Abstract This study employed functional magnetic resonance imaging (fMRI)-based dynamic causal modeling (DCM) to study the effective (directional) neuronal connectivity underlying inhibitory behavioral control. fMRI data were acquired from 15 healthy subjects while they performed a Go/NoGo task with two levels of NoGo difficulty (Easy and Hard NoGo conditions) in distinguishing spatial patterns of lines. Based on the previous inhibitory control literature and the present fMRI activation results, 10 brain regions were postulated as nodes in the effective connectivity model. Due to the large number of potential interconnections among these nodes, the number of models for final analysis was reduced to a manageable level for the whole group by conducting DCM Network Discovery, which is a recently developed option within the Statistical Parametric Mapping software package. Given the optimum network model, the DCM Network Discovery analysis found that the locations of the driving input into the model from all the experimental stimuli in the Go/NoGo task were the amygdala and the hippocampus. The strengths of several cortico-subcortical connections were modulated (influenced) by the two NoGo conditions. Specifically, connectivity from the middle frontal gyrus (MFG) to hippocampus was enhanced by the Easy condition and further enhanced by the Hard NoGo condition, possibly suggesting that compared with the Easy NoGo condition, stronger control from MFG was needed for the hippocampus to discriminate/learn the spatial pattern in order to respond correctly (inhibit), during the Hard NoGo condition.
Recent studies have suggested that heterogeneity in the level of dopamine activity and function might be useful for identifying a subgroup of cocaine-dependent patients responding better to dopamine-enhancement pharmacotherapy. Here we hypothesized that response to levodopa/carbidopa treatment would be greater in patients with genetically determined low levels of the dopamine metabolizing enzyme dopamine ?-hydroxylase (D?H). Seventy-one cocaine-dependent patients who participated in a 12-week randomized double-blind placebo-controlled trial of levodopa/carbidopa were genotyped for the D?H gene (DBH) polymorphism rs1611115. Our results showed that for patients with the low D?H activity genotypes (CT/TT) who received levodopa, the odds of having cocaine-positive urine decreased significantly over treatment compared with placebo-treated patients with the CT/TT genotypes (P=0.004). Individuals with the normal D?H activity genotype (CC) showed no differential response to levodopa. These preliminary results need to be confirmed in a larger sample focusing on the DBH polymorphism.
Individuals with Attention Deficit Hyperactivity Disorder (ADHD) smoke cigarettes at rates higher than the general population and questions have been raised about how stimulant drugs-the frontline pharmacological treatment for ADHD-influence smoking risk and behavior in those with ADHD. In the present study adult regular smokers with (n = 16) and without (n = 17) ADHD participated in 3 experimental sessions in which they completed a Progressive Ratio (PR) task to measure the relative reinforcing effects of cigarette smoking and money after oral administration of placebo and 2 active doses of methylphenidate (10 mg and 40 mg). We also measured attention and inhibitory control via a Continuous Performance Test (CPT). Methylphenidate had no effect on smoking-reinforced responding, attention, or inhibitory control in either group. Attention and inhibitory control were associated with smoking-reinforced responding, but unsystematically and only in the non-ADHD group. Several design features, such as the value of the monetary response option, the PR schedule, and the potential effects of smoking on attention and inhibitory control, could have contributed to the negative findings and are discussed as such. Although inconsistent with some previous human laboratory studies of stimulant drugs and smoking, results are consistent with recent trials of stimulant drugs as adjuncts for smoking cessation in adult smokers with ADHD. In general, methylphenidate at mild and moderate doses did not influence the relative reinforcing effects of cigarette smoking in adults with and without ADHD.
Aggression, impulsivity, and psychopathic traits are prominent in both antisocial personality disorder (ASPD) and substance use disorders (SUD), but have rarely been examined collectively. The authors results show that all three variables were elevated in adults with comorbid ASPD/SUD, relative to SUD-only and control subjects.
Early responses to stimuli can be measured by sensory evoked potentials (EP) using repeated identical stimuli, S1 and S2. Response to S1 may represent efficient stimulus detection, while suppression of response to S2 may represent inhibition. Early responses to stimuli may be related to impulsivity. We compared EP reflecting stimulus detection and inhibition in bipolar disorder and healthy controls, and investigated relationships to impulsivity. Subjects were 48 healthy controls without family histories of mood disorder and 48 with bipolar disorder. EP were measured as latencies and amplitudes for auditory P50 (pre-attentional), N100 (initial direction of attention) and P200 (initial conscious awareness), using a paired-click paradigm, with identical stimuli 0.5 s apart. Impulsivity was measured by questionnaire and by laboratory tests for inability to suppress responses to stimuli or to delay response for a reward. Analyses used general linear models. S1 amplitudes for P50, N100, and P200, and gating of N100 and P200, were lower in bipolar disorder than in controls. P50 S1 amplitude correlated with accurate laboratory-task responding, and S2 amplitude correlated with impulsive task performance and fast reaction times, in bipolar disorder. N100 and P200 EP did not correlate with impulsivity. These findings were independent of symptoms, treatment, or substance-use history. EPs were not related to questionnaire-measured or reward-based impulsivity. Bipolar I disorder is characterized by reduced pre-attentional and early attentional stimulus registration relative to controls. Within bipolar disorder, rapid-response impulsivity correlates with impaired pre-attentional response suppression. These results imply specific relationships between ERP-measured response inhibition and rapid-response impulsivity.
Key characteristics of cocaine dependence include attentional bias to cocaine cues and impaired inhibitory control. Studies suggest that serotonin modulates both cocaine cue reactivity and inhibitory control. We investigated effects of the selective serotonin reuptake inhibitor escitalopram on cocaine cue reactivity and inhibitory processes in cocaine-dependent subjects. In a double-blind placebo-controlled design, cocaine-dependent subjects received placebo (n=12) or escitalopram (n=11; 10 mg on days 1-3, 20 mg on days 4-24 and 10 mg on days 25-28) orally, once daily for 4 weeks. The cocaine Stroop and immediate memory task (IMT) were administered at baseline, days 1, 4, 11, 18 and 25 after placebo or escitalopram initiation. There were no significant between-group differences in baseline performance on the cocaine Stroop task or the IMT. On day 1 (acute phase), escitalopram produced a significantly greater decrease from baseline than placebo in attentional bias measured by cocaine Stroop task 5 hours post-dose. No significant changes from baseline in attentional bias were observed on subsequent test days (chronic phase). Inhibitory control as measured by IMT commission error rate was not significantly different between two groups in either the acute or chronic phase. Consistent with preclinical data, serotonin-modulating drugs like escitalopram may have acute effects on cocaine cue reactivity in human cocaine users.
Rapid-response impulsivity, characterized by inability to withhold response to a stimulus until it is adequately appraised, is associated with risky behavior and may be increased in a state-dependent manner by norepinephrine.
Child abuse and neglect are universal risk factors for delinquency, violence, and aggression; this phenomenon is known as the cycle of violence. Additional factors-psychopathy, impulsiveness, and disruptions in the hypothalamic-pituitary-adrenal (HPA) axis-play a role in aggressive behavior but have rarely been examined in the same conceptual and experimental framework.
Anticonvulsants, notably those which modulate GABA activity, have shown efficacy in reducing aggressive behavior. Previously, we found dose-related decreases in human aggressive responding following acute tiagabine administration. Here, we examined the effects of chronic tiagabine over a 5-week period. Twelve individuals at increased risk for aggressive and violent behavior (currently on parole/probation with personality and/or substance use disorders) were randomly assigned to placebo (n?=?6) or an escalating dose sequence of placebo, 4?mg, 8?mg, 12?mg, placebo (n?=?6). Data were analyzed using both frequentist and Bayesian mixed models, evaluating aggressive behavior as a function of time, dose condition, and their interaction. For aggressive responding, there was a significant interaction of drug condition and time. Aggression in the tiagabine condition decreased for each additional week in the study, while participants in the placebo condition failed to demonstrate similar change over time. For monetary-reinforced responding, no drug or drug by time interactions were observed, suggesting specificity of drug effects on aggression. The small number of subjects limits the generality of the findings, and previous studies with tiagabine are limited to acute dosing and case report investigations. However, the present data provide an indication that tiagabine merits further examination as an agent for management of impulsive aggression.
Several studies provide empirical evidence for the association between impulsivity and time perception. However, little is known about the neural substrates underlying this function. This investigation examined the influence of impulsivity on neural activation patterns during the encoding and reproduction of intervals with durations of 3, 9 and 18s using event-related functional magnetic resonance imaging (fMRI). Twenty-seven subjects participated in this study, including 15 high impulsive subjects that were classified based on their self-rating. FMRI activation during the duration reproduction task was correlated with measures of two self-report questionnaires related to the concept of impulsivity (Barratt Impulsiveness Scale, BIS; Zimbardo Time Perspective Inventory, ZTPI). Behaviorally, those individuals who under-reproduced temporal intervals also showed lower scores on the ZTPI future perspective subscale and higher scores on the BIS. FMRI activation revealed an accumulating pattern of neural activity peaking at the end of the 9- and 18-s intervals within right posterior insula. Activations of brain regions during the reproduction phase of the timing task, such as those related to motor execution as well as to the core control network - encompassing the inferior frontal and medial frontal cortices, the anterior insula as well as the inferior parietal cortex - were significantly correlated with reproduced duration, as well as with BIS and ZTPI subscales. In particular, the greater activation in these regions the shorter were the reproduced intervals, the more impulsive was an individual and the less pronounced the future perspective. Activation in the core control network, thus, may form a biological marker for cognitive time management and for impulsiveness.
Bipolar disorder and antisocial personality disorder (ASPD) overlap in clinical characteristics and behavioral consequences. Impulsivity is prominent in both, but there is little information on how specific mechanisms of impulsivity differentiate, bridge, or underlie the disorders.
Neuroimaging data suggest that impaired performance on response inhibition and information processing tests in cocaine-dependent subjects is related to prefrontal and frontal cortical dysfunction and that dysfunction in these brain areas may underlie some aspects of cocaine addiction. In subjects with attention-deficit hyperactivity disorder and other psychiatric disorders, the Intra-Individual Reaction Time Variability (IIRTV) has been associated with frontal cortical dysfunction. In the present study, we evaluated IIRTV parameters in cocaine-dependent subjects vs. controls using a cocaine Stroop task. Fifty control and 123 cocaine-dependent subjects compiled from three studies completed a cocaine Stroop task. Standard deviation (SD) and coefficient of variation (CV) for reaction times (RT) were calculated for both trials with neutral and trials with cocaine-related words. The parameters mu, sigma, and tau were calculated using an ex-Gaussian analysis employed to characterize variability in RTs. The ex-Gaussian analysis divides the RTs into normal (mu, sigma) and exponential (tau) components. Using robust regression analysis, cocaine-dependent subjects showed greater SD, CV and Tau on trials with cocaine-related words compared to controls (p<0.05). However, in trials with neutral words, there was no evidence of group differences in any IIRTV parameters (p>0.05). The Wilcoxon matched-pairs signed-rank test showed that for cocaine-dependent subjects, both SD and tau were larger in trials with cocaine-related words than in trials with neutral words (p<0.05). The observation that only cocaine-related words increased IIRTV in cocaine-dependent subjects suggests that cocaine-related stimuli might disrupt information processing subserved by prefrontal and frontal cortical circuits.
Aggression is a serious medical problem that can place both the patient and the health care provider at risk. Aggression can result from medical, neurologic, and/or psychiatric disorders. A comprehensive patient evaluation is needed. Treatment options include pharmacotherapy as well as nonpharmacologic interventions, both of which need to be individualized to the patient.
Criminal behavior in bipolar disorder may be related to substance use disorders, personality disorders, or other comorbidities potentially related to impulsivity. We investigated relationships among impulsivity, antisocial personality disorder (ASPD) or borderline personality disorder symptoms, substance use disorder, course of illness, and history of criminal behavior in bipolar disorder.
Cocaine-dependent subjects show attentional bias to cocaine-related stimuli, increased impulsivity on questionnaires, and impaired inhibitory control (one component of impulsivity on behavioral tasks). However, the relationship between attentional bias, impulsivity, and inhibitory control in cocaine-dependent subjects is unknown.
Neuroimaging studies on delay discounting tasks that use reward delays ranging from minutes to days have implicated the insula and striatum in the processing of inter-temporal decisions. This study aimed at assessing whether these brain regions would also be involved in decision-making when subjects have to wait through the delays within the range of seconds. Employing functional magnetic resonance imaging (fMRI) in thirteen healthy volunteers, we repeatedly presented monetaryoptions with delays that differed within the range of multiple seconds. Using a region of interest approach, we found significant activation in the bilateral anterior insula and striatum when subjects chose either the immediate (smaller) or delayed (larger) option. In particular, insular activation was observed after the response and the delay, when the outcome of the immediate or the delayed choice was shown. Significantly greater activation was observed in the ventroanterior striatum while subjects chose the immediate, as opposed to the delayed, options, and also after receiving the outcome of waiting through the longer delay option. The evidence presented here indicates that both the ventral striatum and the insula are involved in the processing of choosing delay options as well as the consequences of choices with delays in the seconds range.
Impulsivity and decision making are associated on a theoretical level in that impaired planning is a component of both. However, few studies have examined the relationship between measures of decision making and impulsivity in clinical populations. The purpose of this study was to compare cocaine-dependent subjects to controls on a measure of decision making (the Iowa Gambling Task or IGT), a questionnaire measure of impulsivity (the Barratt Impulsiveness Scale or BIS-11) and a measure of behavioural inhibition (the immediate memory task or IMT), and to examine the interrelationship among these measures. Results of the study showed that cocaine-dependent subjects made more disadvantageous choices on the IGT, had higher scores on the BIS and more commission errors on the IMT. Cognitive model analysis showed that choice consistency factors on the IGT differed between cocaine-dependent subjects and controls. However, there was no significant correlation between IGT performance and the BIS total score or subscales or IMT commission errors. These results suggest that in cocaine-dependent subjects there is little overlap between decision making as measured by the IGT and impulsivity/behavioural inhibition as measured by the BIS and IMT.
Chronic stimulant abuse is associated with both impairment in decision making and structural abnormalities in brain gray and white matter. Recent data suggest these structural abnormalities may be related to functional impairment in important behavioral processes.
The serotonin 1(B/D) (5-HT1(B/D)) receptor has shown potential as a target for decreasing aggression. The 5-HT1(B/D) agonist zolmitriptans ability to reduce aggressive behavior in humans and its interaction with the well-known aggression-enhancing drug alcohol were examined.
Pathological impulsivity in bipolar disorder could be related to deficiencies in mechanisms involved in attention or response inhibition. We investigated these mechanisms in subjects with bipolar disorder and examined relationships to severity of course of illness, use of medication, affective state, age, education, and gender. We measured two complementary aspects of response inhibition: attention-based and reward-based.
The authors investigated preattentive filtering assessed by P50 gating in nine participants with antisocial personality disorder (ASPD) and seven with adult-onset antisocial behavior (AAB). Relative to 15 comparison subjects, gating was impaired in ASPD, suggesting abnormal pre-attentive filtering in pathological impulsivity.
Previous studies have shown that cocaine users have higher levels of impulsivity and impaired decision making; however, few have examined these factors as predictors of treatment success. We obtained baseline neurocognitive measures from 75 cocaine-dependent individuals participating in a 12-week clinical trial targeting impulsivity with behavioral therapies and pharmacotherapy. Participants treated with citalopram had higher cocaine abstinence rates compared to placebo-treated participants. The aim of this secondary analysis study was to determine whether profiles of performance on neurocognitive measures administered at baseline discriminated among patients who achieved abstinence and those who did not. Participants completed the Immediate and Delayed Memory Task, Barratt Impulsiveness Scale-11, and Iowa Gambling Task. Profile analysis results showed different patterns of performance on these baseline measures as a function of outcome. Compared with non-abstinent participants, abstinent participants had higher scores on the Barratt Impulsiveness Scale-11 Non-Planning subscale and better performance on the Iowa Gambling Task. Profile differences for the two outcome groups did not vary as a function of treatment condition. Results suggest that cocaine-dependent patients entering treatment with higher impulsivity and less impaired decision-making abilities may respond favorably to targeted behavioral interventions. Neurocognitive profiles may be useful in understanding population heterogeneity and predicting differential outcomes in subgroups of cocaine abusers.
Recent work in neuroeconomics has used game theory paradigms to examine neural systems that subserve human social interaction and decision making. Attempts to modify social interaction through pharmacological manipulation have been less common. Here we show dose-dependent modification of human social behavior in a prisoners dilemma model after acute administration of the ?-aminobutyric acid (GABA)-A modulating benzodiazepine alprazolam. Nine healthy adults received doses of placebo, 0.5, 1.0, and 2.0?mg alprazolam in a counterbalanced within-subject design, while completing multiple test blocks per day on an iterated prisoners dilemma game. During test blocks in which peak subjective effects of alprazolam were reported, cooperative choices were significantly decreased as a function of dose. Consistent with previous reports showing that high acute doses of GABA-modulating drugs are associated with violence and other antisocial behavior, our data suggest that at sufficiently high doses, alprazolam can decrease cooperation. These behavioral changes may be facilitated by changes in inhibitory control facilitated by GABA. Game theory paradigms may prove useful in behavioral pharmacology studies seeking to measure social interaction, and may help inform the emerging field of neuroeconomics.
P50, N100, and P200 auditory sensory gating could reflect mechanisms involved in protecting higher-order cognitive functions, suggesting relationships between sensory gating and cognition. This hypothesis was tested in 56 healthy adults who were administered the paired-click paradigm and two adaptations of the continuous performance test (Immediate/Delayed Memory Task, IMT/DMT). Stronger P50 gating correlated with fewer commission errors and prolonged reaction times on the DMT. Stronger N100 and P200 gating correlated with better discriminability on the DMT. Finally, prolonged P200 latency related to better discriminability on the IMT. These findings suggest that P50, N100, and P200 gating could be involved in protecting cognition by affecting response bias, behavioral inhibition, working memory, or attention.
Recent studies demonstrated that diffusion tensor imaging (DTI) can provide information regarding white matter integrity of the corpus callosum (CC). In this study, DTI parameters were compared between cocaine dependent subjects (CDs) and non-drug using controls (NCs) in midsagittal CC. DTI images were acquired from 19 CDs and 18 age-matched NCs. The midsagittal CC was segmented into: genu, rostral body, anterior midbody, posterior midbody, isthmus, and splenium. Linear mixed models analyses showed that, relative to NCs, CDs had lower fractional anisotropy (FA), higher radial diffusivity (lambda(perpendicular)), and higher mean diffusivity (D(av)) in the isthmus; higher lambda(perpendicular) and D(av) in the rostral body; and lower FA in the splenium. After including mass of lifetime alcohol use in the mixed model analysis of covariance (ANCOVA) as a covariate, significant between group differences in lambda(perpendicular) in the rostral body and isthmus remained. These results suggest that alterations in lambda(perpendicular) in the rostral body and isthmus were mainly due to cocaine use, consistent with previous studies showing that cocaine may alter myelin integrity. Between group differences in FA in the isthmus and splenium, and D(av) in the rostral body and isthmus became non-significant after inclusion of alcohol use as a covariate. This is suggestive of alcohol influencing these values, or may be related to the decreased degrees of freedom for these effects. Consistent with clinical data of greater severity of drug use in smoked versus intranasal cocaine, subjects who smoked cocaine showed lower FA and higher lambda(perpendicular) compared to intranasal CDs.
Impulsivity as a trait characteristic is increased in bipolar disorder and may be a core factor of the illness. We have investigated relationships between trait-like impulsivity, measured by the Barratt Impulsiveness Scale (BIS-11), and demographic and illness-course characteristics of bipolar disorder.
Bipolar I disorder is associated with diminished gating of the auditory evoked P50 component. P50 gating may relate to early filtering of sensory information, protecting higher-order cognitive functions. Gating of the auditory evoked N100 and P200 components has not been investigated in bipolar I disorder, although N100 and P200 gating could reflect different mechanisms and functions in the process of filtering sensory information in addition to those reflected by P50 gating. We investigated P50, N100, and P200 gating assessed with the paired-click paradigm in 22 subjects with bipolar I disorder and 54 healthy controls. Peak amplitudes and latencies were assessed at Cz for the P50, N100, and P200 components. Gating was defined as the reduction in peak amplitude from the first (S1) to the second stimulus (S2) of a stimulus pair, and expressed as gating ratio ([S2(amplitude)/S1(amplitude)]()100) and difference score (S1(amplitude)-S2(amplitude)). Group differences were detected with multivariate analyses and controlled for differences in age and ethnicity. Subjects with bipolar I disorder had higher P50, N100 and P200 ratios and lower difference scores compared with findings for controls. These findings extend the existing evidence on impaired sensory gating in bipolar I disorder beyond the P50, suggesting impaired filtering at both pre-attentive and early attentive levels in bipolar I disorder.
Anticonvulsant drugs have demonstrated efficacy in the management of irritability and aggression in a variety of psychiatric populations. We examined the acute effects of topiramate on aggression using a laboratory model of human aggression (PSAP) in individuals at high risk for aggressive and violent behavior.Twelve subjects, on parole/probation and with an Axis-II personality disorder and/or a substance use disorder, received 100, 200, 300, and 400 mg in an ascending sequence, with intervening placebo doses.Subjects participated 2-3 days per week over 4-6 weeks. Due to cognitive side effects at 300 mg, two subjects only completed through the 200 mg dose. Topiramate produced an inverted U-shaped dose response curve, with increases in aggression peaking at 200 mg and a modest decrease at 400 mg. Statistical analysis revealed a polynomial trend for dose (p=0.001). The observed inverted U-shaped function 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.
Impulsive behavior is a prominent characteristic of antisocial personality disorder. Impulsivity is a complex construct, however, representing distinct domains of cognition and action. Leading models refer to impulsivity as an inability to evaluate a stimulus fully before responding to it (rapid-response impulsivity), and as an inability to delay responding despite a larger reward (reward-delay impulsivity). We investigated these models in terms of the diagnosis and severity of antisocial personality disorder.
P50, N100, and P200 auditory sensory gating reflect distinct mechanisms involved in protecting the integrity of higher-order functions. They have been implicated in multiple psychiatric disorders. Recent studies showed the (limited) effects of age and gender on sensory gating in control subjects, suggesting there may be other sources of variance. Two potential sources may be education and intelligence (intellectual capability), variables that frequently differ across studies and across experimental groups. We explored potential effects of age, gender, education, and intelligence (Shipley intelligence scale) on P50, N100, and P200 sensory gating measured with the paired-click paradigm in 60 healthy subjects recruited from the general population. Increased intellectual capability related to stronger N100 and P200 gating and more pronounced N100 and P200 amplitudes. In addition, increased age related to weaker P200 gating and smaller P200 amplitudes. Gender had negligible effects. Intellectual capability or age could contribute to variation in N100 or P200 auditory sensory gating and should be controlled for when studying sensory gating in clinical and control groups.
Individuals with attention deficit hyperactivity disorder (ADHD) have a more difficult time quitting smoking compared to their non-ADHD peers. Little is known about the underlying behavioral mechanisms associated with this increased risk.
Background: Marijuana use is prevalent among patients with cocaine dependence and often non-exclusionary in clinical trials of potential cocaine medications. The dual-focus of this study was to (1) examine the moderating effect of baseline marijuana use on response to treatment with levodopa/carbidopa for cocaine dependence; and (2) apply an informative-priors, Bayesian approach for estimating the probability of a subgroup-by-treatment interaction effect. Method: A secondary data analysis of two previously published, double-blind, randomized controlled trials provided complete data for the historical (Study 1: N?=?64 placebo), and current (Study 2: N?=?113) data sets. Negative binomial regression evaluated Treatment Effectiveness Scores (TES) as a function of medication condition (levodopa/carbidopa, placebo), baseline marijuana use (days in past 30), and their interaction. Results: Bayesian analysis indicated that there was a 96% chance that baseline marijuana use predicts differential response to treatment with levodopa/carbidopa. Simple effects indicated that among participants receiving levodopa/carbidopa the probability that baseline marijuana confers harm in terms of reducing TES was 0.981; whereas the probability that marijuana confers harm within the placebo condition was 0.163. For every additional day of marijuana use reported at baseline, participants in the levodopa/carbidopa condition demonstrated a 5.4% decrease in TES; while participants in the placebo condition demonstrated a 4.9% increase in TES. Conclusion: The potential moderating effect of marijuana on cocaine treatment response should be considered in future trial designs. Applying Bayesian subgroup analysis proved informative in characterizing this patient-treatment interaction effect.
Interactions between characteristics of bipolar and Axis II cluster B disorders are clinically and diagnostically challenging. Characteristics associated with personality disorders may be dimensional aspects of bipolar disorder. We investigated relationships among antisocial personality disorder (ASPD) or borderline personality disorder symptoms, impulsivity, and course of illness in bipolar disorder.
Background: Positron Emission Tomography imaging studies provide evidence of reduced dopamine function in cocaine dependent subjects in the striatum, which is correlated with prefrontal cortical glucose metabolism, particularly in the orbitofrontal cortex. However, whether enhancement of dopamine in the striatum in cocaine dependent subjects would be associated with changes in prefrontal cortical brain activation is unknown. One novel class of medications that enhance dopamine function via heteromer formation with dopamine receptors in the striatum is the selective adenosine A(2A) receptor antagonists. This study sought to determine the effects administration of the selective adenosine A(2A) receptor antagonist SYN115 on brain function in cocaine dependent subjects. Methodology/Principle Findings: Twelve cocaine dependent subjects underwent two fMRI scans (one after a dose of placebo and one after a dose of 100?mg of SYN115) while performing a working memory task with three levels of difficulty (3, 5, and 7 digits). fMRI results showed that for 7-digit working memory activation there was significantly greater activation from SYN115 compared to placebo in portions of left (L) lateral orbitofrontal cortex, L insula, and L superior and middle temporal pole. Conclusion/Significance: These findings are consistent with enhanced dopamine function in the striatum in cocaine dependent subjects via blockade of adenosine A(2A) receptors producing increased brain activation in the orbitofrontal cortex and other cortical regions. This suggests that at least some of the changes in brain activation in prefrontal cortical regions in cocaine dependent subjects may be related to altered striatal dopamine function, and that enhancement of dopamine function via adenosine A(2A) receptor blockade could be explored further for amelioration of neurobehavioral deficits associated with chronic cocaine use.
Limited information is available on the relationship between antisocial personality disorder (ASPD) and early filtering, or gating, of information, even though this could contribute to the repeatedly reported impairment in ASPD of higher-order information processing. In order to investigate early filtering in ASPD, we compared electrophysiological measures of auditory sensory gating assessed by the paired-click paradigm in males with ASPD (n = 37) to healthy controls (n = 28). Stimulus encoding was measured by P50, N100, and P200 auditory evoked potentials; auditory sensory gating (ASG) was measured by a reduction in amplitude of evoked potentials following click repetition. Effects were studied of co-existing past alcohol or drug use disorders, ASPD symptom counts, and trait impulsivity. Controls and ASPD did not differ in P50, N100, or P200 amplitude or ASG. Past alcohol or drug use disorders had no effect. In controls, impulsivity related to improved P50 and P200 gating. In ASPD, P50 or N100 gating was impaired with more symptoms or increased impulsivity, respectively, suggesting impaired early filtering of irrelevant information. In controls the relationship between P50 and P200 gating and impulsivity was reversed, suggesting better gating with higher impulsivity scores. This could reflect different roles of ASG in behavioral regulation in controls versus ASPD.
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