Resources:Electrical stimulation of cranial nerves in cognition and disease

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Title	Electrical stimulation of cranial nerves in cognition and disease
Authors	Devin Adair · Dennis Truong · Zeinab Esmaeilpour · Nigel Gebodh · Helen Borges · Libby Ho · J. Douglas Bremner · Bashar W. Badran · Vitaly Napadow · Vincent P. Clark · Marom Bikson
Source	Document
Original	https://www.brainstimjrnl.com/action/showPdf?pii=S1935-861X%2820%2930041-3
Date	18 July 2019
Journal	Brain Stimulation
DOI	10.1016/j.brs.2020.02.019
PUBMED	https://pubmed.ncbi.nlm.nih.gov/32289703/
License	CC BY
This resource has been identified as a Free Scientific Resource, this is why Masticationpedia presents it here as a mean of gratitude toward the Authors, with appreciation for their choice of releasing it open to anyone's access

Electrical stimulation of cranial nerves in cognition and disease

Free resource by Devin Adair  · Dennis Truong · Zeinab Esmaeilpour  · Nigel Gebodh · Helen Borges  · Libby Ho  · J. Douglas Bremner  · Bashar W. Badran  · Vitaly Napadow  · Vincent P. Clark  · Marom Bikson

Abstract

The cranial nerves are the pathways through which environmental information (sensation) is directly communicated to the brain, leading to perception, and giving rise to higher cognition. Because cranial nerves determine and modulate brain function, invasive and non-invasive cranial nerve electrical stimulation methods have applications in the clinical, behavioral, and cognitive domains. Among other neuromodulation approaches such as peripheral, transcranial and deep brain stimulation, cranial nerve stimulation 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 and biophysics;
2) evidence of the modulatory effects of cranial nerves on cognition;
3) clinical and behavioral outcomes of cranial nerve stimulation; and
4) biomarkers of nerve target engagement including physiology, electroencephalography, neuroimaging, and behavioral metrics.
Existing non-invasive stimulation methods cannot feasibly activate the axons of only individual cranial nerves. Even with invasive stimulation methods, selective targeting of one nerve fiber type requires nuance since each nerve is composed of functionally distinct axon-types that differentially branch and can anastomose onto other nerves. None-the-less, precisely controlling stimulation parameters can aid in affecting distinct sets of axons, thus supporting specific actions on cognition and behavior. To this end, a rubric for reproducible dose-response stimulation parameters is defined here. Given that afferent cranial nerve axons project directly to the brain, targeting structures (e.g. thalamus, cortex) that are critical nodes in higher order brain networks, potent effects on cognition are plausible. We propose an intervention design framework based on driving cranial nerve pathways in targeted brain circuits, which are in turn linked to specific higher cognitive processes. State-of-the-art current flow models that are used to explain and design cranial-nerve-activating stimulation technology require multi-scale detail that includes: gross anatomy; skull foramina and superficial tissue layers; and precise nerve morphology. Detailed simulations also predict that some non-invasive electrical or magnetic stimulation approaches that do not intend to modulate cranial nerves per se, such as transcranial direct current stimulation (tDCS) and transcranial magnetic stimulation (TMS), may also modulate activity of specific cranial nerves. Much prior cranial nerve stimulation work was conceptually limited to the production of sensory perception, with individual titration of intensity based on the level of perception and tolerability. However, disregarding sensory emulation allows consideration of temporal stimulation patterns (axon recruitment) that modulate the tone of cortical networks independent of sensory cortices, without necessarily titrating perception. For example, leveraging the role of the thalamus as a gatekeeper for information to the cerebral cortex, preventing or enhancing the passage of specific information depending on the behavioral state. 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 how specific 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/).

Introduction

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. 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.

Table 1

Summary of cranial nerve modality, conduction direction and function. The modality describes the type of information each nerve conducts. Classic modality are the designations given by anatomists; SVA – special visceral afferent; SSA – special sensory afferent; GSA – general sensory afferent; SVE – special visceral efferent; GVE –general visceral efferent; GSE – general sensory efferent, A– Afferent, E − Efferent. Cranial nerves that contain at least one major afferent branch — characterized fully in this review — are bolded.

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Cranial Nerves	Modality	Classic Modality	↔	Function
I (Olfaction)	Special sensory	SVA	A	Smell
II (Optic)	Special sensory	SSA	A	Vision
III (Oculomotor)	Parasympathetic motor	GVE	E	Parasympathetic control of eye muscles
	Somatic motor	GSE	E
IV (Trochlear)	Somatic motor	GSE	E	Motor control of eye muscles
V (Trigeminal)	Somatic sensory	GSA	A	Touch from face
	Branchial motor	SVE	E	Motor control of mastication
VI (Abducens)	Somatic motor	GSE	E	Control of muscles of the eyes
VII (Facial)	Somatic sensory Visceral sensory	GSA	A	Touch from ear
		SVA	A	Taste
	Parasympathetic motor Branchial motor	GVE	E	Parasympathetic control of oral/nasal/tongue glands
		SVE	E	Muscles of the face
VIII (Vestibulocochlear)	Somatic sensory	SSA	A	Balance/hearing
IX (Glossopharyngeal)	Somatic sensory	GSA	A	Sensation from the tongue
	Visceral sensory	SVA/GVA	A	Sensation from the carotid body and sinus; taste
	Parasympathetic motor	GVE	E	Parasympathetic control of glands and mucosa
	Branchial motor	SVE	E	Control of facial muscles
X (Vagus)	Somatic Sensory	GSA	A	Touch from the ear
	Visceral sensory	SVA/GVA	A	Taste; sensory info from the pharynx, larynx, abdomen, heart
	Parasympathetic motor	GVE	E	Parasympathetic control of smooth muscle and glands in the body and throat
	Branchial motor	SVE	E	Motor control of the pharynx and larynx
XI (Accessory)	Branchial/Somatic motor	SVE	E	Control of sternocleidomastoid and trapezius muscles
XII (Hypoglossal)	Somatic motor	GSE	E	Muscles of the tongue

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Classic modality are the designations given by anatomists; SVA – special visceral afferent; SSA – special sensory afferent; GSA – general sensory afferent; SVE – special visceral efferent; GVE –general visceral efferent; GSE – general sensory efferent, A– Afferent, E − Efferent. Cranial nerves that contain at least a major afferent branch — characterized fully in this review — are bolded.

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Here we develop a formalism to design cranial nerve stimulation by leveraging insight from modern biomedical engineering and neuroscience (i.e. biomarkers) – in order to target specific cognitive constructs and behaviors that may be linked to neuropsychiatric disorders. We focus mainly on nerves that contain a major sensory (or afferent) component, however in some cases it can be challenging to disambiguate the cognitive effects of cranial nerves stimulation on afferents vs. efferents (see sec.5). Our overall approach is to focus on each afferent cranial nerve that modulates a specific brain circuit -- including those circuits involved in lower and higher-level processes - providing a rational basis to target specific cognitive functions by optimized cranial nerve stimulation. Indeed, while transcranial approaches (e.g. TMS and tDCS) or some invasive approaches (e.g. certain forms of DBS) inevitably stimulate a complex constellation of neurons, cranial nerve stimulation allows (with limitations discussed) activation of targeted pathways into the CNS using minimally or non-invasive technology.

There is a large body of literature on the modulation of cranial nerves by electrical stimulation for both therapeutic and experimental applications; however, these studies are variable in methodology and conclusions. The clinical neuroanatomy of each cranial nerve have been explored 5, but nuance continues to emerge in anatomy and function [[6],[7] ]. Some of the earliest applications of electrical stimulation to cranial nerves were to treat neurological disorders such as seizures [[8],[9]] and sensory dysfunctions [e.g., vision loss, equilibrium damage; 10, 11]. Subsequent inclusion of broader clinical indications — including neuropsychiatric disorders -- have furthered knowledge of how activity of early sensory systems through cranial nerves can influence higher cognitive processes [12, 13, 14]. This improved understanding has driven the expansion of devices geared towards a variety of applications including treatment of specific disorders as well as enhancement of cognitive and other functions [15, 16, 17].

Neuroimaging and neurophysiological techniques can further characterize the response of cranial nerve activation, and potentially act as biomarkers of target engagement. For example, electrically induced evoked potentials (EPs) measured using electroencephalography (EEG) can be used to monitor a variety of nerve functions 22. Auditory and visual EPs measured with electroencephalography (EEG) are used for a variety of diagnostic purposes in neurology to validate electrical stimulation of cranial nerves and as an adjunctive tool in neurosurgery [[23],[24]] The use of EEG measurement of EPs has been used to validate non-invasive electrical stimulation of cranial nerves as well [25, 26, 27]. Functional magnetic resonance imaging (fMRI), magnetoencephalography (MEG) and positron emission tomography (PET) can be used to examine both subcortical and cortical activation induced by targeted cranial nerve electrical stimulation [28, 29, 30, 31, 32]. Potential biomarkers can be developed through neural signatures evoked by electrically stimulating cranial nerve(s), in both healthy and dysfunctional subjects [[2],[33]], but only if they are distinct and reliable. Examples of the electrically evoked potentials and induced network effects explored as measures of cranial nerve function are summarized in Table 2 and expanded on for each nerve in the text.

Bibliography & references