If you don't remember your password, you can reset it by entering your email address and clicking the Reset Password button. You will then receive an email that contains a secure link for resetting your password
If the address matches a valid account an email will be sent to __email__ with instructions for resetting your password
Department of Psychiatry & Behavioral Sciences and Radiology, Emory University School of Medicine, Atlanta, GA, USAAtlanta VA Medical Center, Decatur, GA, USA
Psychology Clinical Neuroscience Center, Dept. Psychology, MSC03-2220, University of New Mexico, Albuquerque, NM, 87131, USADepartment of Psychology, University of New Mexico, Albuquerque, NM, 87131, USAThe Mind Research Network of the Lovelace Biomedical Research Institute, 1101 Yale Blvd. NE, Albuquerque, NM, 87106, USA
Cranial nerves are unique neuromodulation targets, with high specificity and minimally-invasive deep brain stimulation.
•
Cranial nerve stimulation activates specific brain circuits linked to specific clinical, behavioral, and cognitive domains.
•
Cranial nerve neuromodulation may leverage or be independent of perception, including modulation of processing thalamus.
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.
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 1Summary 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.
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
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.
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 [
] 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 [
Noninvasive transorbital alternating current stimulation improves subjective visual functioning and vision-related quality of life in optic neuropathy.
]. 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 [
Limited output transcranial electrical stimulation (LOTES-2017): engineering principles, regulatory statutes, and industry standards for wellness, over-the-counter, or prescription devices with low risk.
Drawing from clinical experience, researchers have used electrical stimulation to replace a natural stimulus to measure the response of specific sensory systems. For example, using electrical stimulation to elicit flashes of light rather than using a light source [
Experimental-design specific changes in spontaneous EEG and during intermittent photic stimulation by high definition transcranial direct current stimulation.
]. While delivering light and sound stimuli to their respective sensory systems is a well characterized and more quantifiable process (allowing for a more precise psychophysical measurements), other sensory systems pose more of a challenge. Therefore, the study of touch, olfaction (smell), gustation (taste), and balance have all applied electrical stimulation, in lieu of natural stimuli, to sensory organs or directly to the nerves as a way to investigate the processing pathway of their respective sensory modalities [
]. Such trials are reviewed here and provide guidance on target engagement (evidence a given pathway is activated), while we also propose a framework where brain circuits can be modulated by patterns of cranial nerve stimulation independent of sensory emulation.
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 [
]. 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 [
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 [
]. Potential biomarkers can be developed through neural signatures evoked by electrically stimulating cranial nerve(s), in both healthy and dysfunctional subjects [
], 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.
Table 2Selected electrophysiological markers of electrical stimulation of cranial nerves. Evoked potentials are locked to the presentation of an electrical stimulus. Induced activity is not locked to a stimulus.
Sensory dysfunction has been implicated in range of neurological and psychiatric disorders. Under a hypothesis that primary sensory dysfunction has a causal role in brain disorders, then cranial nerve stimulation that acts as substitute for sensory stimuli may be therapeutic (e.g. directly treat neuro-psychiatric disorders associated with sensory/bottom-up dysregulation). Alternatively, change in sensory function (mediated by cranial nerves) functions are epiphenomena to the neuropsychiatric symptoms (e.g. non-specific neurodegeneration). In any case, the brain circuits involved in processing sensory input from a cranial nerve could overlap with those circuits underlying disease symptoms – in this sense, cranial nerve electrical stimulation provides a direct pathway to those circuits, but not necessarily dependent on sensory stimulus substitution.
We develop here a framework where cranial nerves are viewed as unique brain stimulation targets amenable to targeted therapeutic intervention. Minimally- or non-invasive cranial nerve stimulation can be used to modify higher level cortical function in a more specific fashion than is possible with other brain stimulation techniques, provide a nuanced understanding of the brain circuits specific cranial nerve activity is able to modulate. This review integrates knowledge relevant to electrical neuromodulation of cranial nerves that spans the fields of anatomy, electrophysiology, bioengineering, cognitive and clinical neuroscience, psychiatry and neurology. Advancing the science of cranial nerve stimulation as a path to modulate cognition first requires a detailed review of existing knowledge from these fields. This includes a contextual review by cranial nerve involving stimulation trials where changes in cognition were accessed (Table 3). There is an extensive medical literature on the gross anatomy and function of cranial nerves in health and disease [
]. Electrophysiologists and bioengineers have characterized the biophysics and morphology of axons within these nerves and their cellular response to electrical stimulation [
]. Cognitive neuroscientists are ultimately interested in how signals are integrated along the sensory pathway from the periphery to the brain, and how cranial nerves effect cognition. For the most part, the cranial nerve afferents synapse in the brainstem and are then relayed to the thalamus before branching to other cortical areas [
Table 3Selected studies that electrically stimulate cranial nerves to modulate cognition and behavior. Outcome column lists if results are positive (+), negative, (−), or inconclusive (±) relative to intended rationale. Target nerve and rationale as stated in the original publication.
Perspective taking tasks were impaired (perspective taking, match to sample), object-based transformations were not impaired (Stroop, mental rotation, reaction time, dual tasking).
carbon-rubber
Improve visual memory with low levels of GVS
(+)
VIII
Dilda et al. (2012)
Self-designed optically isolated constant current generator Electrode: 7180, 3 M Health Care, St. Paul, MN
GVS (non-invasive)
(1) session 641 s [CI 9.3]
0.16–0.61 Hz noisy, ≤5 mA; bilaterally over mastoids, cut electrosurgical split grounding plate electrodes coated in EMG electrode gel
Perspective taking tasks were impaired (perspective taking, match to sample), object-based transformations were not impaired (Stroop, mental rotation, reaction time, dual tasking).
(+/−)
X
Jacobs et al. (2015)
TENSTem dental (Schwa-medico BV, Woudenberg, The Netherlands) Electrode: Not Specified
taVNS (non-invasive)
(1) session 17 min
8 Hz pulsed, 200 μs pulse width, 5.0 mA; Active: left external acoustic meatus inner side of the tragus, circular clip, 10 mm diameter. Return: right arm, rectangular solid gel, 35 × 22 mm
a Psychomotor vigilance task. Critical flicker fusion frequency, D2 test.
b Perspective taking tasks were impaired (perspective taking, match to sample), object-based transformations were not impaired (Stroop, mental rotation, reaction time, dual tasking).
This review is focused on development of a holistic scientific understanding of cranial nerve stimulation in order to support a rational approach to neuromodulation. First, we review different approaches to the targeting of cranial nerves with transcranial electrical stimulation including both methodology (Sec. 2) and waveform parameters used in various studies (Sec. 3). We then review cranial nerves based on their composition of afferent axons and connected circuits in the brain (Sec. 4). The role of cranial nerve efferent stimulation is briefly considered (Sec. 5) followed by a detailed review of stimulation of olfactory (Sec. 6.1), optic (Sec. 6.2), trigeminal (Sec. 6.3), facial/glossopharyngeal (Sec 6.4), vestibulocochlear (Sec. 6.5) and vagus nerves (Sec. 6.6). The review concludes with a discussion of future approaches for optimization and specific targeting of cranial nerve for neuromodulation.
Transcranial electrical stimulation and cranial nerves
Transcranial electrical stimulation (tES) techniques include transcranial direct current stimulation (tDCS), transcranial alternating current stimulation (tACS), transcranial random noise stimulation (tRNS) and transcranial pulsed current stimulation (tPCS) [
Limited output transcranial electrical stimulation (LOTES-2017): engineering principles, regulatory statutes, and industry standards for wellness, over-the-counter, or prescription devices with low risk.
] and skull foramina (because of skull resistance to current flow), which may result in the stimulation of cranial nerves that transverse the skin (e.g. forehead, neck) and foramina near or between the electrodes (Fig. 1 and Fig. 2) [
Gyri-precise head model of transcranial direct current stimulation: improved spatial focality using a ring electrode versus conventional rectangular pad.
Fig. 1MRI-derived finite element models of electrode montages typically used in transcranial electrical stimulation (tES) studies. Surrounding tissue were segmented using automatic and manual techniques, referencing prior atlases. Each electrode montage is referenced in accordance with the International 10/20 System of Electrode Placement or other superficial anatomical marker Top row: current streamlines (purple/yellow) during electrical stimulation montages using exemplary electrode montages. Bottom row: cranial nerves overlaid with tDCS montages (trigeminal: orange, vagus: green, vestibular: green, optic: blue, glossopharyngeal: purple, intermediate branch of the facial nerve: pink). a) cerebellar stimulation with a cheek “reference” b) “right DLPFC” stimulation anode over F4 and cathode over the right mastoid (P10) c) M1-SO montage with anode over C3 and cathode over the right supra-orbital area (Fp2). These simulations show the diffuse current pattern produced by tES/tDCS electrode montages will overlap with the anatomical distribution of specific cranial nerves. (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)
Fig. 2MRI-derived finite element models of non-invasive electrical stimulation. Surrounding tissue were segmented using automatic and manual techniques, referencing prior atlases. Each montage is referenced in accordance with the International 10/20 System of Electrode Placement or other superficial landmarks. Top row: current streamlines (purple/yellow) during electrical stimulation using exemplary electrode montages. Bottom row: Cranial nerves overlaid with cranial nerve stimulation montages (trigeminal: orange, vagus: green, vestibular: green, optic: blue, glossopharyngeal: purple, intermediate branch of the facial nerve: pink) a) galvanic vestibular stimulation, electrodes placed over the mastoids (P10/P9) b) transcutaneous auricular vagus nerve stimulation, electrode place on the tragus c) trigeminal nerve stimulation, electrodes roughly over Fp1 and Fp2. (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)
For example, tDCS for the treatment of major depressive disorder (MDD) is applied bilaterally to the forehead in order to target a brain region of interest, the dorsolateral prefrontal cortex (DLPFC) [
The pursuit of DLPFC: non-neuronavigated methods to target the left dorsolateral pre-frontal cortex with symmetric bicephalic transcranial direct current stimulation (tDCS).
]. The forehead, however, is richly innervated with cranial nerves which may be unintentionally stimulated in frontal tDCS interventions (Fig. 1, Fig. 2c). tDCS when used for the purpose of enhancement of cognition in healthy individuals similarly employs electrodes on the forehead with the intention of targeting the frontal cortex; this may also be complicated by stimulation of cranial nerves innervating the skin of the forehead [
Limited output transcranial electrical stimulation (LOTES-2017): engineering principles, regulatory statutes, and industry standards for wellness, over-the-counter, or prescription devices with low risk.
]— often target the motor cortex (M1) with an “active” electrode, while the “return” electrode is placed on the contralateral forehead (called the “supra-orbital” or SO position) (Fig. 1c) [
], resulting in maximal current density to these skin areas with the attendant risk of stimulation of collateral cranial nerves. Some tES approaches use an extracephalic (placing the “return” electrode on the neck, face or arm) rather than a cephalic (on the head) electrode (Fig. 1a) [
Evaluation of local electric fields generated by transcranial direct current stimulation with an extracephalic reference electrode based on realistic 3D body modeling.
Transcranial direct current stimulation of the prefrontal cortex modulates working memory performance: combined behavioural and electrophysiological evidence.
TES methods run the risk of stimulation of cranial nerves innervating areas under and between electrodes. Previous papers have reviewed the use of computational models [
Gyri-precise head model of transcranial direct current stimulation: improved spatial focality using a ring electrode versus conventional rectangular pad.
] to determine optimal tES electrode placements for stimulation of the cortex. Our review of the collateral effects of stimulation of cranial nerves with tES does not obviate study results consistent with direct cortical stimulation. Disambiguating the varying effects of different types of tES (i.e., tDCS, tACS, tRNS, tPCS) on cranial nerves is not within the scope of this review. Rather, we focus on a detailed consideration of the nerve anatomy, as it relates to electrode placement and function, in order to attain a more fundamental assessment of electrical stimulation treatments.
Many techniques that target the cranial nerves use dosages that overlap with “transcranial” methods. For instance, tACS, tRNS and tPCS can elicit the perception of flashes of light known as “phosphenes” [
]. These phosphenes are a known effect of stimulation of the optic nerve, which often employs pulsed current and electrode placements similar to transcranial methods. It is debated where along the visual pathway these electrically induced phosphenes originate [
]; several reports suggest that phosphenes originate primarily at the retina and optic nerve, regardless of the placement of the stimulation electrodes [
A complete understanding of the effects of different electrical stimulation devices and techniques on neurophysiology requires a cataloging of dosing parameters. These include electrical waveform (e.g. intensity, shape, frequency) and electrode type (e.g. material, size, location) which together make up the “dose.” Electrical waveforms are generated and then applied across electrodes. The dose determines how the pattern electrical current flow though the body, so the intensity at any given region [
]. We review below different dosing parameters used for different devices targeted for different cranial nerves to the extent that they are documented in the literature.
This section outlines the terms and reporting style used in this review when describing the dose of electrical stimulation to cranial nerves. These terms are applicable to the targeting of cranial nerves and generally electrical stimulation. While attempting to provide a uniform dose report scheme, some specialized terms may be qualified for a peculiar stimulation technique or cranial nerve target. At the beginning of each section – for each cranial nerve—the most common dose reported in the literature may be noted.
Pulses are a typical waveform used in cranial nerve stimulation. Pulses are applied repetitively in a train, where the inverse time between pulses equals the stimulation frequency. Unless otherwise specified, individual pulses are assumed to be rectangular. Individual pulses have a pulse duration (width) and amplitude. A waveform of pulses can be monophasic or biphasic. A monophasic waveform has pulses of a single polarity (Fig. 3a; z2 = 0), while a biphasic waveform has pulses that invert polarity, typically in paired opposite-polarity pulses [
]. Waveform types besides pulsed typically take the form of a simple periodic waveform, such as sinusoid (Fig. 3d). In the case that pulses are not evenly spaced in time, any burst patterns (Fig. 3b) or on/off times (Fig. 3c) are reported. Unless otherwise stated, the waveform for pulsed stimulation is reported as the following: pulse frequency and feature, pulse width, burst frequency, pulses per burst, time on/off, and peak amplitude (e.g., Fig. 3e-f). In this review, we systematically characterize dose to allow reproduction and reasonable comparison across studies. However, we respect dose as reported in the original papers, and do not attempt to verify the accuracy of reporting. In many cases, not all details about dose (e.g., whether the reported biphasic waveform is symmetric or asymmetric) are reported in the original paper, and so are omitted in our reference. In some cases, where the waveform description was indefinite, the phrasing used in the original report is reproduced in quotes.
Fig. 3Uniform formula of stimulation waveform including as used in cranial electrical nerve stimulation. a-c address waveforms composed of rectangular pulses with expanding temporal scale, while d shows additional waveform types. a) The pulse shape includes the frequency, pulse width, amplitude, and interphase delay where applicable b) The burst stimulation pattern includes the repetition time and number of pulses or cycles per burst – if no burst pattern is reported than the stimulation pattern is continuous. c) The on/off period describes the time the stimulation pattern — continuous or burst—is active/inactive and is typically in the scale of minutes d) Direct current has a fixed amplitude but may include an on/off ramp and is, by definition, monophasic. Unless otherwise indicated, sinusoidal stimulation has a single frequency and symmetric biphasic (no DC offset). There are various types of noise-based stimulation, conventionally with no DC offset. Unless otherwise indicated, a square wave is monophasic. e) Monophasic pulse example. f) Burst example.
When waveforms are either monophasic, asymmetric biphasic, or symmetric biphasic but with importance given to the order of pulses phases, then the polarity of the waveform needs to be defined with respect to the electrodes (e.g. monophasic square wave with 5 V peak from electrode A to electrode B). In electrical stimulation, an anode electrode always indicates an electrode where, at that instant, current (defined as a positive quantity due to historical reasons, and therefore directly opposite to the physical direction taken by electrons in a circuit) enters the body and cathode electrode indicates an electrode when, at that instant, current exits the body [
]. In the context of electrical stimulation, anode/cathode always indicates an electrode location where current is entering/exiting the body – this definition which emphasizes the body-centric perspective should not be confused with how anode/cathode may be used in other specialties (e.g. batteries). However, these terms can be used in varied nuance and context.
When the waveform is monophasic an anode electrode may be defined as the electrode where current always enters the body, and a separate electrode may be defined as the “cathode electrode,” where current always exits the body. Since in all electrical stimulation there is always an anode and a cathode, the terms “anodal” stimulation can simply indicate a statement of hypothesis, that the nominal target is near the anode electrode [
]. “Cathodal” stimulation, indicating that the nominal target is near the cathode electrode. Alternatively, in some cases, like bilateral monophasic stimulation, “anodal”/“cathodal” indicates the polarity of the waveform relative to the head (e.g. an electrode was placed on each mastoid with anodal stimulation on the right). Finally, in some applications where biphasic stimulation is used, and each electrode can alternate between anode and cathode the terms “anodic phase” and “cathodic phase” will be used (e.g. a cathodic phase pulse is followed by an anodic phase pulse). In this sense, when brain stimulation [
] is assumed to be driven by one phase, the terms “anodic stimulation” and “cathodic stimulation” are used (e.g. monopolar cathodic stimulation, where a cathode activating pulse is followed an anodic phase used for charge recovery). In this review, the limited use of anode/cathode related terms is typically qualified and influenced by how they are used in a given field of application.
Electrode shapes, sizes, positions, and materials are noted with the level of detail (and limits) as specified in the original reports. For invasive stimulation (and in electrochemistry), the electrode refers to the metal in contact with the body (tissue), while for non-invasive electrical stimulation, electrode can refer to the entire electrode assembly including electrolyte (e.g. saline, gel) which separates the metal from the skin. Here, unless otherwise indicated, the electrode (assembly) position and area indicates the surface area between the electrode (assembly) and the issue/skin – essentially the area over which current can enter/exit the body. The term “bipolar” and “unipolar” denotes electrode geometry. Unipolar electrode geometry refers to the use of a relatively small electrode placed near the target with another (larger) “return” electrode placed at a distance. However, the “return” is not inert. A bipolar electrode geometry indicates two electrodes of comparable size and proximity to the target(s). When electrodes are placed symmetrically on the head, especially to target structures in both hemispheres, the montage may also be referred to as bilateral. When two electrodes are used for a bilateral montage, it is also termed “bipolar.” To clarify, biphasic/monophasic refer to waveform and are independent of bipolar/unipolar/bilateral electrode geometry.
Beyond reporting complete dose details, in some stimulation applications specific metrics of dose are used to gauge efficacy or safety. These include current density (current/electrode area), charge (current x time per pulse), or charge density (charge/electrode area). However, reliance on such metrics does not negate the need to fully document dose.
Selection and identification of cranial nerves as targets for electrical stimulation
There are twelve cranial nerves, each emerge bilaterally from the brain. They are numbered per their anatomical organization, rostral to caudal. Each cranial nerve synapses (afferent) or originates (efferent) on a set of nuclei in the brainstem (with the exception of the olfactory and optic nerves) and exit through skull foramina, branching out onto the surface of the skull and into the neck, thorax, and abdomen (Fig. 4). The cranial nerves are a part of a neuronal pathway that extends from cortical regions to/from the body (Fig. 5). These pathways are made up of several connecting neurons. Sensory pathways usually begin with primary or “first order” neurons whose cell bodies are located outside the CNS and synapse in the brainstem onto second order neurons. The afferent axons of the first order neurons are axons of cranial nerves, that pass through the cranium and extend superficially to where their specific sensory information is transduced. Second order neurons then synapse in the thalamus onto third order neurons which project to the cortex. In comparison, efferent first order neurons typically originate in the cortex and synapse on secondary neurons in the brainstem, bypassing the thalamus. The efferent axons of the secondary brainstem neurons are axons of cranial nerves which exit the cranium to innervate organs and muscle. The cranial nerves are a part of the PNS (with the exception of the optic and in some cases the olfactory nerve) like the nerves that emerge from the spinal column, but unlike the spinal nerves, they relay information directly (or within one synapse) to and from the brain to the body. Therefore, cranial nerves are special targets for neuromodulation, accessible near the surface of the body and direct afferents to the cerebrum; conceptually “axons of the brain extending to the skin” (Fig. 5).
Fig. 4Anatomy and major axon sub-type of cranial nerves containing a major afferent component. Cranial nerve color key: olfactory tract: yellow, optic: dark blue, trigeminal: green, intermediate branch of the facial nerve: pink, vestibular: teal, glossopharyngeal: purple, vagus: orange. OB: Olfactory Bulb; LGN: Lateral Geniculate Nucleus; TN: Trigeminal Nuclei; NTS: Nucleus Tractus Solitarus; VN – Vestibular Nuclei. IAM: Internal acoustic meatus. Touch fibers (mechano-, chemo-, thermo-receptor and nociceptor) - Aβ: myelinated discriminatory touch fibers; Aδ: myelinated nociceptive thermal and mechanical fiber; C: unmyelinated mechanical, thermal, metabolic fiber. (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)
Fig. 5Anatomical map of connections from the cranial nerve (far left), to the brain stem nuclei (middle), to the cerebral cortex (far right). Specifically, the anatomical connections indicated provide pathways from specific cranial nerves to cortical region involved in higher order cognition as well as deep node structures involved in gating of information processing. Colors represent the sensory modality conveyed by the connection, however we propose that approaches to alter cognition can engage these pathways without necessarily inducing percepts. In this sense, sensory modalities are indicated here to illustrate functional circuit connections for neuromodulation. As explained in this review, cranial nerves offer a unique target for electrical stimulation of the brain circuits of cognition. (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)
When considering the function of cranial nerves, it is important to characterize the types of information that the fibers of the nerve transmit. Classically, anatomists have categorized cranial nerves according to the following: afferents or efferents; special or general; and somatic or visceral. “Afferents” are fibers that send information to the CNS and “efferents” are fibers that carry information from the CNS to the rest of body. “Sensory” and “motor” can be used interchangeably with the terms afferent and efferent, respectively. “Special” nerves are functionally specific to cranial nerves (e.g. sense of smell), while “general” nerves are not functionally specific to cranial nerves (e.g. sense of touch) as this sensation also is carried by spinal nerves. Somatic refers to nerves that receive and transmit information from the skin, skeletal muscles, joints and tendons. Visceral are those nerves that innervate smooth muscles, cardiac muscle and glands [
] as summarized in Table 1. For this review, we consider in detail only the afferent branches of cranial nerves, as the flow of information is toward the brain, usually with a direct connection from the receptor to the brain, and therefore have a more direct effect on cognition, mood and behavior (Cranial nerves I, II, V, VII, VIII, IX, X). This does not exclude any possible contribution from efferent branches in altering cognition through physiological changes (e.g. heart rate) that may then secondarily affect the brain. The Cranial Nerve Efferents section (Sec 5) addresses these connections.
Each main section of this review addresses the afferents of a specified cranial nerves including: the basic anatomy (from sensory transduction to its connection with the brain); the types of electrical stimulation traditionally used to target the nerve (e.g., waveform, dose, montage, invasive/noninvasive, etc.); clinical disorders targeted for treatment by electrical stimulation; imaging/neurophysiological outcomes; and any cognitive, mood, or behavioral outcomes modulated by targeting cranial nerves by electrical stimulation.
Clarification of terminology is needed when discussing cranial nerve stimulation research, including when cranial nerves are not intentionally targeted (e.g., some tES). Afferent cranial nerves do not technically include sensory receptors, rather they are the fibers (axons) that convey signals between the receptors and the brain. However, certain cranial nerves have integrated receptors (e.g. olfactory and certain branches of somatosensory nerves). Due to the nature of the overlapping anatomy of most cranial nerves, between and within, and the heightened sensitivity of the axon terminal to electricity [
], it is unlikely that noninvasive electrical stimulation would only polarize the nerve and not the receptor system attached to it, or vice versa. If an action potential is initiated in any compartment of a cranial nerve or its sensory terminus, an action potential will be conducted along its length. In the following sections, we examine some applications that intend to target receptors (e.g., photoreceptors in the retina), yet remain cranial nerve electrical stimulation (e.g., optic nerve) for our purposes.
Cranial nerve efferents
This review is concerned primarily with the afferent pathways of cranial nerves as they offer a direct (or within one synapse) and targeted pathway to the brain. However, the efferent pathways are an important target for varied cranial nerve stimulation applications, and indeed – due to anatomical considerations -- are co-activated by approaches that target afferent pathways. As noted above, efferent nerves can be somatic (muscle) or visceral (smooth muscle, glands, cardiac muscle), some of which are part of the parasympathetic branch of the autonomic nervous system (ANS). Efferent nerves can be targeted either directly by stimulating axonal pathways from the brain to the body, or indirectly through stimulating afferents that then activate efferents through reflex pathways in the brain stem or cerebellum.
Examples of cranial nerve efferent activation include, electrical stimulation of motor cranial nerves to elicit or suppress muscle movement through efferent fibers of the hypoglossal nerve that innervate muscle, with application in the treatment for sleep apnea (30 Hz pulsed, 100 μs, 1–1.5 s burst duration; half-cuff tripolar electrode around main trunk of hypoglossal nerve [
]). Other examples of studies that aim to stimulate efferents through direct pathways include increasing vascular blood flow (3–60 Hz monophasic pulsed, 500 μs pulse width, 5 V; [
Selective electrical stimulation of postganglionic cerebrovascular parasympathetic nerve fibers originating from the sphenopalatine ganglion enhances cortical blood flow in the rat.
]. In the vestibular system, direct current stimulation applied to the mastoids can induce eye movement ([Direct current, 5 mA; bilateral 1,000 mm∧2 electrodes placed over mastoids; [
]) which in disordered vestibular systems may serve as a measure of remaining function (Direct current 3 s ramp, 4 mA, 35 s; Bilateral and unilateral (return over C7); [
]). The vestibular-ocular reflexive arc acts by modulating the vestibular nerve and/or receptors that send information to the brain stem (nuclei) and then back out via efferents that control muscles in the eye in order to stabilize visual information in the case of head or body movements [
]. The pathway from vestibular nerve to ocular nerve is only three neurons long, so while the original effector may be the afferent, the outcome may be mediated by efferents. Other signaling pathways include vagal efferents in the baroreceptor reflex arc (20 Hz rectangular pulse, 200 μs pulse width, <8 V; stainless steel wire electrodes attached to right vagus nerve; [
]). Both types of stimulation, direct and reflexive are considered efferent stimulation.
There are three cranial nerves that are mixed, containing both afferents and efferents, increasing the likelihood that both pathways might be modulated by electrical stimulation. For example, the vagus nerve contains both sensory and motor nerves, some of which are anatomically adjacent. The afferent and efferent nerves travel alongside each other in the cervical branch in the carotid sheath (section 6). Typically, the afferent fibers in the cervical branch are targeted as a treatment of epilepsy, depression and other neurological and psychiatric disorders [
]. However, it is almost certain that some vagal electrical stimulation (invasive or non-invasive) will also activate efferents. Besides inadvertent involvement, efferent axons in mixed cranial nerves can be explicitly targeted for electrical stimulation. For example, targeted electrical stimulation of efferent vagus nerve fibers invasively has been proposed as a treatment for disorders of the immune system [
]. Consistent with this, cervical vagus nerve stimulation increased survival in sepsis infected mice and attenuated the production of proinflammatory cytokines (1 Hz, 2 ms pulse width, 5 V, 12 min; bipolar platinum electrodes; [
]). In summary, the efferent axons of cranial nerves must be taken into consideration when designing strategies for electrical stimulation of cranial nerves for the enhancement of normal functions including mood and cognition and/or interventions for neurological and psychiatric conditions, even when afferents are the primary target of the intervention [
The olfactory nerve (CN I) conveys information about smell to the brain. Humans have over 350 types of odorant receptors, each of which can recognize multiple odorants [
]. Each odorant can also bind to several different receptors. The unmyelinated olfactory sensory axons project through the cribriform plate (foramina) and synapse ipsilaterally onto the olfactory bulb, a direct outcropping of the neocortex (Fig. 4; yellow). Neurons that have the same receptor type synapse onto a single pair of glomeruli in the olfactory bulb. This convergence enhances the ability to detect small quantities of odorants. In the glomerulus, each olfactory sensory neuron synapses onto a tufted or mitral relay cell. From there, information projects through the olfactory tract to the piriform cortex, amygdala, anterior olfactory nucleus, olfactory tubercle, and entorhinal cortex. The areas that receive direct projections from the olfactory bulb are known collectively as the olfactory cortex [
The organization of the thalamocortical connections of the mediodorsal thalamic nucleus in the rat, related to the ventral forebrain-prefrontal cortex topography.
]. It also makes reciprocal connections with the brain stem nuclei — the locus coeruleus (the olfactory system’s main source of norepinephrine) and raphe nucleus, a major site of serotonin cell bodies in the brain [
The olfactory sensory nerve’s only extracranial projections are the widely dispersed cilia in the nasal mucosa These cilia synapse on the olfactory bulb, an outcropping of the cortex. This means that the olfactory nerve is one synapse away from the cortex. While there is research in animals and humans that target the olfactory nerve proper, the olfactory bulb and tract are commonly targeted for electrical stimulation when investigating the olfactory system. For the purposes of this review, the primary sensory neurons, bulb, and tract make up the olfactory system and are considered olfactory “nerve” stimulation. Noninvasive electrical stimulation targeting the olfactory system in both animals and humans generally use bipolar electrodes placed, usually unilaterally, inside the nostril to touch the nasal epithelium [
]. This section on the olfactory nerve electrical stimulation addresses methodological and conceptual issues.
Electrical stimulation applied to rodents and non-human primates has been used to probe the structural and functional synaptic organization of the olfactory system. By studying the projections from the rat olfactory nerve using electrical stimulation, the organization of the olfactory bulb has been elucidated (0.25 Hz pulsed, 100 μs pulse width; bipolar stainless steel electrodes, placed rostral to cribriform plate; [
]). The topmost layer of the olfactory bulb, the granule cell layer, contains inhibitory interneurons and cortical structures form inhibitory connections within the olfactory bulb. Electrical stimulation of the olfactory mucosa (and thus the olfactory neurons) evokes a weak excitatory response from intracranial recordings in the olfactory bulb of rabbits cells, perhaps indicating that electrical stimulation does not activate the olfactory system in the same way as chemical olfactants (pulsed, 700 μs pulsed width, 5–20 V, 5–20 V; bipolar silver, < 0.5 μ diameter; [
Olfactory receptors are somewhat indiscriminate in which odorants they bind, making the mechanism by which the olfactory system decodes odors complex to deduce. The answer lies partially in the spatiotemporal encoding of signals in the olfactory bulb, which electrical stimulation has helped to explain [
]. For example, rats taught to discriminate between points of electrical stimulation on their olfactory bulb could do so up to a relatively small area of point separation which indicates a topographically precise organization of the bulb (50 Hz sine wave, 4–20 μA; stainless steel wire in olfactory bulb; [
]). However, comparing electrically induced activation to chemically induced activation requires caution, as electrical stimuli do not always yield the same results as direct application of chemical odorants [
]. For example, the pattern of activation in rats olfactory bulb observed during electrical stimulation of the olfactory bulb is more diffuse than the discrete areas of activation induced by odors [
]. Nevertheless, electrical stimulation at the nerve and bulbar level have provided valuable information about the olfactory system’s anatomy, cell morphology, and physiology.
The olfactory nerve is the only cranial nerves to bypass the thalamus, instead olfactory information is projected to the neocortex, and therefore there are less “stops” between the sensory neurons and higher order processes. As mentioned in the introduction to this section, the olfactory system has connections with the OFC, a region imaging studies have implicated in decision making and emotion processing (for review see Refs. [
]). The structures in the olfactory cortex make both direct and indirect projections to the OFC. An indirect route to the OFC through the hypothalamus in nonhuman primates was identified with recordings of extracellular potentials in the OFC and intermediate relay structures, in response to electrical stimulation of the olfactory bulb (square pulse, 10–500 μs pulse width, 2–8 V; bipolar electrodes, stainless steel (0.4–0.5 mm dia.) or tungsten (300 μm dia.); [
]). Consistent with the observation that the OFC is integral to processing olfactory information, patients with OFC lesions are unable to discriminate odors [
]. The OFC is the junction not only for olfactory information, but other sensory systems such as gustatory and visual information, implicating a multimodal role for olfaction [
Relating a neural signal to the onset of a stimuli underlies much of cognitive research; when EEG is used to record neural signals, these timed signals are known as event related potentials (ERPs) [
]. For instance, clinical disorders with deficits in smell can be diagnosed by signal conductance speeds tests. Typically, air puffs are applied inside the nose while measuring EEG from the scalp [
]. The neural signal evoked by the olfactory signal are disturbed in certain psychiatric disorders, such as schizophrenia and Alzheimer’s, and may aid in diagnosing a disorder [
]. Olfactory dysfunction is the earliest clinical symptom of Alzheimer’s disease and quantitative assessment of olfactory system performance is suggested to serve as a potential biomarker for Alzheimer’s disease progression [
]. Given the critical role that smell plays in disgust, it is not surprising that smells are a potent modifier of emotion, and have been used as a probe of symptoms of posttraumatic stress disorder [
]. The olfactory system is the only sensory system with direct connections to the amygdala which as noted above bypass the thalamus and higher cortical areas, highlighting their role in the production of unfiltered emotion [
]. Typically, olfactometers are used to deliver chemical stimuli to a human or animal to modulated neural activity that can be measured by behavior or EEG and neuroimaging methods [
]. Electrical stimuli can alternatively be used to elicit measurable neural changes. Compared with chemical stimuli, this provides a controlled stimulus onset and discrete stimuli. This is especially important when carrying out tests where stimulus timing is important (e.g. electrical conductance tests or ERPs). In humans, electrical evoked ERPs (independent of the dynamics of transducing external chemical olfactants) were characterized following stimulation of the olfactory mucosa (2 Hz monophasic pulsed, 500 μs pulse width, 0.5–4 mA; bipolar stainless steel electrode, nasal mucosa; [
Early clinical research used electrical stimulation applied to the olfactory nerve as a tool to treat temporal lobe epilepsy (TLE) in man. Olfactory hallucinations (phantosmia) are a symptom of TLE, often occurring before the onset of an episode. In both animal models and in humans, chemical olfactants have been used as a way to attempt to control seizures with varying degrees of success [
Betts T. Fox C. MacCallum R. Using olfactory stimuli to abort or prevent SEIZURES-COUNTERMEASURE or CUE-CONTROLLED arousal MANIPULATION-IS there something special about smell. Epilepsia. LIPPINCOTT-RAVEN PUBL 227 EAST WASHINGTON SQ,
PHILADELPHIA, PA1995: 19106
]. The limbic system generates and regulates rhythmic activity in the brain, which is pathological in TLE. Application of electrical stimulation to the human mucosa was hypothesized to attenuate seizure frequency through the activation of the pyriform cortex’s connection with the limbic system and has shown promise as a possible therapeutic intervention for seizures [
]. However, we are aware of no trials in humans to treat epilepsy using electrical stimulation to the olfactory system.
In an attempt to better understand the link between seizures and olfactory hallucinations, clinicians successfully elicited phantosmia by applying intraoperative electrical stimulation to the olfactory bulb in awake patients with epilepsy [
]. In children with epilepsy, stimulation on the orbital frontal cortex produced distinct olfactory perceptions (50 Hz biphasic pulsed, 300 μs pulse width, ≤ 5 s pulse train, 3–9 mA; subdural electrodes on the ventral surface of the frontal lobe; [
]). While transient odors can be experienced using direct olfactory bulb stimulation, subjective experience of a smell has yet to be produced using noninvasive methods of electrical stimulation, e.g. stimulation on the mucosa [
]). This may indicate that cortical neuromodulation without the concurrent subjective sensory experience is plausible during olfactory stimulation.
In summary, the olfactory nerve does not pass through the thalamus, instead it passes directly to the olfactory cortex and neocortex, including the OFC cortex [
]. Approaches to stimulate the olfactory nerve include invasive electrodes placed on the olfactory bulb or non-invasive methods that place electrode in the nostril to touch the nasal mucosa. To date, there have been few studies in humans that have applied electrical stimulation to the olfactory system outside of the olfactory mucosa. Deficits in olfaction are correlated with many psychiatric and neurological conditions (e.g. epilepsy and schizophrenia) and a selective electrical stimulation tool could be used as a way to study disordered neuropsychiatric responses to induced phantosmia [
]. However, electrical stimulation of the olfactory system is rarely used clinically. The lack of subjective smell experience following non-invasive stimulation is argued to be an indication that there is a lack of meaningful olfactory system activation, and therefore cortical activation. However, there is evidence from both EEG and fMRI studies that electrical stimulation, even to the mucosal receptors, modulates cortical activity in olfactory systems [
]. This may indicate that any changes in cognition or behavior due to olfactory stimulation are not just be due to olfactory percepts. While untested, there may be potential for non-invasive electrical stimulation to modulate cortical regions that are difficult to reach using conventional electrical stimulation approaches (i.e. the limbic system), without necessarily producing percepts (a need for sensory substitution).
Optic nerve stimulation
The optic nerve, the second cranial nerve, conveys visual information. Light is transduced into electrical signals by photoreceptors (rods and cones) in the retina. The signal is then propagated through the second layer bipolar cells and then to retinal ganglion cells, whose axons form the optic nerve (Fig. 4; blue). The axons of the ganglion cells become myelinated after exiting the back of the eyeball and leaves the orbit via the optic canal. The optic nerve carries information from the left and right retina and meets in the optic chiasm as the optic nerve enters the middle cranial fossa. There, information from the nasal and temporal half of the retina cross to the opposite optic tract before traveling around the cerebral peduncle to terminate directly onto the brain. The optic nerve does not synapse onto nuclei in the brain stem, but instead synapse directly onto the lateral geniculate nucleus (part of the thalamus), superior colliculus, the pretectal area, and the hypothalamus. Most of the information from the optic tract is conveyed to the visual cortex via the geniculate nucleus. However, some neurons from the optic nerve synapse in areas that are involved in reflexive eye movement and circadian rhythm. Both noninvasive and invasive electrical stimulations have used a range of doses to modulate optic afferents. Applications of pulsed and sinusoidal waves typically use frequencies under 40 Hz when applied non-invasively, while invasive methods of optic nerve electrical stimulation use a range of frequencies [
Progressive enhancement of alpha activity and visual function in patients with optic neuropathy: a two-week repeated session alternating current stimulation study.
]. For example, invasive prostheses that directly stimulate the optic nerve use pulsed waveforms at high frequencies (up to 320 Hz) in order to obtain discrete light points [
]. Electrode placement, when applied non-invasively, is either monopolar (with “return” electrode/s placed either cephalically or extracephalically) or bipolar (with both electrodes around the orbit). Visual implants concentrate electrical stimulation epiretinally (on the retina; [
]. Our focus here is on optic nerve stimulation, however, retinal stimulation is also discussed, as the retina contains the receptors of the optic nerve.
Use of invasive optic nerve stimulation in humans has focused on visual prosthetics that target the optic nerve with electrical current in order to rehabilitate the optic nerve [
] or to activate the remaining undamaged nerves in a pattern replicating visual patterns. Visual prosthetics that invasively target the optic nerve to create visually meaningful signals require that the visual cortex and downstream visual processing centers have retained their function, while bypassing damaged structures in the retina, such as in retinitis pigmentosa [
]. Retinitis pigmentosa causes photoreceptor cells to disappear over time, while ganglion cells and axonal processes remain intact, causing visual loss [
]. In some of these cases, a self-sizing spiral cuff is surgically attached around the optic nerve with the ability to apply either bipolar (stimulation is between two contacts on the cuff) or monopolar (the return is not on the cuff) stimulation. Unless otherwise noted, this type of cuff electrode is used when describing direct optic nerve stimulation (cuff electrode around optic nerve, four platinum contacts placed around the optic nerve at 0.2 mm2 contact area). Another form of direct optic nerve prosthesis device uses small stimulating wires placed at the location where the optic nerve leaves the eyeball to produce a more focal distribution of phosphenes (40–320 Hz biphasic pulsed, 250 μs pulse width, 5–300 μA; 3.5 mm from the limbus, three platinum wires, 0.5 mm dia.; [
]). The first steps in validating an optic nerve stimulating visual prosthesis has been to relate electrical stimulation dose and location to phosphene characteristics (location, intensity, size, etc.). The relationship between electrical stimulation site to the subjective visual perception can be approximated with volume condition models, and validated experimentally in the optic nerve (10–320 Hz biphasic pulsed, 21–400 μs pulse width, ≤17 pulses per burst, < 3.8 mA; [
The ultimate goal of visual prostheses is not simply to elicit visual percepts, but to evoke recognizable patterns and regain some semblance of vision. By collecting data on individual’s subjective activation maps, visual stimuli can theoretically be encoded (captured by head-mounted cameras) into electrical stimuli that appear as patterns to the individual subject. In this manner, a subject with an implanted optic nerve cuff is able to decode simple shapes (1–320 Hz biphasic pulsed, 21–400 μs pulse width, 10 μA-3.8 mA; [
]). However, decoding these subjective flashes of lights into a meaningful visual field is still a daunting tasking. One way to objectively assess the function of optic nerve prostheses following implantation is by measuring visual evoked potentials over the visual cortex to determine if electrical stimulation of the optic nerve is conducting to upstream visual systems (0.3 Hz “single-charge recuperated pulses with a ratio of 1:9”, 213–426 μs pulse width, 92–1,040 μA; [
]). Even with subjective and objective measures of visual activity produced by optic nerve electrical stimulation, progress toward a clinically meaningful prosthesis has been slow. Prostheses targeting other sensory systems have had clinical success, such as with cochlear implants [
], but visual prostheses have not made the same breakthroughs.
While visual prostheses are used as a relay between damaged and healthy parts of the visual system, other forms of optic nerve electrical stimulation are used for neurorehabilitation and recovery of unhealthy sections of the optic system [
]. In rat models, electrical stimulation to the optic nerve improves the chance of retinal ganglion cells recovery following damage (20 Hz monophasic pulsed, 50 μs pulse width, 10–70 μA, 2 h duration; two silver ball electrodes placed on transected end of optic nerve, 1 mm dia.; [
]). In humans, application of electrical stimulation to the optic nerve following surgery to remove tumors that compressed and damaged the optic nerve increased the VF recovery post-surgery, though the recovery was not always predicted by nerve conductance tests during the surgery (25–100 Hz biphasic varied burst pattern, 250–1000 μs pulse width, 1–800 μA; 3-2 gold wire implanted optic nerve bipolar electrodes, 0.1 mm∧2 ellipsoid; [
]). Stimulation with electrodes placed on the cornea, rather than the optic nerve itself was also explored for long term axonal survival and signal transduction to the visual cortex (20 Hz biphasic pulsed, 50 μs pulse width, 50 μA; bipolar electrodes placed on a contact lens; [
]). This technique was reported to improve measures of visual acuity in controlled human trials (20 Hz biphasic pulsed, 10 ms pulse width, current titrated to phosphene thresh.; bipolar electrodes placed on a contact lens; [
]). Research into creating an effective visual prosthesis or rehabilitation device using invasive optic nerve stimulation is long-standing and ongoing; the invasive nature of the approach evidently limits large sample-size research especially for less severely damaged visual systems, such as partial blindness due to stroke [
Invasive methods of optic nerve stimulation may provide a more “direct” route to modulating a nerve but involved surgery with associated complications [
]. Comparatively, non-invasive methods do not require surgery and can therefore be applied to a larger and more varied population. Because they are low resolution and applied for limited time period, non-invasive approached are directed toward neurorehabilitation applications. “Transorbital” alternative current stimulation is a noninvasive technique that targets the retina and optic nerve using electrodes that are applied to the eyelid or around the eye. Conventionally, the transorbital stimulation electrodes are either gold or sintered Ag/AgCl ring electrodes, similar to those used for EEG recordings, or 3 × 3 cm water-soaked pads with rubber electrode inserts. Electrodes are typically positioned around the eye (2–4 per orbit) [
Nigrostriatal dopamine mediates the stimulatory effects of corticotropin releasing factor on methionine-enkephalin and dynorphin release from the rat neostriatum.
]. In some cases of monopolar stimulation, the “return” electrode is positioned on the right upper arm, right shoulder, near the eye, or at EEG location Oz [
Transcranial alternating stimulation in a high gamma frequency range applied over V1 improves contrast perception but does not modulate spatial attention.
Evaluation of residual retinal function by pupillary constrictions and phosphenes using transcorneal electrical stimulation in patients with retinal degeneration.
Evaluation of phosphenes elicited by extraocular stimulation in normals and by suprachoroidal-transretinal stimulation in patients with retinitis pigmentosa.
Evaluation of phosphenes elicited by extraocular stimulation in normals and by suprachoroidal-transretinal stimulation in patients with retinitis pigmentosa.
Patients with vision loss due to optic nerve damage who received transorbital electrical stimulation were reported to display an increase in detection accuracy in their field of defective vision (AC, 2–9 pulses per burst, <1000 μA, 10 days; four sintered Ag/AgCl ring electrodes placed at or near the eye, one return electrodes on the right wrist; [
]). Additionally, these changes in detection were accompanied by changes in EEG alpha spectrum power (here defined as 7.5–12.5 Hz), indicating engagement of cortical effects. A larger (n = 446) open-label observational study of patients with optic nerve lesions similarly reported increases in VF area and visual acuity (VA) associated with changes in EEG alpha power spectra (9–37 Hz varied burst pattern, <500 μA, 25–40 min/day, 10 days; active: 4 periorbital gold electrodes, bilaterally superior and inferior to the eye, return: midline relative to occipital pole, 30 × 30 mm stainless steel; [
Progressive enhancement of alpha activity and visual function in patients with optic neuropathy: a two-week repeated session alternating current stimulation study.
]). These alpha frequency changes may be mediated by thalamo-cortico-thalamic relay circuits, a pathway proposed to “sharpen” or tune receptive fields in the visual system [
Feedback from V1 and inhibition from beyond the classical receptive field modulates the responses of neurons in the primate lateral geniculate nucleus.
]. Bola et al. reported that blind patients who received transorbital electrical stimulation displayed increased coherence in the high alpha/low beta frequencies (11–13 Hz) within the visual cortex and between the visual and frontal cortices [
]. These changes were associated with improvements in visual abilities. These findings point to the ability of this technique to increase inter-area coherence within a power band that may be required for effective perceptual function [
]. It is therefore possible that the entrainment phenomenon seen within certain frequency bands would be valuable for plasticity changes, particularly for remodeling required post injury. A case study of a patient of an 11 year-old optic nerve lesion reported VF and EEG changes associated with transorbital electrical stimulation, even at 1.5 years follow up, demonstrating long term cortical plasticity and rehabilitation (10–30 Hz varied burst pattern, < 600 μA, 30–40 min/day for 10 days; active: four Ag/AgCl ring electrodes around or on the eyelid, return: forearm; [
Noninvasive transorbital alternating current stimulation improves subjective visual functioning and vision-related quality of life in optic neuropathy.
Transorbital electrical stimulation and other optic nerve electrical stimulation methods, differ from “physical” optical stimulation techniques that use light. The application of light to the eye to modulate cognition and in the treatment of psychiatric and neurological disorders has a long history [
]. This includes recent work in mice on showing reduction in peptide amyloid-β plaques -a hallmark of Alzheimer’s disease – following 40 Hz flickering light [
]. These physical (non-electrical) studies offer a comparison for electrical approaches; in many cases the target of activation (retina/optic nerve) may be the same, especially when outcomes are considered secondary to sensory percepts. When physical and electrical approaches engage overlapping brain processes, which technique to use may be based on convenience.
As noted, the optic nerve can be targeted either invasively for prostheses development and rehabilitation, or non-invasively for rehabilitation and potentially other neuropsychiatric indications. Invasive optic nerve stimulation in humans has attempted to bypass damaged retinal cells by electrically stimulating the optic nerve directly using sensor arrays that transduce light into meaningful stimulation of the nerve, using cuff or pin electrodes. In parallel to research on optical nerves stimulation, work has been conducted on cortical visual prostheses, where visual percepts are produced by electrically stimulating the visual cortex [
Eye movements as a marker for visual prosthesis spatial mapping—a feasibility study using a blind patient implanted with the Argus II retinal prosthesis. Engineering in Medicine and Biology Society (EMBC).
in: Caspi A. Dorn J. Helder J.B. Katyal K.D. Roy A. 2016 IEEE 38th annual international conference of the. IEEE,
2016
]. Cortical prostheses offer some notional advantages to optic or retinal prostheses. The cortex has a larger surface which is considered theoretically advantageous for visual resolution by allowing for arrays of cortical stimulation electrode. Cortical implants are also hypothetical option to a wider range of visually impaired patients, those who have damage to both the retina and optic nerve. However, the technological advances necessary to decode the many synaptic connections and visual field areas is a barrier to cortical prostheses success in general. Rather, in considering more diverse cortical targets and indications for use, optic nerve modulation offers the possibility of a more nuanced behavioral effects. The optic nerve is upstream of the visual cortex and of the lateral geniculate nucleus of the thalamus, which may mean that modulation of the optic nerve could result not only in changes to visual sensory information but also to other cortical regions via the thalamo-cortical network [
]. Therefore, studies on behavioral and cognitive effects of transorbital and optic nerve stimulation have centered on vison loss and rehabilitation. However, transorbital electrical stimulation has been linked to changes in EEG and behavior which may suggest cortical changes outside of visual functions, which in turn supports exploration of cognitive modification and clinical indications not specific to vison. Compared to invasive (surgical) approaches, noninvasive optic nerve stimulation (e.g. transorbital electrical stimulation) can more readily be applied to diverse clinical population, as well as to healthy individuals. Future applications of non-invasive optic nerve stimulation may also investigate changes to behavior and cognition independent of sensory percepts (not simply linked to phosphenes).
Trigeminal nerve stimulation
The trigeminal nerve (CN V) is one of the largest cranial nerves. Its afferents transmit general sensory information from the orofacial structures to the brain, while the efferents send motor control information to the muscles of mastication from the brain. The afferent branches are discussed here. There are three main branches (divisions) of the trigeminal nerve that project to three sections of the face (Fig. 4; orange). The ophthalmic (CN V1) nerve exits through the superior orbital fissure and innervates the upper part of the face. The maxillary (CN V2) nerve exits through the foramen rotundum innervates the middle part of the face. Finally, the mandibular nerve (CN V3) exits through the foramen ovale and innervates the lower face. The three branches meet on the floor of the middle cranial fossa where the cell bodies of the sensory neurons are housed in the trigeminal ganglion. The central processes of the neurons synapse onto the second order neurons in the pons on the ventrolateral aspect in one of three trigeminal nuclei. Most of these fibers synapse onto third-order neurons in the ventral posteromedial nucleus (VPM) of the thalamus that relay information to the primary somatosensory cortex, but a small portion of the secondary neurons relay information back to the nucleus tractus solitarius (NTS) in the brain stem and the spinal cord.
The pseudounipolar neurons of somatic afferent nerves encode tactile information, including proprioception, temperature, touch, and pain. Generally, these are A-nerve fibers (myelinated, fast, large) and C fibers (unmyelinated, slow, small) [
30041-3&id=gr1.jpg){kind=link}
30041-3&id=gr2.jpg){kind=link}
30041-3&id=gr3.jpg){kind=link}
30041-3&id=gr4.jpg){kind=link}
30041-3&id=gr5.jpg){kind=link}