Novel Paradigms of Deep Brain Stimulation for Movement Disorders

Investigators will enroll patients who are already selected to undergo deep brain stimulation surgery based on standard of care. The surgical implantation of the leads will be based on standard of care and will be completed with FDA-approved leads that are routinely used at Cleveland Clinic. The pulse generators (i.e. the battery) will also be standard. The research will characterize spontaneous and task-related changes in brain activity recorded from these regions alone and in relation to novel paradigms / settings of stimulation to learn how such paradigms impact both the symptoms of patients with Parkinson's disease and the underlying neural activity of the target brain region. Of particular interest is to learn if the novel paradigms of stimulation will have a lower impact on cognitive function than current settings of stimulation.To date, current DBS settings are continuous. That is, stimulation runs at approximately 200 pulses per second, all day long, day and night.

The novel settings that investigators will study are part of a translational pipeline at Cleveland Clinic. Dr. Ken Baker and Dr. Machado are partners in the lab and in clinical research. Dr. Baker has completed preclinical research that has shown that it is possible to achieve excellent relief of parkinsonian symptoms with intermittent types of stimulation known as coordinated reset. In other words, Dr Baker found that using a lower dose of stimulation in an intermittent fashion can maintain the same level of symptom control. Furthermore, a lower dose of stimulation could have less effects on cognitive symptoms.

In order to test these novel paradigms of stimulation, investigators will study patients immediately after DBS and over time. The immediate research will be done starting on the third day after implantation of the DBS lead(s), having the systems externalized for nine days. The long-term research will be conducted with patients already fully implanted and healed from surgery. In addition to evaluating for motor and cognitive tasks using computer based assessments, investigators will utilize non-invasive electrophysiological measures including EEG, EMG, MEG, and wearable accelerometer/gyroscopes to better characterize the effects of stimulation settings.

Study Overview

• Status: Completed
• Conditions: Parkinson Disease
• Intervention / Treatment: Other: Novel DBS Stimulation

Detailed Description

The experimental design will include procedures to address each specific aim, with most involving a within-subjects approach that examines the effect of different levels of treatment (e.g., no therapy, traditional DBS, novel DBS) on neurological function, including dependent variables derived from tests of motor and cognitive function. This approach will extend to the electrophysiological data as well; where the relative effect of each level of treatment on spontaneous- (e.g., resting beta and gamma band power) and task-related (i.e., evoked or event-related potential latency and amplitude characteristics) cerebral rhythms will be quantified for each subject and further aggregated to characterize group-level effects (see data analysis below).

Prior to surgery, participants will undergo additional brain imaging procedures in order to characterize the anatomical and functional connectivity of the brain region to be targeted during surgical lead placement and the cerebral cortex. The additional imaging sets will include DTI and resting state functional MRI scans that will add an additional 30-45 minutes to the standard of care pre-operative clinical MR procedure.

Following standard of care placement of the DBS lead(s) within the targeted brain region, access to the lead for study-related activities will be achieved by attaching a disposable extension to the end of the lead that is lodged subcutaneously, extracranially. The disposable extension will then be tunneled to a site remote to that of the surgery in order to minimize risk of contamination of the permanently implanted hardware. The recording equipment will then be connected to the externalized extension, thus enabling study-related DBS delivery and the recording of local field potentials (LFP) from the targeted brain region.

Study-related activities will start the third morning after DBS surgery to allow the patient time to recover from the implant procedure (start may be delayed if additional recovery is deemed warranted through consultation with clinical care team). It is expected that the study testing will continue through post-implant day 9, with the second standard of care DBS implant surgery performed on post-implant day 10. During the externalization period, subjects will participate in daily data collection tasks for up to 8 hours per day, with study-related activities performed in short segments, broken up across morning and afternoon sessions. Once testing is completed in the operationally-defined medication OFF state, patients will be permitted to take their usual dose of medication and testing will continue. Frequent rest periods will be included within each testing block to minimize fatigue effects and improve data quality. Electrophysiological recordings may also be performed when the patient is not in the laboratory, including overnight during sleep, using portable recording equipment and activity monitors that resemble a holster device. Recordings will be made using either a commercially-available cap electrode system that is placed temporarily during each experimental session or using standard cup electrodes affixed to the scalp using either standard methods (i.e., collodion or electrode paste). If collodion electrodes are used, collodion electrodes will remain on the patient for several days in a row up to the duration of the externalization period. Daily checks will be performed to ensure the integrity of the electrode interface and electrodes will be re-gelled or re-applied as needed.

Daily study-related activities within the laboratory will include 1) spontaneous recordings made with the patient at rest, 2) motor and cognitive task-synchronized recordings, and 3) somatosensory evoked potentials, and 4) evoked potentials elicited by direct stimulation of the deep brain target region. On the first day of testing, a monopolar threshold review, similar to what is performed as part of standard of care clinical DBS programming may be performed. This involves careful titration of the settings of electrical stimulation delivered via the DBS lead in order to determine thresholds for sensorimotor and other side-effects and will help to set the upper limits of stimulation delivered as part of the experimental procedures. Moreover, this process will be used to characterize the therapeutic benefits derived from DBS. In all cases, stimulation will be limited to less than the approved charge density safety limit of 30 microcoulombs/cm2 per phase. On certain days, patients may be asked to arrive to the test location after an overnight fast from their anti-PD medications in order to characterize the effect of dopaminergic medications on experimental responses. Finally, daily schedules may be altered based upon patient fatigue as well as potential scheduling conflicts (e.g., MRI or MEG availability) and the total number of days the patient is externalized may be shortened at the discretion of the surgical team, including the need to accommodate operating room scheduling.

A minimum of six months after surgery, participants will be asked to return for a follow-up, approximately 4-hour research visit to evaluate therapeutic outcomes. Specifically, patients will be asked to return to the main campus laboratory after an overnight fast from their anti-parkinsonian medications. During that visit, the efficacy of the patient's standard-of-care DBS programming settings (i.e., the settings set by their treating physician as part of their routine, post-op clinical care) will be evaluated through blinded scoring using subscales of the MDS-Unified Parkinson's Disease Rating Scale (MDS-UPDRS).

• Study Type: Interventional
• Enrollment (Actual): 16
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Kenneth Baker, PhD; Phone Number: 216-445-2244; Email: bakerk6@ccf.org
• Study Contact Backup: Name: Karen Stevenson, BS; Phone Number: 216-445-0926; Email: stevenk12@ccf.org

Study Locations

• United States
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 40 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• diagnosis of idiopathic Parkinson's disease for greater than 3 years
• determined appropriate for deep brain stimulation surgery
• able to give consent

Exclusion Criteria:

• secondary Parkinson's disease, stroke, progressive central nervous system disease
• dementia that disallows the subject ability to consent
• current alcohol or substance abuse
• hearing or visual impairment precluding cognitive or sensory testing

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: Novel stimulation; All subjects will undergo periods of stimulation using novel stimulation patterns	Other: Novel DBS Stimulation; Stimulation patterns will vary from the standard therapeutic approach in terms of frequency, contact location, and/or temporal pattern.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Upper extremity motor speed	Patients will complete arm movements in response to cues presented on a computer. The speed of movements will be compared between novel and therapeutic stimulation	Post operative externalization days 1 through 9
Verbal Fluency	Change in the number words that patients generate to letter or semantic category cues will be compared between novel and therapeutic stimulation	Post operative externalization days 1 through 9

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cognitive Reaction Time	Subjects will complete one or more measures of cognitive processing requiring speeded responses to stimuli. Changes in reaction time will be compared between novel and therapeutic stimulation	Post operative externalization days 1 through 9
EEG - sensorimotor evoked potentials	Sensory and motor-locked activity at scalp and deep brain stimulation electrodes will be compared between novel and therapeutic stimulation	Post operative externalization days 1 through 9
EEG - Oscillatory activity	Power in standard frequency bands at both scalp and DBS electrodes will be examined with the patient at rest and compared between novel and therapeutic stimulation	Post operative externalization days 1 through 9
EMG	Electromyography will be recorded in response to active and passive movement and latency and amplitude will be compared between novel and therapeutic stimulation	Post operative externalization days 1 through 9
fMRI - Bold response	Pattern of fMRI activity will be compared between novel and therapeutic stimulation	Post operative externalization days 1 through 9
MEG	Pattern of magnetoencephalogram activity will be compared between novel and therapeutic stimulation	Post operative externalization days 1 through 9
Movement Disorders Society Unified Parkinson Disease Rating Scale - III	Gold standard clinician rating scale of Parkinson's symptoms will be compared between novel and therapeutic stimulation	6 months after DBS surgery

Collaborators and Investigators

• Sponsor: The Cleveland Clinic
• Collaborators: Farmer Foundation
• Investigators: Study Director: Kenneth Baker, PhD, The Cleveland Clinic

Study record dates

Study Major Dates

• Study Start (Actual): January 17, 2020
• Primary Completion (Actual): September 7, 2023
• Study Completion (Actual): September 7, 2023

Study Registration Dates

• First Submitted: April 22, 2020
• First Submitted That Met QC Criteria: September 23, 2020
• First Posted (Actual): September 24, 2020

Study Record Updates

• Last Update Posted (Actual): October 3, 2023
• Last Update Submitted That Met QC Criteria: October 2, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Keywords: deep brain stimulation; cognition; sensorimotor function
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Parkinsonian Disorders; Basal Ganglia Diseases; Synucleinopathies; Neurodegenerative Diseases; Parkinson Disease; Movement Disorders
• Other Study ID Numbers: 19-1637

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No