Deep brain stimulation of the Cuneiform nucleus for levodopa-resistant freezing of gait in Parkinson's disease: study protocol for a prospective, pilot trial

Abstract

Background: Freezing 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.

Methods: 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.

Discussion: This 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 registration: ClinicalTrials.gov identifier: NCT04218526 (registered January 6, 2020).

Keywords: Cuneiform nucleus (CnF); Freezing of gait (FOG); Gait dysfunction; Mesencephalic locomotor region (MLR); Parkinson’s disease; Pedunculopontine nucleus (PPN).

Conflict of interest statement

The study is funded in part by Boston Scientific through their Investigator Sponsored Research Award. JJ and CL have consulting agreements with Medtronic Inc., Boston Scientific, Inc., and Abbott Medical. JJ has two funded grants through Medtronic and Boston Scientific. The other authors declare that they have no competing interests.

Figures

Fig. 1

Three-dimensional anatomy of the human MLR and expected side effects of DBS. Reconstructions were made using Lead-DBS and available MNI-space subcortical atlases [44]. A separate CnF (cyan) NIfTI object was created in relation to the PPN (dark purple) based on Olszewski and Baxter’s Atlas [45]. A Sagittal projection (5 mm lateral to midline) of the CnF (cyan) and PPN (dark purple) with overlay of active contacts from PPN DBS patients with poor (red), good (green), best (blue), and unevaluated (yellow) gait outcomes from Goetz et al. [43]. B Diagonal 3D view with right ML and STT absent to visualize the MLR, projected on to a transverse slice of the brain at the level of the pons. C Chart lists nearby structures, their relation to the CnF, and expected side effects of stimulation. CnF Cuneiform nucleus, CTT central tegmental tract, dSCP decussation of superior cerebellar peduncle, LC locus coeruleus, ML medial lemniscus, PPN Pedunculopontine nucleus, RN red nucleus, STT spinothalamic tract. Adapted from Fig. 2 of [46] with permission

Fig. 2

Flow chart of study outline