Research Findings - Clinical Neuroscience Research
Damage to the Insula Disrupts Addiction to Cigarette Smoking
A number of brain systems have been implicated in addictive behavior, but none have yet been shown to be necessary for maintaining the addiction to cigarette smoking. Authors found that smokers with brain damage involving the insula, a region implicated in conscious urges, were more likely than smokers with brain damage not involving the insula to undergo a disruption of smoking addiction, characterized by the ability to quit smoking easily, immediately, without relapse, and without persistence of the urge to smoke. This result suggests that the insula is a critical neural substrate in the addiction to smoking. Naqvi, N.H., Rudrauf, D. Damasio, H. and Bechara, A. Science. 315(5811), pp. 531-534, January 26, 2007.
Cognitive Deficits and Degeneration of Interneurons in HIV+ Methamphetamine Users
Igor Grant and colleagues at the HIV Neurobehavioral Research Center, USCD explored the cellular basis for cognitive deficits in AIDS positive (HIV+) patients who either used or did not use methamphetamine (METH). The researchers found that HIV+ METH users had more severe loss of connecting neurons that was associated with cognitive impairment. Compared with other markers, loss of specific connecting neurons (i.e., calbindin and parvalbumin interneurons) in the frontal cortex. This loss was most related to memory problems, suggesting that HIV+ METH users were neurologically affected either by the disease, by the HIV+ virus or a combination of the two. Chana, G., Everall, I.P., Crews, L., Langford, D., Adame, A., Grant, I., Cherner, M., Lazzaretto, D., Heaton, R., Ellis, R., Masliah, E., and the HNRC Group*. Neurology, 67, pp, 1486 - 1489, 2006.
Young Adult Stimulant Users' Increased Striatal Activation during Uncertainty Is Related to Impulsivity
Dr. Martin Paulus and colleagues at the University of California, San Diego used fMRI to investigate whether young adults who had used stimulants have different neural responses to uncertainty during decision making than their stimulant-naive peers. Young adults who use stimulants (e.g., cocaine, amphetamines) are at particular risk of transitioning to dependence, and such subjects demonstrate increased risk-taking in laboratory decision-making tasks. Eleven young adults (age 18-25) who had used stimulants were compared with 11 age- and education-matched stimulant-naive controls. Subjects performed a card prediction task with relatively certain/uncertain outcome conditions during the fMRI scans. The caudate, an area involved in processing salient events, was among those regions more active in users than controls in response to uncertainty. Personality measures revealed that stimulant users were more impulsive than controls, and that neural response to uncertainty in a number of areas, including the thalamus/caudate, was positively correlated with impulsivity. These results are consistent with the idea that young adults who have used stimulants find uncertainty particularly salient, due in part to preexisting differences in impulsivity, and may be subject to more "action pressure" when making decisions under uncertainty. This neural and personality profile may constitute a marker for increased risk of stimulant use. Leland, D.S., Arce, E., Feinstein, J.S., and Paulus, M.P. Neuroimage, 33(2), pp. 725-731, 2006.
Cigarette Smoking Saturates Brain Alpha 4 Beta 2 Nicotinic Acetylcholine Receptors
Brody and colleagues at UCLA evaluated a recently developed radioligand (2-FA) that allows one to visualize specific nicotinic receptors (i.e., alpha 4 beta 2* nAChR) with positron emission tomography (PET) scanning in humans to determine the effect of cigarette smoking on the receptors occupancy in tobacco-dependent smokers. During the 2-FA PET scanning sessions, a total of 11 subjects smoked one of 5 amounts (none, 1 puff, 3 puffs, 1 full cigarette, or to satiety [2(1/2) to 3 cigarettes]. Dose-dependent effects of smoking on occupancy of the receptors as measured with 2-FA and PET in nicotine-rich brain regions showed that smoking 0.13 (1 to 2 puffs) of a cigarette resulted in 50% occupancy of the receptors for 3.1 hours after smoking. Smoking a full cigarette (or more) resulted in more than 88% receptor occupancy and was accompanied by a reduction in cigarette craving. Blood nicotine levels were 0.87 ng/mL (roughly 1/25th of the level achieved in typical daily smokers) and was associated with 50% occupancy of the receptors. The researchers concluded that cigarette smoking in the amounts used by typical daily smokers leads to nearly complete occupancy of the nicotine receptors indicating that tobacco-dependent smokers maintain receptor saturation throughout the day. Because prolonged binding of nicotine to these receptors is associated with desensitization of the receptors, the extent of receptor occupancy found in this study suggests that smoking may lead to withdrawal alleviation by maintaining receptors in a desensitized state. Brody, A.L., Mandelkern, M.A., London, E.D., Olmstead, R.E.O., Mukhin, A.G., Farahi, J., Scheibal, D., Jou, J., Allen, V., Tiongson, E., Chefer, S.I., Koren, A. Arch Gen Psychiatry, 63(8), pp. 907-915, 2006.
Human Tobacco Smokers in Early Abstinence Have Higher Levels of Beta2 Nicotinic Acetylcholine Receptors than Nonsmokers
Dr. Julie Staley and her colleagues at Yale School of Medicine used SPECT imaging to examine the effects of cigarette smoking cessation on a specific sub-type nicotine receptors, (beta2-nAChR). The Beta2-nAChRs are the most prevalent subtype of nicotine acetylcholine receptors in the brain and are thought to mediate the addictive chemical in tobacco smoke, nicotine. Thus it is possible that abnormal numbers of these receptors contribute to the continuation of the addiction to tobacco smoking during early abstinence. Initial studies in non-human primates chronically given 7 days of abstinence was required to avoid residual levels of nicotine interfering with radiotracer binding to the nicotine receptors. Therefore, human smokers were asked to abstain from smoking for approximately 7 days. Both urine and breath samples were taken to confirm that smoking had not occurred. Following an average of 7 days of abstinence, there were higher levels of receptors in recently abstinent smokers compared to non-smokers. Radiotracer uptake was highest in the abstinent smokers throughout the cerebral cortex and in the striatum in the smokers, and the elevated amount of ligand binding was related to the number of days since their last cigarette and their reported urge to smoke. These results suggest that the number of nicotine receptors increases in smokers during abstinence and that the elevation in receptor levels may contribute to difficulties in maintaining abstinence. Staley, J.K., Krishnan-Sarin, S., Cosgrove, K.P., Krantzler, E., Frohlich, E., Perry, E., Dubin, J.A., Estok, K., Brenner, E., Baldwin, R.M., Tamagnan, G.D., Seibyl, J.P., Jatlow, P., Picciotto, M.R., London, E.D., O'Malley, S., and van Dyck, C.H. J Neurosci, 26(34), pp. 8707-14, 2006.
Automaticity and Reestablishment of Executive Control - An fMRI Study
Dr. Hugh Garavan and colleagues at Trinity College used fMRI to investigate brain systems involved in reestablishing executive control over previously automatized behavior. The ability to exert control over automatic behavior is of particular importance as it allows the interruption of behavior when the automatic response is no longer adequate or even dangerous. A visual search task was used that enabled participants to automatize according to defined criteria within about 3 hr of practice and then required them to reassert control without changing the stimulus set. Widespread cortical activation was observed early in practice. Activation in all frontal areas and in the inferior parietal lobule decreased significantly with practice. Only selected prefrontal (Brodmann's areas [BAs] 9/46/8) and parietal areas (BAs 39/40) were specifically reactivated when executive control was required, underlining the crucial role of the dorsolateral prefrontal cortex in executive control to guide our behavior. There is emerging evidence that addiction involves automatized substance use behavior (i.e., habits). The present study provides a framework for investigating deficits in executive control in substance abusers. Kubler, A., Dixon, V., and Garavan, H. Journal of Cognitive Neuroscience, 18(8), pp. 1331-1342, 2006.
Activation of Dorsal Nucleus Caudate and Putamen Was Positively Associated with Subjective Ratings of Pain
Dr. Jon-Kar Zubieta and colleagues at University of Michigan investigated the increasing evidence that the dopaminergic system in the basal ganglia are responsive to aversive stimuli as well as reward. This would implicate response relative to saliency rather than valence. Using their standard paradigm of inducing pain by injecting hypertonic saline into a jaw muscle and assessing DA receptor availability in PET with raclopride, results showed that gain in DA release was positively correlated with sensory and pain affect ratings and with the negative affect experienced by healthy volunteers. Nigrostriatal DA D2 system activation was associated exclusively with ratings of sensory and affective qualities of the pain, whereas mesolimbic DA D2/D3 activity was related to the increase in negative affective state and fear ratings. These data suggest that basal ganglia dopamine receptor-mediated neurotransmission is related to individual variation in the pain stress experience. Scott, D.J., Heitzeg, M.M., Koeppe, R.A., Stohler, C.S., Zubieta, J.K. J Neurosci, 26(42), pp. 10789-10795, 2006.
Sex Differences in Amphetamine-Induced Displacement of [F-18] Fallypride in Striatal and Extrastriatal Regions: A PET Study
Dr. David Zald and colleagues at Vanderbilt University used PET to examine gender differences in d- amphetamine-induced dopamine release striatal and extrastriatal brain regions. Dopamine release was indexed by displacements of [F-18]. In addition, these displacements were correlated with cognition and sensation seeking. Method: Six women and seven men underwent positron emission tomography (PET) with [F-18] fallypride before and after an oral dose of d-amphetamine. Percent displacements were calculated using regions of interest and parametric images of dopamine 2 (D-2) receptor binding potential. The results demonstrated that female subjects had greater dopamine release than the male subjects in the right globus pallidus and right inferior frontal gyrus. Gender differences were observed in correlations of changes in cognition and sensation seeking with regional dopamine release. The finding that women exhibit greater dopamine release in response to amphetamine as well as gender differences in the relationship between regional dopamine release and sensation seeking and cognition may underlie gender differences in vulnerability for the abuse of psychostimulants. Schmidt, D., Baldwin, R., and Kessler, R. American Journal of Psychiatry, 163(9), pp. 1639-1641, 2006.
Sex Differences in Orbitofrontal Cortex (OFC) As Assessed by SPECT in Cocaine Dependent Subjects
Dr. Brian Adinoff and associates studied regional cerebral blood (rCBF) flow in treatment-seeking cocaine abusers after at least 11 days abstinence. This study reported relative rCBF between patients and healthy controls following saline infusion. The key finding was a decreased rCBF in the right and left lateral OFC in males but not female cocaine-dependent subjects in contrast with a decreased rCBF in the medial OFC in the female but not males. Additionally, it was found that increases in rCBF were found in diffuse regions in males with no significant increases in females. In other words, cerebral blood flow was disturbed to a greater extent in males and in different areas than in females. Post-hoc inferences based on other reported findings suggested sex differences in responsiveness or brain function during decision-making tasks or, possibly, assessment or suppression of reward saliency. In any case, it is concluded that these findings amplify the relevance of sex-specific differences in drug effects to the orbitofrontal cortex and the implications for clinical course and treatment. Adinoff, B., Williams, M.J., Best, S.E., Harris, T.S., Chandler, P., Devous, M.D. Gender Med, 3(3), pp. 206-222, 2006.
Apparent Transient Effects of Recent "Ecstasy" Use on Cognitive Performance and Extrapyramidal Signs in Human Subjects
Dr. David Beaversdorf and colleagues at Ohio State University investigated cognitive performance and extrapyramidal function early after Ecstasy (MDMA) use. Chronic Ecstasy use has been suggested to lead to cognitive deficits and Parkinsonian signs. Previous research has examined cognitive performance after a period of prolonged abstinence, but research assessing the early effects of ecstasy after recent use is limited. This study compared task performance between 13 ecstasy users (10 to 15 h postdrug use) and a control group on a battery of neuropsychological assessments while matching for education level, sleep deprivation, and premorbid IQ. The groups were also compared on measures relating to parkinsonian signs. The ecstasy subjects showed impairments on measures of executive function as evaluated by Raven's Standard Progressive Matrices (SPM) and the Wisconsin Card Sorting Task (WCST). Short-delay free recall memory was also impaired in ecstasy subjects on the California Verbal Learning Test (CVLT-II). No extrapyramidal motor impairments were detected. These deficits resemble deficits previously reported in chronic ecstasy use but also seem to reveal transient impairments in executive function. Riccardi, P., Zald, D., Li, R., Park, S., Ansari, M.S., Dawant, B., Anderson, S., Woodward, N., Smith, R.M., Tivarus, M., Campbell, H.L., Hillier, A., and Beversdorf, D.Q. Cognitive and Behavioral Neurology, 19(3), pp. 157-164, 2006.
PET Imaging of Norepinephrine Transporters
Dr. Yu-Shin Ding and colleagues at Yale School of Medicine and Brookhaven National Laboratory describe the design and biological evaluation of several radioligands for imaging the brain NET system with PET. The involvement of the norepinephrine transporter (NET) in the pathophysiology and treatment of attention deficit hyperactivity disorder (ADHD), substance abuse, neurodegenerative disorders (e.g., Alzheimer's disease (AD) and Parkinson's disease (PD)) and depression has long been recognized. However, many of these important findings have resulted from studies in vitro using postmortem tissues; as of now, these results have never been verified via in vivo methods because brain imaging of NET in living systems has been hampered due to the lack of suitable radioligands. The fact that all three monoamine (dopamine, norepinephrine, and serotonin) transporters (DAT, NET and SERT) are involved in various neurological and psychiatric diseases further emphasizes the need to develop suitable NET ligands so that researchers will be able to probe the contributions of each monoamine transporter system to specific CNS disorders. In this review article, based on these characterization studies, including C-11 labeled desipramine (DMI), 2-hydroxydesipramine (HDMI), talopram, talsupram, nisoxetine (Nis), oxaprotiline (Oxap), lortalamine (Lort) and C-11 and F-18 derivatives of reboxetine (RB), methylreboxetine (MRB) and their individual (R, R) and (S, S) enantiomers, in conjunction with studies with radiolabeled 4-iodo-tomoxetine and 2-iodo-nisoxetine, we have identified the superiority of (S, S)-[C-11]MRB and the suitability of the MRB analogs as potential NET ligands for PET. In contrast, Nis, Oxap and Lort displayed high uptake in striatum (higher than thalamus). The use of these ligands is further limited by high non-specific binding and relatively low specific signal, as is characteristic of many earlier NET ligands. Thus, to our knowledge, (S, S)-[C-11]MRB remains by far the most promising NET ligand for PET studies. Ding, Y.S., Lin, K.S., and Logan, J. Current Pharmaceutical Design, 12(30), pp. 3831-3845, 2006.
The Effect of Graded Monetary Reward on Cognitive Event-Related Potentials and Behavior in Young Healthy Adults
Dr. Rita Goldstein and colleagues at Brookhaven National Laboratory investigated the temporal correlates of the brain circuits underlying reward processing in healthy adults. The current study investigated the P3 and contingent negative variation (CNV) as putative reward-related temporal markers. The effect of sustained monetary reward on these event-related potentials and on behavior was assessed using a warned reaction-time paradigm in 16 young healthy subjects. Monetary reward (0, 1 and 45 cents) varied across blocks of trials. While the CNV was unaffected by money, P3 amplitude was significantly larger for 45 than the 1 and 0 cent conditions. This effect corresponded to the monotonically positive subjective ratings of interest and excitement on the task (45 > 1 > 0). These findings suggest a difference between the P3 and CNV; the P3 is sensitive to the sustained effect of relative reward value, while the CNV does not vary with reward magnitude. Goldstein, R.Z., Cottone, L.A., Jia, Z.R., Maloney, T., Volkow, N.D., and Squires, N.K. International Journal of Psychophysiology, 62(2), pp. 272-279, 2006.
MDMA Use Is Associated with Increased Spatial BOLD fMRI Visual Cortex Activation in Human MDMA Users
Dr. Ron Cowan and colleagues at McLean Hospital used fMRI to investigate whether MDMA users have altered visual system function. Previous studies have found that human MDMA users have altered serotonergic function and reduced gray matter density in occipital cortex, consistent with animal studies demonstrating that 3,4-methylenedioxymethamphetamine (MDMA) exposure causes serotonin axotomy that is greatest in occipital cortex (including primary visual cortex). BOLD fMRI was used to probe visual cortical activation after photic stimulation in a group of adult MDMA users. Because MDMA users worldwide are polydrug users and therefore difficult to match to comparison groups in terms of polydrug exposure, primary within-group analysis was conducted examining the correlation between lifetime episodes of MDMA exposure and measures of visual cortical activation. The within-group correlational analysis in the MDMA user group revealed that the degree of prior MDMA exposure was significantly positively correlated with the number of activated pixels for photic stimulation (r=0.582, p=0.007). A secondary between-group comparison of MDMA users with non-MDMA users found overall greater levels of polydrug exposure in the MDMA user cohort but no significant differences in visual cortical activation measures between the two groups. Cowan, R.L., Haga, E., Frederick, B.D., Dietrich, M.S., Vimal, R.L.P., Lukas, S.E., and Renshaw, R. Pharmacology Biochemistry and Behavior, 84(2), pp. 219-228, 2006.
Decision-Making and The Iowa Gambling Task: Ecological Validity in Individuals with Substance Dependence
Dr. Antoine Bechara and colleagues investigated whether real-life indices associated with escalation of addiction severity (as measured by the Addiction Severity Index -ASI-) are predictive of risky decisions, as revealed by impaired performance on different versions of the Iowa Gambling Task. Substance Dependent Individuals (SDIs) usually show deficits in real-life decision-making, as illustrated by their persistence in drug use despite a rise in undesirable consequences. Although most SDIs are impaired on the IGT there is a subgroup of them who perform normally on this task. One possible explanation for this differential performance is that impairment in decision-making is largely detected on the IGT when the use of drugs escalates in the face of rising adverse consequences. They administered the Addiction Severity Index (ASI) and different versions of the IGT (the main IGT version, a variant IGT version, and two parallel versions of each) to a large sample of SDI. Authors used regression models to examine the predictive effects of the seven real-life domains assessed by the ASI on decision-making performance as measured by the IGT We included in regression models both ASI-derived objective and subjective measures of each problem domain. Results showed (i) that several aspects of real-life functioning associated with addiction severity were moderate predictors of IGT decision-making performance; (ii) that the combined assessment of decision-making using different versions of the IGT yielded better predictive measures than assessment using isolated versions of the IGT; and (iii) that objective measures of real-life functioning were better predictors of decision-making performance on the IGT than subjective measures based on SDI's insight about their problems. These results support the notion that decision-making deficits as measured by the IGT are associated with a rise in real-life adverse consequences of addiction. Verdejo-Garcia, A., Bechara, A., Recknor, E.C., and Perez-Garcia, M. Psychologica Belgica, 46(1-2), pp. 55-78, 2006.
Blunted Prolactin Response Correlates with Severity of Cocaine Use
In a study to determine damage to serotonin function in cocaine dependent subjects, Dr. Ashwin Patkar and associates at Duke University used a mixed 5-HT agonist/antagonist to assess disturbance by measuring prolactin stimulation. A within-group correlation demonstrated a significant change in prolactin negatively correlated with the Addiction Severity Index--a lesser change corresponded to a high Index score. A between-group comparison with a control group of non-users showed lower levels at 2-3 hours even though cocaine patients had a higher baseline prolactin level. Furthermore, the change in prolactin in the patients seemed to be more related to the severity than to behavioral traits associated with cocaine use, suggesting the 5-HT system was modified by cocaine use. The conjecture for future research is to determine whether these modifications offer a pharmacological site for treatment. Patkar, A.A., Mannelli, P., Hill, K.P., Peindl, K., Pae, C-u, and Lee, T.H. Human Psychopharmacology, Hum Psychopharmaco Clin Exp, 21, pp. 367-375, 2006.
Treatment of Schizophrenia and Comorbid Substance Abuse: Pharmacologic Approaches
Dr. Allen Green of Dartmouth School of Medicine reviewed theories of substance use disorders in schizophrenic patients. These theories include the notion that substance use could trigger psychotic symptoms in vulnerable individuals and the idea that the substances are used to self-medicate symptoms of schizophrenia. The author hypothesizes that a mesocorticolimbic brain reward circuit underlies the substance use disorder in patients with schizophrenia. Treatment of substance use disorder in these patients is best done with integrated treatment programs that combine psychosocial interventions with pharmacotherapy. Recent data suggest that the atypical antipsychotic clozapine and perhaps other atypical agents may lessen substance use in patients with schizophrenia. The author proposes that clozapine's effect in these patients may be related to its ability to decrease the brain reward circuit dysfunction. In addition, the adjunctive use of naltrexone or other agents also may be helpful. Nonetheless, further research on the optimal pharmacologic approach to patients with dual diagnosis is needed. Green, A.I. Journal of Clinical Psychiatry, 67, pp. 31-35 Suppl. 7, 2006.
Emotion-Based Decision-Making in Healthy Subjects: Short-Term Effects of Reducing Dopamine Levels
Dr. A. Bechara and colleagues investigated whether a decrease in dopaminergic activity impairs emotion-based decision-making. Dopamine depletion was induced in 11 healthy human subjects by administration of a mixture containing the branched-chain amino acids (BCAA) valine, isoleucine and leucine. A double-blind, placebo-controlled, within-subject design was used to examine the effect of dopamine depletion on prolactin, IGT performance, perceptual competency and visual aspects of visuospatial working memory, visual attention and working memory, and verbal memory. The expectancy-valence model was used to determine the relative contributions of distinct IGT components (attention to past outcomes, relative weight of wins and losses, and choice strategies) in the decision-making process. Compared to placebo, the BCAA mixture increased prolactin levels and impaired IGT performance. BCAA administration interfered with a particular component process of decision-making related to attention to more recent events as compared to more distant events. There were no differences between placebo and BCAA conditions for other aspects of cognition. These results suggest a direct link between a reduced dopaminergic activity and poor emotion-based decision-making and difficulties resisting short-term reward, despite long-term negative consequences. These findings have implications for behavioral and pharmacological interventions targeting impaired emotion-based decision-making in addictive disorders. Sevy, S., Hassoun, Y., Bechara, A., Yechiam, E., Napolitano, B., Burdick, K., Delman, H., Malhotra, A. Psychopharmacology, 188(2), pp. 228-235, 2006.
Amygdala Response to Facial Expressions Reflects Emotional Learning
Dr. Mark D'Esposito and colleagues at University of California, Berkeley used fMRI to investigate the role of the human amygdala in a fundamental aspect of social communication, the evaluation of emotional facial expressions. Previous animal and human research shows that the amygdala participates in processing positive and negative reinforcement as well as in learning predictive associations between stimuli and subsequent reinforcement. Thus, amygdala response to facial expressions could reflect the processing of primary reinforcement or emotional learning. The results indicated that the amygdala is more responsive to learning object-emotion associations from happy and fearful facial expressions than it is to the presentation of happy and fearful facial expressions alone. The results provide evidence that the amygdala uses social signals to rapidly and flexibly learn threatening and rewarding associations. Since the amygdala is known to play a role in substance abuse, this study forms the foundation for the investigation of altered social interactions in substance abusers. Hooker, C.I., Germine, L.T., Knight, R.T., and D'Esposito, M. Journal of Neuroscience, 26(35), pp. 8915-8922, 2006.
A Low-Cost, MR-Compatible Olfactometer
Drs. Steven Lowen and Scott Lukas of McLean Hospital describe the design for an olfactometer, suitable for fMRI experiments, that can be constructed at extremely low cost. The olfactometer presents odors directly to the nose via a nasal cannula at unobtrusively low flow velocities, with no large assemblies required on or near the subject's face. The olfactometer can be controlled manually, or by computer via a serial interface. A validation study verified that the olfactometer reliably presents odors to test subjects. Errors and response latency times decreased with increased flow rate in an orderly manner, as expected. Since many drugs of abuse produce olfactory stimuli (e.g. nicotine, marijuana), this device will be useful in the study of brain processing of drug-related conditioned cues. Lowen, S.B., and Lukas, S.E. Behavior Research Methods, 38(2), pp. 307-313, 2006.
Topiramate Raises Anterior Cingulate Cortex Glutamine Levels in Healthy Men; A 4.0 T Magnetic Resonance Spectroscopy Study
Dr. Perry Renshaw and colleagues at McLean Hospital used MRS to investigate whether the mechanisms of action of topiramate include alterations of glutamatergic and GABAergic systems. In this study, the effect of acute oral topiramate on the GABA precursors glutamate and glutamine in the anterior cingulate cortex (ACC) and occipital lobe (OL) was measured using high-field (4.0 T) proton MRS (H-1 MRS). Proton MR spectra were acquired from healthy men at three times: at baseline and 2 and 6 h after ingesting 50 (N=5) or 100 mg (N=5) of topiramate. Blood samples were acquired prior to each scan for the purpose of obtaining serum topiramate levels. A 100-mg dose of topiramate significantly increased ACC glutamine levels within 2 h of ingestion and OL glutamine levels within 6 h of ingestion. There were no measured significant effects of topiramate on ACC or OL glutamate levels. Increased brain glutamine levels may be a consequence of topiramate positively modulating GABA(A) receptors. This result is of interest given the possible role for topiramate in the treatment of substance dependence. Moore, C.M., Wardrop, M., Frederick, B.D., and Renshaw, P.F. Psychopharmacology, 188(2), pp. 236-243, 2006.
Individual Differences in the Functional Neuroanatomy of Inhibitory Control
Dr. Hugh Garavan of Trinity University performed combined the data of five event-related fMRI studies of response inhibition. Functional differences were observed between the sexes with greater activity in females in many of these cortical regions. Despite the relatively narrow age range (18-46), cortical activity, on the whole, tended to increase with age, echoing a pattern of functional recruitment often observed in the elderly. More absentminded subjects showed greater activity in fronto-parietal areas, while speed of Go trial responses produced a varied pattern of activation differences in more posterior and subcortical areas. Although response inhibition produces robust activation in a discrete network of brain regions, these results reveal that individual differences impact on the relative contribution made by the nodes of this network. These results provide a framework to interpret changes in brain activity during inhibitory control in substance abusers. Garavan, H., Hester, R., Murphy, K., Fassbender, C., and Kelly, C. Brain Research, 1105, pp. 130-142, 2006.
Behavioral, But Not Reward, Risk Modulates Activation of Prefrontal, Parietal, and Insular Cortices
Dr. Scott Huettel of Duke University used fMRI to determine whether different forms of risk have distinct neural correlates. Risky decisions may involve uncertainty about possible outcomes (i.e., reward risk) or uncertainty about which action should be taken (i.e., behavioral risk). In two functional magnetic resonance imaging experiments, normal subjects viewed shapes that had well-learned response-reward contingencies. Magnitude of a monetary reward was held constant within one experiment, whereas expected value was held constant within the other. Response selection, in the absence of behavioral risk evoked activation within a broad set of brain regions, as had been found in prior studies. However, behavioral risk additionally modulated activation in prefrontal, parietal, and insular regions, within which no effect of reward risk was observed. Reward delivery, in comparison with omission, evoked increased activity in the ventromedial. prefrontal cortex and the nucleus accumbens. Authors conclude that distinct brain systems are recruited for the resolution of different forms of risk. These results provide a foundation for investigating alterations in brain systems involved in the evaluation of risk in substance abusers. Huettel, S.A. Cognitive Affective & Behavioral Neuroscience, 6(2), pp. 141-151, 2006.
Mapping the Functional Anatomy of Task Preparation: Priming Task-Appropriate Brain Networks
Dr. Hugh Garavan of Trinity College used fMRI and a cued version of a flanker paradigm to elucidate the effects of task preparation on subsequent brain activation patterns in healthy subjects. A mixed block and event-related design was employed to examine activations associated with the cue periods themselves and the cued and un-cued correct responses to incongruent flankers. A number of areas were active during the cues, most notably left dorsolateral prefrontal cortex (DLPFC), which was interpreted as subserving a role in task-set maintenance. Widespread activity was noted for correct responses to incongruent flankers, including bilateral parietal and frontal regions, consistent with previous studies. Activation was increased in these regions for correct responses after cue periods. An overlapping network of regions was also noted for cues and correct responses, suggesting preparation of task-appropriate anatomical regions during the cue period. These results suggest that cue periods allow participants to prime task-relevant areas within the brain and highlight the importance of left DLPFC in top-down control. Similar processes may underlie brain activity during presentation of drug-related cues to substance abusers and in the subsequent generation of subjective craving experiences. Fassbender, C., Foxe, J.J., and Garavan, H. Human Brain Mapping, 27(10), pp. 819-827, 2006.
Advances in White Matter Imaging: A Review of In Vivo Magnetic Resonance Methodol-ogies and their Applicability to the Study of Development and Aging
Dr. Kelvin Lim of the University of Minnesota reviewed the magnetic resonance imaging (MRI) techniques that are increasingly being applied to the study of white matter development and pathology across the lifespan. These techniques go beyond traditional macrostructural volumetric methods and provide valuable information about underlying tissue integrity and organization at the microstructural and biochemical levels. An overview of white matter development is first presented along with the role of white matter and myelin in cognitive function. Studies of development that have employed traditional volumetric measures are then reviewed. Finally, the contributions of four newer imaging paradigms to our understanding of brain development and aging are discussed. These paradigms are Diffusion Tensor Imaging (DTI), Magnetization Transfer Imaging (MTI), T2-Relaxography, and Magnetic Resonance Spectroscopy (MRS). Studies examining brain development, during childhood and adulthood as well as studies of the effects of aging are discussed. These new techniques have the potential of providing new information regarding the effects of substance abuse on brain structure. Wozniak, J.R., and Lim, K.O. Neuroscience and Biobehavioral Reviews, 30(6), pp. 762-774, 2006.
A Major Susceptibility Locus Found of Chromosome 10 for Nicotine Dependence in African Americans
Dr. Ming D. Li and associates report several susceptibility loci to one or more measures of nicotine dependence following a genome-wide scan; the strongest linkage was at 10q22 (LOD = 4.17). Suggestive linkages were also found on chromosomes 9, 11, and 13 and possibly 15, 17, and 18. Although chromosome 10 is novel for this population, other studies have also reported sites on chromosomes 9 and 11. Furthermore in a family-based study candidate genes (e.g., GABA-B2 and NTRK2) within the 9q22 region were found to be associated with nicotine dependence. Probands were required to be smoking 20 cigarettes/day for 5 years and have a smoking sibling. Other family members (regardless of smoking status) were recruited as best possible, yielding a final pool of 1261 subjects in 402 families. This study is believed to be the first large study focusing exclusively on African Americans. Li, M.D., Payne, T.J., Ma, J.Z., Lou, X-Y., Zhang, D., Dupont, R.T., Crews, K.M., Somes, G., Williams, N.J., and Elston, R.C., Amer. J. Hum Genet, 79, pp. 745-751, 2006.
Functional Imaging Studies in Cannabis Users
Dr. Linda Chang of the University of Hawaii reviewed neuroimaging studies in cannabis (marijuana) users. The majority of imaging studies examined the acute effects of delta-9-tetrahydrocannabinol (THC) administration, used PET methods and concluded that administration of THC leads to increased activation in specific brain regions (frontal and paralimbic) and the cerebellum. These increases in activation are broadly consistent with the behavioral effects of the drug. Although there is little evidence that chronic cannabis use might result in changing brain structures, specific imaging studies (i.e., BOLD fMRI) in chronic users do show consistent alterations in the activation of brain networks responsible for higher cognitive functions. It is not yet certain whether these changes are reversible with abstinence. Given the high prevalence of cannabis use among adolescents, studies are needed to evaluate whether cannabis use might affect the developing brain. Considerable further work, employing longitudinal designs, is also needed to determine whether cannabis use causes permanent functional alterations in the brains of adults. Chang, L., and Chronicle, E.P. Neuroscientist, 13(4), pp. 1-11, 2007.
Increased Risk for Bacterial Illness in Cocaine Dependent Persons
Dr. Irwin and colleagues found a decreased capacity of monocytes to express TNF-_ and IL-6 in non-treatment-seeking cocaine dependent men. In addition, these people had a further decline in the responsiveness to a bacterial ligand which persisted after cocaine had cleared from blood. These results and measures of heart rate variability suggested that cocaine alters autonomic activity and induces protracted decreases in innate immune mechanisms. Among other implications, a suppressed immune system in these individuals may be responsible, in part, for the increased prevalence of hepatitis C seropositivity. Irwin, M.R., Olmos, L., Wang, M., Valladares, E.M., Motivala, S.J., Fong, T., Newton, T., Anthony, B., Olmstead, R., Cole, S.W. JPET Doi, pp. 10-1124, JPET, pp. 106-112797, 2006.