Quantifying axonal responses in patient-specific models of subthalamic deep brain stimulation

&NA; Medical imaging has played a major role in defining the general anatomical targets for deep brain stimulation (DBS) therapies. However, specifics on the underlying brain circuitry that is directly modulated by DBS electric fields remain relatively undefined. Detailed biophysical modeling of DBS provides an approach to quantify the theoretical responses to stimulation at the cellular level, and has established a key role for axonal activation in the therapeutic mechanisms of DBS. Estimates of DBS‐induced axonal activation can then be coupled with advances in defining the structural connectome of the human brain to provide insight into the modulated brain circuitry and possible correlations with clinical outcomes. These pathway‐activation models (PAMs) represent powerful tools for DBS research, but the theoretical predictions are highly dependent upon the underlying assumptions of the particular modeling strategy used to create the PAM. In general, three types of PAMs are used to estimate activation: 1) field‐cable (FC) models, 2) driving force (DF) models, and 3) volume of tissue activated (VTA) models. FC models represent the “gold standard” for analysis but at the cost of extreme technical demands and computational resources. Consequently, DF and VTA PAMs, derived from simplified FC models, are typically used in clinical research studies, but the relative accuracy of these implementations is unknown. Therefore, we performed a head‐to‐head comparison of the different PAMs, specifically evaluating DBS of three different axonal pathways in the subthalamic region. The DF PAM was markedly more accurate than the VTA PAMs, but none of these simplified models were able to match the results of the patient‐specific FC PAM across all pathways and combinations of stimulus parameters. These results highlight the limitations of using simplified predictors to estimate axonal stimulation and emphasize the need for novel algorithms that are both biophysically realistic and computationally simple.