrast agents were used to map changes in rCBV or dopamine release using microdialysis in response to an amphetamine challenge, pre-treatment and post-treatment with varying doses of the D2 antagonist eticlopride and the D2 agonist quinpirole. Antagonism of D2 receptors with eticlopride potentiated rCBV changes induced by amphetamine in the nucleus accumbens and caudate putamen in a dose-dependent manner. The amphetamine-induced increase in rCBV in the accumbens in animals pre-treated with eticlopride was paralleled by a similar percentage increase in DA release measured by means of microdialysis. Conversely, agonism of D2 receptors using quinpirole reduced amphetamine-induced rCBV changes in the caudate putamen and nucleus accumbens. The effects of both quinpirole and eticlopride on amphetamine-induced rCBV changes were largest in the nucleus accumbens. These results suggest that phMRI may potentially prove useful to map DA receptor function noninvasively in multiple brain regions simultaneously. Chen, Y.C.I., Choi, J.K., Andersen, S.L., Rosen, B.R. and Jenkins, B.G. Psychopharmacology, 180(4), pp. 705-715, 2005.

Startle Modulation during Conscious Emotion Regulation is Arousal-Dependent

LaBar and colleagues at Duke University examined whether conscious regulation of negative emotion affects human eyeblink startle responses through modulation of arousal- or valence-based processes. Healthy, normal control subjects were presented with negative, neutral, and positive pictures and directed to enhance, maintain, and suppress emotional responses. On emotional picture trials, startle responses decreased as a function of cue in the following order, enhance > maintain > suppress. Analysis of negative and positive picture trials separately revealed similar patterns of startle modulation by emotion regulation. There were no effects of emotion regulation on neutral trials. Results indicate that arousal, not valence, may be critical to startle modulation via conscious emotion regulation. These results have implications for understanding the neuronal basis of substance abuse therapies that employ emotional reappraisal approaches, such as cognitive behavioral therapy. Dillon, D.G. and LaBar, K.S. Behavioral Neuroscience, 119(4), pp. 1118-1124, 2005.

Influences of Emotion on Context Memory while Viewing Film Clips

Shimamura and Anderson at the University of California, Berkeley asked healthy normal controls to listen to words while viewing film clips (audio off). Film clips were classified as neutral, positively valenced, negatively valenced, and arousing. Memory was assessed in three ways: 1) recall of film content, 2) recall of words, and 3) context recognition. In the context recognition test, participants were presented a word and determined which film clip was showing when the word was originally presented. In two experiments, context memory performance was disrupted when words were presented during negatively valenced film clips, whereas it was enhanced when words were presented during arousing film clips. Free recall of words presented during the negatively valenced films was also disrupted. These findings suggest multiple influences of emotion on memory performance. Anderson, L. and Shimamura, A.P. American Journal of Psychology, 118(3), pp. 323-337, 2005.

Impulsivity and Decision Making

Bechara and colleagues at the University of Iowa examined the links among the four facets of impulsivity (urgency, lack of premeditation, lack of perseverance, and sensation seeking) proposed by Whiteside and Lynam (2001) and decision-making processes. Thirty undergraduate students completed a self-report questionnaire evaluating impulsivity as well as a task measuring decision-making processes, the Iowa Gambling Task. Zero-order correlations and multilevel analysis revealed that only lack of premeditation was specifically linked to disadvantageous decisions on the Gambling Task. This suggests that premeditation is related to decision making involving assessment of long term outcomes and consequences. Zermatten, A., Van der Linden, M., d'Acremont, M., Jermann, F. and Bechara, A. Journal Of Nervous And Mental Disease, 193(10), pp. 647-650, 2005.

Concurrent CBF and CMRglc Changes During Human Brain Activation By Combined fMRI-PET Scanning

Detre and colleagues at University of Pennsylvania used a novel approach for concurrent measurement of regional cerebral blood flow (CBF) by MRI and regional cerebral metabolic rate for glucose consumption (rCMRglc) with positron emission tomographic (PET) in humans in normal subjects. F-18-labeled fluorodeoxyglucose was administered during the measurement of CBF by continuous arterial spin labeled magnetic resonance imaging (MRI) while subjects viewed a simple visual stimulus. Subsequent PET scanning demonstrated the distribution of labeled deoxyglucose during the MRI acquisition. An excellent concordance between regional CBF and regional fCMRglc during visual stimulation was found, consistent with previously published PET findings. Although initially validated using a brief, non-quantitative protocol, this approach can provide quantitative CBF and rCMRglc, with a broad range of potential applications in functional physiology and pathophysiology. Newberg, A.B., Wang, J.J., Rao, H.Y., Swanson, RL., Wintering, N., Karp JS., Alavi A., Greenberg, J.H. and Detre, J.A Neuroimage, 28(2), pp. 500-506, 2005.