Research Findings - Clinical Neuroscience Research
Brain Response to Drug Prevention Messages
Dr. Daniel Langleben and colleagues at University of Pennsylvania used functional brain imaging to resolve a fundamental debate regarding the processing of information in drug prevention messages. Some communication theories propose that higher message sensation value (MSV), a measure of sensory intensity of audio, visual, and content features of an ad, brings increased attention and cognitive processing, leading to higher ad impact. Others argue that the attention-intensive format result in reduced processing of PSA content and reduced overall effectiveness. In this study, fMRI and recognition memory measures were used to compare high and low MSV, anti-tobacco PSAs and neutral videos. In a short-delay, forced-choice memory test, frames extracted from PSAs were recognized more accurately than frames extracted from the neutral videos (NV). Frames from the low MSV PSAs were better recognized than frames from the high MSV PSAs. The accuracy of recognition of PSA frames was positively correlated with the prefrontal and temporal, and negatively correlated with the occipital cortex activation. The low MSV PSAs were associated with greater prefrontal and temporal activation than the high MSV PSAs. The high MSV PSAs produced greater activation primarily in the occipital cortex. These findings support the "dual processing" and "limited capacity" theories of communication that postulate a competition between ad's content and format for the viewers' cognitive resources and suggest that the "attention-grabbing" high MSV format could impede the learning and retention of an ad. These findings also demonstrate the potential value of using neuroimaging in the design and evaluation of mass media public health communications. Langleben D, Loughead J, Ruparel K, Hakun J, Busch-Winokur S, Holloway M, Strasser A, Cappella J, Lerman C. Reduced prefrontal and temporal processing and recall of high "sensation value" ads. Neuroimage. 2009 May 15;46(1):219-225.
Hijacking the Attentional Network
Dr. Daniel Weissman and colleagues at the University of Michigan used fMRI to investigate whether consciously perceived, irrelevant instructional cues can hijack the attentional network, leading to an enhancement of the perceptual processing of irrelevant stimuli. Using a cross-modal attentional cueing task during fMRI scans, they found that such irrelevant cues increased activity in frontal regions that control attention and sensory cortices that underlie the perceptual processing of task-irrelevant stimuli. Furthermore, in left ventrolateral (but not dorsolateral) prefrontal regions, the magnitude of this increased activity varies with whether an irrelevant instructional cue is presented simultaneously with (versus after) a relevant instructional cue. These findings show that consciously perceived, irrelevant instructional cues can activate inappropriate task objectives in working memory, resulting in a hijacking of the attentional network. Moreover, they reveal different time courses of hijacking effects in ventrolateral and dorsolateral prefrontal regions, consistent with models in which these regions make distinct contributions to cognitive control. These results may provide a foundation for understanding the ability of drug-related stimuli to capture attention. Moore KS, Porter CB, Weissman DH. Made you look! Consciously perceived, irrelevant instructional cues can hijack the attentional network. Neuroimage. 2009 May 15;46(1):270-279.
Enhanced Choice for Viewing Cocaine Pictures in Cocaine Addiction
Dr. Rita Goldstein and colleagues at Brookhaven National Laboratories used two newly designed laboratory tasks with pictures to investigate the bias people with cocaine use disorders (CUD) have to choose cocaine over nondrug rewards. Choice for viewing cocaine, pleasant, unpleasant, or neutral pictures, under explicit contingencies (choice made between two fully visible side-by-side images) and under more implicit contingencies (selections made between pictures hidden under flipped-over cards), was examined in 20 CUD and 20 matched healthy control subjects. Subjects also provided self-reported ratings of each picture's pleasantness and arousal. Under both contingencies, CUD subjects chose to view more cocaine pictures than control subjects, group differences that were not fully explained by the self-reported picture ratings. Healthy control subjects avoided viewing cocaine pictures as frequently as, or even more than, unpleasant pictures. In contrast, CUD subjects' choice for viewing cocaine pictures exceeded choice for viewing unpleasant pictures (but did not exceed choice for viewing pleasant pictures, in contrast to their self-reported ratings). CUD subjects with the most cocaine viewing selections, even when directly compared with selections of the pleasant pictures, also reported the most frequent recent cocaine use. Enhanced drug-related choice in cocaine addiction can be demonstrated even for nonpharmacologic (pictorial) stimuli. This choice, which is modulated by alternative stimuli, partly transcends self-reports (possibly indicative of a discordance in cocaine addiction between self-reports and objective behavior) to provide an objective marker of addiction severity. Moeller S, Maloney T, Parvaz M, Dunning J, Alia-Klein N, Woicik P, Hajcak G, Telang F, Wang G, Volkow N, Goldstein R. Enhanced choice for viewing cocaine pictures in cocaine addiction. Biological Psychiatry. 2009 Jul;66(2):169-176.
Cannabinoid Receptor 1 (CNR1) Gene Haplotype Linkages to Cocaine Disorder in European-Americans Verified in Multiple Sites
Joel Gelernter and colleagues aimed to replicate the association between CNR1 and cocaine disorder (CD) in four independent samples. They examined eight markers across the 45 kb CNR1 region and four large samples, family-based European-American (EA) sample (n=734), case-control EA sample (n=862), family-based African-American (AA) sample (n=834) and case-control AA sample (n=619) . They reported that the interaction between two independent CNR1 variants significantly increased risk for CD in the EA family and EA case-control samples. EA subjects with SNP3(G+) and SNP8(T)/T had higher risk to develop CD than those EA subjects with the other genotypes for these two SNPs. The SNP3(G)-SNP8(T) haplotype also showed significant association with CD in the EA case-control sample. In the AA family sample, SNP8(T)/T significantly conferred higher risk for CD. The authors conclude that two independent CNR1 variants have significant interaction effects on risk for CD in EAs; they may also have effects on risk for CD in AAs. Zuo L, Kranzler HR, Luo X, Yang BZ, Weiss R, Brady K, Poling J, Farrer L, Gelernter J. Interaction between two independent CNR1 variants increases risk for cocaine dependence in European Americans: A replication study in family-based sample and population-based sample. Neuropsychopharmacology. 2009 May;34(6):1504-1513.
Relationship Between Cerebral Morphology and the Expression of Dopamine Receptors in Humans
Drs. David Zald, Ron Cowan and colleagues at Vanderbilt University examined the association between cerebral morphology and dopamine receptor distribution in 45 healthy subjects using structural MRI and PET scanning with the D-2/D-3 ligand [F-18] fallypride. Using voxel-based morphometry, grey matter volume and density images were correlated with binding potential images on a voxel-by-voxel basis. Associations between cerebral morphology and DA receptor binding potential were also examined for selected regions-of-interest (ROIs) after spatial normalization. They found that cerebral morphology, particularly grey matter density, correlated with [F-18] fallypride binding potential in a regionally specific manner. Voxel-wise analyses indicated that grey matter volume and density positively correlated with DA receptor binding throughout the midbrain, including the substantia nigra. Positive correlations were observed in medial cortical areas, including anterior cingulate and medial prefrontal cortex, and circumscribed regions of the temporal, frontal, and parietal lobes. ROI analyses revealed significant positive correlations between DA receptor binding potential and cerebral morphology in the caudate, thalamus, and amygdala. Overall, grey matter density appeared more strongly correlated with DA receptor binding potential than grey matter volume. Woodward N, Zald D, Ding Z, Riccardi P, Ansari M, Baldwin R, Cowan R, Li R, Kessler R. Cerebral morphology and dopamine D-2/D-3 receptor distribution in humans: A combined [F-18] fallypride and voxel-based morphometry study. Neuroimage. 2009 May 15;46(1):31-38.
Dopamine D1 Receptor Availability and Cocaine Self-Administration in Humans
Dr. Diane Martinez and colleagues at Columbia University used PET ligand imaging to determine D(1) receptor availability in human cocaine-dependent (CD) subjects and matched healthy controls (HCs). In addition, the study determined the association between D(1) receptor availability and cocaine-seeking behavior. Twenty-five CD subjects and 23 matched HCs were scanned using the D1 Dopamine receptor PET radiotracer [(11)C]NNC 112. During separate cocaine self-administration sessions, CD volunteers were given the choice to self-administer cocaine (0, 6, and 12 mg) or to receive a monetary voucher worth $5. D(1) receptor availability was measured in the limbic, associative, and sensorimotor striatum in addition to cortical brain regions. No difference in D(1) receptor availability was seen between the two groups. A negative association was seen between D(1) receptor binding potential in the limbic striatum and the choice for the 6 mg dose of cocaine. These results do not support the hypothesis that cocaine dependence is associated with a reduction in D(1) receptor availability in the striatum. However, within the CD subjects, low D(1) receptor availability in the ventral striatum was associated with the choice to self-administer cocaine, suggesting that low D(1) receptor availability may be associated with an increased risk of relapse in cocaine dependence. Martinez D, Slifstein M, Narendran R, Foltin RW, Broft A, Hwang D, Perez A, Abi-Dargham A, Fischman MW, Kleber HD, Laruelle M. Dopamine D1 Receptors in Cocaine Dependence Measured with PET and the Choice to Self-Administer Cocaine. Neuropsychopharmacology. 2009 Jan 28;34(7):1774-1782.
Acute Dopamine Agonist Impairs Reinforcement Learning in Humans
Diane Santesso and colleagues at Harvard demonstrated that a single low dose of a D2/D3 agonist (pramipexole) impaired reward learning in healthy subjects performing a probabilistic reward task, ostensibly by activating DA autoreceptors to reduce phasic DA bursts linked to instrumental learning. This group recently extended these behavioral findings using event-related potentials and computational modeling. Compared with the placebo group, participants receiving pramipexole showed increased feedback-related negativity to probabilistic rewards and decreased activation in dorsal anterior cingulate regions previously implicated in integrating reinforcement history over time. Additionally, findings of blunted reward learning in participants receiving pramipexole were simulated by reduced presynaptic DA signaling in response to reward in a neural network model of striatal-cortical function. These preliminary findings offer important insights on the role of phasic DA signals on reinforcement learning in humans and provide initial evidence regarding the spatiotemporal dynamics of brain mechanisms underlying these processes. Santesso DL, Evins AE, Frank MJ, Schetter EC, Bogdan R, Pizzagalli DA. Single dose of a dopamine agonist impairs reinforcement learning in humans: Evidence from event-related potentials and computational modeling of striatal-cortical function. Hum Brain Mapp. 2009 Jul;30(7):1963-1976.
Brain Response to Drug Words
Dr. Rita Goldstein and colleagues at Brookhaven National Laboratories used functional brain imaging to test the hypothesis that drug-related words can trigger activation in the mesencephalon, where dopaminergic cells are located. Fifteen individuals with cocaine use disorders and 15 demographically matched healthy control subjects pressed buttons in response to drug-related versus neutral words during fMRI scanning. Drug words, but not neutral words, activated the mesencephalon in the cocaine users only. In the cocaine users only, these increased drug-related mesencephalic responses were associated with enhanced verbal fluency specifically for drug words. The correlation between the brief verbal fluency test, which can be easily administered (crucial for clinical studies), and fMRI cue reactivity could be used as a biomarker of neurobiological changes in addiction. Goldstein R, Tomasi D, Alia-Klein N, Carrillo J, Maloney T, Woicik P, Wang R, Telang F, Volkow N. Dopaminergic response to drug words in cocaine addiction. Journal of Neuroscience. 2009 May;29(18):6001-6006.
Effects of Insula Damage on Risky Decision-Making
Dr. Antoine Bechara and colleagues at the University of Southern California used a risky decision-making task with lesion patients and healthy controls to investigate whether the insula is necessary for advantageous decision-making under risk, specifically decisions involving uncertain gains and losses. Compared to healthy controls, insula lesion patients showed an altered decision-making pattern in domains involving both risky gains and risky losses. Specifically, insula damage was associated with insensitivity to differences in expected value between choice options. Additionally, patients made significantly fewer risky choices than healthy adults in the gain domain. In conjunction with earlier findings, these results suggest that risky decision-making is dependent on the integrity of a neural circuit that includes several brain regions known to be critical for the experience and expression of emotions, namely the insula, amygdala, and ventromedial prefrontal cortex. However, each neural region seems to provide a distinct contribution to the overall process of decision-making. Weller J, Levin I, Shiv B, Bechara A. The effects of insula damage on decision-making for risky gains and losses. Social Neuroscience. 2009;4(4):347-358.
Differential Processing of Risk and Reward in Medial Prefrontal Cortex
Antoine Bechara and associates at University of Southern California used functional magnetic resonance imaging (fMRI) and investigated functional specificity in the medial prefrontal cortex regarding decision-making. Using a task that simulates risky decisions, they found that the dorsal region of the medial prefrontal cortex (MPFC) was activated whenever a risky decision was made, but the degree of this activity across subjects was negatively correlated with their risk preference. In contrast, the ventral MPFC was parametrically modulated by the received gain/loss, and the activation in this region was positively correlated with an individual's risk preference. These results demonstrate that the dorsal and ventral MPFC convey different decision signals (i.e., aversion to uncertainty vs. approach to rewarding outcomes), where the relative strengths of these signals determine behavioral decisions involving risk and uncertainty. Xue G, Lu Z, Levin I, Weller J, Li X, Bechara A. Functional dissociations of risk and reward processing in the medial prefrontal cortex. Cerebral Cortex. 2009 May;19(5):1019-1027.
Cocaine Abusers Show Abnormalities in Dorsal Striatum Recruitment by Motor Tasks
Colleen Hanlon and colleagues at Wake Forest scanned non-treatment seeking chronic cocaine users and matched controls during performance of two finger-sequencing paradigms that differentially activate the caudate nucleus (internally-guided) and the putamen (externally-guided) interleaved with blocks of rest. They reported significant deficits in sensorimotor control in cocaine users for both motor tasks, with the most severe impairments present during internally-guided movements dependent on the caudate nucleus. Cocaine users lacked the typical functional segregation observed in the dorsal striatum of the control subjects. The total percent signal change in the dorsal striatum was not significantly different between the groups, but cocaine users activated significantly less contralateral caudate and putamen for internally-guided versus externally-guided movements, respectively. These data provide clear evidence that chronic cocaine users have significant motor performance deficits that are accompanied by altered processing within the dorsal striatum. These data suggest the effects of cocaine extend beyond the confines of the motivational domains of the ventral striatum. Hanlon CA, Wesley MJ, Porrino LJ. Loss of functional specificity in the dorsal striatum of chronic cocaine users. Drug Alcohol Depend. 2009 Jun 1;102(1-3):88-94.
Cocaine Abusers Show Blunted Anterior Cingulate Cortex Recruitment by an Emotional Conflict Task
Rita Goldstein and colleagues at Brookhaven compared individuals with current cocaine use disorders (CUD) and matched healthy controls as they underwent functional magnetic resonance imaging during performance of a rewarded drug cue-reactivity task previously shown to engage the anterior cingulate cortex (ACC). Despite the lack of group differences in task performance, individuals with CUD showed more ACC hypoactivations. Nevertheless, intensity of emotional salience contributed to the results: (1) CUD individuals with the largest rostroventral ACC [Brodmann Area (BA) 10, 11, implicated in default brain function] hypoactivations to the most salient task condition (drug words during the highest available monetary reward) and had the least task-induced cocaine craving; (2) CUD individuals with the largest caudal-dorsal ACC (BA 32) hypoactivations especially to the least salient task condition (neutral words with no reward) had the most frequent current cocaine use; and (3) responses to the most salient task condition in both these ACC major subdivisions were positively intercorrelated in the controls only. ACC hypoactivations in drug users, therefore, cannot be attributed to task difficulty or disengagement. Nevertheless, emotional salience modulates ACC responses in proportion to drug use severity. Interventions to strengthen ACC reactivity or interconnectivity may be beneficial in enhancing top-down monitoring and emotion regulation as a strategy to reduce impulsive and compulsive behavior in addiction. Goldstein RZ, Alia-Klein N, Tomasi D, Carrillo JH, Maloney T, Woicik PA, Wang R, Telang F, Volkow ND. Anterior cingulate cortex hypoactivations to an emotionally salient task in cocaine addiction. Proc Natl Acad Sci U S A. 2009 Jun 9;106(23):9453-9458.
Conflict Effects Without Conflict in the Anterior Cingulate
Dr. Joshua Brown of Indiana University used fMRI to test a computational model of anterior cingulate function that accounts for error likelihood effects, risk prediction effects, and how individual differences in conflict and error likelihood effects vary with trait differences in risk aversion. This study tested the prediction that apparent conflict effects in anterior cingulate cortex (ACC) may result in part from an increasing number of simultaneously active responses, regardless of whether or not the cued responses are mutually incompatible. In Experiment 1, the model prediction was tested with a modification of the Eriksen flanker task, in which some task conditions require two otherwise mutually incompatible responses to be generated simultaneously. In that case, the two response processes are no longer in conflict with each other. The results showed small but significant medial prefrontal cortex (PFC) effects in the incongruent vs. congruent contrast, despite the absence of response conflict, consistent with the multiple response effect of the model. Nonetheless, actual response conflict led to greater ACC activation, suggesting that conflict effects are specific to particular task contexts. In Experiment 2, results from a change signal task suggested that the context dependence of conflict signals does not depend on error likelihood effects. Instead, inputs to ACC may reflect complex and task specific representations of motor acts, such as bimanual responses. Overall, the results suggest the existence of a richer set of motor signals monitored by medial PFC and are consistent with distinct effects of multiple responses, conflict, and error likelihood in medial PFC. These results form the foundation for a better understanding of anterior cingulate dysfunction that has been repeatedly demonstrated in substance abusers. Brown JW. Conflict effects without conflict in anterior cingulate cortex: Multiple response effects and context specific representations. Neuroimage. 2009 Aug;47(1):334-341.
Brain Serotonin Transporter Binding in Former Users of MDMA ('Ecstasy')
Dr. Ronald Cowan at Vanderbilt University used PET ligand brain imaging to determine the status of brain serotonin transporters (SERT) in a group of abstinent MDMA (3,4-methylenedioxy-methamphet-amine) users using [C-11]DASB. Subjects were former MDMA users, polydrug users who had never taken MDMA and controls who reported no history of illicit drug use. There was no significant difference in the binding potential of [C-11]DASB between the groups in any of the brain regions examined. To the extent that [C-11]DASB binding provides an index of the integrity of serotonin axons, these findings suggest that MDMA use may not result in long-term damage to axons when used recreationally in humans. Selvaraj S, Hoshi R, Bhagwagar Z, Murthy N, Hinz R, Cowen P, Curran H, Grasby P. Brain serotonin transporter binding in former users of MDMA ('Ecstasy'). British Journal of Psychiatry. 2009 Apr;194(4):355-359.
Ecstasy Users Require Increased Recruitment of the Basal Ganglia to Accomplish a Motor Performance Task
Dr. Ronald Cowan and colleagues at Vanderbilt used functional brain imaging to determine if MDMA users would show altered activation in motor system brain regions. This hypothesis was based on prior research demonstrating that MDMA (Ecstasy) produces changes in serotonin (5-hydroxytryptamine) terminals, and 5-HT innervates cortical and subcortical brain regions mediating motor function. They used functional magnetic resonance imaging (fMRI) to assay motor task performance-associated brain activation changes in MDMA and non-MDMA users. Fourteen MDMA users and 10 controls performed an event-related motor tapping task during fMRI. Regions of interest analyses were used to measure percent signal change (PSC) and percent activated voxels (PAV) in bilateral motor cortex, sensory cortex, supplementary motor area (SMA), caudate, putamen, pallidum and thalamus. Statistical Parametric Mapping 5 was used to measure brain activation via three methods: T-maps, PSC and PAV. There was no statistically significant difference in reaction time between the two groups. For the Tap 4 condition, MDMA users had more activation than controls in the right SMA for T-score, PSC and PAV. Lifetime episodes of MDMA use were positively correlated with PSC for the Tap 4 condition on the right for putamen and pallidum and with PAV in the right motor and sensory cortex and bilateral thalamus. In conclusion, group differences in the right SMA and positive dose-response association between lifetime exposure to MDMA and signal magnitude and extent were found in several brain regions. This is consistent with MDMA-induced alterations in basal ganglia-thalamocortical circuit neurophysiology and is potentially secondary to neurotoxic effects on 5-HT signaling. Further studies examining behavioral correlates and the specific neurophysiological basis of the observed findings are warranted. Karageorgiou J, Dietrich MS, Charboneau EJ, Woodward ND, Blackford JU, Salomon RM, Cowan RL. Prior MDMA (Ecstasy) use is associated with increased basal ganglia-thalamocortical circuit activation during motor task performance in humans: An fMRI study. Neuroimage. 2009 Jul 1;46(3):817-826.
Stress and HPA Axis Activity Interact to Create Risk For Drug Abuse
Uma Rao and colleagues at UT-Southwestern Medical Center examined whether hypothalamic-pituitary-adrenal (HPA) activity and stressful life experiences are related to the development of substance use disorder in depressed and nondepressed adolescents, and whether substance use disorder predicts a worsening course of depression. They measured urinary free cortisol for 3 nights in adolescents with no prior history of substance use disorder and collected information on recent stressful life experiences. They followed these adolescents for up to 5 years to assess the onset of substance use disorder, course of depression, and stressful experiences. They found that elevated cortisol was associated with onset of substance use disorder and that stressful life experiences moderated this relationship. Cortisol and stress accounted for the effects of a history or risk of depression on the development of substance use disorder. Substance use disorder was associated with higher frequency of subsequent depressive episodes. They concluded that higher cortisol prior to the onset of substance use disorder may indicate vulnerability to substance use disorder and that stressful experiences increase the risk for substance use disorder in such vulnerable youth. The high prevalence of substance use disorders in depressed individuals may be explained, in part, by high levels of stress and increased HPA activity. Rao U, Hammen CL, Poland RE. Mechanisms underlying the comorbidity between depressive and addictive disorders in adolescents: Interactions between stress and HPA activity. Am J Psychiatry. 2009 Mar;166(3):361-369.
PET Studies of Nicotine Effects on Dopamine Turnover
Dr. Edward Domino and colleagues at University of Michigan used PET ligand imaging using L-[beta-(11)C]DOPA to determine the effects of nicotine on regional brain dopamine (DA) utilization. Eight young nonhuman primates were given nicotine in small doses for 9 days to produce minimal dependence. On the tenth day, PET measurements were repeated before and after nicotine administration. PET studies were done in habituated, trained, and fully conscious animals. Acute nicotine administered as a bolus plus infusion for 30 min in similar doses to maintain a steady-state level for 30 min did not affect the utilization rate constant in dorsal or ventral striatum as measured by L-[beta-(11)C]DOPA. When animals were given nicotine repeatedly after overnight nicotine abstinence, DA utilization was reduced. A subsequent nicotine dose normalized utilization to slightly above control levels. Changes in ventral striatum were similar to those in dorsal striatum. The reduced rate of utilization demonstrated with L-[beta-(11)C]DOPA after overnight nicotine abstinence and its reversal by nicotine the next day provides an important PET measure of brain nicotine dependence and withdrawal. Domino EF, Tsukada H, Harada N. Positron emission tomographic measure of brain dopamine dependence to nicotine as a model of drugs of abuse. Psychopharmacology. (Berl.). 2009 May;204(1):149-153.
Nicotine Receptor Changes During Acute and Prolonged Cigarette Abstinence
Dr. Kelly Cosgrove and colleagues at Yale School of Medicine used SPECT ligand imaging to characterizes changes in beta(2)* nicotinic acetylcholine receptor (-nAChR) availability during acute and prolonged abstinence from tobacco smoking. They also investigated how changes in beta(2)*-nAChR availability related to clinical features of tobacco smoking. Participants were tobacco smokers (n = 19) and an age-matched nonsmoker comparison group (n = 20). Tobacco smokers participated in up to 4 single-photon emission computed tomography (SPECT) scans during abstinence at 1 day, and 1, 2 , 4, and 6 to 12 weeks. Age-matched nonsmokers participated in a single SPECT scan. Compared with nonsmokers, beta(2)*-nAChR availability in the striatum, cortex, and cerebellum of smokers was not different at 1 day of abstinence, was significantly higher at 1 week of abstinence, and was not different at 4 or at 6 to 12 weeks of abstinence. In smokers, beta(2)*-nAChR availability was significantly lower in the cortex and cerebellum at 6 to 12 weeks compared with 1 week of abstinence. In addition, cerebellar beta(2)*-nAChR availability at 4 weeks of abstinence was positively correlated with craving on the day of the SPECT scan. These data suggest that higher beta(2)*-nAChR availability persists up to 1 month of abstinence and normalizes to nonsmoker levels by 6 to 12 weeks of abstinence from tobacco smoking. These marked and persistent changes in beta(2)*-nAChR availability may contribute to difficulties with tobacco cessation. Cosgrove KP, Batis J, Bois F, Maciejewski PK, Esterlis I, Kloczynski T, Stiklus S, Krishnan-Sarin S, O'Malley S, Perry E, Tamagnan G, Seibyl JP, Staley JK. Beta2-Nicotinic acetylcholine receptor availability during acute and prolonged abstinence from tobacco smoking. Arch. Gen. Psychiatry. 2009 June;66(6):666-676.
PET Study of Dopaminergic Activity in Depressed Smokers
Dr. Ursula Busto and colleagues at the University of Toronto used PET ligand imaging to assess changes in Dopamine D2 receptors in healthy controls and unmedicated patients with current depression with and without current tobacco dependence. Over a single study day, 2 [(11)C]-raclopride positron emission tomography scans were taken at baseline and 2 h following oral d-amphetamine 30 mg. Striatal [(11)C]-raclopride binding potential was measured before and after d-amphetamine administration. Depressed smokers had a lower baseline [(11)C]-raclopride binding potential compared with both control non-smokers and depressed non-smokers. There was an effect of smoking status on amphetamine-induced change in [(11)C]-raclopride binding potential, but no effect of depression. This may be due to a floor effect because of the low BP at baseline. Depressed subjects reported a significant increase of positive mood after d-amphetamine administration compared with controls (depressed smokers vs. control smokers, and depressed non-smokers vs. controls). Comorbid major depression and tobacco dependence therefore exacerbates tobacco dependence related decreases in d-amphetamine-induced changes in [(11)C]-raclopride binding potential. These results suggest the presence of an altered dopamine system in comorbid patients. Dopaminergic activity in depressed smokers: A positron emission tomography study. Busto UE, Redden L, Mayberg H, Kapur S, Houle S, Zawertailo LA. Synapse. 2009 Aug;63(8):681-689.
Tobacco Abstinence and Brain Responses to Smoking Cues
Dr. Joseph McClernon used fMRI to evaluate the effect of 24-h smoking abstinence on brain responses to smoking-related cues. Adult smokers (N=18) underwent fMRI scanning following smoking as usual (satiated condition) and following 24-h abstinence (abstinent condition). During scanning, they viewed blocks of photographic smoking and control cues. Following abstinence, greater activation was found in response to smoking cues compared to control cues in parietal, frontal, occipital, and central cortical regions and in dorsal striatum (putamen) and thalamus. In contrast, no smoking cue greater than control cue activations were observed following smoking as usual. Direct comparisons between conditions (satiated vs. abstinent) showed greater brain reactivity in response to smoking cues following abstinence. In addition, positive correlations between pre-scan craving in the abstinent condition and smoking cue activation were observed in right dorsomedial prefrontal cortex (dmPFC) including superior frontal gyrus, anterior cingulate gyrus, and supplementary motor area. These findings indicate that smoking abstinence significantly potentiates neural responses to smoking-related cues in brain regions subserving visual sensory processing, attention, and action planning. Moreover, greater abstinence-induced craving was significantly correlated with increased smoking cue activation in dmPFC areas involved in action planning and decision making. These findings suggest that drug abstinence can increase the salience of conditioned cues, which is consistent with incentive-motivation models of addiction. McClernon FJ, Kozink RV, Lutz AM, Rose JE. 24-h smoking abstinence potentiates fMRI-BOLD activation to smoking cues in cerebral cortex and dorsal striatum. Psychopharmacology (Berl). 2009 May;204(1):25-35.
Childhood Experience of ADHD May Predict Adulthood Smoking Behavior
In this large sample study involving over 1100 new mothers, Dr. Kollins and colleagues found self-reported personal history of childhood experience of attention-deficit/hyperactivity disorder (ADHD) associated with five cigarette smoking-related outcomes in adulthood. Women with a history of intermediate levels of hyperactive-impulsive symptoms during their childhood reported smoking more cigarettes per day than women with low or high levels of childhood ADHD symptoms. Past history of hyperactive-impulsive symptoms is linked with the number of cigarettes smoked per day during the pregnancy period, and inattentive behavior was similarly linked to the number of cigarettes currently smoked per day. Childhood inattentive behaviors were predictive of an earlier age onset of smoking only when hyperactive-impulsive behaviors were low, with a stronger association for Black women compared to White females. These findings represent a potential, indirect means through which women with even a moderate childhood history of ADHD symptomatology may create circumstances that compromise the health and well-being of their own children. Willoughby MT, Kollins SH, McClernon FJ; Family Life Investigative Group. Association between smoking and retrospectively reported attention-deficit/hyperactivity disorder symptoms in a large sample of new mothers. Nicotine Tob Res. 2009 Mar;11(3):313-322.
Postnatal Parental Smoking Effects on the Development of ADHD Symptoms and Oppositional Behavior in Children
In addition to genetic determinants, environmental factors such as mothers who smoke during pregnancy are linked to child ADHD. In this study Dr. Kollins and colleagues evaluated the effects of postnatal maternal smoking on ADHD symptoms that were divided into inattentive and hyperactive-impulsive domains and oppositional behavior in a group of 5- to 12-year-old children, ascertained on the basis of an ADHD diagnosis, and their healthy siblings, while controlling for a range of important covariates, including prenatal smoking and self-reported maternal ADHD symptoms. Parents and teachers were asked to complete the DSM-IV ADHD evaluation as outcome of the disruptive behaviors. The study found that postnatal smoke exposure (from either mothers or fathers) was associated with higher ratings of ADHD and oppositional defiant disorder. The findings suggest both prenatal and postnatal maternal smoking impact ADHD development in children. Kollins SH, Garrett ME, McClernon FJ, Lachiewicz AM, Morrissey-Kane E, FitzGerald D, Collins AL, Anastopoulos AD, Ashley-Koch AE. Effects of postnatal parental smoking on parent and teacher ratings of ADHD and oppositional symptoms. J Nerv Ment Dis. 2009 Jun;197(6):442-449.
Risk/Reward Decision-Making in Schizophrenia: The Influence of Tobacco Smoking
Dr. Marc Potenza and his colleagues at Yale University examined the relationship between the deficits in cognitive functioning, and the mixed results previously found from studies of risk/reward decision-making, shown in individuals with schizophrenia. Thirty-two smokers with schizophrenia, ten non-smokers with schizophrenia, nine non-psychiatric non-smokers and ten non-psychiatric smokers were administered computerized versions of the Iowa Gambling Task (IGT) and the Wisconsin Card Sorting Task (WCST). Smokers were allowed to smoke ad libitum during designated breaks in order to prevent deprivation. Subjects with schizophrenia performed significantly worse than non-psychiatric controls on both the IGT and the WCST, and performance on these tasks was significantly correlated across subject groups. Among women with schizo-phrenia, smokers performed significantly better than non-smokers on the IGT. Individuals with schizophrenia performed worse than controls on the IGT, suggesting impairments in risk/reward decision-making. Correlations between IGT and WCST performance suggest a shared element underlying task performance, such as a deficit in set-shifting or perseverance. Further research is needed to establish the relationship between cigarette smoking and IGT performance in schizophrenia. Risk/reward decision-making in schizophrenia: A preliminary examination of the influence of tobacco smoking and relationship to Wisconsin Card Sorting Task performance. Yip SW, Sacco KA, George TP, Potenza MN. Schizophr Res. 2009 May;110(1-3):156-164.
Relationship of Nicotine Dependence, Subsyndromal and Pathological Gambling, and Other Psychiatric Disorders
Dr. Marc Potenza and his colleagues at Yale University used nationally representative data from the National Epidemiologic Survey on Alcohol and Related Conditions to examine the influence of DSM-IV nicotine dependence on the association between pathological gambling severities and other psychiatric disorders. Face-to-face interviews were conducted with 43,093 adults living in households and group-quarters in the United States. The main outcome measure was the co-occurrence of current nicotine dependence and Axis I and II disorders and severity of gambling based on the 10 inclusionary diagnostic criteria for pathological gambling. Among non-nicotine-dependent respondents, increasing gambling severity was associated with greater psychopathology for the majority of Axis I and II disorders. This pattern was not uniformly observed among nicotine-dependent subjects. Significant nicotine-by-gambling-group interactions were observed for multiple Axis I and II disorders. All significant interactions involved stronger associations between gambling and psychopathology in the non-nicotine-dependent group. Additional research is needed to examine specific prevention and treatment for individuals with problem/pathological gambling with and without nicotine dependence. Grant JE, Desai RA, Potenza MN. Relationship of nicotine dependence, subsyndromal and pathological gambling, and other psychiatric disorders: Data from the National Epidemiologic Survey on Alcohol and Related Conditions. J Clin Psychiatry. 2009 Mar;70(3):334-343.
Hybrid SVM-GLM Approach for fMRI Data Analysis
Dr. Ze Wang at University of Pennsylvania developed an optimized method for exploratory analysis of fMRI data. Hypothesis-driven fMRI data analysis methods, represented by the conventional general linear model (GLM), have a strictly defined statistical framework for assessing regionally specific activations but require assumptions about the shape of hemodynamic brain responses that may not be accurate. Exploratory methods, like the support vector machine (SVM), are independent of prior hemodynamic response function (HRF), but generally lack a statistical inference framework. To take the advantages of both kinds of methods, this study describes a composite approach through combining conventional GLM with SVM. This hybrid SVM-GLM concept is to use the power of SVM to obtain a data-derived reference function and enter it into the conventional GLM for statistical inference. The data-derived reference function was extracted from the SVM classifier using a new temporal profile extraction method. In simulations with synthetic fMRI data, SVM-GLM demonstrated a better sensitivity and specificity of performance for detecting the synthetic activations, as compared to the conventional GLM. With real fMRI data, SVM-GLM showed better sensitivity than regular GLM for detecting the sensorimotor activations. Wang Z. A hybrid SVM-GLM approach for fMRI data analysis. Neuroimage. 2009 Jul 1;46(3):608-615.
Selective Dopamine D3 Radioligand
Dr. Robert Mach and colleagues at Washington University performed in vitro evaluation of radiolabled 4-(Dimethylamino)-N-(4-(4-(2-methoxyphenyl)piperazin-1-yl)butyl)benzamide (WC-10), a N-phenyl piperazine analog, which has been shown to have high affinity and selectivity for dopamine D(3) receptors versus dopamine D(2) receptors. In this study, WC-10 was radiolabeled with tritium and [(3)H]WC-10 binding to genetically cloned dopamine D(2L) and D(3) receptors was evaluated in vitro. [(3)H]WC-10 binds with a 66-fold higher affinity to human D(3) than D(2L) receptor. However, [(3)H]WC-10 binds to rat Sf9 rD(3) receptors with a lower affinity than it binds to human HEK D(3) receptors and binds with a higher affinity to rat Sf9 rD(2L) receptors. The pharmacologic profiles of a series of dopaminergic drugs for inhibiting the binding of [(3)H]WC-10 to D(3) receptors was in agreement with previously reported data. In vitro autoradiography studies of rat and non-human primate brains show that [(3)H]WC-10 labeled D(3) sites in the striatal region. Xu J, Chu W, Tu Z, Jones LA, Luedtke RR, Perlmutter JS, Mintun MA, Mach RH. [(3)H]4-(Dimethylamino)-N-[4-(4-(2-methoxyphenyl)piperazin- 1-yl)butyl]benzamide, a selective radioligand for dopamine D(3) receptors. I. In vitro characterization. Synapse. 2009 Sep;63(9):717-728.
Neuronal Mechanism of Anger Regulation
Dr. Alia-Klein and colleagues at Brookhaven National Laboratories examined the influence of the monoamine oxidase A (MAOA) gene (low vs. high transcription variants) on brain response to the emotional word “No” (as an emphatic prohibition of behavior) and in relationship to trait anger reactivity and control. Orbitofrontal activation did not differ as a function of the genotype. Instead, carriers of the low-MAOA genotype had reduced left middle frontal gyrus activation to “No” compared with the high variant. Furthermore, left amygdala and posterior thalamic activation to “No” increased with anger reactivity only for carriers of the low-MAOA genotype. Thus, decreased middle frontal response to No and the unique amygdala/thalamus association pattern in this group with anger reactivity but not anger control may underlie the vulnerability to aggression in carriers of the low-MAOA genotype. Alia-Klein N, Goldstein R, Tomasi D, Woicik P, Moeller S, Williams B, Craig I, Telang F, Biegon A, Wang G, Fowler J, Volkow N. Neural Mechanisms of Anger Regulation as a Function of Genetic Risk for Violence. Emotion. 2009 Jun;9(3):385-396.
Acute Topiramate Exerts Biphasic Dose-Dependent Effects on Laboratory Aggression in Subjects at High Risk for Violent Behavior
Gerry Moeller and colleagues at UT-Houston examined the acute effects of topiramate on aggression using a laboratory model of human aggression in individuals on parole/probation and with an Axis-II personality disorder and/or a substance use disorder. Subjects received 100, 200, 300, and 400 mg in an ascending sequence, with intervening placebo doses. Topiramate produced an inverted U-shaped dose response curve, with increases in aggression peaking at 200 mg and a modest decrease at 400 mg. The pattern in aggressive responding is consistent with non-human aggression studies of GABA-A modulators. Acute topiramate doses >400 mg may have anti-aggressive effects, but dose levels in the 200-300 mg range may produce increases in aggression and side effects. Lane SD, Gowin JL, Green CE, Steinberg JL, Moeller FG, Cherek DR. Acute topiramate differentially affects human aggressive responding at low vs. moderate doses in subjects with histories of substance abuse and antisocial behavior. Pharmacol Biochem Behav. 2009 Apr;92(2):357-362.
White Matter Integrity Predicts Delay Discounting Behavior in 9- to 23-Year-Olds
Dr. Kelvin Lim and colleagues at the University of Minnesota used structural brain imaging to determine whether rapid prefrontal lobe development during adolescence would be associated with alterations in delayed discounting, a measure of impulsivity related to the risk of substance abuse. Healthy participants, aged 9-23, completed a delay discounting task assessing the extent to which the value of a monetary reward declines as the delay to its receipt increases. Diffusion tensor imaging (DTI) was used to evaluate how individual differences in delay discounting relate to variation in fractional anisotropy (FA) and mean diffusivity (MD). The analyses revealed a number of clusters where less impulsive performance on the delay discounting task was associated with higher FA and lower MD. The clusters were located primarily in bilateral frontal and temporal lobes and were localized within white matter tracts, including portions of the inferior and superior longitudinal fasciculi, anterior thalamic radiation, uncinate fasciculus, inferior fronto-occipital fasciculus, corticospinal tract, and splenium of the corpus callosum. FA increased and MD decreased with age in the majority of these regions. Some, but not all, of the discounting/DTI associations remained significant after controlling for age. Olson E, Collins P, Hooper C, Muetzel R, Lim K, Luciana M. White matter integrity predicts delay discounting behavior in 9-to 23-year-olds: A diffusion tensor imaging study. Journal of Cognitive Neuroscience. 2009 Jul;21(7):1406-1421.
Twin Study Suggests Lack of Adolescent Drug Use Specificity in Conferring Risk for Adult Drug Abuse
Past studies have demonstrated the existence of a shared etiology across substances of abuse; however, few have tested developmental models using longitudinal data. Palmer, Crowley and colleagues utilized the longitudinal Colorado twin sample of 1733 respondents to assess: 1) the rates of multiple substance use and disorders at each developmental stage, and the likelihood of a substance use disorder (SUD; i.e., abuse or dependence) diagnosis in young adulthood based on adolescent drug involvement, 2) whether the pattern of multiple substance use and disorders and likelihood ratios across substances support a model of generalized risk, and 3) whether the ranked magnitudes of substance-specific risk match the addiction liability ranking. This analysis provided further evidence that substance use and SUDs are developmental phenomena, which increase from adolescence to young adulthood with few and inconsistent gender differences. Moreover, they reported that adolescents and young adults are not specialized users, but rather tend to use or abuse multiple substances increasingly with age. Risk analyses indicated that progression toward a SUD for any substance was increased with prior involvement with any substances during adolescence. Despite the high prevalence of alcohol use, tobacco posed the greatest substance-specific risk for developing subsequent problems. These data also confirm either a generalized risk or correlated risk factors for early onset substance use and subsequent development of SUDs. Palmer RH, Young SE, Hopfer CJ, Corley RP, Stallings MC, Crowley TJ, Hewitt JK. Developmental epidemiology of drug use and abuse in adolescence and young adulthood: Evidence of generalized risk. Drug Alcohol Depend. 2009 Jun 1;102(1-3):78-87.
Therapeutic Dose of Zolpidem Reduces Thalamic GABA in Healthy Volunteers
Dr. Stephanie Licata and her colleagues at the McLean Hospital/Harvard Medical School evaluated the effects of acute administration of zolpidem on levels of GABA, glutamate, glutamine, and other brain metabolites using magnetic resonance spectroscopy (MRS). Proton MRS ((1)H MRS) was employed to measure the effects of zolpidem on brain chemistry. Participants underwent scanning following acute oral administration of a therapeutic dose of zolpidem (10 mg) in a within-subject, single-blind, placebo-controlled, single-visit study. In addition to neurochemical measurements from single voxels within the anterior cingulate (ACC) and thalamus, a series of questionnaires was administered periodically throughout the experimental session to assess subjective mood states. Zolpidem reduced GABA levels in the thalamus, but not the ACC. There were no treatment effects with respect to other metabolite levels. Self-reported ratings of "dizzy," "nauseous," "confused," and "bad effects" were increased relative to placebo, as were ratings on the sedation/intoxication and psychotomimetic/dysphoria scales of the Addiction Research Center Inventory. Moreover, there was a significant correlation between the decrease in GABA and "dizzy." Zolpidem engendered primarily dysphoric-like effects and the correlation between reduced thalamic GABA and "dizzy" may be a function of zolpidem's interaction with alpha1GABA(A) receptors in the cerebellum, projecting through the vestibular system to the thalamus. Licata SC, Jensen JE, Penetar DM, Prescot AP, Lukas SE, Renshaw PF. A therapeutic dose of zolpidem reduces thalamic GABA in healthy volunteers: A proton MRS study at 4 T. Psychopharmacology (Berl). 2009 May;203(4):819-829.
Behavioral and Neurological Foundations for the Moral and Legal Implications of Intoxication, Addictive Behaviors and Disinhibition
Dr. Marc Potenza and his colleagues at Yale University addressed how disinhibition and addictive behaviors are related and carry moral implications. Both typically involve diminished consideration of negative consequences, which may result in harm to oneself or others. Disinhibition may occur on state and trait levels, and addictive substances may elicit disinhibitory states, particularly when intoxication is reached. Data suggest that trait disinhibition and addictions may be conceptualized as involving misdirected motivation with underlying biological bases including genetic factors, alterations in neurotransmitter systems and differences in regional brain function. The influences of intoxication on the brain share similarities with cognitive impairments in individuals with chronic substance abuse and those with trait disinhibition related to frontal lobe injuries. These findings raise questions about volitional impairment and morality. Although impaired volition related to disinhibition and addictive behaviors has been studied from multiple perspectives, additional research is needed to further characterize mechanisms of impairment. Such findings may have important implications in multiple legal and psychiatric domains. Leeman RF, Grant JE, Potenza MN. Behavioral and neurological foundations for the moral and legal implications of intoxication, addictive behaviors and disinhibition. Behav Sci Law. 2009;27(2):237-259.
Poor Blood-Brain Barrier Penetration of Drugs Continues to Obstruct Effective Anti-HIV Treatment
HIV Protease inhibitors have been the leading effective agent in anti-HIV treatment. A major obstacle for effectively managing the ongoing HIV replication in the brain, with associated neural complications, is that protein inhibitors may not penetrate the central nervous system to achieve therapeutic concentrations. In a multicenter, observational cohort study, Dr. Igor Grant and his group determined the effective penetration of atazanavir, one of the most frequently prescribed antiretrovirals, into cerebrospinal fluid (CSF). It was found that atazanavir concentrations in CSF samples were highly variable and were often 100-fold lower than plasma concentrations. The concomitant administration of ritonavir competitively binding to the host metabolizing enzyme cytochrome P450-3A4, boosted and doubled plasma concentration of atazanavir. However, it failed to significantly elevate CSF concentrations of atazanavir. CSF concentrations were less than one percent of plasma concentration. The study concludes that atazanavir may not protect against HIV replication in the CSF. Best BM, Letendre SL, Brigid E, Clifford DB, Collier AC, Gelman BB, McArthur JC, McCutchan JA, Simpson DM, Ellis R, Capparelli EV, Grant I; CHARTER Group. Low atazanavir concentrations in cerebrospinal fluid. AIDS. 2009 Jan 2;23(1):83-87.
Beta-Adrenergic Activity as a Biomarker for Severity of Chronic, Clinical Pain?
In patients with fibromyalgia syndrome (FMS) and temporomandibular disorder (TMD), stress and pain may chronically enhance sympathetic activity, altering cardiovascular responses and worsening pain. In this study, Dr. Girdler and colleagues examined the association of beta-adrenergic activity and clinical pain responses. The data suggested that beta-adrenergic tone is higher in patients under the influence of these painful episodes than in control patients. With the challenges of experimental stress (e.g. postural alteration, speech and ischemic pain), greater changes in beta-adrenergic activity, including heart rate, blood pressure, and total vascular resistance, was evident in these patients, along with lowered levels of epinephrine and norepinephrine. The beta-antagonist propranolol reversed these symptoms but changes in blood pressure, CO and total vascular resistance persisted. The number of painful body sites and ratings of total clinical pain were also significantly lower after beta-blockade versus placebo tests. These findings indicate that both FMS and TMD may involve dysregulation of beta-adrenergic activity that contributes to altered cardiovascular and catecholamine responses and to the severity of clinical pain. Light KC, Bragdon EE, Grewen KM, Brownley KA, Girdler SS, Maixner W. Adrenergic dysregulation and pain with and without acute beta-blockade in women with fibromyalgia and temporomandibular disorder. J Pain. 2009 May;10(5):542-552.
Higher Sensitivity to Heat Pain, but Not Cold Pain in Patients under Opioid Therapy
Preclinical studies suggest that opioid exposure may induce a paradoxical decrease in the nociceptive threshold, commonly referred to as opioid-induced hyperalgesia. In this study, Dr. Jianren Mao addressed its clinical implications and significance in chronic pain management. Patients with chronic pain and under sustained opioid therapy displayed higher sensitivity to heat pain and exacerbated experimental hyperalgesia (pain windup upon temporal summation of the second pain to thermal stimulation) in comparison to those with no history of opioid use. In contrast, no changes in cold-induced pain or warm sensation were observed. The patients requiring higher doses of opioid for daily pain management were more sensitive to pain and suffered from more severe hyperalgesia, indicating that higher vulnerability to pain and hyperalgesia under quanti-tative thermal testing can be characteristic of subjects with sustained ongoing opioid therapy. The data suggest that quantitative thermal testing may be a useful tool in the clinical assessment of opioid-induced hyperalgesia. Chen L, Malarick C, Seefeld L, Wang S, Houghton M, Mao J. Altered quantitative sensory testing outcome in subjects with opioid therapy. Pain. 2009 May;143(1-2):65-70.
A Potential Marker for Identification of Individuals at Risk for Opioid Medication Misuse
Dr. Ajay Wasan examined the relationship between self-reported cravings for prescription medication and subsequent opioid misuse among chronic pain patients who were prescribed opioids for pain. Six hundred thirteen patients taking opioid medication for chronic noncancer pain were asked to scale how often they have felt a craving for their medication. All participants completed a series of baseline questionnaires. After 6 months the participants were administered the Prescription Drug Use Questionnaire, a structured prescription drug use interview, and submitted a urine sample for toxicology assessment. Their treating physicians also completed a substance misuse behavior checklist (Prescription Opioid Therapy Questionnaire). The study revealed that about 55 percent of participants reported that they never felt a craving for their medication, whereas 45 percent reported some degree of craving their medication. Those who reported craving their medication were significantly more often male, unmarried, had lower scores on social desirability, and had been prescribed opioids for a longer time than those who did not report similar cravings. At a 6-month follow-up, those who reported craving their medication showed higher scores on the Prescription Drug Use Questionnaire, had a higher incidence of physician-rated aberrant drug behavior on the Prescription Opioid Therapy Questionnaire, showed a higher frequency of abnormal urine toxicology screens, and more often had a positive Aberrant Drug Behavior Index. These results suggest that self-reported craving is a potential marker for identification of those at risk for opioid medication misuse. Wasan AD, Butler SF, Budman SH, Fernandez K, Weiss RD, Greenfield SF, Jamison RN. Does report of craving opioid medication predict aberrant drug behavior among chronic pain patients? Clin J Pain. 2009 Mar-Apr;25(3):193-198.
Psychiatric Comorbidity is Associated with Diminished Pain Relief
Comorbid psychopath-ology is an important predictor of poor outcomes in many types of back or neck pain treatments. In this study, Dr. Ajay Wasan explored whether high levels of psychopathology are predictive of pain relief after medial branch block injections in the lumbar or cervical spine. The Low Psychopath-ology (LP) group reported a mean improvement in pain after one month treatment, while the average pain score was worse in High Psychopathology group. Using an analysis of covariance, no baseline demographic, social, or medical variables were significant predictors of pain improvement, nor did they mitigate the effect of psychopathology on the outcome. It was concluded that psychiatric comorbidity is associated with diminished pain relief. Wasan AD, Jamison RN, Pham L, Tipirneni N, Nedeljkovic SS, Katz JN. Psychopathology predicts the outcome of medial branch blocks with corticosteroid for chronic axial low back or cervical pain: A prospective cohort study. BMC Musculoskelet Disord. 2009 Feb 16;10:22.
Neural Bases of Empathic Accuracy
Dr. Kevin Ochsner and colleagues at Columbia University used a functional imaging paradigm to test the hypothesis that an accurate understanding of another's emotions should depend on affective, motor, and/or higher cognitive brain regions. Using fMRI in healthy subjects, empathically accurate, as compared with inaccurate, judgments depended on (i) structures within the human mirror neuron system thought to be involved in shared sensorimotor representations, and (ii) regions implicated in mental state attribution, the superior temporal sulcus and medial prefrontal cortex. These data demonstrate that activity in these two sets of brain regions tracks with the accuracy of attributions made about another's internal emotional state. Taken together, these results provide both an experimental approach and theoretical insights for studying empathy and its dysfunction, such as between drug abusers and therapists. Zaki J, Weber J, Bolger N, Ochsner K. The neural bases of empathic accuracy. Proc. Natl. Acad. Sci. U.S.A. 2009 Jul;106(27):11382-11387.
Brain Responses to Another’s Mistakes
Dr. Mathew Shane and colleagues at the Mind Institute at the University of New Mexico used fMRI to determine the functional role of specific brain areas activated when viewing another person’s mistakes. Previous work identified several regions, including inferior parietal cortex and rostral/ventral anterior cinguli (r/vACC), that show unique sensitivity to the observation of another's errors. The current results found that participants' level of self-reported perspective-taking (but not empathic concern) correlated with fMRI signal changes in inferior parietal cortex (IPC), while participants' level of self-reported empathic concern (but not perspective taking) correlated with fMRI signal changes in r/vACC. This functional dissociation provides strong evidence for separate roles for IPC and r/vACC in the processing of observed errors. IPC may foster a sense of agency by distinguishing self- from other-performed actions; r/vACC may, in turn, promote a more contextually-mediated understanding of the other's failed goal-attainment. These studies provide a foundation for investigating how social interactions may influence drug use, such as seeing positive or negative consequences of drug use by peers. Shane M, Stevens M, Harenski C, Kiehl K. Double dissociation between perspective-taking and empathic-concern as predictors of hemodynamic response to another's mistakes. Social Cognitive and Affective Neuroscience. 2009 Jun;4(2):111-118.