| + | The cranial nerves are the pathways through which environmental information (sensation) is directlycommunicated to the brain, leading to perception, and giving rise to higher cognition. Because cranialnerves determine and modulate brain function, invasive and non-invasive cranial nerve electricalstimulation methods have applications in the clinical, behavioral, and cognitive domains. Among otherneuromodulation approaches such as peripheral, transcranial and deep brain stimulation, cranial nervestimulation is unique in allowing axon pathway-specific engagement of brain circuits, including thalamo-cortical networks. In this review we amalgamate relevant knowledge of 1) cranial nerve anatomy andbiophysics; 2) evidence of the modulatory effects of cranial nerves on cognition; 3) clinical and behav-ioral outcomes of cranial nerve stimulation; and 4) biomarkers of nerve target engagement includingphysiology, electroencephalography, neuroimaging, and behavioral metrics. Existing non-invasivestimulation methods cannot feasibly activate the axons of only individual cranial nerves. Even withinvasive stimulation methods, selective targeting of one nervefiber type requires nuance since eachnerve is composed of functionally distinct axon-types that differentially branch and can anastomose ontoother nerves. None-the-less, precisely controlling stimulation parameters can aid in affecting distinct setsof axons, thus supporting specific actions on cognition and behavior. To this end, a rubric for reproducibledose-response stimulation parameters is defined here. Given that afferent cranial nerve axons projectdirectly to the brain, targeting structures (e.g. thalamus, cortex) that are critical nodes in higher orderbrain networks, potent effects on cognition are plausible. We propose an intervention design frameworkbased on driving cranial nerve pathways in targeted brain circuits, which are in turn linked to specifichigher cognitive processes. State-of-the-art currentflow models that are used to explain and designcranial-nerve-activating stimulation technology require multi-scale detail that includes: gross anatomy;skull foramina and superficial tissue layers; and precise nerve morphology. Detailed simulations alsopredict that some non-invasive electrical or magnetic stimulation approaches that do not intend tomodulate cranial nerves per se, such as transcranial direct current stimulation (tDCS) and transcranialmagnetic stimulation (TMS), may also modulate activity of specific cranial nerves. Much prior cranialnerve stimulation work was conceptually limited to the production of sensory perception, with indi-vidual titration of intensity based on the level of perception and tolerability. However, disregardingsensory emulation allows consideration of temporal stimulation patterns (axon recruitment) thatmodulate the tone of cortical networks independent of sensory cortices, without necessarily titratingperception. For example, leveraging the role of the thalamus as a gatekeeper for information to thecerebral cortex, preventing or enhancing the passage of specific information depending on the behavioralstate. We show that properly parameterized computational models at multiple scales are needed to rationally optimize neuromodulation that target sets of cranial nerves, determining which and howspecific brain circuitries are modulated, which can in turn influence cognition in a designed manner.©2020 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY license(http://creativecommons.org/licenses/by/4.0/). |