Research Findings - Clinical Neuroscience Research
Mesolimbic Dopamine Reward System Hypersensitivity in Individuals with Psychopathic Traits
Zald and colleagues at Vanderbilt University used a combination of PET ligand imaging and BOLD fMRI to determine whether brain responses to reward are modulated by impulsive-antisocial psychopathic traits that are linked to criminal behavior and substance abuse. Using [(18)F]fallypride PET and BOLD fMRI, they found that impulsive-antisocial psychopathic traits selectively predicted nucleus accumbens dopamine release and reward anticipation-related neural activity in response to pharmacological and monetary reinforcers, respectively. These findings suggest that neurochemical and neurophysiological hyper-reactivity of the dopaminergic reward system may comprise a neural substrate for impulsive-antisocial behavior and substance abuse in psychopathy. Buckholtz JW, Treadway MT, Cowan RL, Woodward ND, Benning SD, Li R, Ansari MS, Baldwin RM, Schwartzman AN, Shelby ES, Smith CE, Cole D, Kessler RM, Zald DH. Mesolimbic dopamine reward system hypersensitivity in individuals with psychopathic traits. Nature Neurosci 2010 April; 13(4): 419-421.
Brain Reactivity to Smoking Cues Prior to Smoking Cessation Predicts Ability to Maintain Tobacco Abstinence
Janes and colleagues from McLean Hospital sought to identify nicotine-dependent women at high risk for relapse to aid in prevention therapy. After baseline fMRI, using smoking-related and neutral images, and an Emotional Stroop (ES) test, using smoking-related words, smokers then made an attempt to quit. Subjects who "slipped" (smoked one or more cigarettes after abstinence) had heightened fMRI reactivity to smoking-related images in brain regions implicated in emotion, introspective awareness, and motor planning and execution. Insula and dorsal anterior cingulate cortex (dACC) reactivity induced by smoking images correlated with an attentional bias to smoking-related words. Additionally, smokers who slipped had decreased fMRI functional connectivity between an insula-containing network and brain regions involved in cognitive control, including the dACC and dorsal lateral prefrontal cortex, possibly reflecting reduced top-down control of cue-induced emotions. These findings suggest that the insula and dACC are important substrates of smoking relapse vulnerability. The data also suggest that relapse-vulnerable smokers can be identified before quit attempts with implications for tailoring interventions to the needs of these individuals. Janes AC, Pizzagalli DA, Richard S, Frederick BD, Chuzi S, Pachas G, Culhane MA, Holmes AJ, Fava M, Evins AE, Kaufman MJ. Brain reactivity to smoking cues prior to smoking cessation predicts ability to maintain tobacco abstinence. Biol Psychiatry. 2010 February. [Epub ahead of print].
Toward Discovery Science of Human Brain Function
Kelly of New York University School of Medicine and colleagues from 35 international centers gathered resting-state functional MRI (R-fMRI) data from 1,414 subjects. R-fMRI constitutes a candidate approach to develop common paradigms for interrogating the myriad functional systems in the brain without the constraints of a priori hypotheses. Comprehensive mapping of the "functional connectome," and its subsequent utility for genetics and brain-behavior relationships, will require such multicenter collaborative datasets. A universal architecture of positive and negative functional connections, as well as consistent loci of inter-individual variability, was demonstrated. Age and sex emerged as significant determinants. These results demonstrate that independent R-fMRI datasets can be aggregated and shared. High-throughput R-fMRI can provide quantitative phenotypes for molecular genetic studies and biomarkers of developmental and pathological processes in the brain. To initiate discovery science of brain function, the 1000 Functional Connectomes Project dataset is freely accessible at www.nitrc.org/projects/fcon_1000/. Biswal BB, Mennes M, Zuo XN, Gohel S, Kelly C, Smith SM, Beckmann CF, Adelstein JS, Buckner RL, Colcombe S, Dogonowski AM, Ernst M, Fair D, Hampson M, Hoptman MJ, Hyde JS, Kiviniemi VJ, Kštter R, Li SJ, Lin CP, Lowe MJ, Mackay C, Madden DJ, Madsen KH, Margulies DS, Mayberg HS, McMahon K, Monk CS, Mostofsky SH, Nagel BJ, Pekar JJ, Peltier SJ, Petersen SE, Riedl V, Rombouts SA, Rypma B, Schlaggar BL, Schmidt S, Seidler RD, Siegle GJ, Sorg C, Teng GJ, Veijola J, Villringer A, Walter M, Wang L, Weng XC, Whitfield-Gabrieli S, Williamson P, Windischberger C, Zang YF, Zhang HY, Castellanos FX, Milham MP. Toward discovery science of human brain function. PNAS USA. 2010 Mar 9; 107(10): 4734-4739.
Modafinil Normalizes Sleep in Abstaining Chronic Cocaine Users
Morgan and Malison at Yale and colleagues at Harvard assessed sleep quality after morning doses of modafinil in chronic cocaine users. The subjects were assessed over a three week period of (in-patient) abstinence. Normalization of slow-wave sleep time, total sleep time, and sleep latency improved over the period. These results suggest that modafinil may be relevant in the treatment of cocaine dependence. Morgan PT, Pace-Schott E, Pittman B, Stickgold R, Malison RT. Normalizing effects of modafinil on sleep in chronic cocaine users. Am J Psychiat. 2010; 167(3): 331-340.
Amphetamine Increased Ratings of Stimulation in Individuals with One Gene Variant of the Dopamine Transporter
Hamidovic, de Wit and colleagues at the University of Chicago assessed ratings of d-amphetamine in healthy volunteers divided according to specific gene variants of the dopamine transporter, SLC6A3. Four SNPs were chosen for comparison but only individuals with the C/C allele compared to the A/A/+A/C allele of the rs460000 SNP reported approximately two-fold higher ratings of stimulation and euphoria at both 10 and 20 mg of d-amphetamine administration. This SNP is in linkage disequilibrium with another SNP that is associated with ADHD. These results suggest that this polymorphic locus may have a pleiotropic effect for both ADHD and amphetamine sensitivity. Hamidovic A, Dlugos A, Palmer AA, de Wit H. Polymorphisms in dopamine transporter (SLC6A3) are associated with stimulant effects of d-amphetamine: an exploratory pharmacogenetic study using healthy volunteers. Behav Genet. 2010; 40(2): 255-261.
Sleep Deprivation Differentially Affects Methadone Maintenance Patients Compared to Healthy Controls
Lukas and colleagues at McLean Hospital studied methadone-maintained (MM) participants during recovery from 40 hours of sleep deprivation. The study was motivated by the observation of sleep disturbances in individuals using chronic opiates. Both sleep architecture and brain metabolic activity was assessedŃthe former with polysomnography (PSG), the latter with magnetic resonance spectroscopy (MRS). Results indicated that increases in total sleep time and sleep efficiency commonly associated with recovery sleep were not apparent in the methadone-maintained individuals. These differences were especially apparent for MM individuals who have been in therapy less than a year compared to those whose treatment was much longer. PSG also showed that MM participants had greater power in the delta, theta, and alpha spectral bands. Finally, MRS revealed greater elevations of beta-NTPŃa direct measure of adenosine tri-phosphate following recovery sleep. These results of differences of both sleep architecture and brain chemistry during recovery sleep in MM participants suggest a disruption in homeostatic sleep function. Trksak GH, Jensen JE, Plante DT, Penetar DM, Tartarini WL, Maywalt MA, Brendel M, Dorsey CM, Renshaw PF, Lukas SE. Effects of sleep deprivation on sleep homeostasis and restoration during methadone-maintenance: A P MRS brain imaging study. Drug Alcohol Depend. 2010; 106(2-3): 79-91.
Long Term Neurocognitive and Affective Improvement among Methamphetamine Users Exhibiting Stable Abstinence
Dr. Igor Grant and colleagues found that the neuropsychological disorder and affective distress in methamphetamine-dependent participants continued to recover in those who were able to maintain abstinence at the one-year follow-up. A significantly and disproportionately greater improvement in processing speed and slightly greater improvement in motor abilities were evident in comparison to those who continued to use methamphetamine. Functional recovery to a level comparable to healthy subjects was observed in some long-term abstainers. These results suggest recovery of neuropsychological functioning and improvement in affective distress upon sustained abstinence from methamphetamine may extend beyond a year or more. Iudicello JE, Woods SP, Vigil O, Cobb SJ, Cherner M, Heaton RK, Hampton AJ, Grant I. Longer term improvement in neurocognitive functioning and affective distress among methamphetamine users who achieve stable abstinence. J Clin Exp Neuropsychol. 2010 March. [Epub ahead of print].
Early Detection of Compromised Neurocognitive Dysfunction in Patients Living with HIV
Grant and colleagues reported evidence of a significant interaction between HIV serostatus and performance on mental rotationŃa task widely used to detect the ability to manipulate three-dimensional objects in space that demand neurally complex coordination of spatial cognition. HIV+ individuals committed a greater number of errors than demographically similar seronegative persons on Luria's hand rotation task, but not on the corresponding parallelogram rotation task. Hand rotation errors were associated with worse performance on measures of executive function and working memory, but not with measures of visuoperception. Considered in the context of the preferential frontostriatal neuropathology of HIV-associated neurocognitive disorders, these preliminary findings suggest that the observed deficit in the mental rotation of hands may arise from a disrupted fronto-striato-parietal network. The tasks can be very useful tools for the early detection of compromised neurocognitive capacity in medically stable and clinically asymptomatic HIV+ patients. Weber E, Woods SP, Cameron MV, Gibson SA, Grant I; HIV Neurobehavioral Research Center Group. Mental rotation of hands in HIV infection: Neuropsychological evidence of dysfunction in fronto-striato-parietal networks. J Neuropsychiatry Clin Neurosci. 2010; 22(1): 115-122.
Dissociation of Procedural Learning with Deficit in HIV+ Individuals during Iowa Gambling Decision-making
Martin and colleagues found HIV+ individuals performed poorly in the Iowa Gambling Task (IGT), a complex measure of "decision-making." However, IGT performance was not associated with three measures of procedure learning: The Rotary Pursuit, Mirror Star Tracing, and Weather Prediction tasks. Although other nondeclarative processes (e.g., somatic markers) were found important for IGT performance, it was concluded that differences in the procedural learning performance do not account for the decision-making deficits or variability in the observed performances among HIV+ individuals with a history of substance dependence. Gonzalez R, Wardle M, Jacobus J, Vassileva J, Martin-Thormeyer EM. Influence of procedural learning on Iowa Gambling Task performance among HIV+ individuals with history of substance dependence. Arch Clin Neuropsychol. 2010; 25(1): 28-38.
Relation of Dopamine Type 2/3 Receptor Availability in the Striatum to Social Status in Humans
Martinez and colleagues at Columbia University used PET ligand imaging in humans to extend previous findings in monkeys that striatal dopamine type 2/3 (D-2/3) receptors correlate with social hierarchy and that dominant animals exhibit higher levels of D-2/3 receptor binding. Social status, assessed by the Barratt Simplified Measure of Social Status, was positively correlated with dopamine D-2/3 receptors as was the perceived level of social support, assessed by the Multidimensional Scale of Perceived Social Support; higher [C-11]raclopride binding potential correlated with higher scores. The results of this study support the hypothesis that social status and social support are correlated with D-2/3 receptor binding. Martinez D, Orlowska D, Narendran R, Slifstein M, Liu F, Kumar D, Broft A, Van Heertum R, Kleber HD. Dopamine type 2/3 receptor availability in the striatum and social status in human volunteers. Biol Psychiatry 2010; 67(3): 275-278.
Financial and Psychological Risk Attitudes Associated with Two Single Nucleotide Polymorphisms in the Nicotine Receptor (CHRNA4) Gene
Beversdorf and colleagues at Ohio State University conducted an exploratory study of the genetic basis of risk-taking using constructs from both psychology and economics. Analysis of the genotyping data identified two single nucleotide polymorphisms (SNPs) in the gene encoding the alpha 4 nicotine receptor (CHRNA4, rs4603829 and rs4522666) that were significantly associated with harm avoidance. Novelty seeking was associated with several COMT (catechol-O-methyl transferase) SNPs. Economic risk attitude measures were marginally associated with several VMAT2 (vesicular monoamine transporter) SNPs. These exploratory results provide a starting point for understanding the genetic basis of risk attitudes by considering the range of methods available for measuring risk attitudes and by searching beyond the traditional direct focus on dopamine and serotonin receptor and transporter genes. Roe BE, Tilley MR, Gu HH, Beversdorf DQ, Sadee W, Haab TC, Papp AC. Financial and psychological risk attitudes associated with two single nucleotide polymorphisms in the nicotine receptor (CHRNA4) gene. PLoS ONE 2009; 4(8): e6704.
Gene Polymorphisms in Enzymes that Degrade Endogenous Cannabinoids Influence Acute Response to Amphetamine
DeWit and colleagues at University of Chicago examined whether amphetamine's effects in humans are known to be modulated by genetic differences in the degradation of endogenous cannabinoids. Two single nucleotide polymorphisms (SNPs) in the gene for the enzyme fatty acid amide hydrolase (FAAH) were significantly associated with increased ratings of arousal and fatigue, assessed by the Profile of Mood States, after administration of a10-mg dose of d-amphetamine. Fatigue levels were also found to be associated with two haplotypes, CCC and TAT. These data suggest that the endocannabinoid system influences variation in subjective response to amphetamine. These data suggest a role of endogenous cannabinoids in response to amphetamine which help to understand the genetic determinants of inter-individual differences in stimulant effects. Dlugos AM, Hamidovic A, Hodgkinson CA, Goldman D, Palmer AA, de Wit H. More aroused, less fatigued: fatty acid amide hydrolase gene polymorphisms influence acute response to amphetamine. Neuropsychopharmacology 2010; 35(3): 613-622.
Functional Imaging of Moral Deliberation and Moral Intuition
Kiehl and colleagues at the MIND Institute at the University of New Mexico used BOLD fMRI to determine whether the same brain systems process different types of moral decisions. Prior studies of moral processing have utilized "explicit" moral tasks that involve moral deliberation (e.g., reading statements such as "he shot the victim" and rating the moral appropriateness of the behavior) or "implicit" moral tasks that involve moral intuition (e.g., reading similar statements and memorizing them for a test but not rating their moral appropriateness). Half of the participants performed the explicit task; half performed the implicit task. Participants performing the explicit, but not the implicit task showed increased ventromedial prefrontal activity while viewing moral pictures. Both groups showed increased temporo-parietal junction activity while viewing moral pictures. These results suggest that the ventromedial prefrontal cortex may contribute more to moral deliberation than moral intuition, whereas the temporo-parietal junction may contribute more to moral intuition than moral deliberation. Harenski CL, Antonenko O, Shane MS, Kiehl KA. A functional imaging investigation of moral deliberation and moral intuition. NeuroImage 2010; 49(3): 2707-2716.
Reversal of Error Effects in Anterior Cingulate Cortex with High Error Likelihood
Brown and colleagues at Indiana University used BOLD fMRI to test competing hypotheses about the neural basis of error-related activity in the anterior cingulate cortex and adjacent medial prefrontal cortex (mPFC). Most studies to date use tasks that generate relatively low error rates, confounding the expectedness and the desirability of an error. The present study found that when losses are more frequent than wins, the mPFC error effect disappears, and moreover, exhibits the opposite pattern by responding more strongly to unexpected wins than losses. These findings provide perspective on recent electrophysiological evoked potential studies and suggest that mPFC error effects result from a comparison between actual and expected outcomes. Jessup RK, Busemeyer JR, Brown JW. Error effects in anterior cingulate cortex reverse when error likelihood is high. Journal of Neuroscience 2010; 30(9): 3467-3472.
The Effect of Motivation on Cingulate and Ventral Striatum Activity Related to Executive Function and Error Detection
Garavan and colleagues used BOLD fMRI to determine how motivation modulates brain activity related to error detection in a GO/NOGO task where a financial punishment was introduced for errors. The dorsal anterior cingulate cortex (ACC) had equal trial-specific activity for errors in the neutral and punishment conditions but had greater tonic activity throughout the punishment condition where there were slower responses and fewer commission errors. A region of interest analysis revealed different activation patterns between the dorsal and the rostral parts of the ACC with the rostral ACC having only trial-specific activity for errors in the punishment condition, an activity profile similar to one observed in the nucleus accumbens. This study suggests that there is a motivational influence on cognitive processes in the ACC and nucleus accumbens and hints at a dissociation between tonic proactive activity and phasic reactive error-related activity. Sim›es-Franklin C, Hester R, Shpaner M, Foxe JJ, Garavan H. Executive function and error detection: The effect of motivation on cingulate and ventral striatum activity. Human Brain Mapping 2010; 31(3): 458-469.
Learned Reward and Error Outcome Predictions Compete in the Anterior Cingulate Cortex
Brown and colleagues at Indiana University used fMRI to test a specific hypothesis of anterior cingulate cortex (ACC) function. The fMRI results ruled out a modulatory effect of expected reward on error likelihood effects in favor of a competition effect between expected reward and error likelihood. Dynamic causal modeling showed that error likelihood and expected reward signals are intrinsic to the ACC rather than received from elsewhere. These findings agree with interpretations of ACC activity as signaling both perceptions of risk and predicted reward. Alexander WH, Brown JW. Competition between learned reward and error outcome predictions in anterior cingulate cortex. Neuroimage 2010 February; 49(4): 3210-3218.
Available Alternative Incentives Modulate Anticipatory Nucleus Accumbens Activation
Knutson and colleagues at Stanford used event-related fMRI to investigate how neural representations of an anticipated incentive might be influenced in the context of other available alternatives of a monetary incentive delay task with uncertain or certain gains and losses. The availability of certain gains and losses increased NAcc activation for uncertain losses and decreased the difference between uncertain gains and losses. The results suggest that this pattern of activation can result from reference point changes across blocks, and that the worst available loss may serve as an important anchor for NAcc activation. These findings imply that NAcc activation represents anticipated incentive value relative to the current context of available alternative gains and losses. Cooper JC, Hollon NG, Wimmer GE, Knutson B. Available alternative incentives modulate anticipatory nucleus accumbens activation. Social Cognitive and Affective Neuroscience 2009; 4(4): 409-416.
Primary and Secondary Rewards Differentially Modulate Neural Activity Dynamics during Working Memory
Braver and colleagues at Washington University used fMRI to examine whether brain activity to a reinforcer is different if a secondary (monetary) or primary (liquid) reward was used as an outcome during a working memory task. Performance was dramatically and equivalently enhanced in each incentive condition, where the monetary reward condition was associated with a tonic activation increase in primarily right-lateralized cognitive control regions including anterior prefrontal cortex (PFC), dorsolateral PFC, and parietal cortex. In the liquid reward condition, the identical regions instead showed a shift in transient activation from a reactive control pattern (primary probe-based activation) during no-incentive trials to proactive control (primary cue-based activation) during rewarded trials. Additionally, liquid-specific tonic activation increases were found in subcortical regions (amygdala, dorsal striatum, nucleus accumbens), indicating an anatomical double dissociation in the locus of sustained activation. These different activation patterns suggest that primary and secondary rewards may produce similar behavioral changes through distinct neural mechanisms of reinforcement. Beck SM, Locke HS, Savine AC, Jimura K, Braver TS. Primary and secondary rewards differentially modulate neural activity dynamics during working memory. PLoS ONE 2010; 5(2): e9251.
The Amygdala is Distinctly Responsive to Novel Unusual Stimuli
Zald and colleagues at Vanderbilt University used fMRI to determine whether the amygdala and hippocampus are differentially activated by two types of novelty: Stimuli that are ordinary, but novel in the current context, and stimuli that are unusual. When presented with the novel common stimuli, the BOLD signal increased significantly in both the amygdala and hippocampus. However, for the novel unusual stimuli, only the amygdala showed an increased response compared to the novel common stimuli. These findings suggest that the amygdala is distinctly responsive to novel unusual stimuli, making a unique contribution to the novelty detection circuit. Blackford JU, Buckholtz JW, Avery SN, Zald DH. A unique role for the human amygdala in novelty detection. NeuroImage 2010; 50(3): 1188-1193.
Sex-Related Differences in Amygdala Activity Influences Immediate Memory
Krystal and colleagues at Yale used fMRI to determine whether amygdala responses to emotional pictures would predict performance on an immediate recognition memory test. They found that increased right amygdala activation during unpleasant picture viewing was related to lower false-positive rates (i.e., commission errors) for men and higher false-positive rates for women. Their results indicate that increased amygdala activation while viewing unpleasant pictures may preferentially facilitate immediate recognition memory in men relative to women. Aikins DE, Anticevic A, Kiehl KA, Krystal JH. Sex-related differences in amygdala activity influences immediate memory. NeuroReport 2010; 21(4): 273-276.
Brain Activation during Memory of Emotionally Salient Events Depends on Individual Perspective
LaBar and colleagues at Duke capitalized on the high personal fan investment and rivalry of a Duke-UNC basketball game to examine the neural correlates of emotional memory retrieval of similar events from different perspectives. Male fans watched a video of a past game in a social setting. During a subsequent functional magnetic resonance imaging session, participants viewed video clips depicting individual plays of the game that ended with the ball being released toward the basket. For each play, participants recalled whether or not the shot went into the basket. BOLD fMRI signals time-locked to correct memory decisions were analyzed as a function of emotional intensity and valence, according to the fan's perspective. Intensity-modulated retrieval activity was observed in midline cortical structures, sensorimotor cortex, the striatum, and the medial temporal lobe, including the amygdala. Positively valent memories specifically recruited processing in dorsal frontoparietal regions, and additional activity in the insula and medial temporal lobe for positively valent shots recalled with high confidence. This novel paradigm reveals how brain regions implicated in emotion, memory retrieval, visuomotor imagery, and social cognition contribute to the recollection of specific plays in the mind of a sports fan. Botzung A, Rubin DC, Miles A, Cabeza R, LaBar KS. Mental hoop diaries: Emotional memories of a college basketball game in rival fans. J Neuroscience 2010; 30(6): 2130-2137.
Practiced Visual Characterization Results in Changes in Functional Connectivity Patterns
D'Esposito and colleagues at University of California, Berkeley used fMRI to examine how brain processes related to visual categorization during the transition from initially-learned to well-practiced categorization, i.e., during habit formation. Brain activation with fMRI and functional connectivity scans were obtained when subjects performed an initially learned categorization task (100 trials of training) and during a well-practiced task (4250 trials of training). Connectivity analyses revealed an increased coordination among inferior temporal cortex, medial temporal lobe premotor cortex when making category judgments during the well-practiced task. These results suggest that category learning involves an increased coordination between a distributed network of regions supporting retrieval and representation of categories. DeGutis J, D'Esposito M. Network changes in the transition from initial learning to well-practiced visual categorization. Front Hum Neurosci. 2009; 3: 44-48.
Chronic Cocaine Users Exhibit Loss of Laterality of Motor-Cortical Recruitment
Hanlon and colleagues from Wake Forest used fMRI to investigate whether chronic cocaine abusers exhibit alterations in brain activity related to movement disturbances. BOLD fMRI scans were obtained from 14 chronic cocaine users and 15 age- and gender-matched controls while they performed a sequential finger-tapping task with their dominant, right hand interleaved with blocks of rest. Cocaine users had significantly longer reaction times and higher error rates than controls. Whereas the controls used a left-sided network of motor-related brain areas to perform the task, cocaine users activated a less lateralized pattern of brain activity. Users had significantly more activity in the ipsilateral (right) motor and premotor cortical areas, anterior cingulate cortex and the putamen than controls. These data demonstrate that there are pronounced alterations in sensorimotor control in these individuals, which are associated with functional alterations throughout movement-related neural networks. Hanlon CA, Wesley MJ, Roth AJ, Miller MD, Porrino LJ. Loss of laterality in chronic cocaine users: An fMRI investigation of sensorimotor control. Psychiatry Research: Neuroimaging 2010; 181(1): 15-23.
Smoking Reduces Pain-Related Evoked Potentials
Domino and colleagues at University of Michigan, together with colleagues at the National Institute for Physiological Sciences, Myodaiji-cho (Okazaki, Japan) used evoked potential recordings to investigate the effects of human tobacco smoking and nicotine on pain-related brain activities. EEG responses evoked by a painful laser beam (laser evoked potentials; LEPs), and the plasma nicotine concentration (PNC) were measured. The amplitude of P2 was significantly smaller in the smoking session than in the no-smoking session. A significant negative correlation was found between PNC and the amplitude of N2 as well as P2. The results were consistent with the hypothesis that smoking and/or nicotine have an antinociceptive effect, which supports most non-human studies and some human studies. Smoking of a single tobacco cigarette did not show a subjectively perceivable extent of reduction in the intensity of evoked pain. Miyazaki T, Wang X, Inui K, Domino EF, Kakigi R. The effect of smoking on pain-related evoked potentials. Brain Res 2010; 1313: 185-191.
Assessing Liking and Wanting of Drug and Non-Drug Rewards in Active Cocaine Users
Goldstein and colleagues at Brookhaven National Laboratories developed and tested a questionnaire (STRAP-R) that can assess "liking" and "wanting" of expected "drug" rewards as compared to natural rewards (e.g., "food" and "sex"). In all, 20 cocaine-addicted individuals (mean abstinence = 2 days) and 20 healthy control subjects were administered the questionnaire after receiving an oral dose of the dopamine agonist methylphenidate (20 mg) or placebo. The reinforcers' relative values changed within the addicted sample when reporting about the "under drug influence" situation (drug > food; otherwise, drug < food). This change was highest in the youngest age of onset of cocaine use. Moreover, "drug wanting" exceeded "drug liking" in the addicted subjects when reporting about this situation during methylphenidate. Thus, cocaine-addicted individuals assign the highest subjective valence to "drug" rewards but only when recalling cue-related situations. When recalling this situation, they also report higher drug "wanting" than hedonic "liking," a motivational shift that was only significant during methylphenidate. Together, these valence shifts may underlie compulsive stimulant abuse upon pharmacological or behavioral cue exposure in addicted individuals. Additional studies are required to assess the reliability of the STRAP-R in larger samples and to examine its validity in measuring the subjective value attributed to experienced reinforcers or in predicting behavior. Goldstein R, Woicik P, Moeller S, Telang F, Jayne M, Wong C, Wang G, Fowler J, Volkow N. Liking and wanting of drug and non-drug rewards in active cocaine users: the STRAP-R questionnaire. J Psychopharm 2010; 24(2): 257-266.
Tracking Changes in Control over Smoking during Addiction and Recovery Processes
DiFranza and colleagues at University of Massachusetts created a questionnaire to study how smokers lose autonomy over smoking and regain it after quitting. The Autonomy Over Smoking Scale (AOSS) was developed iteratively through a process involving item generation, focus-group evaluation, testing in adults to winnow items, field testing with adults and adolescents, and head-to-head comparisons with other measures. The final 12-item scale showed excellent reliability (alpha s = .91-97), with a one-factor solution explaining 59% of the variance in adults and 61%-74% of the variance in adolescents. Concurrent validity was supported by associations with age of smoking initiation, lifetime use, smoking frequency, daily cigarette consumption, history of failed cessation, Hooked on Nicotine Checklist scores, and Diagnostic and Statistical Manual of Mental Disorder (4th ed., text rev.; American Psychiatric Association, 2000) nicotine dependence criteria. Potentially useful features of this new instrument include (a) it assesses tobacco withdrawal, cue-induced craving, and psychological dependence on cigarettes; (b) it measures symptom intensity; and (c) it asks about current symptoms only, so it could be administered to quitting smokers to track the resolution of symptoms. DiFranza JR, Wellman RJ, Ursprung WWSA, Sabiston C. The Autonomy Over Smoking Scale. Psychology of Addictive Behaviors 2009; 23(4): 656-665.
Questionnaire for Methamphetamine-Related Paranoia
Salo and colleagues at University of California, Davis developed a questionnaire to characterize paranoia in methamphetamine (MA) users. The Methamphetamine Experience Questionnaire (MEQ), was administered to 274 MA-dependent subjects. Of the total subjects, 45% (123) first experienced paranoia with MA use; 55% did not. Obtaining or using a weapon while paranoid was common (37% and 11% of subjects with MA-induced paranoia, respectively). Test-retest and inter-rater reliability for MA-induced paranoia showed substantial agreement (kappa = .77, p < .05 and kappa = .80, p < .05, respectively). First episodes of paranoia occurred more often with intravenous use of MA, and subsequent episodes at higher doses. There was modest correlation between paranoia on the MEQ and the Brief Symptom Inventory (BSI) paranoid ideation scale (rho = .27, p < .05). As expected, there was a poor correlation between paranoia on the MEQ and the BSI depression scale (rho = .14, p = .07). The MEQ provides useful information on drug use variables that contribute to paranoia commonly associated with MA use. Leamon MH, Flower K, Salo RE, Nordahl TE, Kranzler HR, Galloway GP. Methamphetamine and Paranoia: The Methamphetamine Experience Questionnaire. Am J Addictions 2010; 19(2): 155-168.
Quantitative Analysis of the Serotonin 5-HT1B Receptor Radioligand [11C]P943 in Humans
Ding and colleagues at Yale examined several methods for quantitative analysis of new radioligand [C-11]P943, for imaging serotonin 5-Hydroxytryptamine (5-HT1B) receptors in humans with positron emission tomography (PET). Positron emission tomography data and arterial input function measurements were acquired 32 human subjects. Using arterial input functions, compartmental modeling, the Logan graphical analysis, and the multilinear method MA1 were tested. Both the two tissue-compartment model and MA1 provided good fits of the PET data and reliable distribution volume estimates. Using the cerebellum as a reference region, BPND binding potential estimates were computed. [C-11]P943 BPND estimates were significantly correlated with in vitro measurements of the density of 5-HT1B receptors, with highest values in the occipital cortex and pallidum. To evaluate noninvasive methods, two-and three-parameter graphical analyses, Simplified Reference Tissue Models (SRTM and SRTM2), and Multilinear Reference Tissue Models (MRTM and MRTM2) were tested. The MRTM2 model provided the best correlation with MA1 binding-potential estimates. Parametric images of the volume of distribution or binding potential of [C-11]P943 could be computed using both MA1 and MRTM2. The results show that [C-11]P943 provides quantitative measurements of 5-HT1B binding potential. Gallezot J, Nabulsi N, Neumeister A, Planeta-Wilson B, Williams WA, Singhal T, Kim S, Maguire RP, McCarthy T, Frost JJ, Huang Y, Ding Y, Carson RE. Kinetic modeling of the serotonin 5-HT1B receptor radioligand [11C]P943 in humans. J Cereb Blood Flow Metab 2009; 30(1): 196-210.
Simplified Quantification of 5-HT2A Receptors in the Human Brain
Bhagwagar and colleagues at Yale in collaboration with University Hospital, Freiburg developed simple methods for quantitative analysis of the 5-HT2A PET ligand, [C-11]MDL100,907 using the cerebellum as reference region. Five healthy volunteers underwent two PET scanning sessions; baseline and after pre-treatment with mirtazapine, a drug that binds with high affinity at the serotonin 5-HT2B receptors. Regional time-activity curves of 10 regions of interest (ROI) were analyzed for binding potential (BPND) and mirtazapine receptor occupancy (Occ) using 5 approaches: 1) simplified reference tissue model (SRTM), 2) multi-linear reference tissue model (MRTM), 3) their two-parameter versions (SRTM2/MRTM2), 4) non-invasive graphical analysis (NIGA) and 5) a tissue activity concentration ratio. NIGA was also applied voxel-wise to generate BPND maps. These methods were compared with a two-tissue compartment model with arterial input function (2TCM). SRTM and MRTM frequently failed to yield reliable results. NIGA was found to be well suited for analysis of [C-11]MDL100,907 PET studies, yielding estimates of 5-HT2A receptor availability and changes that are highly correlated with results from invasive 2TCM with arterial input function analyses. Use of NIGA should greatly enhance the applicability of 5-HT2A receptor PET studies. Meyer PT, Bhagwagar Z, Cowen PJ, Cunningham VJ, Grasby PM, Hinz R. Simplified quantification of 5-HT2A receptors in the human brain with [11C]MDL 100,907 PET and non-invasive kinetic analyses. NeuroImage 2010; 50(3): 984-993.
Does D2 Receptor Internalization Alter Binding Affinity of Neuroimaging Ligands?
Abi-Dargham and colleagues at Columbia used an in vitro assay to address whether agonist-induced D2 receptor internalization may contribute to the sustained decrease in D2 receptor-binding potential seen following a DA surge in PET ligand imaging. In PET ligand imaging studies, D2 radiotracer binding is generally thought to be due to competition between endogenous DA and the radioligands for D2 receptors. However, there is a temporal discrepancy between amphetamine-induced increases in DA as measured by microdialysis, which last on the order of 2 h, and the prolonged decrease in ligand binding, which lasts up to a day. To test whether this discrepancy is due to D2 receptor internalization, an in vitro system was developed that exhibits robust agonist-induced D2 receptor internalization following treatment with the agonist quinpirole. All the imaging ligands bound with high affinity to both surface and internalized D2 receptors. Affinity of most of the ligands to internalized receptors was modestly lower, indicating that internalization would reduce the binding potential measured in imaging studies carried out with these ligands. However, between-ligand differences in the magnitude of the internalization-associated affinity shift only partly accounted for the data obtained in neuroimaging experiments, suggesting the involvement of mechanisms beyond competition and internalization. Guo N, Guo W, Kralikova M, Jiang M, Schieren I, Narendran R, Slifstein M, Abi-Dargham A, Laruelle M, Javitch JA, Rayport S. Impact of D2 receptor internalization on binding affinity of neuroimaging radiotracers. Neuropsychopharm 2009; 35(3): 806-817.
MDMA (Ecstasy) Use is Associated with Reduced BOLD Signal Change during Semantic Recognition in Abstinent Human Polydrug Users
Cowan and colleagues at Vanderbilt tested whether MDMA users would show altered brain activation during performance of a functional magnetic resonance imaging (fMRI) task that probed semantic verbal memory. During semantic recognition, lifetime MDMA use was associated with decreased activation in left BA 9, 18 and 21/22 but not 45. This was partly influenced by contributions from cannabis and cocaine use. MDMA exposure was not associated with accuracy or response time during the semantic recognition task. During semantic recognition, MDMA exposure was associated with reduced regional brain activation in regions mediating verbal memory. These findings partially overlap with previous structural evidence for reduced grey matter in MDMA users and may, in part, explain the consistent verbal memory impairments observed in other studies of MDMA users. Raj V, Liang H, Woodward N, Bauernfeind A, Lee J, Dietrich M, Park S, Cowan R. MDMA (ecstasy) use is associated with reduced BOLD signal change during semantic recognition in abstinent human polydrug users: a preliminary fMRI study. J Psychopharm 2009; 24(2): 187-201.
Evidence of Dysregulated Serotonergic Transmission in HIV-Associated Depression
Using [(11)C]DASB positron emission tomography (PET), Nath and colleagues evaluated the association between serotonergic transmission and HIV-associated depression. The serotonin transporter (5-HTT) binding potential was lower in HIV+ individuals than in healthy subjects. A significant change was detected in the insula. There was no correlation between duration of illness and binding potentials. The diminished serotonergic transmission was regarded as a consequence of serotonergic neuronal dysfunction associated with HIV neurodegeneration. Among HIV+ individuals, those comorbid with depression had a higher mean regional biding potential than non-depressed subjects. The observation is consistent with reports of higher transmission and clearance of serotonin in patients with depression. Hammoud DA, Endres CJ, Hammond E, Uzuner O, Brown A, Nath A, Kaplin AI, Pomper MG. Imaging serotonergic transmission with [11C]DASB-PET in depressed and non-depressed patients infected with HIV. NeuroImage. 2010; 49(3): 2588-2595.
Nicotine Reduced ADHD Symptoms and Negative Moods Independent of Smoking Status
Gehricke evaluated the self-medication hypothesis by examining the effects of nicotine in the everyday lives of abstinent smokers and nonsmokers with attention-deficit/hyperactivity disorder (ADHD). Participants were administered one nicotine patch condition and one placebo patch condition in counterbalanced order on two consecutive mornings. The use of nicotine patch reduced reports of ADHD symptoms by 8% and negative moods by 9%, independent of smoking status. In addition, nicotine increased cardiovascular activity during the first 3 to 6 hours after nicotine patch administration. The results support the self-medication hypothesis for nicotine in adults with ADHD and suggest that smoking cessation and prevention efforts for individuals with ADHD will need to address both the symptom reducing and mood enhancing effects of nicotine. Gehricke JG, Hong N, Whalen CK, Steinhoff K, Wigal TL. Effects of transdermal nicotine on symptoms, moods, and cardiovascular activity in the everyday lives of smokers and nonsmokers with attention-deficit/hyperactivity disorder. Psychol Addict Behav. 2009 December; 23(4): 644-655.
Negative Affect and Pain in Children
Tsao and colleagues examined the relationships among anxiety sensitivity, catastrophizing, somatization and pain in children. Children with pain problems reported greater anxiety sensitivity and catastrophizing relative to those without pain problems. Anxiety sensitivity, but not catastrophizing, was significantly associated with current pain while both anxiety sensitivity and catastrophizing were significantly associated with somatization. These findings suggest that anxiety sensitivity and catastrophizing represent related but partially distinct cognitive constructs that may be targeted by interventions aimed at alleviating pain and somatization in children. Tsao JC, Allen LB, Evans S, Lu Q, Myers CD, Zeltzer LK. Anxiety sensitivity and catastrophizing: Associations with pain and somatization in non-clinical children. J Health Psychol. 2009 Nov; 14(8): 1085-1094.
White Matter Architecture Aberrations in Methamphetamine Dependence are Apparent in Early Withdrawal
London and colleagues at UCLA compared brain white matter characteristics in 23 methamphetamine-dependent subjects abstinent from methamphetamine for 7-13 days and 18 healthy comparison subjects. Using diffusion tensor imaging at 1.5 T, they measured fractional anisotropy (FA) in prefrontal and corpus callosum. The methamphetamine group exhibited lower FA in right prefrontal white matter above the AC-PC plane (11.9% lower; p = 0.007), in midline genu corpus callosum (3.9%; p = 0.019), in left and right midcaudal superior corona radiata (11.0% in both hemispheres, p's = 0.020 and 0.016, respectively), and in right perforant fibers (7.3%; p = 0.025). FA in left midcaudal superior corona radiata was correlated with depressive and generalized psychiatric symptoms within the methamphetamine group. These findings support the idea that methamphetamine abuse produces microstructural abnormalities in white matter underlying and interconnecting prefrontal cortices and hippocampal formation. These effects are already present during the first weeks of abstinence from methamphetamine and are linked to psychiatric symptoms assessed during this period. Tobias MC, O'Neill J, Hudkins M, Bartzokis G, Dean AC, London ED. White-matter abnormalities in brain during early abstinence from methamphetamine abuse. Psychopharm (Berl). 2010; 209(1): 13-24.
Stress-induced Changes in Mood Predict Mood Effects of Amphetamine
Hamidovic and de Wit compared responses to a stress-inducing behavior test (Trier Social Stress Test, TSST) to responses after double-blind administration of d-amphetamine. Based on animal model and previous studies in humans, the hypothesis was that individual differences in sensitivity to acute stress may underlie some of the individual differences in vulnerability to addiction. The results substantiated the hypothesis whereby it was found that negative mood states induced by stress were positively related to stimulant and euphoric mood states after d-amphetamine. The highest correlation was between the rating of anxiety after stress and rating of "liking" (from a drug effects questionnaire) after amphetamine. The results suggest that similar neural pathways may underlie both types of responses which may explain the reason that individual differences in stress responsivity are related to vulnerability to taking drugs. Hamidovic A., Childs E., Conrad M., King, A., de Wit H. Stress-induced changes in mood and cortisol release predict mood effects of amphetamine. Drug Alcohol Depend. 2010 February [Epub ahead of print].
Altered Neural Cholinergic Receptor Systems in Cocaine-Addicted Subjects
Adinoff and collaborators at University of Texas SW assessed alterations in cholinergic receptor systems in limbic regions of abstinent cocaine-addicted subjects compared with healthy controls. Cocaine-addicted subjects and control subjects were administered the muscarinic and nicotinic cholinergic agonist physostigmine, the muscarinic antagonist scopolamine, and saline. Regional cerebral blood flow (rCBF) after each infusion was determined using single photon emission-computed tomography. Both cholinergic probes induced rCBF changes (p<.005) in relatively distinct, cholinergic-rich, limbic brain regions. After physostigmine, cocaine-addicted subjects showed altered rCBF, relative to controls, in limbic regions, including the left hippocampus, left amygdala, and right insula. Group differences in the right dorsolateral prefrontal cortex, posterior cingulate, and middle temporal gyrus were also evident. Scopolamine also revealed group differences in the left hippocampus and right insula as well as the posterior cingulate and middle temporal gyrus. Cocaine addicted and controls differed in their subcortical, limbic, and cortical response to cholinergic probes in areas relevant to craving, learning, and memory. Cholinergic systems may offer a pharmacologic target for cocaine addiction treatment. Adinoff B, Devous Sr MD, Williams MJ, Best SE, Harris TS, Minhajuddin A, Zielinski T, Cullum M. Altered neural cholinergic receptor systems in cocaine-addicted subjects. Neuropsychopharm. 2010 March. [Epub ahead of print].
Neurochemistry of Drug Action
Licata, at McLean Hospital, and her colleague compiled a comprehensive review of the use of proton magnetic resonance spectroscopy ((1)H MRS) as a technique that complements other brain imaging techniques in the field of substance abuse research. Drug abuse studies using (1)H MRS have identified several biochemical changes in the brain. The most consistent alterations across drug class were reductions in N-acetylaspartate and elevations in myo-inositol; changes in choline, creatine, and amino acid transmitters also were abundant. Together, the studies provide evidence that drugs of abuse may have a profound effect on neuronal health, energy metabolism and maintenance, inflammatory processes, cell membrane turnover, and neurotransmission, and these biochemical changes may underlie the neuropathology that subsequently gives rise to the cognitive and behavioral impairments associated with drug addiction. Licata SC, Renshaw PF. Neurochemistry of drug action: Insights from proton magnetic resonance spectroscopic imaging and their relevance to addiction. Ann N Y Acad Sci. 2010 Feb; 1187: 148-171.
Impulsive Choice and Response in Dopamine Agonist-Related Impulse Control Behaviors
Potenza and colleagues at Yale investigated impulsive choice in Parkinson's Disease (PD) patients with impulse control disorders (ICDs). PD patients with impulse control disorders (IDC), PD controls without ICDs, and medication-free matched normal controls were tested on the Experiential Discounting Task (EDT), a feedback-based inter-temporal choice task, spatial working memory, and attentional set shifting. PDI patients and PD controls were tested on and off dopamine agonist. On the EDT, there was a group by medication interaction effect with pair-wise analyses demonstrating that DA status was associated with increased impulsive choice in PDI patients but not in PD controls. PDI patients also had faster RT compared to PD controls. DA status was associated with shorter RT and decision conflict RT in PDI patients but not in PD controls. There were no correlations between different measures of impulsivity. PDI patients on DA had greater spatial working memory impairments compared to PD controls on DA. Greater impulsive choice, faster RT, faster decision conflict RT, and executive dysfunction may contribute to ICDs in PD. Understanding the role of impulsivity may contribute to the identification of risk factors and the optimization of treatment modalities. Voon V, Reynolds B, Brezing C, Gallea C, Skaljic M, Ekanayake V, Fernandez H, Potenza MN, Dolan RJ, Hallett M. Impulsive choice and response in dopamine agonist-related impulse control behaviors. Psychopharm (Berl). 2010 January; 207(4): 645-659.