Structural Connectivity of Subthalamic Nucleus Stimulation for Improving Freezing of Gait

Article type: Research Article

Authors: Strelow, Joshua N.^{a; b; 1; *} | Baldermann, Juan C.^{a; c; 1} | Dembek, Till A.^a | Jergas, Hannah^a | Petry-Schmelzer, Jan N.^a | Schott, Frederik^d | Dafsari, Haidar S.^a | Moll, Christian K.E.^e | Hamel, Wolfgang^d | Gulberti, Alessandro^e | Visser-Vandewalle, Veerle^b | Fink, Gereon R.^{a; f} | Pötter-Nerger, Monika^d | Barbe, Michael T.^a

Affiliations: [a] Department of Neurology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany | [b] Department of Stereotactic and Functional Neurosurgery, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany | [c] Department of Psychiatry and Psychotherapy, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany | [d] Department of Neurology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany | [e] Department of Neurophysiology and Pathophysiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany | [f] Cognitive Neuroscience, Institute of Neuroscience and Medicine (INM-3), Jülich Research Center, Jülich, Germany

Correspondence: [*] Correspondence to: Joshua Niklas Strelow, MSc, Department of Neurology, Department of Stereotactic and Functional Neurosurgery, University Hospital Cologne, Kerpenerstr. 62, 50937 Cologne, Germany. E-mail: [email protected].

Note: [1] These authors contributed equally to this work.

Abstract: Background:Freezing of gait (FOG) is among the most common and disabling symptoms of Parkinson’s disease (PD). Studies show that deep brain stimulation (DBS) of the subthalamic nucleus (STN) can reduce FOG severity. However, there is uncertainty about pathways that need to be modulated to improve FOG. Objective:To investigate whether STN-DBS effectively reduces FOG postoperatively and whether structural connectivity of the stimulated tissue explains variance of outcomes. Methods:We investigated 47 patients with PD and preoperative FOG. Freezing prevalence and severity was primarily assessed using the Freezing of Gait Questionnaire (FOG-Q). In a subset of 18 patients, provoked FOG during a standardized walking course was assessed. Using a publicly available model of basal-ganglia pathways we determined stimulation-dependent connectivity associated with postoperative changes in FOG. A region-of-interest analysis to a priori defined mesencephalic regions was performed using a disease-specific normative connectome. Results:Freezing of gait significantly improved six months postoperatively, marked by reduced frequency and duration of freezing episodes. Optimal stimulation volumes for improving FOG structurally connected to motor areas, the prefrontal cortex and to the globus pallidus. Stimulation of the lenticular fasciculus was associated with worsening of FOG. This connectivity profile was robust in a leave-one-out cross-validation. Subcortically, stimulation of fibers crossing the pedunculopontine nucleus and the substantia nigra correlated with postoperative improvement. Conclusion:STN-DBS can alleviate FOG severity by modulating specific pathways structurally connected to prefrontal and motor cortices. More differentiated FOG assessments may allow to differentiate pathways for specific FOG subtypes in the future.

Keywords: Basal-ganglia pathways, deep brain stimulation, dorsolateral prefrontal cortex, freezing of gait, Freezing of Gait Questionnaire, globus pallidus, lenticular fasciculus, nucleus subthalamicus, supplementary motor area, Unified Parkinson’s Disease Rating Scale

DOI: 10.3233/JPD-212997

Journal: Journal of Parkinson's Disease, vol. 12, no. 4, pp. 1251-1267, 2022