Stress and substance use disorders: risk, relapse, and treatment outcomes.

Stress has long been associated with substance misuse and substance use disorders (SUDs). The past two decades have seen a surge in research aimed at understanding the underlying mechanisms driving this association. This Review introduces a multilevel "adaptive stress response" framework, encompassing a stress baseline, acute reaction, and recovery with return-to-homeostasis phase that occurs at varying response times and across domains of analysis. It also discusses evidence showing the disruption of this adaptive stress response in the context of chronic and repeated stressors, trauma, adverse social and drug-related environments, as well as with acute and chronic drug misuse and with drug withdrawal and abstinence sequelae. Subjective, cognitive, peripheral, and neurobiological disruptions in the adaptive stress response phases and their link to inflexible, maladaptive coping; increased craving; relapse risk; and maintenance of drug intake are also presented. Finally, the prevention and treatment implications of targeting this "stress pathophysiology of addiction" are discussed, along with specific aspects that may be targeted in intervention development to rescue stress-related alterations in drug motivation and to improve SUD treatment outcomes.

Drawbacks to strengthening neural salience encoding: a link between cortisol and risky drinking.

Emotionally salient experiences are encoded and remembered more strongly, an effect that can be amplified by hormones like cortisol. Such memories can in turn profoundly influence later behavior. However, little is known about the link between amplified salience encoding and subsequent behavior. This pathway may be particularly important for risky alcohol drinking, which has been linked to sensitized salience responses, memory, and cortisol. To test this possibility, we integrated pharmacology using a double-blind cross-over design with fMRI, cognitive, and motivation assays across a range of healthy male and female social drinkers. As anticipated, cortisol enhanced memory for salient alcohol-related events; critically, this bias was in turn associated with later alcohol motivation. Increased alcohol motivation was particularly pronounced in more susceptible risky drinkers, for whom cortisol enhanced brain salience responses to alcohol. These sensitized salience responses predicted both memory biases and alcohol motivation. Together, these findings reveal maladaptive consequences of enhanced salience encoding.Significance Statement Our memories for salient experiences can strongly influence what we choose to do. Despite the importance of such memories for motivated behaviors like alcohol drinking, the mechanisms by which salient memories are strengthened and influence later behavior are unclear. In the current study, we integrated findings from human research (glucocorticoids enhance salient memory encoding) with findings from rodent models (glucocorticoids enhance alcohol motivation, especially with a history of ethanol exposure) to examine whether these processes are linked in humans. We found evidence for this pathway: hydrocortisone amplified brain signatures of salience (particularly for participants who drank more), which predicted enhanced memory. Both brain salience and enhanced memory predicted increased alcohol motivation. This translational pathway reveals downsides to amplifying salient memories.

Network state dynamics underpin basal craving in a transdiagnostic population.

Emerging fMRI methods quantifying brain dynamics present an opportunity to capture how fluctuations in brain responses give rise to individual variations in affective and motivation states. Although the experience and regulation of affective states affect psychopathology, their underlying time-varying brain responses remain unclear. Here, we present a novel framework to identify network states matched to an affective experience and examine how the dynamic engagement of these network states contributes to this experience. We apply this framework to investigate network state dynamics underlying basal craving, an affective experience with important clinical implications. In a transdiagnostic sample of healthy controls and individuals diagnosed with or at risk for craving-related disorders (total N = 252), we utilized connectome-based predictive modeling (CPM) to identify brain networks predictive of basal craving. An edge-centric timeseries approach was leveraged to quantify the moment-to-moment engagement of the craving-positive and craving-negative subnetworks during independent scan runs. We found that dynamic markers of network engagement, namely more persistence in a craving-positive network state and less dwelling in a craving-negative network state, characterized individuals with higher craving. We replicated the latter results in a separate dataset, incorporating distinct participants (N = 173) and experimental stimuli. The associations between basal craving and network state dynamics were consistently observed even when craving-predictive networks were defined in the replication dataset. These robust findings suggest that network state dynamics underpin individual differences in basal craving. Our framework additionally presents a new avenue to explore how the moment-to-moment engagement of behaviorally meaningful network states supports our affective experiences.

Sex differences in binge drinking-related higher morning cortisol levels and in prospective association with future alcohol intake.

AIMS: Peripheral cortisol represents one biological measure of the hypothalamic-pituitary-adrenal (HPA) axis, a significant component of the stress system, which is altered by chronic alcohol consumption. However, whether heavy alcohol use affects the HPA axis differentially between the sexes and whether basal cortisol levels are a biomarker of prospective alcohol intake is unknown. METHODS: We recruited light moderate (LM) and binge-heavy (BH) drinkers of alcohol (n = 118). Repeated fasting morning cortisol levels were studied over a 2-hour period to assess basal levels while participants underwent a neuroimaging scan. RESULTS: Significantly higher average cortisol levels in BH compared to LM groups across four timepoints were observed (P < .018). Overall sex differences were observed with women showing higher initial cortisol levels at the first timepoint with a blunted decrease over the morning relative to men (P < .003). Average morning cortisol differentially predicted prospective future 30-day daily reports of alcohol consumption by sex and group, such that LM males had a positive significant relationship and BH males had a negative non-significant relationship between cortisol and drinking. CONCLUSIONS: Findings indicate that morning plasma cortisol is upregulated in the BH vs. LM group. Although females had higher initial morning cortisol levels, BH males showed a dysregulated negative relationship between stress and binge drinking in contrast to the LM group. Future work should further investigate the role of cortisol and other stress hormones as biomarkers of problematic drinking behaviors in men and women.

Brain correlates and functional connectivity linking stress, autonomic dysregulation, and alcohol motivation.

High stress is a key risk factor for alcohol use disorder (AUD) and often accompanied by physiological dysregulation including autonomic nervous system (ANS) disruptions. However, neural mechanisms underlying drinking behaviors associated with stress and ANS disruptions remain unclear. The current study aims to understand neural correlates of stress, ANS disruptions, and subsequent alcohol intake in social drinkers with risky drinking. Using functional magnetic resonance imaging (fMRI), we investigated brain and heart rate (HR) autonomic responses during brief exposure to stress, alcohol, and neutral cues utilizing a well-validated, individualized imagery paradigm in 48 social drinkers of which 26 reported high-risk drinking (HD) while 22 reported low-risk drinking (LD) patterns. Results indicated that HD individuals showed stress and ANS disruptions with increased basal HR, stress-induced craving, and decreased brain response to stress exposure in frontal-striatal regions including the ventromedial prefrontal cortex (VmPFC), anterior cingulate cortex, striatum, insula, and temporal gyrus. Furthermore, whole-brain correlation analysis indicated that greater basal HR was associated with hypoactive VmPFC, but hyperactive medulla oblongata (MOb) responses during stress, with an inverse association between activity in the VmPFC and Mob (whole-brain corrected (WBC), p < 0.05). Functional connectivity with the MOb as a seed to the whole brain indicated that HD versus LD had decreased functional connectivity between the VmPFC and MOb during stress (WBC, p < 0.05). In addition, those with more compromised functional connectivity between the VmPFC and MOb during stress consumed greater amount of alcohol beverage during an experimental alcohol taste test conducted on a separate day, as well as in their self-reported weekly alcohol intake. Together, these results indicate that stress-related, dysfunctional VmPFC control over brain regions of autonomic arousal contributes to greater alcohol motivation and may be a significant risk factor for hazardous alcohol use in non-dependent social drinkers. Findings also suggest that restoring VmPFC integrity in modulating autonomic arousal during stress may be critical for preventing the development of AUD.

Low-calorie diet-induced weight loss is associated with altered brain connectivity and food desire in obesity.

OBJECTIVE: The main objective of this study is to better understand the effects of diet-induced weight loss on brain connectivity in response to changes in glucose levels in individuals with obesity. METHODS: A total of 25 individuals with obesity, among whom 9 had a diagnosis of type 2 diabetes, underwent functional magnetic resonance imaging (fMRI) scans before and after an 8-week low-calorie diet. We used a two-step hypereuglycemia clamp approach to mimic the changes in glucose levels observed in the postprandial period in combination with task-mediated fMRI intrinsic connectivity distribution (ICD) analysis. RESULTS: After the diet, participants lost an average of 3.3% body weight. Diet-induced weight loss led to a decrease in leptin levels, an increase in hunger and food intake, and greater brain connectivity in the parahippocampus, right hippocampus, and temporal cortex (limbic-temporal network). Group differences (with vs. without type 2 diabetes) were noted in several brain networks. Connectivity in the limbic-temporal and frontal-parietal brain clusters inversely correlated with hunger. CONCLUSIONS: A short-term low-calorie diet led to a multifaceted body response in patients with obesity, with an increase in connectivity in the limbic-temporal network (emotion and memory) and hormone and eating behavior changes that may be important for recovering the weight lost.

Neural Correlates of Stress and Alcohol Cue-Induced Alcohol Craving and of Future Heavy Drinking: Evidence of Sex Differences.

OBJECTIVE: Stress and alcohol cue reactivity are associated with poor treatment outcomes in alcohol use disorder (AUD), but sex-specific neural correlates of stress and alcohol cue-induced craving compared with neutral cue-induced craving and of heavy drinking outcomes in AUD have not been examined. Thus, this study prospectively examined these associations and assessed sex differences. METHODS: Treatment-seeking adults with AUD (N=77; 46 men and 31 women) completed a functional MRI task involving stress, alcohol, and neutral cue exposure with repeated assessments of alcohol craving. Most of these participants (N=72; 43 men and 29 women) then participated in an 8-week standardized behavioral AUD treatment program, during which the percentage of heavy drinking days was assessed. RESULTS: Significant increases in both stress and alcohol cue-induced craving relative to neutral cue-induced craving were observed, with a greater alcohol-neutral contrast in craving relative to the stress-neutral contrast among men and equivalent stress-neutral and alcohol-neutral contrasts in craving among women. Whole-brain voxel-based regression analyses showed craving-associated hyperactivation in the neutral condition, but hypoactive prefrontal (ventromedial and lateral prefrontal, supplementary motor, and anterior cingulate regions) and striatal responses during exposure to stressful images (stress-neutral contrast) and alcohol cues (alcohol-neutral contrast), with significant sex differences. Additionally, a higher percentage of heavy drinking days was associated with hypoactivation of the subgenual anterior cingulate cortex and the bed nucleus of the stria terminalis in the stress-neutral contrast among women, hyperactivation of the hypothalamus in the stress-neutral contrast among men, and hyperactivation of the hippocampus in the alcohol-neutral contrast among men. CONCLUSIONS: Sex differences in stress- and alcohol cue-induced responses in the cortico-striatal-limbic network related to subjective alcohol craving and to heavy drinking indicated that distinct brain circuits underlie alcohol use outcomes in women and men. These findings underscore the need for sex-specific therapeutics to address this neural dysfunction effectively.

Childhood adversity, accelerated GrimAge, and associated health consequences.

Childhood adversity is linked to psychological, behavioral, and physical health problems, including obesity and cardiometabolic disease. Epigenetic alterations are one pathway through which the effects of early life stress and adversity might persist into adulthood. Epigenetic mechanisms have also been proposed to explain why cardiometabolic health can vary greatly between individuals with similar Body Mass Index (BMIs). We evaluated two independent cross-sectional cohorts of adults without known medical illness, one of which explicitly recruited individuals with early life stress (ELS) and control participants (n = 195), and the other a general community sample (n = 477). In these cohorts, we examine associations between childhood adversity, epigenetic aging, and metabolic health. Childhood adversity was associated with increased GrimAge Acceleration (GAA) in both cohorts, both utilizing a dichotomous yes/no classification (both p < 0.01) as well as a continuous measure using the Childhood Trauma Questionnaire (CTQ) (both p < 0.05). Further investigation demonstrated that CTQ subscales for physical and sexual abuse (both p < 0.05) were associated with increased GAA in both cohorts, whereas physical and emotional neglect were not. In both cohorts, higher CTQ was also associated with higher BMI and increased insulin resistance (both p < 0.05). Finally, we demonstrate a moderating effect of BMI on the relationship between GAA and insulin resistance where GAA correlated with insulin resistance specifically at higher BMIs. These results, which were largely replicated between two independent cohorts, suggest that interactions between epigenetics, obesity, and metabolic health may be important mechanisms through which childhood adversity contributes to long-term physical and metabolic health effects.

Evidence that personalized racial stress procedures elicit a stress response and increases alcohol craving among Black adults with alcohol use disorder: A laboratory pilot study.

BACKGROUND: The objective of this study was to pilot test newly developed personalized imagery procedures to investigate the impact of racial stress on alcohol craving and emotional and physiological response in Black adults with alcohol use disorder (AUD). METHODS: Twenty Black adults (45% women, meanage=37.05, SDage=13.19) with AUD participated in two sessions. In the first, participants described a stressful personal event involving their race and a neutral relaxing situation and these descriptions were used to develop scripts for the subsequent laboratory exposure session. The second session was an experimental provocation session in which participants reported on alcohol craving and emotional response before and after imagined exposure to stress and neutral conditions using personalized racial stress and neutral/relaxing scripts. Conditions were randomized and counterbalanced across subjects, and heart rate and blood pressure were assessed before and after each image. RESULTS: Alcohol craving and negative emotions significantly increased, and positive emotions decreased following the racial stress script relative to the neutral/relaxing script. We found no differences in physiological response. Exploratory analyses found that increase in alcohol craving was correlated with racial identity exploration but not racial identity commitment, men reported greater reductions in anger than women in the neutral condition only, and income was correlated with fear in the racial stress condition only. CONCLUSIONS: This study provides evidence that personalized racial stress procedures elicit a stress response and increases alcohol craving and emotional response but not physiological response among Black adults with AUD. These findings warrant replication in a larger study.

Substance use patterns, quantities, and associated risk factors in women with polysubstance misuse.

Polysubstance use (PSU), the use of two or more substances proximally, is highly prevalent and has amplified the risk for morbidity and mortality. However, PSU patterns and associated risk factors are not well characterized. This may be especially relevant to women who are known to be vulnerable to stress/trauma, craving, pain, and anxious and depressive symptoms as associated risk factors for PSU. A cross-sectional observational study was conducted to characterize substance use patterns in women who regularly used cocaine, opioids, marijuana, alcohol, benzodiazepines and/or nicotine and were being assessed for a placebo-controlled study of guanfacine treatment (n = 94; ages 19-65). Data on stress/traumatic life events, drug cravings for each substance, pain ratings, and anxiety and depressive symptoms were also obtained using standardized well-validated surveys. High use per day of two or more drugs was observed (72.7% ± 33.3%) and opioid amounts were high relative to other drug amounts (p's < 0.001). Notably, higher stress/trauma events and higher cravings are each associated with cumulative PSU days, amounts and probability of an individual PSU day (p's < 0.02). This remained when PSU versus single substance use was compared. Pain, anxiety and depressive symptoms were not associated with PSU metrics. These findings characterize specific patterns of PSU in women and show that average drug craving and stress/trauma events are associated with PSU. Interventions that focus on stress/trauma and craving management could be of benefit in reducing PSU risk in women.

Cumulative adversity and emotion dysregulation effects on suicidal ideation and attempts in a community sample.

Adversity, trauma, and emotion dysregulation are commonly cited risk factors for suicidal thoughts and behaviors. Thus, the role of these factors in conferring risk for suicidal ideation (SI) and suicide attempts (SA) amongst community adults was assessed. A cross-sectional cohort-based study with community adults (n=757; female=55.0%) assessed emotion dysregulation, cumulative adversity including highly stressful and traumatic events, as well as other known risk factors for suicidality (e.g., self-reported depression and anxiety history) to predict a lifetime history of SI or SA, SI but no SA, or SI and SA. Higher cumulative stress and trauma scores conferred risk for SI, specifically on the subscales major life events, recent life events, and chronic stressors. Higher emotion dysregulation was associated with an increased risk for a SA relative to no SI or SA, particularly nonacceptance of emotional responses. Lifetime trauma was the only predictor of SA relative to SI. Nonacceptance of emotions significantly mediated the association between life traumas and suicidality. Cumulative adversity and emotion dysregulation confer risk for suicidal ideation and attempts, and higher lifetime trauma predicted attempts over ideation. These findings suggest that targeting emotion dysregulation, and specifically nonacceptance of difficult emotions, may be a useful strategy in reducing suicidal behaviors in individuals with trauma history and concurrent suicidal ideation.

Effects of prazosin treatment on liver enzymes are moderated by alcohol withdrawal symptoms in individuals with alcohol use disorder.

BACKGROUND: Alcohol use disorder (AUD) is associated with significant liver pathology marked by elevated liver enzymes. Prazosin, an alpha1-noradrenergic antagonist significantly improves alcohol drinking outcomes in individuals with alcohol withdrawal symptoms (AW), but effects on liver enzymes are unknown. We assessed the effects of prazosin treatment on the liver enzymes alanine transaminase (ALT), aspartate transaminase (AST), and gamma-glutamyltransferase (GGT) in individuals with AUD. METHODS: Participants (N=100) with AUD were enrolled in a 12-week randomized controlled trial and received either placebo or 16 mg/day of prazosin. Whole blood was drawn from 92 participants to measure liver enzyme levels every 4 weeks, and severity of AW was assessed weekly. Analysis predicting liver function outcomes used linear mixed effects models. RESULTS: Controlling for alcohol consumption, a significant AW × treatment effect was seen for ALT (p < 0.05), AST (p < 0.05) and GGT (p < 0.01). Additionally, AST (b = 0.2, p < 0.01), ALT (b = 0.2, p < 0.05), and GGT (b = 0.3, p < 0.01) were elevated in individuals with higher AW in the placebo but not in the prazosin group (AST: p > 0.66; ALT: p > 0.65). Only in the prazosin group were lower GGT levels associated with higher withdrawal severity (b = -0.16, p < 0.05). CONCLUSIONS: We found an interaction of alcohol withdrawal symptoms and prazosin treatment on liver enzyme levels, which were not influenced by week in the trial or the amount of alcohol consumed. Together, these findings suggest that prazosin treatment reduces liver enzymes over the course of AUD treatment among individuals with significant AW, though replication to establish clinical utility is needed.

A thematic analysis of stress, substance-cue, and neutral/relaxing events to inform approaches for improving treatment among Black adults who use substances.

INTRODUCTION: To inform approaches for adapting substance use treatment for Black adults, the aim of this study was to thematically analyze the stressors, triggers for substance use, and neutral/relaxing events reported among Black adults who participated in a lab paradigm. METHODS: The sample included 36 Black adults (mean age [years] = 37.47, SD = 7.30; 53 % male, 12 (33 %) with alcohol use disorder, 12 (33 %) with cocaine use disorder, and 12 (33 %) healthy controls). All participants provided detailed stimulus and response context information on the most stressful event they experienced in the past year, an event that involved substance use, and a neutral/relaxing event in a structured interview using a scene development questionnaire, and this information was utilized to generate a personalized imagery script for each event using standardized procedures. Thematic analyses identified the key themes reported within scripts. RESULTS: Consistent with a prior thematic analysis on a majority White sample, we found the following themes for the stress scripts: Relational (Violation, Loss, Parenting, Betrayal, Isolation vs. support), Environmental (Housing, Legal), and Achievement (Employment, Role in household). However, our analyses also resulted in new stress themes: Relational (Violation-Racial Microaggressions) and Institutional (Time Wasted). The substance use scripts consisted of the following trigger themes: Social (Social Facilitation, Socially-Sanctioned Substance Use Event, Exposure to Substance Use Friends/Associates), Internal (Free Time, Boredom, Thoughts of Using Substance, Frustration, Reward), and Environment (Availability of Substance, Celebration, Party Environment, Food, Hot Day, Money/Payday). The neutral/relaxing scripts themes were: Outdoor Activities (Admiring Nature, People Watching, Observing Surroundings, Enjoying the Sun, Playing in the Sand, Walking), Quiet Activities (Silence/Quiet, Prayer, Reading), and Indoor Activities (Radio, Television, Bath/Shower, Bed/Chair, Observing from a Window). We found sex differences across scripts. CONCLUSIONS: The results suggest that Black people experience unique stressors (e.g., institutional and racial stressors) that are important to consider when modifying treatment to improve outcomes among this group. In addition to stressors, this study also identified high-risk situations involving triggers for use. Taken together these findings suggest targets for the tailoring of coping strategies that could be incorporated for the development of culturally relevant behavioral treatment for SUD.

Laboratory and Real-World Experimental Approaches to Understanding Alcohol Relapse.

Alcohol use disorder is highly prevalent and high risk of relapse remains a significant treatment challenge. Therefore, the utility of human laboratory models of relapse to further the understanding of psychobiological mechanisms that precipitate relapse risk and allow testing of novel interventions could be of benefit in expediting the development of effective treatments to target high relapse risk. Stress is a risk factor for the development of AUD and for relapse, and furthermore, chronic alcohol use leads to adaptations in central and peripheral stress biology. Here, we review our efforts to assess the integrity of these stress pathways in individuals with alcohol use disorder and whether adaptations in these systems play a role in relapse risk. Using validated human laboratory procedures to model two of the most common situations that contribute to relapse risk, namely stress and alcohol cues, we review how such models in the laboratory can predict subsequent relapse, and how we can measure specific identified biobehavioral markers of relapse effectively and ecologically in the real world. Finally, we discuss the significant implications of these findings for the development of novel and effective interventions that target stress dysregulation and craving as risk factors to treatment.

Network state dynamics underpin craving in a transdiagnostic population.

Emerging fMRI brain dynamic methods present a unique opportunity to capture how brain region interactions across time give rise to evolving affective and motivational states. As the unfolding experience and regulation of affective states affect psychopathology and well-being, it is important to elucidate their underlying time-varying brain responses. Here, we developed a novel framework to identify network states specific to an affective state of interest and examine how their instantaneous engagement contributed to its experience. This framework investigated network state dynamics underlying craving, a clinically meaningful and changeable state. In a transdiagnostic sample of healthy controls and individuals diagnosed with or at risk for craving-related disorders (N=252), we utilized connectome-based predictive modeling (CPM) to identify craving-predictive edges. An edge-centric timeseries approach was leveraged to quantify the instantaneous engagement of the craving-positive and craving-negative networks during independent scan runs. Individuals with higher craving persisted longer in a craving-positive network state while dwelling less in a craving-negative network state. We replicated the latter results externally in an independent group of healthy controls and individuals with alcohol use disorder exposed to different stimuli during the scan (N=173). The associations between craving and network state dynamics can still be consistently observed even when craving-predictive edges were instead identified in the replication dataset. These robust findings suggest that variations in craving-specific network state recruitment underpin individual differences in craving. Our framework additionally presents a new avenue to explore how the moment-to-moment engagement of behaviorally meaningful network states supports our changing affective experiences.

Hippocampal Mechanisms Support Cortisol-Induced Memory Enhancements.

Stress can powerfully influence episodic memory, often enhancing memory encoding for emotionally salient information. These stress-induced memory enhancements stand at odds with demonstrations that stress and the stress-related hormone cortisol can negatively affect the hippocampus, a brain region important for episodic memory encoding. To resolve this apparent conflict and determine whether and how the hippocampus supports memory encoding under cortisol, we combined behavioral assays of associative memory, high-resolution fMRI, and pharmacological manipulation of cortisol in a within-participant, double-blinded procedure (in both sexes). Behaviorally, hydrocortisone promoted the encoding of subjectively arousing, positive associative memories. Neurally, hydrocortisone led to enhanced functional connectivity between hippocampal subregions, which predicted subsequent memory enhancements for emotional associations. Cortisol also modified the relationship between hippocampal representations and associative memory: whereas hippocampal signatures of distinctiveness predicted memory under placebo, relative integration predicted memory under cortisol. Together, these data provide novel evidence that the human hippocampus contains the necessary machinery to support emotional associative memory enhancements under cortisol.SIGNIFICANCE STATEMENT Our daily lives are filled with stressful events, which powerfully shape the way we form episodic memories. For example, stress and stress-related hormones can enhance our memory for emotional events. However, the mechanisms underlying these memory benefits are unclear. In the current study, we combined functional neuroimaging, behavioral tests of memory, and double-blind, placebo-controlled hydrocortisone administration to uncover the effects of the stress-related hormone cortisol on the function of the human hippocampus, a brain region important for episodic memory. We identified novel ways in which cortisol can enhance hippocampal function to promote emotional memories, highlighting the adaptive role of cortisol in shaping memory formation.

Patients with AUD exhibit dampened heart rate variability during sleep as compared to social drinkers.

Chronic heavy alcohol use profoundly affects the cardiovascular system, contributing to several life-threatening cardiovascular diseases. Heart rate variability (HRV), or the fluctuations in heart rate, reflects dynamic autonomic nervous system processes that change to meet biological demands and environmental challenges. In the current study, we examined whether HRV metrics are altered in alcohol use disorder (AUD) during waking and sleeping with passive biomonitoring as participants went about their daily lives. Social drinkers (standard deviation: n = 10, 5 female) and treatment-seeking individuals with moderate to severe AUD (n = 16, 7 female) provided continuous, real-world heart rate monitoring for 5 days of monitoring on average (M = 5.27 ± 2.22). Five indices of respiration and HRV-respiratory sinus arrhythmia (RSA) amplitude, high frequency (HF), low frequency (LF), HF/LF ratio, root-mean-square standard deviation (RMSSD), and standard deviation of the N-N intervals (SDNN)-were analyzed separately for waking and sleeping hours. Both RMSSD and SDNN decreased the longer the participants were awake (Ps < .013). During sleeping hours, HF, RSA amplitude, RMSSD, and SDNN were significantly higher in light social drinkers as compared to patients with AUD (all Ps < .009), indicating higher parasympathetic activation during sleep in the SD versus AUD group. Sleep and waking HRV measures were significantly correlated with patient-reported symptoms of depression and sleep difficulties in the AUD group (Ps < .05). This natural observational study utilizing continuous autonomic biomonitoring in the real world indicates parasympathetic dysfunction that is clearly detectable during sleep in AUD and HRV measures, which are also related to clinical, patient-related symptoms of AUD.

The CRAVE and ARGE scales for motivation states for physical activity and sedentarism: Brazilian Portuguese translation and single-item versions.

Motivation states for physical activity and sedentarism potentially vary from moment to moment. The CRAVE scale (Cravings for Rest and Volitional Energy Expenditure) was developed to assess transient wants and desires to move. Three studies were conducted with the aims of: (1) translating and validating the scale in Brazilian Portuguese, (2) examining changes with exercise, and (3) determining the best single-item for Move and Rest subscales for English and Portuguese. In Study 1, six bilingual speakers translated the scale into Brazilian Portuguese [named Anseios por Repouso e Gastos com Energia (ARGE)]. The ARGE had good content validity coefficients across three dimensions (0.89-0.91), as determined by three independent, bilingual referees. 1,168 participants (mean age = 30.6, SD = 12.2) from across Brazil completed an online version of the ARGE. An Exploratory Factor Analysis found two clear, oblique, and inversely related factors (Move and Rest; GFI = 1.00, RMSR = 0.03). Reliability was good (Cronbach α's: 0.93 and 0.92). Two models of the scale (10 vs. 13 items) were compared with Confirmatory Factor Analysis. The previously validated version using 10 scored items (GFI = 1.00, RMSEA = 0.07, RMSR = 0.02) outperformed the version scored with 13 items. State anxiety and exercise behavior had small associations with Move and Rest (-0.20 to 0.26). In Study 2, ARGE Move scores had high correspondence post-session (ICC = 0.83) for 9 women performing short Sprint Interval Training (sSIT; 6 sessions). Large, but non-significant, effects were detected for changes in motivation states with sSIT. In Study 3, IRT analyses found that for the United States sample, "be physically active" and "be still" were the most representative items for Move and Rest, respectively, while for the Brazil sample they were "exert my muscles" and "be a couch potato." Overall, it was found that: (A) the ARGE scale demonstrated good psychometric properties, (B) the original scoring (with 10 items) resulted in the best model, (C) it had small associations with exercise behavior, and (D) the subscales were reduced to single items that varied by country, indicating potential cultural differences in the concept of motivation states for physical activity.

Therapeutics for Substance-Using Women: The Need to Elucidate Sex-Specific Targets for Better-Tailored Treatments.

In the last decade, alcohol consumption in the US has risen by 84% in women compared with 35% in men. Furthermore, research has shown that sex- and gender-related differences may disadvantage women in terms of developing a range of psychological, cognitive, and medical problems considerably earlier in their drinking history than men, and despite consuming a similar quantity of substances. While this "telescoping" process has been acknowledged in the literature, a concomitant understanding of the underlying biobehavioral mechanisms, and an increase in the development of specific treatments tailored to women, has not occurred. In the current chapter we focus on understanding why the need for personalized, sex-specific medications is imperative, and highlight some of the potential sex-specific gonadal and stress-related adaptations underpinning the accelerated progress from controlled to compulsive drug and alcohol seeking in women. We additionally discuss the efficacy of these mechanisms as novel targets for medications development, using exogenous progesterone and guanfacine as examples. Finally, we assess some of the challenges faced and progress made in terms of developing innovative medications in women. We suggest that agents such as exogenous progesterone and adrenergic medications, such as guanfacine, may provide some efficacy in terms of attenuating stress-induced craving for several substances, as well as improving the ability to emotionally regulate in the face of stress, preferentially in women. However, to fully leverage the potential of these therapeutics in substance-using women, greater focus needs to the placed on reducing barriers to treatment and research by encouraging women into clinical trials.

Greater stress and trauma mediate race-related differences in epigenetic age between Black and White young adults in a community sample.

Black Americans suffer lower life expectancy and show signs of accelerated aging compared to other Americans. While previous studies observe these differences in children and populations with chronic illness, whether these pathologic processes exist or how these pathologic processes progress has yet to be explored prior to the onset of significant chronic illness, within a young adult population. Therefore, we investigated race-related differences in epigenetic age in a cross-sectional sample of young putatively healthy adults and assessed whether lifetime stress and/or trauma mediate those differences. Biological and psychological data were collected from self-reported healthy adult volunteers within the local New Haven area (399 volunteers, 19.8% Black, mean age: 29.28). Stress and trauma data was collected using the Cumulative Adversity Inventory (CAI) interview, which assessed specific types of stressors, including major life events, traumatic events, work, financial, relationship and chronic stressors cumulatively over time. GrimAge Acceleration (GAA), determined from whole blood collected from participants, measured epigenetic age. In order to understand the impact of stress and trauma on GAA, exploratory mediation analyses were then used. We found cumulative stressors across all types of events (mean difference of 6.9 p = 2.14e-4) and GAA (ß = 2.29 years [1.57-3.01, p = 9.70e-10] for race, partial η2 = 0.091, model adjusted R2 = 0.242) were significantly greater in Black compared to White participants. Critically, CAI total score (proportion mediated: 0.185 [0.073-0.34, p = 6e-4]) significantly mediated the relationship between race and GAA. Further analysis attributed this difference to more traumatic events, particularly assaultive traumas and death of loved ones. Our results suggest that, prior to development of significant chronic disease, Black individuals have increased epigenetic age compared to White participants and that increased cumulative stress and traumatic events may contribute significantly to this epigenetic aging difference.