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Key Points Neuroimaging studies have revealed an emerging pattern of generalized prefrontal cortex (PFC) dysfunction in drug-addicted individuals that is associated with worse outcome — more drug use, worse PFC-related task performance and greater likelihood of relapse. Widespread PFC activation in drug-addicted individuals upon taking cocaine or other drugs and upon presentation of drug-related cues is replaced by widespread PFC hypoactivity during exposure to higher-order emotional and cognitive challenges and/or during protracted withdrawal when not stimulated. The nature of the findings in PFC is different when abusers are studied during intoxication or craving and when they are studied during acute or protracted withdrawal, and this is to be expected considering the distinct role of the PFC in these processes. PFC regions may be implicated in what seem to be opposite processes. This may reflect the limited temporal resolution of imaging technologies or methodological variability. Processes also reflect the function of networks rather than isolated regions, so that the output of a region will differ as it connects with different networks. Although activity among PFC regions is highly integrated and flexible, such that any one region is involved in multiple functions, the dorsal PFC (including the dorsal anterior cingulate cortex, dorsolateral PFC and inferior frontal gyrus) has been predominantly implicated in top-down control and meta-cognitive functions (including awareness), the ventromedial PFC (including subgenual ACC and medial orbitofrontal cortex) in emotion regulation (including conditioning and assigning incentive salience to drugs and drug-related cues), and the ventrolateral PFC and lateral OFC in automatic response tendencies (for example, drug-related attention bias) and impulsivity. Dysfunction of these PFC regions may contribute to impaired response inhibition and salience attribution (iRISA) in addiction, neuropsychological mechanisms that underlie the development of craving, compulsive use and impaired self-awareness (previously labelled 'denial' of illness and/or need for treatment), which are characteristic symptoms of drug addiction. PFC dysfunction may in some instances precede drug use and confer vulnerability for (or protection against) developing substance use disorders. Specific biomarkers could be targeted for intervention purposes. For example, PFC abnormalities could be used to identify the children and adolescents who would benefit most from intensive drug abuse prevention efforts. The combination of targeted pharmacological interventions (for example, to enhance dopaminergic neurotransmission) with cognitive–behavioural exercises (for example, to enhance inhibitory control and non drug-related motivation, and reduce drug-related attention bias) could normalize select PFC functions. Ameliorating these deficits could help addicted subjects to engage in rehabilitation treatment. Functional imaging studies have pointed to a key role for the prefrontal cortex (PFC) in addiction, both through its regulation of limbic regions and its involvement in higher-order executive function. Goldstein and Volkow review these studies, showing that disruption of the PFC in addiction not only underlies compulsive drug taking but also accounts for the disadvantageous behaviours that are associated with addiction and the erosion of non-drug related motivation and self-control. 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.

Drug overdoses from opioids and stimulants are a major cause of mortality in the United States. It is unclear if there are stable sex differences in overdose mortality for these drugs across states, whether these differ across the lifespan, and if so, whether they can be accounted for by different levels of drug misuse. This was a state-level analysis of epidemiological data on overdose mortality, across 10-year age bins (age range: 15–74), using the CDC WONDER platform for decedents in the United States in 2020–1. The outcome measure was rate of overdose death (per 100,000) for: synthetic opioids (e.g., fentanyl), heroin, psychostimulants with potential for misuse (e.g., methamphetamine), and cocaine. Multiple linear regressions controlled for ethnic-cultural background, household net worth, and sex-specific rate of misuse (from NSDUH, 2018-9). For all these drug categories, males had greater overall overdose mortality than females, after controlling for rates of drug misuse. The mean male/female sex ratio of mortality rate was relatively stable across jurisdictions: synthetic opioids (2.5 [95% CI, 2.4–7]), heroin, (2.9 [95% CI, 2.7–3.1], psychostimulants (2.4 [95% CI, 2.3–5]), and cocaine (2.8 [95% CI, 2.6–9]). With data stratified in 10-year age bins, the sex difference generally survived adjustment (especially in the 25–64 age range). Results indicate that males are significantly more vulnerable than females to overdose deaths caused by opioid and stimulant drugs, taking into account differing state-level environmental conditions and drug misuse levels. These results call for research into diverse biological, behavioral, and social factors that underlie sex differences in human vulnerability to drug overdose.

Impairments in response inhibition and salience attribution (iRISA) have been proposed to underlie the clinical symptoms of drug addiction as mediated by cortico-striatal-thalamo-cortical networks. The bulk of evidence supporting the iRISA model comes from neuroimaging research that has focused on cortical and striatal influences with less emphasis on the role of the thalamus. Here, we highlight the importance of the thalamus in drug addiction, focusing on animal literature findings on thalamic nuclei in the context of drug-seeking, structural and functional changes of the thalamus as measured by imaging studies in human drug addiction, particularly during drug cue and non-drug reward processing, and response inhibition tasks. Findings from the animal literature suggest that the paraventricular nucleus of the thalamus, the lateral habenula and the mediodorsal nucleus may be involved in the reinstatement, extinction and expression of drug-seeking behaviours. In support of the iRISA model, the human addiction imaging literature demonstrates enhanced thalamus activation when reacting to drug cues and reduced thalamus activation during response inhibition. This pattern of response was further associated with the severity of, and relapse in, drug addiction. Future animal studies could widen their field of focus by investigating the specific role(s) of different thalamic nuclei in different phases of the addiction cycle. Similarly, future human imaging studies should aim to specifically delineate the structure and function of different thalamic nuclei, for example, through the application of advanced imaging protocols at higher magnetic fields (7 Tesla). This article is part of a discussion meeting issue ‘Of mice and mental health: facilitating dialogue between basic and clinical neuroscientists’.

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 cognitivebehavioral and personalized intervention for drug addiction.

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. 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. 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. 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 (t =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. 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.

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. •A systematic review of 32 neuroimaging studies on cognitive reappraisal in patients•Lower vlPFC/dlPFC activation is a core deficit in downregulation across patients.•Amygdala hyperactivity is a specific deficit in downregulation in mood disorders.•dACC/parietal hypoactivity specific deficit in downregulation in anxiety disorders•Implications: neural targets for therapeutic interventions need to be tailored

Abnormalities in goal-directed behavior, mediated by mesocorticolimbic reward system, contribute to worse clinical outcomes including higher risk of treatment dropout and drug relapse in opioid users (OU). Despite efforts to counteract such neural alterations, brain-based interventions for this disorder remain ineffective. In this sham-controlled randomized study, we report the initial results on the efficacy of transcranial magnetic stimulus (TMS) in normalizing reward functioning in this population. During a reward-based choice task, we applied robot-assisted 10-Hz TMS to the prefrontal cortex in OU (Active = 16, Sham = 18) and matched healthy controls (HC, Active = 22, Sham = 24) while we recorded the reward positivity — an electrophysiological signal believed to index sensitivity of the anterior midcingulate cortex (MCC) to rewards. A robotic arm positioned a TMS coil over a prefrontal cortex target, and 50 pulses were delivered at 10-Hz before every 10 trials (2000 pulses, 400 trials). Our results revealed an interaction between TMS (Active vs Sham) and Group (OU vs HC) (F 1,72  = 6.9, p = 0.01, η 2  = 0.09). First, in the Sham TMS condition, OU exhibited a blunted reward positivity compared to HC (p = 0.01, d = 0.84). Second, OU receiving active TMS displayed a larger reward positivity compared to OU receiving sham (p = 0. 003, d = 0.98), and no differences were observed between OU and HC (p = 0.42, d = 0.17) or HC receiving sham (p = 0.48, d = 0.11). We envision that targeting a specific frontal-cingulate reward pathway is an important first step to maintain long-terms effect of TMS on MCC reward function, which may enhance treatment success through the maintenance of treatment goals.

Opioid use disorders cause major morbidity and mortality, and there is a pressing need for novel mechanistic targets and biomarkers for diagnosis and prognosis. Exposure to mu-opioid receptor (MOR) agonists causes changes in cytokine and inflammatory protein networks in peripheral blood, and also in brain glia and neurons. Individuals with heroin use disorder (iHUD) show dysregulated levels of several cytokines in the blood. However, there is limited data on a comprehensive panel of such markers in iHUD versus healthy controls (HC), especially considered as a multi-target biomarker. We used a validated proximity extension assay for the relative quantification of 92 cytokines and inflammatory proteins in the serum of iHUD on medication-assisted therapy (MAT; n = 21), compared to HC (n = 24). Twenty-nine targets showed significant group differences (primarily iHUD>HC), surviving multiple comparison corrections (p = 0.05). These targets included 19 members of canonical cytokine families, including specific chemokines, interleukins, growth factors, and tumor necrosis factor (TNF)-related proteins. For dimensionality reduction, data from these 19 cytokines were entered into a principal component (PC) analysis, with PC1 scores showing significant group differences (iHUD > HC; p < 0.0001). A receiver-operating characteristic (ROC) curve analysis yielded an AUROC = 91.7% (p < 0.0001). This PC1 score remained a positive predictor of being in the HUD group in a multivariable logistic regression, that included select demographic/clinical variables. Overall, this study shows a panel of cytokines that differ significantly between iHUD and HC, providing a multi-target “cytokine biomarker score” for potential diagnostic purposes, and future examination of disease severity.

A growing preclinical and clinical body of work on the effects of chronic drug use and drug addiction has extended the scope of inquiry from the putative reward-related subcortical mechanisms to higher-order executive functions as regulated by the prefrontal cortex. Here we review the neuroimaging evidence in humans and non-human primates to demonstrate the involvement of the prefrontal cortex in emotional, cognitive, and behavioral alterations in drug addiction, with particular attention to the impaired response inhibition and salience attribution (iRISA) framework. In support of iRISA, functional and structural neuroimaging studies document a role for the prefrontal cortex in assigning excessive salience to drug over non-drug-related processes with concomitant lapses in self-control, and deficits in reward-related decision-making and insight into illness. Importantly, converging insights from human and non-human primate studies suggest a causal relationship between drug addiction and prefrontal insult, indicating that chronic drug use causes the prefrontal cortex damage that underlies iRISA while changes with abstinence and recovery with treatment suggest plasticity of these same brain regions and functions. We further dissect the overlapping and distinct characteristics of drug classes, potential biomarkers that inform vulnerability and resilience, and advancements in cutting-edge psychological and neuromodulatory treatment strategies, providing a comprehensive landscape of the human and non-human primate drug addiction literature as it relates to the prefrontal cortex.

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). 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). 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. 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. 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.