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1.  Lower cumulative stress is associated with better health for physically active adults in the community 
Stress (Amsterdam, Netherlands)  2014;17(2):157-168.
Both cumulative adversity, an individual's lifetime exposure to stressors, and insufficient exercise are associated with poor health outcomes. The purpose of this study was to ascertain whether exercise buffers the association of cumulative adverse life events (CALE) with health in a community-wide sample of healthy adults (ages 18–50 years; women: n 219, 29.5 ± 9.2 years; men: n = 176, 29.4 ± 8.7 years, mean ± standard deviation). Participants underwent the Cumulative Adversity Interview, which divides life events into three subsets: major life events (MLE), recent life events (RLE) and traumatic experiences (TLE). These individuals also completed the Cornell Medical Index and a short assessment for moderate or greater intensity exercise behavior, modified from the Nurses’ Health Study. Results indicated that higher CALE was associated with greater total health problems (r = 0.431, p<0.001). Interactions between stress and exercise were not apparent for RLE and TLE. However, at low levels of MLE, greater exercise was related to fewer total, physical, cardiovascular and psychological health problems (p value<0.05). Conversely, at high levels of MLE, the benefits of exercise appear to be absent. Three-way interactions were observed between sex, exercise and stress. Increased levels of exercise were related to better physical health in men, at all levels of CALE. Only women who reported both low levels of CALE and high levels of exercise had more favorable physical health outcomes. A similar pattern of results emerged for RLE. Together, these data suggest that increased exercise is related to better health, but these effects may vary by cumulative stress exposure and sex.
PMCID: PMC4548889  PMID: 24392966
Cumulative adversity; exercise; health complaints; life events; physical activity; stress
2.  Food cravings, food intake, and weight status in a community-based sample 
Eating behaviors  2014;15(3):478-482.
The aims of this study were to 1) determine the relationships between BMI and the frequency of food cravings for different categories of foods, 2) examine the associations between cravings for different types of foods and self-reported, habitual intake of these foods, and 3) assess how these relationships differ by BMI. Six hundred and forty-six participants (55.7% female; 66.4% White; mean age 29.5±9.1 years; mean BMI 27.3±5.5 kg/m2) completed a comprehensive assessment battery including the Food Craving Inventory (FCI) and a semi-quantitative food frequency questionnaire (FFQ). There was a significant positive relationship between BMI and food cravings. There were significant positive associations of cravings for sweets, high fats, carbohydrates/starches, and fast-food fats on respective intake of these types of foods; however, there were no significant interactions between food cravings and BMI on the respective type of food intake. This study indicates significant positive relationships between specific categories of food cravings and habitual intake of those foods.
PMCID: PMC4115250  PMID: 25064302
Food cravings; food intake; nutrition; obesity
3.  Prenatal cocaine exposure differentially affects stress responses in girls and boys: Associations with future substance use 
Development and psychopathology  2014;27(1):163-180.
Prenatal cocaine exposure may affect developing stress response systems in youth, potentially creating risk for substance use in adolescence. Further, pathways from prenatal risk to future substance use may differ for girls versus boys. The present longitudinal study examined multiple biobehavioral measures, including heart rate, blood pressure, emotion, and salivary cortisol and salivary alpha amylase (sAA), in response to a stressor in 193 low-income 14- to 17-year-olds, half of whom were prenatally cocaine exposed (PCE). Youth’s lifetime substance use was assessed with self-report, interview, and urine toxicology/breathalyzer at Time 1 and at Time 2 (6–12 months later). PCExGender interactions were found predicting anxiety, anger, and sadness responses to the stressor, with PCE girls showing heightened responses as compared to PCE boys on these indicators. Stress Response × Gender interactions were found predicting Time 2 substance use in youth (controlling for Time 1 use) for sAA and sadness; for girls, heightened sadness responses predicted substance use, but for boys, dampened sAA responses predicted substance use. Findings suggest distinct biobehavioral stress response risk profiles for boys and girls, with heightened arousal for girls and blunted arousal for boys associated with prenatal risk and future substance use outcomes.
PMCID: PMC4469069  PMID: 25036298
4.  Childhood Maltreatment, Altered Limbic Neurobiology, and Substance Use Relapse Severity via Trauma-Specific Reductions in Limbic Gray Matter Volume 
JAMA psychiatry  2014;71(8):917-925.
Substance use disorders (SUDs) are among the most common sequelae of childhood maltreatment, yet the independent contributions of SUDs and childhood maltreatment to neurobiological changes and the effect of the latter on relapse risk (a critical variable in addiction treatment) are relatively unknown.
To identify structural neural characteristics independently associated with childhood maltreatment (CM; a common type of childhood adversity), comparing a sample with SUD with a demographically comparable control sample, and to examine the relationship between CM-related structural brain changes and subsequent relapse.
Structural magnetic resonance imaging study comparing 79 treatment-engaged participants with SUD in acute remission in inpatient treatment at a community mental health center vs 98 healthy control participants at an outpatient research center at an academic medical center. Both groups included individuals with a range of CM experiences. Participants with SUD were followed up prospectively for 90 days to assess relapse and relapse severity.
Standard 12-step, recovery-based, inpatient addiction treatment for all participants with SUD.
Gray matter volume (GMV), subsequent substance use relapse, days to relapse, and severity of relapse.
Controlling for SUD and psychiatric comorbidity, CM (dichotomously classified) was uniquely associated with lower GMV across all participants in the left hippocampus (cornu ammonis 1-3, dentate gyrus), parahippocampus (presubiculum, parasubiculum, prosubiculum, subiculum, and entorhinal cortex), and anterior fusiform gyrus (corrected P < .05; uncorrected P = .001). Among the sample with SUD, CM prospectively predicted a shorter relapse to use of any drug (P = .048), while CM-related GMV reductions predicted severity of substance use relapse (P = .04).
Findings indicate that CM was related to decreased GMV in limbic regions, which in turn predicted increased risk of relapse in SUD. These results suggest that CM may significantly affect the course of SUD treatment outcomes and that SUD treatment planning may benefit from identifying and addressing CM.
PMCID: PMC4437819  PMID: 24920451
5.  Guanfacine enhances inhibitory control and attentional shifting in early abstinent cocaine-dependent individuals 
Attenuation of adrenergic drive and cognitive enhancement, via stimulation of alpha2 pre- and post-synaptic receptors, may selectively enhance executive performance in early abstinent cocaine-dependent individuals. As these cognitive processes underpin important treatment-related behaviors, the alpha2 agonist, guanfacine HCl, may represent an effective pharmaco-therapeutic intervention.
Twenty-five early abstinent cocaine-dependent individuals were administered a battery of neurocognitive tasks on entry into treatment (baseline) and again following 3 weeks of either placebo or guanfacine treatment (up to 3 mg). Tasks included: Stop Signal, Stroop, 3-Dimentional Intra-dimensional/Extra-dimensional (IDED) task, Spatial Working Memory (SWM), Paired Associates Learning (PAL), Verbal Fluency and the Rey Auditory Verbal Learning Test (RAVLT).
Compared with placebo, the guanfacine group demonstrated attenuated anxiety and negative affect as well as improved performance on selective executive tests. This included fewer directional errors on the stop signal task, fewer errors on the extra-dimensional shift component of the IDED task and better attentional switching during verbal fluency. Guanfacine did not improve strategic working memory or peripheral memory.
Guanfacine improves selective cognitive processes which may underlie salient treatment-related regulatory behaviors. Alpha2 agonists may therefore represent important agents for cocaine dependence.
PMCID: PMC4432477  PMID: 25567555
Guanfacine; cocaine dependence; inhibitory response; alpha2 agonists; executive function; verbal fluency; stop signal
6.  Sex Differences in Guanfacine Effects on Drug Craving and Stress Arousal in Cocaine-Dependent Individuals 
Neuropsychopharmacology  2014;39(6):1527-1537.
Currently, no FDA-approved medication exists for the treatment of cocaine use disorder. Furthermore, as women become increasingly more at risk for the consequences of cocaine addiction, the need to establish better-tailored treatment medications is paramount. We examine the effects of the alpha2 adrenergic agonist, guanfacine HCl, on responses to stress and drug cue in a group of cocaine-dependent men and women who also abuse alcohol and nicotine. Forty early abstinent treatment-seeking cocaine-dependent males and females were randomly assigned to receive either daily placebo (12 M/7 F) or guanfacine (2 or 3 mg) (15 M/6 F) for 3 weeks. In week 4, they participated in a laboratory experiment and were exposed to three 10-min guided imagery conditions (stress/stress, cue/cue, and stress/cue), one per day, consecutively in a random, counterbalanced order. Craving, negative emotion, anxiety, and cardiovascular function were assessed at baseline, immediately following imagery exposure, and at various recovery time points. Guanfacine significantly attenuated cocaine craving, alcohol craving, anxiety, and negative emotion following exposure to all three imagery conditions in females, but not males. Guanfacine did, however, reduce sympathetic tone as well as stress and cue-induced nicotine craving and systolic blood pressure (SBP) in both males and females. These findings highlight sex-specific effects of guanfacine on drug craving, anxiety, and negative mood with significant effects in women and not men. The findings suggest further evaluation of guanfacine in the treatment of cocaine use disorder with a specific focus on sex differences in treatment response.
PMCID: PMC3988558  PMID: 24395021
addiction & substance abuse; cocaine dependence; drug cue; drug discovery; development; guanfacine; mood; anxiety; stress disorders; psychopharmacology; sex; stress; guanfacine; stress; drug cue; cocaine use disorder; sex-craving
7.  Neural correlates of preparatory and regulatory control over positive and negative emotion 
This study used functional magnetic resonance imaging to investigate brain activation during preparatory and regulatory control while participants (N = 24) were instructed either to simply view or decrease their emotional response to, pleasant, neutral or unpleasant pictures. A main effect of emotional valence on brain activity was found in the right precentral gyrus, with greater activation during positive than negative emotion regulation. A main effect of regulation phase was evident in the bilateral anterior prefrontal cortex (PFC), precuneus, posterior cingulate cortex, right putamen and temporal and occipital lobes, with greater activity in these regions during preparatory than regulatory control. A valence X regulation interaction was evident in regions of ventromedial PFC and anterior cingulate cortex, reflecting greater activation while regulating negative than positive emotion, but only during active emotion regulation (not preparation). Conjunction analyses revealed common brain regions involved in differing types of emotion regulation including selected areas of left lateral PFC, inferior parietal lobe, temporal lobe, right cerebellum and bilateral dorsomedial PFC. The right lateral PFC was additionally activated during the modulation of both positive and negative valence. Findings demonstrate significant modulation of brain activity during both preparation for, and active regulation of positive and negative emotional states.
PMCID: PMC3989138  PMID: 23887812
cognitive control; positive emotion; negative emotion; fMRI; brain
Eating behaviors  2014;15(2):286-290.
Background & Aims
Restrained food consumption may alter metabolic function and contribute to eventual weight gain; however, sex differences in these relationships have not been assessed. The objective of this study was to examine the relationship between restrained eating and insulin resistance and the influence of body mass index and sex on this relationship in a large community sample of both men and women. We hypothesized that restrained eating would be related to insulin resistance and this relationship would be influenced by sex and body mass index.
In this cross-sectional, observational study, we studied 487 individuals from the community (men N=222, women N=265), who ranged from lean (body mass index 18.5–24.9kg/m2, N=173), overweight (body mass index 25–29.9kg/m2, N=159) and obese (body mass index >30kg/m2, N=155) weight categories. We assessed restrained eating using the Dutch Eating Behavior Questionnaire and obtained fasting morning plasma insulin and glucose on all subjects.
In men, but not in women, restrained eating was related to homeostatic model assessment of insulin resistance (HOMA-IR) (p<0.0001). Furthermore, homeostatic model assessment of insulin resistance levels were significantly higher in men who were high-versus low-restrained eaters (p=0.0006).
This study is the first to report sex differences with regard to the relationship between restrained eating and insulin resistance. Our results suggest that high restraint eating is associated with insulin resistance in men but not in women.
PMCID: PMC4032476  PMID: 24854820
sex differences; restrained eating; insulin resistance; obesity; dietary restraint
Stress and pre-frontal cognitive dysfunction have key roles in driving smoking, however, there are no therapeutics for smoking cessation which attenuate the effects of stress on smoking and enhance cognition. Central noradrenergic pathways are involved in stress-induced reinstatement to nicotine and in the prefrontal executive control of adaptive behaviors. We used a novel translational approach employing a validated laboratory analogue of stress-precipitated smoking, fMRI, and a proof-of-concept treatment period to evaluate whether the noradrenergic α2a agonist, guanfacine (3mg/day) versus placebo (0mg/day) reduced stress-precipitated smoking in the laboratory, altered cortico-striatal activation during the Stroop cognitive-control task, and reduced smoking following a quit attempt. In nicotine-deprived smokers (n=33), stress versus a neutral condition significantly decreased the latency to smoke, and increased tobacco craving, ad-libitum smoking, and systolic blood pressure in placebo-treated subjects, and these effects were absent or reduced in guanfacine-treated subjects. Following stress, placebo-treated subjects demonstrated decreased cortisol levels whereas guanfacine-treated subjects demonstrated increased levels. Guanfacine, compared to placebo, altered prefrontal activity during a cognitive control task, and reduced cigarette use but did not increase complete abstinence during treatment. These preliminary laboratory, neuroimaging and clinical outcome data were consistent and complementary and support further development of guanfacine for smoking cessation.
PMCID: PMC4376109  PMID: 25516371
guanfacine; smoking cessation; stress; fMRI; Stroop; lapse; ad-lib smoking; craving
10.  Conflict anticipation in alcohol dependence — A model-based fMRI study of stop signal task 
NeuroImage : Clinical  2015;8:39-50.
Our previous work characterized altered cerebral activations during cognitive control in individuals with alcohol dependence (AD). A hallmark of cognitive control is the ability to anticipate changes and adjust behavior accordingly. Here, we employed a Bayesian model to describe trial-by-trial anticipation of the stop signal and modeled fMRI signals of conflict anticipation in a stop signal task. Our goal is to characterize the neural correlates of conflict anticipation and its relationship to response inhibition and alcohol consumption in AD.
Twenty-four AD and 70 age and gender matched healthy control individuals (HC) participated in the study. fMRI data were pre-processed and modeled with SPM8. We modeled fMRI signals at trial onset with individual events parametrically modulated by estimated probability of the stop signal, p(Stop), and compared regional responses to conflict anticipation between AD and HC. To address the link to response inhibition, we regressed whole-brain responses to conflict anticipation against the stop signal reaction time (SSRT).
Compared to HC (54/70), fewer AD (11/24) showed a significant sequential effect — a correlation between p(Stop) and RT during go trials — and the magnitude of sequential effect is diminished, suggesting a deficit in proactive control. Parametric analyses showed decreased learning rate and over-estimated prior mean of the stop signal in AD. In fMRI, both HC and AD responded to p(Stop) in bilateral inferior parietal cortex and anterior pre-supplementary motor area, although the magnitude of response increased in AD. In contrast, HC but not AD showed deactivation of the perigenual anterior cingulate cortex (pgACC). Furthermore, deactivation of the pgACC to increasing p(Stop) is positively correlated with the SSRT in HC but not AD. Recent alcohol consumption is correlated with increased activation of the thalamus and cerebellum in AD during conflict anticipation.
The current results highlight altered proactive control that may serve as an additional behavioral and neural marker of alcohol dependence.
•We addressed the neural correlates of conflict anticipation in AD and HC in an SST.•AD showed greater activation in preSMA and less deactivation in pgACC.•Deactivation in pgACC inversely correlated with SSRT in HC but not AD.•Alcohol use is correlated with greater thalamic and cerebellar activations in AD.
PMCID: PMC4473266  PMID: 26106526
Cognitive control; Conflict; Alcoholism; Neuroimaging; Medial prefrontal cortex
11.  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
12.  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
13.  Neuroplasticity and Predictors of Alcohol Recovery 
Chronic alcohol-related neuroadaptations in key neural circuits of emotional and cognitive control play a critical role in the development of, and recovery from, alcoholism. Converging evidence in the neurobiological literature indicates that neuroplastic changes in the prefrontal–striatal–limbic circuit, which governs emotion regulation and decisionmaking and controls physiological responses in the autonomic nervous system and hypothalamic–pituitary–adrenal axis system, contribute to chronic alcoholism and also are significant predictors of relapse and recovery. This paper reviews recent evidence on the neuroplasticity associated with alcoholism in humans, including acute and chronic effects, and how these neurobiological adaptations contribute to alcohol recovery, along with the discussion of relevant clinical implications and future research directions.
PMCID: PMC4476600
Alcohol use, abuse, and dependence; alcoholism; alcohol effects and consequences; alcohol-related neuroadaptations; neurobiology; brain; neuroplasticity; prefrontal-striatal-limbic circuit; autonomic nervous system; hypothalamic-pituitary-adrenal axis system; recovery; relapse
14.  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
15.  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
16.  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
17.  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
18.  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
19.  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
20.  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
21.  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
22.  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
23.  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
24.  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
25.  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

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