Deep Brain Stimulation for Addictive Disorders-Where Are We Now?

Abstract

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.

Keywords: Addiction; Animal models; Biomarkers; Deep brain stimulation; Neuromodulation; Neuropsychiatry.

Fig. 1

Biopsychosocial model depicting the different dimensions in consideration of addiction treatment. The stages of the addiction cycle of behavior are shown (inset) [140]. Interactions between components in different domains lead to addictive behaviors. Created with Biorender.com

Fig. 2

A simplified illustration of the neurotransmitters and neuroanatomical structures involved in the pathophysiology of addiction [13, 19, 20]. Other relevant areas are omitted for clarity. The effect of dopamine receptors D₁-R and D₂-R is shown in inset. D₁-R mediates the direct pathway (positive reinforcement) and D₂-R mediates the indirect pathway (negative reinforcement). Italic descriptions denote changes secondary to chronic drug use. 5-HT, serotonin; AMPAR, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor; D1/2R, dopamine 1/2 receptors; DA, dopamine; GABA, gamma aminobutyric acid; NAc, nucleus accumbens; NMDAR, N-methyl-d-aspartate receptor; VTA, ventral tegmental area. Created with Biorender.com

Fig. 3

Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow chart of literature search. Other sources include those found by reviewing the references from included papers

Fig. 4

Illustration of two most widely used experimental paradigms for the study of drug addiction in animals. On the left, conditioned place preference (CPP) is shown, where “non-contingent” drug-administration is associated with one side of the chamber during drug-side associated conditioning. If the drug is experienced as rewarding, the animal will spend more time in the drug-administered side relative to the other side, even in the absence of further drug administration. On the right, “contingent” drug self-administration paradigm allows the animal to regulate its own drug intake (e.g., via nose-poke or lever-pressing). A discrete light and/or tone cue may be provided in association with the drug intake to serve as a drug-associated cue. In extinction, the animal is placed back into the environment where CPP or self-administration is acquired but without drug availability. Extinction sessions lead to reduced place preference or drug seeking. During reinstatement, the drug, the drug-associated cue, and/or stress can be given, which can lead to “relapse” measured by preference or drug seeking. Created with Biorender.com