Deep Brain Stimulation (DBS) of the Pedunculopontine Nucleus (PPN)

Not Applicable

• Conditions: Parkinson Disease
• Interventions: Procedure: Deep Brain Stimulation Surgery (DBS); Device: STN-PPN DBS Surgery

• Registration Number: NCT04605263
• Lead Sponsor: St. Joseph's Hospital and Medical Center, Phoenix

Brief Summary

This is a mechanistic study to determine the differential effects of the dopaminergic and cholinergic systems on attention, gait, and balance. The primary goal of the study is to evaluate the relative effects of pedunculopontine nucleus (PPN) and subthalamic nucleus (STN) Deep Brain Stimulation (DBS) on these features in persons with Parkinson's Disease (PD) who are eligible for DBS for improvement of their motor symptoms and exhibit gait instability with falls. Patients will be enrolled and implanted with bilateral electrodes in one of the approved DBS locations (subthalamic nucleus: STN), but additionally electrodes will be inserted into the experimental target, namely the PPN bilaterally.

Detailed Description

This is a prospective, single-center randomized controlled trial designed to estimate the potential clinical benefit, and associated risks, of deep brain stimulation of the of the PPN and STN in patients with PD that are candidates for DBS for improvement of their motor symptoms and exhibit gait instability with falls. Patients will be enrolled and implanted with additional bilateral electrodes in the PPN. Each subject will be randomized 1:1 to one of the following sequences: Bilateral STN+PPN stimulation or Bilateral STN stimulation alone. The addition of a bilateral STN stimulation only group allows for the research of potential micro-lesioning effects of the PPN which might affect features of interest even in the absence of PPN stimulation.

Study Timeline

• Study First Submitted: 2020-08-31
• Study First Submitted QC: 2020-10-26
• Study First Posted: 2020-10-27
• Study Start: 2021-11-01
• Status Verified: 2024-11
• Last Update Submitted: 2024-11-26
• Last Update Posted: 2024-11-29
• Primary Completion: 2026-09-01
• Study Completion: 2027-09-01

Recruitment & Eligibility

• Status: ENROLLING_BY_INVITATION
• Sex: All
• Target Recruitment: 8

Inclusion Criteria

• Inclusion Criteria

  1. Informed consent signed by the subject.
  2. Diagnosed with Parkinson's disease per UK Parkinson's Disease Society Brain Bank (Queens Square) criteria for at least 4 years
  3. Demonstrates levodopa responsiveness of at least 30%
  4. Experiences tremor or motor complications including wearing off and/or dyskinesia
  5. DBS candidate per FDA guidelines as outlined in criteria 2-4
  6. Candidate for STN targeting per the consensus committee
  7. Subject exhibits gait instability, or a history of at least one fall within the last year, or a history of falls on tests of Static or Dynamic Stability.
  8. PD Stage 2-3 with predominant axial symptoms or FOG refractory to Levodopa > 600 mg and UPDRS Part III Subscore of >6.
  9. Subject is ambulatory and able to walk for limited periods of time without using an assistive device.
  10. 18-75 years of age
  11. Primary English speaking
  12. Physically and cognitively capable of completing evaluations and consent
  13. Medically cleared for surgery and anesthesia
  14. Female subjects with child-bearing potential have a negative serum pregnancy test prior to DBS surgery

Exclusion Criteria

Exclusion Criteria:

1. Dementia per DSM-V criteria
2. Condition precluding MRI
3. History of supraspinal CNS disease other than PD
4. History of schizophrenia, delusions, or currently uncontrolled visual hallucinations
5. Subjects who require rTMS, ECT, diathermy, or repeat MRI procedures to treat a medical condition.
6. Subjects with a history of seizure disorder
7. Subjects who have made a suicide attempt within the prior year,
8. Subjects with any medical contraindications to undergoing DBS surgery (eg, infection, coagulopathy, or significant cardiac or other medical risk factors for surgery)
9. Subjects with an implanted stimulator such as a cardiac pacemaker, defibrillator, neurostimulator and cochlear implant
10. Subjects who are pregnant or nursing.
11. Patient that is unwilling or unable to comply with the requirements of this protocol, including the presence of any condition (physical, mental, or social) that is likely to affect the subject's ability to comply with the protocol.
12. Any other reasons that, in the opinion of the investigator, the candidate is determined to be unsuitable for entry into the study.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
STN DBS	Deep Brain Stimulation Surgery (DBS)	Subjects will receive traditional bilateral STN devices and stimulation.
STN-PPN DBS	STN-PPN DBS Surgery	Patients will be implanted with both bilateral STN and bilateral PPN devices. These patients will undergo a crossover between 3 and 15 months post-op in which they will double-blindly receive PPN stimulation for six months and have stimulation turned off for six months. All patients will receive stimulation from 0-3 months post-op (mapping visits occur in this window) and from 15-27 months.

Primary Outcome Measures

Name	Time	Method
STN-PPN Stimulation Effect on Fall Risk	27 months	The purpose of this study is to measure the effect and the mechanism of deep brain stimulation (DBS) of the pedunculopontine nucleus (PPN) on fall risk as established by quantitative gait and balance analysis.

Secondary Outcome Measures

Name	Time	Method
STN-PPN on Attention	27 months	The effect of PPN stimulation, in comparison to that of STN alone, on attention, with be measured using the Conners Continuous Auditory Test of Attention and Continuous Performance Test 3.
STN-PPN on Subjective Measures of Balance in Daily Life	27 months	The effects of PPN stimulation on subjective function will be measured using the Activity-specific Balance Confidence Scale, graded on a scale of 0-100, with higher scores being better.
STN-PPN on Linear and Nonlinear Measures of Balance	27 months	Linear and nonlinear measures of balance will be collected during eyes open, eyes closed, and perturbed (dyanic balance) conditions.
STN-PPN on Linear and Nonlinear Measures of Gait	27 months	Linear and nonlinear measured of gait will be measured during straight walking, turning, and arising and returning to a chair.
STN-PPN on Subjective Measures of Alertness	27 months	The effects of PPN stimulation on subjective function will be measured using the Toronto Alertness Scale, graded 0-50, with higher scores being better.
STN-PPN on Subjective Measures of Sleep	27 months	The effects of PPN stimulation on subjective function will be measured using the Epworth Sleep Scale, graded 0-24, with lower scores being better.
STN-PPN on Subjective Measures of Non-Motor Symptoms	27 months	The effects of PPN stimulation on subjective function will be measured using the Non-Motor Symptom Assessment, graded 0-360, with lower scores being better.

Trial Locations

Locations (1)

St. Joseph's Hospital & Medical Center / Barrow Neurological Institute; 🇺🇸 Phoenix, Arizona, United States