Neural responses to reward, threat, and emotion regulation and transition to hazardous alcohol use.

AIMS: Reward processing and regulation of emotions are thought to impact the development of addictive behaviors. In this study, we aimed to determine whether neural responses during reward anticipation, threat appraisal, emotion reactivity, and cognitive reappraisal predicted the transition from low-level to hazardous alcohol use over a 12-month period. METHODS: Seventy-eight individuals aged 18-22 with low-level alcohol use [i.e. Alcohol Use Disorder Identification Test (AUDIT) score <7] at baseline were enrolled. They completed reward-based and emotion regulation tasks during magnetic resonance imaging to examine reward anticipation, emotional reactivity, cognitive reappraisal, and threat anticipation (in the nucleus accumbens, amygdala, superior frontal gyrus, and insula, respectively). Participants completed self-report measures at 3-, 6-, 9-, and 12-month follow-up time points to determine if they transitioned to hazardous use (as defined by AUDIT scores ≥8). RESULTS: Of the 57 participants who completed follow-up, 14 (24.6%) transitioned to hazardous alcohol use. Higher baseline AUDIT scores were associated with greater odds of transitioning to hazardous use (odds ratio = 1.73, 95% confidence interval 1.13-2.66, P = .005). Brain activation to reward, threat, and emotion regulation was not associated with alcohol use. Of the neural variables, the amygdala response to negative imagery was numerically larger in young adults who transitioned to hazardous use (g = 0.31), but this effect was not significant. CONCLUSIONS: Baseline drinking levels were significantly associated with the transition to hazardous alcohol use. Studies with larger samples and longer follow-up should test whether the amygdala response to negative emotional imagery can be used to indicate a future transition to hazardous alcohol use.

Neuromodulation for Cannabis Use: A Scoping Review.

This scoping review explores the use of neuromodulation techniques in individuals with cannabis use. Our goal was to determine whether cannabis use alters cortical excitation and inhibition in the context of neuromodulation and to determine whether neuromodulation affects craving and cannabis use patterns. A systematic search was conducted using PubMed, OVID Medline, and PsycINFO from inception to 20 December 2022. Our review identified ten relevant studies, eight of which used Transcranial Magnetic Stimulation (TMS), while two employed Transcranial Direct Current Stimulation (tDCS). Findings from TMS studies suggest that cannabis users exhibit altered cortical inhibition, with decreased short interval intracortical inhibition (SICI) compared to non-users. Single sessions of rTMS did not have any impact on cannabis craving. By contrast, two studies found that multiple sessions of rTMS reduced cannabis use, but these changes did not meet the threshold for statistical significance and both studies were limited by small sample sizes. The two included tDCS studies found contradictory results, with one showing reduced cannabis craving with active treatment and another showing no effect of active treatment on craving compared to sham. Future studies should further explore the effects of multiple treatment sessions and different neuromodulation modalities.

Neural response to threat and reward among young adults at risk for alcohol use disorder.

Alcohol use disorder (AUD) is heritable. Thus, young adults with positive family histories represent an at-risk group relative to those without a family history, and if studied at a time when both groups have similar levels of alcohol use, it provides an opportunity to identify neural processing patterns associated with risk for AUD. Previous studies have shown that diminished response to potential reward is associated with genetic risk for AUD, but it is unclear how threat may modulate this response. We used a modified Monetary Incentive Delay task during fMRI to examine neural correlates of the interaction between threat and reward anticipation in a sample of young adults with (n = 31) and without (n = 44) family histories of harmful alcohol use. We found an interaction (p = 0.048) between cue and group in the right nucleus accumbens where the family history positive group showed less differentiation to the anticipation of gaining $5 and losing $5 relative to gaining $0. The family history-positive group also reported less excitement for trials to gain $5 relative to gaining $0 (p < 0.001). Family history-positive individuals showed less activation in the left insula during both safe and threat blocks compared to family history-negative individuals (p = 0.005), but the groups did not differ as a function of threat (p > 0.70). Young adults with, relative to without, enriched risk for AUD may have diminished reward processing via both neural and behavioural markers to potential rewarding and negative consequences. Neural response to threat may not be a contributing factor to risk at this stage.

Neural signatures of emotion regulation.

Emotional experience is central to a fulfilling life. Although exposure to negative experiences is inevitable, an individual's emotion regulation response may buffer against psychopathology. Identification of neural activation patterns associated with emotion regulation via an fMRI task is a promising and non-invasive means of furthering our understanding of the how the brain engages with negative experiences. Prior work has applied multivariate pattern analysis to identify signatures of response to negative emotion-inducing images; we adapt these techniques to establish novel neural signatures associated with conscious efforts to modulate emotional response. We model voxel-level activation via LASSO principal components regression and linear discriminant analysis to predict if a subject was engaged in emotion regulation and to identify brain regions which define this emotion regulation signature. We train our models using 82 participants and evaluate them on a holdout sample of 40 participants, demonstrating an accuracy up to 82.5% across three classes. Our results suggest that emotion regulation produces a unique signature that is differentiable from passive viewing of negative and neutral imagery.

Delay discounting and family history of psychopathology in children ages 9-11.

Delay discounting is a tendency to devalue delayed rewards compared to immediate rewards. Evidence suggests that steeper delay discounting is associated with psychiatric disorders across diagnostic categories, but it is unclear whether steeper delay discounting is a risk factor for these disorders. We examined whether children at higher risk for psychiatric disorders, based on family history, would demonstrate steeper delay discounting behavior using data from the Adolescent Brain Cognitive Development (ABCD) study, a nationally representative sample of 11,878 children. We looked at associations between delay discounting behavior and family history of alcohol problems, drug problems, depression, mania, schizophrenia, and suicidal behavior. Correlations between family history of psychopathology and delay discounting behavior were small, ranging from ρ = - 0.02 to 0.04. In mixed effects models controlled for sociodemographic factors, family history of psychopathology was not associated with steeper delay discounting behavior. Sociodemographic factors played a larger role in predicting delay discounting behavior than family history of psychopathology. These results do not support the hypothesis that children with greater risk for psychopathology display steeper delay discounting behavior.

Opioid receptor antagonism and neural response to monetary rewards: Pilot studies in light and heavy alcohol users.

Alcohol use disorder (AUD) is a prevalent condition associated with high degree of comorbidity and mortality. Among the few approved pharmacotherapies for AUD, two involve opioid receptor antagonism. Naltrexone and nalmefene are thought to act via opioid receptor blockage to reduce neural response to alcohol and drug-associated cues and consumption, but there have been limited efforts to characterize these effects in humans. In these studies, we sought to test the magnitude of opioid antagonism effects on neural response to monetary rewards in two groups: light drinkers (for the naltrexone study) and heavy drinkers (for the nalmefene study). We conducted double-blind, randomized, crossover pilot studies of reward activation in the brain following acute administration of opioid antagonist and placebo in 11 light and 9 heavy alcohol users. We used a monetary incentive delay task during functional MRI. We found a main effect of cue type on BOLD activation in the nucleus accumbens, demonstrating a neural reward response. The effect of opioid antagonism, relative to placebo, was small and nonsignificant for reward activation in the accumbens for both light and heavy alcohol users. Based on the results of two pilot studies, opioid antagonist medications do not appear to decrease neural activation to monetary rewards in the nucleus accumbens relative to placebo.

NEURAL RESPONSE TO THREAT AND REWARD AMONG YOUNG ADULTS AT RISK FOR ALCOHOL USE DISORDER.

Alcohol use disorder is 50% heritable; those with positive family histories represent an at-risk group within which we can test anticipation of threat and reward prior to development of harmful alcohol use. We examined neural correlates of the interaction between family history, threat anticipation (unpredictable threat), and monetary reward anticipation, in a sample of healthy young adults with (n=31) and without (n=44) family histories of harmful alcohol use. We used a modified Monetary Incentive Delay task with sustained threat of hearing a scream during fMRI. We examined the interaction between family history group, anticipation of threat, and anticipation of reward in the insula, nucleus accumbens, and medial prefrontal cortex. Family history positive individuals showed less activation in the left insula during both safe and threat blocks compared to family history negative individuals (p=0.005), but the groups did not differ as a function of unpredictable threat (p>0.70). We found an interaction (p=0.048) between cue and group in the right nucleus accumbens where the family history positive group showed less differentiation to the anticipation of gaining $5 and losing $5 relative to gaining $0. The family history positive group also reported less excitement for trials to gain $5 relative to gaining $0 (p<0.001). Prior to chronic heavy alcohol use, individuals with, relative to without, enriched risk may have diminished reward processing via both neural and behavioral markers to potential rewarding and negative consequences. Neural response to unpredictable threat may not be a contributing factor to risk at this stage.

Emotion regulation in young adults with family history of harmful alcohol use: A fMRI study.

BACKGROUND: Alcohol use disorder is associated with difficulties in emotion regulation and cognitive reappraisal. Family history of harmful alcohol use increases risk of substance use disorders, but no studies have examined whether family history is associated with altered neural activation during cognitive reappraisal relative to passive viewing of negative images in a sample of young adults without current substance use disorders. METHODS: Participants (N = 75 with positive [n = 31] or negative [n = 44] family histories of harmful alcohol use) completed the emotion regulation task during an MRI scan, and the Emotion Regulation Questionnaire to assess use of emotion regulation and suppression strategies. Whole-brain analyses and amygdala region of interest analyses using linear mixed-effects models assessed family history group and cue effects on neural activation during the task. RESULTS: The groups did not differ on trait reappraisal, suppression, or negative emotion following reappraisal. In general, group effects in whole-brain and amygdala activation during the cognitive reappraisal contrast indicated small effect sizes (2.2% of voxels had d>0.20) that were not significantly different. Participants with positive family histories engaged the right middle and superior frontal gyri to a greater extent than participants with negative family histories during the decrease-negative cue (t = 4.14, p = .001). CONCLUSIONS: For at-risk young adults without current harmful substance use, family history of harmful alcohol use does not appear to be associated with disrupted emotion regulation when instructed to apply cognitive reappraisal. Reappraisal may be a feasible therapeutic target for those who develop a substance use disorder with associated emotion dysregulation.

Emotion regulation in substance use disorders: a systematic review and meta-analysis.

BACKGROUND AND AIMS: The ability to regulate emotions effectively has been associated with resilience to psychopathology. Individuals with substance use disorders (SUDs) have been shown to have higher levels of negative emotionality, with some evidence suggesting impairment in emotion regulation compared with individuals without SUDs. However, no previous attempt has been made to systematically review the literature to assess the magnitude of this difference. We aimed to assess the association between SUD diagnosis and emotion regulation as measured by the Difficulties in Emotion Regulation Scale (DERS) and Emotion Regulation Questionnaire (ERQ) through a systematic review and meta-analysis of existing findings. METHODS: The systematic review was conducted using PubMed, PsycINFO and Embase. We examined cross-sectional studies that compared a SUD group with a control group and measured emotion regulation using the DERS or the ERQ. The primary analysis focused on papers using the DERS, as this was the predominant instrument in the literature. RESULTS: Twenty-two studies met our primary analysis criteria, representing 1936 individuals with a SUD and 1567 controls. Individuals with SUDs relative to controls had significantly greater DERS scores, with a mean difference of 21.44 [95% confidence interval (CI) = 16.49-26.40, P < 0.001] and Hedges' g = 1.05 (95% CI = 0.86-1.24, P < 0.001). The difference was robust, remaining significant after removing outliers and studies with high risk of bias. Individuals with SUDs demonstrated poorer emotion regulation on each subscale of the DERS, with the largest deficits in the Strategies and Impulse subscales. The ERQ analysis revealed greater use of expressive suppression in those with SUDs relative to controls (Hedges' g = 0.76, 95% CI = 0.25-1.28, P = 0.004). CONCLUSIONS: People with substance use disorders appear to have greater difficulties in emotion regulation than people without substance use disorders.

Modeling ability to resist alcohol in the human laboratory: A pilot study.

Background: Roughly half of patients with alcohol use disorder prefer non-abstinence based approaches to treatment. However, only individuals who can limit their alcohol use after low-risk consumption are most likely to benefit from these approaches. This pilot study developed a laboratory-based intravenous alcohol self-administration paradigm to determine the characteristics of individuals who could successfully resist consuming alcohol after an initial exposure. Methods: Seventeen non-treatment seeking heavy drinkers completed two versions of an intravenous alcohol self-administration paradigm designed to assess impaired control over alcohol use. In the paradigm, participants received a priming dose of alcohol and then entered a 120-min resist phase, in which they received monetary rewards if they resisted self-administering alcohol. We used Cox proportional hazards regression to determine the impact of craving and Impaired Control Scale scores on rate of lapse. Results: 64.7% of participants across both versions of the paradigm were unable to resist alcohol for the duration of the session. Craving at baseline (HR = 1.07, 95% CI 1.01-1.13, p = 0.02) and following priming (HR = 1.08, 95% CI 1.02-1.15, p = 0.01) were associated with rate of lapse. Individuals who lapsed endorsed greater attempts to control their drinking over the prior six months compared to individuals who resisted. Conclusions: This study provides preliminary evidence that craving may be predictive of risk of lapse in individuals who are trying to limit alcohol intake after consuming a small initial amount of alcohol. Future studies should test this paradigm in a larger and more diverse sample.

The Neural Circuitry of Reward During Sustained Threat.

Reward processing is important for understanding behavior in psychopathology. Opportunities to earn money activate the ventral striatum, as shown by the monetary incentive delay (MID) task. Anxiety conditions have been modeled by presenting shocks and startling sounds. To further investigate the co-occurrence of an anxiety condition and a rewarding stimulus, we modified the MID to include a sustained threat of scream. This study investigated neural patterns of the MID task with an uncertain threat of a startling scream. Forty-three young adults completed a functional MRI scan. The task included two conditions (scream and safe) and three cues (gain $5, gain $0, lose $5). Analyses included a whole brain, group analysis using a linear mixed-effects model and a paired t-test. The whole brain analysis revealed a main effect of cue, with increased ventral striatal activation (F2,210 = 58.8, p < 0.001) during cues to gain or lose $5. We observed a main effect of condition during cue presentation, such that bilateral insula and putamen activation was diminished (p < 0.001) in the scream versus the safe condition. A t-test of condition showed increased activation during threat blocks in the insula and putamen. A time course graph revealed that activation in the insula and putamen responded similarly to incentive but had an overall elevation during the scream condition. These results replicated expected activation in reward and in the setting of uncertain threat. Our results show that uncertain threat increases the magnitude of activation in the dorsal striatum.

Characteristics Associated With High-Intensity Binge Drinking in Alcohol Use Disorder.

High-intensity binge drinking, defined as consuming 2-3 times the level of a binge (4 or 5 drinks for women or men), increases the risks of overdose and alcohol-related cancer relative to lower levels of drinking. This study examined the relationship between high-intensity binge drinking and three domains hypothesized to contribute to alcohol use disorder (AUD): incentive salience, negative emotionality, and executive function. This cross-sectional study at the National Institute on Alcohol Abuse and Alcoholism examined 429 adults with AUD and 413 adults without a history of AUD. Drinking was assessed using the 90-day Timeline Followback interview. The AUD sample was divided into training and testing sets, and a machine learning model was generated in the training set and then applied to the testing set, to classify individuals based on if they had engaged in high-intensity binge drinking. We also conducted regression models for the following dependent variables: the presence of high-intensity binge drinking, frequency of high-intensity binge drinking, and number of drinks per of binge. Independent variables in these regression models were determined by variable selection from the machine learning algorithm and included time thinking about alcohol, depression rating, and positive urgency as representative variables for the three domains. These variables were assessed using self-report measures. The models were applied to the adults without a history of AUD to determine generalizability. The machine learning algorithm displayed reasonable accuracy when classifying individuals as high-intensity binge drinkers (area under ROC=0.74, 95% CI 0.67, 0.80). In adults with AUD, greater depression rating (OR=1.04, 95% CI 1.01, 1.070) and amount of time thinking about alcohol (OR=1.48, 95% CI 1.20, 1.91) were associated with greater likelihood of high-intensity binge drinking. They were also associated with greater frequency of high-intensity binge drinking days and greater number of drinks on binge occasions. Our findings suggest that incentive salience may contribute to high-intensity binge drinking in both controls and individuals with AUD. Negative emotionality was only associated with high-intensity binge drinking in individuals diagnosed with AUD, suggesting that it may be a consequence rather than a cause of high-intensity binge drinking.

Neuropsychosocial markers of binge drinking in young adults.

Binge drinking is associated with disease and death, and developing tools to identify risky drinkers could mitigate its damage. Brain processes underlie risky drinking, so we examined whether neural and psychosocial markers could identify binge drinkers. Reward is the most widely studied neural process in addiction, but processes such as emotion, social cognition, and self-regulation are also involved. Here we examined whether neural processes apart from reward contribute to predicting risky drinking behaviors. From the Human Connectome Project, we identified 177 young adults who binged weekly and 309 nonbingers. We divided the sample into a training and a testing set and used machine-learning algorithms to classify participants based on psychosocial, neural, or both (neuropsychosocial) data. We also developed separate models for each of the seven fMRI tasks used in the study. An ensemble model developed in the training dataset was then applied to the testing dataset. Model performance was assessed by the area under the receiver operating characteristic curve (AUC) and differences between models were assessed using DeLong's test. The three models performed better than chance in the test sample with the neuropsychosocial (AUC = 0.86) and psychosocial (AUC = 0.84) performing better than the neural model (AUC = 0.64). Two fMRI-based models predicted binge drinking status better than chance, corresponding to the social and language tasks. Models developed with psychosocial and neural variables could contribute as diagnostic tools to help classify risky drinkers. Since social and language fMRI tasks performed best among the neural discriminators (including those from gambling and emotion tasks), it suggests the involvement of a broader range of brain processes than those traditionally associated with binge drinking in young adults.

History of suicidality and alcohol craving trajectories during inpatient treatment for alcohol use disorder.

BACKGROUND: Alcohol use is associated with an increased risk of completed suicide, but it is unclear whether past suicidality affects the course of alcohol use disorder (AUD). We examined whether a history of suicidal ideation or attempts is associated with treatment response in individuals with AUD. METHODS: 146 participants underwent inpatient detoxification and residential treatment for AUD. Reductions in craving during treatment were used as an index of treatment response. Participants were assessed for history of suicidality using the Columbia-Suicide Severity Rating Scale and divided into three groups: no history of suicidal ideation or attempts (N = 76), history of suicidal ideation without attempts (N = 50), and history of suicide attempts (N = 20). Alcohol craving was measured weekly during treatment using the Penn Alcohol Craving Scale and compared across groups. RESULTS: Individuals with a history of suicide attempts showed higher levels of craving throughout treatment compared to those without a history of suicidality. Associations between past suicide attempts and craving remained significant after adjusting for age, sex, alcohol use disorder severity, comorbid psychopathology, and benzodiazepine treatment. Participants in all groups had significant reductions in alcohol craving by the end of treatment. CONCLUSIONS: Our findings suggest that a history of suicide attempts is associated with higher levels of craving throughout inpatient treatment for AUD. These results support current guidelines on assessing suicidal ideation in patients with substance use disorders.

High-risk social drinkers and heavy drinkers display similar rates of alcohol consumption.

Alcohol consumption is often assessed over weeks to months, but few attempts have been made to characterize alcohol consumption rates at the level of an individual drinking session. Here, we aimed to compare the rate of alcohol consumption in social drinkers at high risk for alcohol use disorder (AUD) and heavy drinkers. One hundred and sixty social drinkers and 48 heavy drinkers participated in an alcohol self-administration study. Social drinkers were classified as low risk or high risk for AUD based on sex, impulsivity, and family history of alcoholism. Participants received a priming dose of intravenous alcohol to assess alcohol-induced craving and completed a 125-minute intravenous alcohol self-administration session to assess rate of achieving a binge-level exposure (blood alcohol concentration greater than or equal to 80 mg%). There were no differences between rates of binging in high-risk and heavy drinkers (hazard ratio = 0.87; 95% CI, 0.48-1.56). Heavy drinkers reported higher levels of craving than high-risk and low-risk drinkers at baseline. However, following a priming dose of alcohol, there were no longer differences in craving between high-risk and heavy drinkers. These results indicate that high-risk social drinkers demonstrate binging behavior that is similar to heavy drinkers, which may be driven by alcohol-induced craving. Prospective studies are needed to elucidate whether these patterns of craving and consumption in high-risk social drinkers are predictive of future AUD.

The insula in nicotine use disorder: Functional neuroimaging and implications for neuromodulation.

Insula dysfunction contributes to nicotine use disorders. Yet, much remains unknown about how insular functions promote nicotine use. We review current models of brain networks in smoking and propose an extension to those models that emphasizes the role of the insula in craving. During acute withdrawal, the insula provides the sensation of craving to the cerebrum and is thought to negotiate craving sensations with cognitive control to guide behavior - either to smoke or abstain. Recent studies have shown that insula processing is saturable, such that different insular functions compete for limited resources. We propose that this saturability explains how craving during withdrawal can overload insular processing to the exclusion of other functions, such as saliency and network homeostasis. A novel signal flow model illustrates how limited insular capacity leads to breakdown of normal function. Finally, we discuss suitability of insula as a neuromodulation target to promote cessation. Given the limited efficacy of standard-of-care treatments for nicotine use disorder, insular neuromodulation offers an innovative, potentially therapeutic target for improving smoking cessation.

Neuroimaging reward, craving, learning, and cognitive control in substance use disorders: review and implications for treatment.

Substance use disorder is a leading causes of preventable disease and mortality. Drugs of abuse cause molecular and cellular changes in specific brain regions and these neuroplastic changes are thought to play a role in the transition to uncontrolled drug use. Neuroimaging has identified neural substrates associated with problematic substance use and may offer clues to reduce its burden on the patient and society. Here, we provide a narrative review of neuroimaging studies that have examined the structures and circuits associated with reward, cues and craving, learning, and cognitive control in substance use disorders. Most studies use advanced MRI or positron emission tomography (PET). Many studies have focused on the dopamine neurons of the ventral tegmental area, and the regions where these neurons terminate, such as the striatum and prefrontal cortex. Decreases in dopamine receptors and transmission have been found in chronic users of drugs, alcohol, and nicotine. Recent studies also show evidence of differences in structure and function in substance users relative to controls in brain regions involved in salience evaluation, such as the insula and anterior cingulate cortex. Balancing between reward-related bottom-up and cognitive-control-related top-down processes is discussed in the context of neuromodulation as a potential treatment. Finally, some of the challenges for understanding substance use disorder using neuroimaging methods are discussed.

Sketching the Power of Machine Learning to Decrypt a Neural Systems Model of Behavior.

Uncovering brain-behavior mechanisms is the ultimate goal of neuroscience. A formidable amount of discoveries has been made in the past 50 years, but the very essence of brain-behavior mechanisms still escapes us. The recent exploitation of machine learning (ML) tools in neuroscience opens new avenues for illuminating these mechanisms. A key advantage of ML is to enable the treatment of large data, combing highly complex processes. This essay provides a glimpse of how ML tools could test a heuristic neural systems model of motivated behavior, the triadic neural systems model, which was designed to understand behavioral transitions in adolescence. This essay previews analytic strategies, using fictitious examples, to demonstrate the potential power of ML to decrypt the neural networks of motivated behavior, generically and across development. Of note, our intent is not to provide a tutorial for these analyses nor a pipeline. The ultimate objective is to relate, as simply as possible, how complex neuroscience constructs can benefit from ML methods for validation and further discovery. By extension, the present work provides a guide that can serve to query the mechanisms underlying the contributions of prefrontal circuits to emotion regulation. The target audience concerns mainly clinical neuroscientists. As a caveat, this broad approach leaves gaps, for which references to comprehensive publications are provided.

Using neuroimaging to predict relapse in stimulant dependence: A comparison of linear and machine learning models.

OBJECTIVE: Relapse rates are consistently high for stimulant user disorders. In order to obtain prognostic information about individuals in treatment, machine learning models have been applied to neuroimaging and clinical data. Yet few efforts have been made to test these models in independent samples or show that they can outperform linear models. In this exploratory study, we examine whether machine learning models relative to linear models provide greater predictive accuracy and less overfitting. METHOD: This longitudinal study included 63 methamphetamine-dependent (training sample) and 29 cocaine-dependent (test sample) individuals who completed an MRI scan during residential treatment. Linear and machine learning models predicting relapse at a one-year follow up that were previously developed in the methamphetamine-dependent sample using neuroimaging and clinical variables were applied to the cocaine-dependent sample. Receiver operating characteristic analysis was used to assess performance using area under the curve (AUC) as the primary outcome. RESULTS: Twelve individuals in the cocaine-dependent sample remained abstinent, and 17 relapsed. The linear models produced more accurate prediction in the training sample than the machine learning models but showed reduced performance in the testing sample, with AUC decreasing by 0.18. The machine learning models produced similar predictive performance in the training and test samples, with AUC changing by 0.03. In the test sample, neither the linear nor the machine learning model predicted relapse at rates above chance. CONCLUSIONS: Although machine learning algorithms may have advantages, in this study neither model's performance was sufficient to be clinically useful. In order to improve predictive models, stronger predictor variables and larger samples are needed.

Endocannabinoid signaling in psychiatric disorders: a review of positron emission tomography studies.

Endocannabinoid signaling is implicated in an array of psychopathologies ranging from anxiety to psychosis and addiction. In recent years, radiotracers targeting the endocannabinoid system have been used in positron emission tomography (PET) studies to determine whether individuals with psychiatric disorders display altered endocannabinoid signaling. We comprehensively reviewed PET studies examining differences in endocannabinoid signaling between individuals with psychiatric illness and healthy controls. Published studies evaluated individuals with five psychiatric disorders: cannabis use disorder, alcohol use disorder, schizophrenia, post-traumatic stress disorder, and eating disorders. Most studies employed radiotracers targeting cannabinoid receptor 1 (CB1). Cannabis users consistently demonstrated decreased CB1 binding compared to controls, with normalization following short periods of abstinence. Findings in those with alcohol use disorder and schizophrenia were less consistent, with some studies demonstrating increased CB1 binding and others demonstrating decreased CB1 binding. Evidence of aberrant CB1 binding was also found in individuals with anorexia nervosa and post-traumatic stress disorder, but limited data have been published to date. Thus, existing evidence suggests that alterations in endocannabinoid signaling are present in a range of psychiatric disorders. Although recent efforts have largely focused on evaluating CB1 binding, the synthesis of new radiotracers targeting enzymes involved in endocannabinoid degradation, such as fatty acid amide hydrolase, will allow for other facets of endocannabinoid signaling to be evaluated in future studies.