Learning can be guided by unexpected success or failure, signaled via dopaminergic positive reward prediction error (ϩRPE) and negative reward-prediction error (ϪRPE) 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 (CUDϩ), indicating cocaine use within the past 72 h; and in 25 individuals with CUD who tested negative for cocaine (CUDϪ). 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 ϩRPE) and decreased FN to unpredicted compared with predicted losses (i.e., intact ϪRPE). However, neither CUD subgroup showed FN modulation to loss (i.e., impaired ϪRPE), and unlike CUDϩ individuals, CUDϪ individuals also did not show FN modulation to win (i.e., impaired ϩRPE). Thus, using FN, the current study directly documents ϪRPE deficits in CUD individuals. The mechanisms underlying ϪRPE 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).

IntroductionDrug addiction is a neuropsychiatric disorder characterized by attentional abnormalities whereby enhanced attention is afforded to drugs and drug-related cues at the expense of other (including intrinsically pleasant) reinforcers (e.g., food, sex or money).1,2 This attention bias toward drug-related cues is posited to result from conditioning to drug-related cues, which become excessively and motivationally salient through habitual use. 1,3,4 The underlying mechanism invokes changes to mesolimbic dopamine transmission, associated with an increased incentive salience that is automatically attributed to drug-related cues. 5,6 Ultimately, this drug-related attention bias influences drug-seeking behaviour, which in turn is associated with increased craving 7-9 and relapse susceptibility. [10][11][12][13] Abstinence from drug use improves cognitive and affective functioning, including attentional bias/ dysregulation, in drug-addicted individuals.14 To objectively quantify attention to salient cues, several prior studies have used the late positive potential (LPP), an event-related potential (ERP) component that marks motivated attention to emotionally salient stimuli. 15,16 Specifically, increased LPP amplitude in response to drug-related compared with neutral cues has consistently been shown across all substance use disorders [17][18][19][20][21][22][23] and has further been linked with cue-induced craving.24 Importantly, cross-sectional studies have shown that the LPP amplitude to drug-related cues is decreased 25,26 while that to non-drug-related cues is increased 19,27 after a period of reduced drug use (3 d to about 1 yr). Moreover, prospective neuroimaging studies modelling relapse vulnerability and future drug use have shown that reduced attention toward drug-related cues 11,12,[28][29][30] and increased attention toward non-drug-related reinforcers [31][32][33] predicted longer abstinence durations in individuals with substance use disorders. Although these studies are highly informative, many have been limited to the cross-sectional 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 drugrelated 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...

Dysfunctional self-awareness has been posited as a key feature of drug addiction, contributing to compromised control over addictive behaviors. In the present investigation, we showed that, compared with healthy controls (n=13) and even individuals with remitted cocaine use disorder (n=14), individuals with active cocaine use disorder (n=8) exhibited deficits in basic metacognition, defined as a weaker link between objective performance and self-reported confidence of performance on a visuo-perceptual accuracy task. This metacognitive deficit was accompanied by gray matter volume decreases, also most pronounced in individuals with active cocaine use disorder, in the rostral anterior cingulate cortex, a region necessary for this function in health. Our results thus provide a direct unbiased measurement – not relying on long-term memory or multifaceted choice behavior – of metacognition deficits in drug addiction, which are further mapped onto structural deficits in a brain region that subserves metacognitive accuracy in health and self-awareness in drug addiction. Impairments of metacognition could provide a basic mechanism underlying the higher-order self-awareness deficits in addiction, particularly among recent, active users.

Functional neuroimaging studies have long implicated the mid-cingulate cortex (MCC) in conflict monitoring, but it is not clear whether its structural integrity (i.e., the gray matter volume) influences its conflict monitoring function. In this multimodal study, we used T1-weighted MRI scans as well as event-related potentials (ERPs) to test whether the MCC gray matter volume is associated with the electrocortical marker (i.e., No-go N200 ERP component) of conflict monitoring in healthy individuals. The specificity of such a relationship in health was determined in two ways: by (A) acquiring the same data from individuals with cocaine use disorder (CUD), known to have deficits in executive function including behavioral monitoring; and (B) acquiring the P300 ERP component that is linked with attention allocation and not specifically with conflict monitoring. Twenty-five (39.1 ± 8.4 years; 8 females) healthy individuals and 25 (42.7 ± 5.9 years; 6 females) individuals with CUD underwent a rewarded Go/No-go task during which the ERP data was collected, and they also underwent a structural MRI scan. The whole brain regression analysis showed a significant correlation between MCC structural integrity and the well-known ERP measure of conflict monitoring (N200, but not the P300) in healthy individuals, which was absent in CUD who were characterized by reduced MCC gray matter volume, N200 abnormalities as well as reduced task accuracy. In individuals with CUD instead, the N200 amplitude was associated with drug addiction symptomatology. These results show that the integrity of MCC volume is directly associated with the electrocortical correlates of conflict monitoring in healthy individuals, and such an association breaks down in psychopathologies that impact these brain processes. Taken together, this MCC–N200 association may serve as a biomarker of improved behavioral monitoring processes in diseased populations.

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.

Background Hyposensitivity to non-drug reward, behaviorally manifested as anhedonia, is a hallmark of chronic substance use. Anhedonia is a transdiagnostic symptom underpinned by neurobiochemical disturbances in the reward circuit, yet an objective measure to assess anhedonia severity still eludes the field. We hypothesized that the Reward Positivity (RewP) component of the event-related potentials (ERPs) will specifically track anhedonia as the RewP is attributed to the same brain regions that are also implicated in anhedonia. Methods Forty-six individuals with cocaine use disorders (iCUD) performed a gambling task predicting whether they would win or lose money on each trial, while ERP data was acquired. RewP in response to predicted win trials was extracted from the ERPs using the principal component analysis. State anhedonia and depression severity were assessed using the Cocaine Selective Severity Assessment (CSSA). Results Although RewP amplitude correlated with both anhedonia and depression, only the RewP-anhedonia correlation survived a correction for depression severity. Further, a hierarchical multiple regression analysis revealed that anhedonia explained a significant amount of variance in the RewP amplitude, and this variance was significantly greater than that explained by demographics, severity and recency of drug use and even depression. Conclusions These results show that RewP amplitude in response to rewarded trials tracks state anhedonia severity in iCUD. We argue that this association is perhaps driven by the activity in the dopaminergic mesocorticolimbic reward pathway that may underlie anhedonia symptomology as well as modulate RewP amplitude.

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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 gray matter volume (GMV) changes associated with human heroin or cocaine use disorder (HUD/CUD): lower GMV of vmPFC/NAcc in HUD and IFG in CUD, and putamen GMV to be associated with addiction severity measures (including craving) across both. In this cross-sectional study, we quantified GMV (p < 0.05-corrected) in age/sex/IQ-matched individuals with HUD (n = 32; 7 women), CUD (n = 32; 6 women), and healthy controls (HC; n = 32; 6 women) and compared fronto-striatal volume between groups using voxelwise general linear models and non-parametric permutation based tests. Overall, individuals with HUD had smaller vmPFC and NAcc/putamen volumes than HC. Bilateral lower IFG GMV patterns were specifically evident in CUD vs. HUD. Correlations between addiction severity measures and putamen GMV 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 GMV specifically in CUD as compared to HUD, suggesting a signature of reduced inhibitory control, which remains to be tested directly using select behavioral 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.