Connectome-based prediction of craving in gambling disorder and cocaine use disorder.

INTRODUCTION: Craving, involving intense and urgent desires to engage in specific behaviours, is a feature of addictions. Multiple studies implicate regions of salience/limbic networks and basal ganglia, fronto-parietal, medial frontal regions in craving in addictions. However, prior studies have not identified common neural networks that reliably predict craving across substance and behavioural addictions. METHODS: Functional magnetic resonance imaging during an audiovisual cue-reactivity task and connectome-based predictive modelling (CPM), a data-driven method for generating brain-behavioural models, were used to study individuals with cocaine-use disorder and gambling disorder. Functions of nodes and networks relevant to craving were identified and interpreted based on meta-analytic data. RESULTS: Craving was predicted by neural connectivity across disorders. The highest degree nodes were mostly located in the prefrontal cortex. Overall, the prediction model included complex networks including motor/sensory, fronto-parietal, and default-mode networks. The decoding revealed high functional associations with components of memory, valence ratings, physiological responses, and finger movement/motor imagery. CONCLUSIONS: Craving could be predicted across substance and behavioural addictions. The model may reflect general neural mechanisms of craving despite specificities of individual disorders. Prefrontal regions associated with working memory and autobiographical memory seem important in predicting craving. For further validation, the model should be tested in diverse samples and contexts.

Sex differences in neural responses to stress and drug cues predicts future drug use in individuals with substance use disorder.

BACKGROUND: Substance use disorders (SUDs) are chronically recurring illnesses, where stress and drug cues significantly increase drug craving and risk of drug use recurrence. This study examined sex differences in functional magnetic resonance imaging (fMRI) brain responses to stress and drug cue exposure and assessed their prospective association with future drug use post-treatment. METHODS: Inpatient, treatment engaged men (N = 46) and women (N = 26) with SUDs, including alcohol, cocaine and/or cannabis use disorders, participated in an fMRI scan that assessed subjective (anxiety, drug craving), heart rate and neural responses to brief individualized script-driven imagery of stress, drug, and neutral-relaxing trials. Prospective follow-up interviews post-treatment assessed future drug use recurrence over 90 days. RESULTS: During fMRI, stress and drug versus neutral cue exposure led to increased anxiety, heart rate and craving responses (p's < 0.004) in both men and women, but greater drug cue-induced anxiety (p < .017) and higher drug use days during follow-up (p < .006) in women relative to men. In whole brain analyses of stress and drug cues (p < .05 FWE corrected), and in whole brain correlation (p < .05, FWE corrected) with drug use days, significant sex differences revealed drug cue-related striatal hyperactivation (caudate, putamen) in men, but drug cue-related cortico-limbic (insula and dorsolateral prefrontal cortex) hypoactivation and stress-related hypoactivation in the ventromedial prefrontal cortex (VmPFC) in women; and these were significantly associated with higher future drug use days. CONCLUSIONS: Findings indicate sex-specific pathophysiology of SUD recurrence and support the need for differential treatment development for men and women with SUD to improve drug use outcomes.

Neural Correlates of Personalized Spiritual Experiences.

Across cultures and throughout history, human beings have reported a variety of spiritual experiences and the concomitant perceived sense of union that transcends one's ordinary sense of self. Nevertheless, little is known about the underlying neural mechanisms of spiritual experiences, particularly when examined across different traditions and practices. By adapting an individualized guided-imagery task, we investigated neural correlates of personally meaningful spiritual experiences as compared with stressful and neutral-relaxing experiences. We observed in the spiritual condition, as compared with the neutral-relaxing condition, reduced activity in the left inferior parietal lobule (IPL), a result that suggests the IPL may contribute importantly to perceptual processing and self-other representations during spiritual experiences. Compared with stress cues, responses to spiritual cues showed reduced activity in the medial thalamus and caudate, regions associated with sensory and emotional processing. Overall, the study introduces a novel method for investigating brain correlates of personally meaningful spiritual experiences and suggests neural mechanisms associated with broadly defined and personally experienced spirituality.

Altered functional connectivity to stressful stimuli in prenatally cocaine-exposed adolescents.

BACKGROUND: Prenatal cocaine exposure (PCE) is linked to addiction and obesity vulnerability. Neural responses to stressful and appetitive cues in adolescents with PCE versus those without have been differentially linked to substance-use initiation. However, no prior studies have assessed cue-reactivity responses among PCE adolescents using a connectivity-based approach. METHODS: Twenty-two PCE and 22 non-prenatally drug-exposed (NDE) age-, sex-, IQ- and BMI-matched adolescents participated in individualized guided imagery with appetitive (favorite-food), stressful and neutral-relaxing cue scripts during functional magnetic resonance imaging. Subjective favorite-food craving scores were collected before and after script exposure. A data-driven voxel-wise intrinsic connectivity distribution analysis was used to identify between-group differences and examine relationships with craving scores. RESULTS: A group-by-cue interaction effect identified a parietal lobe cluster where PCE versus NDE adolescents showed less connectivity during stressful and more connectivity during neutral-relaxing conditions. Follow-up seed-based connectivity analyses revealed that, among PCE adolescents, the parietal seed was positively connected to inferior parietal and sensory areas and negatively connected to corticolimbic during both stress and neutral-relaxing conditions. For NDE, greater parietal connectivity to parietal, cingulate and sensory areas and lesser parietal connectivity to medial prefrontal areas were found during stress compared to neutral-relaxing cueing. Craving scores inversely correlated with corticolimbic connectivity in PCE, but not NDE adolescents, during the favorite-food condition. CONCLUSIONS: Findings from this first data-driven intrinsic connectivity analysis of PCE influences on adolescent brain function indicate differences relating to PCE status and craving. These findings provide insight into the developmental impact of in utero drug exposure.

Neural Correlates and Connectivity Underlying Stress-Related Impulse Control Difficulties in Alcoholism.

BACKGROUND: Stress triggers impulsive and addictive behaviors, and alcoholism has been frequently associated with increased stress sensitivity and impulse control problems. However, neural correlates underlying the link between alcoholism and impulsivity in the context of stress in patients with alcohol use disorders (AUD) have not been well studied. METHODS: This study investigated neural correlates and connectivity patterns associated with impulse control difficulties in abstinent AUD patients. Using functional magnetic resonance imaging, brain responses of 37 AUD inpatients, and 37 demographically matched healthy controls were examined during brief individualized imagery trials of stress, alcohol cue, and neutral-relaxing conditions. Stress-related impulsivity was measured using a subscale score of impulse control problems from Difficulties in Emotion Regulation Scale. RESULTS: Impulse control difficulties in AUD patients were significantly associated with hypo-active response to stress in the ventromedial prefrontal cortex (VmPFC), right caudate, and left lateral PFC (LPFC) compared to the neutral condition (p < 0.01, whole-brain corrected). These regions were used as seed regions to further examine the connectivity patterns with other brain regions. With the VmPFC seed, AUD patients showed reduced connectivity with the anterior cingulate cortex compared to controls, which are core regions of emotion regulation, suggesting AUD patients' decreased ability to modulate emotional response under distressed state. With the right caudate seed, patients showed increased connectivity with the right motor cortex, suggesting increased tendency toward habitually driven behaviors. With the left LPFC seed, decreased connectivity with the dorsomedial PFC (DmPFC), but increased connectivity with sensory and motor cortices were found in AUD patients compared to controls (p < 0.05, whole-brain corrected). Reduced connectivity between the left LPFC and DmPFC was further associated with increased stress-induced anxiety in AUD patients (p < 0.05, with adjusted Bonferroni correction). CONCLUSIONS: Hypo-active response to stress and altered connectivity in key emotion regulatory regions may account for greater stress-related impulse control problems in alcoholism.

Functional Connectivity During Exposure to Favorite-Food, Stress, and Neutral-Relaxing Imagery Differs Between Smokers and Nonsmokers.

INTRODUCTION: Tobacco-use disorder is a complex condition involving multiple brain networks and presenting with multiple behavioral correlates including changes in diet and stress. In a previous functional magnetic resonance imaging (fMRI) study of neural responses to favorite-food, stress, and neutral-relaxing imagery, smokers versus nonsmokers demonstrated blunted corticostriatal-limbic responses to favorite-food cues. Based on other recent reports of alterations in functional brain networks in smokers, the current study examined functional connectivity during exposure to favorite-food, stress, and neutral-relaxing imagery in smokers and nonsmokers, using the same dataset. METHODS: The intrinsic connectivity distribution was measured to identify brain regions that differed in degree of functional connectivity between groups during each imagery condition. Resulting clusters were evaluated for seed-to-voxel connectivity to identify the specific connections that differed between groups during each imagery condition. RESULTS: During exposure to favorite-food imagery, smokers versus nonsmokers showed lower connectivity in the supramarginal gyrus, and differences in connectivity between the supramarginal gyrus and the corticostriatal-limbic system. During exposure to neutral-relaxing imagery, smokers versus nonsmokers showed greater connectivity in the precuneus, and greater connectivity between the precuneus and the posterior insula and rolandic operculum. During exposure to stress imagery, smokers versus nonsmokers showed lower connectivity in the cerebellum. CONCLUSIONS: These findings provide data-driven insights into smoking-related alterations in brain functional connectivity patterns related to appetitive, relaxing, and stressful states. IMPLICATIONS: This study uses a data-driven approach to demonstrate that smokers and nonsmokers show differential patterns of functional connectivity during guided imagery related to personalized favorite-food, stress, and neutral-relaxing cues, in brain regions implicated in attention, reward-related, emotional, and motivational processes. For smokers, these differences in connectivity may impact appetite, stress, and relaxation, and may interfere with smoking cessation.

Prenatal cocaine exposure, illicit-substance use and stress and craving processes during adolescence.

BACKGROUND: Prenatal cocaine exposure (PCE) is associated with increased rates of illicit-substance use during adolescence. In addition, both PCE and illicit-substance use are associated with alterations in cortico-striato-limbic neurocircuitry, development of which is ongoing throughout adolescence. However, the relationship between illicit-substance use, PCE and functional neural responses has not previously been assessed concurrently. METHODS: Sixty-eight adolescents were recruited from an ongoing longitudinal study of childhood and adolescent development. All participants had been followed since birth. Functional magnetic resonance imaging (fMRI) data were acquired during presentation of personalized stressful, favorite-food and neutral/relaxing imagery scripts and compared between 46 PCE and 22 non-prenatally-drug-exposed (NDE) adolescents with and without lifetime illicit-substance use initiation. Data were analyzed using multi-level ANOVAs (pFWE<.05). RESULTS: There was a significant three-way interaction between illicit-substance use, PCE status and cue condition on neural responses within primarily cortical brain regions, including regions of the left and right insula. Among PCE versus NDE adolescents, illicit-substance use was associated with decreased subcortical and increased cortical activity during the favorite-food condition, whereas the opposite pattern of activation was observed during the neutral/relaxing condition. Among PCE versus NDE adolescents, illicit-substance use during stress processing was associated with decreased activity in cortical and subcortical regions including amygdala, hippocampus and prefrontal cortex. Neural activity within cortico-striato-limbic regions was significantly negatively associated with subjective ratings of anxiety and craving among illicit-substance users, but not among non-users. CONCLUSIONS: These findings suggest different neural substrates of experimentation with illicit drugs between adolescents with and without in utero cocaine exposure.

Blunted striatal responses to favorite-food cues in smokers.

BACKGROUND: Although tobacco-smoking is associated with relatively leaner body mass and smoking cessation with weight gain, the brain mechanisms underlying these relationships are not well understood. Smokers compared to non-smokers have shown diminished neural responses to non-tobacco rewarding stimuli (e.g., monetary rewards), but brain responses to favorite-food cues have not been investigated relative to smoking status. We hypothesized that smokers would exhibit diminished neural responses compared to non-smokers in response to favorite-food cues in motivation-reward and emotion-regulating regions of the brain. METHODS: Twenty-three smokers and 23 non-smokers matched based on body mass index (BMI), age, and gender listened to personalized favorite-food cue, stress, and neutral-relaxing audiotapes during fMRI. RESULTS: During favorite-food cue exposure, smokers versus non-smokers exhibited diminished activations in the caudate, putamen, insula, and thalamus. Neural responses during stress and neutral-relaxing conditions were similar across groups. Subjective food-craving ratings were similar across groups. CONCLUSIONS: The relatively diminished neural responses to favorite-food cues in smokers may contribute to lower BMI.

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

IMPORTANCE: Alcohol dependence is a chronic relapsing illness; stress, alcohol-related cues, and neutral-relaxing states significantly influence craving and relapse risk. However, neural mechanisms underlying the association between these states and alcohol craving and relapse risk remain unclear. OBJECTIVES: To identify neural correlates associated with alcohol craving and relapse outcomes in 45 treatment-engaged, 4- to 8-week abstinent alcohol-dependent (AD) patients, and to compare brain responses of 30 demographically matched AD patients and 30 healthy control subjects during stress, alcohol, and neutral-relaxing cues. DESIGN: Functional magnetic resonance imaging study while participants were engaging in brief individualized script-driven imagery trials of stress, alcohol cues, and neutral-relaxing scenarios, and a prospective clinical outcome design to assess alcohol relapse 90 days postdischarge from inpatient treatment in the AD group. SETTINGS: Inpatient treatment setting in a community mental health center and hospital-based research unit. PATIENTS: Forty-five recovering AD patients in inpatient treatment for examining relapse, and 30 healthy control subjects demographically matched to 30 AD patients (subgroup of the relapse sample) for group comparisons. INTERVENTION: Twelve-step recovery-based addiction treatment for the patient group. MAIN OUTCOMES AND MEASURES: Brain response, alcohol craving, and relapse outcome measures (time to relapse and relapse severity). RESULTS: Increased ventromedial prefrontal cortex (vmPFC) and anterior cingulate cortex (ACC) activation during neutral-relaxing trials was correlated with high alcohol cue-induced and stress-induced craving in early recovering AD patients (x = 6, y = 43, z = -6; P < .01, whole-brain corrected). This vmPFC/ACC hyperactivity significantly predicted subsequent alcohol relapse, with a hazards ratio greater than 8 for increased relapse risk. Additionally, vmPFC/ACC hyperactivation during neutral trials and reduced activity during stress trials were each predictive of greater days of alcohol used after relapse (P < .01, whole-brain corrected). In contrast, matched control subjects showed the reverse pattern of vmPFC/ACC responses to stress, alcohol cues, and relaxed trials (F = 6.42; P < .01, whole-brain corrected). CONCLUSIONS AND RELEVANCE: Findings indicate that disrupted vmPFC/ACC function plays a role in jeopardizing recovery from alcoholism and may serve as a neural marker to identify those at risk for alcohol relapse.

Neural correlates of stress and favorite-food cue exposure in adolescents: a functional magnetic resonance imaging study.

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. This 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 with 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 with 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. These 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.

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

OBJECTIVE: Although stress and drug cue exposure each increase drug craving and contribute to relapse in cocaine dependence, no previous research has directly examined the neural correlates of stress-induced and drug cue-induced craving in cocaine-dependent women and men relative to comparison subjects. METHOD: Functional MRI was used to assess responses to individualized scripts for stress, drug/alcohol cue and neutral-relaxing-imagery conditions in 30 abstinent cocaine-dependent individuals (16 women, 14 men) and 36 healthy recreational-drinking comparison subjects (18 women, 18 men). RESULTS: Significant three-way interactions between diagnostic group, sex, and script condition were observed in multiple brain regions including the striatum, insula, and anterior and posterior cingulate. Within women, group-by-condition interactions were observed involving these regions and were attributable to relatively increased regional activations in cocaine-dependent women during the stress and, to a lesser extent, neutral-relaxing conditions. Within men, group main effects were observed involving these same regions, with cocaine-dependent men demonstrating relatively increased activation across conditions, with the main contributions from the drug and neutral-relaxing conditions. In men and women, subjective drug-induced craving measures correlated positively with corticostriatal-limbic activations. CONCLUSIONS: In cocaine dependence, corticostriatal-limbic hyperactivity appears to be linked to stress cues in women, drug cues in men, and neutral-relaxing conditions in both. These findings suggest that sex should be taken into account in the selection of therapies in the treatment of addiction, particularly those targeting stress reduction.

Sex differences in neural responses to stress and alcohol context cues.

Stress and alcohol context cues are each associated with alcohol-related behaviors, yet neural responses underlying these processes remain unclear. This study investigated the neural correlates of stress and alcohol context cue experiences and examined sex differences in these responses. Using functional magnetic resonance imaging, brain responses were examined while 43 right-handed, socially drinking, healthy individuals (23 females) engaged in brief guided imagery of personalized stress, alcohol-cue, and neutral-relaxing scenarios. Stress and alcohol-cue exposure increased activity in the cortico-limbic-striatal circuit (P < 0.01, corrected), encompassing the medial prefrontal cortex (mPFC), orbitofrontal cortex (OFC), anterior cingulate cortex (ACC), left anterior insula, striatum, and visuomotor regions (parietal and occipital lobe, and cerebellum). Activity in the left dorsal striatum increased during stress, while bilateral ventral striatum activity was evident during alcohol-cue exposure. Men displayed greater stress-related activations in the mPFC, rostral ACC, posterior insula, amygdala, and hippocampus than women, whereas women showed greater alcohol-cue-related activity in the superior and middle frontal gyrus (SFG/MFG) than men. Stress-induced anxiety was positively associated with activity in emotion-modulation regions, including the medial OFC, ventromedial PFC, left superior-mPFC, and rostral ACC in men, but in women with activation in the SFG/MFG, regions involved in cognitive processing. Alcohol craving was significantly associated with the striatum (encompassing dorsal, and ventral) in men, supporting its involvement in alcohol "urge" in healthy men. These results indicate sex differences in neural processing of stress and alcohol-cue experiences and have implications for sex-specific vulnerabilities to stress- and alcohol-related psychiatric disorders.

Biofeedback of real-time functional magnetic resonance imaging data from the supplementary motor area reduces functional connectivity to subcortical regions.

Recent studies have reported that biofeedback of real-time functional magnetic resonance imaging data can enable people to gain control of activity in specific parts of their brain and can alter functional connectivity between brain areas. Here we describe a study using biofeedback of real-time functional magnetic resonance imaging data to train healthy subjects to control activity in their supplementary motor area (SMA), a region of interest in Tourette syndrome (TS). Although a significant increase in control over the SMA during biofeedback was not found, subjects were able to exert significant control over the SMA in later biofeedback sessions despite not having control in the first biofeedback session. Further, changes were found in their resting state functional connectivity. Specifically, when comparing functional connectivity to the SMA before and after biofeedback, the strength of functional connectivity with subcortical regions was reduced after the biofeedback. This suggests that biofeedback may allow subjects to develop greater conscious control over activity in their SMA by reducing the influence of corticostriatothalamocortical loops on the region. This possibility is promising for TS, where aberrant dynamics in corticostriatothalamocortical loops have long been suspected to give rise to tic symptoms. Further studies in TS patients are needed.

Sensory and cognitive mechanisms of change detection in the context of speech.

The aim of this study was to dissociate the contributions of memory-based (cognitive) and adaptation-based (sensory) mechanisms underlying deviance detection in the context of natural speech. Twenty healthy right-handed native speakers of English participated in an event-related design scan in which natural speech stimuli, /de:/ ("deh") and /deI/ ("day"); (/te:/ ("teh") and /teI/ ("tay") served as standards and deviants within functional magnetic resonance imaging event-related "oddball" paradigm designed to elicit the mismatch negativity component. Thus, "oddball" blocks could involve either a word deviant ("day") resulting in a "word advantage" effect, or a non-word deviant ("deh" or "tay"). We utilized an experimental protocol controlling for refractoriness similar to that used previously when deviance detection was studied in the context of tones. Results showed that the cognitive and sensory mechanisms of deviance detection were located in the anterior and posterior auditory cortices, respectively, as was previously found in the context of tones. The cognitive effect, that was most robust for the word deviant, diminished in the "oddball" condition. In addition, the results indicated that the lexical status of the speech stimulus interacts with acoustic factors exerting a top-down modulation of the extent to which novel sounds gain access to the subject's awareness through memory-based processes. Thus, the more salient the deviant stimulus is the more likely it is to be released from the effects of adaptation exerted by the posterior auditory cortex.