Deep Brain Stimulation for Patients with Treatment-Resistant Obsessive Compulsive Disorder: Identifying electrophysiological biomarkers

The study will consist of 5 different phases including: 1. Baseline (assessment and pre-surgery) 2 Surgery & Randomisation 3 Recovery (day 1 post-surgery to 1 month post-surgery) 4 Double blind phase (1 month post-surgery to 4 months post-surgery) 5 Open label phase (4 months post-surgery to 24 months post-surgery) Baseline: Participants are assessed by 2 neuropsychiatrists and their eligibility for Deep Brain Stimulation (DBS) is considered by an independent mental health review tribunal. Successful participants are enrolled in the trial and complete the following: Neuropsychological rating scales Magnetic resonance imaging (MRI) brain scan Electroencephalography (EEG) Computerised reward task (Monetary Incentive Delay task) Computerised symptom provocation (International Affective Picture Scale) Surgery & Randomisation: At surgery, patients are implanted with the Activa PC+S (Medtronic, Minneapolis, USA) device. Product description is as follows: The Model 37604 Activa PC+S system is a multiprogrammable device that both delivers electrical stimulation and records bioelectric data through one or two leads implanted in the brain. Activa PC+S electrical stimulation is based on the Model 37610 Activa PC neurostimulator but adds the functionality of bioelectrical data recording (sensing). Activa PC and Activa PC+S share the same therapy and form factor. There are no new tissue contacting materials in the Activa PC+S. Stimulation is provided by controlled delivery of current from a battery in an implantable neurostimulator (INS) to metal electrodes surgically implanted in the brain in the same manner as ACTIVA PC. The INS is typically placed in the pectoral location. Current is conducted to the electrodes via electrical conduits, including extensions and leads, which are tunnelled sub dermally through the neck, travel through the skull, and terminate in a neural structure appropriate to the neurological disease being treated. Like Activa PC, The Active PC+S system is capable of providing stimulation to 2 leads, each with 4 electrode contacts. Stimulation parameters are adjusted to optimise therapy for the patient. They can be independently controlled and include the following: active electrodes(s), electrode polarity, pulse, width, amplitude, and frequency. The stimulation settings are stored in programs. A program is a specific combination of pulse width, rate and amplitude settings acting on a specific electrode combination on a lead, or on a lead and the INS, in unipolar mode. Up to four programs can be combined into a group. Pulse width, amplitude and electrode polarity are independently programmed for each program within a group. Rate, rate limits and cycling for each program within a group must have the same values. Stimulation is delivered to a maximum of two implanted leads (one lead per hemisphere), with a maximum of 4 electrodes per lead. Rate is limited to 250 Hz, pulse width is limited to 450 micro-sec, amplitude is limited to 10.5 V (or 22.5 mA) and the charge density warning threshold is 30 micro-Coulomb/cm^2/phase. Stimulation programs are controlled by the clinician via the N'Vision Clinician Programmer. Sensing functions. The recording of bioelectric data is controlled by a separate sensing clinician programmer. The total procedure is approximately 3.5 hours in duration. Patients are woken intra-operatively to complete the following tasks: Computerised reward task (Monetary Incentive Delay task) Computerised symptom provocation (International Affective Picture Scale) Randomisation to ON or OFF stimulation in the blinded phase will occur at this time point in a 50:50 ratio. Randomisation will take place externally and allocation will be concealed from participants and investigators, excepting those responsible for DBS programming. Recovery: Participants are assessed fortnightly during the recovery phase and will complete: Neuropsychological rating scales Computerised reward task (Monetary Incentive Delay task) Computerised symptom provocation (International Affective Picture Scale) Neuronal recordings Double Blind Phase Participants are initially assessed weekly and this will increase to fortnightly. They will complete: Neuropsychological rating scales Computerised reward task (Monetary Incentive Delay task) Computerised symptom provocation (International Affective Picture Scale) Participants randomised into the ON stimulation group will begin active treatment during this phase. Active treatment is continuous stimulation. This will commence using predetermined stimulation parameters with increments at each visit according to a titration protocol, with regard to prevailing symptoms. Those participants in the OFF stimulation group will receive sham treatment during this phase. Open Label Phase Participants will initially be assessed fortnightly and this will increase in increments to a maximum of 3-monthly. They will complete: Neuropsychological rating scales Computerised reward task (Monetary Incentive Delay task) Computerised symptom provocation (International Affective Picture Scale) Neuronal recordings Cognitive behavioural therapy (CBT) All participants will receive active treatment during this phase. Active treatment is continuous stimulation. Stimulation parameters may be adjusted at each visit, with regard to prevailing symptoms. Further information on data collected at each visit is described below: Neuropsychological rating scales 1 Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) – A 10 item scale, administered as a semi structured interview for assessing the severity of obsessions and compulsions. This test is considered the “gold standard” for rating OCD. Each item is rated on a 5 point severity scale (0-4), giving a maximum total score of 40. Scores above 24 are considered “severe”. Assessments will be completed at Visit 1,2,6,7,10,12,14,17,19, 21, 23-28. 2 Vancouver Obsessive-Compulsive Inventory (VOCI), a self-report questionnaire comprised of six subscales, including Contamination (12 items), Checking (6 items), Obsessions (12 items), Hoarding (7 items), Just Right (12 items), and Indecisiveness (6 items). Assessments will be completed from Visit 1,2,6,7,10,12,14,17,19, 21, 23-28. 3 Montgomery-Asberg Depression Rating Scale - A 10 item rating scale, completed by the clinician for assessing overall depression severity. Assessments will be completed at Visit 1,2,6,7,10,12,14,17,19, 21, 23-28. 4 Spielberger State-trait Anxiety Inventory (STA-I) – For assessing comorbid anxiety symptoms. Assessments will be completed at Visit 1,2,6,7,10,12,14,17,19, 21, 23-28. 5 Clinical Global Impression (CGI) – The raters’ clinical impression of the patient’s condition, rated on a 7-point scale. Assessments will be completed at Visit 1,2,6,7,10,12,14,17,19, 21, 23-28. 6 NEO-Five Factor Inventory (NEO-FFI-3) – a 60-item measure of the personality traits of Extraversion, Agreeableness, Conscientiousness, Neuroticism and Openness to Experience. Assessments will be completed at Visit 1,2, 19, 24, 28. 7 Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q-SF) – a 16 item self-report measure of enjoyment and satisfaction in the past week. Assessments will be completed at Visit 1,2, 19, 24, 28. 8 Assessment of tics - We will administer a brief, 8-item, screening questionnaire to ascertain the presence of tics, either currently or in the past. If patient is clinically judged to have tics as per this brief screen, then the Yale Global Tic Severity Scale (YGTSS) will be administered. Assessments will be completed at Visit 1 and not thereafter if there are no tics. If Tics, then at 1,2,6,7,10,12,14,17,19, 21, 23-28. 9 YGTSS (Yale Global Tic Severity Scale) - This is a validated, standardized rating scale for motor and phonic tics, yielding a total possible tic severity score of 50 and a total possible functional tic-related impairment score of 50, for a final total possible score of 100. Higher scores indicate a greater number and severity of tics and a higher degree of functional impairment. Assessments will be completed at Visit 1 and not thereafter if there are no tics. If Tics, then at 1,2,6,7,10,12,14,17,19, 21, 23-28. Neuronal Recordings Local field potentials from the implanted DBS electrodes are recorded directly during postoperative visits at rest and during the performance of the computerised tasks below. Additionally, the device is programmed to record short (30 second) field potentials every 12 hours between visits. This data is subsequently downloaded at each scheduled assessment. Computerised Tasks Computerised Symptom Provocation Patients view a series of images with neutral, negative or positive emotional connotations. The images are chosen from a standardised image database called the International Affective Picture System (IAPS). Each patient in the cohort for this clinical trial has different emotional triggers salient to their specific obsessions, so for our purposes, these images are divided into 18 different categories with different emotional significance. Images are chosen randomly from each category. At the start of each image trial, the image is displayed. Inter-trial interval is 3 seconds for the MRI condition to allow a short time for separability of BOLD responses, and 0 seconds for the other conditions. Monetary Incentive Delay Task The ‘Monetary Incentive Delay’ (MID) task has been used in a large number of brain-imaging studies. This task has been used to implicate the striatum in the neural response to anticipation of reward delivery. In the task, subjects see a cue that indicates the amount of monetary reward or loss at stake on a given trial, followed by a target to which they must make a speeded response, followed, finally, by feedback indicating whether or not they received the reward or lost money. Participants undertake these tasks at all stages of the trial. At baseline the trials are additionally conducted during functional MRI imaging and EEG. They are conducted during surgery. Post-operatively the tasks are conducted during recording of neuronal activity from the DBS device. The total duration of the tasks is determined by the number of trial blocks, but typically takes approximately 20 minutes to complete. The intraoperative task is much shorter (5 minutes). The tasks will be conducted during the imaging assessments and intraoperatively to investigate patterns of electrophysiological brain activity with specific focus on the nucleus accumbens (NAcc). These two measures will provide detailed information on the response of the patients to specific reward stimuli and we will be able to assess the impact of DBS protocols on this activity to subsequently correlate with clinical outcome. Cognitive Behavioural Therapy: Participants will receive 8-12 individual OCD-oriented CBT sessions with a clinical psychologist with expertise in OCD, using the principles of exposure and response prevention. The duration of these sessions will be approximately 1 hour. CBT will commence during the open label phase when the response to active treatment with neurostimulation has plateaued (3 consecutive Yale-Brown Obsessive-Compulsive Scale scores within 3 point range). Sessions will be initially weekly and will extend to fortnightly and then monthly depending on patient response. Adherence will be monitored as part of the trial protocol using a register. The CBT sessions will include assessments and therapy with the device switched on. Cognitive Behaviour Therapy (CBT) is a relatively short term, focused approach to the treatment of many types of emotional, behavioural and psychiatric problems. The application of CBT varies according to the problem being addressed, but is essentially a collaborative and individualized program that helps individuals to identify unhelpful thoughts and behaviours and learn or re-learn healthier skills and habits.