Research Findings - Clinical Neuroscience Research

Impulsive Personality Predicts Dopamine-Dependent Changes in Frontostriatal Activity During Working Memory

Dr. Mark D'Esposito and colleagues at University of California, Berkeley used fMRI to demonstrate that individual differences in impulsive personality account for the contrasting effects of dopaminergic drugs on working memory and associated frontostriatal activity. Prior studies have shown that dopaminergic drugs affect a variety of cognitive processes, but the direction and extent of effects vary across individuals and tasks. Paradoxical effects are observed, by which the same drug causes cognitive enhancing as well as adverse effects. In the present study, administration of the dopamine D2 receptor agonist bromocriptine to healthy volunteers improved the flexible updating (switching) of relevant information in working memory in high-impulsive subjects, but not in low-impulsive subjects. These behavioral effects in high-impulsive subjects accompanied dissociable effects on frontostriatal activity. Bromocriptine modulated the striatum during switching but not during distraction from relevant information in working memory. Conversely, the lateral frontal cortex was modulated by bromocriptine during distraction but not during switching. The present results provide a key link between dopamine D2 receptor function, impulsivity, and frontostriatal activity during component processes of working memory. Given the high association of impulsivity with drug abuse, the present findings provide insight into cognitive sequelae of addiction. Cools, R., Sheridan, M., Jacobs, E., and D'Esposito, M. Impulsive Personality Predicts Dopamine-Dependent Changes in Frontostriatal Activity During Component Processes of Working Memory. Journal of Neuroscience, 27(20), pp. 5506-5514, 2007.

Cingulate Cortex Involvement in Error Detection With and Without Awareness

Dr. Hugh Garavan and colleagues at Trinity University used high density electrical recording of brain activity to demonstrate that specific regions of the Cingulate cortex have a differential relationship with awareness of task-related errors. Error-processing research has demonstrated that the brain uses a specialized neural network to detect errors during task performance, but the brain regions necessary for conscious awareness of an error are poorly understood. Two well known error-related event-related potential (ERP) components, the error-related negativity (ERN) and error positivity (Pe) have a differential relationship with awareness of task-related errors. In the present study healthy volunteers performed a manual response inhibition task that was optimized to examine error awareness. While the ERN was unaffected by the participants' conscious experience of errors, the Pe was only seen when participants were aware of committing an error. Source localization of these components indicated that the ERN was generated by a caudal region of the anterior cingulate cortex (ACC) while the Pe was associated with contributions from a more anterior ACC region and the posterior cingulate-precuneus. Tonic EEG measures of cortical arousal were correlated with individual rates of error awareness and showed a specific relationship with the amplitude of the Pe. The latter finding is consistent with evidence that the Pe represents a P3-like facilitation of information processing modulated by subcortical arousal systems. These data suggest that the ACC might participate in both preconscious and conscious error detection and that cortical arousal provides a necessary setting condition for error awareness. These findings may be particularly important in the context of substance abuse in which a proper understanding of self-monitoring deficits requires an explicit measurement of error awareness. O'Connell R.G., Dockree P.M., Bellgrove M.A., Kelly S.P., Hester R., Garavan H., Robertson I.H., Foxe J.J. The Role of Cingulate Cortex In The Detection Of Errors With And Without Awareness: A High-Density Electrical Mapping Study. European Journal of Neuroscience, 25(8), pp. 2571-2579, 2007.

Activation of Prefrontal Cortex Reduces Risky Decision Making under Ambiguous Conditions

Dr. David Zald of Vanderbilt University collaborated with scientists at the NIH to investigate the role of the dorsolateral prefrontal cortex (DLPFC) on risky decision-making. Weighing of risks and benefits toward decision making involves a complex neural network that includes the DLPFC, but the role of the DLPFC remains unclear. Repetitive transcranial magnetic stimulation studies have shown that disruption of the DLPFC increases risk-taking behavior. Transcranial direct current stimulation (tDCS) allows upregulation of activity in the DLPFC, and it was predicted that this might promote more cautious decision-making. Healthy participants received one of the following treatments while they performed the Balloon Analog Risk Task: (1) right anodal/left cathodal DLPFC tDCS, (2) left anodal/right cathodal DLPFC tDCS, or (3) sham tDCS. This experiment revealed that participants receiving either one of the bilateral DLPFC tDCS strategies adopted a risk-averse response style. In a control experiment, they tested whether unilateral DLPFC stimulation (anodal tDCS over the right or left DLPFC with the cathodal electrode over the contralateral supraorbital area) was sufficient to decrease risk-taking behaviors. This experiment showed no difference in decision-making behaviors between the groups of unilateral DLPFC stimulation and sham stimulation. These findings extend the notion that DLPFC activity is critical for adaptive decision making, possibly by suppressing riskier responses. Anodal tDCS over DLPFC by itself did not significantly change risk-taking behaviors; however, when the contralateral DLPFC was modulated with cathodal tCDS, an important decrease in risk-taking was observed. Also, the induced cautious decision-making behavior was observed only when activity of both left and right DLPFC was modulated. The ability to modify risk-taking behavior may be translated into therapeutic interventions for disorders such as drug abuse, overeating, or pathological gambling. Fecteau, S., Pascual-Leone, A., Zald, D.H., Liguori, P., Theoret, H., Boggio, P.S., and Fregni, F. Activation of Prefrontal Cortex By Transcranial Direct Current Stimulation Reduces Appetite For Risk During Ambiguous Decision Making. Journal of Neuroscience, 27(23), pp. 6212-6218, 2007.

Cortical Inhibition and Excitation in Abstinent Cocaine-Dependent Patients: A Transcranial Magnetic Stimulation Study

Prior transcranial magnetic stimulation studies showed that resting motor threshold is elevated in abstinent cocaine-dependent patients, suggesting a decrease in axonal excitability. In contrast, the increased incidence of seizures and psychosis in this group suggests increased excitability or decreased inhibition. Here, Dr. Nashaat Boutros and colleagues at the Wayne State University School of Medicine, studied long-interval intracortical facilitation and long-interval intracortical inhibition, paired-pulse transcranial magnetic stimulation measures that are more directly linked to glutamatergic cortical facilitation and GABAergic inhibition, respectively. Ten cocaine dependent and 10 healthy controls were examined. Resting motor threshold, long-interval intracortical facilitation and long-interval intracortical inhibition were tested from the left motor cortex. The cocaine group showed an elevated resting motor threshold and an increased long-interval intracortical facilitation, whereas long-interval intracortical inhibition was normal. Although the increase in long-interval intracortical facilitation suggests exaggerated cortical glutamatergic excitability, the increase in resting motor threshold may signify a protective mechanism against seizures and psychosis. Sundaresan, K., Ziemann, U., Stanley, J., and Boutros, N. Cortical Inhibition and Excitation in Abstinent Cocaine-Dependent Patients: A Transcranial Magnetic Stimulation Study. Neuroreport, 18(3), pp. 289-292, 2007.

Short-Term Naturalistic Treatment Outcomes in Cigarette Smokers with Substance Abuse and/or Mental Illness

The majority of cigarette smokers have a lifetime diagnosis of substance abuse and/or mental illness, and treatment outcomes for smokers with these comorbidities are generally reported to be worse than for smokers without comorbidities. Dr. Arthur Brody and colleagues at the University of California, Los Angeles sought to examine the effect of specific substance abuse/mental illness diagnoses compared to one another on treatment outcomes. A retrospective chart review of naturalistic treatment for nicotine dependence was performed on male smokers (N = 231) who enrolled in the Greater Los Angeles Veterans Affairs Mental Health Clinic Smoking Cessation Program (Los Angeles, Calif.) over a 1.5-year period (January 2004 to June 2005). Subjects in this program, who were diagnosed with nicotine dependence on the basis of a DSM-IV-based interview and a Fagerstro_m Test for Nicotine Dependence score of >= 3, underwent comprehensive treatment for nicotine dependence (including, but not limited to, group psychotherapy, nicotine replacement therapy, and bupropion hydrochloride). Quitting smoking was defined as a report of at least 1 week of abstinence and an exhaled carbon monoxide less than or equal to 8 parts per million at the final clinic visit. Of the total group, 36.4% (84/231) quit smoking at the end of treatment. Quit rates were affected by the presence of specific diagnoses, with smokers with a history of alcohol abuse/dependence or schizophrenia/schizoaffective disorder having poorer response rates than smokers without such diagnoses. Other substance abuse and mental illness diagnoses did not affect quit rates. Lower quit rates among patients with alcohol abuse/dependence or schizophrenia/schizoaffective disorder may be due to the severity of these conditions and suggest that specialized treatment is needed for these populations of smokers. Smokers with most comorbid diagnoses are successfully treated with standard treatment methods. Gershon Grand, R.B., Hwang, S., Han, J., George, T., and Brody, A.L. Short-Term Naturalistic Treatment Outcomes in Cigarette Smokers with Substance Abuse and/or Mental Illness. The Journal of Clinical Psychiatry, 68(6), pp. 892-898, 2007.

[123I]5-IA-85380 SPECT Imaging of Beta2-Nicotinic Acetylcholine Receptor Availability in the Aging Human Brain

Dr. Kelly Cosgrove and colleagues at Yale University School of Medicine have been investigating in vivo the availability of the beta(2)-containing nicotinic acetylcholine receptor (beta(2)-nAChR) in healthy nonsmokers (18-85 years of age) using [(123)I]5-IA-85380 SPECT imaging. Human postmortem studies have reported decreases with age in high-affinity nicotine binding in brain. Age and regional beta(2)-nAChR availability (VT_) have been observed to be inversely correlated in all brain regions analyzed, with decline ranging from 21% (cerebellum) to 36% (thalamus), or by up to 5% per decade of life. Preliminary results have confirmed postmortem reports of age-related decline in high-affinity nicotine binding with age and may elucidate the role of beta(2)-nAChRs in the cognitive decline associated with aging. Mitsis, E.M., Cosgrove, K.P., Staley, J.K., Frohlich, E.B., Bois, F., Namangan, G.D., Estok, K.M., Seibyl, J.P., and Van Dyck, C.H. [123I]5-IA-85380 SPECT Imaging of Beta2-Nicotinic Acetylcholine Receptor Availability in the Aging Human Brain. Annals of the New York Academy of Science, 1097, pp. 168-170, 2007.

The Effects of Foods, Beverages, and other Factors on Cigarette Palatability

While smokers commonly report that various foods and beverages worsen or enhance the taste of cigarettes, the prevalence and diversity of these phenomena have not been studied. Dr. Francis McClernon and colleagues at Duke University Medical Center administered an open-ended questionnaire to 209 smokers asking for reports of foods or beverages that worsen or enhance the taste of cigarettes. Commonly reported categories that worsen the taste of cigarettes were fruits/vegetables, noncaffeinated beverages, and dairy products. Commonly reported categories that enhance the taste of cigarettes were caffeinated and alcoholic beverages and meat products. Regression analyses indicated that increased sensitivity to both taste-worsening and taste-enhancing were associated with smoking nonmenthol cigarettes. These findings suggest smoking menthol cigarettes reduces both negative and positive effects of food and beverage consumption on smoking satisfaction - thus "evening-out" the smoking experience. McClernon, F.J., Westman, E.C., Rose, J.E., and Lutz, A.M. The effects of foods, beverages, and other factors on cigarette palatability. Nicotine & Tobacco Research, 9(4), pp. 505-510, 2007.

Relationship Between N-Acetyl-Aspartate in Gray and White Matter of Abstinent Methamphetamine Abusers and Their History of Drug Abuse: A Proton Magnetic Resonance Spectroscopy Study

Altered concentrations of the brain metabolites, including N-acetyl-aspartate (NAA) and myo-inositol (MI), may indicate neurotoxicity associated with drug abuse. In this study, Dr. Perry Renshaw of McLean Hospital, along with his colleagues at Seoul National University College of Medicine and Hospital, explored differences in brain metabolites between abstinent methamphetamine (MA) abusers and healthy comparison subjects and the associations between metabolite concentrations and clinical characteristics. Proton magnetic resonance spectroscopy (MRS) was performed on 30 abstinent MA abusers and 20 healthy comparison subjects. Two sets of MA user subgroups were defined depending on abstinence duration (greater or less than 6 months) or the total cumulative MA dose (greater or less than 100 g lifetime). NAA and other metabolites were measured in the frontal gray and white matter and compared between MA abuser groups and healthy comparison subjects. MI concentrations were higher for the MA abusers relative to healthy comparison subjects. NAA concentration was lower in frontal white matter of MA abusers with a 'large' cumulative dose relative to those with a 'small' cumulative dose and to healthy comparison subjects. Additionally, in MA abusers NAA concentrations in frontal white matter correlated inversely with the cumulative MA dose. In contrast, there was no significant difference in frontal gray matter NAA concentration among the three groups. However, frontal gray matter NAA concentrations for MA abusers correlated negatively with the total cumulative MA dose and positively with the duration of abstinence. There were no differences between the different MA user groups for MI. The current findings suggest that MA-induced metabolic alterations of frontal gray and white matter are dose-dependent. Additionally, these findings suggest that the MA-related abnormalities in gray matter may recover, in part, with abstinence but this is not the case in white matter regions. Sung, Y.H., Cho, S.C., Hwang, J., Kim, S.J., Kim, H., Bae, S., Kim, N., Chang, K.H., Daniels, M., Renshaw, P.F., and Lyoo, I.K. Relationship Between N-Acetyl-Aspartate in Gray and White Matter of Abstinent Methamphetamine Abusers and Their History of Drug Abuse: A Proton Magnetic Resonance Spectroscopy Study. Drug and Alcohol Dependence, (Epub 2006 Nov 7), 88(1), pp. 28-35, 2007.

Reproducibility of GABA Measurements Using 2D J-resolved Magnetic Resonance Spectroscopy

Dr. Napapon Sailasuta of the Huntington Medical Research Institutes and her colleagues from the Royal Edinburgh Hospital determined the reproducibility of GABA (gamma-aminobutyric acid) measurements using 2D J-resolved magnetic resonance spectroscopy (MRS) on a clinical 1.5-T MR imaging scanner. Two-dimensional J-resolved spectra were acquired in vitro across five GABA concentrations using a volume head coil and a 5-in. surface coil. Additional spectra using a sixth GABA phantom with a very low concentration and from a healthy volunteer were recorded in the 5-in. surface coil only. In each case, the 3.01-ppm GABA resonance was quantified; for comparison, the peak integrals of choline (3.2 ppm) and creatine (3.03 ppm) were recorded. At a physiological concentration (1.2 mM), in vitro GABA measurement was significantly more reproducible in the surface coil than in the volume coil (P=.005), with coefficients of variation (CVs) being less than 16% with the surface coil and up to 68% with the volume head coil. At the smallest concentration of in vivo GABA reported using other spectroscopy techniques (0.8 mM) and detected only using the surface coil, the CV for GABA was 23% and was less than 10% for choline and creatine, which compare favorably with results from published studies. In vivo, the CV for GABA measurement was 26%, suggesting that 2D J-resolved MRS would be suitable for detecting physiological changes in GABA similar to those reported using other methods. Lymer, K., Haga, K., Marshall, I., Sailasuta, N., and Wardlaw, J. Reproducibility of GABA Measurements Using 2D J-resolved Magnetic Resonance Spectroscopy. Magnetic Resonance Imaging, (Epub 2006 Nov 30), 25(5), pp. 634-640, 2007.

Cybertherapy—New Applications for Discomfort Reductions. Surgical Care Unit of Heart, Neonatology Care Unit, Transplant Kidney Care Unit, Delivery Room-Cesarean Surgery and Ambulatory Surgery, 27 Case Reports

Dr. Brenda Wiederhold, along with her colleagues at Clinica de Especialidades (Mexico), demonstrated the feasibility of virtual reality scenarios to reduce discomfort in patients during ambulatory and obstetric surgeries and patients hospitalized in postoperative care units from cardiac, nephrology, and neonatology units. Twenty seven patients have participated in these preliminary reports from 3 public hospitals from Mexico City in 2006. The majority of patients demonstrated comfort with virtual scenarios during surgical procedures or hospitalization. In ambulatory surgeries the reduction of medication dosage was real. The authors present the first applications in surgery, obstetrics and care units. The preliminary results must be supported in the future with a greater number of cases and statistical results; however the authors predict the usefulness of this finding because they have found a reduction of medication dosing in ambulatory surgeries. Mosso, J.L., Rizzo, S., Wiederhold, B., Lara, V., Flores, J., Espiritusanto, E., Minor, A., Santander, A., Avila, O., Balice, O., and Benavides, B. Cybertherapy--New Applications for Discomfort Reductions. Surgical Care Unit of Heart, Neonatology Care Unit, Transplant Kidney Care Unit, Delivery Room-Cesarean Surgery and Ambulatory Surgery, 27 Case Reports. Studies in Health Technology and Informatics, 125, pp. 334-336, 2007.

Evidence of Corticostriatal Circuit as a Reservoir of HCV Alerts a Productive Coinfection Associated with Cognitive Impairment in Individuals Living with HIV

Dr. Igor Grant and associates at the University of California, San Diego reported that Hepatitis C virus (HCV) infection augmented cognitive deficits in HIV+ individuals and methamphetamine-dependent populations. The detection in this study of NS5A and NS3, integral parts of HCV essential for the virus replication, and core antigen of the virus in post-mortem brain samples of HCV/HIV positive subjects, in combination with previous studies detecting negative-strand RNA in the brains of HCV-positive patients, supports the contention that replicating HCV capable of contributing to neurological damage is present in patients co-infected with HIV. HCV immunoreactivity was present in astroglial cells and perivascular macrophages. Abundant astrogliosis was detectable in frontal cortex and basal ganglia with considerable antemortem cognitive impairment. The results support the view that HCV traffics into the HIV-infected brain, where it leads to a productive coinfection associated with cognitive impairment. However, it is not clear whether the neuropsychological dysfunction mirrored HCV penetration into and replication in the brain, or resulted from indirect influence of hepatic HCV products. Letendre, S., Paulino, A.D., Rockenstein, E., Adame, A., Crews, L., Cherner, M., Heaton, R., Ellis, R., Everall, I.P., Grant, I., and Masliah E. HIV Neurobehavioral Research Center Group. Pathogenesis of Hepatitis C Virus Coinfection in the Brains of Patients Infected with HIV, J Infect Dis., 196(3), pp. 361-370, 2007. Letendre, S.L., Cherner, M., Ellis, R.J., Marquie-Beck, J., Gragg, B., Marcotte, T., Heaton, R.K., McCutchan, J.A., and Grant, I. HNRC Group. The Effects of Hepatitis C, HIV, and Methamphetamine Dependence on Neuropsychological Performance: Biological Correlates of Disease, AIDS, 19 Suppl. 3, pp. S72-78, 2005.

Genetic Linkage to Chromosome 22q12 for a Heavy-Smoking Quantitative Trait in Two Independent Samples

Dr. Pamela Madden and her teams at Washington University and in Australia and Finland conducted a genome-wide linkage screen using a "phenotype" described by the quantitative trait of maximum number of cigarettes smoked in a day, which was considered the best self-report measure of nicotine dependence. A panel of 381 autosomal microsatellite markers--spaced at about 10 cM--were assessed in 289 Australian and 155 Finnish families, all of European descent. Suggestive linkage was found for each sample on Chromosome 22 with a LOD score of nearly 6 in the combined sample. The marker giving the strongest signal is located in the intron of the gene DRBK2, encoding the beta-adrenergic receptor kinase 2. This is the first report of consistent evidence of genetic linkage with use of the same trait assessed identically in two independent samples. The next step is to do a fine mapping of the region to determine if there are gene variants that may confer specific vulnerability to nicotine dependence. Saccone, S.F., Pergadia, M.L., Loukola, A., Broms, U., Montgomery, G.W., Wang, J.C. Agrawal, A., Dick, D.M., Heath, A.C., Todorov, A.A., Maunu, H., Heikkliae, Morley, K.I., Rice, J.P., Todd, R.D., Kaprio, J., Peltonen, L., Martin, A.M., and Madden, P.A.F. Genetic Linkage to Chromosome 22q12 for a Heavy-Smoking Quantitative Trait in Two Independent Samples. The American Journal of Human Genetics, 80, pp. 856-866, 2007.

Genetic Linkage to Chromosomes 3 and 9 for Cannabis Dependence Symptoms

Dr. Thomas Crowley and his team at the University of Colorado conducted a genome-wide scan using a "phenotype" of symptom counts for cannabis dependence. A panel of 374 microsatellite markers--spaced about 9.2 cM--were assessed in 324 sibling pairs from 192 families recruited from consecutive admissions to substance abuse treatment facilities. Suggestive linkage was found on chromosome 3q21 (LOD 2.61) and on chromosome 9q34 (LOD 2.57). This is the first study to report linkage for cannabis dependence symptoms. The LOD scores are somewhat low so that replication is required. However, other reports for illicit substances have located peaks near the one on chromosome 3. Hopfer, C.J., Lessem, J.M., Hartman, C.A., Stallings, M.C., Cherny, S.S., Corley, R.P., Hewitt, J.K., Krauter, K.S., Mikulich-Gilbertson, S.K., Rhee, S.H., Smolen, A., Young, S.E., and Crowley, T.J. A Genome-Wide Scan for Loci Influencing Adolescent Cannabis Dependence Symptoms: Evidence for Linkage on Chromosomes 3 and 9. Drug and Alcohol Dependence, 89, pp. 34-42, 2007.

Transient Catecholamine Depletion Enhances Cognitive Deficits and Differentially Affects Sleep in Abstinent MDMA Users

Dr. Una McCann and colleagues at Johns Hopkins University investigated whether alterations in sleep associated with MDMA use may involve changes in catecholamine neurotransmission in addition to the known effects of MDMA on serotonin. Abstinent MDMA users and non-MDMA using controls were studied to determine whether transient depletion of brain catecholamines (dopamine and norepinephrine) by alpha-methyl-para-tyrosine (AMPT, which inhibits catecholamine synthesis) would differentially affect MDMA users on measures of cognition and sleep, two processes dually modulated by brain serotonergic and catecholaminergic neurons. During a 5-day in-patient study, all subjects underwent formal neuropsychiatric testing, repeated computerized cognitive testing, and all-night sleep studies. At baseline, MDMA users had performance deficits on tasks of verbal and visuospatial working memory and displayed increased impulsivity on several tasks (i.e., performing quickly at the expense of accuracy). Baseline sleep architecture was also altered in abstinent MDMA users compared to controls. AMPT produced larger deficits in MDMA users compared to controls on several cognitive measures, and differential effects on sleep measures. Differences in cognitive performance, impulsivity, and sleep were significantly correlated with MDMA use. These data suggest that lasting effects of MDMA lead to alterations in behaviors reciprocally influenced by 5-HT and catecholamines. McCann, U.D., Peterson, S.C., and Ricaurte, G.A. The Effect of Catecholamine Depletion by Alpha-Methyl-Para-Tyrosine on Measures of Cognitive Performance and Sleep in Abstinent MDMA Users. Neuropsychopharmacology, 32(8), 1695-706, 2007.

Placebo Effects On Human Mu-Opioid Activity During Pain

Dr. Jon-Kar Zubieta and colleagues used PET ligand imaging to investigate central brain mechanisms of opioid release during placebo treatment. This study examined placebo effects in pain by using positron-emission tomography with [(11)C]carfentanil, which measures regional mu-opioid receptor availability in vivo. Noxious thermal stimulation was applied at the same temperature for placebo and control conditions. Placebo treatment affected endogenous opioid activity in a number of predicted mu-opioid receptor-rich regions that play central roles in pain and affect, including periaqueductal gray and nearby dorsal raphe and nucleus cuneiformis, amygdala, orbitofrontal cortex, insula, rostral anterior cingulate, and lateral prefrontal cortex. These regions appeared to be subdivided into two sets, one showing placebo-induced opioid activation specific to noxious heat and the other showing placebo-induced opioid reduction during warm stimulation in anticipation of pain. These findings suggest that a mechanism of placebo analgesia is the potentiation of endogenous opioid responses to noxious stimuli. Opioid activity in many of these regions was correlated with placebo effects in reported pain. Connectivity analyses on individual differences in endogenous opioid system activity revealed that placebo treatment increased functional connectivity between the periaqueductal gray and rostral anterior cingulate, as hypothesized a priori, and also increased connectivity among a number of limbic and prefrontal regions, suggesting increased functional integration of opioid responses. Overall, the results suggest that endogenous opioid release in core affective brain regions is an integral part of the mechanism whereby expectancies regulate affective and nociceptive circuits. Wager, T.D., Scott, D.J., and Zubieta, J.K. Placebo Effects On Human Mu-Opioid Activity During Pain. Proc. Natl. Acad. Sci. U S A., 104(26), pp. 11056-11061, 2007.

Amphetamine-Induced Dopamine Release: Markedly Blunted In Cocaine Dependence and Predictive Of the Choice To Self-Administer Cocaine

Dr. Diana Martinez and colleagues at Columbia University used PET ligand imaging to characterize pre- and postsynaptic dopamine function in recently detoxified cocaine-dependent subjects. Dopamine response to an acute amphetamine challenge was assessed in striatal subregions in cocaine-dependent and healthy comparison participants using positron emission tomography (PET). The relationship between this dopamine response and the choice to self-administer cocaine in a laboratory model of relapse was investigated. Twenty-four cocaine-dependent participants and 24 matched healthy subjects underwent [C-11] raclopride scans under a baseline condition and following intravenous amphetamine administration (0.3 mg/ kg). Cocaine-dependent participants also completed cocaine self-administration sessions in which a priming dose of cocaine was followed by the choice to either self-administer subsequent cocaine doses or receive a monetary reward. Cocaine dependence was associated with a marked reduction in amphetamine-induced dopamine release in each of the functional subregions of the striatum (limbic striatum: -1.2% in cocaine-dependent participants versus -12.4% in healthy subjects; associative striatum: -2.6% versus -6.7%, respectively; sensorimotor striatum: -4.3% versus -14.1%). Blunted dopamine transmission in the ventral striatum and anterior caudate was predictive of the choice for cocaine over money. Cocaine dependence is associated with impairment of dopamine function, and this impairment appears to bias choices in a way that would promote relapse. Martinez, D., Narendran, R., Foltin, R.W., Slifstein, M., Hwang, D.R., Broft, A., Huang, Y.Y., Cooper, T.B., Fischman, M.W., Kleber, H.D., and Laruelle, M. Amphetamine-Induced Dopamine Release: Markedly Blunted In Cocaine Dependence and Predictive of the Choice To Self-Administer Cocaine. American Journal of Psychiatry, 164(4), pp. 622-629, 2007.

Beta-Adrenergic Modulation of Cognitive Flexibility During Stress

Dr. Beversdorf and colleagues at Ohio State University investigated the role of the brain norepinephrine system on stress-induced impairments in cognitive flexibility performance in healthy individuals. Cognitive performance, plus psychological and physiological parameters for 16 adults without any history of anxiety disorders, was assessed during four test sessions: stress and no-stress, with each condition tested after administration of propranolol and placebo. The Trier Social Stress Test, a public-speaking and mental arithmetic stressor, was presented to participants for the stress sessions, whereas a similar, but nonstressful, control task (reading, counting) was utilized for the no-stress sessions. Tests of cognitive flexibility included lexical-semantic and associative problem-solving tasks (anagrams, Compound Remote Associates Test). Visuospatial memory and motor processing speed tests served as control tasks. Results indicate that (1) stress impaired performance on cognitive flexibility tasks, but not control tasks; (2) compared to placebo, cognitive flexibility improved during stress with propranolol. These results support the hypothesis that stress-related impairments in cognitive flexibility are related to the noradrenergic system. Decreased cognitive flexibility mediated through the noradrenergic system may contribute to the increased likelihood of substance abuse relapse in response to stress, and that beta-adrenergic antagonists may be a potential treatment for stress-induced relapse. Alexander J.K., Hillier, A., Smith, R.M., Tivarus, M.E., and Beversdorf, D.Q. Beta-Adrenergic Modulation Of Cognitive Flexibility During Stress. Journal of Cognitive Neuroscience, 19(3), pp. 468-478, 2007.

Yoga Increases Brain GABA Levels

Dr. Chris Streeter and colleagues at McLean Hospital used MRS to determine whether an individual yoga session would be associated with an increase in brain GABA levels. GABA-to-creatine ratios were measured in a 2-cm axial slab using magnetic resonance spectroscopic imaging immediately prior to and immediately after interventions. Eight yoga practitioners completed a 60-minute yoga session and 11 comparison subjects completed a 60-minute reading session prior to obtaining MRS scans. There was a 27% increase in GABA levels in the yoga practitioner group after the yoga session (0.20 mmol/kg) but no change in the comparison subject group after the reading session (-0.001 mmol/kg). These findings demonstrate that in experienced yoga practitioners brain GABA levels increase after a session of yoga. This suggests that the practice of yoga might be explored as a treatment for disorders with low GABA levels such substance abuse. Streeter, C.C., Jensen, J.E., Perlmutter, R.M., Cabral, H.J., Tian, H., Terhune, D.B., Ciraulo, D.A., and Renshaw, P.F. Yoga Asana Sessions Increase Brain GABA Levels: A Pilot Study. Journal of Alternative and Complementary Medicine 13(4), pp. 419-426, 2007.

Effects of Smoking Marijuana on Focal Attention and Brain Blood Flow

Dr. Daniel O'Leary and colleagues at University of Iowa used PET blood flow imaging to determine the effects of marijuana on selective attention using a dichotic listening task requiring attention to left and right ears. Twelve occasional marijuana users (mean age 23.5 years) were imaged with PET using [15-O]water after smoking marijuana or placebo cigarettes as they performed a reaction time (RT) baseline task, and a dichotic listening task with attend-right- and attend-left-ear instructions. Smoking marijuana, but not placebo, resulted in increased rCBF in orbital frontal cortex, anterior cingulate, temporal pole, insula, and cerebellum. rCBF was reduced in visual and auditory cortices. These changes occurred in all three tasks and appear to reflect the direct effects of marijuana on the brain. Smoking marijuana lowered rCBF in auditory cortices compared to placebo but did not alter the normal pattern of attention-related rCBF asymmetry (i.e., greater rCBF in the temporal lobe contralateral to the direction of attention) that was also observed after placebo. These data indicate that marijuana has dramatic direct effects on rCBF, but causes relatively little change in the normal pattern of task-related rCBF on this auditory focused attention task. O'Leary, D.S., Block, R.I., Koeppel, J.A., Schultz, SK., Magnotta, V.A., Ponto, L.B., Watkins, GL., and Hichwa, R.D. Effects of Smoking Marijuana on Focal Attention and Brain Blood Flow. Human Psychopharmacology-Clinical and Experimental, 22(3), pp. 135-148, 2007.

Differential Contribution of the Posterior Insular Cortex and the Striatum to Delay Discounting

Dr. Martin Paulus and colleagues at the University of California, San Diego used fMRI to examine the neural substrates of delayed discounting. Delay discounting refers to the fact that an immediate reward is valued more than the same reward if it occurs some time in the future. Healthy volunteers were instructed to decide between an immediate and parametrically-varied delayed hypothetical reward during event-related functional magnetic resonance imaging. Subject's preference judgments resulted in different discounting slopes for shorter (< 1 year) and for longer (>= 1 year) delays. Neural activation associated with the shorter delays relative to the longer delays was associated with increased activation in the head of the left caudate nucleus and putamen. When individuals selected the delayed relative to the immediate reward, a strong activation was found in bilateral posterior insular cortex. Several brain areas including the left caudate nucleus showed a correlation between the behaviorally determined discounting and brain activation for the contrast of intervals with delays < 1 and >= 1 year. These results suggest that (1) the posterior insula, which is a critical component of the decision-making neural network, is involved in delaying gratification and (2) the degree of neural activation in the striatum, which plays a fundamental role in reward prediction and in time estimation, may code for the time delay. Wittmann, M., Leland, D.S., and Paulus, M.P. Time and Decision Making: Differential Contribution of the Posterior Insular Cortex and the Striatum During a Delay Discounting Task. Experimental Brain Research, 179 (4), pp. 643-653, 2007.

Attentional Control and Brain Metabolite Levels in Methamphetamine Abusers

Dr. Ruth Salo and colleagues at University of California, Davis combined a computerized measure of selective attention and single-voxel proton magnetic resonance spectroscopy to examine effects of methamphetamine on the relationship between attentional control and brain metabolite levels in the anterior cingulate cortex (ACC) and primary visual cortex (PVC). Subjects were 36 currently abstinent methamphetamine abusers and 16 non-substance-using controls. The methamphetamine abusers exhibited reduced attentional control (i.e., increased Stroop interference) compared with the controls. ACC levels of N-acetyl aspartate (NAA)-creatine and phosphocreatine (Cr) were lower and levels of choline (Cho)-NAA were higher in the methamphetamine abusers compared with the controls. Levels of NAA-Cr, but not of Cho-NAA, within the ACC correlated with measures of attentional control in the methamphetamine abusers (r = -.41), but not in controls (r =.22). No significant correlations were observed in the PVC (methamphetamine abusers, r =.19; controls, r =.38). These results suggest that neurochemical alterations within frontostriatal brain regions, including ACC, may contribute to deficits in attentional control among chronic methamphetamine abusers. Salo, R., Nordahl, T.E., Natsuaki, Y., Leamon, M.H., Galloway, G.P., Waters, C., Moore, C.D., and Buonocore, M.H. Attentional Control and Brain Metabolite Levels in Methamphetamine Abusers. Biological Psychiatry, 61(11), pp. 1272-1280, 2007.

An MR-Compatible Device for Delivering Smoked Marijuana during Functional Imaging

For two of the most commonly abused drugs, nicotine and marijuana, the preferred route of administration is by smoking. Moreover, functional magnetic resonance imaging (fMRI) is becoming a widely-adopted methodology for studying the neurobiological effects acute drug administration. In this publication, Dr. Lisa Nickerson and her colleagues describe the design and testing of an apparatus that allows a subject to smoke a cigarette (whether marijuana or tobacco) while in the bore of a scanner that is acquiring images designed to measure the effects of the drug. The system that is described is shown to contain all smoke and odors from the cigarette and also not to interfere with the imaging protocol (by introducing motion artifacts, for example). This device, therefore, will allow research on the effects of smoked drugs while tests that are compatible with the scanner environment are simultaneously performed. Frederick, B., Lindsey, K., Nickerson, L.., Ryan, E., and Lukas, S. An MR-Compatible Device for Delivering Smoked Marijuana during Functional Imaging. Pharmacology, Biochemistry and Behavior, 87, pp. 81-89, 2007.