Eight-hours adaptive deep brain stimulation in patients with Parkinson disease

Methods

We enrolled 13 rigid-akinetic patients with advanced PD who underwent surgery for subthalamic nucleus DBS electrode implantation in the Neurosurgery Unit at Fondazione IRCCS Ca'Granda Ospedale Maggiore Policlinico in Milan from March 2016 to January 2017 without experiencing any surgical complication. The study was approved by the institutional review board and conformed with the Declaration of Helsinki, and all patients provided written informed consent to the experimental procedures. Patients were implanted bilaterally but studied unilaterally. The choice of the side is detailed in appendix e-1, http://links.lww.com/WNL/A238.

The experimental sessions took place after DBS surgery before the leads were connected to the subcutaneous pulse generator.

Before the experimental session started, a calibration session was performed to verify the presence of a significant beta peak in at least 1 side, to establish the best side for recording LFPs and testing aDBS, and to establish effective stimulation parameters (appendix e-1, http://links.lww.com/WNL/A238). Because, according to the literature,⁹ we expected that the beta peak was not detectable in all patients and because the current aDBS algorithm is based on beta band modulations, those not showing a beta peak were excluded from the study.

The experimental protocol (figure 1A) included two 8-hour sessions (1 per day) conducted with a portable aDBS prototype device⁹: day 1, stimulation “off” and LFP recordings “on”; and day 2, stimulation “on” (aDBS) and LFP recordings “on.”

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Figure 1 Experimental protocol and aDBS functioning

(A) Top timeline shows the activities recorded during the 8 hours (10 am–6 pm) for a representative patient. Middle plot represents the activity index (i.e., a custom index based on accelerometer data in the band of 0.5–4 Hz representing the amount of motor activity) corresponding to each activity, and the bottom trace is beta power percentage change from baseline throughout the 8 hours. Bottom arrows show the times in which the patient was assessed (baseline, peak dose 1, end dose 1, peak dose 2, end dose 2) and received levodopa. (B) Beta power changes from baseline in day 1 (top trace) and day 2 (bottom trace) of a representative patient (patient 4). The x-axis represents time (hours) and y-axis represents percent beta power change from baseline. Gray rectangles highlight beta power during clinical assessments (baseline, peak dose 1, end dose 1, peak dose 2, end dose 2). (C) Average beta power changes from baseline in day 1 (top trace) and day 2 (bottom trace). Only the time windows of ±10 minutes around clinical assessments were represented to allow averaging among patients. The x-axis represents time (hours) and y-axis represents percent beta power change from baseline. Gray rectangles highlight beta power during clinical assessments (baseline, peak dose 1, end dose 1, peak dose 2, end dose 2). aDBS = adaptive deep brain stimulation; AU = arbitrary units; UPDRS = Unified Parkinson's Disease Rating Scale.

After 12 hours of medication withdrawal, each session started with a baseline assessment (medication “off,” stimulation “off”). The patient took his/her first morning medication afterward and was then assessed when his/her medication was effective (medication “on,” peak dose ≈45–60 minutes after medication intake) and then when the medication ended its effects (medication “off,” end dose 60–90 minutes after the peak dose). The same procedure was repeated throughout the 8 hours (figure 1A). According to the personal response timing, each patient took 2 or 3 medications. Hence, to allow comparisons, we considered the clinical assessments related to the first 2 administrations. On day 2, DBS was switched “on” at the beginning of the experimental session, immediately after the baseline assessment. The clinical assessments on day 2 followed the same schema as on day 1, according to levodopa response (peak dose, end dose).

For the clinical assessment, we collected the Unified Parkinson's Disease Rating Scale, part III, motor part (UPDRS III), the Unified Dyskinesias Rating Scale (UDysRS), parts 3 and 4, and the adverse events (AEs) experienced by the patient (appendix e-1, http://links.lww.com/WNL/A238 for AE classification).

To assess the aDBS device function throughout the whole 8-hour session, we collected the beta band power and, on day 2, the stimulation amplitude. We correlated the clinical assessment with the beta power corresponding to the time at which the UPDRS III was assessed (±10 minutes). We also collected the patient's physical activity using a wearable commercial bracelet equipped with a 3-axis accelerometer. A dedicated application was developed to acquire and store data and to provide a clinical diary (sleep, rest, walk, talk, eat, other) to be filled in by the patient every 30 minutes.

We used data on day 1 to verify the ability of beta band power to act as a biomarker of patient's state, and more specifically, we tested whether the beta power was modulated by levodopa using nonsupraliminar levodopa doses (paired t test beta power “off” vs beta power “on,” p < 0.05), the beta power correlated to the patient's clinical state as measured by the UPDRS III (Pearson correlation coefficient, p < 0.05), and the beta power correlated with the specific physical activities as measured by the wearable bracelet (Pearson correlation coefficient, p < 0.05).

aDBS efficacy was assessed by a comparison of clinical data (UPDRS III and UDysRS) collected on day 1 vs 2 (3-way analysis of variance [ANOVA] with the factors day [2 levels, day 1 and day 2], condition [2 levels, medication “on” and medication “off”], and administration [2 levels, administration 1 and administration 2]). aDBS safety was verified by the occurrence and intensity of AEs related to stimulation. Data here are reported as mean ± standard error.