Towards Optimizing Target Engagement in Non-Invasive Trigeminal Nerve Stimulation: Anatomical Characterization and Computational Modeling of the Human Trigeminal Nerve

ObjectiveCranial nerve stimulation (CNS) uses electric current to modulate higher-order brain activity and organ function via nerves, including the vagus and trigeminal, with applications in migraine, epilepsy, and pediatric ADHD. The trigeminal nerve is an emerging target for non-invasive neuromodulation due to the superficial trajectory of its branches, the supraorbital (SON), infraorbital (ION), and mental nerves (MN), and the predominantly sensory composition of the SON and ION. However, the parameters and outcomes of trigeminal nerve stimulation (TNS) remain varied. ApproachThis study characterizes the anatomical course, tissue composition, and activation profiles of the SON, ION, and MN using five human donors. CT imaging was utilized to localize each nerves exit foramen and distance to midline. Microdissections quantified nerve circumference and depth relative to the skin surface. Histological analysis described the number of fascicles and fascicular tissue area. Nerve depths were incorporated into computational models to illustrate the activation function across tissue layers, comparing expected nociceptor and nerve trunk activation functions as a measure of neural engagement. Main ResultsThe SON was found to be significantly more superficial than the ION and MN and had a higher nerve-to-connective tissue ratio relative to the MN. Computational modeling demonstrated that the activation function at the depths of nociceptors was orders of magnitude greater than within the main nerve trunks, suggesting preferential recruitment of cutaneous nociceptors, dependent on nociceptor density. SignificanceThe SON presents the most accessible and anatomically favorable target for transcutaneous trigeminal nerve stimulation among the branches examined due to its superficial location. However, preferential activation of low-threshold nociceptors compared to nerve trunks may lead to treatment-limiting off-target side effects, favoring strategies that target fibers of interest within the skin. These findings offer an anatomically informed framework to guide further computational modeling and electrode design for targeted trigeminal neuromodulation.