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.

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.

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.

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.

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.

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.

Neural mechanisms of extinguishing drug and pleasant cue associations in human addiction: role of the VMPFC.

The neurobiological mechanisms that underlie the resistance of drug cue associations to extinction in addiction remain unknown. Fear extinction critically depends on the ventromedial prefrontal cortex (VMPFC). Here, we tested if this same region plays a role in extinction of non-fear, drug and pleasant cue associations. Eighteen chronic cocaine users and 15 matched controls completed three functional MRI scans. Participants first learned to associate an abstract cue (the conditioned stimulus, CS) with a drug-related (CSD+ ) or pleasant (CSP+ ) image. Extinction immediately followed where each CS was repeatedly presented without the corresponding image. Participants underwent a second identical session 24 hours later to assess retention of extinction learning. Results showed that like fear extinction, non-fear-based extinction relies on the VMPFC. However, extinction-related changes in the VMPFC differed by cue valence and diagnosis. In controls, VMPFC activation to the CSD+ (which was unpleasant for participants) gradually increased as in fear extinction, while it decreased to the CSP+ , consistent with a more general role of the VMPFC in flexible value updating. Supporting a specific role in extinction retention, we further observed a cross-day association between VMPFC activation and skin conductance, a classic index of conditioned responses. Finally, cocaine users showed VMPFC abnormalities for both CSs, which, in the case of the CSD+ , correlated with craving. These data suggest a global deficit in extinction learning in this group that may hinder extinction-based treatment efforts. More broadly, these data show that the VMPFC, when functionally intact, supports extinction learning in diverse contexts in humans.

Neuroimaging cognitive reappraisal in clinical populations to define neural targets for enhancing emotion regulation. A systematic review.

Reduced capacity to cognitively regulate emotional responses is a common impairment across major neuropsychiatric disorders. Brain systems supporting one such strategy, cognitive reappraisal of emotion, have been investigated extensively in the healthy population, a research focus that has led to influential meta-analyses and literature reviews. However, the emerging literature on neural substrates underlying cognitive reappraisal in clinical populations is yet to be systematically reviewed. Therefore, the goal of the current review was to summarize the literature on cognitive reappraisal and highlight common and distinct neural correlates of impaired emotion regulation in clinical populations. We performed a two-stage systematic literature search, selecting 32 studies on cognitive reappraisal in individuals with mood disorders (n=12), anxiety disorders (n=14), addiction (n=2), schizophrenia (n=2), and personality disorders (n=5). Comparing findings across these disorders allowed us to determine underlying mechanisms that were either disorder-specific or common across disorders. Results showed that across clinical populations, individuals consistently demonstrated reduced recruitment of the ventrolateral prefrontal cortex (vlPFC) and dorsolateral prefrontal cortex (dlPFC) during downregulation of negative emotion, indicating that there may be a core deficit in selection, manipulation and inhibition during reappraisal. Further, in individuals with mood disorders, amygdala responses were enhanced during downregulation of emotion, suggesting hyperactive bottom-up responses or reduced modulatory capacity. In individuals with anxiety disorders, however, emotion regulation revealed reduced activity in the dorsal anterior cingulate cortex (dACC) and inferior/superior parietal cortex, possibly indicating a deficit in allocation of attention. The reviewed studies thus provide evidence for both disorder-specific and common deficits across clinical populations. These findings highlight the role of distinct neural substrates as targets for developing/assessing novel therapeutic approaches that are geared towards cognitive regulation of emotion, as well as the importance of transdiagnostic research to identify both disorder specific and core mechanisms.

Abstinence reverses EEG-indexed attention bias between drug-related and pleasant stimuli in cocaine-addicted individuals.

BACKGROUND: Increased attention bias toward drug-related cues over non-drug-related intrinsically pleasant reinforcers is a hallmark of drug addiction. In this study we used the late positive potential (LPP) to investigate whether such increased attention bias toward drug-related relative to non-drug-related cues changes over a protracted period of reduced drug use in treatment-seeking individuals with a cocaine use disorder (CUD). METHODS: Treatment-seeking individuals with CUD and matched healthy controls passively viewed a series of pleasant, neutral and drug-related pictures while their event-related potentials were recorded at baseline (≤ 3 weeks after treatment initiation) and at 6-month follow-up (only CUD). RESULTS: We included 19 treatment-seeking individuals with CUD and 18 matched controls in our analyses. The results showed a reversal in attention bias (i.e., LPP amplitude) from baseline (i.e., drug > pleasant) to follow-up (i.e., pleasant > drug) driven by an increased attentional engagement with pleasant pictures; this LPP reversal was paralleled by a concomitant reduction in self-reported wanting and craving for cocaine in the CUD group. Furthermore, reduced attention bias toward drug-related cues (relative to pleasant cues) was correlated with longer duration of abstinence at baseline, and the extent of its longitudinal reversal was correlated with decreased craving at follow-up, providing support for abstinence as a putative mechanism of this bottom-up attentional change. LIMITATIONS: A limited sample size and the use of the same set of pictures at baseline and follow-up were the major limitations of this study. CONCLUSION: Results collectively indicate that, by tracking with drug abstinence, LPP in response to drug-related relative to pleasant cues may serve as an indicator of clinical progress in treatment-seeking individuals with CUD.

Prefrontal gray matter volume recovery in treatment-seeking cocaine-addicted individuals: a longitudinal study.

Deficits in prefrontal cortical (PFC) function have been consistently reported in individuals with cocaine use disorders (iCUD), and have separately been shown to improve with longer-term abstinence. However, it is less clear whether the PFC structural integrity possibly underlying these deficits is also modulated by sustained reduction in drug use in iCUD. Here, T1-weighted magnetic resonance imaging scans were acquired, and performance on a neuropsychological test battery was assessed, in 19 initially abstinent treatment-seeking iCUD, first at baseline and then after six months of significantly reduced or no drug use (follow-up). A comparison cohort of 12 healthy controls was also scanned twice with a similar inter-scan interval. The iCUD showed increased gray matter volume in the left inferior frontal gyrus and bilaterally in the ventromedial prefrontal cortex at follow-up compared to baseline; healthy controls, as expected, showed no changes over this same time period. The iCUD also showed improved decision making and cognitive flexibility, with the latter correlated significantly with the gray matter volume increases in the inferior frontal gyrus. Given its association with improved cognitive function, the longitudinal recovery in cortical gray matter volume, particularly in regions where structure and function are adversely affected by chronic drug use, reflects a quantifiable positive impact of significantly reduced drug use on cortical structural integrity.

Impaired neural response to negative prediction errors in cocaine addiction.

Learning can be guided by unexpected success or failure, signaled via dopaminergic positive reward prediction error (+RPE) and negative reward-prediction error (-RPE) signals, respectively. Despite conflicting empirical evidence, RPE signaling is thought to be impaired in drug addiction. To resolve this outstanding question, we studied as a measure of RPE the feedback negativity (FN) that is sensitive to both reward and the violation of expectation. We examined FN in 25 healthy controls; 25 individuals with cocaine-use disorder (CUD) who tested positive for cocaine on the study day (CUD+), indicating cocaine use within the past 72 h; and in 25 individuals with CUD who tested negative for cocaine (CUD-). EEG was acquired while the participants performed a gambling task predicting whether they would win or lose money on each trial given three known win probabilities (25, 50, or 75%). FN was scored for the period in each trial when the actual outcome (win or loss) was revealed. A significant interaction between prediction, outcome, and group revealed that controls showed increased FN to unpredicted compared with predicted wins (i.e., intact +RPE) and decreased FN to unpredicted compared with predicted losses (i.e., intact -RPE). However, neither CUD subgroup showed FN modulation to loss (i.e., impaired -RPE), and unlike CUD+ individuals, CUD- individuals also did not show FN modulation to win (i.e., impaired +RPE). Thus, using FN, the current study directly documents -RPE deficits in CUD individuals. The mechanisms underlying -RPE signaling impairments in addiction may contribute to the disadvantageous nature of excessive drug use, which can persist despite repeated unfavorable life experiences (e.g., frequent incarcerations).

Abstinence reverses EEG-indexed attention bias between drug-related and pleasant stimuli in cocaine-addicted individuals.

BACKGROUND: Increased attention bias toward drug-related cues over non-drug-related intrinsically pleasant reinforcers is a hallmark of drug addiction. In this study we used the late positive potential (LPP) to investigate whether such increased attention bias toward drug-related relative to non-drug-related cues changes over a protracted period of reduced drug use in treatment-seeking individuals with a cocaine use disorder (CUD). METHODS: Treatment-seeking individuals with CUD and matched healthy controls passively viewed a series of pleasant, neutral and drug-related pictures while their event-related potentials were recorded at baseline (≤ 3 weeks after treatment initiation) and at 6-month follow-up (only CUD). RESULTS: We included 19 treatment-seeking individuals with CUD and 18 matched controls in our analyses. The results showed a reversal in attention bias (i.e., LPP amplitude) from baseline (i.e., drug > pleasant) to follow-up (i.e., pleasant > drug) driven by an increased attentional engagement with pleasant pictures; this LPP reversal was paralleled by a concomitant reduction in self-reported wanting and craving for cocaine in the CUD group. Furthermore, reduced attention bias toward drug-related cues (relative to pleasant cues) was correlated with longer duration of abstinence at baseline, and the extent of its longitudinal reversal was correlated with decreased craving at follow-up, providing support for abstinence as a putative mechanism of this bottom-up attentional change. LIMITATIONS: A limited sample size and the use of the same set of pictures at baseline and follow-up were the major limitations of this study. CONCLUSION: Results collectively indicate that, by tracking with drug abstinence, LPP in response to drug-related relative to pleasant cues may serve as an indicator of clinical progress in treatment-seeking individuals with CUD.

Methylphenidate enhances executive function and optimizes prefrontal function in both health and cocaine addiction.

Previous studies have suggested dopamine to be involved in error monitoring/processing, possibly through impact on reinforcement learning. The current study tested whether methylphenidate (MPH), an indirect dopamine agonist, modulates brain and behavioral responses to error, and whether such modulation is more pronounced in cocaine-addicted individuals, in whom dopamine neurotransmission is disrupted. After receiving oral MPH (20 mg) or placebo (counterbalanced), 15 healthy human volunteers and 16 cocaine-addicted individuals completed a task of executive function (the Stroop color word) during functional magnetic resonance imaging (fMRI). During MPH, despite not showing differences on percent accuracy and reaction time, all subjects committed fewer total errors and slowed down more after committing errors, suggestive of more careful responding. In parallel, during MPH all subjects showed reduced dorsal anterior cingulate cortex response to the fMRI contrast error>correct. In the cocaine subjects only, MPH also reduced error>correct activity in the dorsolateral prefrontal cortex (controls instead showed lower error>correct response in this region during placebo). Taken together, MPH modulated dopaminergically innervated prefrontal cortical areas involved in error-related processing, and such modulation was accentuated in the cocaine subjects. These results are consistent with a dopaminergic contribution to error-related processing during a cognitive control task.

Gene x abstinence effects on drug cue reactivity in addiction: multimodal evidence.

Functional polymorphisms in the dopamine transporter gene (DAT1 or SLC6A3) modulate responsiveness to salient stimuli, such that carriers of one 9R-allele of DAT1 (compared with homozygote carriers of the 10R-allele) show heightened reactivity to drug-related reinforcement in addiction. Here, using multimodal neuroimaging and behavioral dependent variables in 73 human cocaine-addicted individuals and 47 healthy controls, we hypothesized and found that cocaine-addicted carriers of a 9R-allele exhibited higher responses to drug cues, but only among individuals who had used cocaine within 72 h of the study as verified by positive cocaine urine screens (a state characterized by intense craving). Importantly, this responsiveness to drug cues was reliably preserved across multimodal imaging and behavioral probes: psychophysiological event-related potentials, self-report, simulated cocaine choice, and fMRI. Because drug cues contribute to relapse, our results identify the DAT1R 9R-allele as a vulnerability allele for relapse especially during early abstinence (e.g., detoxification).

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.

Psychophysiological prediction of choice: relevance to insight and drug addiction.

An important goal of addiction research and treatment is to predict behavioural responses to drug-related stimuli. This goal is especially important for patients with impaired insight, which can interfere with therapeutic interventions and potentially invalidate self-report questionnaires. This research tested (i) whether event-related potentials, specifically the late positive potential, predict choice to view cocaine images in cocaine addiction; and (ii) whether such behaviour prediction differs by insight (operationalized in this study as self-awareness of image choice). Fifty-nine cocaine abusers and 32 healthy controls provided data for the following laboratory components that were completed in a fixed-sequence (to establish prediction): (i) event-related potential recordings while passively viewing pleasant, unpleasant, neutral and cocaine images, during which early (400-1000 ms) and late (1000-2000 ms) window late positive potentials were collected; (ii) self-reported arousal ratings for each picture; and (iii) two previously validated tasks: one to assess choice for viewing these same images, and the other to group cocaine abusers by insight. Results showed that pleasant-related late positive potentials and arousal ratings predicted pleasant choice (the choice to view pleasant pictures) in all subjects, validating the method. In the cocaine abusers, the predictive ability of the late positive potentials and arousal ratings depended on insight. Cocaine-related late positive potentials better predicted cocaine image choice in cocaine abusers with impaired insight. Another emotion-relevant event-related potential component (the early posterior negativity) did not show these results, indicating specificity of the late positive potential. In contrast, arousal ratings better predicted respective cocaine image choice (and actual cocaine use severity) in cocaine abusers with intact insight. Taken together, the late positive potential could serve as a biomarker to help predict drug-related choice--and possibly associated behaviours (e.g. drug seeking in natural settings, relapse after treatment)--when insight (and self-report) is compromised.

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.

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.