Biomarkers to Guide Directional DBS for Parkinson's Disease

Although deep brain stimulation (DBS) can be remarkable for treating symptoms of Parkinson's
disease, improvement varies across clinical trials, individual patients, and over time. A
major limitation to the advancement of DBS therapy is that there are no established
biomarkers to tailor stimulator settings in individuals. Emerging segmented ("directional")
lead technology allows current steering, a new opportunity to improve tolerability and
efficacy by shaping the DBS electrical field. This novel lead design has 8 contacts rather
than the 4 available with currently available leads. How do the investigators optimally
adjust stimulation parameters when there are far more potentially useful settings than can be
practically evaluated in clinic? How do the investigators know that DBS settings in a given
patient are optimal or appropriate? The investigators have pioneered minimally invasive,
rapidly acquired biomarkers to solve these important problems. Using electrocorticography,
electroencephalography, and subcortical local field potentials, the investigators will
measure whether resting or stimulus-evoked electrophysiology can serve as a predictive
biomarker to guide activation and adjustment of a directional DBS system. The purpose of this
randomized, double-blind crossover study is to measure the clinical efficacy of directional
versus omnidirectional stimulation and to explore whether electrophysiology biomarkers can
rapidly predict effective, well-tolerated contacts for directional DBS therapy.

Inclusion Criteria:

1. Age ≥18 years and ≤70 years.

2. Clinically definite, advanced idiopathic PD based on at least 2 of 3 cardinal PD
features (tremor, rigidity, or bradykinesia).

3. Disease duration of 4 years or more.

4. Participant has elected to undergo DBS surgery as part of routine care, and the
subthalamic nucleus (STN) is recommended as the surgical target.

5. Participant agrees to not undergo contralateral DBS for the other side of the brain
until ≥ 12 months after initial DBS surgery.

6. Participant is healthy enough to undergo surgery and the research protocol.

7. Normal, or essentially normal, preoperative brain MRI.

8. Willingness and ability to cooperate during awake DBS surgery, as well as during
post-operative evaluations, adjustments of medications and stimulator settings.

9. Participant's health insurance and/or Medicare covers DBS surgery as part of routine
care.

10. Refractory motor symptoms such as tremor, dyskinesias, wearing off, and/or motor
fluctuations, causing significant disability or occupational dysfunction, despite
reasonable attempts at medical management, as determined by our consensus DBS
committee.

11. Stable doses of PD medications for at least 28 days prior to baseline assessments.

12. Improvement of motor signs ≥30% with dopaminergic medication as assessed with the use
of the Movement Disorders - Unified Parkinson's Disease Rating Scale, part III
(MDS-UPDRS III; scores range from 0 to 108, with higher scores indicating worse
functioning).

13. Disease severity ratings above Hoehn and Yahr stage 1, defined as unilateral
involvement only with minimal or no functional disability, with scores ranging from 0
to 5 and higher scores indicating more severe disease.

14. Score of more than 6 for activities of daily living in the worst "off" medication
condition despite medical treatment, as assessed with the use of the MDS-UPDRS II
(scores range from 0 to 52, with higher scores indicating worse functioning), or
mild-to-moderate impairment in social and occupational functioning (score of 51 to 80%
on the Social and Occupational Functioning Assessment Scale with scores ranging from 1
to 100 and lower scores indicating worse functioning).

15. Dementia Rating Scale-2 (DRS-2) score of ≥130 on medications.

16. Beck Depression Inventory II (BDI-II) score of ≤25 on medications.

17. Participant expresses understanding of the consent process, terms of the study
protocol, is available for follow-up over the length of the study, and signs informed
consent.

Exclusion Criteria:

1. Age <18 years or >70 years.

2. Participant's insurance will not cover the costs of surgery with the investigational
device.

3. Medical contraindications such as current uncontrolled hypertension, heart disease,
coagulopathy, or other conditions contraindicating DBS surgery or stimulation.

4. Duration of disease of <4 years

5. Participant or care team determine that contralateral DBS for the other side of the
brain will likely be clinically indicated <12 months after initial DBS surgery.

6. Diagnosis or suspicion of atypical parkinsonism (progressive supranuclear palsy,
multiple system atrophy, corticobasal syndrome) or drug-induced parkinsonism, or
significant neurological disease other than Parkinson's disease.

7. Disease severity ratings of Hoehn and Yahr stage 1, defined as unilateral involvement
only with minimal or no functional disability, with scores ranging from 0 to 5 and
higher scores indicating more severe disease.

8. Diagnosis of psychogenic movement disorder based on consensus criteria.

9. Score of >25 on the Beck Depression Inventory II, with scores ranging from 0 to 63 and
higher scores indicating worse functioning), or history of suicide attempt.

10. Any current acute psychosis, alcohol abuse or drug abuse.

11. Clinical dementia (score of ≤130 on the Mattis Dementia Rating Scale with scores
ranging from 0 to 144 and higher scores indicating better functioning).

12. Ongoing or pervasive impulse control disorder not resolved by reduction of
dopaminergic medications.

13. Use of anticoagulant medications that cannot be discontinued during perioperative
period.

14. History of hemorrhagic stroke.

15. Current or future risk of immunocompromise that might significantly increase risk of
infection.

16. History of recurrent of unprovoked seizures.

17. Lack of clear levodopa responsiveness.

18. Any medical condition requiring repeated MRI.

19. The presence of an implanted device (e.g., cochlear implant, pacemaker,
neurostimulators), whether turned on or off.

20. Prior DBS surgery or ablation within the affected basal ganglion.

21. A condition requiring or likely to require the use of diathermy.

22. Structural lesions such as basal ganglionic stroke, tumor or vascular malformation as
etiology of the movement disorder.

23. Any medical or psychological problem that would interfere with the conduction of the
study protocol

24. A female who is breastfeeding or of child-bearing potential with a positive urine
pregnancy test or not using adequate contraception.