Combined Cortical/Subcortical Recording and Stimulation as a Circuit-Oriented Treatment for Obsessive-Compulsive Disorder

The goal of this proposal is to provide therapy to patients with severe, treatment-refractory
obsessive-compulsive disorder (OCD) by stimulating in two separate, but related, brain
regions, the dorsolateral prefrontal cortex (dlPFC) and the ventral anterior limb of the
internal capsule and adjacent ventral striatum (VC/VS) with a novel Medtronic PC+S deep brain
stimulation (DBS) system. While providing this DBS therapy, use of this new,
recording-capable device will allow collection of data about brain activity in these two
regions. This data will enable researchers to further elucidate the exact mechanisms of DBS
therapy, as well as the neuropathophyisiology of OCD. This study aims to 1) gather evidence
for corticostriatal changes in OCD in response to acute and chronic VC/VS DBS treatment and
2) specifically disrupt or enhance synchrony in the cortico-striato-thalamo-cortical (CSTC)
circuit.

Deep Brain stimulation involves bilateral stereotactic placement of stimulating "leads" into
specific brain structures. Leads are attached to permanent subcutaneous wires and
battery-powered implantable neurostimulators (INSs). Noninvasive INS programming can achieve
a balance between maximal benefit (reduction in disabling OCD symptoms), while minimizing
adverse effects (eg sensorimotor effects such as dysarthria or paresthesias; as well as
behavioral side effects, e.g., hypomania, insomnia, or increased anxiety). HDE approval was
granted in February 2009, and IDE approval was granted in February 2016. Multiple hospitals
around the country have established HDE protocols to implant patients with intractable OCD
who have failed conventional therapies, and some hospitals, like us, have obtained
Investigational Device Exemption (IDE) approval to conduct pilot clinical trials. The
existing model of DBS for OCD only addresses one aspect of the brain circuit implicated in
the CSTC circuit, the VC/VS target. Therapy with this device, under this protocol, will also
be able to provide stimulation to the cortical part of this circuit. Single-site VC/VS DBS
may not adequately target the putative circuit. If OCD symptoms do arise from CSTC loop
dysfunction, this implies that the problem is one of improper information flow between
connected brain areas. Thus, modifying circuit activity may require coordinated intervention
at multiple points to effectively synchronize or de-synchronize the full loop. Stimulation
that specifically interrupts reverberant activity between prefrontal cortex and striatum will
be superior to VC/VS DBS alone at relieving symptoms of OCD. We will test this by
simultaneously implanting stimulating/recording electrodes at both VC/VS and a dorsolateral
prefrontal cortex (dlPFC) target bilaterally.

Inclusion Criteria:

1. OCD, diagnosed by Structured Clinical Interview for DSM-5 (SCID-5), judged of
disabling severity with a Yale-Brown Obsessive Compulsive Scale (YBOCS) score of at
least 28.

2. Persistence of severe symptoms and impairment for five or more years despite: i. at
least three adequate (≥3 months at the maximum tolerated dose) serotonin transporter
inhibitor trials (may use any serotonin or serotonin-norepinephrine inhibitors, but
must include a trial of clomipramine) alone or in combination with ii. adequate
behavior therapy (≥20 sessions of expert exposure and response prevention; At least 20
sessions of behavioral therapy must be attempted), and iii. augmentation of one of the
selective SRIs with a neuroleptic or clonazepam.

3. Age between 21 and 64 years.

4. Able to understand and comply with instructions.

5. Able to give fully informed, written consent in the judgment of the site Consent
Monitor.

6. Either drug free or on a stable drug regimen for at least 6 weeks.

7. Good general health.

8. A family member or significant other, in contact with the patient every 1-3 days, is
available and willing to communicate with the research team if the patient's clinical
status worsens, and if necessary to accompany patients to study visits.

9. The local referring psychiatrist is willing to provide ongoing care during and after
the trial.

10. Patient is aware of, able to adhere to, and willing to tolerate the frequency of
visits associated with adjustment of the dual-stimulation configuration and/or
collection of brain recordings. This will usually mean limitation to patients who live
close to the study site.

11. Platelet count greater than 125,000 per cubic millimeter and a PT and PTT within
normal limits.

Exclusion Criteria:

1. Current or past psychotic disorder.

2. Full-scale IQ below 75 on the Wechsler Abbreviated Scale of Intelligence (WAIS) or
cognitive impairment that would affect a participant's ability to give informed
consent or provide interview or self-report data reliably, as determined by the
consent monitor and the site psychiatrist. A questionnaire assessing consent
comprehension will be used with all study subjects, to ensure that they understand the
key procedures of the study, and its risks and benefits. An independent monitor will
administer that questionnaire.

3. A clinical history of bipolar mood disorder. We will not exclude substance-induced
mania or hypomania.

In our prior studies, a history of induced hypomanic symptoms did not predict
DBS-related hypomania.

4. Any current clinically significant neurological disorder or medical illness affecting
brain function, other than tic disorders or Tourette syndrome.

5. Any clinically significant abnormality on preoperative magnetic resonance imaging
(MRI).

6. Any labeled DBS contraindication and/or inability to undergo presurgical MRI (cardiac
pacemaker, pregnancy, metal in body, severe claustrophobia), infection, coagulopathy,
inability to undergo an awake operation, significant cardiac or other medical risk
factors for surgery.

7. Current or unstably remitted substance abuse, dependence, or a positive urine
toxicology screen.

8. Pregnancy and women of childbearing age not using effective contraception.

9. Unable to adhere to operational and administrative study requirements (in the
investigators' judgment).

10. Clinical history of severe personality disorder.

11. Imminent risk of suicide or an inability to control suicide attempts (in the
investigators' judgment).

History of serious suicidal behavior or one or more interrupted suicide attempts with
potential lethality judged to result in serious injury or death.

12. Diagnosis of body dysmorphic or hoarding disorder.

13. Evidence of dementia or other significant cognitive impairment on neuropsychological
evaluation or through cognitive screening (MOCA).