Dynamic alterations in gene co-expression networks and gene-transcript associations characterize co-morbidities in cocaine use disorder.

Background: Individuals with cocaine use disorder (CUD) who attempt abstinence experience craving and relapse, which poses challenges in treatment. Longitudinal studies linking behavioral manifestations in CUD to the blood transcriptome in living individuals are limited. Therefore, we investigated the connection between drug use behaviors during abstinence with blood transcriptomics. Methods: We conducted a comprehensive longitudinal study involving 12 subjects (9 males, 3 females) with CUD and RNA sequencing on blood collected at a drug-free baseline, and 3, 6 & 9 months thereafter. We categorized subjects into 2 responder groups (high-low) based on scores of drug use variables, and 3 responder groups (low-intermediate-high) on days of abstinence. We investigated differential expression and gene-transcript associations across responder groups at each time point. Lastly, we examined genes that are both co-expressed and showed dynamic expression with time. Results: Genes with significant transcript associations between high and. intermediate days of abstinence at 9 months were notably enriched for cannabis use disorder, drinks weekly, and coronary artery disease risk genes. Time-specific gene co-expression analysis prioritized transcripts related to immune processes, cell cycle, RNA-protein synthesis, and second messenger signaling for days of abstinence. Conclusion: We demonstrate that abstinence reflects robust changes in drug use behaviors and the blood transcriptome in CUD. We also highlight the importance of longitudinal studies to capture complex biological processes during abstinence in CUD.

Robust identification of a neuromarker of methamphetamine craving.

In the January issue of Cell Reports Medicine, Tian et al.1 apply high-density 128-channel resting-state electroencephalography (EEG) to examine the neurophysiological connectomes in individuals with methamphetamine use disorder (MUD). They identify neurobiological connectome biomarkers for craving prediction in MUD.

Effects of Stimulant Treatment on Changes in Brain Activation During Reward Notifications in Drug Naïve Youth With ADHD.

BACKGROUND: Research examining the potential effects of stimulant exposure in childhood on subsequent development of substance use disorder (SUD) have focused on differences in the brain reward system as a function of risk. METHODS: 18 drug naïve children ages 7 to 12 years (11 High Risk [ADHD + ODD/CD]; 7 Low Risk [ADHD only]), underwent fMRI scans before and after treatment with mixed amphetamine salts, extended release (MAS-XR). We examined correlations between clinical ratings and fMRI activation at baseline and following treatment as a function of risk status. RESULTS: High Risk children had higher activation than Low Risk children at baseline during both the Reward and Surprising Non-Reward conditions. Treatment produced strong differential effects on brain activation pertinent to group and reward outcome. CONCLUSIONS: Findings support the hypothesized role of reward mechanisms in SUD risk, and suggest that stimulant treatment may have differential effects on reward processing in relation to SUD risk.

Association of Cortico-Striatal Engagement During Cue Reactivity, Reappraisal, and Savoring of Drug and Non-Drug Stimuli With Craving in Heroin Addiction.

OBJECTIVE: The authors investigated cortico-striatal reactivity to drug cues (as compared with neutral and food cues), drug cue reappraisal, food cue savoring, and their correlations with heroin craving in individuals with heroin use disorder compared with healthy control subjects. METHODS: Cross-sectional changes in functional MRI blood-oxygen-level-dependent signal during a novel cue reactivity task were assessed in 32 individuals with heroin use disorder (mean age, 40.3 years; seven women) and 21 age- and sex-matched healthy control subjects (mean age, 40.6 years; eight women). RESULTS: Drug cue reactivity (vs. neutral cues) was significantly higher in the nucleus accumbens in the heroin use disorder group compared with the control group and nominally significantly higher in the orbitofrontal cortex (OFC); ventromedial prefrontal cortex (vmPFC) activity positively correlated with drug craving. Drug cue reactivity (vs. salient food cues) was also higher in the inferior frontal gyrus (IFG) in the heroin use disorder group compared with the control group. Drug reappraisal and food savoring (vs. passive viewing) showed increased IFG and supplementary motor area activity in all participants; in the heroin use disorder group, higher IFG/dorsolateral PFC (dlPFC) activity during drug reappraisal and rostral anterior cingulate cortex (ACC) activity during food savoring were associated with lower drug cue-induced craving and longer treatment, respectively. A direct comparison of regulation of reactivity to both salient cues revealed widespread group differences such that drug reappraisal activity was higher in the heroin use disorder group and food savoring activity was higher in the control group in both cortical (e.g., OFC, IFG, ACC, vmPFC, and insula) and subcortical (e.g., dorsal striatum and hippocampus) regions. Higher drug reappraisal versus food savoring in the dlPFC was associated with higher self-reported methadone dosage in the heroin use disorder group. CONCLUSIONS: The results demonstrate cortico-striatal upregulation during drug cue exposure and impaired reactivity during processing of alternative non-drug rewards in the heroin use disorder group. Normalizing cortico-striatal function by reducing drug cue reactivity and enhancing natural reward valuation may inform therapeutic mechanisms for reducing drug craving and seeking in heroin addiction.

Whole-brain resting-state connectivity underlying impaired inhibitory control during early versus longer-term abstinence in cocaine addiction.

Lapses in inhibitory control have been linked to relapse in human drug addiction. Evidence suggests differences in inhibitory control depending on abstinence duration, but the underlying neural mechanisms remain unknown. We hypothesized that early abstinence (2-5 days) would be characterized by the strongest impairments of inhibitory control and most wide-spread deviations in resting-state functional connectivity of brain networks, while longer-term abstinence (>30 days) would be characterized by weaker impairments as compared to healthy controls. In this laboratory-based cross-sectional study, we compared individuals with Cocaine Use Disorder (iCUD) during early (cocaine urine-positive: N = 19, iCUD+; 32% female; mean age: 46.8 years) and longer-term abstinence (cocaine urine-negative: N = 29, iCUD-; 15% female; mean age: 46.6 years) to healthy controls (N = 33; 24% female; mean age: 40.9 years). We compared the groups on inhibitory control performance (Stop-Signal Task) and, using a whole-brain graph theory analysis (638 region parcellation) of functional magnetic resonance imaging (fMRI) data, we tested for group differences in resting-state brain function (local/global efficiency). We characterized how resting-state brain function was associated with inhibitory control performance within iCUD. Inhibitory control performance was worst in the early abstinence group, and intermediate in the longer-term abstinence group, as compared to the healthy control group (P < 0.01). More recent use of cocaine (CUD+ > CUD- > healthy controls) was characterized by decreased efficiency in fronto-temporal and subcortical networks (primarily in the salience, semantic, and basal ganglia networks) and increased efficiency in visual networks. Importantly, a similar functional connectivity pattern characterized impaired inhibitory control performance within iCUD (all brain analyses P < 0.05, FWE-corrected). Together, we demonstrated that a similar pattern of systematic and widespread deviations in resting-state brain efficiency, extending beyond the networks commonly investigated in human drug addiction, is linked to both abstinence duration and inhibitory control deficits in iCUD.

Speak and you shall predict: speech at initial cocaine abstinence as a biomarker of long-term drug use behavior.

Importance: Valid biomarkers that can predict longitudinal clinical outcomes at low cost are a holy grail in psychiatric research, promising to ultimately be used to optimize and tailor intervention and prevention efforts. Objective: To determine if baseline linguistic markers in natural speech, as compared to non-speech clinical and demographic measures, can predict drug use severity measures at future sessions in initially abstinent individuals with cocaine use disorder (iCUD). Design: A longitudinal cohort study (August 2017 - March 2020), where baseline measures were used to predict outcomes collected at three-month intervals for up to one year of follow-up. Participants: Eighty-eight initially abstinent iCUD were studied at baseline; 57 (46 male, age 50.7+/-7.9 years) came back for at least another session. Main Outcomes and Measures: Outcomes were self-reported symptoms of withdrawal, craving, abstinence duration and frequency of cocaine use in the past 90 days at each study session. The predictors were derived from 5-min recordings of vocal descriptions of the positive consequences of abstinence and the negative consequences of using cocaine; the baseline cocaine and other common drug use measures, demographic and neuropsychological variables were used for comparison. Results: Models using the non-speech variables showed the best predictive performance at three(r>0.45, P<2×10-3) and six months follow-up (r>0.37, P<3×10-2). At 12 months, the natural language processing-based model showed significant correlations with withdrawal (r=0.43, P=3×10-2), craving (r=0.72, P=5×10-5), days of abstinence (r=0.76, P=1×10-5), and cocaine use in the past 90 days (r=0.61, P=2×10-3), significantly outperforming the other models for abstinence prediction. Conclusions and Relevance: At short time intervals, maximal predictive power was obtained with models that used baseline drug use (in addition to demographic and neuropsychological) measures, potentially reflecting a slow rate of change in these measures, which could be estimated by linear functions. In contrast, short speech samples predicted longer-term changes in drug use, implying deeper penetrance by potentially capturing non-linear dynamics over longer intervals. Results suggest that, compared to the common outcome measures used in clinical trials, speech-based measures could be leveraged as better predictors of longitudinal drug use outcomes in initially abstinent iCUD, as potentially generalizable to other substance use disorders and related comorbidity.

Computational models of behavioral addictions: State of the art and future directions.

Non-pharmacological behavioral addictions, such as pathological gambling, videogaming, social networking, or internet use, are becoming major public health concerns. It is not yet clear how behavioral addictions could share many major neurobiological and behavioral characteristics with substance use disorders, despite the absence of direct pharmacological influences. A deeper understanding of the neurocognitive mechanisms of addictive behavior is needed, and computational modeling could be one promising approach to explain intricately entwined cognitive and neural dynamics. This review describes computational models of addiction based on reinforcement learning algorithms, Bayesian inference, and biophysical neural simulations. We discuss whether computational frameworks originally conceived to explain maladaptive behavior in substance use disorders can be effectively extended to non-substance-related behavioral addictions. Moreover, we introduce recent studies on behavioral addictions that exemplify the possibility of such extension and propose future directions.

Altered prefrontal signaling during inhibitory control in a salient drug context in cocaine use disorder.

INTRODUCTION: Drug addiction is characterized by impaired response inhibition and salience attribution (iRISA), where the salience of drug cues is postulated to overpower that of other reinforcers with a concomitant decrease in self-control. However, the neural underpinnings of the interaction between the salience of drug cues and inhibitory control in drug addiction remain unclear. METHODS: We developed a novel stop-signal functional magnetic resonance imaging task where the stop-signal reaction time (SSRT-a classical inhibitory control measure) was tested under different salience conditions (modulated by drug, food, threat, or neutral words) in individuals with cocaine use disorder (CUD; n = 26) versus demographically matched healthy control participants (n = 26). RESULTS: Despite similarities in drug cue-related SSRT and valence and arousal word ratings between groups, dorsolateral prefrontal cortex (dlPFC) activity was diminished during the successful inhibition of drug versus food cues in CUD and was correlated with lower frequency of recent use, lower craving, and longer abstinence (Z > 3.1, P < 0.05 corrected). DISCUSSION: Results suggest altered involvement of cognitive control regions (e.g. dlPFC) during inhibitory control under a drug context, relative to an alternative reinforcer, in CUD. Supporting the iRISA model, these results elucidate the direct impact of drug-related cue reactivity on the neural signature of inhibitory control in drug addiction.

A scoping review of electroencephalographic (EEG) markers for tracking neurophysiological changes and predicting outcomes in substance use disorder treatment.

Substance use disorders (SUDs) constitute a growing global health crisis, yet many limitations and challenges exist in SUD treatment research, including the lack of objective brain-based markers for tracking treatment outcomes. Electroencephalography (EEG) is a neurophysiological technique for measuring brain activity, and although much is known about EEG activity in acute and chronic substance use, knowledge regarding EEG in relation to abstinence and treatment outcomes is sparse. We performed a scoping review of longitudinal and pre-post treatment EEG studies that explored putative changes in brain function associated with abstinence and/or treatment in individuals with SUD. Following PRISMA guidelines, we identified studies published between January 2000 and March 2022 from online databases. Search keywords included EEG, addictive substances (e.g., alcohol, cocaine, methamphetamine), and treatment related terms (e.g., abstinence, relapse). Selected studies used EEG at least at one time point as a predictor of abstinence or other treatment-related outcomes; or examined pre- vs. post-SUD intervention (brain stimulation, pharmacological, behavioral) EEG effects. Studies were also rated on the risk of bias and quality using validated instruments. Forty-four studies met the inclusion criteria. More consistent findings included lower oddball P3 and higher resting beta at baseline predicting negative outcomes, and abstinence-mediated longitudinal decrease in cue-elicited P3 amplitude and resting beta power. Other findings included abstinence or treatment-related changes in late positive potential (LPP) and N2 amplitudes, as well as in delta and theta power. Existing studies were heterogeneous and limited in terms of specific substances of interest, brief times for follow-ups, and inconsistent or sparse results. Encouragingly, in this limited but maturing literature, many studies demonstrated partial associations of EEG markers with abstinence, treatment outcomes, or pre-post treatment-effects. Studies were generally of good quality in terms of risk of bias. More EEG studies are warranted to better understand abstinence- or treatment-mediated neural changes or to predict SUD treatment outcomes. Future research can benefit from prospective large-sample cohorts and the use of standardized methods such as task batteries. EEG markers elucidating the temporal dynamics of changes in brain function related to abstinence and/or treatment may enable evidence-based planning for more effective and targeted treatments, potentially pre-empting relapse or minimizing negative lifespan effects of SUD.

A Meta-Analysis of fMRI Studies of Youth Cannabis Use: Alterations in Executive Control, Social Cognition/Emotion Processing, and Reward Processing in Cannabis Using Youth.

Background: Adolescent cannabis use (CU) is associated with adverse health outcomes and may be increasing in response to changing cannabis laws. Recent imaging studies have identified differences in brain activity between adult CU and controls that are more prominent in early onset users. Whether these differences are present in adolescent CU and relate to age/developmental stage, sex, or cannabis exposure is unknown. Methods: A systematic review and subsequent effect-size seed-based d mapping (SDM) meta-analysis were conducted to examine differences in blood-oxygen-level-dependent (BOLD) response during fMRI studies between CU and non-using typically developing (TD) youth. Supplemental analyses investigated differences in BOLD signal in CU and TD youth as a function of sex, psychiatric comorbidity, and the dose and severity of cannabis exposure. Results: From 1371 citations, 45 fMRI studies were identified for inclusion in the SDM meta-analysis. These studies compared BOLD response contrasts in 1216 CU and 1486 non-using TD participants. In primary meta-analyses stratified by cognitive paradigms, CU (compared to TD) youth showed greater activation in the rostral medial prefrontal cortex (rmPFC) and decreased activation in the dorsal mPFC (dmPFC) and dorsal anterior cingulate cortex (dACC) during executive control and social cognition/emotion processing, respectively. In meta-regression analyses and subgroup meta-analyses, sex, cannabis use disorder (CUD) severity, and psychiatric comorbidity were correlated with brain activation differences between CU and TD youth in mPFC and insular cortical regions. Activation differences in the caudate, thalamus, insula, dmPFC/dACC, and precentral and postcentral gyri varied as a function of the length of abstinence. Conclusions: Using an SDM meta-analytic approach, this report identified differences in neuronal response between CU and TD youth during executive control, emotion processing, and reward processing in cortical and subcortical brain regions that varied as a function of sex, CUD severity, psychiatric comorbidity, and length of abstinence. Whether aberrant brain function in CU youth is attributable to common predispositional factors, cannabis-induced neuroadaptive changes, or both warrants further investigation.

Effects of Transcranial Direct Current Stimulation on Attentional Bias to Methamphetamine Cues and Its Association With EEG-Derived Functional Brain Network Topology.

BACKGROUND: Although transcranial direct current stimulation (tDCS) has shown to potentially mitigate drug craving and attentional bias to drug-related stimuli, individual differences in such modulatory effects of tDCS are less understood. In this study, we aimed to investigate a source of the inter-subject variability in the tDCS effects that can be useful for tDCS-based treatments of individuals with methamphetamine (MA) use disorder (IMUD). METHODS: Forty-two IMUD (all male) were randomly assigned to receive a single-session of either sham or real bilateral tDCS (anodal right/cathodal left) over the dorsolateral prefrontal cortex. The tDCS effect on MA craving and biased attention to drug stimuli were investigated by quantifying EEG-derived P3 (a measure of initial attentional bias) and late positive potential (LPP; a measure of sustained motivated attention) elicited by these stimuli. To assess the association of changes in P3 and LPP with brain connectivity network (BCN) topology, the correlation between topology metrics, specifically those related to the efficiency of information processing, and the tDCS effect was investigated. RESULTS: The P3 amplitude significantly decreased following the tDCS session, whereas the amplitudes increased in the sham group. The changes in P3 amplitudes were significantly correlated with communication efficiency measured by BCN topology metrics (r = -0.47, P = .03; r = -0.49, P = .02). There was no significant change in LPP amplitude due to the tDCS application. CONCLUSIONS: These findings validate that tDCS mitigates initial attentional bias, but not the sustained motivated attention, to MA stimuli. Importantly, however, results also show that the individual differences in the effects of tDCS may be underpinned by communication efficiency of the BCN topology, and therefore, these BCN topology metrics may have the potential to robustly predict the effectiveness of tDCS-based interventions on MA craving and attentional bias to MA stimuli among IMUD.

Social Isolation-Mediated Exacerbation of Negative Affect in Young Drinkers during the COVID-19 Pandemic.

Emerging research on psychological adjustment during the COVID-19 outbreak has suggested that young people may be particularly vulnerable to increases in negative affect during the pandemic. However, the association between alcohol use in youth and change in negative affect during this unprecedented time is not clear. Using an online survey, this study obtained scores on negative affect (before and during the COVID-19 pandemic), pandemic-related stress, change in drinking frequency, and traits including resilience, impulsivity and anhedonia, from a sample of drinkers and non-drinkers, up to the age of 21. Young drinkers experienced a greater increase in negative affect during the pandemic compared to non-drinkers, and this differential rise in negative affect was mediated by the pandemic-related stress of social isolation. Young drinkers also experienced a decrease in alcohol use during the pandemic, but this was not associated with a change in negative affect. Interestingly, young drinkers with greater resilience and lower anhedonia reported less increase in negative affect during the COVID-19 pandemic. Taken together, these results show that the greater increase in negative affect that young drinkers experienced during the COVID-19 pandemic, compared to their non-drinking counterparts, was mediated by pandemic-related social isolation. Moreover, greater resilience and lower anhedonia may have served as protective factors for mitigating the social isolation-induced worsening of negative affect in young drinkers during the pandemic. These findings may inform future studies investigating potential indicators of maladaptive affective responses to public health crises in vulnerable adolescent populations.

Construct validity for computational linguistic metrics in individuals at clinical risk for psychosis: Associations with clinical ratings.

Language deficits are prevalent in psychotic illness, including its risk states, and are related to marked impairment in functioning. It is therefore important to characterize language impairment in the psychosis spectrum in order to develop potential preventive interventions. Natural language processing (NLP) metrics of semantic coherence and syntactic complexity have been used to discriminate schizophrenia patients from healthy controls (HC) and predict psychosis onset in individuals at clinical high-risk (CHR) for psychosis. To date, no studies have yet examined the construct validity of key NLP features with respect to clinical ratings of thought disorder in a CHR cohort. Herein we test the association of key NLP metrics of coherence and complexity with ratings of positive and negative thought disorder, respectively, in 60 CHR individuals, using Andreasen's Scale of Assessment of Thought, Language and Communication (TLC) Scale to measure of positive and negative thought disorder. As hypothesized, in CHR individuals, the NLP metric of semantic coherence was significantly correlated with positive thought disorder severity and the NLP metrics of complexity (sentence length and determiner use) were correlated with negative thought disorder severity. The finding of construct validity supports the premise that NLP analytics, at least in respect to core features of reduction of coherence and complexity, are capturing clinically relevant language disturbances in risk states for psychosis. Further psychometric study is required, in respect to reliability and other forms of validity.

Structural and functional brain recovery in individuals with substance use disorders during abstinence: A review of longitudinal neuroimaging studies.

BACKGROUND: Neuroimaging studies reveal structural and functional including neurochemical brain abnormalities in individuals with substance use disorders compared to healthy controls. However, whether and to what extent such dysfunction is reversible with abstinence remains unclear, and a review of studies with longitudinal within-subject designs is lacking. We performed a systematic review of longitudinal neuroimaging studies to explore putative brain changes associated with abstinence in treatment-seeking individuals with substance use disorders. METHODS: Following PRISMA guidelines, we examined articles published up to May 2021 that employed a neuroimaging technique and assessed neurobiological recovery in treatment-seeking participants at a minimum of two time-points separated by a period of abstinence (longer than 24 h apart) or significant reduction in drug use. RESULTS: Forty-five studies met inclusion criteria. Encouragingly, in this limited but growing literature, the majority of studies demonstrated at least partial neurobiological recovery with abstinence. Structural recovery appeared to occur predominantly in frontal cortical regions, the insula, hippocampus, and cerebellum. Functional and neurochemical recovery was similarly observed in prefrontal cortical regions but also in subcortical structures. The onset of structural recovery appears to precede neurochemical recovery, which begins soon after cessation (particularly for alcohol); functional recovery may require longer periods of abstinence. CONCLUSIONS: The literature is still growing and more studies are warranted to better understand abstinence-mediated neural recovery in individuals with substance use disorders. Elucidating the temporal dynamics between neuronal recovery and abstinence will enable evidence-based planning for more effective and targeted treatment of substance use disorders, potentially pre-empting relapse.

Common and gender-specific associations with cocaine use on gray matter volume: Data from the ENIGMA addiction working group.

Gray matter volume (GMV) in frontal cortical and limbic regions is susceptible to cocaine-associated reductions in cocaine-dependent individuals (CD) and is negatively associated with duration of cocaine use. Gender differences in CD individuals have been reported clinically and in the context of neural responses to cue-induced craving and stress reactivity. The variability of GMV in select brain areas between men and women (e.g., limbic regions) underscores the importance of exploring interaction effects between gender and cocaine dependence on brain structure. Therefore, voxel-based morphometry data derived from the ENIGMA Addiction Consortium were used to investigate potential gender differences in GMV in CD individuals compared to matched controls (CTL). T1-weighted MRI scans and clinical data were pooled from seven sites yielding 420 gender- and age-matched participants: CD men (CDM, n = 140); CD women (CDW, n = 70); control men (CTLM, n = 140); and control women (CTLW, n = 70). Differences in GMV were assessed using a 2 × 2 ANCOVA, and voxelwise whole-brain linear regressions were conducted to explore relationships between GMV and duration of cocaine use. All analyses were corrected for age, total intracranial volume, and site. Diagnostic differences were predominantly found in frontal regions (CD < CTL). Interestingly, gender × diagnosis interactions in the left anterior insula and left lingual gyrus were also documented, driven by differences in women (CDW < CTLW). Further, lower right hippocampal GMV was associated with greater cocaine duration in CDM. Given the importance of the anterior insula to interoception and the hippocampus to learning contextual associations, results may point to gender-specific mechanisms in cocaine addiction.

Sleep Disturbance in Individuals at Clinical High Risk for Psychosis.

INTRODUCTION: Disturbed sleep is a common feature of psychotic disorders that is also present in the clinical high risk (CHR) state. Evidence suggests a potential role of sleep disturbance in symptom progression, yet the interrelationship between sleep and CHR symptoms remains to be determined. To address this knowledge gap, we examined the association between disturbed sleep and CHR symptoms over time. METHODS: Data were obtained from the North American Prodrome Longitudinal Study (NAPLS)-3 consortium, including 688 CHR individuals and 94 controls (mean age 18.25, 46% female) for whom sleep was tracked prospectively for 8 months. We used Cox regression analyses to investigate whether sleep disturbances predicted conversion to psychosis up to >2 years later. With regressions and cross-lagged panel models, we analyzed longitudinal and bidirectional associations between sleep (the Pittsburgh Sleep Quality Index in conjunction with additional sleep items) and CHR symptoms. We also investigated the independent contribution of individual sleep characteristics on CHR symptom domains separately and explored whether cognitive impairments, stress, depression, and psychotropic medication affected the associations. RESULTS: Disturbed sleep at baseline did not predict conversion to psychosis. However, sleep disturbance was strongly correlated with heightened CHR symptoms over time. Depression accounted for half of the association between sleep and symptoms. Importantly, sleep was a significant predictor of CHR symptoms but not vice versa, although bidirectional effect sizes were similar. DISCUSSION: The critical role of sleep disturbance in CHR symptom changes suggests that sleep may be a promising intervention target to moderate outcome in the CHR state.

Emotion recognition in individuals with cocaine use disorder: the role of abstinence length and the social brain network.

RATIONALE: Emotion recognition is impaired in drug addiction. However, research examining the effects of cocaine use on emotion recognition yield mixed evidence with contradictory results potentially reflecting varying abstinence durations. OBJECTIVES: Therefore, we investigated emotion recognition and its neural correlates in individuals with cocaine use disorder (CUD) parsed according to abstinence duration. METHODS: Emotion recognition performance was compared between current cocaine users (CUD + , n = 28; cocaine-positive urine), short-term abstainers (CUD-ST, n = 23; abstinence < 6 months), long-term abstainers (CUD-LT, n = 20; abstinence ≥ 6 months), and controls (n = 45). A sample subset (n = 73) underwent structural magnetic resonance imaging to quantify regional gray matter volume (GMV) using voxel-based morphometry. RESULTS: CUD + demonstrated greater difficulty recognizing happiness than CUD-ST and controls, and sadness and fear compared to controls (p < 0.01). For fear, CUD-ST also performed worse than controls (p < 0.01), while no differences emerged between CUD-LT and controls. Whole-brain analysis revealed lower GMV in the bilateral cerebellum in CUD + compared to CUD-LT and controls; a similar pattern was observed in the amygdala (CUD + < CUD-LT) (pFWE < 0.01). Collapsed across all participants, poorer recognition for happiness was associated with lower right cerebellar GMV (pFWE < 0.05). CONCLUSIONS: Emotion recognition is impaired with current cocaine use, and selective deficits (in fear) may persist with up to 6 months of abstinence. Lower cerebellar GMV may underlie deficits in positive emotion recognition. Interventions targeting emotional-social-cognitive deficits, especially among active users, may enhance treatment success for individuals with CUD.

Attention bias modification in drug addiction: Enhancing control of subsequent habits.

A relapse in addiction is often precipitated by heightened attention bias to drug-related cues, underpinned by a subcortically mediated transition to habitual/automatized responding and reduced prefrontal control. Modification of such automatized attention bias is a fundamental, albeit elusive, target for relapse reduction. Here, on a trial-by-trial basis, we used electroencephalography and eye tracking with a task that assessed, in this order, drug cue reactivity, its instructed self-regulation via reappraisal, and the immediate aftereffects on spontaneous (i.e., not instructed and automatized) attention bias. The results show that cognitive reappraisal, a facet of prefrontal control, decreased spontaneous attention bias to drug-related cues in cocaine-addicted individuals, more so in those with less frequent recent use. The results point to the mechanisms underlying the disruption of automatized maladaptive drug-related attention bias in cocaine addiction. These results pave the way for future studies to examine the role of such habit disruption in reducing compulsive drug seeking outside the controlled laboratory environment, with the ultimate goal of developing a readily deployable cognitive-behavioral and personalized intervention for drug addiction.

A double-blind sham-controlled phase 1 clinical trial of tDCS of the dorsolateral prefrontal cortex in cocaine inpatients: Craving, sleepiness, and contemplation to change.

Impaired inhibitory control accompanied by enhanced salience attributed to drug-related cues, both associated with function of the dorsolateral prefrontal cortex (dlPFC), are hallmarks of drug addiction, contributing to worse symptomatology including craving. dlPFC modulation with transcranial direct current stimulation (tDCS) previously showed craving reduction in inpatients with cocaine use disorder (CUD). Our study aimed at assessing feasibility of a longer tDCS protocol in CUD (15 versus the common five/10 sessions) and replicability of previous results. In a randomized double-blind sham-controlled protocol, 17 inpatients with CUD were assigned to either a real-tDCS (right anodal/left cathodal) or a sham-tDCS condition for 15 sessions. Following the previous report, primary outcome measures were self-reported craving, anxiety, depression, and quality of life. Secondary measures included sleepiness, readiness to change drug use, and affect. We also assessed cognitive function including impulsivity. An 88% retention rate demonstrated feasibility. Partially supporting the previous results, there was a trend for self-reported craving to decrease in the real-tDCS group more than the sham-group, an effect that would reach significance with 15 subjects per group. Quality of life and impulsivity improved over time in treatment in both groups. Daytime sleepiness and readiness to change drug use showed significant Group × Time interactions whereby improvements were noted only in the real-tDCS group. One-month follow-up suggested transient effects of tDCS on sleepiness and craving. These preliminary results suggest the need for including more subjects to show a unique effect of real-tDCS on craving and examine the duration of this effect. After replication in larger sample sizes, increased vigilance and motivation to change drug use in the real-tDCS group may suggest fortification of dlPFC-supported executive functions.