Abstract
BackgroundFreezing of gait (FOG) is a particularly debilitating motor deficit seen in a subset of Parkinson’s disease (PD) patients that is poorly responsive to standard levodopa therapy or deep brain stimulation (DBS) of established PD targets such as the subthalamic nucleus and the globus pallidus interna. The proposal of a DBS target in the midbrain, known as the pedunculopontine nucleus (PPN) to address FOG, was based on its observed pathology in PD and its hypothesized involvement in locomotor control as a part of the mesencephalic locomotor region, a functionally defined area of the midbrain that elicits locomotion in both intact animals and decerebrate animal preparations with electrical stimulation. Initial reports of PPN DBS were met with much enthusiasm; however, subsequent studies produced mixed results, and recent meta-analysis results have been far less convincing than initially expected. A closer review of the extensive mesencephalic locomotor region (MLR) preclinical literature, including recent optogenetics studies, strongly suggests that the closely related cuneiform nucleus (CnF), just dorsal to the PPN, may be a superior target to promote gait initiation.MethodsWe will conduct a prospective, open-label, single-arm pilot study to assess safety and feasibility of CnF DBS in PD patients with levodopa-refractory FOG. Four patients will receive CnF DBS and have gait assessments with and without DBS during a 6-month follow-up.DiscussionThis paper presents the study design and rationale for a pilot study investigating a novel DBS target for gait dysfunction, including targeting considerations. This pilot study is intended to support future larger scale clinical trials investigating this target.Trial registrationClinicalTrials.gov identifier: NCT04218526 (registered January 6, 2020)
Highlights
Freezing of gait (FOG) is a debilitating motor deficit seen in a subset of Parkinson’s disease (PD) patients that is poorly responsive to standard levodopa therapy or deep brain stimulation (DBS) of established PD targets such as the subthalamic nucleus and the globus pallidus interna
The importance of electrode targeting on efficacy in this region is reinforced by computer modeling studies, demonstrating that targeting errors of 1 mm can significantly decrease target activation selectivity [50]. This pilot study is designed to test the safety, feasibility, and preliminary efficacy of cuneiform nucleus (CnF) DBS in alleviating FOG. Through this and future larger scale studies, we aim to explore the hypothesis that the CnF represents the neuroanatomic basis of the mesencephalic locomotor region (MLR) and that suboptimal targeting may have played a role in the equivocal results of prior pedunculopontine nucleus (PPN) DBS studies
We hope to confirm the findings in Goetz et al [43], which suggest that minute changes in DBS target location in this area have significant impacts on clinical outcome and determine if CnF DBS may be a viable therapy for FOG and other gait dysfunctions
Summary
We will conduct a prospective, open-label, single-arm pilot study to assess safety and feasibility of CnF DBS in PD patients with levodopa-refractory FOG. Four patients will receive CnF DBS and have gait assessments with and without DBS during a 6-month follow-up
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