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Adaptive Deep Brain Stimulation to Improve Motor and Gait Functions in Parkinson's Disease

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ClinicalTrials.gov Identifier: NCT04675398
Recruitment Status : Not yet recruiting
First Posted : December 19, 2020
Last Update Posted : December 19, 2020
Sponsor:
Collaborators:
Michael J. Fox Foundation for Parkinson's Research
Burroughs Wellcome
Information provided by (Responsible Party):
University of California, San Francisco

Brief Summary:
This is a single-center phase I clinical study aiming to improve gait functions in patients with Parkinson's disease (PD) by using adaptive neurostimulation to the pallidum. The investigators will use a bidirectional deep brain stimulation device with sensing and stimulation capabilities to 1) decode the physiological signatures of gait and gait adaptation by recording neural activities from the motor cortical areas and the globus pallidus during natural walking and a gait adaptation task, and 2) develop an adaptive deep brain stimulation (DBS) paradigm to selectively stimulate the pallidum during different phases of the gait cycle and measure improvements in gait parameters. This is the first exploration of network dynamics of gait in PD using chronically implanted cortical and subcortical electrodes. In addition to providing insights into a fundamental process, the proposed therapy will deliver personalized neurostimulation based on individual physiological biomarkers to enhance locomotor skills in patients with PD. Ten patients with idiopathic Parkinson's disease undergoing evaluation for DBS implantation will be enrolled in this single treatment arm study.

Condition or disease Intervention/treatment Phase
Parkinson Disease Device: Summit RC+S Not Applicable

Detailed Description:

This study will allow the investigators to evaluate the efficacy of an adaptive stimulation paradigm in deep brain stimulation (DBS) to treat motor-related behaviours and motor skill learning in Parkinson's disease (PD). Parkinson's disease patients will be implanted unilaterally or bilaterally with a totally internalized bidirectional neural interface, Medtronic Summit RC+S.

While current DBS therapy improves motor symptoms of PD, it does not address problems with acquiring additional motor skills (i.e. adapting gait patterns to avoid falls)) in PD, therefore, limiting benefits of physical rehabilitation programs aimed at improving mobility. Motor skill learning is critical in acquiring any new behaviors related to motor function. The overall objective is to identify personalized electrophysiological signatures of motor skill learning in PD patients and use adaptive control algorithms to enhance these signatures. The study will discover new ways to rehabilitate the disease brain circuits using adaptive neuromodulation.

In a small, double-blinded trial, ten patients with idiopathic PD and motor fluctuations will be implanted with unilateral or bilateral RC+S devices, each connected to a standard quadripolar DBS lead implanted in the basal ganglia, along with a 4-contact paddle type electrode placed subdurally over the motor cortex. The investigators will compare the overall efficacy of closed-loop and open-loop paradigms in terms of behavioral performance improvements in validated motor skill learning tasks and measurements from wearable devices. During this chronic adaptive DBS phase, adaptive DBS and open-loop stimulation settings will be randomized for 30-day periods and motor skill and gait related measurements will be obtained from a combination of computerized motor tasks and wearable devices that track movement kinematics. Patients will participate in daily, if possible, motor learning and gait tasks at home with triggered stimulation settings and recordings.

The investigators expect to successfully develop a prototype adaptive DBS algorithm based on cortical and / or basal ganglia LFPs (local field potentials). The investigators hypothesize that an adaptive paradigm will provide improvements in motor skilled learning compared to the conventional, open-loop paradigm, in which stimulation parameters remain constant until changed by the patient or clinician using an external programmer.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 10 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Intervention Model Description: In a small, double-blinded trial, the investigators will compare the overall efficacy of closed-loop and open-loop paradigms in terms of behavioral performance improvements in validated motor skill learning tasks and measurements from wearable devices. During this chronic aDBS phase, aDBS and open-loop stimulation settings will be randomized for 30-day periods and motor skill and gait related measurements will be obtained from a combination of computerized motor tasks and wearable devices that track movement kinematics. Patients will participate in daily, if possible, motor learning and gait tasks at home with triggered stimulation settings and recordings. Data will be collected and reviewed from the wearable monitors, Summit RC+S, and home motor learning tasks remotely. Researchers will have weekly check-in sessions with patients by video conferencing or in-person meetings. At minimum, researchers will have in-person sessions with patients every 4 weeks during Phase 3.
Masking: Double (Participant, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Adaptive Cortical and Subcortical Brain Stimulation to Improve Motor Behaviors and Gait in Parkinson's Disease
Estimated Study Start Date : December 1, 2021
Estimated Primary Completion Date : December 1, 2022
Estimated Study Completion Date : September 1, 2023

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Active Comparator: Open-loop deep brain stimulation
Parkinson's disease patients implanted with Summit RC+S and brain lead implanted in the pallidal/striatal region receiving open-loop deep brain stimulation.
Device: Summit RC+S
Using the RC+S pulse generator, patients receive clinically-optimized open loop DBS stimulation to the pallidum.
Other Name: continuous deep brain stimulation

Active Comparator: Randomized deep brain stimulation
Parkinson's disease patients implanted with Summit RC+S and brain lead implanted in the pallidal/striatal region receiving closed-loop stimulation at random time points.
Device: Summit RC+S
Using the RC+S pulse generator, the patients will receive closed-loop stimulation at random time points. These random stimulation times will in total equal the total amount of time of active movement.
Other Name: random stimulation

Active Comparator: Deep brain stimulation during contralateral limb movement
Parkinson's disease patients implanted with Summit RC+S and brain lead implanted in the pallidal/striatal region receiving closed-loop stimulation during time of contralateral limb movement.
Device: Summit RC+S
Using the RC+S pulse generator, the patients will receive closed-loop stimulation during time of contralateral limb movement (e.g. left brain stimulation during right leg/arm movement).
Other Name: adaptive stimulation

Active Comparator: Deep brain stimulation during contralateral limb rest
Parkinson's disease patients implanted with Summit RC+S and brain lead implanted in the pallidal/striatal region receiving closed-loop stimulation during time of no movement for contralateral limb.
Device: Summit RC+S
Using the RC+S pulse generator, the patients will receive closed-loop stimulation during time of no movement for the contralateral limb (e.g. left brain stimulation while right leg/arm is not moving).
Other Name: adaptive stimulation




Primary Outcome Measures :
  1. Change in motor learning task completion with closed-loop compared to open-loop deep brain stimulation (DBS) [ Time Frame: Baseline and 2 years ]
    Change in percentage of motor learning task trials that were completed with closed-loop compared to open-loop deep brain stimulation (DBS). The task is made up of 840 trials, completion will be measured by percent of trials completed (e.g. 750/840 trials completed would be 89%). The task has a built in function which logs completed trials in a CSV document.

  2. Change in motor learning task reaction times with closed-loop compared to open-loop deep brain stimulation (DBS) [ Time Frame: Baseline and 2 years ]
    Change in gait sequence motor learning task reaction times (measured in milliseconds) with closed-loop compared to open-loop deep brain stimulation (DBS).

  3. Change in motor learning task mean accuracy with closed-loop compared to open-loop deep brain stimulation (DBS). [ Time Frame: Baseline and 2 years ]
    Change in motor learning task mean accuracy with closed-loop compared to open-loop deep brain stimulation (DBS). Accuracy will be measured as a percent using the tasks proprietary output log which records which trials out of the 840 total trials were target hits (i.e. correct trials). Mean accuracy will be calculated by taking the average of each patient's accuracy score across all attempts of the task done by said patient.


Secondary Outcome Measures :
  1. Change in Gait [ Time Frame: Baseline and 2 years ]
    Change in gait measurements using the 10-meter walk timed test. The 10-Meter Walk Test (10MWT) is a performance measure used to assess walking speed in meters per second over a short distance of 10 meters. It is employed to determine functional mobility and gait. The gait speed is used as the outcome by which to compare change in performance capacity. Lower times indicate higher levels of physical functioning.

  2. Change in Balance [ Time Frame: Baseline and 2 years ]

    Change in balance measurements using:

    Mini-Best Test: Clinical balance assessment tool. The score range is 0-2 with high score indicating higher levels of physical functioning.

    Activities-Specific Balance Confidence Scale (ABC): Measures of confidence in performing various ambulatory activities without falling or experiencing a sense of unsteadiness. The score range is 0-100 with higher scores indicating higher levels of physical functioning.


  3. Change in MDS-UPDRS III scores [ Time Frame: Baseline and 2 years ]
    Change in Movement Disorders Society Unified Parkinson Disease Rating Scale (MDS-UPDRS) III score. The scale consists of 18 items that are each scored 0 to 3, making the total score out of 72 points, with higher scores indicating higher impairment.

  4. Change in NIHTB Cognition Battery Test [ Time Frame: Baseline and 2 years ]
    Change in National Institute of Health Toolbox (NIHTB) Cognition battery test (during adaptive stimulation compared to open loop stimulation). A score known as a theta score is calculated for each participant; it represents the relative overall ability or performance of the participant. The theta score is converted to a Computed Score which ranges from roughly 0 to 2000 depending on the age-adjusted averages, with higher scores indicating higher levels of cognitive functioning.

  5. Change in Five-Times Sit to Stand Test Results [ Time Frame: Baseline and 2 years ]
    Five-Times Sit to Stand Test: Assesses functional lower extremity strength, transitional movements, balance, and fall risk in older adults. Scoring based on amount of time a patient is able to transfer from a seated to a standing position and back to sitting five times, with lower times indicating higher levels of physical functioning.

  6. Change in Stride Length [ Time Frame: Baseline and 2 years ]
    Change in stride length measured by Rover (a gait measurement device) and Xsens (a kinematic measurement device) with closed-loop compared to open-loop deep brain stimulation (DBS). Stride length is measured in meters.

  7. Change in Stride Time [ Time Frame: Baseline and 2 years ]
    Change in stride time measured by Rover (a gait measurement device) and Xsens (a kinematic measurement device) with closed-loop compared to open-loop deep brain stimulation (DBS). Stride time is measured in seconds.

  8. Change in double support time [ Time Frame: Baseline and 2 years ]
    Change in double support time measured by Rover (a gait measurement device). Each gait cycle consists of two phases, where both feet are in contact with the ground, called Double Support. Double support time will be measured in seconds (i.e. amount of time both feet are in contact with the ground).



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Ability to give informed consent for the study
  • Movement disorder symptoms that are sufficiently severe, in spite of best medical therapy, to warrant surgical implantation of deep brain stimulators according to standard clinical criteria
  • Patient has requested surgical intervention with deep brain stimulation for their disorder
  • No movement -elated abnormalities that suggest an alternative diagnosis or contraindicate surgery
  • Absence of significant cognitive impairment (score of 21 or greater on the Montreal Cognitive Assessment (MoCA),
  • Signed informed consent
  • Ability to comply with study follow-up visits for brain recording, testing of adaptive stimulation, and clinical assessment.
  • Age 21-75
  • Diagnosis of idiopathic PD with duration of motor symptoms for 3 years or greater
  • Patient has undergone appropriate therapy with oral medications with inadequate relief as determined by a movement disorders neurologist.
  • UPDRS-III score off medication between 20 and 80 and an improvement of at least 30% in the baseline UPDRS-III on medication score, compared to the baseline off-medication score, and motor fluctuations with at least 2 hours per day of on time without dyskinesia or with non-bothersome dyskinesia. OR Patients with tremor-dominant PD (a tremor score of at least 2 on a UPDRS-III sub-score for tremor), treatment resistant, with significant functional disability despite maximal medical management
  • Patients with gait impairments: slowed gait, shuffling steps, postural instability, or freezing of gait off medication.
  • Ability of patient and/or caregivers to recharge the system evaluated by all clinicians and study personnel.
  • Geographical proximity and/or ability to travel to study sites for patient to receive re-programming via investigational devices (e.g. Summit Research Laboratory Programmer).

Exclusion Criteria:

  • Coagulopathy, anticoagulant medications, uncontrolled hypertension, history of seizures, heart disease, or other medical conditions considered to place the patient at elevated risk for surgical complications
  • Evidence of a psychogenic movement disorder: Motor symptoms that remit with suggestion or "while unobserved", symptoms that are inconsistent over time or incongruent with clinical condition, plus other manifestation such as "false" signs, multiple somatizations, or obvious psychiatric disturbance.
  • Pregnancy: all women of child bearing potential will have a negative urine pregnancy test prior to undergoing their surgical procedure.
  • Significant untreated depression (BDI-II score >20). History of suicidal attempt or active suicidal ideation (Yes to #2-5 on C-SSRS)
  • Any personality or mood symptoms that study personnel believe will interfere with study requirements.
  • Subjects who require electroconvulsive therapy (ECT), repetitive transcranial magnetic stimulation (rTMS) or diathermy
  • Implanted stimulation systems such as; cochlear implant, pacemaker, defibrillator, or neurostimulator
  • Previous cranial surgery
  • Drug or alcohol abuse
  • Meets criteria for Parkinson's disease with mild cognitive impairment (PD-MCI). These criteria are: performance of more than two standard deviations below appropriate norms, for tests from two or more of these five cognitive domains: attention, executive function, language, memory, and visuospatial tests.
  • Known allergies to the implantable device components including titanium, polyurethane, silicone, and nylon.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04675398


Contacts
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Contact: Doris Wang, MD, PhD 415-514-7333 doris.wang@ucsf.edu
Contact: Maria Yaroshinsky, BA 415-514-0855 maria.yaroshinsky@ucsf.edu

Locations
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United States, California
UCSF
San Francisco, California, United States, 94134
Contact: Doris Wang, MD, PhD    415-514-7333    doris.wang@ucsf.edu   
Contact: Maria Yaroshinsky, BA    4155140855    maria.yaroshinsky@ucsf.edu   
Sponsors and Collaborators
University of California, San Francisco
Michael J. Fox Foundation for Parkinson's Research
Burroughs Wellcome
Investigators
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Principal Investigator: Doris Wang, MD, PhD University of California, San Francisco
Publications:
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Responsible Party: University of California, San Francisco
ClinicalTrials.gov Identifier: NCT04675398    
Other Study ID Numbers: 18649
First Posted: December 19, 2020    Key Record Dates
Last Update Posted: December 19, 2020
Last Verified: December 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: Yes
Product Manufactured in and Exported from the U.S.: Yes
Keywords provided by University of California, San Francisco:
neuromodulation
closed-loop deep brain stimulation
gait impairments
motor learning
parkinson's disease
Additional relevant MeSH terms:
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Parkinson Disease
Parkinsonian Disorders
Basal Ganglia Diseases
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Movement Disorders
Neurodegenerative Diseases