Clinical trial NCT04675398: Adaptive Deep Brain Stimulation to Improve Motor and Gait Functions in Parkinson's Disease
Official title: Adaptive Cortical and Subcortical Brain Stimulation to Improve Motor Behaviors and Gait in Parkinson's Disease
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: NA
Conditions: Parkinson Disease
Keywords: neuromodulation
closed-loop deep brain stimulation
gait impairments
motor learning
parkinson's disease
Lead sponsor: University of California, San Francisco
Sponsor class: OTHER
Collaborators: name: Michael J. Fox Foundation for Parkinson's Research
name: Burroughs Wellcome
First posted: 2020-12-19
Enrollment: 10
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
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.
Primary purpose: TREATMENT

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.

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.

Eligibility 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.

Primary outcomes:
measure: Change in motor learning task completion with closed-loop compared to open-loop deep brain stimulation (DBS)
timeFrame: Baseline and 2 years
measure: Change in motor learning task reaction times with closed-loop compared to open-loop deep brain stimulation (DBS)
timeFrame: Baseline and 2 years
measure: Change in motor learning task mean accuracy with closed-loop compared to open-loop deep brain stimulation (DBS).
timeFrame: Baseline and 2 years
Secondary outcomes:
measure: Change in Gait
timeFrame: Baseline and 2 years
measure: Change in Balance
timeFrame: Baseline and 2 years
measure: Change in MDS-UPDRS III scores
timeFrame: Baseline and 2 years
measure: Change in NIHTB Cognition Battery Test
timeFrame: Baseline and 2 years
measure: Change in Five-Times Sit to Stand Test Results
timeFrame: Baseline and 2 years
measure: Change in Stride Length
timeFrame: Baseline and 2 years
measure: Change in Stride Time
timeFrame: Baseline and 2 years
measure: Change in double support time
timeFrame: Baseline and 2 years
Other outcomes:
Locations:
city: San Francisco
country: United States
facility: UCSF
state: California
Study officials:
affiliation: University of California, San Francisco
name: Doris Wang, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Swann NC, de Hemptinne C, Miocinovic S, Qasim S, Ostrem JL, Galifianakis NB, Luciano MS, Wang SS, Ziman N, Taylor R, Starr PA. Chronic multisite brain recordings from a totally implantable bidirectional neural interface: experience in 5 patients with Parkinson's disease. J Neurosurg. 2018 Feb;128(2):605-616. doi: 10.3171/2016.11.JNS161162. Epub 2017 Apr 14.
citation: Little S, Pogosyan A, Neal S, Zavala B, Zrinzo L, Hariz M, Foltynie T, Limousin P, Ashkan K, FitzGerald J, Green AL, Aziz TZ, Brown P. Adaptive deep brain stimulation in advanced Parkinson disease. Ann Neurol. 2013 Sep;74(3):449-57. doi: 10.1002/ana.23951. Epub 2013 Jul 12.