MR Tractography-Based Targeting and Physiological Identification of the Cuneiform Nucleus for Directional DBS in a Parkinson’s Disease Patient With Levodopa-Resistant Freezing of Gait

Abstract

BackgroundFreezing of gait (FOG) is a debilitating motor deficit in a subset of Parkinson’s Disease (PD) patients that is poorly responsive to levodopa or deep brain stimulation (DBS) of established PD targets. The proposal of a DBS target in the midbrain, known as the pedunculopontine nucleus (PPN), to address FOG was based on its observed neuropathology in PD and its hypothesized involvement in locomotor control as a part of the mesencephalic locomotor region (MLR). Initial reports of PPN DBS were met with enthusiasm; however, subsequent studies reported mixed results. A closer review of the MLR basic science literature, suggests that the closely related cuneiform nucleus (CnF), dorsal to the PPN, may be a superior site to promote gait. Although suspected to have a conserved role in the control of gait in humans, deliberate stimulation of a homolog to the CnF in humans using directional DBS electrodes has not been attempted.MethodsAs part of an open-label Phase 1 clinical study, one PD patient with predominantly axial symptoms and severe FOG refractory to levodopa therapy was implanted with directional DBS electrodes (Boston Science Vercise CartesiaTM) targeting the CnF bilaterally. Since the CnF is a poorly defined reticular nucleus, targeting was guided both by diffusion tensor imaging (DTI) tractography and anatomical landmarks. Intraoperative stimulation and microelectrode recordings were performed near the targets with leg EMG surface recordings in the subject.ResultsPost-operative imaging revealed accurate targeting of both leads to the designated CnF. Intraoperative stimulation near the target at low thresholds in the awake patient evoked involuntary electromyography (EMG) oscillations in the legs with a peak power at the stimulation frequency, similar to observations with CnF DBS in animals. Oscillopsia was the primary side effect evoked at higher currents, especially when directed posterolaterally. Directional DBS could mitigate oscillopsia.ConclusionDTI-based targeting and intraoperative stimulation to evoke limb EMG activity may be useful methods to help target the CnF accurately and safely in patients. Long term follow-up and detailed gait testing of patients undergoing CnF stimulation will be necessary to confirm the effects on FOG.Clinical Trial RegistrationClinicaltrials.gov identifier: NCT04218526.

Stimulation of the cuneiform nucleus enables training and boosts recovery after spinal cord injury

“…Acute deep brain stimulation (DBS) of the MLR transiently improved hindlimb stepping in a first study in rats with incomplete SCI. 22 DBS is considered minimally invasive and safe, 33 and stimulating the PPN 34 , 35 and CNF 36 can reduce locomotor symptoms associated with Parkinson’s disease. Even though the relative contribution of PPN and CNF to observed locomotor effects is still a matter of debate, 6 , 37 current literature suggests the CNF as promising target for therapeutic DBS to improve impaired locomotion after neurotrauma.…”

Functional contribution of mesencephalic locomotor region nuclei to locomotor recovery after spinal cord injury

“… 54 Such variability, also reported in several animal models of PD, 55 , 56 has recently raised questions about the efficacy of the stimulation parameters and the anatomic correlates of the MLR. 57 , 58 …”

Neurophysiological mechanisms of gait disturbance in advanced Parkinson's disease patients

“… 27,54–56 Because ACh, NA, and 5‐HT neurons exhibit firing alteration according to awake–sleep cycles, 38,53 the cholinergic–monoaminergic reciprocity may contribute to state‐dependent excitability modification of the cortical and subcortical structures. It should be noted that the PPN/MLR area is one of the targets of deep brain stimulation (DBS) for surgical therapeutics of posture‐gait disturbance in PD 57 …”

“…It should be noted that the PPN/MLR area is one of the targets of deep brain stimulation (DBS) for surgical therapeutics of posture-gait disturbance in PD. 57…”