Dissecting the Network Physiology of Pallidal Burst Stimulation

About This Grant

PROJECT SUMMARY Despite being an established RCT-supported therapy, the adoption of deep brain stimulation (DBS) for Parkinson’s disease (PD) remains relatively low. While partly due to being a surgical therapy, adoption is further hindered by limited clinical benefit, off-target side-effects, and the burden of generator replacement surgery or battery charging. These limitations are at least in part attributable to the use of relatively simplistic fixed high- frequency stimulation. Recent optogenetic and computational modeling work has shown that finely tuned intermittent burst-patterned pallidal DBS can differentially modulate specific cell types and produce motor benefits that endure beyond stimulation cessation. Our team’s pilot study in people with Parkinson's disease (PwPD) comparing conventional and burst-DBS in globus pallidus internus (GPi) showed equal efficacy and tolerability, motivating further investigation. A mechanistic understanding of the physiological underpinning of therapeutic benefits of burst-DBS is critical to optimizing and ultimately facilitating translation of pallial burst DBS for PwPD, thereby addressing the limitations of fixed high-frequency DBS. While early results are encouraging, questions remain about the relevance and optimal location and burst-DBS frequency for long-lasting benefits in the human basal-ganglia-thalamo-cortical (BGTC) motor network. We will utilize our team’s expertise in intracranial physiology and PD to analyze BGTC circuits through recordings of single-neuron and evoked potential dynamics, local field potentials (LFP), electrocorticography, and network physiology. We focus on the GPi because its main sources of input are the two basal ganglia structures implicated in preclinical work (striatum and globus pallidus externus), both of which are underactive in circuit theories of PD. We address our hypothesis through 3 aims. AIM 1: Identify the optimal location and frequency for GPi burst-DBS through functional circuit mapping: We will define human-specific settings and location for producing the most potent antiparkinsonian modulations of BGTC neurophysiological PD readouts in response to intraoperative burst-DBS. AIM 2: Validate LTP effects of the optimized burst-DBS paradigm and derive brain-behaviour relationships: We will critically assess spatiotemporal neural features to demonstrate that burst DBS produces beneficial forms of LTP in the BGTC circuit, and to provide proof-of-principle of sustained benefit on a short timescale in response to intraoperative burst-DBS. AIM 3: Demonstrate subacute neural corelates of personalized burst-DBS benefit & relapse dynamics: We will leverage sensing-enabled DBS devices to evaluate acute (during burst-DBS) and enduring (beyond stimulation cessation) antiparkinsonian therapeutic effects and neurophysiology of personalized burst-DBS in the outpatient setting, in order to determine whether LFP and/or cortical recordings can be used as functional proxies to track enduring motor benefits and as biomarkers for closed-loop burst-DBS. Our work has the potential to improve therapy by providing a biological foundation for future large scale clinical trials assessing long-term outcomes of optimized GPi burst-DBS.