Towards optimizing target engagement in non-invasive trigeminal nerve stimulation: anatomical characterization of the human trigeminal nerve

<i>Objective.</i>Cranial nerve stimulation 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 attention deficit hyperactivity disorder. 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.<i>Approach.</i>This study characterizes the anatomical course and tissue composition of the SON, ION, and MN using five human donors. Computed tomography imaging was used to localize each nerve's 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 an illustrative finite element model to assess the effect of interface properties on activation of on- and off-target neural pathways.<i>Main results.</i>Cadaveric measurements, histological analyses, and imaging outline the depths, branching patterns, and fascicular organization within the trigeminal nerve branches. The SON was found to be significantly more superficial than the ION and MN with a higher nerve-to-connective tissue ratio compared to the MN. Our illustrative modeling demonstrated that depth was a driving factor for neural activation and sensitivity to skin impedance properties.<i>Significance.</i>The SON presents the most accessible and anatomically favorable target for transcutaneous TNS among the branches examined due to its superficial location. Consistent with our previous work, however, preferential activation of low-threshold nociceptors compared to nerve trunks may lead to treatment-limiting off-target side effects. These findings offer an anatomically informed framework to guide further modeling, electrode design, and<i>in situ</i>imaging of nerve branching patterns to better estimate activation of on- and off- target pathways.