Deep Brain Stimulation for Treatment-Refractory Obsessive-Compulsive Disorder: Understanding the Mechanism of Action.

Participants with severe, treatment-refractory obsessive-compulsive disorder (OCD) will be implanted with Medtronic electrodes bilaterally in the bed nucleus of the stria terminalis (BNST). The Medtronic Model B35200 Percept PC Neurostimulator is part of an active implantable device system for deep brain stimulation and brain sensing. The DBS system delivers electrical stimulation to targeted regions of the brain to suppress symptoms associated with a neurological or psychiatric disorder. The neurostimulator generates electrical current that is conducted through DBS extensions and leads to the implanted electrodes. The electrical current leaves the electrodes and interacts with the targeted brain tissue to achieve the desired effect. The Medtronic Percept PC Neurostimulator is approved by the Australian Therapeutic Goods Association for the treatment of obsessive-compulsive disorder. Electrodes will be placed in the BNST in a neurosurgical procedure, led by a specialist neurosurgeon and neurologist, and connected to an implantable pulse generator. Over the following six months, electrical stimulation will be titrated in the BNST by a neuropsychiatrist with 10 years of experience in deep brain stimulation. Stimulation will be titrated in an identical manner for all participants. In each hemisphere, the active contact will be selected based upon postoperative imaging, which will identify the contact closest to the bed nucleus of the stria terminalis. Stimulation will be commenced at 1.5 Volts bilaterally in a monopolar configuration, with a pulse width of 90 microseconds and a frequency of 130 Hertz. Stimulation amplitude will initially be increased by 0.5 Volts weekly to a maximum of 5 Volts, with the final stimulation amplitude determined by clinical response and the emergence of adverse effects. If negligible clinical benefit is observed at this maximum amplitude, a second adjacent contact will be activated and following a further assessment interval the pulse width will be increased to a maximum of 120 microseconds. If intolerable side effects during the initial titration of stimulation limit further increases in the stimulation amplitude and clinical benefit is not forthcoming, then the pulse width will be reduced to 60 microseconds and titration will be re-attempted. Postoperative neuroimaging of the electrodes will be used to inform the choice of the optimal contact on each electrode. The primary target guiding stimulation adjustment will be reduction of OCD symptoms as assessed by the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS), a validated semi-structured interview rating OCD symptom severity. Once participants have accrued a stable response to stimulation (reduced Y-BOCS score of at least 30% from baseline), they will receive a manualised course (10-12 weekly sessions) of exposure-oriented psychotherapy with a clinical psychologist trained in this modality of therapy. The manual is designed specifically for this study. Twelve months after stimulation commencement, participants will enter a counterbalanced, randomised, double-blind, sham-controlled crossover phase during which time each participant will receive a month ‘on’ and a month ‘off’ stimulation in random order before resuming open-label therapy. The primary outcome will be the difference in Y-BOCS between treatment periods. Participants and those clinicians completing rating scales will be blinded to treatment allocation. The purpose of this crossover phase is to directly compare clinical (Y-BOCS) and electrophysiological data with and without effective treatment. All participants will have their DBS device turned back on at the end of the crossover trial to continue open-label treatment. At baseline, prior to DBS device implantation, participants will undertake a functional brain scan during which brain activity will be measured at rest and during a symptom provocation task. In this task, participants will be presented with a set of images drawn from the International Affective Picture System, a database of stimuli designed to elicit attention and emotion. Alongside, positive and neutral pictures, each set of images will contain a number of pictures chosen to provoke discomfort in each participant according to their symptoms (e.g. a person with harm-oriented OCD will be shown images of a knife or blood). In the scanner, participants will rate the emotional valence of the picture from negative to positive on a Likert scale. Postoperatively, functional brain imaging will be repeated at three-monthly intervals: during DBS titration, before and after psychotherapy and finally monthly during each phase of the crossover trial. The purpose of the functional imaging is to understand how regional and network-wise brain activity changes in parallel with context (rest and symptom-induced) and with progressive symptom alleviation in severe OCD. Participants will attend weekly for a 60-minute one-on-one session of psychotherapy. Sessions will focus on the establishment of an exposure hierarchy (i.e. a list of anxiety-provoking situations from least to most distressing) tailored to the participant's OCD. Participants will be gradually guided through deliberate exposure to these anxiety-provoking situations under the expectation that their anxiety will gradually reduce with repeated exposure. Recordings of electrophysiological signals from the implanted DBS lead will also be obtained in parallel with functional neuroimaging acquisition during symptom provocation in the MRI scanner: during DBS titration, before and after psychotherapy and then during each phase of the crossover trial. Recordings will occur whilst the participant ‘behaves’ in their natural environment, particularly during exposure to anxiety-provoking situations (e.g. a person with contamination-oriented OCD will be asked to touch a dirty surface and refrain from handwashing). The purpose of acquiring electrophysiological data is to understand how local neural activity changes in parallel with OCD symptom severity. Adherence to the protocol will be assessed through monitoring of the Case Report Forms (CRFs), which will be undertaken by the study sponsor QIMR Berghofer Medical Research Institute. A CRF will be completed at each attendance by the participant.