LAUSR

The motor hyperdirect pathway (HDP) is considered a key target in the treatment of Parkinson's disease with subthalamic deep brain stimulation (DBS). This hypothesis is partially derived from the association of HDP activation with evoked potentials (EPs) generated in the motor cortex and subthalamic nucleus (STN) after a DBS pulse. However, the biophysical details of how and when DBS-induced action potentials (APs) in HDP neurons reach their terminations in the cortex or STN remain unclear. Therefore, we used an anatomically detailed representation of the motor HDP, as well as the internal capsule (IC), in a model of human subthalamic DBS to explore AP activation and transmission in the HDP and IC. Our results show that small diameter HDP axons exhibited AP initiation in their subthalamic terminal arbor, which resulted in relatively long transmission latencies to cortex (~3.5-8 ms). Alternatively, large diameter HDP axons were most likely to be directly activated in the capsular region, which resulted in short transmission times to cortex (~1-3 ms). However, those large diameter HDP antidromic APs would be indistinguishable from any other IC axons that were also activated by the stimulus. Conversely, DBS-induced APs in both small and large diameter HDP axons reached their synaptic boutons in the STN with similar timings, but both spanned a wide temporal range. We also found that using anodic or bipolar stimulation helped to bias activation of the HDP over the IC. These computational results provide useful information for linking HDP activation with EP recordings in clinical experiments.