Joshua L. Gowin

Altered risk-related processing in substance users: Imbalance of pain and gain

BACKGROUND Substance use disorders (SUDs) can be conceptualized as a form of risk-taking behavior with the potential for highly aversive outcomes such as health or legal problems. Risky decision-making likely draws upon several related brain processes involved in estimations of value and risk, executive control, and emotional processing. SUDs may result from a dysfunction in one or more of these cognitive processes. METHODS We performed a systematic literature review of functional neuroimaging studies examining risk-related decision making in individuals with SUDs. A quantitative meta-analysis tool (GingerALE) and qualitative approach was used to summarize the imaging results. RESULTS Meta-analysis findings indicate that individuals with SUDs exhibit differences in neural activity relative to healthy controls during risk-taking in the anterior cingulate cortex, orbitofrontal cortex, dorsolateral prefrontal cortex, striatum, insula, and somatosensory cortex. In addition, a qualitative review of the literature suggests that individuals with SUDs may have altered function in the amygdala and ventromedial prefrontal cortex. CONCLUSIONS The neuroimaging literature reveals that several neural substrates involved in the computation of risk may function suboptimally in SUDs. Future research is warranted to elucidate which computational processes are affected, whether dysfunctional risk-related processing recovers with sobriety, and whether different drugs of abuse have specific effects on risk-taking.

Individualized relapse prediction: Personality measures and striatal and insular activity during reward-processing robustly predict relapse

BACKGROUND Nearly half of individuals with substance use disorders relapse in the year after treatment. A diagnostic tool to help clinicians make decisions regarding treatment does not exist for psychiatric conditions. Identifying individuals with high risk for relapse to substance use following abstinence has profound clinical consequences. This study aimed to develop neuroimaging as a robust tool to predict relapse. METHODS 68 methamphetamine-dependent adults (15 female) were recruited from 28-day inpatient treatment. During treatment, participants completed a functional MRI scan that examined brain activation during reward processing. Patients were followed 1 year later to assess abstinence. We examined brain activation during reward processing between relapsing and abstaining individuals and employed three random forest prediction models (clinical and personality measures, neuroimaging measures, a combined model) to generate predictions for each participant regarding their relapse likelihood. RESULTS 18 individuals relapsed. There were significant group by reward-size interactions for neural activation in the left insula and right striatum for rewards. Abstaining individuals showed increased activation for large, risky relative to small, safe rewards, whereas relapsing individuals failed to show differential activation between reward types. All three random forest models yielded good test characteristics such that a positive test for relapse yielded a likelihood ratio 2.63, whereas a negative test had a likelihood ratio of 0.48. CONCLUSIONS These findings suggest that neuroimaging can be developed in combination with other measures as an instrument to predict relapse, advancing tools providers can use to make decisions about individualized treatment of substance use disorders.

Attenuated insular processing during risk predicts relapse in early abstinent methamphetamine-dependent individuals.

There is some evidence that neuroimaging can be used to predict relapse among abstinent methamphetamine-dependent (MD) individuals. However, it remains unclear what cognitive and neural processes contribute to relapse. This investigation examined whether insula activation during risk-taking decisions—a process shown to be disrupted in MD—is able to predict susceptibility for relapse. Sixty-eight MD enrolled in a treatment program during early abstinence completed a risk-taking task during functional magnetic resonance imaging. Sixty-three of the sixty-eight individuals were followed up 1 year after the study. Of these, 18 MD reported relapse. The 45 abstinent MD showed patterns of insula activation during risky decisions that resembled those found in prior studies of healthy controls, consisting of lower insula activation during safe decisions paired with higher activation during risky decisions. In contrast, the 18 relapsed MD showed similar insula activation during safe and risky decisions. An increase in one standard deviation in the difference in insula activation between risky and safe choices was associated with a 0.34 odds ratio for relapse at any given time. A median split of insula activation (difference between risky and safe) showed that individuals in the bottom half were two times more likely to relapse. In addition, a model that included several other brain regions increased prediction accuracy compared with insula-based model alone. These results suggest that failure to differentially activate the insula as a function of risk is a part of an altered risk-processing network associated with an increased susceptibility to relapse.

Effects of Varenicline on Neural Correlates of Alcohol Salience in Heavy Drinkers.

Background: Preclinical and emerging clinical evidence indicates that varenicline, a nicotinic partial agonist approved for smoking cessation, attenuates alcohol seeking and consumption. Reductions of alcohol craving have been observed under varenicline treatment and suggest effects of the medication on alcohol reward processing, but this hypothesis remains untested. Methods: In this double-blind, placebo-controlled randomized experimental medicine study, 29 heavy drinkers underwent a functional magnetic resonance imaging scan after 2 weeks of varenicline (2mg/d) or placebo administration. During functional magnetic resonance imaging, participants performed the Alcohol-Food Incentive Delay task, where they could earn points for snacks or alcohol. At baseline and after 3 weeks of medication, participants underwent intravenous alcohol self-administration sessions in the laboratory. Results: During the functional magnetic resonance imaging scan, participants in the varenicline group (N=17) reported lower feelings of happiness and excitement on subjective mood scales when anticipating alcohol reward compared with the placebo group (N=12). Linear mixed effects analysis revealed that anticipation of alcohol reward was associated with significant blood oxygen level dependent activation of the ventral striatum, amygdala, and posterior insula in the placebo group; this activation was attenuated in the varenicline group. The varenicline group showed no difference in intravenous alcohol self-administration relative to the placebo group for either session. Participants with higher insula activation when anticipating alcohol reward showed higher alcohol self-administration behavior across groups. Conclusions: Our findings suggest that varenicline decreases blood oxygen level dependent activation in striato-cortico-limbic regions associated with motivation and incentive salience of alcohol in heavy drinkers. This mechanism may underlie the clinical effectiveness of varenicline in reducing alcohol intake and indicates its potential utility as a pharmacotherapy for alcohol use disorders.

The endocannabinoid system as a target for addiction treatment: Trials and tribulations

Abstract Addiction remains a major public health concern, and while pharmacotherapies can be effective, clinicians are limited by the paucity of existing interventions. Endocannabinoid signaling is involved in reward and addiction, which raises the possibility that drugs targeting this system could be used to treat substance use disorders. This review discusses findings from randomized controlled trials evaluating cannabinergic medications for addiction. Current evidence suggests that pharmacotherapies containing delta‐9‐tetrahydrocannabinol, such as dronabinol and nabiximols, are effective for cannabis withdrawal. Dronabinol may also reduce symptoms of opioid withdrawal. The cannabinoid receptor 1 (CB1) inverse agonist rimonabant showed promising effects for smoking cessation but also caused psychiatric side effects and currently lacks regulatory approval. Few trials have investigated cannabinergic medications for alcohol use disorder. Overall, the endocannabinoid system remains a promising target for addiction treatment. Development of novel medications such as fatty acid amide hydrolase inhibitors and neutral CB1 antagonists promises to extend the range of available interventions. This article is part of the Special Issue entitled “A New Dawn in Cannabinoid Neurobiology”. HighlightsThe endocannabinoid system plays an important role in reward signaling.Clinical trials evaluating cannabinergic medications for addiction were reviewed.Drugs containing the CB1 partial agonist &Dgr;9‐THC are effective for cannabis withdrawal.CB1 inverse agonists have shown promise for smoking cessation, but cause psychiatric side effects.FAAH inhibitors reduce cannabis and opioid withdrawal in rodents, but have not been tested for these indications in humans.

Acute topiramate differentially affects human aggressive responding at low vs. moderate doses in subjects with histories of substance abuse and antisocial behavior

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.

Resting state functional connectivity analysis for addiction medicine: From individual loci to complex networks

Resting state functional connectivity (rsFC) has provided a new and valuable tool for investigating network-level dysfunction in addiction. Following the recent development of a framework of large scale network disruptions, we have been able to arrive at unique insights into craving-related aspects of addiction using rsFC. However, such network-level advancement has thus far eluded our understanding of mesocorticolimbic involvement in addiction. Given the importance of this system in vulnerability and resilience to addiction, understanding mesocorticolimbic dynamics to the same extent could provide critical insights into the disease. To this end, we review here recent studies on addiction that employ rsfC and suggest a new approach, one that combines a novel model for addiction with new experimental techniques as well as participant groups, to accelerate progress in this arena.

Neural correlates of impulsive aggressive behavior in subjects with a history of alcohol dependence

Alcohol-related aggression is a complex and problematic phenomenon with profound public health consequences. We examined neural correlates potentially moderating the relationship between human aggressive behavior and chronic alcohol use. Thirteen subjects meeting DSM-IV criteria for past alcohol-dependence in remission (AD) and 13 matched healthy controls (CONT) participated in an fMRI study adapted from a laboratory model of human aggressive behavior (Point Subtraction Aggression Paradigm, or PSAP). Blood oxygen level dependent (BOLD) activation was measured during bouts of operationally defined aggressive behavior, during postprovocation periods, and during monetary-reinforced behavior. Whole brain voxelwise random-effects analyses found group differences in brain regions relevant to chronic alcohol use and aggressive behavior (e.g., emotional and behavioral control). Behaviorally, AD subjects responded on both the aggressive response and monetary response options at significantly higher rates than CONT. Whole brain voxelwise random-effects analyses revealed significant group differences in response to provocation (monetary subtractions), with CONT subjects showing greater activation in frontal and prefrontal cortex, thalamus, and hippocampus. Collapsing data across all subjects, regression analyses of postprovocation brain activation on aggressive response rate revealed significant positive regression slopes in precentral gyrus and parietal cortex; and significant negative regression slopes in orbitofrontal cortex, prefrontal cortex, caudate, thalamus, and middle temporal gyrus. In these collapsed analyses, response to provocation and aggressive behavior were associated with activation in brain regions subserving inhibitory and emotional control, sensorimotor integration, and goal directed motor activity.

Vulnerability for Alcohol Use Disorder and Rate of Alcohol Consumption

OBJECTIVE Although several risk factors have been identified for alcohol use disorder, many individuals with these factors do not go on to develop the disorder. Identifying early phenotypic differences between vulnerable individuals and healthy control subjects could help identify those at higher risk. Binge drinking, defined as reaching a blood alcohol level of 80 mg%, carries a risk of negative legal and health outcomes and may be an early marker of vulnerability. Using a carefully controlled experimental paradigm, the authors tested the hypothesis that risk factors for alcohol use disorder, including family history of alcoholism, male sex, impulsivity, and low level of response to alcohol, would predict rate of binging during an individual alcohol consumption session. METHOD This cross-sectional study included 159 young social drinkers who completed a laboratory session in which they self-administered alcohol intravenously. Cox proportional hazards models were used to determine whether risk factors for alcohol use disorder were associated with the rate of achieving a binge-level exposure. RESULTS A greater percentage of relatives with alcoholism (hazard ratio: 1.04, 95% CI=1.02-1.07), male sex (hazard ratio: 1.74, 95% CI=1.03-2.93), and higher impulsivity (hazard ratio: 1.17, 95% CI=1.00 to 1.37) were associated with a higher rate of binging throughout the session. Participants with all three risk factors had the highest rate of binging throughout the session compared with the lowest risk group (hazard ratio: 5.27, 95% CI=1.81-15.30). CONCLUSIONS Binge drinking may be an early indicator of vulnerability to alcohol use disorder and should be carefully assessed as part of a thorough clinical evaluation.

Severity of alcohol dependence is associated with the fatty acid amide hydrolase Pro129Thr missense variant

The endocannabinoid system plays an important role in reward and addiction. One of the two main endocannabinoid neurotransmitters, anandamide, is metabolized by fatty acid amide hydrolase, an enzyme with a functional genetic polymorphism (FAAH Pro129Thr, rs324420). The Thr129 allele has been linked to problem drug and alcohol use, but the association has not been widely replicated and may be stronger for clinical measures of severity rather than categorical diagnosis. In the present study, we sought to determine whether the Thr129 allele was associated with both alcohol dependence (AD) diagnosis and severity in a sample of 1434 European American and African American individuals, 952 of whom were diagnosed with lifetime AD. Participants were genotyped for FAAH rs324420, and ancestry was determined via a genome‐wide panel of ancestry informative markers. Subjects participated in Structured Clinical Interviews for psychiatric disorders and 90‐day Timeline Followback interviews to assess recent alcohol use. European American participants with current AD had a higher Thr129 allele frequency than non‐dependent controls. In European Americans with lifetime AD, there were significantly different distributions of drinking days and binge drinking days between the two genotype groups, with Thr129 carriers reporting a median of 10 fewer abstinent days and 13 more binge drinking days than Pro129/Pro129 homozygotes. In African American participants, there were no significant differences between Thr129 allele frequency in cases and controls and no significant differences in measures of AD severity by genotype. These findings provide evidence that the Pro129Thr missense variant is associated with AD severity in European Americans.