Development of Adaptive Deep Brain Stimulation for OCD (Phase 1a)

RECRUITMENT:

Potential participants will be referred to our program by their treating clinicians, who will be made aware of our study through direct clinician-clinician letters and emails. Subjects may also learn of the study through consumer advocacy groups such as the International OCD Foundation (IOCDF), local non-profit organizations and local support group meetings and through the normals avenues that they share information.

ENROLLMENT:

A subject is considered enrolled upon signing informed consent, deemed eligible to be screened by the investigator. Decision-making capacity, which includes understanding, appreciation, reasoning and ability to express a choice, will be assessed as part of the informed consent process. The informed consent process will include discussions with the patient's family and referring clinician. Medical records will be carefully reviewed to determine adequacy of past treatments including CBT.

SCREENING:

Potential subjects meeting inclusion/exclusion criteria and willing to participate in the study as demonstrated by signing the informed consent will be enrolled in the study and undergo screening.

After the participant signs the required documents, he/she will undergo two baseline evaluations spaced over an approximate 1 month period. Diagnostic and screening ratings are completed, followed by complete medical, neurological and neurosurgical evaluations. The raters will be trained and certified in the use of the clinician-administered scales of the study. The purpose of the screening evaluations is to demonstrate that subject is in a stable clinical situation including a stable medical regimen, and are severely symptomatic. If this is the case, and they continue to meet inclusion/exclusion criteria, the participant will proceed to treatment (surgery to implant the DBS system. Final selection of candidates will be made by consensus of the multi-disciplinary investigator team ("Project Advisory Committee").

TREATMENT:

Subjects treated in Phase 1a will undergo a single stage DBS surgery, in which bilateral deep brain leads will be implanted under conscious sedation, followed by implantation of a single Implantable NeuroStimulator (INS), Activa PC+S, under general anesthesia.

1. A head CT will be performed on the morning of surgery for stereotactic planning.
2. Employing local anesthetic (with or without sedation as clinically indicated), a stereotactic headframe (Leksell Model G, Elekta Instruments, Atlanta, GA, USA) will be attached to the subject's skull on the morning of surgery in the operating room.
3. A 3D volumetric image (O-Arm 2, Medtronic Inc,, Boulder, CO, USA) will be performed for purposes of defining the volumetric stereotactic headspace.
4. The images will be uploaded onto a Computer Workstation (Stealth S7, Medtronic, Inc., Boulder, CO, USA) equipped with stereotactic planning software (Cranial 3.0) for the purpose of planning the surgery. The preoperative 3T MRI obtained prior to the surgical date, will be fused with the CT scan in the surgical planning station. The initial target point within the ventral striatum will be chosen based on the subject's specific anatomy. The surgical trajectory to this point will also be planned in order to avoid prominent vessels, the sulci, and the ventricles. The computer will generate the X, Y and Z coordinates to set on the frame as well as the coronal and sagittal angles of approach required to establish the desired trajectory and target point. This initial target point will be modified by the subject's specific anatomy as determined by the preoperative 3T MRI. The final target coordinates will be determined during this analysis.
5. While the surgeon is planning the procedure, the subject will be positioned supine on the operating table. A Foley catheter will be inserted. Antibiotics will be administered intravenously and vital signs will be monitored. The stereotactic head frame will be fixed to the operating table for subject safety, with the head elevated for subject comfort. A sterile prep and drape will be performed.
6. The target coordinates will be set on the stereotactic frame bringing the target point to the center of the operating arc. Additional local anesthetic will be given at the point of incision. Following incision, a 14 mm burr hole will be made employing a self-stopping perforator. The burr hole cap provided with the DBS lead will be secured to the skull with two screws. The dura will be coagulated and incised. The pial surface will be gently coagulated and a small incision will be made to allow easy entry of the electrode guides, which will be inserted to the brain according to standard stereotactic protocol.
7. A microelectrode (MER) probe will be inserted through the cannula and advanced in sub mm steps until the target is reached. Intraoperative image guidance will be obtained to ensure the MER probe is not mechanically deviated from target. If a deviation is identified, the stereotactic headframe will be adjusted accordingly.
8. Once the above adjustments have been made, the DBS quadripolar electrode (model 3387; Medtronic Inc., Minneapolis, MN, USA) will be inserted through the guide tube to the target point. Reticles will be attached to the frame and intraoperative imaging will be employed to confirm that the lead tip is positioned at the target and assess for the presence of intracerebral hemorrhage. Sedation will be withdrawn. An extension cable will be connected to the lead sterilely and the other end will be passed off the field to be connected to an external pulse generator so that test stimulation may be performed. Test stimulation will be performed via each contact to 1) assess for stimulation-induced side effects and 2) monitor for acute changes in behavior using a Likert-type scale to assess anxiety, arousal, and mood.
9. Intra-operative X-ray imaging may be performed as needed (up to 4 times per side) to ensure proper target has been reached.
10. A post-implantation 3D volumetric scan will be performed to confirm the electrode position.
11. Intra operative MER and behavioral testing of Stimulation with AFAR video recording will be performed.
12. Steps 5-9 above will be performed to insert the second electrode on the other side of the brain to complete implantation of both electrodes.
13. If there are no untenable side effects, the leads will be secured to the skull with the burr hole caps. The free end of the leads will be left in the sub-galeal space and the incisions will be closed in anatomical layers.
14. The headframe will be removed and general anesthesia will be induced. The Activa PC+S pulse generator will then be implanted and connected to the brain lead via extension cables.
15. A post-operative CT scan will be performed prior to discharge -to ensure that an intracerebral hemorrhage has not occurred.
16. The subject will be taken to the Recovery Room or the Neurosurgery ICU for post-operative monitoring (See below) and will be discharged from the hospital after at least one night of observation and when clinically stable. A Basic Metabolic Panel (BMP) may be run on the subject to confirm they are clinically stable.
17. The subject will return to the neurosurgery clinic (Visit 4) for post-operative evaluation according to normal clinical practice (approx 1 week after surgery). The wounds will be inspected and the subject's neurological status will be assessed. Sutures will be removed.

The subject will return to clinic about 2 weeks post-surgery for their post-surgical psychiatric symptom baseline and recording visit (Visit 5). Programming of the DBS device will occur at Visit 6, 1 week later.

The subject will return to clinic every 2 weeks for the first 2 months following the system activation. Each visit will last about 3-4 hours and will include clinician administered assessments, self-rated assessments, recordings and tasks to be performed.

Post-surgical 1.5 rs-fMRI scans will also be performed according to Medtronic standard post-implant MRI guidelines for deep brain stimulation systems to ensure safety.

Participants will be asked to keep their current medications constant for the first 6 months post-surgery. However, clinical circumstances which mandate changes will be allowed and notated should this occur.

Provocation Tasks:

The Provocation OC task (Provoc) and the Trier Social Stress Test (TSST) will be used to start OC-related distress and distress unrelated to OCD (e.g., performance anxiety), respectively. Three sessions will be videotaped with Automated Facial Affect Recognition (AFAR) system concurrent to recording of local field potentials (LFPs) from VS and scalp electroencephalography (EEG).

CBT Augmentation:

Starting at Month 7, subjects will receive a two-month (15 session) cognitive behavioral therapy (CBT) course where exposure and response prevention (ERP) for OCD will be delivered. Subjects already receiving stable CBT will be allowed to continue it during the study. Instead, we have developed standardized instructions to encourage exposure and resist compulsions (ERP) during this portion of the trial. Participants will be encouraged at study visits to actively confront OC triggers while refraining from ritual engagement. Subjects, especially those who are still habitually avoiding, will be given the opportunity to derive maximal clinical benefit by receiving a two-month "refresher" course of CBT prior to entering the double-blind discontinuation phase at 9 months.

Double Blinded Discontinuation:

The purpose of the one-month blinded discontinuation period is to confirm clinical benefit. At the end of month 8, subjects will enter a one-month delayed onset withdrawal period in which the subject and Independent Evaluators are blinded to timing of discontinuation. The decision whether to reinstate active DBS at the end of the discontinuation will be based on clinical considerations in discussion with the subject and significant others. The benefits and discomforts will be carefully weighed in arriving at a long-term plan. Escape criteria will include withdrawing consent or significant clinical deterioration warranting unblinding or reinstatement of treatment. Following exit from the discontinuation period, treatment will recommence as clinically indicated, including stimulation resumption or continued observation with the device off.

Monthly Programming/Classification/Evaluation Visits until End of Study (EOS):

Months 10-18 (Visits 20-28) - Following exit from the discontinuation phase based on clinical indication, treatment will recommence as clinically indicated around Month 10, including stimulation resumption or continued observation with device off. Refining state classifications and testing machine learning will continue, if stimulation is reinstated. Subjects that participated in the discontinuation phase will be considered off-treatment once Month 18 visit (Visit 298) has occurred.These visits will take place monthly for 9 months. Each visit will last approximately 3-4 hours.

Long-Term Follow-Up:

After the 18 months of the study, the device will remain implanted in those subjects who are doing well clinically. For subjects who are not responsive, it will be explanted, if the surgical risks of explantation are deemed acceptable by the treatment team. The follow-up management will be arranged on a case-by-case basis, depending on geographic location and desires of the subject, and DBS therapy management by our team will be guaranteed for at least two years if subjects continue to receive DBS therapy and do not arrange alternative management during that period. Attempts will be made to collect all device-related adverse events in all willing participants at 6-month intervals after they exit the currently proposed study.

Subject participation is anticipated to continue for a minimum of 18 months.