Abstract
Coordinated reset deep brain stimulation (CR DBS) in the subthalamic nucleus (STN) has been demonstrated effective for the treatment of the motor signs associated with Parkinson's disease (PD). A critical CR parameter is an order in which stimulation is delivered across contacts. The relative effect of alternating vs. not alternating this order, i.e., shuffling vs. non-shuffling, however, has not been evaluated in vivo. The objective of this study is to compare the effect of shuffled vs. non-shuffled STN CR DBS on Parkinsonian motor signs. Two Parkinsonian non-human primates were implanted with a DBS lead in the STN. The effects of STN CR DBS with and without shuffling were compared with the traditional isochronal DBS (tDBS) using a within-subject design. For each stimulation setting, DBS was delivered for 2 or 4 h/day for 5 consecutive days. The severity of PD was assessed using a modified clinical rating scale immediately before, during, and 1 h after DBS, as well as on days following the discontinuation of the 5 days of daily stimulation, i.e., carryover effect. Shuffled STN CR DBS produced greater acute and carryover improvements on Parkinsonian motor signs compared with non-shuffled CR. Moreover, this difference was more pronounced when more effective stimulation intensity and burst frequency settings were used. tDBS showed limited carryover effects. Given the significant effect of shuffling on the effectiveness of CR DBS, it will be critical for future studies to further define the relative role of different CR parameters for the clinical implementation of this novel stimulation paradigm.
Highlights
High frequency isochronal “traditional” deep brain stimulation is an established treatment for the motor signs associated with Parkinson’s disease (PD)
We present a case series of two Parkinsonian non-human primates (NHPs) where we explored the relative effect of shuffled vs. non-shuffled subthalamic nucleus (STN) coordinated reset (CR) deep brain stimulation (DBS) using a within-subject design
Carryover effects: the sub-acute carryover effect gradually improved over days in the shuffled Coordinated reset deep brain stimulation (CR DBS) condition, achieving up to 21% improvement in the modified Unified Parkinson’s Disease Rating Scale (mUPDRS) during stimulation days 3–5, while non-shuffled CR DBS fluctuated in the range of −12–4% change in the mUPDRS (Figure 2B)
Summary
High frequency isochronal “traditional” deep brain stimulation (tDBS) is an established treatment for the motor signs associated with Parkinson’s disease (PD). DBS lead and is hypothesized to induce a desynchronizing effect at lower current intensities than that required with tDBS [6, 7]. CR DBS has been shown in both preclinical and clinical studies to produce acute motor improvement similar to tDBS with the added benefit that motor improvement would persist for hours, days, or weeks following discontinuation of stimulation, i.e., carryover effect [8,9,10]. It may reduce the incidence of side effects by minimizing the current spread
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