Striatal bases of temporal discounting in early adolescents.

Steeper rates of temporal discounting-the degree to which smaller-sooner (SS) rewards are preferred over larger-later (LL) ones-have been associated with impulsive and ill-advised behaviors in adolescence. Yet, the underlying neural systems remain poorly understood. Here we used a well-established temporal discounting paradigm and functional MRI (fMRI) to examine engagement of the striatum-including the caudate, putamen, and ventral striatum (VS)-in early adolescence (13-15 years; N = 27). Analyses provided evidence of enhanced activity in the caudate and VS during impulsive choice. Exploratory analyses revealed that trait impulsivity was associated with heightened putamen activity during impulsive choices. A more nuanced pattern was evident in the cortex, with the dorsolateral prefrontal cortex mirroring the putamen and posterior parietal cortex showing the reverse association. Taken together, these observations provide an important first glimpse at the distributed neural systems underlying economic choice and trait-like individual differences in impulsivity in the early years of adolescence, setting the stage for prospective-longitudinal and intervention research.

Open-label dose-extending placebos for opioid use disorder: a protocol for a randomised controlled clinical trial with methadone treatment.

INTRODUCTION: More than 2 million individuals in the USA have an opioid use disorder (OUD). Methadone maintenance treatment is the gold standard of medication-based treatment for OUD, but high-dose methadone is associated with cardiotoxicity and respiratory complications, among other side effects. These adverse effects make enhancing the effectiveness of lower doses of methadone an attractive therapeutic goal. Long recognised for its capacity to enhance treatment outcomes for a wide range of neuropsychiatric disorders including pain, the placebo effect offers an as-yet untested avenue to such an enhancement. This approach is particularly compelling given that individuals with substance use disorder tend to have higher salience attribution and may thereby be more sensitive to placebo effects. Our study combines two promising clinical methodologies-conditioning/dose-extension and open-label placebo-to investigate whether placebo effects can increase the effective potency of methadone in treatment-seeking OUD patients. METHODS AND ANALYSIS: A total of 120 newly enrolled treatment-seeking OUD patients will be randomly assigned to one of two different groups: either methadone plus daily placebo dose-extension (PDE; treatment group) or methadone/treatment as usual (control). Participants will meet with study team members five times over the course of 3 months of treatment with methadone (baseline, 2 weeks, and 1, 2 and 3 months postbaseline). Throughout this study time period, methadone dosages will be adjusted by an addiction clinician blind to patient assignment, per standard clinical methods. The primary outcome is methadone dose at 3 months. Secondary outcomes include self-report of drug use; 3-month urine toxicology screen results; and treatment retention. Exploratory outcomes include several environmental as well as personality factors associated with OUD and with propensity to demonstrate a placebo effect. ETHICS AND DISSEMINATION: Human subjects oversight for this study is provided by the University of Maryland, Baltimore and University of Maryland, College Park Institutional Review Boards. Additionally, the study protocol is reviewed annually by an independent Data and Safety Monitoring Board. Study results will be disseminated via research conference presentations and peer-reviewed publications. TRIAL REGISTRATION NUMBER: NCT02941809.

Trait impulsivity during early adolescence predicts steepness of alcohol use escalation across adolescence.

BACKGROUND AND AIMS: Alcohol use during adolescence is a significant public health concern with serious implications. Both early initiation and rate of escalation of alcohol use during adolescence forecast long-term alcohol-related difficulties and alcohol use disorders (AUDs), underscoring the need to understand psychological factors that contribute to these risk behaviors. One factor that contributes to alcohol use during adolescence is trait impulsivity. The purpose of the present prospective study was to examine associations between trait impulsivity and changes in alcohol use from early adolescence through late adolescence. METHODS: Two hundred forty-six participants (45% female; M age = 13.06; 52.5% Caucasian ethnicity) were drawn from a larger study. Levels of impulsivity and alcohol use were measured at every assessment using self-report questionnaires. Data were analyzed using a latent growth modeling approach (LGM) and fit was examined across four indices. RESULTS: Consistent with previous studies, our findings indicate that trait impulsivity decreased and alcohol use increased during adolescence, and initial levels of impulsivity were associated with concurrent levels of alcohol use. Further, level of trait impulsivity during early adolescence predicted the rate of escalation of alcohol use during adolescence. CONCLUSIONS: In the present research, trait impulsivity assessed during early adolescence predicted the steepness of alcohol use escalation during adolescence, a variable with significant prognostic value for long-term AUDs and behavioral problems. This research underscores the importance of understanding trait impulsivity during early adolescence, and suggests that early trait impulsivity may have predictive value with respect to later alcohol abuse and behavioral problems.

White-matter crossing-fiber microstructure in adolescents prenatally exposed to cocaine.

BACKGROUND: Prenatal cocaine exposure (PCE) is associated with risk-taking behaviors, including increased initiation of substance use in adolescence. The neurobiological underpinnings of these behaviors in adolescents with PCE are not well understood. The goal of this study was to compare diffusion-weighted imaging data between adolescents with and without PCE using crossing-fiber models, which may provide more comprehensive estimates of white-matter microstructure within regions of multiple (e.g., primary and secondary) fiber orientations. METHODS: Thirty-nine PCE individuals and 17 comparably aged prenatally non-drug-exposed (NDE) youths were recruited from a longitudinal cohort followed since birth. White matter was examined using tensor-derived and crossing-fiber models. Whole-brain investigations were performed, as were analyses on seven white-matter regions, which included the splenium, body and genu of the corpus callosum, bilateral cingulum, and the right and left superior longitudinal fasciculus (SLF). RESULTS: Whole-brain analyses revealed no group differences. However, ROI analyses for anisotropy estimates derived from the crossing-fiber model revealed significant group differences for secondary fibers, with reduced anisotropy among PCE adolescents compared to prenatally non-exposed youth in the right cingulum and the left SLF, and increased anisotropy in the genu. CONCLUSIONS: Our findings suggest that white-matter differences in PCE adolescents are subtle and localized primarily within secondary fiber orientations, perhaps arising from altered white-matter development.

Rapid-response impulsivity: definitions, measurement issues, and clinical implications.

Impulsivity is a multifaceted construct that is a core feature of multiple psychiatric conditions and personality disorders. However, progress in understanding and treating impulsivity is limited by a lack of precision and consistency in its definition and assessment. Rapid-response impulsivity (RRI) represents a tendency toward immediate action that occurs with diminished forethought and is out of context with the present demands of the environment. Experts from the International Society for Research on Impulsivity (InSRI) met to discuss and evaluate RRI measures in terms of reliability, sensitivity, and validity, with the goal of helping researchers and clinicians make informed decisions about the use and interpretation of findings from RRI measures. Their recommendations are described in this article. Commonly used clinical and preclinical RRI tasks are described, and considerations are provided to guide task selection. Tasks measuring two conceptually and neurobiologically distinct types of RRI, "refraining from action initiation" (RAI) and "stopping an ongoing action" (SOA) are described. RAI and SOA tasks capture distinct aspects of RRI that may relate to distinct clinical outcomes. The InSRI group recommends that (a) selection of RRI measures should be informed by careful consideration of the strengths, limitations, and practical considerations of the available measures; (b) researchers use both RAI and SOA tasks in RRI studies to allow for direct comparison of RRI types and examination of their associations with clinically relevant measures; and (c) similar considerations be made for human and nonhuman studies in an effort to harmonize and integrate preclinical and clinical research.

Choice impulsivity: Definitions, measurement issues, and clinical implications.

Impulsivity critically relates to many psychiatric disorders. Given the multifaceted construct that impulsivity represents, defining core aspects of impulsivity is vital for the assessment and understanding of clinical conditions. Choice impulsivity (CI), involving the preferential selection of smaller sooner rewards over larger later rewards, represents one important type of impulsivity. The International Society for Research on Impulsivity (InSRI) convened to discuss the definition and assessment of CI and provide recommendations regarding measurement across species. Commonly used preclinical and clinical CI behavioral tasks are described, and considerations for each task are provided to guide CI task selection. Differences in assessment of CI (self-report, behavioral) and calculating CI indices (e.g., area-under-the-curve, indifference point, and steepness of discounting curve) are discussed along with properties of specific behavioral tasks used in preclinical and clinical settings. The InSRI group recommends inclusion of measures of CI in human studies examining impulsivity. Animal studies examining impulsivity should also include assessments of CI and these measures should be harmonized in accordance with human studies of the disorders being modeled in the preclinical investigations. The choice of specific CI measures to be included should be based on the goals of the study and existing preclinical and clinical literature using established CI measures.

Brief report: The interaction of impulsivity with risk-taking is associated with early alcohol use initiation.

Early alcohol use initiation is a well-established risk factor for the subsequent development of alcohol abuse and dependence. Separate lines of research indicate that impulsivity and risk-taking each are associated with early alcohol use. In this research, the association of the interaction of risk-taking and impulsivity with early alcohol initiation was examined. Results suggest the interaction between impulsivity and risk-taking was related to early alcohol initiation. Among children with lower levels of risk-taking, level of impulsivity was associated with beginning to drink. By contrast, among children with higher levels of risk-taking, level of impulsivity was not associated with the likelihood of initiating alcohol use. These findings suggest that early adolescence is a critical developmental period in which implementing an intervention to reduce impulsivity and risk-taking may be particularly effective to prevent the early initiation of alcohol use.

Environmental enrichment attenuates nicotine behavioral sensitization in male and female rats.

Environmental enrichment decreases nicotine reactivity in male rats, but these effects have not been examined in females. This research was conducted to examine the effects of enrichment on nicotine behavioral sensitization (i.e., nicotine reactivity) in male and female rats. One hundred forty-four Sprague-Dawley rats (72 male, 72 female) were raised in isolation, social enrichment (groups of three rats [SE]), or combined physical enrichment and social enrichment (groups of three rats with novel toys [PESE]) housing conditions. As adults, they received daily subcutaneous injections of saline or nicotine (0.1, 0.5, or 1.0 mg/kg) for 12 days; locomotor activity was measured on drug days 1, 5, 9, and 12. Before drug administration, PESE and SE decreased activity in males; only PESE decreased activity in females, F(2, 120) = 6.51, p < .01. In the drug phase, nicotine behavioral sensitization occurred, F(8.46, 341.04) = 20.71, p < .001, and was greater in females than males, F(8.340, 319.715) = 2.072, p < .05. Enrichment decreased nicotine behavioral sensitization in both sexes, F(16.91, 341.04) = 2.48, p < .01. In conclusion, nicotine behavioral sensitization occurred in male and female rats and was attenuated by environmental enrichment. This research has implications for treatment and prevention strategies in humans. Programs that incorporate aspects of social and environmental stimulation may have enhanced effectiveness in preventing and reducing cigarette smoking and may have implications for relapse prevention.

Lewis rats have greater response impulsivity than Fischer rats.

Impulsivity, a tendency toward immediate action without consideration of future consequences, is associated with a wide array of problematic behaviors. Response impulsivity, a type of behaviorally-assessed impulsivity characterized by behavioral disinhibition, is also associated with health risk behaviors. Response impulsivity is distinct from choice impulsivity, which is characterized by intolerance for delay. Lewis rats have higher levels of choice impulsivity than Fischer rats (Anderson & Woolverton, 2005; Madden et al., 2008; Stein et al., 2012). However, no studies have examined whether Lewis and Fischer rats have different levels of response impulsivity. The present research examined response impulsivity in the two rat strains. Subjects were 16 male Lewis and Fischer rats. Rats' response impulsivity was measured using the Five Choice Serial Reaction Time Task (5-CSRTT). In addition, their locomotor activity was measured in locomotor activity chambers. Lewis rats had more premature responses than Fischer rats during the 5-CSRTT assessment [F(1, 14)=5.34, p<0.05], indicating higher levels of response impulsivity. Locomotor activity did not differ between rat strain groups [F(1, 14)=3.05, p=.10], suggesting that overall movement did not account for group differences in response impulsivity on the 5-CSRTT. It can be concluded from this research that Lewis rats have higher levels of response impulsivity than Fischer rats, and therefore provide a valid rat model of individual differences in impulsivity.

Self-reported impulsivity, but not behavioral approach or inhibition, mediates the relationship between stress and self-control.

Stress has been associated with poor self-control. Individual differences in impulsivity and other behavioral tendencies may influence the relationship of stress with self-control, although this possibility has not been examined to date. The present research investigated whether cumulative stress is associated with poor self-control, and whether this relationship is mediated by impulsivity, behavioral approach, and behavioral inhibition in men and women. A community sample of 566 adults (319 women and 247 men) was assessed on the Cumulative Adversity Interview, Brief Self-control Scale, Barratt Impulsivity Scale, and Behavioral Activation System and Behavioral Inhibition System Scale (BIS/BAS). Data were analyzed using regression and bootstrapping techniques. In the total sample, the effects of cumulative stress on self-control were mediated by impulsivity. Neither behavioral inhibition nor behavioral approach mediated the association between cumulative stress and self-control in the total sample. Results were similar when men and women were considered separately, with impulsivity, but not behavioral inhibition or approach, mediating the association between cumulative stress and self-control. Impulsive individuals might benefit preferentially from interventions focusing on stress management and strategies for improving self-control.

Self-reported impulsivity, but not behavioral choice or response impulsivity, partially mediates the effect of stress on drinking behavior.

Stress and impulsivity contribute to alcohol use, and stress may also act via impulsivity to increase drinking behavior. Impulsivity represents a multi-faceted construct and self-report and behavioral assessments may effectively capture distinct clinically relevant factors. The present research investigated whether aspects of impulsivity mediate the effect of stress on alcohol use. A community-based sample of 192 men and women was assessed on measures of cumulative stress, alcohol use, self-reported impulsivity, and behavioral choice and response impulsivity. Data were analyzed using regression and bootstrapping techniques to estimate indirect effects of stress on drinking via impulsivity. Cumulative adversity exhibited both direct effects and indirect effects (via self-reported impulsivity) on drinking behavior. Additional models examining specific types of stress indicated direct and indirect effects of trauma and recent life events, and indirect effects of major life events and chronic stressors on drinking behavior. Overall, cumulative stress was associated with increased drinking behavior, and this effect was partially mediated by self-reported impulsivity. Self-reported impulsivity also mediated the effects of different types of stress on drinking behavior. These findings highlight the value of mediation models to examine the pathways through which different types of stress increase drinking behavior. Treatment and prevention strategies should focus on enhancing stress management and self-control.

Nicotine behavioral sensitization in Lewis and Fischer male rats.

Individuals with greater nicotine-reactivity may be more likely to initiate and maintain cigarette-smoking behavior than individuals with less nicotine-reactivity. In rats, behavioral sensitization reflects a progressive increase in the psychomotor response to drugs of abuse thought to result from neuroplasticity in brain regions that mediate their motivational effects. Studying nicotine behavioral sensitization in rats with differential nicotine preference and intake, such as Lewis and Fischer rats, may provide clues about the role of nicotine-reactivity in tobacco use. Rat strain differences in nicotine behavioral sensitization may contribute to strain differences in nicotine preference, sensitivity, and intake. In the present research, nicotine behavioral sensitization to multiple doses was examined in Lewis and Fischer rats. Subjects were 96 late adolescent male (48 Fischer, 48 Lewis) rats. Rats received subcutaneous injections of nicotine (0.2, 0.4, 0.7, 1.4, 2.8 mg/kg) or saline daily, and locomotor activity was measured immediately following injections on alternating days to examine sensitization. Behavioral sensitization occurred in both rat strains at the 0.2, 0.4, 0.7, and 1.4 mg/kg nicotine doses, but did not differ between Lewis and Fischer rats. The pattern of horizontal activity that occurred in response to the 2.8 mg/kg nicotine dose did not reflect behavioral sensitization. Results indicate that nicotine behavioral sensitization occurred in Lewis and Fischer rats, and did not differ between the two rat strains. It can be concluded that reported rat strain differences in nicotine intake, sensitivity, and preference do not result from rat strain differences in nicotine behavioral sensitization.

Hazardous drinking and dimensions of impulsivity, behavioral approach, and inhibition in adult men and women.

INTRODUCTION: Hazardous drinking is characterized by decisions to engage in excessive or risky patterns of alcohol consumption. Levels of impulsivity and behavioral approach and inhibition may differ in hazardous drinkers and nonhazardous drinkers. A comparison of the relative levels of dimensions of impulsivity and behavioral inhibition and approach in adult men and women hazardous and nonhazardous drinkers may inform treatment and prevention efforts. METHODS: In the present research, 466 men and women from a community sample were administered the Alcohol Use Disorders Identification Test (AUDIT), the Behavioral Inhibition System/Behavioral Approach System (BIS/BAS) scale, and the Barratt Impulsiveness Scale, version 11 (BIS-11). Relations among the dimensions of these constructs were examined using multivariate analysis of covariance (MANCOVA), with age and race as covariates. RESULTS: There were main effects of hazardous drinking on all 3 dimensions of impulsivity, the behavioral inhibition system, and the behavioral activation system Reward Responsiveness, and Fun-Seeking components, with hazardous drinkers scoring higher than nonhazardous drinkers. CONCLUSIONS: This research provides a better understanding of the manner in which impulsivity and behavioral inhibition and approach tendencies relate to hazardous alcohol use in men and women. The present results have implications for alcohol-related prevention and treatment strategies for adult men and women.

Relations among delay discounting, addictions, and money mismanagement: implications and future directions.

BACKGROUND: Delay discounting is a reduction in the subjective value of a delayed outcome. Elevated delay discounting is a type of impulsivity that is associated with harmful behaviors, including substance abuse and financial mismanagement. METHODS: Elevated delay discounting as related to addiction and financial mismanagement was reviewed from psychological, neurobiological, and behavioral economic perspectives. RESULTS: Addiction and financial mismanagement frequently co-occur, and elevated delay discounting may be a common mechanism contributing to both of these problematic behaviors. CONCLUSIONS: Future research on the relationships between delay discounting, substance abuse, and financial mismanagement can provide important insights for developing improved prevention and treatment strategies.

Behavioral effects of nicotine withdrawal differ by genetic strain in male and female adolescent rats.

INTRODUCTION: Gender and ethnicity are powerful predictors of initiation and maintenance of cigarette smoking in adults but less is known about their role in smoking in adolescents. Consistent with human studies, rat models also reveal sex and strain differences in response to nicotine administration. METHODS: This research examined nicotine withdrawal behaviors in 96 adolescent, male and female, Sprague Dawley (SD) and Long Evans (LE) rats. Rats received seven days continuous subcutaneous infusion of saline or 3.16 mg/kg nicotine via Alzet osmotic minipumps. Behavioral observations were made before, during, and after saline or nicotine administration. Occurrences of six specific behaviors were quantified: abnormal posture or movement, abnormal grooming, whole-body shakes, ptosis, empty-mouth chewing/teeth chattering, and diarrhea. RESULTS: SD male and female rats that received nicotine displayed significantly more withdrawal behaviors 1 and 2 days after cessation of nicotine administration compared with rats that had received saline. LE male rats that received nicotine displayed significantly more withdrawal behaviors 1 day but not 2 days after cessation of nicotine administration compared with males that received saline. LE females showed no significant withdrawal behaviors after cessation of nicotine administration. CONCLUSION: Results indicate that nicotine withdrawal in adolescent rats depends on sex and strain.

Behavioral effects of nicotine withdrawal in adult male and female rats.

Nicotine withdrawal may differ between men and women but clinical reports are inconsistent. Two experiments were conducted to examine behavioral effects of nicotine withdrawal in male and female adult rats in dimly-lit and brightly-lit environments. Ninety-six Sprague-Dawley male and female rats received 7 days continuous subcutaneous infusion via ALZET osmotic minipumps filled with saline or 3.16 mg/kg/day nicotine hydrogen tartrate expressed as base. Behavioral observations were made before, during, and after drug administration. During observations, occurrences of empty-mouth-chewing, whole-body-shakes, abnormal grooming, abnormal posture/movement, diarrhea, ptosis, eyeblinks, and any other abnormal behaviors were counted. Cessation of nicotine administration upon pump removal caused a significant increase in withdrawal behaviors in males and females in both environments. In the dimly-lit environment, females showed more withdrawal behavior than males; there was no sex difference in the brightly-lit environment. Males that had received nicotine displayed more withdrawal behavior in the brightly-lit environment than in the dimly-lit environment, while females that had received nicotine displayed similar amounts of withdrawal behavior in both environments. Behavioral symptoms of withdrawal may be more affected by the environment in male rats than in female rats. These experiments are the first to compare nicotine withdrawal in adult male and female rats.