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== Introduction ==

== Introduction ==

Cognition is conceptualized as the processing of informationacquired through the senses. The central nervous system (CNS;nerves within the brain and spine) integrates and responds tosignals transmitted by the peripheral nervous system (PNS; nervesoutside the brain and spine), whose primary function is to connectthe CNS with the rest of the body and the environment [1]. Thecranial nerves are a specialized part of the PNS that emerge directlyfrom the brain rather than through the spine and include both af-ferents and efferents. Afferent cranial nerve axons convey sensoryinformationdsight, hearing, taste (gustation), touch (heat, pres-sure, pain, proprioception), smell (olfaction), interoception (inputfrom the gut and internal organs), and equilibriumdto the brain.Efferent cranial nerves’axons regulate muscles (smooth, skeletal,and cardiac) and glands (either directly or through a postganglionicaxon;Table 1). In contrast to other peripheral nerves thatfirst routethrough the spinal cord, cranial nerves project directly through theskull into the brain, which makes them a special target for neuro-modulation. For each cranial nerve, there is a portion that is rela-tively accessible (extra-cranial), and each nerve is intimately linkedto perception and regulation of CNS function, including established“bottom-up”functions in cognition and clinical disorders [2e4].Here we develop a formalism to design cranial nerve stimulationby leveraging insight from modern biomedical engineering andneuroscience (i.e. biomarkers)ein order to target specificcognitiveconstructs and behaviors that may be linked to neuropsychiatricdisorders. We focus mainly on nerves that contain a major sensory(or afferent) component, however in some cases it can be chal-lenging to disambiguate the cognitive effects of cranial nervesstimulation on afferents vs. efferents (see sec.5). Our overallapproach is to focus on each afferent cranial nerve that modulates aspecific brain circuit–including those circuits involved in lower andhigher-level processes - providing a rational basis to target specificcognitive functions by optimized cranial nerve stimulation. Indeed,while transcranial approaches (e.g. TMS and tDCS) or some invasiveapproaches (e.g. certain forms of DBS) inevitably stimulate a com-plex constellation of neurons, cranial nerve stimulation allows (withlimitations discussed) activation of targeted pathways into the CNSusing minimally or non-invasive technology.There is a large body of literature on the modulation of cranialnerves by electrical stimulation for both therapeutic and experi-mental applications; however, these studies are variable in meth-odology and conclusions. The clinical neuroanatomy of each cranialnerve have been explored [5], but nuance continues to emerge inanatomy and function [6,7]. Some of the earliest applications ofelectrical stimulation to cranial nerves were to treat neurologicaldisorders such as seizures [8,9] and sensory dysfunctions [e.g.,vision loss, equilibrium damage; 10, 11]. Subsequent inclusion ofbroader clinical indicationsdincluding neuropsychiatric disorders–have furthered knowledge of how activity of early sensory sys-tems through cranial nerves can influence higher cognitive pro-cesses [12e14]. This improved understanding has driven theexpansion of devices geared towards a variety of applicationsincluding treatment of specific disorders as well as enhancement ofcognitive and other functions [15e17]

Cognition is conceptualized as the processing of information acquired through the senses. The central nervous system (CNS; nerves within the brain and spine) integrates and responds to signals transmitted by the peripheral nervous system (PNS; nerves outside the brain and spine), whose primary function is to connect the CNS with the rest of the body and the environment [[1]

]. The cranial nerves are a specialized part of the PNS that emerge directly from the brain rather than through the spine and include both afferents and efferents. Afferent cranial nerve axons convey sensory information —sight, hearing, taste (gustation), touch (heat, pressure, pain, proprioception), smell (olfaction), interoception (input from the gut and internal organs), and equilibrium— to the brain. Efferent cranial nerves’ axons regulate muscles (smooth, skeletal, and cardiac) and glands (either directly or through a postganglionic axon; Table 1). In contrast to other peripheral nerves that first route through the spinal cord, cranial nerves project directly through the skull into the brain, which makes them a special target for neuromodulation. For each cranial nerve, there is a portion that is relatively accessible (extra-cranial), and each nerve is intimately linked to perception and regulation of CNS function, including established “bottom-up” functions in cognition and clinical disorders [2, 3, 4].

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