Cumulative stress and autonomic dysregulation in a community sample.

Whether cumulative stress, including both chronic stress and adverse life events, is associated with decreased heart rate variability (HRV), a non-invasive measure of autonomic status which predicts poor cardiovascular outcomes, is unknown. Healthy community dwelling volunteers (N = 157, mean age 29 years) participated in the Cumulative Stress/Adversity Interview (CAI), a 140-item event interview measuring cumulative adversity including major life events, life trauma, recent life events and chronic stressors, and underwent 24-h ambulatory ECG monitoring. HRV was analyzed in the frequency domain and standard deviation of NN intervals (SDNN) calculated. Initial simple regression analyses revealed that total cumulative stress score, chronic stressors and cumulative adverse life events (CALE) were all inversely associated with ultra low-frequency (ULF), very low-frequency (VLF) and low-frequency (LF) power and SDNN (all p < 0.05). In hierarchical regression analyses, total cumulative stress and chronic stress each was significantly associated with SDNN and ULF even after the highly significant contributions of age and sex, with no other covariates accounting for additional appreciable variance. For VLF and LF, both total cumulative stress and chronic stress significantly contributed to the variance alone but were not longer significant after adjusting for race and health behaviors. In summary, total cumulative stress, and its components of adverse life events and chronic stress were associated with decreased cardiac autonomic function as measured by HRV. Findings suggest one potential mechanism by which stress may exert adverse effects on mortality in healthy individuals. Primary preventive strategies including stress management may prove beneficial.

Stress-related alcohol consumption in heavy drinkers correlates with expression of miR-10a, miR-21, and components of the TAR-RNA-binding protein-associated complex.

BACKGROUND: Alterations in stress-related gene expression may play a role in stress-related drinking and the risk of alcohol dependence. METHODS: Microarrays were used to measure changes in gene expression in peripheral blood in nonsmoking, social drinking subjects exposed to 3 types of personalized imagery: neutral, stressful (but not alcohol related), and alcohol-related cues. Gene expression was measured at baseline, immediately after, and 1 hour after stimulus presentation. Subjects were allowed to drink up to 750 cc of beer in a "taste test" following stimulus presentation in each imagery condition, and the amount of beer consumed was recorded. Gene-expression levels were compared in 2 groups of nonsmoking subjects (n = 11/group): heavy drinkers (HD; defined as regular alcohol use over the past year of at least 8 standard drinks per week for women and at least 15 standard drinks per week for men), and moderate drinkers (MD; defined as up to 7 standard drinks per week for women and 14 standard drinks per week for men). Expression of microRNA-10a (miR-10a) and microRNA-21 (miR-21) was assessed by quantitative real-time polymerase chain reaction. RESULTS: After correction for multiple testing (false discovery rate < 0.05), 79 genes were identified that changed by >1.3-fold in the HD group, but not the MD group, following exposure to stress. No changes were observed for any of these genes in either group following exposure to neutral or alcohol-related imagery. Pathway analysis suggested that many of these genes, form part of the transactivation responsive (TAR)-RNA-binding protein (TRBP)-associated complex and are positively regulated by miR-10a and miR-21. Expression of both miR-10a and miR-21 was up-regulated following psychological stress in HD, but not MD subjects; however, the differences between groups were not statistically significant. Expression levels of both microRNAs was correlated (miR-10a, R(2)  = 0.59, miR-21 R(2)  = 0.57) with amount drunk in HD, but not MD subjects. CONCLUSIONS: Expression of miR-10a, miR-21, and several of their target genes is regulated by acute psychological stress and is correlated with stress-induced drinking in a laboratory setting. Alterations in miRNA expression may be one mechanism linking psychological stress with changes in gene expression and increased alcohol intake in binge/HD.

Adjudication of etiology of acute kidney injury: experience from the TRIBE-AKI multi-center study.

BACKGROUND: Adjudication of patient outcomes is a common practice in medical research and clinical trials. However minimal data exists on the adjudication process in the setting of Acute Kidney Injury (AKI) as well as the ability to judge different etiologies (e.g. Acute Tubular Necrosis (ATN), Pre-renal Azotemia (PRA)). METHODS: We enrolled 475 consecutive patients undergoing cardiac surgery at four sites of the Translational Research Investigating Biomarker Endpoints in AKI (TRIBE-AKI) study. Three expert nephrologists performed independent chart review, utilizing clinical variables and retrospective case report forms with pre intra and post-operative data, and then adjudicated all cases of AKI (n = 67). AKI was defined as a > 50% increase in serum creatinine for baseline (RIFLE Risk). We examined the patterns of AKI diagnoses made by the adjudication panel as well as association of these diagnoses with pre and postoperative kidney injury biomarkers. RESULTS: There was poor agreement across the panel of reviewers with their adjudicated diagnoses being independent of each other (Fleiss' Kappa = 0.046). Based on the agreement of the two out of three reviewers, ATN was the adjudicated diagnosis in 41 cases (61%) while PRA occurred in 13 (19%). Neither serum creatinine or any other biomarker of AKI (urine or serum), was associated with an adjudicated diagnosis of ATN within the first 24 post-operative hours. CONCLUSION: The etiology of AKI after cardiac surgery is probably multi-factorial and pure forms of AKI etiologies, such as ATN and PRA may not exist. Biomarkers did not appear to correlate with the adjudicated etiology of AKI; however the lack of agreement among the adjudicators impacted these results. TRIAL REGISTRATION: Clinicaltrials.gov: NCT00774137.

Blood transfusions are associated with urinary biomarkers of kidney injury in cardiac surgery.

OBJECTIVE: Cardiac surgery is a major cause of acute kidney injury. In this setting, receipt of blood transfusions seems to be associated with a higher risk of acute kidney injury, as measured using serum creatinine values. We examined this association further by using urinary biomarkers of kidney injury. METHODS: A total of 1210 adults underwent cardiac surgery and were divided into 3 groups on the basis of the receipt of intraoperative packed red blood cell units: no blood (n = 894), 2 or less packed red blood cell units (n = 206), and more than 2 packed red blood cell units (n = 110). Acute kidney injury was defined as (1) doubling of serum creatinine from the preoperative value; (2) first postoperative urinary interleukin-18 in the fifth quintile; and (3) first postoperative urinary neutrophil gelatinase-associated lipocalin in the fifth quintile. We determined the relative risk for acute kidney injury outcome according to packed red blood cell units group after adjusting for 12 preoperative and surgical variables. By using the Sobel test for mediation analysis, we also evaluated the role of biomarkers in causing acute kidney injury through alternative pathways. RESULTS: Acute kidney injury was more common in those who received more than 2 packed red blood cell units. In patients receiving more than 2 packed red blood cell units, the adjusted relative risks were 2.3 (95% confidence interval, 1.2-4.4, P .01), 1.36 (95% confidence interval, 1.0-1.9, P .05), and 1.34 (95% confidence interval, 1.0-1.8, P .06) for doubling of serum creatinine, urinary interleukin-18 in the fifth quintile (>60 pg/mL), and urinary neutrophil gelatinase-associated lipocalin in the fifth quintile (>102 ng/mL), respectively. Furthermore, the effect of packed red blood cell units transfusion on acute kidney injury was partially mediated by interleukin-18. CONCLUSIONS: Receipt of 2 or more packed red blood cell units during cardiac surgery is associated with a greater risk of acute kidney injury defined by serum creatinine and kidney injury biomarkers.

Serum brain natriuretic peptide and risk of acute kidney injury after cardiac operations in children.

BACKGROUND: Acute kidney injury (AKI) after pediatric cardiac operations is associated with poor outcomes and is difficult to predict. We conducted a prospective study to evaluate whether preoperative brain natriuretic peptide (BNP) levels predict postoperative AKI among children undergoing cardiac operations. METHODS: This was a three-center, prospective study (2007-2009) of 277 children undergoing cardiac operations (n = 121, aged <2 years) with available preoperative BNP values. Preoperative BNP was measured and categorized into tertiles. The performance of BNP was evaluated alone and in combination with clinical factors. AKI was defined as doubling of serum creatinine or need for acute dialysis. RESULTS: Postoperative AKI occurred in 165 children (60%), with 118 cases (43%) being mild and 47 cases (17%) severe. Preoperative BNP was not associated with increased risk of mild or severe postoperative AKI and did not significantly improve AKI risk prediction when added to clinical models. Preoperative BNP was, however, associated with several clinical outcomes, including length of stay and mechanical ventilation. The results were similar when the analysis was repeated in the subset of children younger than 2 years of age or when the association of postoperative BNP and AKI was evaluated. CONCLUSIONS: Preoperative BNP levels did not predict postoperative AKI in this cohort of children undergoing cardiac operations. Both preoperative and postoperative BNP levels are associated with postoperative outcomes. Clinical Trial Registration at Clinicaltrials.gov as NCT00774137.

Preimplant histologic acute tubular necrosis and allograft outcomes.

BACKGROUND AND OBJECTIVES: The influence of deceased-donor AKI on post-transplant outcomes is poorly understood. The few published studies about deceased-donor preimplant biopsy have reported conflicting results regarding associations between AKI and recipient outcomes. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This multicenter study aimed to evaluate associations between deceased-donor biopsy reports of acute tubular necrosis (ATN) and delayed graft function (DGF), and secondarily for death-censored graft failure, first adjusting for the kidney donor risk index and then stratifying by donation after cardiac death (DCD) status. RESULTS: Between March 2010 and April 2012, 651 kidneys (369 donors, 4 organ procurement organizations) were biopsied and subsequently transplanted, with ATN reported in 110 (17%). There were 262 recipients (40%) who experienced DGF and 38 (6%) who experienced graft failure. DGF occurred in 45% of kidneys with reported ATN compared with 39% without ATN (P=0.31) resulting in a relative risk (RR) of 1.13 (95% confidence interval [95% CI], 0.9 to 1.43) and a kidney donor risk index-adjusted RR of 1.11 (95% CI, 0.88 to 1.41). There was no significant difference in graft failure for kidneys with versus without ATN (8% versus 5%). In stratified analyses, the adjusted RR for DGF with ATN was 0.97 (95% CI, 0.7 to 1.34) for non-DCD kidneys and 1.59 (95% CI, 1.23 to 2.06) for DCD kidneys (P=0.02 for the interaction between ATN and DCD on the development of DGF). CONCLUSIONS: Despite a modest association with DGF for DCD kidneys, this study reveals no significant associations overall between preimplant biopsy-reported ATN and the outcomes of DGF or graft failure. The potential benefit of more rigorous ATN reporting is unclear, but these findings provide little evidence to suggest that current ATN reports are useful for predicting graft outcomes or deciding to accept or reject allograft offers.

Preoperative angiotensin-converting enzyme inhibitors and angiotensin receptor blocker use and acute kidney injury in patients undergoing cardiac surgery.

BACKGROUND: Using either an angiotensin-converting enzyme inhibitor (ACEi) or an angiotensin receptor blocker (ARB) the morning of surgery may lead to 'functional' postoperative acute kidney injury (AKI), measured by an abrupt increase in serum creatinine. Whether the same is true for 'structural' AKI, measured with new urinary biomarkers, is unknown. METHODS: The TRIBE-AKI study was a prospective cohort study of 1594 adults undergoing cardiac surgery at six hospitals between July 2007 and December 2010. We classified the degree of exposure to ACEi/ARB into three categories: 'none' (no exposure prior to surgery), 'held' (on chronic ACEi/ARB but held on the morning of surgery) or 'continued' (on chronic ACEi/ARB and taken the morning of surgery). The co-primary outcomes were 'functional' AKI based upon changes in pre- to postoperative serum creatinine, and 'structural AKI', based upon peak postoperative levels of four urinary biomarkers of kidney injury. RESULTS: Across the three levels (none, held and continued) of ACEi/ARB exposure there was a graded increase in functional AKI, as defined by AKI stage 1 or worse; (31, 34 and 42%, P for trend 0.03) and by percentage change in serum creatinine from pre- to postoperative (25, 26 and 30%, P for trend 0.03). In contrast, there were no differences in structural AKI across the strata of ACEi/ARB exposure, as assessed by four structural AKI biomarkers (neutrophil gelatinase-associated lipocalin, kidney injury molecule-1, interleukin-18 or liver-fatty acid-binding protein). CONCLUSIONS: Preoperative ACEi/ARB usage was associated with functional but not structural acute kidney injury. As AKI from ACEi/ARB in this setting is unclear, interventional studies testing different strategies of perioperative ACEi/ARB use are warranted.

Disrupted ventromedial prefrontal function, alcohol craving, and subsequent relapse risk.

IMPORTANCE: 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. OBJECTIVES: 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. DESIGN: 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. SETTINGS: Inpatient treatment setting in a community mental health center and hospital-based research unit. PATIENTS: 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. INTERVENTION: 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). RESULTS: 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.

Error processing and gender-shared and -specific neural predictors of relapse in cocaine dependence.

Deficits in cognitive control are implicated in cocaine dependence. Previously, combining functional magnetic resonance imaging and a stop signal task, we demonstrated altered cognitive control in cocaine-dependent individuals. However, the clinical implications of these cross-sectional findings and, in particular, whether the changes were associated with relapse to drug use, were not clear. In a prospective study, we recruited 97 treatment-seeking individuals with cocaine dependence to perform the stop signal task during functional magnetic resonance imaging and participate in follow-up assessments for 3 months, during which time cocaine use was evaluated with timeline follow back and ascertained by urine toxicology tests. Functional magnetic resonance imaging data were analysed using general linear models as implemented in Statistical Parametric Mapping 8, with the contrast 'stop error greater than stop success trials' to index error processing. Using voxelwise analysis with logistic and Cox regressions, we identified brain activations of error processing that predict relapse and time to relapse. In females, decreased error-related activations of the thalamus and dorsal anterior cingulate cortex predicted relapse and an earlier time to relapse. In males, decreased error-related activations of the dorsal anterior cingulate cortex and left insula predicted relapse and an earlier time to relapse. These regional activations were validated with data resampling and predicted relapse with an average area under the curve of 0.849 in receiver operating characteristic analyses. These findings provide direct evidence linking deficits in cognitive control to clinical outcome in a moderate-sized cohort of cocaine-dependent individuals. These results may provide a useful basis for future studies to examine how psychosocial factors interact with cognitive control to determine drug use and to evaluate the efficacy of pharmacological or behavioural treatment in remediating deficits of cognitive control in cocaine addicts.

Urinary cystatin C and acute kidney injury after cardiac surgery.

BACKGROUND: Acute kidney injury (AKI) is common after cardiac surgery and is associated with adverse patient outcomes. Urinary cystatin C (CysC) level is a biomarker of proximal tubule function and may increase earlier in AKI than serum creatinine level. STUDY DESIGN: Prospective cohort study. SETTINGS & PARTICIPANTS: The TRIBE AKI (Translational Research Investigating Biomarker Endpoints in AKI) Consortium prospectively enrolled 1,203 adults and 299 children and adolescents at 8 institutions in 2007-2009. INDEX TEST: Urinary CysC (in milligrams per liter) within the first 12 hours after surgery. OUTCOME: Serum creatinine-based AKI was defined as AKI Network stage 1 (mild AKI) and doubling of serum creatinine from the preoperative value or need for dialysis during hospitalization (severe AKI). OTHER MEASUREMENTS: Analyses were adjusted for characteristics used clinically for AKI risk stratification, including age, sex, race, estimated glomerular filtration rate, diabetes, hypertension, heart failure, nonelective surgery, cardiac catheterization within 72 hours, type of surgery, myocardial infarction, and cardiopulmonary bypass time longer than 120 minutes. RESULTS: Urinary CysC level measured in the early postoperative period (0-6 and 6-12 hours postoperatively) correlated with both mild and severe AKI in adults and children. However, after analyses were adjusted for other factors, the effect was attenuated for both forms of AKI in both cohorts. LIMITATIONS: Limited numbers of patients with severe AKI and in-hospital dialysis treatment. CONCLUSIONS: Urinary CysC values are not associated significantly with the development of AKI after cardiac surgery in adults and children.

Altered expression of cytokine signaling pathway genes in peripheral blood cells of alcohol dependent subjects: preliminary findings.

BACKGROUND: Preclinical 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. METHODS: 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/wk for women and at least 15 standard drinks/wk for men, n = 13), and moderate drinkers (MD; defined as up to 7 standard drinks/wk for women and 14 standard drinks/wk for men, n = 17). RESULTS: Four hundred and thirty-six genes were differentially expressed among the 3 groups of subjects (false discovery rate corrected p-value < 0.05). Two hundred and ninety-one 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 Janus kinase-Signal transducer and activator of transcription (JAK-Stat) signaling. CONCLUSIONS: 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.

Neural correlates of stress-induced and cue-induced drug craving: influences of sex and cocaine dependence.

OBJECTIVE: 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. METHOD: 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). RESULTS: 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. CONCLUSIONS: 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.

Genetic modulation of plasma NPY stress response is suppressed in substance abuse: association with clinical outcomes.

BACKGROUND: 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. METHODS: Thirty-seven treatment-engaged, abstinent substance dependent (SD) patients and 28 healthy controls (HCs) 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. RESULTS: 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. CONCLUSION: 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.

Deficits in default mode network activity preceding error in cocaine dependent individuals.

BACKGROUND: Cocaine dependence is associated with cognitive deficits and altered task-related cerebral activation in cognitive performance (see Li and Sinha, 2008, for a review). Relatively little is known whether these individuals are also impaired in regional brain activation of the default mode network (DMN). We demonstrated previously that greater activation of the default brain regions precedes errors in a stop signal task performed by healthy controls (SST, Li et al., 2007). We seek to determine whether individuals with cocaine dependence are impaired in DMN activity, specifically activity preceding error, as compared to the healthy people. We also examine the relation to years of cocaine use. METHODS: Individuals with cocaine dependence (CD, n=23) and demographics-matched healthy controls (HC, n=27) performed a SST that employed a tracking procedure to adjust the difficulty of stop trials and elicit errors approximately half of the time. Blood oxygenation level dependent (BOLD) signals of go trials preceding stop error as compared to those preceding stop success trials were extracted with generalized linear models using statistical parametric mapping. RESULTS: HC showed activation of bilateral precuneus and posterior cingulate cortices and ventromedial prefrontal cortex (vmPFC) preceding errors during the SST. In contrast, despite indistinguishable stop signal performance, CD did not show these error predicting activations. Furthermore, the effect size of error-preceding vmPFC activation was inversely correlated with years of cocaine use. CONCLUSIONS: These findings indicate DMN deficits and could potentially add to our understanding of the effects of chronic cocaine use on cerebral functions in cocaine dependence. Work to further clarify potential changes in functional connectivity and gray matter volume is warranted to understand the relevance of DMN to the pathology of cocaine misuse.

Effects of adrenal sensitivity, stress- and cue-induced craving, and anxiety on subsequent alcohol relapse and treatment outcomes.

CONTEXT: 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. OBJECTIVES: 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). DESIGN: 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. SETTING: Inpatient treatment in a community mental health center and hospital-based research unit. PARTICIPANTS: Treatment-engaged alcohol-dependent individuals and healthy controls. MAIN OUTCOME MEASURES: Time to alcohol relapse and to heavy drinking relapse. RESULTS: 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. CONCLUSIONS: 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.

Body mass index, metabolic factors, and striatal activation during stressful and neutral-relaxing states: an FMRI study.

Stress is associated with alterations in neural motivational-reward pathways in the ventral striatum (VS), hormonal/metabolic changes, and weight increases. The relationship between these different factors is not well understood. We hypothesized that body mass index (BMI) status and hormonal/metabolic factors would be associated with VS activation. We used functional magnetic resonance imaging (fMRI) to compare brain responses of overweight and obese (OW/OB: BMI ≥ 25 kg/m(2): N=27) individuals with normal weight (NW: BMI<18.5-24.9 kg/m(2): N=21) individuals during exposure to personalized stress, alcohol cue, and neutral-relaxing situations using a validated, autobiographical, script-driven, guided-imagery paradigm. Metabolic factors, including fasting plasma glucose (FPG), insulin, and leptin, were examined for their association with VS activation. Consistent with previous studies, stress and alcohol cue exposure each increased activity in cortico-limbic regions. Compared with NW individuals, OW/OB individuals showed greater VS activation in the neutral-relaxing and stress conditions. FPG was correlated with VS activation. Significant associations between VS activation and metabolic factors during stress and relaxation suggest the involvement of metabolic factors in striatal dysfunction in OW/OB individuals. This relationship may contribute to non-homeostatic feeding in obesity.

Association of frontal and posterior cortical gray matter volume with time to alcohol relapse: a prospective study.

OBJECTIVE: 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. METHOD: Forty-five abstinent alcohol-dependent patients in treatment and 50 healthy comparison subjects were scanned once using high-resolution (T(1)-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. RESULTS: 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. CONCLUSIONS: 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.

Behavioral arousal in response to stress and drug cue in alcohol and cocaine addicted individuals versus healthy controls.

UNLABELLED: Negative emotional arousal in response to stress and drug cues is known to play a role in the development and continuation of substance use disorders. However, studies have not examined behavioral indicators of such arousal. OBJECTIVE: The current study examined behavioral and bodily arousal in response to stress and drug cue in individuals with alcohol dependence and cocaine dependence as compared to healthy controls using a new scale. METHODS: Fifty-two alcohol dependent (AD group), 45 cocaine dependent (COC group), and 68 healthy controls (HC group) were exposed to individually developed stressful, drug-cue, and neutral-relaxing imagery. Behavioral and bodily responses were assessed with a new scale, the Behavioral Arousal Scale (BAS). RESULTS: The BAS showed acceptable inter-rater reliability and internal consistency and correlated with subjective negative emotion and craving. BAS scores were higher in stress than neutral conditions for all three groups. COC participants showed higher BAS response to stress than AD or HC participants. COC and AD participants showed greater BAS response to drug cue than HC participants. CONCLUSION: Behavioral arousal is a domain in which stress and drug related arousal is expressed and assessment of this domain could provide unique information about vulnerability to craving and relapse in addicted populations.

A stress-coping profile of opioid dependent individuals entering naltrexone treatment: a comparison with healthy controls.

BACKGROUND: Stress is known to increase addiction vulnerability and risk of relapse to substance use. PURPOSE & METHOD: We compared opioid dependent individuals entering naltrexone treatment (n = 57) with healthy controls (n = 75) on measures of stress, coping, and social support and examined the relative contribution of group membership, coping, and social support to stress within the sample. Analyses of variance (ANOVA) and covariance (ANCOVA), and stepwise multiple regression were conducted. RESULTS: Compared with controls, opioid dependent subjects reported greater stress, less use of adaptive coping, but comparable use of maladaptive/avoidant coping. No group differences were found with respect to social support. Perceived stress was predicted by group membership, low social support, and greater use of maladaptive/avoidant coping, and the prediction by social support and maladaptive/avoidant coping did not differ by group. CONCLUSION: Opioid dependent individuals entering naltrexone treatment experience higher levels of stress and report less use of adaptive coping strategies when compared with controls. Group membership, maladaptive/avoidant coping, and social support independently contribute to perceived stress. Findings suggest that novel treatment approaches that decrease maladaptive/avoidant coping and improve social support are important aspects of decreasing stress during early recovery from opioid addiction.

Sex-specific dissociations in autonomic and HPA responses to stress and cues in alcohol-dependent patients with cocaine abuse.

AIMS: Chronic alcohol and drug dependence leads to neuroadaptations in hypothalamic-pituitary-adrenal (HPA) and sympathetic adrenal medullary (SAM) stress systems, which impact response sensitivity to stress and alcohol cue and facilitates risk of relapse. To date, gender variations in these systems have not been fully assessed in abstinent alcohol-dependent individuals who also met criteria for cocaine abuse. METHODS: Forty-two (21 M/21 F) early abstinent treatment-seeking substance-abusing (SA) men and women and 42 (21 M/21 F) healthy control (HC) volunteers were exposed to three 5-min guided imagery conditions (stress, alcohol/drug cue, neutral relaxing), presented randomly, one per day across three consecutive days. Alcohol craving and anxiety ratings were obtained as well as measures of heart rate (HR), blood pressure, plasma ACTH, cortisol, norepinephrine (NE) and epinephrine (EPI). RESULTS: SA males showed increased ACTH and EPI basal tone compared with HC males and SA females. However, they demonstrated no increase in ACTH and cortisol levels following stress and alcohol cue imagery exposure compared to the neutral condition. SA females demonstrated a typically increased stress response in both measures. In addition, SA males showed no increase in cardiovascular response to either stress or cue, and no increase in catecholamine response to cue compared with their response to neutral imagery. Again, this dampening was not observed in HC males who produced significantly higher levels of cue-related HR and EPI, and significantly higher stress-related DBP. In contrast, SA females showed an enhanced ACTH and cortisol response to stress and cue compared with neutral imagery and this was not observed in the HC females. They also demonstrated a reduced increase in NE and EPI compared with both SA males and HC females as well as reduced HR compared with HC females. CONCLUSIONS: While SA males showed a generalized suppression of HPA, SAM system and cardiovascular markers following both stress and cue, SA women demonstrated a selective sympatho-adrenal suppression to stress only and an enhanced HPA response to both stress and cue. These gender variations are discussed in terms of their potential impact on relapse vulnerability and treatment outcome.