Modulation of Attentional Bias to Drug and Affective Cues by Therapeutic and Neuropsychological Factors in Patients With Opioid Use Disorder on Methadone Maintenance Therapy

Objective: Abnormal selective attention to drug cues and negative affect is observed in patients with substance dependence, and it is closely associated with drug addiction and relapse. Methadone maintenance is an effective replacement therapy to treat heroin addiction, which significantly reduces the relapse rate. The present study examines whether the patients with opioid use disorder on chronic methadone maintenance therapy exhibit abnormal attentional bias to drug cues and negative-affective cues. Moreover, its relation to therapeutic and neuropsychological factors is also examined.Methods: Seventy-nine patients with opioid use disorder under chronic methadone maintenance therapy and 73 age-, sex-, and education-matched healthy controls were recruited and assessed for attentional bias to drug cues and negative affect using a dot-probe detection task. Correlational analysis was used to examine the relationships between the attentional bias and the demographic, therapeutic, and neuropsychological factors.Results: No significant overall patient-control group difference is observed in drug-related or negative-affective-related attentional bias scores. In the patient group, however, a significant negative correlation is found between the attentional bias scores to negative-affective cues and the duration of methadone treatment (p = 0.027), with the patients receiving longer methadone treatment showing less attentional avoidance to negative-affective cues. A significant positive correlation is found between the negative affect-induced bias and the impulsivity score (p = 0.006), with more impulsive patients showing higher attentional avoidance to negative affective cues than less impulsive patients. Additionally, the patients detect a smaller percentage of probe stimuli following the drug (p = 0.029) or negative-affective pictures (p = 0.009) than the healthy controls.Conclusion: The results of the present study indicate that the patients under chronic methadone maintenance therapy show normalized attentional bias to drug and negative-affective cues, confirming the involuntary attention of the patients is not abnormally captured by external drug or negative-affective clues. Our findings also highlight that the attentional avoidance of negative-affective cues is modulated by the duration of methadone treatment and the impulsivity level in the patients.

Circuit Investigation of Social Interaction and Substance Use Disorder Using Miniscopes

Substance use disorder (SUD) is comorbid with devastating health issues, social withdrawal, and isolation. Successful clinical treatments for SUD have used social interventions. Neurons can encode drug cues, and drug cues can trigger relapse. It is important to study how the activity in circuits and embedded cell types that encode drug cues develop in SUD. Exploring shared neurobiology between social interaction (SI) and SUD may explain why humans with access to social treatments still experience relapse. However, circuitry remains poorly characterized due to technical challenges in studying the complicated nature of SI and SUD. To understand the neural correlates of SI and SUD, it is important to: (1) identify cell types and circuits associated with SI and SUD, (2) record and manipulate neural activity encoding drug and social rewards over time, (3) monitor unrestrained animal behavior that allows reliable drug self-administration (SA) and SI. Miniaturized fluorescence microscopes (miniscopes) are ideally suited to meet these requirements. They can be used with gradient index (GRIN) lenses to image from deep brain structures implicated in SUD. Miniscopes can be combined with genetically encoded reporters to extract cell-type specific information. In this mini-review, we explore how miniscopes can be leveraged to uncover neural components of SI and SUD and advance potential therapeutic interventions.

Altered prefrontal signaling during inhibitory control in a salient drug context in human cocaine addiction

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. We developed a novel stop-signal fMRI 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) vs. demographically matched healthy control participants (HC; n=26). Despite similarities in drug cue-related SSRT and valence and arousal word ratings between groups, the 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 < .05 corrected). Results suggest reduced 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.Significance statementExcessive salience attribution to drugs and related cues at the expense of nondrug reinforcers and cues and inhibitory control impairments are hallmark symptoms of drug addiction. Although these neuropsychological functions have been investigated independently, brain representations of their interaction are less clear. We illustrate that, despite matched behavioral performance and valence and arousal ratings, the dorsolateral prefrontal cortex—a key node of the cognitive control network also associated with craving—exhibits decreased signaling when successfully inhibiting responses to drug compared to nondrug (food) cues (words) in cocaine-addicted individuals. Modulating salience while taxing self-control permits the study of their combined impact, an ecologically valid examination of the addiction experience. Better understanding inhibitory control under drug cue-reactivity may refine targeted neuromodulatory interventions.

Temporally Dynamic Interaction between Drug Cue Reactivity and Response Inhibition: An fMRI Study among People with Methamphetamine Use Disorder

Cue-induced drug craving and disinhibition are two essential components of continued drug use and relapse in substance use disorders. While these two phenomena develop and interact across time, the temporal dynamics of their underlying neural activity and their interaction remain under-investigated. To explore these dynamics, an analysis of time-varying activation was applied to fMRI data from 62 men with methamphetamine use disorder in their first weeks of recovery in abstinence-based treatment program. Using a mixed block-event, factorial cue-reactivity/Go-NoGo task, and a sliding window across the task duration, dynamically-activated regions were identified in linear mixed effects models (LMEs). Habituation to drug cues across time was observed in the superior temporal gyri, amygdalae, left hippocampus, and right precuneus, while response-inhibition was associated with the sensitization of temporally-dynamic activations across many regions of the inhibitory frontoparietal network. Cue-reactivity and response-inhibition dynamically interact in the parahippocampal gyri and right precuneus (corrected p-value < 0.001) regions, which show a declining cue-reactivity contrast and an increasing response-inhibition contrast. Overall, the declining craving-related activations (habituation) and increasing inhibition-associated activations (sensitization) along the task duration suggest the gradual recruitment of response-inhibition process and the concurrent habituation to drug cues in areas with significant dynamic interaction. This exploratory study demonstrates the time-variance of the neural activations undergirding cue-reactivity, response-inhibition, and their interaction, and suggests potentials to assess this dynamic interaction. This preliminary evidence provides justifications for new avenues in biomarker development and interventions using cue exposure paradigms, which could promote habituation to drug cues and sensitization in inhibitory control regions.

Drug-associated cues and drug dosage contribute to increased opioid seeking after abstinence

Patients with opioid use disorder experience high rates of relapse during recovery, despite successful completion of rehabilitation programs. A key factor contributing to this problem is the long-lasting nature of drug-seeking behavior associated with opioid use. We modeled this behavior in a rat drug self-administration paradigm in which drug-seeking is higher after extended abstinence than during the acute abstinence phase. The goal of this study was to determine the contribution of discrete or discriminative drug cues and drug dosage to time-dependent increases in drug-seeking. We examined heroin-seeking after 2 or 21 days of abstinence from two different self-administration cue-context environments using high or low doses of heroin and matched animals for their drug intake history. When lower dosages of heroin are used in discriminative or discrete cue protocols, drug intake history contributed to drug-seeking after abstinence, regardless of abstinence length. Incubation of opioid craving at higher dosages paired with discrete drug cues was not dependent on drug intake. Thus, interactions between drug cues and drug dosage uniquely determined conditions permissible for incubation of heroin craving. Understanding factors that contribute to long-lasting opioid-seeking can provide essential insight into environmental stimuli and drug-taking patterns that promote relapse after periods of successful abstinence.

How the harm of drugs and their availability affect brain reactions to drug cues: a meta-analysis of 64 neuroimaging activation studies

Visual drug cues are powerful triggers of craving in drug abusers contributing to enduring addiction. According to previous qualitative reviews, the response of the orbitofrontal cortex to such cues is sensitive to whether subjects are seeking treatment. Here we re-evaluate this proposal and assessed whether the nature of the drug matters. To this end, we performed a quantitative meta-analysis of 64 neuroimaging studies on drug-cue reactivity across legal (nicotine, alcohol) or illegal substances (cocaine, heroin). We used the ALE algorithm and a hierarchical clustering analysis followed by a cluster composition statistical analysis to assess the association of brain clusters with the nature of the substance, treatment status, and their interaction. Visual drug cues activate the mesocorticolimbic system and more so in abusers of illegal substances, suggesting that the illegal substances considered induce a deeper sensitization of the reward circuitry. Treatment status had a different modulatory role for legal and illegal substance abusers in anterior cingulate and orbitofrontal areas involved in inter-temporal decision making. The class of the substance and the treatment status are crucial and interacting factors that modulate the neural reactivity to drug cues. The orbitofrontal cortex is not sensitive to the treatment status per se, rather to the interaction of these factors. We discuss that these varying effects might be mediated by internal predispositions such as the intention to quit from drugs and external contingencies such as the daily life environmental availability of the drugs, the ease of getting them and the time frame of potential reward through drug consumption.