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).
