In vivo human addiction biomarkers: towards closed loop deep brain stimulation

Disorders of addiction like alcohol and opioid use disorder are major public health issues with marked morbidity, mortality and financial burden. Many remain refractory to treatment. Addiction disorders are characterized by abnormal brain networks. This study proposes to use neurosurgical procedure, deep brain stimulation, designed to deliver stimulation to change brain networks, with longstanding established safety and therapeutic efficacy for movement disorders and obsessive-compulsive disorder. Here we propose a deep brain stimulation study in treatment refractory alcohol and opioid use disorder, targeting the nucleus accumbens and ventral internal capsule. Stimulation of these brain regions is potentially effective in drug addictions.

This proposal focuses on theoretical mechanisms underlying addictions recording directly from deep brain structures and the ability to modify core addiction processes in a personalised manner. We assess the neurophysiology of incentive cues and negative emotionality underlying cue- and stress-induced relapse. We track these process over the course of abstinence and link them with other core addiction cognitive processes including impulse control and behavioural flexibility. We ask how these processes are influenced by key neurochemicals relevant to addictions. Critically, we then ask how stimulation treatment might influence neurophysiology, networks and behaviour with the goal to identify stimulation-responsive specific biomarkers. This leads us towards the development of closed-loop responsive neurostimulation and real-time feedback for behavioural regulation in the treatment of a relapsing remitting illness. We further assess the potential therapeutic efficacy of deep brain stimulation for addiction in a pilot randomized controlled trial.

Together these studies provide novel direct mechanistic insights of core theoretical mechanisms of addictions in the living human brain with immediate therapeutic impact leading to the emerging potential for precise responsive neuromodulation.

Drug and alcohol addictions are major public health issues; yet, existing therapeutic approaches show high treatment refractoriness. Addictions are disorders of brain networks. Deep brain stimulation (DBS) is a relatively safe potentially reversible neurosurgical procedure that modifies brain networks and is effective for movement disorders and obsessive-compulsive disorder. Case series show potential DBS efficacy for drug addictions. Critically, the DBS procedure also allows capture of in vivo neurophysiological measures, allowing for anatomically precise direct studies of disease processes in a human model.

We propose a theory-driven multidisciplinary study using DBS in treatment refractory alcohol and opioid use disorder targeting the nucleus accumbens and ventral internal capsule. We address core theoretical mechanisms underlying disorders of addiction using direct in vivo recordings of the nucleus accumbens and prefrontal network connectivity. We examine the role of incentive cues and negative emotion, their longitudinal role during abstinence and relationship with addiction-related cognitive processes and underlying neurochemistry. We then address the causal role of time-locked and chronic stimulation on neurophysiology and behaviour to identify stimulation-responsive specific biomarkers. We will begin to develop closed loop feedback stimulation and behavioural regulation targeting these biomarkers. Finally, we assess the potential therapeutic efficacy of DBS for addiction in a pilot randomized controlled trial.

Together these studies provide novel direct in vivo mechanistic insights of core theoretical mechanisms of addictions in the living human brain with immediate translational therapeutic impact leading to the emerging potential for precise efficient responsive neuromodulation.