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1.  Cerebral gray matter volumes and low-frequency fluctuation of BOLD signals in cocaine dependence: duration of use and gender difference 
Drug and alcohol dependence  2013;0:10.1016/j.drugalcdep.2013.09.004.
Magnetic resonance imaging has provided a wealth of information on altered brain activations and structures in individuals addicted to cocaine. However, few studies have considered the influence of age and alcohol use on these changes.
We examined gray matter volume with voxel based morphometry (VBM) and low frequency fluctuation (LFF) of BOLD signals as a measure of cerebral activity of 84 cocaine dependent (CD) and 86 healthy control (HC) subjects. We performed a covariance analysis to account for the effects of age and years of alcohol use.
Compared to HC, CD individuals showed decreased gray matter (GM) volumes in frontal and temporal cortices, middle/posterior cingulate cortex, and the cerebellum, at p<0.05, corrected for multiple comparisons. The GM volume of the bilateral superior frontal gyri (SFG) and cingulate cortices were negatively correlated with years of cocaine use, with women showing a steeper loss in the right SFG in association with duration of use. In contrast, the right ventral putamen showed increased GM volume in CD as compared to HC individuals. Compared to HC, CD individuals showed increased fractional amplitude of LFF (fALFF) in the thalamus, with no significant overlap with regions showing GM volume loss.
These results suggested that chronic cocaine use is associated with distinct changes in cerebral structure and activity that can be captured by GM volume and fALFF of BOLD signals.
PMCID: PMC3865077  PMID: 24090712
stimulant; cerebral morphometry; prefrontal; low-frequency fluctuation; thalamus; gender difference
2.  The Effects of Stress on Physical Activity and Exercise 
Sports medicine (Auckland, N.Z.)  2014;44(1):81-121.
Psychological stress and physical activity (PA) are believed to be reciprocally related; however, most research examining the relationship between these constructs is devoted to the study of exercise and/or PA as an instrument to mitigate distress.
The aim of this paper was to review the literature investigating the influence of stress on indicators of PA and exercise.
A systematic search of Web of Science, Pub-Med, and SPORTDiscus was employed to find all relevant studies focusing on human participants. Search terms included “stress”, “exercise”, and “physical activity”. A rating scale (0–9) modified for this study was utilized to assess the quality of all studies with multiple time points.
The literature search found 168 studies that examined the influence of stress on PA. Studies varied widely in their theoretical orientation and included perceived stress, distress, life events, job strain, role strain, and work–family conflict but not lifetime cumulative adversity. To more clearly address the question, prospective studies (n = 55) were considered for further review, the majority of which indicated that psychological stress predicts less PA (behavioral inhibition) and/or exercise or more sedentary behavior (76.4 %). Both objective (i.e., life events) and subjective (i.e., distress) measures of stress related to reduced PA. Prospective studies investigating the effects of objective markers of stress nearly all agreed (six of seven studies) that stress has a negative effect on PA. This was true for research examining (a) PA at periods of objectively varying levels of stress (i.e., final examinations vs. a control time point) and (b) chronically stressed populations (e.g., caregivers, parents of children with a cancer diagnosis) that were less likely to be active than controls over time. Studies examining older adults (>50 years), cohorts with both men and women, and larger sample sizes (n > 100) were more likely to show an inverse association. 85.7 % of higher-quality prospective research (≥7 on a 9-point scale) showed the same trend. Interestingly, some prospective studies (18.2 %) report evidence that PA was positively impacted by stress (behavioral activation). This should not be surprising as some individuals utilize exercise to cope with stress. Several other factors may moderate stress and PA relationships, such as stages of change for exercise. Habitually active individuals exercise more in the face of stress, and those in beginning stages exercise less. Consequently, stress may have a differential impact on exercise adoption, maintenance, and relapse. Preliminary evidence suggests that combining stress management programming with exercise interventions may allay stress-related reductions in PA, though rigorous testing of these techniques has yet to be produced.
Overall, the majority of the literature finds that the experience of stress impairs efforts to be physically active. Future work should center on the development of a theory explaining the mechanisms underlying the multifarious influences of stress on PA behaviors.
PMCID: PMC3894304  PMID: 24030837
3.  Prenatal Cocaine Exposure and Gray Matter Volume in Adolescent Boys and Girls: Relationship to Substance Use Initiation 
Biological psychiatry  2013;74(7):482-489.
Studies of prenatal cocaine exposure have primarily examined childhood populations. Studying adolescents is especially important because adolescence is a time of changing motivations and initiation of substance use.
Using magnetic resonance imaging and whole-brain voxel-based morphometry, we assessed gray matter volume (GMV) differences in 42 prenatally cocaine exposed (PCE) and 21 noncocaine-exposed (NCE) adolescents, aged 14 to 17 years. Associations between GMV differences in significant clusters and the probability of substance use initiation were examined.
PCE relative to NCE adolescents demonstrated three clusters of lower GMV involving a limbic and paralimbic (p < .001, family-wise error [FWE] corrected), superior frontal gyrus (p = .001, FWE corrected), and precuneus (p = .019, FWE corrected) cluster. GMVs in the superior frontal and precuneus clusters were associated with initiation of substance use. Each 1-mL decrease in GMV increased the probability of initiating substance use by 69.6% (p = .01) in the superior frontal cluster and 83.6% (p = .02) in the precuneus cluster.
PCE is associated with structural differences in cortical and limbic regions. Lower GMVs in frontal cortical and posterior regions are associated with substance use initiation and may represent biological risk markers for substance use.
PMCID: PMC3775853  PMID: 23751204
Adolescence; gray matter volume; prenatal cocaine exposure; substance use initiation; voxel-based morphometry; whole brain
4.  Neural Correlates of Stress and Favorite-Food Cue Exposure in Adolescents: A Functional Magnetic Resonance Imaging Study 
Human brain mapping  2012;34(10):2561-2573.
Adolescence is a critical period of neurodevelopment for stress and appetitive processing, as well as a time of increased vulnerability to stress and engagement in risky behaviors. The current study was conducted to examine brain activation patterns during stress and favorite-food-cue experiences relative to a neutral-relaxing condition in adolescents. Functional magnetic resonance imaging was employed using individualized script-driven guided imagery to compare brain responses to such experiences in 43 adolescents. Main effects of condition and gender were found, without a significant gender-by-condition interaction. Stress imagery, relative to neutral, was associated with activation in the caudate, thalamus, left hippocampus/parahippocampal gyrus, midbrain, left superior/middle temporal gyrus, and right posterior cerebellum. Appetitive imagery of favorite food was associated with caudate, thalamus, and midbrain activation compared to the neutral-relaxing condition. To understand neural correlates of anxiety and craving, subjective (self-reported) measures of stress-induced anxiety and favorite-food-cue-induced craving were correlated with brain activity during stress and appetitive food-cue conditions, respectively. High self-reported stress-induced anxiety was associated with hypoactivity in the striatum, thalamus, hippocampus and midbrain. Self-reported favorite-food-cue-induced craving was associated with blunted activity in cortical-striatal regions, including the right dorsal and ventral striatum, medial prefrontal cortex, motor cortex, and left anterior cingulate cortex. The current findings in adolescents indicate the activation of predominantly subcortical-striatal regions in the processing of stressful and appetitive experiences and link hypoactive striatal circuits to self-reported stress-induced anxiety and cue-induced favorite-food craving.
PMCID: PMC3479342  PMID: 22504779
Stress; Psychological; Adolescence; Motivation; Appetite; fMRI
5.  Naltrexone with or without guanfacine for preventing relapse to opiate addiction in St.-Petersburg, Russia 
Drug and alcohol dependence  2013;132(3):674-680.
Stress is a key precipitant to discontinuing naltrexone and relapsing to opiate abuse. Alpha-2 adrenergic agonists like guanfacine may reduce stress induced craving and have reduced opiate relapse in small clinical trials.
This randomized, double blind double dummy placebo-controlled 6-month trial tested oral naltrexone with or without guanfacine for reducing stress and preventing opiate relapse. We randomized 301 patients to: naltrexone 50 mg/day + guanfacine 1 mg/day (n = 75) (N/G), naltrexone + guanfacine placebo (N/P) (n = 76), naltrexone placebo + guanfacine (n = 75) (P/G), and double placebo (n = 75) (P/P).
Among the 75 patients in each group the percentage still retained on naltrexone treatment at six months was: N/G 26.7%, N/P 19.7% (p = 0.258 to N/G), P/G 6.7% (p < 0.05 to both N groups), and P/P 10.7% (p = 0.013 to N + G). Guanfacine reduced the severity of stress particularly at weeks 10 and 18. Adverse events (AE) were infrequent (4.7%) without group differences, with most common AEs: headache, poor appetite, insomnia, and dizziness.
Adding guanfacine to naltrexone did not improve treatment retention or opiate free urines, but it reduced both stress and craving at later time points in treatment, which may be related to stress-induced craving and the animal model of incubation of reinstatement. During treatment, HIV risk, anxiety, and depression reduced among all patients in treatment, regardless of group.
PMCID: PMC3971535  PMID: 23683793
Naltrexone; Guanfacine; Opiate dependence; Stress; Clinical trial
6.  The effects of exogenous progesterone on drug craving and stress arousal in cocaine dependence: Impact of gender and cue type 
Psychoneuroendocrinology  2013;38(9):1532-1544.
Exogenous progesterone has been shown to attenuate the rewarding effects of cocaine. However, its effects on provoked drug craving, stress arousal and cognitive performance has not been systematically investigated in cocaine dependent men and women. Thus, we conducted a double-blind placebo-controlled study assessing the efficacy of progesterone in reducing provoked drug craving, stress system arousal and improving cognitive performance in cocaine dependent men and women.
Forty-two early abstinent treatment-seeking cocaine dependent individuals were randomly assigned to either daily doses of placebo (12M/9F) or micronized progesterone (12M/9F) (400 mg/day), for 7 days. Under experimental conditions, all subjects were exposed to three 5-min personalized guided imagery conditions (stress, cocaine cue, relaxing), one per day, consecutively in a random, counterbalanced order. Subjective craving, mood, hypothalamicpituitary-adrenal (HPA) and cardiovascular output, and a cognitive measure of inhibitory control (Stroop Color Word Task) were assessed pre- and post imagery.
Progesterone relative to placebo significantly decreased cue-induced craving and cortisol responses and increased cue-induced ACTH. In addition, women but not men receiving progesterone reported lower ratings of negative emotion and higher ratings of relaxed mood following stress exposure. Improved Stroop performance was observed in all participants receiving progesterone, across all conditions.
Progesterone was selectively effective in reducing cocaine cue-induced but not stress-related cocaine craving as well as specific measures of the provoked arousal state. Findings suggest that progesterone’s effects on drug craving and arousal are moderated by both the type of environmental cue exposure and gender.
PMCID: PMC3772967  PMID: 23374328
Progesterone; Gender; Cocaine dependence; Stress; Drug cue; Stroop
7.  The Clinical Neurobiology of Drug Craving 
Current opinion in neurobiology  2013;23(4):649-654.
Drug craving has re-emerged as a relevant and important construct in the pathophysiology of addiction with its inclusion in DSM-V as a key clinical symptom of addictive disorders. This renewed focus has been due in part to the recent neurobiological evidence on craving- related neural activation and clinical evidence supporting its association with drug use, relapse and recovery processes. This review covers the neurobiology of drug craving and relapse risk with a primary focus on cocaine addiction and a secondary emphasis on alcohol addiction. A conceptualization of drug craving on the continuum of healthy desire and compulsive seeking, and the associated neurobiological adaptations associated with the development of an increased craving/wanting state is presented. Altered dopamine neurochemistry as well as disrupted prefrontal control and hyperactive striatal-limbic responses in experiencing drug cues, stress, drug intake and in basal relaxed states are identified as neurobiological signatures that predict drug craving and drug use. Thus, the clinical and neurobiological features of the craving/wanting state are presented with specific attention to alterations in these cortico-limbic-striatal and prefrontal self-control circuits that predict drug craving and relapse risk. The methodological challenges that need to be addressed to further develop the evolving conceptual approach in the neuroscience of drug craving is presented, with a focus on identification and validation of biomarkers associated with the craving state and treatment approaches that may be of benefit in reversing the neurobiological adaptations associated with drug craving to improve treatment outcomes in addiction.
PMCID: PMC3735834  PMID: 23764204
8.  Effects of Fructose vs Glucose on Regional Cerebral Blood Flow in Brain Regions Involved With Appetite and Reward Pathways 
Increases in fructose consumption have paralleled the increasing prevalence of obesity, and high-fructose diets are thought to promote weight gain and insulin resistance. Fructose ingestion produces smaller increases in circulating satiety hormones compared with glucose ingestion, and central administration of fructose provokes feeding in rodents, whereas centrally administered glucose promotes satiety.
To study neurophysiological factors that might underlie associations between fructose consumption and weight gain.
Design, Setting, and Participants
Twenty healthy adult volunteers underwent 2 magnetic resonance imaging sessions at Yale University in conjunction with fructose or glucose drink ingestion in a blinded, random-order, crossover design.
Main Outcome Measures
Relative changes in hypothalamic regional cerebral blood flow (CBF) after glucose or fructose ingestion. Secondary outcomes included whole-brain analyses to explore regional CBF changes, functional connectivity analysis to investigate correlations between the hypothalamus and other brain region responses, and hormone responses to fructose and glucose ingestion.
There was a significantly greater reduction in hypothalamic CBF after glucose vs fructose ingestion (–5.45 vs 2.84 mL/g per minute, respectively; mean difference, 8.3 mL/g per minute [95% CI of mean difference, 1.87-14.70]; P=.01). Glucose ingestion (compared with baseline) increased functional connectivity between the hypothalamus and the thalamus and striatum. Fructose increased connectivity between the hypothalamus and thalamus but not the striatum. Regional CBF within the hypothalamus, thalamus, insula, anterior cingulate, and striatum (appetite and reward regions) was reduced after glucose ingestion compared with baseline (P<.05 significance threshold, family-wise error [FWE] whole-brain corrected). In contrast, fructose reduced regional CBF in the thalamus, hippocampus, posterior cingulate cortex, fusiform, and visual cortex (P<.05 significance threshold, FWE whole-brain corrected). In whole-brain voxel-level analyses, there were no significant differences between direct comparisons of fructose vs glucose sessions following correction for multiple comparisons. Fructose vs glucose ingestion resulted in lower peak levels of serum glucose (mean difference, 41.0 mg/dL [95% CI, 27.7-54.5]; P<.001), insulin (mean difference, 49.6 μU/mL [95% CI, 38.2-61.1]; P<.001), and glucagon-like polypep-tide 1 (mean difference, 2.1 pmol/L [95% CI, 0.9-3.2]; P=.01).
Conclusion and Relevance
In a series of exploratory analyses, consumption of fructose compared with glucose resulted in a distinct pattern of regional CBF and a smaller increase in systemic glucose, insulin, and glucagon-like polypeptide 1 levels.
PMCID: PMC4076145  PMID: 23280226
9.  The Role of Guanfacine as a Therapeutic Agent to Address Stress-related Pathophysiology in Cocaine Dependent Individuals 
The pathophysiology of cocaine addiction is linked to changes within neural systems and brain regions that are critical mediators of stress system sensitivity as well as behavioral processes associated with the regulation of adaptive goal-directed behavior. This is characterized by the up-regulation of core adrenergic and corticotrophin releasing factor (CRF) mechanisms which sub-serve negative affect and anxiety and impinge upon intracellular pathways in the prefrontal cortex underlying cognitive regulation of stress and negative emotional state. Not only are these mechanisms essential to the severity of cocaine withdrawal symptoms, and hence the trajectory of clinical outcome, but they may also be particularly pertinent to the demography of cocaine dependence. The ability of guanfacine to target overlapping stress, reward and anxiety pathophysiology suggests that it may be a useful agent for attenuating the stress and cue-induced craving state in women especially, but also in men. This is supported by recent research findings from our own laboratory. Additionally, the ability of guanfacine to improve regulatory mechanisms that are key to exerting cognitive and emotional control over drug seeking behavior also suggest that guanfacine may be an effective medication for reducing craving and relapse vulnerability in many drugs of abuse. As cocaine dependent individuals are typically polydrug abusers, and women may be at a greater disadvantage for compulsive drug use than men, it is plausible that medications which target catecholaminergic fronto-striatal inhibitory circuits and simultaneously reduce stress system arousal may provide added benefits for attenuating cocaine dependence.
PMCID: PMC4017947  PMID: 24484979
10.  Stress as a common risk factor for obesity and addiction 
Biological psychiatry  2013;73(9):827-835.
Stress is associated with obesity and the neurobiology of stress overlaps significantly with that of appetite and energy regulation. This review will discuss stress, allostasis, the neurobiology of stress and its overlap with neural regulation of appetite and energy homeostasis. Stress is a key risk factor in the development of addiction and in addiction relapse. High levels of stress changes eating patterns and augments consumption of highly palatable (HP) foods, which in turn, increases incentive salience of HP foods and allostatic load. The neurobiological mechanisms by which stress affects reward pathways to potentiate motivation and consumption of HP foods as well as addictive drugs is discussed. With enhanced incentive salience of HP foods and over-consumption of these foods, there are adaptations in stress and reward circuits that promote stress-related and HP food-related motivation as well as concomitant metabolic adaptations, including alterations in glucose metabolism, insulin sensitivity, and other hormones related to energy homeostatsis. These metabolic changes in turn may also affect dopaminergic activity to influence food motivation and intake of HP foods. An integrative heuristic model is proposed wherein repeated high levels of stress alter the biology of stress and appetite/energy regulation, with both components directly affecting neural mechanisms contributing to stress-induced and food cue-induced HP food motivation and engagement in overeating of such foods to enhance risk of weight gain and obesity. Future directions in research are identified to increase understanding of the mechanisms by which stress may increase risk of weight gain and obesity.
PMCID: PMC3658316  PMID: 23541000
Obesity; Stress; Addiction; Metabolism; Neuroendocrine; Reward
11.  Monetary Reward Processing in Obese Individuals With and Without Binge Eating Disorder 
Biological psychiatry  2013;73(9):877-886.
An important step in obesity research involves identifying neurobiological underpinnings of nonfood reward processing unique to specific subgroups of obese individuals.
Nineteen obese individuals seeking treatment for binge eating disorder (BED) were compared with 19 non-BED obese individuals (OB) and 19 lean control subjects (LC) while performing a monetary reward/loss task that parses anticipatory and outcome components during functional magnetic resonance imaging. Differences in regional activation were investigated in BED, OB, and LC groups during reward/loss prospect, anticipation, and notification.
Relative to the LC group, the OB group demonstrated increased ventral striatal and ventromedial prefrontal cortex activity during anticipatory phases. In contrast, the BED group relative to the OB group demonstrated diminished bilateral ventral striatal activity during anticipatory reward/loss processing. No differences were observed between the BED and LC groups in the ventral striatum.
Heterogeneity exists among obese individuals with respect to the neural correlates of reward/loss processing. Neural differences in separable groups with obesity suggest that multiple, varying interventions might be important in optimizing prevention and treatment strategies for obesity.
PMCID: PMC3686098  PMID: 23462319
Binge eating disorder; fMRI; inferior frontal gyrus; insula; obesity; reward; ventral striatum
12.  Error processing and gender-shared and -specific neural predictors of relapse in cocaine dependence 
Brain  2013;136(4):1231-1244.
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.
PMCID: PMC3613717  PMID: 23485852
cocaine; relapse; cognitive control; error processing; gender difference
13.  Coupled Intrinsic Connectivity Distribution Analysis: A Method for Exploratory Connectivity Analysis of Paired fMRI Data 
PLoS ONE  2014;9(3):e93544.
We present a novel voxel-based connectivity approach for paired functional magnetic resonance imaging (fMRI) data collected under two different conditions labeled the Coupled Intrinsic Connectivity Distribution (coupled-ICD). Our proposed method jointly models both conditions to incorporate additional paired information into the connectivity metric. Voxel-based connectivity holds promise as a clinical tool to characterize a wide range of neurological and psychiatric diseases, and monitor their treatment. As such, examining paired connectivity data such as scans acquired pre- and post-intervention is an important application for connectivity methodologically. When presented with data from paired conditions, conventional voxel-based methods analyze each condition separately. However, summarizing each connection separately can misrepresent patterns of changes in connectivity. We show that commonly used methods can underestimate functional changes and subsequently introduce and evaluate our solution to this problem, the coupled-ICD metric, using two studies: 1) healthy controls scanned awake and under anesthesia, and 2) cocaine-dependent subjects and healthy controls scanned while being presented with relaxing or drug-related imagery cues. The coupled-ICD approach detected differences between paired conditions in similar brain regions as the conventional approaches while also revealing additional changes in regions not identified using conventional voxel-based connectivity analyses. Follow-up seed-based analyses on data independent from the voxel-based results also showed connectivity differences between conditions in regions detected by coupled-ICD. This approach of jointly analyzing paired resting-state scans provides a new and important tool with many applications for clinical and basic neuroscience research.
PMCID: PMC3968179  PMID: 24676034
14.  Neural Correlates of Stress- and Food Cue–Induced Food Craving in Obesity 
Diabetes Care  2013;36(2):394-402.
Obesity is associated with alterations in corticolimbic-striatal brain regions involved in food motivation and reward. Stress and the presence of food cues may each motivate eating and engage corticolimibic-striatal neurocircuitry. It is unknown how these factors interact to influence brain responses and whether these interactions are influenced by obesity, insulin levels, and insulin sensitivity. We hypothesized that obese individuals would show greater responses in corticolimbic-striatal neurocircuitry after exposure to stress and food cues and that brain activations would correlate with subjective food craving, insulin levels, and HOMA-IR.
Fasting insulin levels were assessed in obese and lean subjects who were exposed to individualized stress and favorite-food cues during functional MRI.
Obese, but not lean, individuals exhibited increased activation in striatal, insular, and hypothalamic regions during exposure to favorite-food and stress cues. In obese but not lean individuals, food craving, insulin, and HOMA-IR levels correlated positively with neural activity in corticolimbic-striatal brain regions during favorite-food and stress cues. The relationship between insulin resistance and food craving in obese individuals was mediated by activity in motivation-reward regions including the striatum, insula, and thalamus.
These findings demonstrate that obese, but not lean, individuals exhibit increased corticolimbic-striatal activation in response to favorite-food and stress cues and that these brain responses mediate the relationship between HOMA-IR and food craving. Improving insulin sensitivity and in turn reducing corticolimbic-striatal reactivity to food cues and stress may diminish food craving and affect eating behavior in obesity.
PMCID: PMC3554293  PMID: 23069840
15.  Sex differences in decreased limbic and cortical grey matter volume in cocaine dependence: a voxel-based morphometric study 
Addiction biology  2012;18(1):147-160.
Structural neuroimaging studies have provided evidence of differences in local brain volume between cocaine-dependent and healthy control individuals. While sex differences in aetiology, course and brain dysfunction associated with chronic cocaine abuse have been previously documented, evidence of sex-specific differences in brain volume has not been examined thus far. This study examined sex-related differences in grey matter volume between cocaine-dependent and healthy control subjects using voxel-based morphometry. High-resolution T1 structural scans were obtained from 36 inpatient, treatment-engaged 3-week abstinent cocaine-dependent (CD) individuals. Fifty healthy control subjects were also scanned. Segmentation and registration were performed in SPM8, using New Segment and DARTEL, respectively. The whole-brain statistical analysis was conducted in SPM8 using random field-based cluster-size testing and family-wise error rate correction for multiple comparisons. CD patients were found to have less grey matter volume in anterior prefrontal cortex, including frontopolar and orbitofrontal cortices, and a posterior region surrounding the parietal-occipital sulcus. Female CD patients had less grey matter volume than female controls in left inferior frontal gyrus, insula, superior temporal gyrus and hippocampus. Male CD patients had less grey matter in a superior cortical region that included the precentral gyrus and the mid-cingulate. These sex differences in lower grey matter volume add to the evidence from functional neuroimaging for sex-specific differences in the neurophysiological changes associated with chronic cocaine use.
PMCID: PMC3651026  PMID: 23167305
Cocaine dependence; sex; voxel-based morphometry
16.  Stress system changes associated with marijuana dependence may increase craving for alcohol and cocaine 
Human psychopharmacology  2012;28(1):40-53.
To date, little research exists defining bio-behavioral adaptations associated with both marijuana abuse and risk of craving and relapse to other drugs of abuse during early abstinence.
Fifty-nine treatment-seeking individuals dependent on alcohol and cocaine were recruited. Thirty of these individuals were also marijuana (MJ) dependent; 29 were not. Twenty-six socially drinking healthy controls were also recruited. All participants were exposed to three 5-min guided imagery conditions (stress, alcohol/cocaine cue and relaxing), presented randomly, one per day across three consecutive days. Measures of craving, anxiety, heart rate, blood pressure, plasma adrenocorticotrophic hormone and cortisol were collected at baseline and subsequent recovery time points.
The MJ-dependent group showed increased basal anxiety ratings and cardiovascular output alongside enhanced alcohol craving and cocaine craving, and dampened cardiovascular response to stress and cue. They also demonstrated elevated cue-induced anxiety and stress-induced cortisol and adrenocorticotrophic hormone levels, which were not observed in the non-MJ-dependent group or controls. Cue-related alcohol craving and anxiety were both predictive of a shorter number of days to marijuana relapse following discharge from inpatient treatment.
Findings provide some support for drug cross-sensitization in terms of motivational processes associated with stress-related and cue-related craving and relapse.
PMCID: PMC3660143  PMID: 23280514
marijuana; stress; drug cue; cocaine craving; alcohol craving; relapse
17.  Positron Emission Tomography Shows Elevated Cannabinoid CB1 Receptor Binding in Men with Alcohol Dependence 
Several lines of evidence link cannabinoid (CB) type 1 (CB1) receptor-mediated endogenous CB (eCB) signaling to the etiology of alcohol dependence (AD). However, to date, only peripheral measures of eCB function have been collected in living humans with AD and no human in vivo data on the potentially critical role of the brain CB1 receptor in AD have been published. This is an important gap in the literature, because recent therapeutic developments suggest that these receptors could be targeted for the treatment of AD.
Medication-free participants were scanned during early abstinence 4 weeks after their last drink. Using positron emission tomography (PET) with a high resolution research tomograph and the CB1 receptor selective radiotracer [11C]OMAR, we determined [11C]OMAR volume of distribution (VT) values, a measure of CB1 receptor density, in a-priori selected brain regions in men with AD (N=8, age 37.4± 7.9 years; 5 smokers) and healthy control (HC) men (N=8, age 32.5± 6.9 years; all non-smokers). PET images reconstructed using the MOLAR algorithm with hardware motion correction were rigidly aligned to the subject-specific magnetic resonance (MR) image, which in turn was warped to an MR template. Time-activity curves (TACs) were extracted from the dynamic PET data using a priori selected regions of interest delineated in the MR template space.
In AD relative to HC, [11C]OMAR VT values were elevated by ~20% (p=.023) in a circuit, including the amygdala, hippocampus, putamen, insula, anterior and posterior cingulate cortices and orbitofrontal cortex. Age, body mass index or smoking status did not influence the outcome.
These findings agree with preclinical evidence and provide the first, albeit still preliminary in vivo evidence suggesting a role for brain CB1 receptors in AD. The current study design does not answer the important question of whether elevated CB1 receptors are a pre-existing vulnerability factor for AD or whether elevations develop as a consequence of AD.
PMCID: PMC3418442  PMID: 22551199
alcohol dependence; brain imaging; positron emission tomography; endogenous cannabinoids; CB1 receptor
18.  Enhanced midbrain response at 6-month follow-up in cocaine addiction, association with reduced drug-related choice 
Addiction biology  2012;17(6):1013-1025.
Drug addiction is characterized by dysregulated dopamine neurotransmission. Although dopamine functioning appears to partially recover with abstinence, the specific regions that recover and potential impact on drug seeking remain to be determined. Here we used functional magnetic resonance imaging (fMRI) to study an ecologically valid sample of 15 treatment-seeking cocaine addicted individuals at baseline and 6-month follow-up. At both study sessions, we collected fMRI scans during performance of a drug Stroop task, clinical self-report measures of addiction severity, and behavioral measures of cocaine seeking (simulated cocaine choice); actual drug use in between the two study sessions was also monitored. At 6-month follow-up (compared with baseline) we predicted functional enhancement of dopaminergically-innervated brain regions, relevant to the behavioral responsiveness toward salient stimuli. Consistent with predictions, whole-brain analyses revealed responses in the midbrain (encompassing the ventral tegmental area/substantia nigra complex) and thalamus (encompassing the mediodorsal nucleus) that were higher (and more positively correlated) at follow-up than baseline. Increased midbrain activity from baseline to follow-up correlated with reduced simulated cocaine choice, indicating that heightened midbrain activations in this context may be marking lower approach motivation for cocaine. Normalization of midbrain function at follow-up was also suggested by exploratory comparisons with active cocaine users and healthy controls (who were assessed only at baseline). Enhanced self-control at follow-up was suggested by a trend for the commonly hypoactive dorsal anterior cingulate cortex to increase response during a drug-related context. Together, these results suggest that fMRI could be useful in sensitively tracking follow-up outcomes in drug addiction.
PMCID: PMC3394885  PMID: 22458423
cocaine addiction; follow-up outcome; fMRI; midbrain; thalamus; dopamine; anterior cingulate cortex; drug Stroop
19.  How Does Stress Lead to Risk of Alcohol Relapse? 
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
PMCID: PMC3788822  PMID: 23584109
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
20.  Disrupted Ventromedial Prefrontal Function, Alcohol Craving, and Subsequent Relapse Risk 
JAMA psychiatry (Chicago, Ill.)  2013;70(7):727-739.
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.
PMCID: PMC3788824  PMID: 23636842
21.  HPA axis response to psychological stress and treatment retention in residential substance abuse treatment: A prospective study 
Drug and alcohol dependence  2009;105(3):202-208.
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.
PMCID: PMC3774292  PMID: 19713052
Endocrinology; Stress; Cortisol; HPA axis; Residential; Treatment
22.  Clinical Laboratory Stressors Used to Study Alcohol–Stress Relationships 
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.
PMCID: PMC3763687  PMID: 23584112
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
23.  Altered expression of cytokine signaling pathway genes in peripheral blood cells of alcohol dependent subjects: Preliminary findings 
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.
PMCID: PMC3393821  PMID: 22471388
alcohol dependence; IL-15; IL-21; Janus kinase; Signal transducer and activator of transcription; microarray
24.  Divergent neural substrates of inhibitory control in binge eating disorder relative to other manifestations of obesity 
Obesity (Silver Spring, Md.)  2013;21(2):367-377.
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.
PMCID: PMC3610836  PMID: 23404820
binge eating disorder; obesity; inhibition; ventromedial prefrontal cortex; inferior frontal gyrus; restraint; fMRI
25.  Cumulative Adversity and Smaller Gray Matter Volume in Medial Prefrontal, Anterior Cingulate, and Insula Regions 
Biological Psychiatry  2012;72(1):57-64.
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.
PMCID: PMC3391585  PMID: 22218286
Brain MRI; chronic stress; cumulative adversity; gray matter volume; life trauma; prefrontal cortex; recent adverse life events

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