Susan K. Mikulich-Gilbertson

Risky Decisions and Their Consequences: Neural Processing by Boys with Antisocial Substance Disorder

Background Adolescents with conduct and substance problems (“Antisocial Substance Disorder” (ASD)) repeatedly engage in risky antisocial and drug-using behaviors. We hypothesized that, during processing of risky decisions and resulting rewards and punishments, brain activation would differ between abstinent ASD boys and comparison boys. Methodology/Principal Findings We compared 20 abstinent adolescent male patients in treatment for ASD with 20 community controls, examining rapid event-related blood-oxygen-level-dependent (BOLD) responses during functional magnetic resonance imaging. In 90 decision trials participants chose to make either a cautious response that earned one cent, or a risky response that would either gain 5 cents or lose 10 cents; odds of losing increased as the game progressed. We also examined those times when subjects experienced wins, or separately losses, from their risky choices. We contrasted decision trials against very similar comparison trials requiring no decisions, using whole-brain BOLD-response analyses of group differences, corrected for multiple comparisons. During decision-making ASD boys showed hypoactivation in numerous brain regions robustly activated by controls, including orbitofrontal and dorsolateral prefrontal cortices, anterior cingulate, basal ganglia, insula, amygdala, hippocampus, and cerebellum. While experiencing wins, ASD boys had significantly less activity than controls in anterior cingulate, temporal regions, and cerebellum, with more activity nowhere. During losses ASD boys had significantly more activity than controls in orbitofrontal cortex, dorsolateral prefrontal cortex, brain stem, and cerebellum, with less activity nowhere. Conclusions/Significance Adolescent boys with ASD had extensive neural hypoactivity during risky decision-making, coupled with decreased activity during reward and increased activity during loss. These neural patterns may underlie the dangerous, excessive, sustained risk-taking of such boys. The findings suggest that the dysphoria, reward insensitivity, and suppressed neural activity observed among older addicted persons also characterize youths early in the development of substance use disorders.

A randomized controlled trial of pemoline for attention-deficit/hyperactivity disorder in substance-abusing adolescents.

OBJECTIVE In adolescents with substance use disorder (SUD), comorbid attention-deficit/hyperactivity disorder (ADHD) is associated with greater severity of substance abuse, conduct problems, and worse treatment outcomes. Although many controlled trials have established the efficacy of psychostimulants, including pemoline, for ADHD in children and adolescents, none have been conducted in adolescents with SUD. This randomized, placebo-controlled trial, conducted between 1996 and 2000, evaluated the safety and efficacy of pemoline on substance abuse and conduct problems. METHOD Sixty-nine adolescents (aged 13-19) with conduct disorder (CD), SUD, and ADHD were recruited from the community and randomly assigned to a 12-week clinical trial of pemoline (n = 35) or placebo (n = 34), titrated over 4 weeks to a single morning dose of 75 to 112.5 mg as tolerated. RESULTS Pemoline had greater efficacy than placebo for ADHD as determined by significantly more Clinicians Global Impression-Improvement (CGI-I) ratings of 1 (very much improved) or 2 (much improved) at the study endpoint (n = 69; p <.05). There was also greater reduction in ADHD severity on the parent-rated Conners Hyperactivity-Impulsivity scale in pemoline-treated study completers compared to placebo-treated completers (pemoline, n = 17; placebo, n = 16; p <.01), but no difference between groups in the intent-to-treat analysis (n = 68; p <.13). Substance use did not decline in either group, and there was no difference between groups in baseline to study endpoint change in substance use or CD symptoms. Overall, pemoline was well tolerated, demonstrating a good safety profile and no elevation in liver enzyme levels. CONCLUSIONS Pemoline was efficacious for ADHD but did not have an impact on CD or substance abuse in the absence of specific treatment for SUD.

Randomized Controlled Trial of Osmotic-Release Methylphenidate with Cognitive-Behavioral Therapy in Adolescents with Attention-Deficit/Hyperactivity Disorder and Substance Use Disorders.

OBJECTIVE To evaluate the efficacy and safety of osmotic-release methylphenidate (OROS-MPH) compared with placebo for attention-deficit/hyperactivity disorder (ADHD), and the impact on substance treatment outcomes in adolescents concurrently receiving cognitive-behavioral therapy (CBT) for substance use disorders (SUD). METHOD This was a 16-week, randomized, controlled, multi-site trial of OROS-MPH + CBT versus placebo + CBT in 303 adolescents (aged 13 through 18 years) meeting DSM-IV diagnostic criteria for ADHD and SUD. Primary outcome measures included the following: for ADHD, clinician-administered ADHD Rating Scale (ADHD-RS), adolescent informant; for substance use, adolescent-reported days of use in the past 28 days. Secondary outcome measures included parent ADHD-RS and weekly urine drug screens (UDS). RESULTS There were no group differences on reduction in ADHD-RS scores (OROS-MPH: -19.2, 95% confidence interval [CI], -17.1 to -21.2; placebo, -21.2, 95% CI, -19.1 to -23.2) or reduction in days of substance use (OROS-MPH: -5.7 days, 95% CI, 4.0-7.4; placebo: -5.2 days, 95% CI, 3.5-7.0). Some secondary outcomes favored OROS-MPH, including lower parent ADHD-RS scores at 8 (mean difference = 4.4, 95% CI, 0.8-7.9) and 16 weeks (mean difference =6.9; 95% CI, 2.9-10.9) and more negative UDS in OROS-MPH (mean = 3.8) compared with placebo (mean = 2.8; p = .04). CONCLUSIONS OROS-MPH did not show greater efficacy than placebo for ADHD or on reduction in substance use in adolescents concurrently receiving individual CBT for co-occurring SUD. However, OROS-MPH was relatively well tolerated and was associated with modestly greater clinical improvement on some secondary ADHD and substance outcome measures. Clinical Trial Registration Information-Attention Deficit Hyperactivity Disorder (ADHD) in Adolescents with Substance Use Disorders (SUD); http://www.clinicaltrials.gov; NCT00264797.

Randomized, Controlled Trial of Atomoxetine for Attention-Deficit/Hyperactivity Disorder in Adolescents with Substance Use Disorder.

OBJECTIVE To evaluate the effect of atomoxetine hydrochloride versus placebo on attention-deficit/hyperactivity disorder (ADHD) and substance use disorder (SUD) in adolescents receiving motivational interviewing/cognitive behavioral therapy (MI/CBT) for SUD. METHOD This single-site, randomized, controlled trial was conducted between December 2005 and February 2008. Seventy adolescents (13 through 19 years of age) with Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) (DSM-IV) ADHD, a DSM-IV ADHD checklist score greater than or equal to 22, and at least one nontobacco SUD were recruited from the community. All subjects received 12 weeks of atomoxetine hydrochloride + MI/CBT versus placebo + MI/CBT. The main outcome measure for ADHD was self-report DSM-IV ADHD checklist score. For SUD, the main outcome was self-report number of days used nontobacco substances in the past 28 days using the Timeline Followback interview. RESULTS Change in ADHD scores did not differ between atomoxetine + MI/CBT and placebo + MI/CBT (F4,191 = 1.23, p = .2975). Change in days used nonnicotine substances in the last 28 days did not differ between groups (F3,100 = 2.06, p = .1103). CONCLUSIONS There was no significant difference between the atomoxetine + MI/CBT and placebo + MI/CBT groups in ADHD or substance use change. The MI/CBT and/or a placebo effect may have contributed to a large treatment response in the placebo group. Clinical Trials Registry Information-A Randomized, Placebo-Controlled Trial of Atomoxetine for Attention-Deficit/Hyperactivity Disorder in Adolescents with Substance Use Disorder. URL: http://www.clinicaltrials.gov. Unique identifier: NCT00399763.

Predictors of self-reported HIV infection among drug injectors in Ukraine.

ObjectiveTo identify characteristics, including current high-risk drug and sex behaviors, associated with self-reported HIV infection among injection drug users (IDUs) in Ukraine. DesignTargeted sampling of IDUs from Kiev, Odessa, and Makeevka/Donetsk, Ukraine. MethodsFrom June through August 2002, 100 IDUs from each site were recruited through street outreach, including 212 who had previously been tested for HIV and knew their serostatus. Subjects were administered a standardized computer-assisted interview assessing HIV-related drug and sex risk behaviors and history of HIV testing. ResultsTwenty six percent of the 212 participants reported they were HIV-positive. Univariate followed by multiple logistic regression analyses were used to identify factors associated with HIV infection. In the 30-day period before their interview, HIV-infected IDUs were significantly more likely to have injected with a needle previously used by another injector without disinfecting, frontloaded and/or backloaded, and shared the drug solution from a common container. In addition, they had higher prevalence rates for hepatitis B virus and hepatitis C virus than those not infected with HIV. On the other hand, they were more likely to have reported no sex partners and, if sexually active, more likely to have used a condom. ConclusionThe high HIV seroprevalence among IDUs in Ukraine, combined with their continued engagement in needle-related risk behaviors, assures the continuance of the epidemic in this region, a region that is the epicenter of HIV in Europe.

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 persons 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.

Default mode network activity in male adolescents with conduct and substance use disorder

BACKGROUND Adolescents with conduct disorder (CD) and substance use disorders (SUD) experience difficulty evaluating and regulating their behavior in anticipation of future consequences. Given the role of the brains default mode network (DMN) in self-reflection and future thought, this study investigates whether DMN is altered in adolescents with CD and SUD, relative to controls. METHODS Twenty adolescent males with CD and SUD and 20 male controls of similar ages underwent functional magnetic resonance imaging as they completed a risk-taking decision task. We used independent component analysis as a data-driven approach to identify the DMN spatial component in individual subjects. DMN activity was then compared between groups. RESULTS Compared to controls, patients showed reduced activity in superior, medial and middle frontal gyrus (Brodmann area (BA) 10), retrosplenial cortex (BA 30) and lingual gyrus (BA 18), and bilateral middle temporal gryus (BA 21/22) - DMN regions thought to support self-referential evaluation, memory, foresight, and perspective taking. Furthermore, this pattern of reduced activity in patients remained robust after adjusting for the effects of depression and attention-deficit hyperactivity disorder (ADHD). Conversely, when not adjusting for effects of depression and ADHD, patients demonstrated greater DMN activity than controls solely in the cuneus (BA 19). CONCLUSIONS Collectively, these results suggest that comorbid CD and SUD in adolescents is characterized by atypical activity in brain regions thought to play an important role in introspective processing. These functional imbalances in brain networks may provide further insight into the neural underpinnings of conduct and substance use disorders.

Predictors of risky needle use following interventions with injection drug users in Ukraine

This study was designed to assess factors associated with change in needle-related risk behaviors as well as predictors of continued high-risk behavior following intervention efforts among injection drug users (IDUs) in Ukraine. In each of three locations--Kiev, Odessa, and Makeevka/Donesk--100 IDUs were recruited using modified targeted sampling methods. Following a baseline interview, participants were offered free HIV testing and, over the course of the next 5 months, individualized interventions focusing on reducing HIV-related risk behaviors. Former IDUs conducted interventions through street outreach. The intervention model was based on the Indigenous Leader Outreach Model (ILOM) and stressed assessing an individuals unique risks and developing strategies by which to minimize those risks. Follow-up assessments showed significant reductions in every risk behavior measured. Following the intervention, however, approximately one of four participants reported front- or backloading, using drugs obtained from a common container or injecting with a used needle/syringe. Although the sample as a whole averaged only 28 years of age, those who were younger were significantly more likely to engage in each of these behaviors than those who were older. In light of the overall young age of the Ukrainian IDUs observed in this study, the consistent finding that younger IDUs were at highest risk foreshadows a worsening HIV epidemic in Ukraine.

Conduct Disorder and Initiation of Substance Use: A Prospective Longitudinal Study

OBJECTIVE To examine the influence of conduct disorder (CD) on substance use initiation. METHOD Community adolescents without CD (n = 1,165, mean baseline age = 14.6 years), with CD (n = 194, mean baseline age = 15.3 years), and youth with CD recruited from treatment (n = 268, mean baseline age = 15.7 years) were prospectively followed and re-interviewed during young adulthood (mean ages at follow-up respectively: 20, 20.8, and 24). Young adult retrospective reports of age of substance initiation for 10 substance classes were analyzed using Cox regression analyses. Hazard ratios of initiation for the CD cohorts (community without CD as the reference) at ages 15, 18, and 21 were calculated, adjusting for baseline age, gender, and race/ethnicity. RESULTS Among community subjects, CD was associated with elevated adjusted hazards for initiation of all substances, with comparatively greater hazard ratios of initiating illicit substances at age 15 years. By age 18, the adjusted hazard ratios remained significant except for alcohol. At age 21, the adjusted hazard ratios were significant only for cocaine, amphetamines, inhalants, and club drugs. A substantial portion of community subjects without CD never initiated illicit substance use. Clinical youth with CD demonstrated similar patterns, with comparatively larger adjusted hazard ratios. CONCLUSIONS CD confers increased risk for substance use initiation across all substance classes at age 15 years, with greater relative risk for illicit substances compared to licit substances. This effect continues until age 18 years, with the weakest effect for alcohol. It further diminishes for other substances by age 21, However, the likelihood of initiating cocaine, amphetamines, inhalants and club drug use among those who have not initiated yet continues to be highly elevated by age 21.

Insula and Orbitofrontal Cortical Morphology in Substance Dependence Is Modulated by Sex

BACKGROUND AND PURPOSE: Frontolimbic circuits are involved in learning and decision-making processes thought to be affected in substance-dependent individuals. We investigated frontolimbic cortical morphometry in substance-dependent men and women and determined whether morphometric measurements correlated with decision-making performance. MATERIALS AND METHODS: Twenty-eight abstinent SDI (17 men/11 women) were compared with 28 controls (13 men/15 women). Cortical thicknesses and volumes were computed by using FreeSurfer. After controlling for age and intracranial volume, group and sex effects were analyzed in 3 a priori regions of interest: the insula, orbitofrontal cortex, and anterior cingulate cortex by using analysis of covariance. A secondary whole-brain analysis was conducted to verify region-of-interest results and to explore potential differences in other brain regions. RESULTS: Region-of-interest analyses revealed a main effect of group on the left insula cortex, which was thinner in SDI compared with controls (P = .02). There was a group by sex interaction on bilateral insula volume (left, P = .02; right, P = .001) and right insula cortical thickness (P = .007). Compared with same-sex controls, female SDI had smaller insulae, whereas male SDI had larger insulae. Neither ACC nor OFC significantly differed across group. Performance on a decision-making task was better in controls than SDI and correlated with OFC measurements in the controls. CONCLUSIONS: SDI and controls differed in insula morphology, and those differences were modulated by sex. No group differences in OFC were observed, but OFC measurements correlated with negative-reinforcement learning in controls. These preliminary results are consistent with a hypothesis that frontolimbic pathways may be involved in behaviors related to substance dependence.