Early life stress is associated with greater negative emotionality and peripheral inflammation in alcohol use disorder.

Early life stress (ELS) increases risk for psychiatric illness, including alcohol use disorder (AUD). Researchers have hypothesized that individuals with and without a history of ELS who have the same primary DSM-5 diagnosis are clinically and biologically distinct. While there is strong support for this hypothesis in the context of mood disorders, the hypothesis remains largely untested in the context of AUD. This study investigated the impact of ELS on the neuroclinical phenomenology and inflammatory profile of individuals with AUD. Treatment-seeking adults with AUD (N = 163) completed the Adverse Childhood Experiences (ACE) Questionnaire and phenotypic battery as part of a pharmacotherapy trial for AUD (NCT03594435). Participants were classified as having "no-ELS," (ACE = 0) "moderate-ELS," (ACE = 1, 2 or 3) or "high-ELS" (ACE = 4 + ). The Addictions Neuroclinical Assessment domains incentive salience and negative emotionality were derived and used to assess the neuroclinical phenomenology of AUD. We tested (1) cumulative ELS as a predictor of ANA domains and (2) ELS group differences in ANA domains. A subset of participants (N = 98) provided blood samples for a biomarker of peripheral inflammation (C-reactive protein; CRP); analyses were repeated with CRP as the outcome variable. Greater ELS predicted higher negative emotionality and elevated CRP, but not incentive salience. The high-ELS group exhibited greater negative emotionality compared with the no-ELS and moderate-ELS groups, with no difference between the latter two groups. The high-ELS group exhibited elevated CRP compared with the no/moderate-ELS group. Findings suggest that high-ELS exposure is associated with a unique AUD neuroclinical presentation marked by greater negative emotionality, and inflammatory profile characterized by elevated peripheral CRP.

Characterizing alcohol cue reactive and non-reactive individuals with alcohol use disorder.

PURPOSE: Exposure to alcohol-related cues is thought to elicit a conditional response characterized by increased craving in individuals with alcohol use disorder (AUD). In the context of AUD research, it is important to consider that not all individuals with an AUD are alcohol cue reactive. This study systematically examined subjective alcohol cue reactivity and its clinical and drinking correlates in individuals with an AUD enrolled in a human laboratory pharmacotherapy trial. METHODS: Individuals with current moderate-to-severe AUD (N = 52) completed a standard alcohol cue exposure paradigm and individual difference assessments as part of a human laboratory pharmacotherapy trial (NCT04249882). We classified participants as cue reactive (CR+) and cue non-reactive (CR-), as indicated by self-reported, subjective alcohol urge, and examined group differences in baseline clinical characteristics and drinking outcomes over the course of the trial. RESULTS: Twenty participants (38%) were identified as CR+, while 32 participants (62%) were identified as CR-. The CR+ and CR- groups did not differ in baseline drinking and AUD clinical characteristics, but the groups differed in race composition (p = 0.02) and smoking prevalence (p = 0.04) such that the CR+ group had lower prevalence of smokers. The CR+, compared with the CR-, group drank more during the trial titration period (p = 0.03). Both groups reduced drinking across the trial (p's < 0.001), but the CR+ group exhibited a smaller reduction in drinking, compared with the CR- group (time x group, p = 0.029; CR-, p < 0.0001; CR+: p = 0.01). CONCLUSION: Results indicate that cue reactivity is a heterogenous construct. Recognizing this heterogeneity, and the clinical factors associated with it, is critical to advancing this paradigm as an early efficacy marker in AUD research.

Anterior cingulate and medial prefrontal cortex alcohol cue reactivity varies as a function of drink preference in alcohol use disorder.

BACKGROUND: Functional MRI visual cue reactivity studies have not considered that brain responses to various alcohol-containing beverage types may vary as a function of an individual's drinking patterns and preferences. This study tested whether the brain's reward system responds differently to visual cues associated with an individuals' most commonly consumed ("preferred") alcohol beverage compared with less commonly consumed ("non-preferred") alcohol beverages in individuals with alcohol use disorder (AUD). METHODS: Participants (N=70) with current AUD completed a standard visual alcohol cue reactivity procedure during fMRI and reported recent alcohol use through the Timeline Followback interview. Alcohol use patterns were used to infer drink preference. Repeated measure ANCOVAs were used to evaluate differences in subjective craving (alcohol urge) and neural reactivity to cues of individual's "preferred" versus "non-preferred" alcohol beverages. RESULTS: Fifty-four (77%) participants were determined to have a "preferred" alcohol beverage, as defined by their pattern of alcohol use. These participants reported greater subjective alcohol urge (p=0.02) and activation in the anterior cingulate cortex (ACC) (p=0.005) and medial prefrontal cortex (mPFC) (p=0.001)) in response to visual cues associated with their "preferred" versus "non-preferred" alcohol beverage. Individuals with an alcohol preference did not differ from those with no alcohol preference on subjective or neural responses to their "preferred" and "non-preferred" alcohol cues. DISCUSSION: Results suggest alcohol cue-elicited subjective and neural responses vary as a function of alcohol beverage preference in individuals with AUD and a behaviorally defined alcohol preference. Stronger ACC and mPFC activation may reflect greater subjective value of an individual's "preferred" alcohol beverage cue.

Ventral prefrontal network response to alcohol in young adults with bipolar disorder: a within-subject randomized placebo-controlled alcohol administration study.

Bipolar disorder co-occurs with alcohol use disorder at a rate 3-5 times higher than the general population. We recently reported that individuals with bipolar disorder differ in the positive stimulating and anxiolytic effects of alcohol compared with healthy peers. This study used a randomized, placebo-controlled, cross-over, within-subject alcohol administration design to investigate neurobiological mechanisms within ventral prefrontal cortical (vPFC) systems that may underlie altered sensitivity to alcohol in bipolar disorder (NCT04063384). Forty-seven young adults (n = 23 with bipolar disorder, 64% women) completed clinical assessment and two beverage administration sessions (alcohol and placebo, counter-balanced). Participants were dosed to 0.08 g% breath alcohol concentration during the alcohol condition and completed measures of subjective response to alcohol and an emotional processing fMRI task during the ascending limb. Timing during the placebo condition mirrored the alcohol session. Acute alcohol was associated with reduced functional connectivity between the insula - subcallosal cingulate cortex, and increased connectivity between the left nucleus accumbens - ventromedial PFC in bipolar disorder, but with no change in functional connectivity between these regions in healthy peers. Alcohol-related increases in nucleus accumbens - ventromedial PFC functional connectivity was associated with greater positive stimulating effects of alcohol in bipolar disorder and heavier recent alcohol use. Results suggest vPFC brain systems respond differently to acute alcohol during emotional processing in young adults with bipolar disorder compared with healthy peers, and that vPFC system responses relate to the subjective experience of intoxication and recent alcohol use.

Subjective response to alcohol: Interactive effects of early life stress, parental risk for mood and substance use disorders, and drinking context.

Early life stress, specifically childhood maltreatment, and parental risk for mood and substance use disorders (SUDs) are associated with increased risk for alcohol use disorder (AUD). There is limited data on how these factors interact to contribute to alcohol-related outcomes. Prior work has suggested early life stress may increase sensitivity to psychostimulants and that subjective response to alcohol is heritable. It is unclear if early life stress alters sensitivity to alcohol and interacts with parental risk for mood/SUDs, which in turn may act as a risk factor for AUD. The current study uses within-subjects placebo-controlled alcohol administration methods to investigate the effects of childhood maltreatment on subjective response to alcohol in young adults with and without parental risk of mood/SUDs. Additionally, we explored interactions with drinking context (i.e., drinking in a bar vs. non-bar context). Within individuals with parental risk for mood/SUDs, there was a positive relation between total Childhood Trauma Questionnaire (CTQ) score and how drunk individuals reported feeling across both alcohol and placebo conditions (parental risk group-by-CTQ interaction p = .01; main effect of CTQ within individuals with parental risk for mood/SUDs p = .005). When exploring interactions with drinking context (bar vs. non-bar context), we observed a significant drinking context-by-parental risk-by-CTQ interaction (p = .03), with CTQ score positively associated with greater positive valence/positive arousal feelings in the parental risk group if they consumed their beverages in the bar context (p = .004) but not if they consumed their beverages in the non-bar context. Results suggest childhood maltreatment may contribute to variation in subjective response to the positive effects of alcohol-possibly mediated by alcohol cues and/or expectancies-in young adults with parental risk for mood/SUDs.

Subjective response to alcohol in young adults with bipolar disorder and recent alcohol use: a within-subject randomized placebo-controlled alcohol administration study.

Limited data exists on mechanisms contributing to elevated risk for alcohol use disorder (AUD) in bipolar disorder. Variation in subjective response to alcohol may relate to alcohol use and risk for AUD. This study used a randomized, placebo-controlled, cross-over, within-subjects design to investigate differences in subjective response to alcohol in 50 euthymic young adults (n = 24 with and n = 26 without bipolar disorder type I). Eighty-three percent of participants with bipolar disorder were medicated. Participants completed assessments of clinical history, alcohol expectancies, and recent alcohol use. Participants were dosed to a .08 g% breath alcohol concentration. The placebo condition occurred on a separate counter-balanced day. Subjective response to alcohol was investigated at similar time points during both conditions. Group, condition, and group-by-condition interactions were modeled, with condition and time of subjective response assessment as repeated within-subject variables, and subjective response to alcohol as the dependent variable. Greater stimulating effects and liking of alcohol were reported in people with bipolar disorder (group-by-condition interactions, p < .05) than healthy young adults. While young adults with bipolar disorder reported anticipating feeling less "mellow/relaxed" when drinking (p = .02), during both beverage conditions they reported feeling more "mellow/relaxed" (main effect of group, p = .006). Feeling more "mellow/relaxed" during the alcohol condition related to greater recent alcohol use in bipolar disorder (p = .001). Exploratory analyses suggested anticonvulsants and sedatives/antihistamines may relate to differences in subjective response to alcohol in bipolar disorder. Results suggest young adults with bipolar disorder may differ in alcohol expectancies and experience alcohol intoxication differently-with distinct relations between subjective response to alcohol and alcohol use-compared to healthy young adults.

Coping drinking motives, neural functional coupling during emotion processing, and alcohol use in young adults with bipolar disorder.

BACKGROUND: Rates of alcohol use disorders in individuals with bipolar disorder are 3 to 5 times greater than in the general population and exceed rates of alcohol use disorders reported in other affective and anxiety disorders. Despite this high rate of comorbidity, our understanding of the psychosocial and neural mechanisms that underlie the initiation of alcohol misuse in young adults with bipolar disorder remains limited. Prior work suggests that individuals with bipolar disorder may misuse alcohol as a coping mechanism, yet the neural correlates of coping drinking motives and associated alcohol use have not been previously investigated in this population. METHODS: Forty-eight young adults (22 bipolar disorder type I, 26 typically developing; 71% women; average age ± standard deviation = 22 ± 2 years) completed the Drinking Motives and Daily Drinking Questionnaires, and a Continuous Performance Functional magnetic resonance imaging (fMRI) Task with Emotional and Neutral Distracters. We calculated the relative difference in anterior cingulate cortex (ACC) functional coupling with the anterior insula and amygdala in response to emotional distracters compared with neutral stimuli and investigated the relations with coping drinking motives and alcohol use. RESULTS: Across all participants, coping drinking motives were associated with greater quantity of recent alcohol use. In individuals with bipolar disorder, greater ACC-anterior insula functional coupling was associated with greater coping drinking motives, and greater quantity and frequency of recent alcohol use. The relative difference in ACC-anterior insula functional coupling was not associated with coping drinking motives or alcohol use in the typically developing group. Greater ACC-anterior insula functional coupling in individuals with bipolar disorder was also associated with greater anxiety symptoms and recent perceived psychological stress. Exploratory analyses suggest that the relations between ACC-anterior insula functional coupling and coping drinking motives may be confounded by anticonvulsant use. CONCLUSION: Results suggest that a difference in ACC-anterior insula functional coupling during emotion processing may underlie alcohol use as a maladaptive coping mechanism in young adults with bipolar disorder.

Alcohol Use and Prefrontal Cortex Volume Trajectories in Young Adults with Mood Disorders and Associated Clinical Outcomes.

(1) Background: Alcohol use in the course of mood disorders is associated with worse clinical outcomes. The mechanisms by which alcohol use alters the course of illness are unclear but may relate to prefrontal cortical (PFC) sensitivity to alcohol. We investigated associations between alcohol use and PFC structural trajectories in young adults with a mood disorder compared to typically developing peers. (2) Methods: 41 young adults (24 with a mood disorder, agemean = 21 ± 2 years) completed clinical evaluations, assessment of alcohol use, and two structural MRI scans approximately one year apart. Freesurfer was used to segment PFC regions of interest (ROIs) (anterior cingulate, orbitofrontal cortex, and frontal pole). Effects of group, alcohol use, time, and interactions among these variables on PFC ROIs at baseline and follow-up were modeled. Associations were examined between alcohol use and longitudinal changes in PFC ROIs with prospective mood. (3) Results: Greater alcohol use was prospectively associated with decreased frontal pole volume in participants with a mood disorder, but not typically developing comparison participants (time-by-group-by-alcohol interaction; p = 0.007); however, this interaction became a statistical trend in a sensitivity analysis excluding one outlier in terms of alcohol use. Greater alcohol use and a decrease in frontal pole volume related to longer duration of major depression during follow-up (p's < 0.05). (4) Conclusion: Preliminary findings support more research on alcohol use, PFC trajectories, and depression recurrence in young adults with a mood disorder including individuals with heavier drinking patterns.

Early life stress and substance use disorders: The critical role of adolescent substance use.

Early life stress (ELS) is a well-established risk factor for many psychiatric and medical disorders, including substance use disorders (SUDs). The relationship between ELS and SUDs is complex and there are likely multiple pathways from ELS to adverse substance use outcomes. The association between ELS and substance use emerges in adolescence. Adolescence is a critical period in development during which substance exposure markedly increases risk for SUDs. Therefore, this review focuses on the literature supporting the hypothesis that ELS increases risk for the development of SUDs through its influence on adolescent substance use. We discuss studies substantiating the role of ELS in adolescent substance use and explore how internalizing and externalizing psychopathology may be antecedents of substance use in adolescence. We examine clinical work suggesting ELS sculpts the Hypothalamic-Pituitary-Adrenal (HPA) Axis and developing brain-particularly subcortical brain regions that underlie stress response, mesocorticolimbic brain systems associated with reward sensitivity, and prefrontal regions that underlie executive control-in a way that increases risk for adolescent substance use and SUDs. We further explore how substance use during adolescence alters structure and function of these same systems, and how brain changes following ELS and adolescent substance use may independently, additively, or interactively contribute to risk for addiction. We conclude by discussing how the current literature can inform interventions aimed at reducing risk for SUDs in individuals with a history of ELS.

Neural functional connectivity changes to psychosocial stress in young adults with bipolar disorder and preliminary associations with clinical trajectories.

BACKGROUND: Stress-related mechanisms are implicated in the pathophysiology of bipolar disorder and may contribute to heterogeneity in illness course. Yet, there is a lack of study investigating the neural mechanisms underlying the stress response in this condition. This study investigated changes in amygdala activation and functional connectivity in response to acute psychosocial stress in young adults with bipolar disorder and explored relations with clinical phenotype and prospective mood symptoms. METHODS: 42 young adults [19 with bipolar disorder, agemean  ± SD =21.4 ± 2.2 years] completed a modified version of the Montreal Imaging Stress Task. Amygdala activation and functional connectivity with prefrontal cortex (PFC) regions of interest was calculated for control and stress conditions. Main effects of group, condition, and group by condition interaction on amygdala activation and connectivity were modeled. A subset of bipolar participants completed 1-year follow-up assessments. Relations between neural responses to stress with concurrent substance use and prospective mood symptoms were explored. RESULTS: There were no between-group differences in amygdala activation or functional connectivity during the control condition. Increased right amygdala-right rostral PFC (rPFC) functional connectivity to stress was observed in bipolar disorder, compared to typically developing controls. In bipolar disorder, greater increase in right amygdala-right rPFC functional connectivity to stress was associated with less frequent cannabis use, and prospectively with shorter duration and lower severity of depression symptoms over follow-up. CONCLUSION: Results from this preliminary study suggest differences in frontolimbic functional connectivity responses to stress in young adults with bipolar disorder and associations with cannabis use and prospective mood symptoms.

Recent Perceived Stress, Amygdala Reactivity to Acute Psychosocial Stress, and Alcohol and Cannabis Use in Adolescents and Young Adults With Bipolar Disorder.

Background: Psychosocial stress negatively affects the clinical course of bipolar disorder. Studies primarily focused on adults with bipolar disorder suggest the impact of stress is progressive, i.e., stress response sensitizes with age. Neural mechanisms underlying stress sensitization are unknown. As stress-related mechanisms contribute to alcohol/substance use disorders, variation in stress response in youth with bipolar disorder may contribute to development of co-occurring alcohol/substance use disorders. This study investigated relations between psychosocial stress, amygdala reactivity, and alcohol and cannabis use in youth with bipolar disorder, compared to typically developing youth. Methods: Forty-two adolescents/young adults [19 with bipolar disorder, 23 typically developing, 71% female, agemean ± SD = 21 ± 2 years] completed the Perceived Stress Scale (PSS), Daily Drinking Questionnaire modified for heaviest drinking week, and a modified Montreal Imaging Stress functional MRI Task. Amygdala activation was measured for both the control and stress conditions. Main effects of group, condition, total PSS, and their interactions on amygdala activation were modeled. Relationships between amygdala response to acute stress with recent alcohol/cannabis use were investigated. Results: Greater perceived stress related to increased right amygdala activation in response to the stress, compared to control, condition in bipolar disorder, but not in typically developing youth (group × condition × PSS interaction, p = 0.02). Greater amygdala reactivity to acute stress correlated with greater quantity and frequency of alcohol use and frequency of cannabis use in bipolar disorder. Conclusion: Recent perceived stress is associated with changes in amygdala activation during acute stress with amygdala reactivity related to alcohol/cannabis use in youth with bipolar disorder.

Childhood maltreatment, prefrontal-paralimbic gray matter volume, and substance use in young adults and interactions with risk for bipolar disorder.

Childhood maltreatment is associated with adverse effects on the brain, and an increased risk for psychopathology, including mood and substance use disorders. Individuals vary on the degree to which they exhibit neurobiological and clinical differences following maltreatment. Individuals with bipolar disorder exhibit greater magnitude of maltreatment-related prefrontal-paralimbic gray matter volume (GMV) deficits compared to typically developing individuals. It is unclear if greater structural differences stem from greater neural vulnerability to maltreatment in bipolar disorder, or if they relate to presence of other clinical features associated with childhood maltreatment, e.g., elevated prevalence of comorbid substance use disorders. To investigate this, we compared young adults with a family history of bipolar disorder (n = 21), but who did not fulfill diagnostic criteria for bipolar disorder, with typically developing young adults without a family history of bipolar disorder (n = 26). Participants completed structural neuroimaging, clinical and family history interviews, and assessment of childhood maltreatment and recent alcohol and cannabis use patterns. We examined relations between childhood maltreatment and prefrontal-paralimbic GMV by modeling main effects of maltreatment and family history group by maltreatment interactions on prefrontal-paralimbic GMV. We also examined relations between maltreatment and associated GMV changes with recent alcohol and cannabis use. Childhood maltreatment correlated with lower ventral, rostral and dorsolateral prefrontal and insular cortical GMV across all participants regardless of the presence or absence of familial history of bipolar disorder. However, exploratory analyses did reveal greater maltreatment-related GMV differences in individuals with prodromal symptoms of depression. Lower insula GMV was associated with greater frequency of cannabis use across all participants and greater quantity of alcohol use only in those with familial risk for bipolar disorder. Results suggest familial risk for bipolar disorder, and presumably genetic risk, may relate to outcomes following childhood maltreatment and should be considered in prevention/early intervention strategies.

Subjective response to alcohol: Associated alcohol use and orbitofrontal gray matter volume in bipolar disorder.

BACKGROUND: Alcohol use disorders (AUDs) are highly prevalent in bipolar disorder, however the developmental etiology of this comorbidity remains unknown. Structural differences in the orbitofrontal cortex (OFC) have been linked to problematic drinking in bipolar disorder and typically developing youth, with evidence implicating variations in OFC in differential subjective response to alcohol in typical development. METHODS: Subjective response to alcohol, recent alcohol use, impulsivity, and variation in OFC gray matter volume were investigated in 48 emerging adults (24 with bipolar disorder, 24 typically developing). On average 1.5 years later, drinking patterns were reassessed and relations between subjective response and changes in alcohol use were explored. RESULTS: Groups did not differ in baseline alcohol use or subjective response. At baseline, decreased subjective response to alcohol was associated with increased alcohol use in both groups. Lower gray matter volume in medial OFC in bipolar disorder was associated with increased subjective response to alcohol, whereas lower gray matter volume in OFC in typically developing participants was associated with decreased subjective response to alcohol. Increase in alcohol use (baseline to follow-up) was associated with increased baseline subjective response to alcohol in bipolar disorder, and decreased baseline subjective response in the typically developing group. LIMITATIONS: Preliminary study with a small sample size. CONCLUSION: Underlying OFC biology may contribute to differences in alcohol sensitivity in bipolar disorder which may also relate to prospective changes in alcohol use patterns. Future studies are needed to examine how these factors prospectively relate to development of AUDs in bipolar disorder.