Development of Adaptive Deep Brain Stimulation for OCD

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.

Inclusion Criteria:

- OCD DBS Subject Inclusion criteria:

1. Signed informed consent prior to any study specific procedures being performed

2. Male or female between ages 21 and 70;

3. At least a five-year history of treatment-refractory OCD that causes substantial
subjective distress and impairment in functioning;

4. Y-BOCS minimum score of 28;

5. Failed an adequate trial of at least three of the following SSRIs:

Fluoxetine; fluvoxamine; citalopram; escitalopram; sertraline; paroxetine;

6. Failed an adequate trial of clomipramine;

7. Failed augmentation of one or more of the aforementioned drugs with at least one
of the following antipsychotics: haloperidol; risperidone; quetiapine;
ziprasidone; aripiprazole;

8. Failed an adequate trial of CBT for OCD, defined as 25 hours of documented
exposure and response prevention (ERP) by an expert therapist;

9. Stable psychotropic medical regimen for the month preceding surgery

- Non-Implanted Control Subject Inclusion criteria:

1. Signed informed consent prior to any study specific procedures being performed

2. Male or female between ages 21 and 70

- Implanted ET Subject Inclusion criteria:

1. Signed informed consent prior to any study specific procedures being performed

2. Male or female between ages 21 and 70

3. Diagnosed with Essential Tremor (ET) chronically, EXCLUDING head tremor, and
implanted with DBS

Exclusion Criteria:

- OCD DBS Subject Exclusion criteria:

1. Inability or refusal to give informed consent.

2. Lifetime diagnosis of psychotic disorders such as schizophrenia;

3. Alcohol or substance abuse/dependence within 6 months, excluding nicotine;

4. Deemed at high risk of suicidal behavior or impulsivity, per clinical opinion
assessments.

5. Any Neurological/Medical condition that makes the subject, in the opinion of the
surgeon, a poor candidate.

6. Pregnant (confirmed by serum pregnancy test on females of child bearing age) or
plans to become pregnant in the next 24 months.

7. Need for Diathermy

8. Contraindications to MRI

- Non-Implanted Control Subject Exclusion criteria:

1. Inability or refusal to give informed consent.

2. Lifetime diagnosis of mental illness

3. A score of 8 or greater on part B of the Florida Obsessive Compulsive Inventory

4. Any neurological disorders (i.e., MS, Parkinson's Disease, seizure disorders,
etc.) or evidence of brain abnormalities/injury, such as tumor, stroke, or
traumatic brain injury

5. Pregnant (confirmed by self-report for females of child bearing age)

6. Contraindications to MRI

- Implanted ET Subject Exclusion criteria

1. ET subjects (with DBS implanted), WITH head tremor, may exacerbate artifact,
therefore they will be excluded.

2. Inability or refusal to give informed consent.

3. Lifetime diagnosis of mental illness

4. A score of 8 or greater on part B of the Florida Obsessive Compulsive Inventory

5. Any other neurological disorder other than ET (i.e., MS, Parkinson's Disease,
seizure disorders, etc.) or evidence of brain abnormalities/injury, such as
tumor, stroke, or traumatic brain injury

6. Contraindications to MRI