ORIGINAL RESEARCH published: 08 June 2021 doi: 10.3389/fnhum.2021.676755 Edited by: Casey Halpern, Stanford University, United States Reviewed by: Arun Singh, University of South Dakota, United States Gabriel Gonzalez-Escamilla, Johannes Gutenberg University Mainz, Germany *Correspondence: Stephano J. Chang jxc1557@med.miami.edu Jonathan R. Jagid jjagid@miami.edu Specialty section: This article was submitted to Brain Imaging and Stimulation, a section of the journal Frontiers in Human Neuroscience Received: 05 March 2021 Accepted: 11 May 2021 Published: 08 June 2021 Citation: Chang SJ, Cajigas I, Guest JD, Noga BR, Widerström-Noga E, Haq I, Fisher L, Luca CC and Jagid JR (2021) 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. Front. Hum. Neurosci. 15:676755. doi: 10.3389/fnhum.2021.676755 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 Stephano J. Chang 1,2 * , Iahn Cajigas 1,3 , James D. Guest 1,3 , Brian R. Noga 1,3 , Eva Widerström-Noga 1,3 , Ihtsham Haq 4 , Letitia Fisher 1,3 , Corneliu C. Luca 1,4 and Jonathan R. Jagid 1,3 * 1 The Miami Project to Cure Paralysis, Miami, FL, United States, 2 Department of Neurosurgery, University of British Columbia, Vancouver, BC, Canada, 3 Department of Neurological Surgery, University of Miami Miller School of Medicine, Miami, FL, United States, 4 Department of Neurology, University of Miami Miller School of Medicine, Miami, FL, United States Background: Freezing 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. Methods: As 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 Cartesia TM ) 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. Results: Post-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. Frontiers in Human Neuroscience | www.frontiersin.org 1 June 2021 | Volume 15 | Article 676755