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.

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.

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.

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.

Binge drinking is associated with higher cortisol and lower hippocampal and prefrontal gray matter volume: Prospective association with future alcohol intake.

Background: Cortisol is a significant driver of the biological stress response that is potently activated by acute alcohol intake and increased with binge drinking. Binge drinking is associated with negative social and health consequences and risk of developing alcohol use disorder (AUD). Both cortisol levels and AUD are also associated with changes in hippocampal and prefrontal regions. However, no previous research has assessed structural gray matter volume (GMV) and cortisol concurrently to examine BD effects on hippocampal and prefrontal GMV and cortisol, and their prospective relationship to future alcohol intake. Methods: Individuals who reported binge drinking (BD: N = 55) and demographically matched non-binge moderate drinkers (MD: N = 58) were enrolled and scanned using high-resolution structural MRI. Whole brain voxel-based morphometry was used to quantify regional GMV. In a second phase, 65% of the sample volunteered to participate in prospective daily assessment of alcohol intake for 30 days post-scanning. Results: Relative to MD, BD showed significantly higher cortisol and smaller GMV in regions including hippocampus, dorsal lateral prefrontal cortex (dlPFC), prefrontal and supplementary motor, primary sensory and posterior parietal cortex (FWE, p < 0.05). GMV in bilateral dlPFC and motor cortices were negatively associated with cortisol levels, and smaller GMV in multiple PFC regions was associated with more subsequent drinking days in BD. Conclusion: These findings indicate neuroendocrine and structural dysregulation associated with BD relative to MD. Notably, BD-associated lower GMV regions were those involved in stress, memory and cognitive control, with lower GMV in cognitive control and motor regions also predicting higher levels of future alcohol intake in BD.

Blunted neural reward response to alcohol and greater alcohol motivation in binge drinkers in a randomized clinical experiment.

BACKGROUND: Alcohol stimulates cerebral blood flow (CBF) in brain reward regions. However, neural processes that support sustained alcohol motivation after the first drink are not well understood. METHODS: Using a novel placebo-controlled, randomized, crossover experiment, 27 individuals who binge drink (BD; 15 M, 12 F) and 25 social drinkers (SD; 15 M, 10 F) underwent a behavioral test of self-motivated alcohol consumption using an Alcohol Taste Test (ATT) involving alcoholic and nonalcoholic beer on separate days. The test was followed immediately by perfusion functional magnetic resonance imaging (fMRI). On both days, participants then engaged in a post-scan ATT with placebo beer to assess sustained alcohol self-motivation without active alcohol effects. Linear mixed effects models were used to examine the effects of drinking group on the placebo-controlled effect of initial alcohol motivation on brain perfusion (whole brain corrected p < 0.001, cluster corrected p < 0.025) and on the relationship between placebo-controlled brain perfusion and sustained alcohol motivation. RESULTS: Initial alcohol self-motivation in the alcohol relative to placebo session led to markedly decreased activation in the medial orbitofrontal cortex (OFC) and the ventral striatum in BD relative to SD, indicative of neural reward tolerance. The BD group also showed an enhanced neural response in behavioral intention regions of the supplementary motor area (SMA) and inferior frontal gyrus (IFG) regions. Moreover, there was greater sustained alcohol motivation in BD than SD in the post-scan ATT in the alcohol relative to placebo session. Correspondingly, only in BD and only in the alcohol session, lower alcohol-induced OFC response correlated with concurrent sensitized SMA response, and each predicted the subsequent sustained higher alcohol motivation in the post-scan ATT. CONCLUSIONS: Alcohol-related OFC tolerance may play an important role in sustained alcohol motivation. Furthermore, both specific alcohol-related neural reward tolerance and premotor sensitization responses may contribute to escalating alcohol motivation to drive excessive alcohol intake, even in individuals without alcohol use disorder.

Association between specific types of parent stressors and fast-food consumption among parents and children.

INTRODUCTION: Although stress has been associated with eating behaviors, such as overeating and eating less healthy foods, the relationships between specific types of parent stressors and fast-food consumption in parents and young children have not been well studied. We hypothesized that parent perceived stress, parenting stress, and household chaos would be positively associated with fast-food consumption for parents and their young children. METHODS: Parents of 2-5 year olds and with Body Mass Index >27 kg/m2 (N = 234, parent mean age: 34.3 (±5.7); child age: 44.9 (±13.8) months; 65.8 % from two parent households) completed surveys on parent perceived stress, parenting stress, household chaos, and their fast-food intake and that of their child. RESULTS: In separate regression models, controlling for covariates, parent perceived stress (ß = 0.21, p < 0.01; R2 = 0.10, p < 0.01), parenting stress (ß = 0.26, p < 0.01; R2 = 0.13, p < 0.01), and household chaos (ß = 0.25, p < 0.01; R2 = 0.12, p < 0.01) were each significantly associated with parent fast-food consumption, and separately with child fast-food consumption [Parent perceived stress (ß = 0.05, p = 0.02; R2 = 0.14, p < 0.01); parenting stress (ß = 0.14, p = 0.03; R2 = 0.14, p < 0.01); parent fast-food consumption (ß = 0.40, p < 0.01; R2 = 0.27, p < 0.01)]. However, combined final models showed parenting stress (p < 0.01) as the only significant predictor of parent fast-food consumption, which in turn was the only significant predictor of child fast-food consumption (p < 0.01). DISCUSSION: The findings support the inclusion of parenting stress interventions that target fast-food eating behaviors in parents, which may in turn, reduce fast-food intake in their young children.

Sex differences in neural responses to stress and drug cues predicts future drug use in individuals with substance use disorder.

BACKGROUND: Substance use disorders (SUDs) are chronically recurring illnesses, where stress and drug cues significantly increase drug craving and risk of drug use recurrence. This study examined sex differences in functional magnetic resonance imaging (fMRI) brain responses to stress and drug cue exposure and assessed their prospective association with future drug use post-treatment. METHODS: Inpatient, treatment engaged men (N = 46) and women (N = 26) with SUDs, including alcohol, cocaine and/or cannabis use disorders, participated in an fMRI scan that assessed subjective (anxiety, drug craving), heart rate and neural responses to brief individualized script-driven imagery of stress, drug, and neutral-relaxing trials. Prospective follow-up interviews post-treatment assessed future drug use recurrence over 90 days. RESULTS: During fMRI, stress and drug versus neutral cue exposure led to increased anxiety, heart rate and craving responses (p's < 0.004) in both men and women, but greater drug cue-induced anxiety (p < .017) and higher drug use days during follow-up (p < .006) in women relative to men. In whole brain analyses of stress and drug cues (p < .05 FWE corrected), and in whole brain correlation (p < .05, FWE corrected) with drug use days, significant sex differences revealed drug cue-related striatal hyperactivation (caudate, putamen) in men, but drug cue-related cortico-limbic (insula and dorsolateral prefrontal cortex) hypoactivation and stress-related hypoactivation in the ventromedial prefrontal cortex (VmPFC) in women; and these were significantly associated with higher future drug use days. CONCLUSIONS: Findings indicate sex-specific pathophysiology of SUD recurrence and support the need for differential treatment development for men and women with SUD to improve drug use outcomes.

Regular cannabis use is associated with history of childhood and lifetime trauma in a non-clinical community sample.

Higher rate of substance use, including cannabis, has been reported in individuals with a history of childhood trauma, but less is known about the association between cannabis use with lifetime history of trauma and chronic stress, and potential gender differences in this association. This study systematically examined this association in a cross-sectional study of 841 individuals recruited between 2007 and 2012 from the community in New Haven, Connecticut. The Cumulative Adversity Index (CAI) was used to measure cumulative lifetime major life events, life trauma, and recent life events and chronic stress. Childhood Trauma Questionnaire (CTQ) was used to measure childhood trauma. Current and regular use of drugs were assessed using self-report questionnaires and objectively verified with urine drug testing. Higher rates of childhood trauma as well as lifetime trauma, and major life events were found in cannabis users, compared to non-users. The association between cannabis use with childhood trauma (total CTQ scores) was significant after controlling for age, gender, ethnicity and regular use of alcohol or cocaine. In logistic regression analysis, cannabis use had a significant positive association with major life events and lifetime trauma, but not with chronic stress, controlling for confounding factors including age, gender, ethnicity, and regular use of alcohol and cocaine. When analyzed separately, only in women the association between cannabis use and childhood trauma was significant. These associations point to further assessment of the impact of these gender differences on neurobiology of stress and cannabis misuse risk.

Pregnenolone effects on provoked alcohol craving, anxiety, HPA axis, and autonomic arousal in individuals with alcohol use disorder.

RATIONALE: Chronic alcohol intake down-regulates GABAergic transmission and reduces levels of neuroactive steroids. These changes are associated with greater stress dysregulation and high alcohol craving which in turn increases relapse risk. OBJECTIVES: This study tested whether potentiation of the neurosteroid system with pregnenolone (PREG), a precursor to neuroactive steroids and known to increase GABAergic transmission, will normalize chronic alcohol-related stress adaptations in the hypothalamic-pituitary-adrenal (HPA) axis and autonomic responses and reduce alcohol craving to significantly impact relapse risk. METHODS: Forty-three treatment-seeking individuals with alcohol use disorder (AUD) were randomized to placebo (PBO) or supraphysiologic pregnenolone doses of 300 mg or 500 mg treatment using a parallel-between subject design as part of a larger 8-week pilot clinical trial. In week 2, they participated in a 3-day laboratory experiment where on each day they self-administered the assigned study drug in the laboratory and were then exposed to 5-min personalized guided imagery provocation of stress, alcohol, or neutral/relaxing cues, one condition per day on separate days, in a random, counterbalanced order. Repeated assessments of alcohol craving, anxiety, HPA axis, heart rate (HR), systolic (SBP), and diastolic blood pressure (DBP) and serum pregnenolone levels were made on each day. RESULTS: Pregnenolone levels were significantly increased in the PREG groups versus PBO. PREG treatment decreased stress- and alcohol cue- induced craving and dose-specifically reduced stress-induced anxiety in the 300 mg/day group. Both PREG doses compared to PBO also normalized CORT/ACTH and increased stress-induced HR, stress- and cue-induced SBP, and in the 300 mg PREG group cue-induced DBP responses relative to neutral condition. CONCLUSIONS: Findings indicate that pregnenolone decreases stress- and alcohol cue-provoked craving and normalizes HPA axis and autonomic arousal in individuals with AUD, thereby supporting the need for further assessment of pregnenolone in the treatment of AUD.

Parent Stress and Trauma, Autonomic Responses, and Negative Child Behaviors.

Cumulative stress and trauma in parents may alter autonomic function. Both may negatively impact child behaviors, however these links have not been well established. We tested hypotheses that parent stress and trauma are associated with and interact with altered autonomic function during the toy wait task, an acute parent-child interaction challenge, to predict greater negative child behaviors. Sixty-eight parents and their 2-5 year old children were enrolled. More parent major and traumatic life events, and more parent recent life events coupled with increased heart rate and decreased heart rate variability (HRV), each related to more child disruptive/aggressive behavior. More major life and traumatic life events coupled with greater HRV predicted more child attention seeking behavior. Our novel approach to assessing parental life stress offers a unique perspective. Interventions mitigating parent stress and regulating physiological coping during parent-child interactions may both promote better parent health and improve child behavioral outcomes.

Pregnenolone Reduces Stress-Induced Craving, Anxiety, and Autonomic Arousal in Individuals with Cocaine Use Disorder.

Chronic cocaine use leads to adaptations in stress biology and in neuroactive steroid system. These adaptations are associated with high cocaine craving and increased relapse risk. This study tested whether potentiation of the neuroactive steroid system with the precursor pregnenolone (PREG) affects stress- and cue-induced cocaine craving, anxiety and autonomic response in individuals with cocaine use disorder (CUD). Thirty treatment-seeking individuals (21 Male, 9 Female) with CUD were randomized to placebo (PBO) or supraphysiologic PREG doses of 300 mg or 500 mg per day for 8 weeks. After 2 weeks of treatment, participants were exposed to 5-min personalized guided imagery provocation of stress, cocaine, or neutral/relaxing cues in a 3-day experiment, one condition per day on separate days, in a random, counterbalanced order. Repeated assessment of cocaine craving, anxiety, heart rate (HR), systolic (SBP) and diastolic blood pressure (DBP) were assessed on each day. PREG significantly increased pregnenolone levels compared to PBO. Both PREG doses decreased stress- and cocaine cue-induced craving and reduced both stress- and cue-induced anxiety only in the 500 mg/day group. The 500 mg/day PREG group also displayed decreased stress-induced HR, SBP and DBP. Findings indicate that pregnenolone decreases stress- and cocaine cue-provoked craving and anxiety and reduces stress-induced autonomic arousal in individuals with CUD.

COVID-19 Traumatic Disaster Appraisal and Stress Symptoms Among Health Care Workers: Insights From the Yale Stress Self-assessment.

OBJECTIVE: To determine to what extent did health care workers experience the pandemic as a severe stress event. METHODS: This cross-sectional evaluation of 8299 health care workers, representing a 22% response rate, utilized machine learning to predict high levels of escalating stress based on demographics and known predictors for adverse psychological outcomes after trauma. RESULTS: A third of health care workers experienced the pandemic as a potentially traumatic stress event; a greater proportion of health care workers experienced high levels of escalating stress. Predictive factors included sense of control, ability to manage work-life demands, guilt or shame, age, and level of education. Gender was no longer predictive after controlling for other factors. Escalating stress was especially high among nonclinical academics and clinical private practitioners. CONCLUSION: Findings suggest adverse effects on total worker health, care quality, professionalism, retention, and acute and chronic mental health.

High-Risk Drinkers Engage Distinct Stress-Predictive Brain Networks.

BACKGROUND: Excessive alcohol intake is a major public health problem and can be triggered by stress. Heavy drinking in patients with alcohol use disorder also alters neural, physiological, and emotional stress responses. However, it is unclear whether adaptations in stress-predictive brain networks can be an early marker of risky drinking behavior. METHODS: Risky social drinkers (regular bingers; n = 53) and light drinker control subjects (n = 51) aged 18 to 53 years completed a functional magnetic resonance imaging-based sustained stress protocol with repeated measures of subjective stress state, during which whole-brain functional connectivity was computed. This was followed by prospective daily ecological momentary assessment for 30 days. We used brain computational predictive modeling with cross-validation to identify unique brain connectivity predictors of stress in risky drinkers and determine the prospective utility of stress-brain networks for subsequent loss of control over drinking. RESULTS: Risky drinkers had anatomically and functionally distinct stress-predictive brain networks (showing stronger predictions from visual and motor networks) compared with light drinkers (default mode and frontoparietal networks). Stress-predictive brain networks defined for risky drinkers selectively predicted future real-world stress levels for risky drinkers and successfully predicted prospective future real-world loss of control over drinking across all participants. CONCLUSIONS: These results indicate adaptations in computationally derived stress-related brain circuitry among high-risk drinkers, suggesting potential targets for early preventive intervention and revealing the malleability of the neural processes that govern stress responses.

Alcohol craving and withdrawal at treatment entry prospectively predict alcohol use outcomes during outpatient treatment.

OBJECTIVE: Chronic alcohol use increases risk of alcohol craving and withdrawal symptoms (AW) as well as abstinence-related distress symptoms, in those entering alcohol use disorder (AUD) treatment. Here, we examined whether AW and alcohol craving in AUD patients entering outpatient treatment prospectively predicts future heavy drinking days/week (HDD) and additional alcohol use outcomes during 8-weeks of outpatient treatment, and their relationship to abstinence symptoms of depression, anxiety and sleep difficulties. METHODS: Participants were 80 treatment-seeking adults with current DSM-5 AUD (39% female; 43% White; 20-60 years) who completed assessments of AW and alcohol craving and also alcohol abstinence symptoms of depression, anxiety, and sleep quality at treatment intake. Participants were prospectively followed using daily diaries for alcohol intake during 8-week of standardized weekly relapse prevention counseling to support recovery. RESULTS: After accounting for demographic and pre-treatment alcohol use, greater alcohol craving at treatment entry predicted higher HDD (p < .013) as well as greater drinking days (DD: p < .004), average drinks per drinking day/week (AvgD: p < .001) and relapse to heavy drinking (p < .05), while higher levels of pretreatment AW symptoms interacted with treatment week to predict greater HDD (p < .018). Abstinence symptoms of depression, anxiety, and sleep difficulties were associated with craving and AW but did not predict any drinking-related outcomes. CONCLUSIONS: These results provide evidence that increased alcohol craving and AW may serve as prognostic indicators of greater risk of heavy drinking in outpatient treatment. Findings suggest the need to evaluate craving and AW at outpatient treatment entry and develop targeted treatments to specifically address the effects of craving and AW on drinking outcomes in outpatient AUD treatment.

A Longitudinal Study of Life Trauma, Chronic Stress and Body Mass Index on Weight Gain over a 2-Year Period.

The United States is facing an alarming and increasing obesity epidemic. Stress is associated with obesity, but specific longitudinal effects of life trauma on weight gain have not been assessed. Here we examined if life trauma and chronic stress predicted weight gain while also measuring the impact of body mass index (BMI). Life trauma and chronic stress were assessed with the Cumulative Adversity Interview (CAI). Weight and BMI were captured repeatedly over a two-year period. Results show significant increases in weight gain over time. Individuals with obesity (IOb) reported significantly higher levels of life trauma at the onset compared to overweight (IOw) and lean individuals (Il). Greater numbers of trauma events were associated with increased weight gain for both IOb and IOw but not for Il. Increased chronic stress was not consistently associated with weight gain over time. Current findings suggest the need to address trauma coping, especially in vulnerable individuals to prevent greater weight gain and curb obesity-related health outcomes.

Social Support Effects on Neural Stress and Alcohol Reward Responses.

Social support (SS), or having people to depend on during times of stress, may offer an emotional and neurological buffer to problem drinking. Specifically, SS may modulate reward and stress-related brain responses to mitigate perceptions of alcohol reward and stress. There is limited evidence, however, on this topic and specifically on brain networks that may modulate SS effects on stress and alcohol reward. Here we present a review of the current literature on this topic as well as data from a large community sample of 115 social drinkers. Findings from a novel fMRI task viewing alcohol cue, stress, and neutral images, in separate blocks, while providing ratings on subjective feelings of alcohol craving, stress, and arousal are included. Lower SS significantly predicted greater alcohol craving during alcohol cue and stress conditions, higher baseline levels of stress, and greater arousal in the alcohol cue, relative to neutral condition. Remarkably, individuals with low SS showed greater reward activation (ventral medial prefrontal cortex (VmPFC) and ventral striatum) during alcohol cue exposure, while those with high SS showed no such activation (p < 0.001, family wise error corrected at 0.05). Furthermore, individuals with lower SS showed greater stress circuit (VmPFC, dorsal striatum, and periaqueductal gray) activation not observed in the high SS groups. Both groups showed increased amygdala activation under stress condition. The findings support the notion that SS is a powerful modulator of stress response and reward motivation. High SS buffers neural and subjective stress responses, while low SS potentiates greater reward seeking with higher alcohol craving and greater brain activation during alcohol cue exposure. Previous research and current results suggest the need to further explore the role of SS in those at risk of developing alcohol use disorder and assess novel prevention strategies to boost SS in at-risk drinkers.

Alcohol withdrawal symptoms predict corticostriatal dysfunction that is reversed by prazosin treatment in alcohol use disorder.

Chronic alcohol use increases risk of alcohol withdrawal symptoms (AW) and disrupts stress biology and resilient coping, thereby promoting excessive alcohol intake. Chronic alcohol intake and multiple alcohol detoxifications are known to impair brain medial prefrontal cortex (mPFC) and striatal functioning, regions involved in regulating stress, craving and alcohol intake. In two related studies, we examined whether AW predicts this functional brain pathology and whether Prazosin versus Placebo treatment may reverse these effects. In Study 1, patients with Alcohol Use Disorder (AUD) (N = 45) with varying AW levels at treatment entry were assessed to examine AW effects on corticostriatal responses to stress, alcohol cue and neutral visual images with functional magnetic resonance imaging (fMRI). In Study 2, 23 AUD patients entering a 12-week randomised controlled trial (RCT) of Prazosin, an alpha1 adrenergic antagonist that decreased withdrawal-related alcohol intake in laboratory animals, participated in two fMRI sessions at pretreatment and also at week 9-10 of chronic treatment (Placebo: N = 13; Prazosin: N = 10) to assess Prazosin treatment effects on alcohol-related cortico-striatal dysfunction. Study 1 results indicated that higher AW predicted greater disruption in brain mPFC and striatal response to stress and alcohol cues (p < 0.001, family-wise error [FWE] correction) and also subsequently greater heavy drinking days (HDD) in early treatment (p < 0.01). In Study 2, Prazosin versus Placebo treatment reversed mPFC-striatal dysfunction (p < 0.001, FWE), which in turn predicted fewer drinking days (p < 0.01) during the 12-week treatment period. These results indicate that AW is a significant predictor of alcohol-related prefrontal-striatal dysfunction, and Prazosin treatment reversed these effects that in turn contributed to improved alcohol treatment outcomes.

Psychological and biological resilience modulates the effects of stress on epigenetic aging.

Our society is experiencing more stress than ever before, leading to both negative psychiatric and physical outcomes. Chronic stress is linked to negative long-term health consequences, raising the possibility that stress is related to accelerated aging. In this study, we examine whether resilience factors affect stress-associated biological age acceleration. Recently developed "epigenetic clocks" such as GrimAge have shown utility in predicting biological age and mortality. Here, we assessed the impact of cumulative stress, stress physiology, and resilience on accelerated aging in a community sample (N = 444). Cumulative stress was associated with accelerated GrimAge (P = 0.0388) and stress-related physiologic measures of adrenal sensitivity (Cortisol/ACTH ratio) and insulin resistance (HOMA). After controlling for demographic and behavioral factors, HOMA correlated with accelerated GrimAge (P = 0.0186). Remarkably, psychological resilience factors of emotion regulation and self-control moderated these relationships. Emotion regulation moderated the association between stress and aging (P = 8.82e-4) such that with worse emotion regulation, there was greater stress-related age acceleration, while stronger emotion regulation prevented any significant effect of stress on GrimAge. Self-control moderated the relationship between stress and insulin resistance (P = 0.00732), with high self-control blunting this relationship. In the final model, in those with poor emotion regulation, cumulative stress continued to predict additional GrimAge Acceleration even while accounting for demographic, physiologic, and behavioral covariates. These results demonstrate that cumulative stress is associated with epigenetic aging in a healthy population, and these associations are modified by biobehavioral resilience factors.

Integrated microRNA and mRNA gene expression in peripheral blood mononuclear cells in response to acute psychosocial stress: a repeated-measures within-subject pilot study.

OBJECTIVE: The impact of psychosocial stress on a variety of negative health outcomes is well documented, with current research efforts directed at possible mechanisms. Here, we focused on a potential mechanism involving differential expression of mRNA and microRNA in response to acute psychosocial stress. We utilized a validated behavioral paradigm, the Trier Social Stress Test (TSST), to induce acute psychosocial stress in a cohort of volunteers. Stress reactivity was assessed repeatedly during the TSST using saliva samples that were analyzed for levels of cortisol. Peripheral blood mononuclear cells were extracted from blood drawn at baseline and at two time points following the stress paradigm. Total RNA was extracted, and mRNA and microRNA microarrays were utilized to assess within-subject changes in gene expression between baseline and the two post-stressor time points. RESULTS: For microarray gene expression analysis, we focused on 12 participants who showed a robust cortisol response to the task, as an indicator of robust HPA-axis activation. We discovered a set of mRNAs and miRNAs that exhibited dynamic expression change in response to the TSST in peripheral blood mononuclear cells, further characterizing the link between psychosocial stress and cellular response mechanisms.