Correspondence

Deep Brain Stimulation of Nucleus Accumbens on Heroin-Seeking Behaviors: A Case Report

The present study examined the effect of deep brain stimulation (DBS) in the nucleus accumbens shell on cocaine seeking and neuronal plasticity in rats. Electrical DBS of the accumbens shell attenuated cocaine primed reinstatement across a range of frequencies as low as 12 Hz in male rats. Nucleus accumbens medium spiny neurons (MSNs) can be differentiated by expression of dopamine D1 receptors (D1DRs) or D2DRs. Low-frequency optogenetic-DBS in D1DR- or D2DR-containing neurons attenuated cocaine seeking in male but not female rats. In slice electrophysiology experiments, 12 Hz electrical stimulation evoked long term potentiation (LTP) in D1DR-MSNs and D2DR-MSNs from cocaine naive male and female rats. However, in cocaine-experienced rats, electrical and optical DBS only elicited LTP in D2DR-MSNs from male rats. These results suggest that low frequency DBS in the nucleus accumbens shell effectively, but sex-specifically, suppresses cocaine seeking, which may be associated with the reversal of synaptic plasticity deficits in D2DR-MSNs.

As the opioid epidemic presents an ever-expanding public health threat, there is a growing need to identify effective new treatments for opioid use disorder (OUD). OUD is characterized by a behavioral misallocation in choice behavior between opioids and other rewards, as opioid use leads to negative consequences, such as job loss, family neglect, and potential overdose. Preclinical models of addiction that incorporate choice behavior, as opposed to self-administration of a single drug reward, are needed to understand the neural circuits governing opioid choice. These choice models recapitulate scenarios that humans suffering from OUD encounter in their daily lives. Indeed, patients with substance use disorders (SUDs) exhibit a propensity to choose drug under certain conditions. While most preclinical addiction models have focused on relapse as the outcome measure, our data suggest that choice is an independent metric of addiction severity, perhaps relating to loss of cognitive control over choice, as opposed to excessive motivational drive to seek drugs during relapse. In this review, we examine both preclinical and clinical literature on choice behavior for drugs, with a focus on opioids, and the neural circuits that mediate drug choice versus relapse. We argue that preclinical models of opioid choice are needed to identify promising new avenues for OUD therapy that are translationally relevant. Both forward and reverse translation will be necessary to identify novel treatment interventions.

This article is part of the Special Issue on “Opioid-induced changes in addiction and pain circuits”.

Opioid use disorder (OUD) is a chronic and complex disease characterized by repeated relapses and remissions. Deep brain stimulation (DBS) has been discussed again and again as a potentially helpful neuromodulatory procedure in this context. In this review, for the first time, we intended to systematically identify the positive and negative effects of DBS in human and animal models of opioid dependence to assess the viability of DBS as a treatment of OUD. Eligible studies were incorporated by a comprehensive literature search and evaluated through proper methodological quality assessment tools. Findings showed that the nucleus accumbens was the most stimulated brain target in human and animal studies, and DBS was applied chiefly in the form of high-frequency stimulation (HFS). DBS administration effectively reduced opioid craving and consumption in human and animal subjects dependent on opioids. DBS represents a valuable alternative strategy for treating intractable opioid addiction. Based on our systematic literature analysis, research efforts in this field should be continued.

In the face of a global epidemic of drug addiction, neglecting to develop new effective therapies will perpetuate the staggering human and economic costs of substance use. This review aims to summarize and evaluate the preclinical and clinical studies of deep brain stimulation (DBS) as a novel therapy for refractory addiction, in hopes to engage and inform future research in this promising novel treatment avenue. An electronic database search (MEDLINE, EMBASE, Cochrane library) was performed using keywords and predefined inclusion criteria between 1974 and 6/18/2021 (registered on Open Science Registry). Selected articles were reviewed in full text and key details were summarized and analyzed to understand DBS' therapeutic potential and possible mechanisms of action. The search yielded 25 animal and 22 human studies. Animal studies showed that DBS of targets such as nucleus accumbens (NAc), insula, and subthalamic nucleus reduces drug use and seeking. All human studies were case series/reports (level 4/5 evidence), mostly targeting the NAc with generally positive outcomes. From the limited evidence in the literature, DBS, particularly of the NAc, appears to be a reasonable last resort option for refractory addictive disorders. We propose that future research in objective electrophysiological (e.g., local field potentials) and neurochemical (e.g., extracellular dopamine levels) biomarkers would assist monitoring the progress of treatment and developing a closed-loop DBS system. Preclinical literature also highlighted the prefrontal cortex as a promising DBS target, which should be explored in human research.

While pharmacological and/or behavioral treatments are effective in managing symptoms for many patients with psychiatric diagnoses and disorders with behavioral/cognitive manifestations, a subset of individuals are treatment-refractory, unable to achieve appreciable benefit or symptom relief from traditional methods. In recent years, neuromodulation has gained momentum as an adjunctive treatment for improving outcomes in patients who are treatment-refractory. One form of neuromodulation, deep brain stimulation (DBS), has been investigated for the treatment of various psychiatric disorders and behavioral/cognitive symptoms. The following article provides a review of DBS investigations for several psychiatric and behavioral-related disorders, including depression, obsessive-compulsive disorder, substance use disorder, Alzheimer's disease, anorexia, obesity, schizophrenia, and posttraumatic stress disorder. PubMed, PsycINFO, Scopus, Ovid MEDLINE, and Web of Science were used to identify published articles, and Clinicaltrials.gov was used to identify currently ongoing or planned studies. Findings revealed the potential utility of DBS in improving outcomes for various psychiatric and behavioral/cognitive-related disorders. While promising, there are several limitations present in the available literature, and further well-designed clinical trials are necessary before conclusive decisions regarding the utility of DBS for the treatment of these psychiatric/behavioral/cognitive-related disorders can be made. Regardless, the studies included in this review demonstrate positive preliminary findings for the potential benefit of DBS for treatment of a variety of psychiatric disorders, and further research is warranted to better determine the potential utility of DBS for those who are treatment-refractory and unable to achieve symptom relief with standard care.

Substance addiction encompasses the incapacity to discontinue urgent drug use; many severely disabled patients might be considered appropriate candidates for surgery due to the high rates of relapse despite conservative treatment. A crucial finding in the brain of these patients is increased extracellular concentrations of dopamine in the nucleus accumbens (NAcc).

To determine the efficacy and safety of NAcc surgery for the treatment of substance dependence.

Adhering to PRISMA guidelines, we performed a systematic review to identify all original studies in which NAcc surgery was performed to treat relapsing drug addiction with a minimum follow-up of six months. From database inception to April 10, 2020, we searched PubMed, Scopus, and LILACS. Two reviewers independently selected studies and extracted data. The main outcome was the relapse rate. The GRADE methods were applied to evaluate the quality of evidence. This study was registered with PROSPERO CRD42020177054.

Fifteen studies involving 359 participants met inclusion criteria; eight (56%) included NAcc deep brain stimulation (DBS) in 13 patients with addiction for alcohol (N = 6, 46.1%), opioid (N = 4, 30.7%), and nicotine (N = 3, 15.3%); seven studies (N = 346, 44%) performed NAcc radiofrequency (RF) ablation for opioid (N = 334) and alcohol (N = 12) dependence. Relapse rates were 38.4% for DBS and 39% for RF ablation.

Despite available studies reporting a benefit in the treatment of drug addictions with NAcc surgery, this systematic review stresses the need for carefully planned prospective studies in order to further address the efficacy and indications.