Impaired Decision-Making, Higher Impulsivity, and Drug Severity in Substance Dependence and Pathological Gambling.

OBJECTIVES: Substance use disorder is characterized by impaired decision making, impulsivity, and risk taking. Pathological gambling shares many of these characteristics, and having both diagnoses may be associated with greater problems than either diagnosis alone. We investigated whether among substance-dependent individuals, comorbid pathological gambling would be associated with worse decision making, greater impulsivity, risk taking, and drug severity. METHODS: Ninety-six substance-dependent individuals were recruited from a residential treatment program and divided into 1 of the 2 groups depending on whether they met Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, criteria for pathological gambling (SDPG, n = 26) or not (SD, n = 70). Ninety-two controls were recruited from the community. Participants completed a decision-making task (modified Iowa Gambling Task), measures of impulsivity (Barratt Impulsivity Scale and Delay Discounting), and risk taking (Balloon Analog Risk Task). Decision making was analyzed using a computational model. We tested for group differences using analysis of covariance or Kruskal-Wallis and appropriate post-hoc tests. RESULTS: The groups differed in decision-making parameters (P < 0.001) and self-reported impulsivity (P < 0.001). All post-hoc comparisons were significant on these measures, and indicated stepwise changes in controls, followed by SD, followed by SDPG, with SDPG performing worse on decision making and being more impulsive. Compared with SD, SDPG had greater drug severity (P < 0.001). No group differences were observed in delay discounting or risk taking. CONCLUSIONS: Compared with individuals with substance dependence without pathological gambling, those with both disorders demonstrated worse decision making and significantly more drug-related symptoms. When evaluating patients with substance dependence, clinicians should consider diagnostic assessments for gambling, as the co-occurrence of both disorders may impact clinical characteristics.

Temporal profile of fronto-striatal-limbic activity during implicit decisions in drug dependence.

BACKGROUND: Substance dependence is associated with impaired decision-making and altered fronto-striatal-limbic activity. Both greater and lesser brain activity have been reported in drug users compared to controls during decision-making. Inconsistent results might be explained by group differences in the temporal profile of the functional magnetic resonance imaging (fMRI) response. While most previous studies model a canonical hemodynamic response, a finite impulse response (FIR) model measures fMRI signal at discrete time points without assuming a temporal profile. We compared brain activity during decision-making and feedback in substance users and controls using two models: a canonical hemodynamic response function (HRF) and a FIR model. METHODS: 37 substance-dependent individuals (SDI) and 43 controls performed event-related decision-making during fMRI scanning. Brain activity was compared across group using canonical HRF and FIR models. RESULTS: Compared to controls, SDI were impaired at decision-making. The canonical HRF model showed that SDI had significantly greater fronto-striatal-limbic activity during decisions and less activity during feedback than controls. The FIR model confirmed greater activity in SDI during decisions. However, lower activity in SDI during feedback corresponded to a lower post-stimulus undershoot of the hemodynamic response. CONCLUSIONS: Greater activity in fronto-striatal-limbic pathways in SDI compared to controls is consistent with prior work, further supporting the hypothesis that abnormalities in these circuits underlie impaired decision-making. We demonstrate for the first time using FIR analysis that lower activity during feedback may simply reflect the tail end of the hemodynamic response to decision, the post-stimulus undershoot, rather than an actual difference in feedback response.

Reduced neural tracking of prediction error in substance-dependent individuals.

OBJECTIVE: Substance-dependent individuals make poor decisions on the Iowa Gambling Task, a reward-related decision-making task that involves risk and uncertainty. Task performance depends on several factors, including how sensitive individuals are to feedback and how well they learn based on such feedback. A physiological signal that guides decision making based on feedback is prediction error. The authors investigated whether disruptions in the neural systems underlying prediction error processing in substance-dependent individuals could account for decision-making performance on a modified Iowa Gambling Task. METHODS: Thirty-two substance-dependent individuals and 30 healthy comparison subjects played a modified version of the Iowa Gambling Task during MR scanning. Trial-to-trial behavior and functional MRI (fMRI) blood-oxygen-level-dependent (BOLD) signal were analyzed using a computational model of prediction error based on internal expectancies. The authors investigated how well BOLD signal tracked prediction error in the striatum and the orbitofrontal cortex as well as over the whole brain in patients relative to comparison subjects. RESULTS: Compared with healthy subjects, substance-dependent patients were less sensitive to loss compared with gain, made less consistent choices, and performed worse on the modified Iowa Gambling Task. The ventral striatum and medial orbitofrontal cortex did not track prediction error as strongly in patients as in healthy subjects. CONCLUSIONS: Weaker tracking of prediction error in substance-dependent relative to healthy individuals suggests that altered frontal-striatal error learning signals may underlie decision-making impairments in drug abusers. Computational fMRI may help bridge the knowledge gap between physiology and behavior to inform research aimed at substance abuse treatment.

Sex modulates approach systems and impulsivity in substance dependence.

BACKGROUND: Personality traits such as pathological engagement in approach behaviors, high levels of impulsivity and heightened negative affect are consistently observed in substance dependent individuals (SDI). The clinical course of addiction has been shown to differ between sexes. For example, women increase their rates of consumption of some drugs of abuse more quickly than men. Despite the potential influence of personality and sex on features of addiction, few studies have investigated the interaction of these factors in substance dependence. METHODS: Fifty-one SDI (26 males, 25 females) and 66 controls (41 males, 25 females) completed the Behavioral Inhibition/Behavioral Activation System (BIS/BAS) Scales, the Barratt Impulsiveness Scale, and the Positive and Negative Affect Schedule (PANAS-X). Data were analyzed with 2×2 ANCOVAs testing for main effects of group, sex and group by sex interactions, adjusting for education level. RESULTS: Significant group by sex interactions were observed for BAS scores [F(1,116)=7.03, p<.01] and Barratt Motor Impulsiveness [F(1,116)=6.11, p<.02] with female SDI showing the highest approach tendencies and impulsivity followed by male SDI, male controls, and finally female controls. SDI scored higher on negative affect [F(1,116)=25.23, p<.001] than controls. Behavioral Inhibition System scores were higher in women than men [F(1,116)=14.03, p<.001]. CONCLUSION: Higher BAS and motor impulsivity in SDI women relative to SDI men and control women suggest that personality traits that have been previously associated with drug use may be modulated by sex. These factors may contribute to differences in the disease course observed in male compared to female drug users.

Resting-state activity in the left executive control network is associated with behavioral approach and is increased in substance dependence.

BACKGROUND: Individuals with drug addictions report increased willingness to approach rewards. Approach behaviors are thought to involve executive control processes and are more strongly represented in the left compared to right prefrontal cortex. A direct link between approach tendencies and left hemisphere activity has not been shown in the resting brain. We hypothesized that compared to controls, substance dependent individuals (SDI) would have greater left hemisphere activity in the left executive control network (ECN) at rest. METHODS: Twenty-five SDI and 25 controls completed a Behavioral Inhibition System/Behavioral Activation System (BIS/BAS) questionnaire and underwent a resting-state fMRI scan. Group independent component analysis was performed. We used template matching to identify the left and right ECN separately and compared the corresponding components across groups. Across group, BAS scores were correlated with signal fluctuations in the left ECN and BIS scores with right ECN. RESULTS: BAS scores were higher in SDI compared to controls (p<.003) and correlated with signal fluctuation in the left ECN. SDI showed significantly more activity than controls in the left prefrontal cortex of the left ECN. Conversely, SDI showed less activity than controls in the right prefrontal cortex of the right ECN. CONCLUSIONS: Results from this study suggest that approach tendencies are related to the left ECN, even during rest. Higher resting-state signal in the left ECN may play a role in heightened approach tendencies that contribute to drug-seeking behavior.

Negative reinforcement learning is affected in substance dependence.

BACKGROUND: Negative reinforcement results in behavior to escape or avoid an aversive outcome. Withdrawal symptoms are purported to be negative reinforcers in perpetuating substance dependence, but little is known about negative reinforcement learning in this population. The purpose of this study was to examine reinforcement learning in substance dependent individuals (SDI), with an emphasis on assessing negative reinforcement learning. We modified the Iowa Gambling Task to separately assess positive and negative reinforcement. We hypothesized that SDI would show differences in negative reinforcement learning compared to controls and we investigated whether learning differed as a function of the relative magnitude or frequency of the reinforcer. METHODS: Thirty subjects dependent on psychostimulants were compared with 28 community controls on a decision making task that manipulated outcome frequencies and magnitudes and required an action to avoid a negative outcome. RESULTS: SDI did not learn to avoid negative outcomes to the same degree as controls. This difference was driven by the magnitude, not the frequency, of negative feedback. In contrast, approach behaviors in response to positive reinforcement were similar in both groups. CONCLUSIONS: Our findings are consistent with a specific deficit in negative reinforcement learning in SDI. SDI were relatively insensitive to the magnitude, not frequency, of loss. If this generalizes to drug-related stimuli, it suggests that repeated episodes of withdrawal may drive relapse more than the severity of a single episode.

Reduced cortical gray matter volume in male adolescents with substance and conduct problems.

UNLABELLED: Boys with serious conduct and substance problems (Antisocial Substance Dependence (ASD)) repeatedly make impulsive and risky decisions in spite of possible negative consequences. Because prefrontal cortex (PFC) is involved in planning behavior in accord with prior rewards and punishments, structural abnormalities in PFC could contribute to a person's propensity to make risky decisions. METHODS: We acquired high-resolution structural images of 25 male ASD patients (ages 14-18 years) and 19 controls of similar ages using a 3T MR system. We conducted whole-brain voxel-based morphometric analysis (p<0.05, corrected for multiple comparisons at whole-brain cluster-level) using Statistical Parametric Mapping version-5 and tested group differences in regional gray matter (GM) volume with analyses of covariance, adjusting for total GM volume, age, and IQ; we further adjusted between-group analyses for ADHD and depression. As secondary analyses, we tested for negative associations between GM volume and impulsivity within groups and separately, GM volume and symptom severity within patients using whole-brain regression analyses. RESULTS: ASD boys had significantly lower GM volume than controls in left dorsolateral PFC (DLPFC), right lingual gyrus and bilateral cerebellum, and significantly higher GM volume in right precuneus. Left DLPFC GM volume showed negative association with impulsivity within controls and negative association with substance dependence severity within patients. CONCLUSIONS: ASD boys show reduced GM volumes in several regions including DLPFC, a region highly relevant to impulsivity, disinhibition, and decision-making, and cerebellum, a region important for behavioral regulation, while they showed increased GM in precuneus, a region associated with self-referential and self-centered thinking.

Reducing HIV-related risk behaviors among injection drug users in residential detoxification.

This study of 632 drug injectors enrolled in eight residential detoxification centers within the National Drug Abuse Treatment Clinical Trials Network tested three interventions to reduce drug and sex risk behaviors. Participants were randomized to: (a) a two-session, HIV/HCV counseling and education (C&E) model added to treatment as usual (TAU), (b) a one-session, therapeutic alliance (TA) intervention conducted by outpatient counselors to facilitate treatment entry plus TAU, or (c) TAU. Significant reductions in drug and sex risk behaviors occurred for all three conditions over a 6-month follow-up period. C&E participants reported significantly greater rates of attending an HIV testing appointment, but this was not associated with better risk reduction outcomes. Reporting treatment participation within 2 months after detoxification and self-efficacy to practice safer injection behavior predicted reductions in injection risk behaviors. Findings indicate that participation in detoxification was followed by significant decreases in drug injection and risk behaviors for up to 6-months; interventions added to standard treatment offered no improvement in risk behavior outcomes.

Do physicians referred for competency evaluations have underlying cognitive problems?

PURPOSE: Research suggests that there are concerns about the neuropsychological functioning of physicians who undergo physician competency evaluation. Academic health center faculty often participate in the evaluation and remediation of these physicians. The purpose of this study was to compare the cognitive abilities between a group of physicians referred for competency evaluations and a control group. METHOD: Using the MicroCog, a computerized neuropsychological screen originally designed for physicians, the authors compared the cognitive performance of 267 physicians referred for competency evaluations with a control group of 68 recruited physicians. Physicians referred for competency evaluations took the MicroCog as a part of their evaluation at CPEP, the national Center for Personalized Education for Physicians, from January 1997 to January 2004. The control group comprised practicing physicians whose competency was not in question. RESULTS: Compared with the control group, the competency evaluation group had a greater proportion of physicians with scores suggesting possible cognitive impairment and performed significantly lower on scores of processing speed, processing accuracy, and cognitive proficiency. The control group of physicians performed significantly better than the age- and education-corrected normative sample. CONCLUSIONS: Because there were significant neuropsychological differences between physicians referred for competency evaluations and physicians whose competency was not in question, it is important that neuropsychological screening be included as part of physicians' competency evaluations.

Medial orbitofrontal cortex gray matter is reduced in abstinent substance-dependent individuals.

BACKGROUND: Chronic exposure to drugs of addiction induces cellular adaptations in orbitofrontal cortex (OFC) and associated limbic-prefrontal pathways that might underlie abuse-related behavior. A propensity to make risky decisions in spite of substantial negative consequences might be mediated by medial OFC dysfunction in substance-dependent individuals (SDI). We tested the hypothesis that medial OFC gray matter (GM) volume would be lower in SDI compared with control subjects. METHODS: Nineteen SDI and 20 control subjects participated. The SDI were dependent on two or more substances, most often cocaine, amphetamine, and alcohol, with mean duration of abstinence 4.7, 2.4, and 3.2 years, respectively. High-resolution T1-weighted images were acquired on a 3-T magnetic resonance system. Image processing and analyses were conducted with voxel-based morphometry (VBM) implemented in Statistical Parametric Mapping (SPM) 5. Differences in regional GM volume were tested with an analysis of covariance model, co-varying for global GM and age. Statistical maps were set at p < .05, corrected for multiple comparisons. Medial OFC GM volume was correlated with behavioral performance on a modified gambling task. RESULTS: There was lower GM volume specifically in bilateral medial OFC in SDI compared with control subjects. There was a small but significant correlation between medial OFC GM and persistence of playing high-risk decks on a modified gambling task. CONCLUSIONS: This is the first study to use VBM with whole brain correction for multiple comparisons in SDI after prolonged abstinence. Reduced medial OFC GM might reflect long-term adaptations within the reward-learning circuit underlying pathological decision-making in substance dependence.

Brain activation during the Stroop task in adolescents with severe substance and conduct problems: A pilot study.

BACKGROUND: Although many neuroimaging studies have examined changes in brain function in adults with substance use disorders, far fewer have examined adolescents. This study investigated patterns of brain activation in adolescents with severe substance and conduct problems (SCP) compared to controls. METHODS: Functional magnetic resonance imaging (fMRI) at 1.5Tesla assessed brain activation in 12 adolescent males with SCP, ranging in age from 14 to 18, and 12 controls similar in age, gender, and neighborhood while performing the attentionally demanding Stroop task. RESULTS: Even though the adolescents with SCP performed as well as the controls, they activated a more extensive set of brain structures for incongruent (e.g., "red" in blue ink) versus congruent (e.g. "red" in red ink) trials. These regions included parahippocampal regions bilaterally, posterior regions involved in language-related processing, right-sided medial prefrontal areas, and subcortical regions including the thalamus and caudate. CONCLUSION: These preliminary results suggest that the neural mechanisms of attentional control in youth with SCP differ from youth without such problems. This difficulty may prevent SCP youth from ignoring salient but distracting information in the environment, such as drug-related information.

Prefrontal cortex activity is reduced in gambling and nongambling substance users during decision-making.

OBJECTIVE: Poor decision-making is a hallmark of addiction, whether to substances or activities. Performance on a widely used test of decision-making, the Iowa Gambling Task (IGT), can discriminate controls from persons with ventral medial frontal lesions, substance-dependence, and pathological gambling. Positron emission tomography (PET) studies indicate that substance-dependent individuals show altered prefrontal activity on the task. Here we adapted the IGT to an fMRI setting to test the hypothesis that defects in ventral medial and prefrontal processing are associated with impaired decisions that involve risk but may differ depending on whether substance dependence is comorbid with gambling problems. METHOD: 18 controls, 14 substance-dependent individuals (SD), and 16 SD with gambling problems (SDPG) underwent fMRI while performing a modified version of the IGT. RESULT: Group differences were observed in ventral medial frontal, right frontopolar, and superior frontal cortex during decision-making. Controls showed the greatest activity, followed by SDPG, followed by SD. CONCLUSION: Our results support a hypothesis that defects in ventral medial frontal processing lead to impaired decisions that involve risk. Reductions in right prefrontal activity during decision-making appear to be modulated by the presence of gambling problems and may reflect impaired working memory, stimulus reward valuation, or cue reactivity in substance-dependent individuals.

A risk-taking "set" in a novel task among adolescents with serious conduct and substance problems.

OBJECTIVE: Adolescent patients' conduct disorder and substance use disorder symptoms are "risky behaviors" with unpredictable rewards and punishments. The authors asked whether such youths also take excessive risks in new situations without prior learning, peer pressure, or intoxication. METHOD: Subjects were 20 adolescent patients in a program treating conduct disorder and substance use disorder and 20 controls. All were substance free > or =7 days; underwent substance-related, psychological, and social assessments; and performed the Balloon Analogue Risk Task: mouse presses inflated a computerized "balloon" image, each press earning 1 cent. The 30 balloons "popped" at unpredictable sizes; earnings from popped balloons were lost. A "Collect" response saved current earnings and advanced to the next balloon. RESULTS: Mean number of inflating presses: patients, 1021 and controls, 705 (p = .001); group differences were stable from the task's beginning. Mean inflating presses before a "collect" response: patients, 38.6 and controls, 24.0 (p = .0005). Mean balloons popped: patients, 9.8 and controls, 6.3 (p = .001). Patients (versus controls) reported more aggressiveness and substance use and perceived less risk from substances. Patients' responses were significantly slower than those of controls. CONCLUSIONS: From the beginning of this novel task, conduct disorder and substance use disorder patients (compared with controls) took more risks, indicating an initial risk-taking propensity, although patients' slower responses argued against "impulsive, thoughtless" behavior.

Measuring impulsivity in adolescents with serious substance and conduct problems.

Adolescents with substance use and conduct disorders have high rates of aggression and attention deficit hyperactivity disorder (ADHD), all of which have been characterized in part by impulsivity. Developing measures that capture impulsivity behaviorally and correlate with self-reported impulsivity has been difficult. One promising behavioral measure, however, is a variant of the continuous performance test, the Immediate Memory Test/Delayed Memory Test (IMT/DMT). The authors showed significant group differences between adolescents in treatment for serious substance and conduct problems and community controls on impulsivity measures, both behavioral and self-report, as well as on aggression and problem behavior measures. Furthermore, the IMT/DMT correlated significantly with self-reported impulsivity. In summary, the IMT/DMT may be an effective behavioral measure of impulsivity in adolescents.

Reliable screening for neuropsychological impairment in multiple sclerosis.

In an earlier study, we developed the Multiple Sclerosis Neuropsychological Screening Questionnaire (MSNQ) to assist in the screening for neuropsychological (NP) impairments. Self-report MSNQ scores correlated significantly with measures of depression, whereas informant-report MSNQ scores correlated with cognitive performance, but not depression. This study was criticized for use of a small sample and lack of data regarding normal performance and test-retest reliability. The present study was designed to replicate the earlier work with a larger sample of patients and normal controls obtained from multiple sites. We also evaluated the test-retest reliability and predictive validity of the MSNQ. The sample included 85 multiple sclerosis (MS) patients and 40 normal controls, matched on demographic variables. All participants completed the MSNQ and underwent NP testing. Thirty-four patients were re-examined at one week. Pearson and ANOVA techniques were utilized for univariate comparisons. Bayesian statistics were calculated to assess predictive validity. Patient self- and informant-report MSNQ scores differed from normal and test retest reliability indices were high. Both self- and informant-reports were correlated with cognitive dysfunction and depression scales. Self-report MSNQ scores correlated more strongly with depression than cognitive performance, whereas the opposite pattern was observed with informant-report scores. Bayesian statistics showed that informant-report MSNQ scores predict cognitive impairment and patient self-report scores identify patients with cognitive impairment or depression. It is concluded that the MSNQ is useful, although patient self-reports may be exaggerated in depressed patients or reduced in patients with severe cognitive impairment.

Do patients with Parkinson's disease benefit from embryonic dopamine cell transplantation?

Embryonic dopamine cell transplants survive in nearly all patients regardless of age and without immunosuppression. Transplants can improve Parkinson "off" symptoms up to the best effects of L-dopa observed preoperatively. They cannot improve the "best on" state. Transplants appear to survive indefinitely. In 10 to 15% of patients, transplants can reproduce the dyskinetic effects of L-dopa even after discontinuing all L-dopa. Neurotransplantation should be tried earlier in the clinical course of Parkinson's to see if earlier intervention can prevent progression of the disease, particularly the dyskinetic responses seen after longterm L-dopa treatment.