Hollis C. Karoly

Genetic Influences on Physiological and Subjective Responses to an Aerobic Exercise Session among Sedentary Adults

Objective. To determine whether genetic variants suggested by the literature to be associated with physiology and fitness phenotypes predicted differential physiological and subjective responses to a bout of aerobic exercise among inactive but otherwise healthy adults. Method. Participants completed a 30-minute submaximal aerobic exercise session. Measures of physiological and subjective responding were taken before, during, and after exercise. 14 single nucleotide polymorphisms (SNPs) that have been previously associated with various exercise phenotypes were tested for associations with physiological and subjective response to exercise phenotypes. Results. We found that two SNPs in the FTO gene (rs8044769 and rs3751812) were related to positive affect change during exercise. Two SNPs in the CREB1 gene (rs2253206 and 2360969) were related to change in temperature during exercise and with maximal oxygen capacity (VO2 max). The SLIT2 SNP rs1379659 and the FAM5C SNP rs1935881 were associated with norepinephrine change during exercise. Finally, the OPRM1 SNP rs1799971 was related to changes in norepinephrine, lactate, and rate of perceived exertion (RPE) during exercise. Conclusion. Genetic factors influence both physiological and subjective responses to exercise. A better understanding of genetic factors underlying physiological and subjective responses to aerobic exercise has implications for development and potential tailoring of exercise interventions.

Does incentive-elicited nucleus accumbens activation differ by substance of abuse? An examination with adolescents

Highlights • We measure brain activation during anticipation of reward and loss in adolescents.• We compare incentive responses in six groups formed based on substance use patterns.• No activation differences emerge between the cannabis-only group and the other groups.• Tobacco-only users have less reward response than polysubstance and alcohol-only users.• Tobacco-only users show decreased reward activation compared to the control group.

Substance use disorders: a theory-driven approach to the integration of genetics and neuroimaging.

The etiology of substance use disorders is related to changes in neuronal systems involved in reward anticipation, negative affect, and withdrawal, as well as to alterations in inhibition and executive control. Genetic and epigenetic variation associated with individual differences in these mechanisms may be important for predicting the effectiveness of current treatments and informing future pharmacogenomic investigations. Genetic research efforts have increasingly involved the use of approaches that leverage neurobiological phenotypes to link changes at the molecular level (e.g., genetic and epigenetic variation) to changes in intermediate neuroimaging phenotypes, and ultimately to clinical outcomes. The current review summarizes recent efforts that utilize neuroimaging and genetic approaches in the context of a three‐stage model of addiction. In addition, this review explores how these approaches have been used to study the progression from impulsive, recreational substance use to the compulsive, addicted state. Finally, this review describes future ways that research may incorporate these approaches to examine important stage‐specific mechanisms of addiction.

Evaluating the Hispanic Paradox in the Context of Adolescent Risky Sexual Behavior: The Role of Parent Monitoring

OBJECTIVE In the United States, Hispanic adolescents are at elevated risk for negative outcomes related to risky sexual behavior. To evaluate potential protective factors for this group, we examined the fit of the Hispanic Paradox for sexual behavior among high-risk youth and the moderating role of parent monitoring. METHOD We enrolled 323 justice-involved Hispanic youth (73% male; mean age 16 years), and measured generational status, parent monitoring (monitoring location, who children spend time with outside of school, family dinner frequency), and sexual risk behavior. RESULTS There were no main effects for generational status on sexual behavior. Parent monitoring of location moderated the relationship between generational status and sexual behavior, such that greater monitoring of location was associated with less risky sexual behavior, but only for youth second generation and above. CONCLUSIONS Rather than direct evidence supporting the Hispanic Paradox, we found a more nuanced relationship for generational status in this sample.

Aerobic Exercise Moderates the Effect of Heavy Alcohol Consumption on White Matter Damage

BACKGROUND Chronic alcohol abuse is related to numerous deleterious neurobiological consequences, including loss of gray matter, damage to white matter (WM), and impairment of cognitive and motor functions. Aerobic exercise has been demonstrated to slow cognitive decline and decrease the negative neural changes resulting from normal aging and from several diseases. It is possible that exercise may also prevent or repair alcohol-related neurological damage. This study tested the hypothesis that aerobic exercise protects WM in anterior and dorsal areas of the brain from damage related to heavy alcohol use. METHODS Sixty individuals underwent a diffusion tensor imaging session and completed measures of alcohol consumption, loss of control over drinking, and aerobic exercise participation. Analyses examined the relationship of exercise, alcohol, and their interaction to fractional anisotropy (FA) in the superior longitudinal fasciculus (SLF), external capsule (EC), superior and anterior corona radiata, and fornix. The relationship of aerobic exercise and alcohol consumption to self-reported loss of control over drinking were also examined. RESULTS A significant interaction was observed between alcohol consumption and aerobic exercise participation on FA in the SLF and EC. In the models examining loss of control over drinking, a significant interaction between aerobic exercise and alcohol consumption was observed, such that alcohol consumption was associated with loss of control more strongly for low exercisers than high exercisers. CONCLUSIONS These results indicate that the association between heavy alcohol consumption and WM damage in the EC and SLF and the association between alcohol consumption and loss of control over drinking are greater among individuals who do not exercise regularly. These results are consistent with the notion that exercise may protect WM integrity from alcohol-related damage.

Deconstructing the Neural Substrates of Motivational Interviewing: A New Look at an Unresolved Question

The evaluation of substance use disorder (SUD) treatment mechanisms is rapidly becoming an area of great interest and importance (Potenza et al., 2011; Hutchison, 2010). However, only a few innovative studies have empirically evaluated how psychotherapy influences the brain, how brain-based factors influence psychotherapy response (Stanger et al., 2013), and how the brain changes as a result of behavioral interventions (DeVito et al., 2012; Kober et al., in press; Vollstadt-Klein et al., 2011). Despite its widespread prevalence as a treatment approach across addiction (Lundahl et al., 2010; Rubak et al., 2005; Jensen et al., 2011a) and other health behaviors (Vanbuskirk & Wetherell, in press), fewer studies have evaluated these brain-behavioral relationships in the context of Motivational Interviewing (MI; Miller & Rollnick, 2013).

Interactions between TLR4 methylation and alcohol consumption on subjective responses to an alcohol infusion

Aims Converging evidence has implicated perturbed inflammatory signaling in alcohol use disorders (AUDs), and both animal and human studies suggest that alcohol-induced inflammatory signaling is mediated by Toll-Like Receptor 4 (TLR4). We previously demonstrated that TLR4 is hypermethylated in subjects with AUD compared to control individuals. Examining the relationship between TLR4 methylation and subjective alcohol responses could shed light on the role of TLR4 in promoting AUDs, thereby highlighting its potential as a treatment target. Short summary Significant interactions were demonstrated between Toll-like Receptor 4 (TLR4) methylation and human alcohol consumption patterns, such that greater methylation was associated with decreased positive and negative self-reported arousal during an alcohol infusion among light-to-moderate drinkers, but increased self-reported positive arousal and physiological arousal (i.e. systolic blood pressure) among heavy drinkers. Methods Latent growth models were used to examine the relationship between TLR4 methylation and subjective responses and physiological measures of arousal during an alcohol infusion across 222 drinkers. Results We observed significant interactions of TLR4 methylation and alcohol use (drinks per week) on intercepts for self-report and physiological arousal measures. Specifically, light-to-moderate drinkers had positive associations between methylation and stimulation and tension (rs = 0.21-0.24), and heavy drinkers had negative associations (rs = -0.15 to -0.21). There were also significant interaction effects on changes in tension (β = 0.31, P < 0.01), systolic blood pressure (β = 0.74, P < 0.01) and marginal effects on stimulation (β = 0.15, P = 0.07) during the infusion, such that methylation was associated with decreased arousal among light-to-moderate drinkers (rs = -0.12 to -0.25) but stable or increased arousal among heavy drinkers (rs = 0.05-0.19). Conclusions Findings suggest that the relationship between TLR4 methylation and subjective and physiological arousal during acute alcohol intoxication depends upon on self-reported alcohol use. These data demonstrate the influence of TLR4 on subjective responses to alcohol, thereby supporting the need for further research on its potential as a pharmacological treatment target.

ADHD symptoms impact smoking outcomes and withdrawal in response to Varenicline treatment for smoking cessation

INTRODUCTION Attention-Deficit/Hyperactivity Disorder (ADHD) is associated with nicotine dependence and difficulty quitting smoking. Few cessation trials specifically consider the impact of ADHD on treatment outcomes, including those testing established pharmacological therapies, such as varenicline. METHODS The current study focused on the impact of pretreatment ADHD inattention (IN) and hyperactivity-impulsivity (HI) symptoms on treatment outcome in a randomized controlled trial of varenicline [N=205, average age=34.13(10.07), average baseline cigarettes per day=14.71(7.06)]. Given that vareniclines putative therapeutic mechanism is attenuation of withdrawal severity during abstinence, we also tested changes in withdrawal as a mediator of treatment effects in high and low ADHD groups. RESULTS ADHD symptom severity in this sample was in the subclinical range. Cessation was associated with HI, but not IN, such that high HI individuals on varenicline reported the lowest smoking levels at the end of treatment across all groups (3.06cig/day for high HI vs 4.02cig/day for low HI). Individuals with high HI who received placebo had the highest smoking at the end of treatment (7.69cigs/day for high HI vs 5.56cig/day for low HI). Patterns continued at follow-up. Varenicline significantly reduced withdrawal for those with high HI, but not low HI. However, path models did not support an indirect effect of medication on reducing smoking via withdrawal in either group, suggesting that unmeasured variables are involved in vareniclines effect on reducing smoking. CONCLUSIONS These data add to a gap in the smoking cessation literature regarding the impact of ADHD symptoms on the efficacy and mechanisms of frontline pharmacological treatments.

Erratum to: Developing Neurobiological Endophenotypes that Reflect Failure to Control Alcohol Consumption and Dependence

This progression is accompanied by neurobiological adaptations that promote the addicted state. Recently, Karoly and colleagues [52] have extended the three-stage theoretical model to demonstrate the shifting imbalance between reward and control networks across each stage of the addiction cycle; as an individual progresses from recreational use to an addicted (dependent) neural state. Briefly, the extended model states that during stage 1 (i.e., binge/intoxication), the reward network seems to be dysregulated with repeated drug use, such that responses to drug-related rewards increase, whereas the incentive value of natural reinforcers decreases [4, 27, 74, 88]. Repeated drug use is associated with an increase in connectivity between regions involved in negative affect and withdrawal [13, 68, 75, 99]. These changes lead to a downstream strengthening of reward areas in response to drug related cues, and concurrent weakening of control regions [45, 108], which serve to perpetuate compulsive substance use, characteristic of the preoccupation/anticipation stage. An example of an endophenotype derived from the three-stage model might involve targeting neurobiological adaptations characteristic of the withdrawal/negative affect stage, and might measure brain activation in response to visual alcohol cues among heavy drinkers undergoing acute or protracted withdrawal [52]. Additional work should implement cue-elicited craving paradigms among individuals experiencing acute or protracted alcohol withdrawal, to examine the role of craving and reward-responsivity during the withdrawal/negative affect stage.

DRD2 promoter methylation and measures of alcohol reward: functional activation of reward circuits and clinical severity: DRD2 methylation and alcohol

Studies have identified strong associations between D2 receptor binding potential and neural responses to rewarding stimuli and substance use. Thus, D2 receptor perturbations are central to theoretical models of the pathophysiology of substance dependence, and epigenetic changes may represent one of the fundamental molecular mechanisms impacting the effects of alcohol exposure on the brain. We hypothesized that epigenetic alterations in the promoter region of the dopamine D2 receptor (DRD2) gene would be associated with cue‐elicited activation of neural reward regions, as well as severity of alcohol use behavior. The current study leveraged functional neuroimaging (fMRI) during an alcohol reward paradigm (n = 383) to test associations among DRD2 promoter methylation in peripheral tissue, signal change in the striatum during the presentation of alcohol cues, and severity of alcohol use disorder (AUD). Controlling for age, DRD2 promoter methylation was positively associated with responses to alcohol cues in the right accumbens (partial r = 0.144, P = 0.005), left putamen (partial r = 0.133, P = 0.009), right putamen (partial r = 0.106, P = 0.039), left caudate (partial r = 0.117, P = 0.022), and right caudate (partial r = 0.133, P = 0.009), suggesting that DRD2 methylation was positively associated with robust activation in the striatum in response to reward cues. DRD2 methylation was also positively associated with clinical metrics of AUD severity. Specifically, controlling for age, DRD2 methylation was associated with Alcohol Use Disorders Identification Test total (partial r = 0.140, P = 0.002); Impaired Control Scale total (partial r = 0.097, P = 0.044) and Alcohol Dependence Scale total (partial r = 0.152, P = 0.001). Thus, DRD2 methylation may be a critical mechanism linking D2 receptors with functional striatal brain changes and clinical severity among alcohol users.