Deep brain stimulation of terminating axons

Background: Deep brain stimulation (DBS) of the subthalamic region is an established treatment for the motor symptoms of Parkinson's disease. Several types of neural elements reside in the subthalamic region, including subthalamic nucleus (STN) neurons, fibers of passage, and terminating afferents. Recent studies suggest that direct activation of a specific population of subthalamic afferents, known as the hyperdirect pathway, may be responsible for some of the therapeutic effects of subthalamic DBS. Objective: The goal of this study was to quantify how axon termination affects neural excitability from DBS. We evaluated how adjusting different stimulation parameters influenced the relative excitability of terminating axons (TAs) compared to fibers of passage (FOPs). Methods: We used finite element electric field models of DBS, coupled to multi-compartment cable models of axons, to calculate activation thresholds for populations of TAs and FOPs. These generalized models were used to evaluate the response to anodic vs. cathodic stimulation, with short vs. long stimulus pulses. Results: Terminating axons generally exhibited lower thresholds than fibers of passage across all tested parameters. Short pulse widths accentuated the relative excitability of TAs over FOPs. Conclusion(s): Our computational results demonstrate a hyperexcitability of terminating axons to DBS that is robust to variation in the stimulation parameters, as well as the axon model parameters. (C) 2020 The Author(s). Published by Elsevier Inc.