Frontoparietal Synchronization to Modulate Drug Craving in Opioid Use Disorder: A Randomized Experimental Trial

A. Background:

Opioid use disorder (OUD) is among the costliest and deadliest substance use disorders (SUDs) in the US and world-wide. Opioids (including prescription opioids, heroin, and fentanyl) were involved in more than 42,000 deaths in 2016 in US, more than any year on record and accounting for more deaths than due to road accidents and gun violence combined1. Over 4.3 million Americans engaged in non-medical use of prescription opioids each month and 4.8 million people have used heroin at some point in their lives. From each year since 2002, past month heroin use, past year heroin use, and heroin use disorder have increased among 18-25 years old. Among new heroin users, approximately three out of four reported using prescription opioids prior to using heroin. Available treatment options for OUD are limited and long-term efficacy to return to a normal life is very low. During the last two decades, advancements in human neuroscience research have provided new hope for targeting neurocognitive processes underlying drug addictions, including OUD, to introduce new therapeutic interventions. In reality, however, neuroscience has played a very minimal role, if any, in changing clinical practices for OUD, until now.

Although DSM V has added "drug craving" as a criterion for SUDs, it has been well-known as a core process in drug dependence and addiction for many years. Exposure to drug-related cues to induce drug craving, which is called "Cue Induced Craving" or "CIC", is one of the main paradigms used to study the drug craving phenomenon2. There are many studies that have shown CIC to be a valid core construct for continued drug use and relapse. Therefore, reduction of CIC is now one of the main targets for enhancing substance use recovery2. Different brain areas and networks are involved in CIC. In particular, top down modulation by frontoparietal areas involved in the executive control network (ECN) including dorsolateral prefrontal cortex (DLPFC), and inferior parietal cortex (IPC), over subcortical areas such as ventral striatum (VSt) and amygdala, is thought to be the critical process underlying CIC. Failure of top down modulation by ECN in relation to other large-scale networks is reported to be a predictor of relapse among both cocaine and heroin users. Furthermore, improvement in ECN top-down regulation has been reported in trials with medications that reduce drug craving3. This is in line with current evidence from animal models for the central role of frontoparietal network in top-down attention and executive control. It is frequently reported that coherence in the theta band (4-8 Hz) within the frontoparietal network plays a central role in executive functions including working memory and cognitive control. There is a growing body of evidence that transcranial alternating current stimulation (tACS) can increase this coherence, entrain ECN connectivity and improve its function. tACS is a device-based technology employed to change cortical oscillations by applying a very weak (0.1 to 2mAmp) alternating current over the skull. In vivo studies show that tACS can modulate ongoing neural rhythms by shifting spike timing and firing rates towards the stimulation frequency (external synchronization)4. Meanwhile, it is strongly proposed that synchronized oscillation plays the major role in communication and connection between nodes within a network5. Based on this background, there is hope that multisite tACS (mtACS), with synchronized current delivered to the sites (network nodes), can offer the potential to enhance connectivity between nodes of these large-scale networks. FrontoParietal Synchronization (FPS), defined as a double site, DLPFC and IPC, tACS both with in-phase (synchronic) oscillatory electric current, more frequently in the theta or alpha bands, has received particular attention among other mtACS methods. The goal of FPS is to improve ECN connectivity and improve functions like working memory6-8 and attention control9. Most tACS studies have explored the online effects of synchronization. However, recent evidence for the long-lasting entraining effect of tACS after termination of stimulation (offline effect) has increased the potential for meaningful clinical applications. Nevertheless, there are no published fMRI studies to date (Dec 2018) that have aimed to delineate how FPS might modulate top-down ECN regulatory control over the amygdala and ventral striatum. The overall aim of the proposed research is thus to determine whether FPS can amplify top down modulation of ECN over subcortical-limbic areas (VSt and Amygdala) during CIC among people with OUD. Furthermore, the investigators will explore whether connectivity between these areas before FPS along with other clinical and behavioral factors can predict inter- individual differences in subjective response to FPS in CIC. This line of research will provide a mechanistic background to use context-dependent tACS to enhance cognitive control in drug craving to improve long term drug addiction treatment outcomes.

B. Significance:

This study combines an active intervention with behavioral and neuroimaging assessments in people suffering from OUD, a target population in the US with extensive need for new treatment options. tACS involves simple and low-cost technology without any significant side effects that is largely scalable as a potential non-invasive therapeutic tool to help people during addiction recovery. Results will help provide a mechanism for how transcranial electrical current interventions can affect neurocognitive processes involved in drug addiction with the long-term goal of improving treatment outcomes.