Empirical findings from human laboratory and brain-imaging studies are consistent with clinical observations and indicate that chronic alcohol-related dysfunction in emotional and stress responses plays a role in motivation to consume alcohol in people with alcohol use disorders. Recent findings on differences in stress responsivity in alcohol-dependent versus nondependent social drinkers demonstrate alterations in stress pathways that partially may explain the significant contribution of stress-related mechanisms on craving and relapse susceptibility. These findings have significant implications for clinical practice, including (1) the development of novel brain and stress biology–related measures of relapse risk that could serve as biomarkers to identify those most at risk of alcohol relapse during early recovery from alcoholism; and (2) the development of novel interventions that target stress-related effects on the motivation to drink alcohol and on relapse outcomese
Alcoholism; alcohol dependence; alcohol and other drug (AOD)-seeking behavior; AOD craving; alcohol cue; relapse; relapse prevention; recovery; motivation; risk factors; stress; stress response; brain; brain imaging; biomarker; intervention; human studies
Alcohol dependence is a chronic relapsing illness; stress, alcohol-related cues, and neutral-relaxing states significantly influence craving and relapse risk. However, neural mechanisms underlying the association between these states and alcohol craving and relapse risk remain unclear.
To identify neural correlates associated with alcohol craving and relapse outcomes in 45 treatment-engaged, 4- to 8-week abstinent alcohol-dependent (AD) patients, and to compare brain responses of 30 demographically matched AD patients and 30 healthy control subjects during stress, alcohol, and neutral-relaxing cues.
Functional magnetic resonance imaging study while participants were engaging in brief individualized script-driven imagery trials of stress, alcohol cues, and neutral-relaxing scenarios, and a prospective clinical outcome design to assess alcohol relapse 90 days postdischarge from inpatient treatment in the AD group.
Inpatient treatment setting in a community mental health center and hospital-based research unit.
Forty-five recovering AD patients in inpatient treatment for examining relapse, and 30 healthy control subjects demographically matched to 30 AD patients (subgroup of the relapse sample) for group comparisons.
Twelve-step recovery–based addiction treatment for the patient group.
Main Outcomes and Measures
Brain response, alcohol craving, and relapse outcome measures (time to relapse and relapse severity).
Increased ventromedial prefrontal cortex (vmPFC) and anterior cingulate cortex (ACC) activation during neutral-relaxing trials was correlated with high alcohol cue–induced and stress-induced craving in early recovering AD patients (x=6, y=43, z= −6; P <.01, whole-brain corrected). This vmPFC/ACC hyperactivity significantly predicted subsequent alcohol relapse, with a hazards ratio greater than 8 for increased relapse risk. Additionally, vmPFC/ACC hyperactivation during neutral trials and reduced activity during stress trials were each predictive of greater days of alcohol used after relapse (P <.01, whole-brain corrected). In contrast, matched control subjects showed the reverse pattern of vmPFC/ACC responses to stress, alcohol cues, and relaxed trials (F=6.42; P <.01, whole-brain corrected).
Conclusions and Relevance
Findings indicate that disrupted vmPFC/ACC function plays a role in jeopardizing recovery from alcoholism and may serve as a neural marker to identify those at risk for alcohol relapse.
Substance abuse treatment programs are often characterized by high rates of premature treatment dropout, which increases the likelihood of relapse to drug use. Negative reinforcement models of addiction emphasize an individual’s inability to tolerate stress as a key factor for understanding poor substance use treatment outcomes, and evidence indicates that dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis contributes to an individual’s inability to respond adaptively to stress. The aim of the current study was to examine whether HPA axis response to stress is predictive of treatment retention among a sample of drug users in residential substance abuse treatment.
Prospective study assessing treatment retention among 102 individuals enrolled in residential substance abuse treatment. Participants completed two computerized stress tasks, and HPA axis response to stress was measured via salivary cortisol at five time points from baseline (pre-stress) to 30 min post-stress exposure.
The main outcome measures were treatment dropout (categorical) and total number of days in treatment (continuous). A significantly higher salivary cortisol response to stress was observed in treatment dropouts compared to treatment completers. Further, Cox proportional hazards survival analyses indicated that a higher peak cortisol response to stress was associated with a shorter number of days to treatment dropout.
Results indicate that a higher salivary cortisol level in response to stress is associated with an inability to remain in substance abuse treatment. These findings are the first to document a biological marker of stress as a predictor of substance abuse treatment dropout, and support the development and implementation of treatments targeting this vulnerability.
Endocrinology; Stress; Cortisol; HPA axis; Residential; Treatment
Understanding the biologic systems that underlie the relationship between stress and alcohol consumption may lead to better prevention efforts and more effective treatments for alcoholism. Clinical laboratory studies offer a unique opportunity to examine these relationships by using a controlled environment to study how an acute stressor affects alcohol drinking and alcohol craving, how individuals in recovery or those at risk for alcoholism may respond differently to stressors relative to control subjects, and how alcohol differentially affects stress reactivity in these groups. This article reviews some of the most common physical, psychological, and pharmacological stressors used in stress-induction studies designed to reveal details about the relationship between stress reactivity and alcohol use and abuse.
Alcohol consumption; alcohol use and abuse; alcoholism; stress; stressor; physiological stressor; psychological stressor; pharmacological stressor; biological adaptation to stress; stress reactivity; stress-induction study; clinical study; laboratory study; controlled study
Pre-clinical and clinical studies have implicated changes in cytokine and innate immune gene-expression in both the development of and end-organ damage resulting from alcohol dependence. However, these changes have not been systematically assessed on the basis of alcohol consumption in human subjects.
Illumina Sentrix Beadchip (Human-6v2) microarrays were used to measure levels of gene-expression in peripheral blood in 3 groups of subjects: those with alcohol dependence (AD, n=12), heavy drinkers (HD, defined as regular alcohol use over the past year of at least 8 standard drinks/week for women and at least 15 standard drinks/week for men, n=13), and moderate drinkers (MD, defined as up to 7 standard drinks/week for women and 14 standard drinks/week for men, n=17).
436 genes were differentially expressed among the three groups of subjects (FDR corrected p-value < 0.05). 291 genes differed between AD and MD subjects, 240 differed between AD and HD subjects, but only 6 differed between HD and MD subjects. Pathway analysis using DAVID and GeneGO Metacore software showed that the most affected pathways were those related to T-cell receptor and JAK-Stat (Janus kinase-Signal transducer and activator of transcription) signaling.
These results suggest the transition from heavy alcohol use to dependence is accompanied by changes in the expression of genes involved in regulation of the innate immune response. Such changes may underlie some of the previously described changes in immune function associated with chronic alcohol abuse. Early detection of these changes may allow individuals at high risk for dependence to be identified.
alcohol dependence; IL-15; IL-21; Janus kinase; Signal transducer and activator of transcription; microarray
An important endeavor involves increasing our understanding of biobehavioral processes underlying different types of obesity. The current study investigated the neural correlates of cognitive control (involving conflict monitoring and response inhibition) in obese individuals with binge eating disorder (BED) as compared to BMI-matched non-BED obese (OB) individuals and lean comparison (LC) participants. Alterations in cognitive control may contribute to differences in behavioral control over eating behaviors in BED and obesity. Participants underwent functional magnetic resonance imaging (fMRI) while completing the Stroop color-word interference task. Relative to the OB and LC groups, activity in the BED group was differentiated by relative hypoactivity in brain areas involved in self-regulation and impulse control. Specifically, the BED group showed diminished activity in the ventromedial prefrontal cortex (vmPFC), inferior frontal gyrus (IFG) and insula during Stroop performance. In addition, dietary restraint scores were negatively correlated with right IFG and vmPFC activation in the BED group, but not in the OB or HC groups. Thus, BED individuals’ diminished ability to recruit impulse-control-related brain regions appears associated with impaired dietary restraint. The observed differences in neural correlates of inhibitory processing in BED relative to OB and LC groups suggest distinct neurobiological contributions to binge eating as a subgroup of obese individuals.
binge eating disorder; obesity; inhibition; ventromedial prefrontal cortex; inferior frontal gyrus; restraint; fMRI
Cumulative adversity and stress are associated with risk of psychiatric disorders. While basic science studies show repeated and chronic stress effects on prefrontal and limbic neurons, human studies examining cumulative stress and effects on brain morphology are rare. Thus, we assessed whether cumulative adversity is associated with differences in gray matter volume, particularly in regions regulating emotion, self-control, and top-down processing in a community sample.
One hundred three healthy community participants, aged 18 to 48 and 68% male, completed interview assessment of cumulative adversity and a structural magnetic resonance imaging protocol. Whole-brain voxel-based-morphometry analysis was performed adjusting for age, gender, and total intracranial volume.
Cumulative adversity was associated with smaller volume in medial prefrontal cortex (PFC), insular cortex, and subgenual anterior cingulate regions (familywise error corrected, p <.001). Recent stressful life events were associated with smaller volume in two clusters: the medial PFC and the right insula. Life trauma was associated with smaller volume in the medial PFC, anterior cingulate, and subgenual regions. The interaction of greater subjective chronic stress and greater cumulative life events was associated with smaller volume in the orbitofrontal cortex, insula, and anterior and subgenual cingulate regions.
Current results demonstrate that increasing cumulative exposure to adverse life events is associated with smaller gray matter volume in key prefrontal and limbic regions involved in stress, emotion and reward regulation, and impulse control. These differences found in community participants may serve to mediate vulnerability to depression, addiction, and other stress-related psychopathology.
Brain MRI; chronic stress; cumulative adversity; gray matter volume; life trauma; prefrontal cortex; recent adverse life events
Cocaine dependence is associated with increased stress and drug cue-induced craving and physiological arousal but decreased prefrontal activity to emotional and cognitive challenge. As these changes are associated with relapse risk, we investigated the effects of α2 receptor agonist guanfacine on these processes. Twenty-nine early abstinent treatment-seeking cocaine dependent individuals were randomly assigned to either daily placebo or guanfacine (up to 3 mg) for four weeks. In a laboratory experiment, all patients were exposed to three 10-min guided imagery conditions (stress/stress, drug cue/drug cue, stress/drug cue), one per day, consecutively in a random, counterbalanced order. Subjective craving, anxiety and arousal as well as cardiovascular output were assessed repeatedly. Brain response to stress, drug cue and relaxing imagery was also assessed during a functional magnetic resonance (fMRI) imaging session. In the current study, guanfacine was found to be safe and well-tolerated. Lower basal heart rate and blood pressure was observed in the guanfacine versus placebo group. Guanfacine lowered stress and cue-induced nicotine craving and cue-induced cocaine craving, anxiety and arousal. The guanfacine group also showed increased medial and lateral prefrontal activity following stress and drug cue exposure compared with placebo. Data suggest further exploration of guanfacine is warranted in terms of its potential for reducing stress-induced and cue-induced drug craving and arousal.
Cocaine abuse; drug craving; drug cue; fMRI; guanfacine; prefrontal activation; stress
Cocaine dependence is associated with neuroadaptations in stress and reward pathways that could alter stress and drug-related experiences and associated interoceptive sensations and result in enhanced craving states. Subjective interoceptive emotional and physiological responses experienced in stressful and drug cue situations were examined in abstinent cocaine-dependent individuals. Fifty-six treatment engaged cocaine-dependent patients with comorbid alcohol abuse or dependence were interviewed to identify personal stressful, drug cue, and neutral situations using a scene construction questionnaire (SCQ) that includes an emotional and physiological response checklist. Using this checklist, subjects identified emotional and bodily sensations that they recently experienced in the stress- and drug-related scenarios. Kappa coefficients indicated fair to moderate but significant degree of concordance in heart (p < .01), perspiration (p < .05), stomach (p < .05), and blood flow (p < .01) sensations for both stress and drug cue scenarios, while the McNemar change test indicated differential endorsement of interoceptive responses in stress and drug cue situations for breathing (p < .05), stomach (p < .05), tension (p < .05), and chest (p < .05) sensations, and for sad (p < .01), anger (p < .01), and excitement (p < .01) responses. Increased heartbeat and tension, tears, and anger urges were most commonly endorsed in the stress scenarios (between 50% and 79%), whereas butterflies in stomach, increased heartbeat and tension, jittery, restless, and warm excitement (53%–73%) were the most frequently endorsed sensations in the drug cue-related experiences. These self-reported sensations comprise both general arousal and specific interoceptive responses pertaining to stress or drug cue-related experiences in cocaine dependence, with potential value in guiding treatments targeting craving reduction.
cocaine dependence; stress and drug cues; interoceptive responses; drug craving
Although stress and drug cue exposure each increase drug craving and contribute to relapse in cocaine dependence, no previous research has directly examined the neural correlates of stress-induced and drug cue-induced craving in cocaine-dependent women and men relative to comparison subjects.
Functional MRI was used to assess responses to individualized scripts for stress, drug/alcohol cue and neutral-relaxing-imagery conditions in 30 abstinent cocaine-dependent individuals (16 women, 14 men) and 36 healthy recreational-drinking comparison subjects (18 women, 18 men).
Significant three-way interactions between diagnostic group, sex, and script condition were observed in multiple brain regions including the striatum, insula, and anterior and posterior cingulate. Within women, group-by-condition interactions were observed involving these regions and were attributable to relatively increased regional activations in cocaine-dependent women during the stress and, to a lesser extent, neutral-relaxing conditions. Within men, group main effects were observed involving these same regions, with cocaine-dependent men demonstrating relatively increased activation across conditions, with the main contributions from the drug and neutral-relaxing conditions. In men and women, subjective drug-induced craving measures correlated positively with corticostriatal-limbic activations.
In cocaine dependence, corticostriatal-limbic hyperactivity appears to be linked to stress cues in women, drug cues in men, and neutral-relaxing conditions in both. These findings suggest that sex should be taken into account in the selection of therapies in the treatment of addiction, particularly those targeting stress reduction.
It is well known that alcoholism is a chronic relapsing illness. While stress significantly impacts alcoholism risk, there is also evidence that increasing levels of alcohol use affect peripheral and central stress and reward pathways thereby setting up a reciprocal relationship among the effects of alcohol consumption of the development, course of and recovery from alcoholism. This chapter reviews our efforts in assessing the integrity of stress pathways in alcoholism by examining whether altered responses of the stress pathways play a role in relapse risk. Using validated human laboratory procedures to model two of the most common situations that contribute to relapse risk, we review how such models in the laboratory can predict subsequent alcohol relapse. Empirical findings from human laboratory and brain imaging studies are reviewed to show that specific stress-related dysregulation accompanies the alcohol craving state in alcohol-dependent individuals, and such dysregulation along with increases in alcohol seeking are predictive of increased alcohol relapse risk. Finally, the significant implications of these findings for the development of novel treatment interventions that target stress processes and alcohol craving to improve alcoholism relapse outcomes are discussed.
Relapse precipitants; Human laboratory models; Stress; Drug cues; Drug craving; Relapse risk
Alcohol addiction may reflect adaptations to stress, reward, and regulatory brain systems. While extensive research has identified both stress and impulsivity as independent risk factors for drinking, few studies have assessed the interactive relationship between stress and impulsivity in terms of hazardous drinking within a community sample of regular drinkers.
One hundred and thirty regular drinkers (56M/74F) from the local community were assessed for hazardous and harmful patterns of alcohol consumption using the Alcohol Use Disorders Identification Test (AUDIT). All participants were also administered the Barratt Impulsiveness Scale (BIS-11) as a measure of trait impulsivity and the Cumulative Stress/Adversity Checklist (CSC) as a comprehensive measure of cumulative adverse life events. Standard multiple regression models were used to ascertain the independent and interactive nature of both overall stress and impulsivity as well as specific types of stress and impulsivity on hazardous and harmful drinking.
Recent life stress, cumulative traumatic stress, overall impulsivity, and nonplanning-related impulsivity as well as cognitive and motor-related impulsivity were all independently predictive of AUDIT scores. However, the interaction between cumulative stress and total impulsivity scores accounted for a significant amount of the variance, indicating that a high to moderate number of adverse events and a high trait impulsivity rating interacted to affect greater AUDIT scores. The subscale of cumulative life trauma accounted for the most variance in AUDIT scores among the stress and impulsivity subscales.
Findings highlight the interactive relationship between stress and impulsivity with regard to hazardous drinking. The specific importance of cumulative traumatic stress as a marker for problem drinking is also discussed.
Impulsivity; Cumulative Stress; Alcohol Consumption; Trauma; Community Sample
Relapse is a highly prevalent phenomenon in addiction. This paper examines the new research on identifying biological factors that contribute to addiction relapse risk. Prospective studies examining relapse risk are reviewed, and clinical, biological, and neural factors that predict relapse risk are identified. Clinical factors, patient-related factors, and subjective and behavioral measures such as depressive symptoms, stress, and drug craving all predict future relapse risk. Among biological measures, endocrine measures such as cortisol and cortisol/corticotropin (ACTH) ratio as a measure of adrenal sensitivity and serum brain-derived neurotrophic factor were also predictive of future relapse risk. Among neural measures, brain atrophy in the medial frontal regions and hyperreactivity of the anterior cingulate during withdrawal were identified as important in drug withdrawal and relapse risk. Caveats pertaining to specific drug abuse type and phase of addiction are discussed. Finally, significant implications of these findings for clinical practice are presented, with a specific focus on determining biological markers of relapse risk that may be used to identify those individuals who are most at risk of relapse in the clinic. Such markers may then be used to assess treatment response and develop specific treatments that will normalize these neural and biological sequelae so as to significantly improve relapse outcomes.
Addiction relapse; Stress dysregulation; Drug craving; Cortisol; Cortisol/ACTH ratio; Serum BDNF; Anterior cingulate; Biomarkers; Human studies; Biological factors; Vulnerability
Cocaine dependence is a chronic stress state. Furthermore, both stress and substance abuse have robust and reciprocal effects on immune system cytokines, which are known to be powerful modulators of mood. We therefore examine basal and provoked changes in peripheral cytokines in cocaine dependent individuals to better understand their role in the negative reinforcing effects of cocaine.
Twenty-eight (16 F/12 M) treatment-seeking cocaine dependent individuals and 27 (14 F/13 M) social drinkers were exposed to three 5-min guided imagery conditions (stress, drug cue, relaxing) presented randomly across consecutive days. Measures of salivary cortisol, tumor necrosis factor alpha (TNFα), interleukin-10 (IL-10), and interleukin-1 receptor antagonist (IL-1ra) were collected at baseline and various post-imagery time-points.
Cocaine abusers demonstrated decreased basal IL-10 compared with social drinkers. They also showed significant elevations in pro-inflammatory TNFα when exposed to stress compared with when they were exposed to relaxing imagery. This was not observed in the social drinkers. Conversely, social drinkers demonstrated increases in the anti-inflammatory markers, IL-10 and IL-1ra, following exposure to cue, which were not seen in the dependent individuals.
Cocaine dependent individuals demonstrate an elevated inflammatory state both at baseline and following exposure to the stress imagery condition. Cytokines may reflect potentially novel biomarkers in addicted populations for treatment development.
cocaine dependence; HPA axis; cytokines; TNFα; IL-10; IL-1ra
Although the effects of alcohol on brain-derived neurotrophic factor (BDNF) have been extensively studied in rodents, BDNF levels have rarely been measured in abstinent, alcohol-dependent (AD) individuals. Interpretation of reported group comparisons of serum BDNF levels is difficult due to limited information regarding analytical variance, biological variability, and the relative contribution of platelet and plasma pools to serum BDNF. Analytical variance (intra- and inter-assay coefficients of variation) of the enzyme-linked immunosorbent assay (ELISA) was characterized. Within- and between-subject variability, and group differences in serum and plasma BDNF, was assessed on three separate days in 16, 4-week abstinent AD individuals (7M/9F) and 16 social drinkers (SDs; 8M/8F). Significantly higher mean (±sd) serum BDNF levels were observed for the AD group compared to the SD (p = 0.003). No significant difference in mean baseline plasma BDNF levels was observed between AD and SD groups. The low analytical variance, high day-to-day within-individual stability and the high degree of individuality demonstrates the potential clinical utility of measuring serum BDNF levels. The low correlations that we observed between plasma and serum levels are congruent with their representing separate pools of BDNF. The observation of higher basal serum BDNF in the AD group without a concomitant elevation in plasma BDNF levels indicates that the elevated serum BDNF in AD patients is not due to greater BDNF exposure. Further research is warranted to fully elucidate mechanisms underlying this alteration and determine the utility of serum BDNF as a predictor or surrogate marker of chronic alcohol abuse.
Alcoholism; BDNF; ELISA; Plasma; Serum; Abstinence
Stress and impulsivity contribute to alcohol use, and stress may also act via impulsivity to increase drinking behavior. Impulsivity represents a multi-faceted construct and self-report and behavioral assessments may effectively capture distinct clinically relevant factors. The present research investigated whether aspects of impulsivity mediate the effect of stress on alcohol use. A community-based sample of 192 men and women was assessed on measures of cumulative stress, alcohol use, self-reported impulsivity, and behavioral choice and response impulsivity. Data were analyzed using regression and bootstrapping techniques to estimate indirect effects of stress on drinking via impulsivity. Cumulative adversity exhibited both direct effects and indirect effects (via self-reported impulsivity) on drinking behavior. Additional models examining specific types of stress indicated direct and indirect effects of trauma and recent life events, and indirect effects of major life events and chronic stressors on drinking behavior. Overall, cumulative stress was associated with increased drinking behavior, and this effect was partially mediated by self-reported impulsivity. Self-reported impulsivity also mediated the effects of different types of stress on drinking behavior. These findings highlight the value of mediation models to examine the pathways through which different types of stress increase drinking behavior. Treatment and prevention strategies should focus on enhancing stress management and self-control.
Alcohol use; self-reported impulsivity; choice impulsivity; response impulsivity; mediation; stress
Hazardous drinking is characterized by decisions to engage in excessive or risky patterns of alcohol consumption. Levels of impulsivity and behavioral approach and inhibition may differ in hazardous drinkers and nonhazardous drinkers. A comparison of the relative levels of dimensions of impulsivity and behavioral inhibition and approach in adult men and women hazardous and nonhazardous drinkers may inform treatment and prevention efforts.
In the present research, 466 men and women from a community sample were administered the Alcohol Use Disorders Identification Test (AUDIT), the Behavioral Inhibition System/Behavioral Approach System (BIS/BAS) Scale, and the Barratt Impulsiveness Scale, version 11 (BIS-11). Relations among the dimensions of these constructs were examined using Multivariate Analysis of Covariance (MANCOVA), with age and race as covariates.
There were main effects of hazardous drinking on all three dimensions of impulsivity, the behavioral inhibition system, and the behavioral activation system Reward-Responsiveness, and Fun-Seeking components, with hazardous drinkers scoring higher than non-hazardous drinkers.
This research provides a better understanding of the manner in which impulsivity and behavioral inhibition and approach tendencies relate to hazardous alcohol use in men and women. The present results have implications for alcohol-related prevention and treatment strategies for adult men and women.
impulsivity; behavioral approach; behavioral inhibition; hazardous drinking; sex
Alcoholism is associated with gray matter volume deficits in frontal and other brain regions. Whether persistent brain volume deficits in abstinence are predictive of subsequent time to alcohol relapse has not been established. The authors measured gray matter volumes in healthy volunteers and in a sample of treatment-engaged, alcohol-dependent patients after 1 month of abstinence and assessed whether smaller frontal gray matter volume was predictive of subsequent alcohol relapse outcomes.
Forty-five abstinent alcohol-dependent patients in treatment and 50 healthy comparison subjects were scanned once using high-resolution (T1-weighted) structural MRI, and voxel-based morphometry was used to assess regional brain volume differences between the groups. A prospective study design was used to assess alcohol relapse in the alcohol-dependent group for 90 days after discharge from 6 weeks of inpatient treatment.
Significantly smaller gray matter volume in alcohol-dependent patients relative to comparison subjects was seen in three regions: the medial frontal cortex, the right lateral prefrontal cortex, and a posterior region surrounding the parietal-occipital sulcus. Smaller medial frontal and parietal-occipital gray matter volumes were each predictive of shorter time to any alcohol use and to heavy drinking relapse.
These findings are the first to demonstrate that gray matter volume deficits in specific medial frontal and posterior parietal-occipital brain regions are predictive of an earlier return to alcohol use and relapse risk, suggesting a significant role for gray matter atrophy in poor clinical outcomes in alcoholism. Extent of gray matter volume deficits in these regions could serve as useful neural markers of relapse risk and alcoholism treatment outcome.
Alcoholism is a chronic, relapsing illness in which stress and alcohol cues contribute significantly to relapse risk. Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, increased anxiety, and high alcohol craving have been documented during early alcohol recovery, but their influence on relapse risk has not been well studied.
To investigate these responses in treatment-engaged, 1-month-abstinent, recovering alcohol-dependent patients relative to matched controls (study 1) and to assess whether HPA axis function, anxiety, and craving responses are predictive of subsequent alcohol relapse and treatment outcome (study 2).
Experimental exposure to stress, alcohol cues, and neutral, relaxing context to provoke alcohol craving, anxiety, and HPA axis responses (corticotropin and cortisol levels and cortisol to corticotropin ratio) and a prospective 90-day follow-up outcome design to assess alcohol relapse and aftercare treatment outcomes.
Inpatient treatment in a community mental health center and hospital-based research unit.
Treatment-engaged alcohol-dependent individuals and healthy controls.
Main Outcome Measures
Time to alcohol relapse and to heavy drinking relapse.
Significant HPA axis dysregulation, marked by higher basal corticotropin level and lack of stress- and cue-induced corticotropin and cortisol responses, higher anxiety, and greater stress- and cue-induced alcohol craving, was seen in the alcohol-dependent patients vs the control group. Stress- and cue-induced anxiety and stress-induced alcohol craving were associated with fewer days in aftercare alcohol treatment. High provoked alcohol craving to both stress and to cues and greater neutral, relaxed-state cortisol to corticotropin ratio (adrenal sensitivity) were each predictive of shorter time to alcohol relapse.
These results identify a significant effect of high adrenal sensitivity, anxiety, and increased stress- and cue-induced alcohol craving on subsequent alcohol relapse and treatment outcomes. Findings suggest that new treatments that decrease adrenal sensitivity, stress- and cue-induced alcohol craving, and anxiety could be beneficial in improving alcohol relapse outcomes.
Experience with and management of stress has implications for adolescents’ behavioral and socioemotional development. This study examined the relationship between adolescents’ physiological response to an acute laboratory stressor (i.e., Trier Social Stress Test; TSST) and anger regulation and interpersonal competence in a sample of 175 low-income urban adolescents (51.8% girls). Findings suggested that heightened reactivity as indicated by cortisol, heart rate, and blood pressure was associated with increased interpersonal competence and anger regulation. However, these findings were context dependent such that, for youth high in self-reported child maltreatment, heightened reactivity was associated with decreased interpersonal competence and anger regulation. Results highlight the importance of considering how context may condition the effect of stress reactivity on functioning during adolescence.
Adolescence; Anger regulation; Child maltreatment; Interpersonal competence; Stress reactivity
We examined male and female adolescents (8–18 years of age) that were scanned with structural brain MRI and looked for a correlation between volume of the right or the left amygdala and parent-reported ability of emotional control. A sex difference was found in the correlation between emotional control and the corrected volume of the left amygdala (that is the amygdala volume adjusted for total cranial volume). In girls, smaller left amygdala volumes were associated with better emotional control. In boys, larger left amygdala volumes were associated with better emotional control. These findings suggest that healthy girls and boys show a difference in the correlation between parental reports of emotional control and the left amygdala volume.
adolescents; amygdala volume; MRI
One important factor in adolescents’ development of problem alcohol use is their family environment. Yet, the mechanisms that relate parenting to youth alcohol use are not well characterized. This study employed a naturalistic laboratory-based approach to observe parenting behaviors (support, structure, criticism) and adolescents’ physiological and emotional responses to parent-adolescent interactions to examine associations with adolescent alcohol use.
Fifty eight 10–16 year olds and their parents completed a 10 minute Parent Adolescent Interaction Task (PAIT) in which they discussed a mutually highly-rated conflict topic. Parental support, structure, and critcism were coded from the interaction. Adolescents’ heart rate (HR), blood pressure (BP), reported emotions, and salivary cortisol were assessed before, during, and after the interaction.
Findings indicated that lower parental structure and support were associated with youth’s greater diastolic BP and anger arousal in response to the PAIT. Furthermore, higher HR, systolic BP, and cortisol responses to the interaction were associated with youth’s alcohol use.
Findings suggest that heightened emotional and physiological responses to parent-adolescent conflict interactions in youth may be one pathway by which parenting is associated with youth’s alcohol use and risk for abuse.
alcohol use; adolescence; emotion; HPA axis; parent-child interaction; parenting
Overweight or obese body habitus is associated with cognitive deficits, impaired brain function, gray matter atrophy, and white matter (WM) hyperintensities. However, few diffusion tensor imaging (DTI) studies have assessed WM integrity in relation to overweight or obese status. This study assessed relationships between body mass index (BMI) and values of DTI parameters among 51 normal-weight (lean), overweight and obese participants who were otherwise healthy. BMI correlated negatively with fractional anisotropy (FA) and axial eigenvalues (λ1) in the body of corpus callosum (CC), positively with mean diffusivity and radial eigenvalues (λ□) in the fornix and splenium of CC, and positively with λ1 in the right corona radiata (CR) and superior longitudinal fasciculus (SLF). These data indicate that BMI correlates negatively with WM integrity in the fornix and CC. Furthermore, the different patterns of BMI-related differences in DTI parameters at the fornix, body and splenium of the CC, and the right CR and SLF suggest that different biological processes may underlie BMI-related impairments of WM integrity in different brain regions.
DTI; obese; overweight; neuroimaging; BMI; brain structure
Neuropeptide Y (NPY) is involved in stress regulation. Genetic variations predict plasma NPY and neural correlates of emotion and stress. We examined whether the functional NPY haplotype modulates stress-induced NPY and anxiety responses, and if plasma NPY stress responses are associated with substance dependence outcomes.
Thirty-seven treatment-engaged, abstinent substance dependent patients (SD) and 28 controls (HC) characterized on NPY diplotypes (HH: high expression; HLLL: intermediate/low expression) were exposed to stress, alcohol/drug cues and neutral relaxing cues, using individualized guided imagery, in a 3-session laboratory experiment. Plasma NPY, heart rate and anxiety were assessed. Patients were prospectively followed for 90-days post-treatment to assess relapse outcomes.
HH individuals showed significantly lower stress-induced NPY with greater heart rate and anxiety ratings, while the HLLL group showed the reverse pattern of NPY, anxiety and heart rate responses. This differential genetic modulation of NPY stress response was suppressed in the SD group, who showed no stress-related increases in NPY and higher heart rate and greater anxiety, regardless of diplotype. Lower NPY predicted subsequent higher number of days and greater amounts of post-treatment drug use.
These preliminary findings are the first to document chronic drug abuse influences on NPY diplotype expression where NPY diplotype modulation of stress-related plasma NPY, heart rate and anxiety responses was absent in the substance abuse sample. The finding that lower stress-related NPY is predictive of greater relapse severity provides support for therapeutic development of neuropeptide Y targets in the treatment of substance use disorders.
Neuropepetide Y; Functional Haplotype; Stress; Substance Use Disorders
To study the relationship between self-reported childhood maltreatment and cerebral gray matter in adolescents without psychiatric diagnoses.
Associations between childhood maltreatment (measured by a childhood trauma self-report questionnaire for physical, emotional and sexual abuse, and physical and emotional neglect) and regional gray matter were examined.
42 adolescents without psychiatric disorders.
Correlations between childhood trauma questionnaire scores and regional gray matter volume were assessed in voxel-based analyses of structural magnetic resonance scans. Relationships between gray matter volume and childhood maltreatment subtypes and gender where explored.
Total childhood trauma questionnaire scores correlated negatively (p<0.005) with gray matter volumes in prefrontal cortex, striatum, amygdala, sensory association cortices and cerebellum. Physical abuse, physical neglect and emotional neglect were associated with rostral prefrontal reductions. Additionally, decreases in dorsolateral and orbitofrontal cortices, insula, and ventral striatum were associated with physical abuse, in cerebellum with physical neglect, and in dorsolateral, orbitofrontal and subgenual prefrontal cortices, striatum, amygdala, hippocampus and cerebellum with emotional neglect. These latter emotion regulation regions were also associated with childhood trauma questionnaire scores in females, while caudate reductions, which may relate to impulse dyscontrol, were seen in males.
Childhood maltreatment was associated with corticostriatal-limbic gray matter reductions in adolescents. These findings suggest that even if adolescents reporting childhood maltreatment exposure do not present with symptoms that meet full criteria for psychiatric disorders, they may have corticostriatal-limbic changes that place them at risk for behavioral difficulties. Vulnerabilities may be moderated by gender and maltreatment subtype.