The Neural Signature of Impaired Inhibitory Control in Individuals with Heroin Use Disorder.

Heroin addiction imposes a devastating toll on society, with little known about its neurobiology. Excessive salience attribution to drug over nondrug cues/reinforcers, with concomitant inhibitory control decreases, are common mechanisms underlying drug addiction. Although inhibitory control alterations generally culminate in prefrontal cortex (PFC) hypoactivations across drugs of abuse, patterns in individuals with heroin addiction (iHUDs) remain unknown. We used a stop-signal fMRI task designed to meet recent consensus guidelines in mapping inhibitory control in 41 iHUDs and 24 age- and sex-matched healthy controls (HCs). Despite group similarities in the stop-signal response time (SSRT; the classic inhibitory control measure), compared with HCs, iHUDs exhibited impaired target detection sensitivity (proportion of hits in go vs false alarms in stop trials; p = 0.003). Additionally, iHUDs exhibited lower right anterior PFC (aPFC) and dorsolateral PFC (dlPFC) activity during successful versus failed stops (the hallmark inhibitory control contrast). Lower left dlPFC/supplementary motor area (SMA) activity was associated with slower SSRT specifically in iHUDs and lower left aPFC activity with worse target sensitivity across all participants (p < 0.05 corrected). Importantly, in iHUDs, lower left SMA and aPFC activity during inhibitory control was associated with shorter time since last use and higher severity of dependence, respectively (p < 0.05 corrected). Together, results revealed lower perceptual sensitivity and hypoactivations during inhibitory control in cognitive control regions (e.g., aPFC, dlPFC, SMA) as associated with task performance and heroin use severity measures in iHUDs. Such neurobehavioral inhibitory control deficits may contribute to self-control lapses in heroin addiction, constituting targets for prevention and intervention efforts to enhance recovery.SIGNIFICANCE STATEMENT Heroin addiction continues its deadly impact, with little known about the neurobiology of this disorder. Although behavioral and prefrontal cortical impairments in inhibitory control characterize addiction across drugs of abuse, these patterns remain underexplored in heroin addiction. Here, we illustrate a significant behavioral impairment in target discrimination in individuals with heroin addiction compared with matched healthy controls. We further show lower engagement during inhibitory control in the anterior and dorsolateral prefrontal cortex (key regions that regulate cognitive control) as associated with slower stopping, worse discrimination, and heroin use measures. Mapping the neurobiology of inhibitory control in heroin addiction for the first time, we identify potential treatment targets inclusive of prefrontal cortex-mediated cognitive control amenable for neuromodulation en route to recovery.

Whole-brain white matter abnormalities in human cocaine and heroin use disorders: association with craving, recency, and cumulative use.

Neuroimaging studies in substance use disorder have shown widespread impairments in white matter (WM) microstructure suggesting demyelination and axonal damage. However, substantially fewer studies explored the generalized vs. the acute and/or specific drug effects on WM. Our study assessed whole-brain WM integrity in three subgroups of individuals addicted to drugs, encompassing those with cocaine (CUD) or heroin (HUD) use disorder, compared to healthy controls (CTL). Diffusion MRI was acquired in 58 CTL, 28 current cocaine users/CUD+, 32 abstinent cocaine users/CUD-, and 30 individuals with HUD (urine was positive for cocaine in CUD+ and opiates used for treatment in HUD). Tract-Based Spatial Statistics allowed voxelwise analyses of diffusion metrics [fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD), and axial diffusivity (AD)]. Permutation statistics (p-corrected < 0.05) were used for between-group t-tests. Compared to CTL, all individuals with addiction showed widespread decreases in FA, and increases in MD, RD, and AD (19-57% of WM skeleton, p < 0.05). The HUD group showed the most impairments, followed by the CUD+, with only minor FA reductions in CUD- (<0.2% of WM skeleton, p = 0.05). Longer periods of regular use were associated with decreased FA and AD, and higher subjective craving was associated with increased MD, RD, and AD, across all individuals with drug addiction (p < 0.05). These findings demonstrate extensive WM impairments in individuals with drug addiction characterized by decreased anisotropy and increased diffusivity, thought to reflect demyelination and lower axonal packing. Extensive abnormalities in both groups with positive urine status (CUD+ and HUD), and correlations with craving, suggest greater WM impairments with more recent use. Results in CUD-, and correlations with regular use, further imply cumulative and/or persistent WM damage.

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.

Tobacco Images Choice and Its Association with Craving and Dependence in People who Smoke Cigarettes.

INTRODUCTION: Increased salience of drug-related cues over non-drug reinforcers can drive drug use and contribute to tobacco use disorder (TUD). An important scientific and clinical goal is to effectively measure this elevated drug-seeking behavior in TUD. However, most TUD assessments rely on self-reported cravings and cigarette consumption, not providing an objective measure of the impact of drug-cues on biasing behavior towards drugs. The probabilistic image choice (PIC) task investigates the choice of viewing drug-related pictures as compared to other salient pictures (e.g., pleasant and unpleasant). This study aimed to develop and validate the PIC task for TUD and evaluate the associations between behavioral choice and tobacco craving, daily cigarette consumption, quit attempts and motivation to quit, and nicotine dependence (the Fagerström score). METHODS: We recruited 468 smokers and 121 nonsmokers using the Prolific online platform. Participants performed the PIC task twice (at a one-month interval) and completed other measures relevant to TUD. RESULTS: compared to nonsmokers, tobacco smokers selected to view significantly more tobacco images and less pleasant (non-drug reinforcer) images, a profile that remained stable at retest. Individual differences in choice of tobacco as compared to pleasant images on the PIC task were associated with craving but not with the other tobacco dependence measures, suggesting that the task may serve as a behavioral proxy measure of drug "wanting" rather than of cumulative nicotine exposure or physical dependence. CONCLUSIONS: these results suggest that the PIC task can be a valuable tool for objectively assessing craving-associated tobacco seeking in TUD. IMPLICATIONS SECTION: which should provide a brief description about what the study addsMost of the current measures of tobacco use disorder (TUD) rely on self-reports of consumption, dependence and craving and do not take into consideration the role of drug-related cues in driving tobacco seeking. This study shows that the probabilistic image choice (PIC) task provides an objective, reliable proxy measure of tobacco image seeking behavior in people who smoke cigarettes that is linked to craving (desire) for smoking but not to other measures of TUD. Therefore, the PIC task may be a useful complementary tool for the classification, diagnosis, and prognosis of TUD.

Common and distinct fronto-striatal volumetric changes in heroin and cocaine use disorders.

Different drugs of abuse impact the morphology of fronto-striatal dopaminergic targets in both common and unique ways. While dorsal striatal volume tracks with addiction severity across drug classes, opiates impact ventromedial prefrontal cortex (vmPFC) and nucleus accumbens (NAcc) neuroplasticity in preclinical models, and psychostimulants alter inhibitory control, rooted in cortical regions such as the inferior frontal gyrus (IFG). We hypothesized parallel grey matter volume changes associated with human heroin or cocaine use disorder: lower grey matter volume of vmPFC/NAcc in heroin use disorder and IFG in cocaine use disorder, and putamen grey matter volume to be associated with addiction severity measures (including craving) across both. In this cross-sectional study, we quantified grey matter volume (P < 0.05-corrected) in age/sex/IQ-matched individuals with heroin use disorder (n = 32, seven females), cocaine use disorder (n = 32, six females) and healthy controls (n = 32, six females) and compared fronto-striatal volume between groups using voxel-wise general linear models and non-parametric permutation-based tests. Overall, individuals with heroin use disorder had smaller vmPFC and NAcc/putamen volumes than healthy controls. Bilateral lower IFG grey matter volume patterns were specifically evident in cocaine versus heroin use disorders. Correlations between addiction severity measures and putamen grey matter volume did not reach nominal significance level in this sample. These results indicate alterations in dopamine-innervated regions (in the vmPFC and NAcc) in heroin addiction. For the first time we demonstrate lower IFG grey matter volume specifically in cocaine compared with heroin use disorder, suggesting a signature of reduced inhibitory control, which remains to be tested directly using select behavioural measures. Overall, results suggest substance-specific volumetric changes in human psychostimulant or opiate addiction, with implications for fine-tuning biomarker and treatment identification by primary drug of abuse.

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.

Emotional Expression on Social Media Support Forums for Substance Cessation: Observational Study of Text-Based Reddit Posts.

BACKGROUND: Substance use disorder is characterized by distinct cognitive processes involved in emotion regulation as well as unique emotional experiences related to the relapsing cycle of drug use and recovery. Web-based communities and the posts they generate represent an unprecedented resource for studying subjective emotional experiences, capturing population types and sizes not typically available in the laboratory. Here, we mined text data from Reddit, a social media website that hosts discussions from pseudonymous users on specific topic forums, including forums for individuals who are trying to abstain from using drugs, to explore the putative specificity of the emotional experience of substance cessation. OBJECTIVE: An important motivation for this study was to investigate transdiagnostic clues that could ultimately be used for mental health outreach. Specifically, we aimed to characterize the emotions associated with cessation of 3 major substances and compare them to emotional experiences reported in nonsubstance cessation posts, including on forums related to psychiatric conditions of high comorbidity with addiction. METHODS: Raw text from 2 million posts made, respectively, in the fall of 2020 (discovery data set) and fall of 2019 (replication data set) were obtained from 394 forums hosted by Reddit through the application programming interface. We quantified emotion word frequencies in 3 substance cessation forums for alcohol, nicotine, and cannabis topic categories and performed comparisons with general forums. Emotion word frequencies were classified into distinct categories and represented as a multidimensional emotion vector for each forum. We further quantified the degree of emotional resemblance between different forums by computing cosine similarity on these vectorized representations. For substance cessation posts with self-reported time since last use, we explored changes in the use of emotion words as a function of abstinence duration. RESULTS: Compared to posts from general forums, substance cessation posts showed more expressions of anxiety, disgust, pride, and gratitude words. "Anxiety" emotion words were attenuated for abstinence durations >100 days compared to shorter durations (t12=3.08, 2-tailed; P=.001). The cosine similarity analysis identified an emotion profile preferentially expressed in the cessation posts across substances, with lesser but still prominent similarities to posts about social anxiety and attention-deficit/hyperactivity disorder. These results were replicated in the 2019 (pre-COVID-19) data and were distinct from control analyses using nonemotion words. CONCLUSIONS: We identified a unique subjective experience phenotype of emotions associated with the cessation of 3 major substances, replicable across 2 time periods, with changes as a function of abstinence duration. Although to a lesser extent, this phenotype also quantifiably resembled the emotion phenomenology of other relevant subjective experiences (social anxiety and attention-deficit/hyperactivity disorder). Taken together, these transdiagnostic results suggest a novel approach for the future identification of at-risk populations, allowing for the development and deployment of specific and timely interventions.

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.

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).

Dysfunction of the prefrontal cortex in addiction: neuroimaging findings and clinical implications.

The loss of control over drug intake that occurs in addiction was initially believed to result from disruption of subcortical reward circuits. However, imaging studies in addictive behaviours have identified a key involvement of the prefrontal cortex (PFC) both through its regulation of limbic reward regions and its involvement in higher-order executive function (for example, self-control, salience attribution and awareness). This Review focuses on functional neuroimaging studies conducted in the past decade that have expanded our understanding of the involvement of the PFC in drug addiction. Disruption of the PFC in addiction underlies not only compulsive drug taking but also accounts for the disadvantageous behaviours that are associated with addiction and the erosion of free will.

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).