DRD2 methylation is associated with executive control network connectivity and severity of alcohol problems among a sample of polysubstance users.

Chronic exposure to alcohol and other drugs of abuse has been associated with deleterious consequences, including functional connectivity deficits within neural networks associated with executive control. Altered functional connectivity within the executive control network (ECN) might underlie the progressive inability to control consumption of alcohol and other drugs as substance use disorders progress. Genetic and epigenetic factors have been associated with substance use disorders (SUDs). For example, dopamine receptor 2 (DRD2) functioning has been associated with alcohol use disorder (AUD) and related phenotypes, including correlates of executive functioning. The present study aims to explore the relationship between a continuous measure of alcohol-related problems, epigenetic markers (methylation) within the DRD2 gene, and functional connectivity within the ECN among a sample of polysubstance users. A community sample of 658 subjects, whose consumption of alcohol, nicotine, and cannabis span across a spectrum of quantity and frequency of use, were obtained across previous studies in polysubstance using populations. Resting state functional magnetic resonance imaging was analyzed to identify intrinsic connectivity networks using a priori regions of interest. Methylation measurement of functionally relevant sites within the DRD2 gene was achieved via pyrosequencing. Regression-based models, including mediation and moderation models, tested the association between DRD2 methylation, functional connectivity within intrinsic neural networks (including the ECN), and severity of alcohol problems. Results suggest that average DRD2 methylation was negatively associated with right ECN (RECN) and left ECN (LECN) connectivity, but not associated with other networks tested, and DRD2 methylation was significantly associated with alcohol problems severity. Mediation models were not supported, although moderation models suggested that connectivity between edges within the RECN moderated the relationship between DRD2 methylation and AUD severity. Results support a theoretical model in which epigenetic factors are associated with neurobiological correlates of alcohol consumption among a sample of polysubstance users.

Best Practices for Approaching Cognitive Processing Therapy and Prolonged Exposure During the COVID-19 Pandemic.

The COVID-19 pandemic presents major challenges for mental health care providers. In particular, providers who treat posttraumatic stress disorder (PTSD) are now tasked with determining whether to initiate trauma-focused therapy during the pandemic and, if so, whether and how to adapt treatment. The purpose of this communication is to identify and organize key considerations for whether and how to deliver commonly used evidence-supported therapy protocols for trauma treatment-specifically, cognitive processing therapy (CPT) and prolonged exposure (PE) therapy-during the ongoing COVID-19 pandemic for adults who currently meet the criteria for PTSD. Based on relevant public health and clinical literature, we present a structured guide that can be used by treatment teams and individual providers to evaluate whether initiating CPT or PE is indicated given a particular patient-provider pair and system context amidst pandemic conditions. In addition, we suggest appropriate action steps, including problem-solving strategies, evidence-informed modifications to CPT and PE, and alternative intervention approaches.

Negative and interactive effects of sex, aging, and alcohol abuse on gray matter morphometry.

Chronic alcohol use is associated with declines in gray matter (GM) volume, as is the normal aging process. Less apparent, however, is how the interaction between aging and heavy alcohol use affects changes in GM across the lifespan. There is some evidence that women are more vulnerable to the negative effects of alcohol use on GM than men. In the current study, we examined whether localized GM was related to measures of alcohol use disorder (e.g., AUDIT score) in a large sample (N = 436) of participants, ages 18-55 years, with a range of disease severity, using both voxel-based morphometry (VBM) and surface-based morphometry (SBM). We also explored whether GM associations with alcohol use disorder (AUD) severity are moderated by sex and age. Results showed significant negative associations between AUD severity and GM volume throughout temporal, parietal, frontal, and occipital lobes. Women showed more negative effects of alcohol use than men for cortical thickness in left orbitofrontal cortex, but evidence for increased vulnerability based on sex was limited overall. Similarly, a specific age by alcohol use interaction was observed for volume of right insula, but other regional or global interactions were not statistically supported. However, significant negative associations between heavy alcohol use and GM volumes were observed as early as 18-25 years. These findings support that alcohol has deleterious effects on global and regional GM above and beyond age, and, of particular importance, that regional associations emerge in early adulthood. Hum Brain Mapp 37:2276-2292, 2016. © 2016 Wiley Periodicals, Inc.

An Exploratory Association Study of Alcohol Use Disorder and DNA Methylation.

BACKGROUND: Epigenetic factors, including DNA methylation, play an important role in the etiology of alcohol use disorders (AUDs). Noncandidate-based methylome-wide studies leveraging multiple tissue types are needed in order to identify a set of CpG targets that reliably differentiate AUD patients from controls and strongly correlate across brain tissue and more commonly collected tissue types (e.g., buccal cells). METHODS: Postmortem precuneus brain tissue samples were collected from 49 alcohol-dependent (AD) cases and 47 controls (sample I), and DNA was extracted from precuneus and putamen brain tissue and buccal cells in 24 postmortem subjects (sample II). Methylation levels were analyzed at over 450,000 CpG sites in both samples. CpGs that demonstrated significant methylation differences between cases and controls were advanced for further analysis with the goal of identifying CpGs that also demonstrated consistent methylation correlations across tissue type. RESULTS: In the primary analysis, 244 hypomethylated and 188 hypermethylated CpGs met a priori criteria for both significant methylation differences between cases and controls as well as significant correlation across brain and buccal cell tissue types, employing stringent Bonferroni p-value correction. Many of these CpGs were involved in gene networks related to lipid metabolism, immune response, inflammatory response/disease, and gastro-intestinal disease. CONCLUSIONS: More than 400 CpGs demonstrated differences in methylation between AD cases and controls and showed significant correlation across tissue types. Several genes and pathways (e.g., inflammation and immune functioning) that have been previously associated with AUD were identified in the current analyses.

Toward Precision Characterization and Treatment of Psychopathology: A Path Forward and Integrative Framework of the Hierarchical Taxonomy of Psychopathology and the Research Domain Criteria.

A critical mission of psychological science is to conduct research that ultimately improves the lives of individuals who experience psychopathology. One important aspect of accomplishing this mission is increasing the likelihood that treatments will work for each person. I contend that treatment prognosis can be improved by moving toward a precision-medicine model. I advance a principle-driven framework for working toward these objectives. First, I synthesize the Hierarchical Taxonomy of Psychopathology and the Research Domain Criteria and demonstrate how integrating these models facilitates precision characterization of psychopathology. Second, I outline and demonstrate a systematic process for approaching treatment selection by leveraging precisely characterized representations of psychopathology. Finally, I advocate the research and clinical applications of this framework. Although clinical and psychological scientists are conducting exciting, multidisciplinary, and methodologically rigorous research in their respective domains, the impact of these pursuits will be maximized in the context of a unifying theoretical framework that supports a clear guiding mission.

Comparing the Efficacy of Mindfulness-Based Relapse Prevention Versus Relapse Prevention for Alcohol Use Disorder: A Randomized Control Trial.

OBJECTIVE: This study compared the efficacy of mindfulness-based relapse prevention (MBRP) with relapse prevention (RP) on reducing alcohol consumption. Secondary, exploratory aims assessed moderation of treatment effects by sex and cannabis use. METHOD: A total of 182 individuals (48.4% female; 21-60 years old) who reported drinking more than 14/21 drinks/week (for women and men, respectively) in the past 3 months but who wished to quit/reduce their drinking were recruited from Denver and Boulder, Colorado. Individuals were randomly assigned to 8 weeks of individual-based MBRP or RP treatment. Participants completed substance use assessments at baseline, halfway through and at the end of treatment, and 20 and 32 weeks after treatment. Primary outcomes were Alcohol Use Disorders Identification Test-consumption questions (AUDIT-C) scores, heavy drinking days (HDD), and drinks per drinking day (DDD). RESULTS: Across treatments, drinking decreased over time (ps < .001), with a significant time-by-treatment interaction found for HDD (F = 3.50, p < .01). HDD initially decreased in both treatments but remained stable or increased after treatment for MBRP and RP participants, respectively. At follow-up, MBRP participants had significantly less HDD than RP participants. Sex did not moderate treatment effects (ps > .17), whereas cannabis use moderated treatment effects on DDD and HDD (F = 4.89, p < .001, and F = 4.30, p < .005, respectively). High cannabis use frequency was associated with continued posttreatment decreases in HDD/DDD for MBRP participants but increased HDD for RP participants. At low cannabis use frequency levels, HDD/DDD remained stable after treatment across groups. CONCLUSIONS: Drinking decreases were comparable across treatments, but HDD improvements diminished for RP participants after treatment. In addition, cannabis use moderated treatment efficacy for HDD/DDD.

Stress and number of servings of fruit and vegetables consumed: Buffering effects of monetary incentives.

Diet is a key factor of human health, and additional research is needed in order to understand the psychological causes, consequences, and moderators of dietary behavior. Participants in two studies in the United States completed a 21-day intervention that involved either self-monitoring their fruit and vegetable consumption or self-monitoring combined with earning monetary incentives for behavior. Each day, participants reported their stress, affect, and consumption of fruits and vegetables. Hierarchical linear mixed effects model results suggest that on average, daily reports of higher stress were associated with fewer fruits and vegetables consumed on that day. This effect was moderated by incentive condition, such that the relationship between stress and fruit and vegetable consumption was reduced among incented participants. There was also a marginal negative effect of time on consumption of fruits and vegetables, but this was also significantly moderated by condition, such that those participants who did not receive incentives decreased their daily servings, while incented participants did not decrease over the course of the intervention. These studies suggest that incentives may be a novel method for buffering against the negative effect of daily stress on eating a healthy diet.

The impact of COVID-19 on mental health: The interactive roles of brain biotypes and human connection.

COVID-19 along with the mitigation strategies being used to address the virus pose significant threats to our individual and collective mental health. As the crisis evolves and persists, it will be increasingly important for the research community to conduct investigations that address the mental health consequences of COVID-19. The causes of mental health effects in the context of COVID-19 are multifactorial and likely include biological, behavioral, and environmental determinants. We argue that the COVID-19 crisis significantly threatens our basic human need for human connection, which might serve as a crucial environmental factor that could underlie the overall insult to our mental health. Furthermore, "brain styles," which we have previously conceptualized as "biotypes" that are informed by a neural taxonomy, might interact with the universal threat to our need for human connection to explain the mental health consequences of COVID-19 from a precision psychiatry perspective. The goal of this viewpoint is to inspire research on the mental health consequences of COVID-19 from an individualized, brain-based perspective that honors the profound threat that the virus poses to our basic human motivations.

An empirically derived method for measuring human gut microbiome alpha diversity: Demonstrated utility in predicting health-related outcomes among a human clinical sample.

The human gut microbiome has emerged as a potential key factor involved in the manifestation of physical and mental health. Despite an explosion of cross-disciplinary interest in researching the gut microbiome, there remains to be a gold-standard method for operationalizing gut microbiome alpha diversity. Given researchers' interest in examining the relationships among gut microbiome alpha diversity and health-related outcomes of interest, a way of operationalizing the microbiome that yields a numeric value, which could be used in common statistical approaches, is needed. Thus, the current study aims to provide methodological guidance for how to operationalize microbiome alpha diversity. Findings suggest that alpha diversity of the human gut microbiome is comprised of two sub-constructs (richness and evenness), and we propose a step-by-step method of creating alpha diversity composite measures based on this key insight. Finally, we demonstrate that our empirically derived richness and evenness composite measures are significantly associated with health-related variables of interest (alcohol use, symptoms of depression) among a human clinical sample.

Cannabinoids, Pain, and Opioid Use Reduction: The Importance of Distilling and Disseminating Existing Data.

The high prevalence of chronic pain conditions combined with an over-reliance on opioid prescriptions has resulted in an opioid epidemic and a desperate need for solutions. There is some debate about whether cannabis might play a role in addressing chronic pain conditions as well as the opioid epidemic. Recent surveys suggest that a large number of people are using cannabis as a treatment for pain and to reduce use of opioids, and cannabis-derived products demonstrate at least modest efficacy in the treatment of pain in randomized controlled trials. In addition, surveillance studies from countries that have approved the use of Sativex, which is a cannabis-based product, have demonstrated that a combination of Δ9-tetrahydrocannabinol and cannabidiol has low potential for harm, is well tolerated, and is helpful to patients. Given the number of people in the United States who are already using cannabis to manage pain and opioid use in state-regulated markets, it is imperative to conduct additional research in these areas, and to disseminate information on how to minimize harm and maximize any benefits of using cannabinoids to mitigate pain and reduce opioid use. The purpose of this article is to call attention to the fact that cannabis is being used in the management of chronic pain. Thus, this article also provides a set of guidelines on how to approach using cannabis to treat pain.

An Overview and Proposed Research Framework for Studying Co-Occurring Mental- and Physical-Health Dysfunction.

Mental- and physical-health conditions co-occur at a rate much higher than chance. Of patients who have a mental-health condition, more than half also have a physical disease, and these cases are associated with increased human suffering and societal cost. Comorbidity research to date has focused on co-occurring mental- and physical-health disorders separately, and relatively little research has examined the co-occurrence of mental- and physical-health dysfunction. In addition, even less is known about why mental- and physical-health dysfunction co-occurs or how to treat these cases. Thus, the aims of this article are to highlight the need for research at the intersection of physical- and mental-health dysfunction and to provide guidance on how to research cases of comorbidity. Toward these ends, we begin by presenting a selective overview of the possible role of biological processes in the co-occurrence of physical- and mental-health dysfunction using specific illustrative examples. Specifically, we outline how biological processes within the immune system and gastrointestinal system could underlie depression, irritable bowel syndrome, and their co-occurrence. We then advance and discuss a proposed research framework, including methodological and analytic guidance, that researchers could use when studying the phenomenon of co-occurring physical- and mental-health dysfunction.

An Examination of Behavioral and Neuronal Effects of Comorbid Traumatic Brain Injury and Alcohol Use.

BACKGROUND: Chronic alcohol use disorders (AUDs) and traumatic brain injury (TBI) are highly comorbid and share commonly affected neuronal substrates (i.e., prefrontal cortex, limbic system, and cerebellum). However, no studies have examined how combined physical trauma and heavy drinking affect neurocircuitry relative to heavy drinking alone. METHODS: The current study investigated whether comorbid AUDs and mild or moderate TBI (AUDs+TBI) would negatively affect maladaptive drinking behaviors (n = 90 AUDs+TBI; n = 62 AUDs) as well as brain structure (i.e., increased atrophy; n = 62 AUDs+TBI; n = 44 AUDs) and function (i.e., activation during gustatory cue reactivity; n = 55 AUDs+TBI; n = 37 AUDs) relative to AUDs alone. RESULTS: Participants reported a much higher incidence of trauma (59.2%) compared with the general population. There were no differences in demographic and clinical measures between groups, suggesting that they were well matched. Although maladaptive drinking behaviors tended to be worse for the AUDs+TBI group, effect sizes were small and not statistically significant. Increased alcohol-cue reactivity was observed in bilateral anterior insula and orbitofrontal cortex, anterior cingulate cortex, medial prefrontal cortex, posterior cingulate cortex, dorsal striatum, thalamus, brainstem, and cerebellum across both groups relative to a carefully matched appetitive control. However, there were no significant differences in structural integrity or functional activation between AUDs+TBI and AUDs participants, even when controlling for AUD severity. CONCLUSIONS: Current results indicate that a combined history of mild or moderate TBI was not sufficient to alter drinking behaviors and/or underlying neurocircuitry at detectable levels relative to heavy drinking alone. Future studies should examine the potential long-term effects of combined alcohol and trauma on brain functioning.

TLR4 Methylation Moderates the Relationship Between Alcohol Use Severity and Gray Matter Loss.

OBJECTIVE: Alcohol use disorders (AUDs) are associated with decreased gray matter, and neuroinflammation is one mechanism through which alcohol may confer such damage, given that heavy alcohol use may promote neural damage via activation of toll-like receptor 4 (TLR4)-mediated inflammatory signaling cascades. We previously demonstrated that TLR4 is differentially methylated in AUD compared with control subjects, and the present study aims to extend this work by examining whether TLR4 methylation moderates the relationship between alcohol use and gray matter. METHOD: We examined TLR4 methylation and gray matter thickness in a large sample (N = 707; 441 males) of adults (ages 18-56) reporting a range of AUD severity (mean Alcohol Use Disorders Identification Test score = 13.18; SD = 8.02). We used a series of ordinary least squares multiple regression equations to regress gray matter in four bilateral brain regions (precuneus, lateral orbitofrontal, inferior parietal, and superior temporal) on alcohol use, TLR4 methylation, and their interaction, controlling for demographic, psychological, and other substance use variables. RESULTS: After we corrected for multiple tests, a significant Alcohol × TLR4 Methylation interaction emerged in the equations modeling left precuneus and right inferior parietal gray matter. Follow-up analyses examining the nature of these interactions demonstrated a significant negative association between alcohol and precuneus and inferior parietal gray matter in individuals with low TLR4 methylation, but no relationship between alcohol and gray matter in the high methylation group. CONCLUSIONS: These findings suggest that TLR4 methylation may be protective against the damage conferred by alcohol on precuneus and inferior parietal gray matter, thereby implicating TLR4 for further investigation as a possible AUD treatment target.