(J-361) Optimal Location for Levodopa and Dyskinesia Reduction in Subthalamic Deep Brain Stimulation for Parkinson Disease

Introduction:: Parkinson disease (PD) is a neurodegenerative disorder resulting from the death of dopamine-releasing neurons. Levodopa, a precursor of dopamine, is a medication used to treat PD. However, as PD symptoms progress over time, levodopa dosage tends to increase. Like many medications, there may be a greater chance of side effects with increasing dosage, which can negatively impact overall patient outcome. Dyskinesia, characterized by involuntary and uncontrollable movements, is a common side effect of levodopa. When levodopa-induced side effects diminish the effectiveness of treatment, deep brain stimulation (DBS) becomes another option for PD patients. DBS involves the implantation of electrodes into the brain to deliver electrical impulses to specific regions. For PD, the standard target is the subthalamic nucleus (STN). STN DBS has been shown to reduce both levodopa and dyskinesia [1]. However, the mechanism of dyskinesia reduction is unclear because reduction may be due to stimulation directly or levodopa reduction indirectly. Thus, the optimal stimulation location for dyskinesia reduction in STN DBS is uncertain due to its connection with levodopa. Volume of tissue activation (VTA) modeling can be used to quantify the amount of stimulation within and around the DBS target. The aim of this study was to determine the optimal stimulation locations for levodopa and dyskinesia reduction to see if the locations overlapped or were distinct.


Materials and Methods:: Building on a modeling study that utilized individual neuroanatomy, electrode position, and electrical tissue conductivity from magnetic resonance, computed tomography, and diffusion tensor imaging, respectively [2], patient-specific STN and VTA point cloud data from 40 PD patients who received bilateral STN DBS were analyzed in MATLAB. Activation in the dorsal-ventral, lateral-medial, and anterior-posterior subthalamic regions was computed. STN activation was defined as the amount of VTA overlap with the STN (Figure 1). External activation was defined as the amount of the VTA outside the STN. Levodopa equivalent daily dose (LEDD) and dyskinesia scores for each patient were obtained from pre- and post-operative assessments (MDS-Unified Parkinson’s Disease Rating Scale Part IV). Stepwise regression was performed to evaluate the relationship between stimulation location and reduction in LEDD and dyskinesia. Additionally, the amount of activation in different subthalamic regions was compared between high responders (≥ 70%) and responders (< 70%) in terms of LEDD and dyskinesia reduction using Wilcoxon rank sum tests.


Results, Conclusions, and Discussions:: From pre- to post-operative assessment, LEDD (p = 3.72 x 10-7) and dyskinesia (p = 8.51 x 10-6) decreased significantly. However, LEDD and dyskinesia reduction did not correlate (r = 0.14, p = 0.45), suggesting that stimulation location may directly affect the reduction of dyskinesia, rather than indirectly via levodopa reduction. Dorsal STN activation correlated positively with LEDD reduction (r = 0.32, p = 0.01), whereas posterior external activation correlated negatively (r = -0.27, p = 0.03). Ventral external activation correlated negatively with dyskinesia reduction (r = -0.38, p = 0.003). High responders had significantly more dorsal (p = 0.0007), lateral (p = 0.006), and anterior (p = 0.02) STN activation than responders in terms of LEDD reduction. For dyskinesia reduction, high responders had significantly more dorsal external activation than responders (p = 0.006).
Overall, stimulation within the STN appears to explain LEDD reduction, whereas stimulation above the STN appears to explain dyskinesia reduction. Dyskinesia reduction after STN DBS may be due to stimulating the pallidothalamic fibers dorsal to the STN [1], specifically the lenticular fasciculus, which originates from the globus pallidus internus (GPi). Stimulation of these fibers may be comparable to GPi DBS, an alternative treatment for PD patients with low levodopa tolerance that is reported to have a direct effect on dyskinesia [3].


Acknowledgements (Optional): : The authors thank the patients included in this study for voluntary participation and their collaborators from the University of Michigan for clinical data.

References (Optional): : [1] Kim JH, Chang WS, Jung HH, Chang JW. Yonsei Med J. 2015 Sep;56(5):1316-21. [2] Malaga KA, Costello JT, Chou KL, Patil PG. Neuroimage Clin. 2021;29:102518. [3] Munhoz RP, Cerasa A, Okun MS. Front Neurol. 2014 Apr 29;5:65.