Vestibular-Evoked Cerebral Potentials – Frontiers

Introduction

The vestibular system has lengthy been related to postural, oculomotor, and autonomic reflexes. Current research from neuroscience and neurology have offered a big corpus of information displaying that vestibular features attain far past oculomotor and postural reflex management (1, 2). For instance, vestibular alerts have been concerned in a number of elements of spatial cognition and reminiscence (3, 4), affective processing (5), persona (6), consciousness (7), physique representations (8), and self-consciousness (9).

The vestibular contributions to sensorimotor management, consciousness, and cognition depend on neural pathways from the inside ear to the vestibular nuclei, thalamus, and cerebral cortex (10, 11), in addition to on vestibular pathways to the cerebellum and basal ganglia (12). Purposeful magnetic resonance imaging (fMRI) or positron emission tomography (PET) research mixed with caloric and galvanic vestibular stimulation recognized a big thalamo-cortical vestibular community within the human mind (11, 13–16). The vestibular cortex encompasses the parieto-insular and operculo-insular cortex, the MT/MST complicated, inferior parietal lobe (angular and supramarginal gyri), somatosensory cortex, precuneus, frontal cortex (premotor cortex and frontal eye fields), cingulate gyrus, and the hippocampus. Though there appears to be no major vestibular cortex, useful and anatomical information counsel that the parietal operculum (space OP2), the posterior insula, and/or the retroinsular cortex are the core space underpinning vestibular data processing (11, 15–18). The operculo-insular and retroinsular cortex is taken into account the human homologue of the parieto-insular vestibular cortex (PIVC) described in a number of non-human primate species (19, 20). Anatomical research and direct electrophysiological recordings in non-human primates corroborate outcomes from fMRI and PET research relating to the localization of the vestibular cortex [reviewed in (10)].

Understanding vestibular projections to the central nervous system is essential to foster the analysis of central vestibular issues, which concern 25% of sufferers referred to otoneurology models specialised in dizziness and vertigo (21). We notice that regardless of the progress made during the last 20 years to localize the human vestibular cortex, the spatiotemporal dynamics of vestibular data processing continues to be poorly described when in comparison with the wealth of information accrued in non-human primates utilizing single cell recordings [e.g., (22–24)]. That is primarily because of the limitations of the imaging methods that had been largely used to determine the vestibular cortex (fMRI, PET). The lengthy latency of hemodynamic response and poor sampling frequency of fMRI and PET didn’t permit to exactly describe the time course of vestibular responses within the human mind. One other limitation of fMRI and PET research is that the majority of them didn’t use pure vestibular stimulation—with physiologically related patterns of angular and linear accelerations—as head actions are precluded in scanners [for exceptions, see (25), and more recently (26, 27)]. As an alternative, fMRI and PET research have used synthetic vestibular stimulation, together with caloric, galvanic, acoustic, and magnetic stimulation of the vestibular receptors or nerve. Synthetic vestibular stimulation don’t permit to discover mind responses to the vary of head translations and rotations concerned in on a regular basis actions (28), which can hamper a full understanding of the vestibulo-thalamo-cortical features. Furthermore, the usage of synthetic vestibular stimulation [such as caloric vestibular stimulation] in an MRI scanner could create battle between vestibular alerts—indicating self-motion—and visible, somatosensory, and interoceptive alerts—indicating that the participant is immobile within the scanner. Thus, a few of the mind areas proven to answer vestibular stimulation in neuroimaging research, such because the temporo-parietal cortex (29), might also be concerned in monitoring, processing, or fixing multisensory conflicts (30).

In distinction with fMRI and PET, electroencephalography (EEG) and evoked potentials (EPs) permit to review vestibular data processing with a decision under the millisecond quite than seconds. Electroencephalography permits to detect, quantify, and analyze mind electrical exercise, together with responses to sensory stimuli (31). Importantly, EEG is suitable with pure vestibular stimulation (i.e., whole-body rotations and translations) that limits the induction of multisensory conflicts inherent to synthetic vestibular stimulation. Rotatory chairs and whole-body movement platforms permit to discover a wide range of vestibular stimuli with extremely exact and reproducible movement parameters (32, 33). As EEG permits to measure mind responses throughout the first milliseconds after a sensory stimulation is utilized, neurologists and neurophysiologists generally use sensory EPs to evaluate the integrity and functioning of sensory programs. Each latency and supply localization of somatosensory EPs (34), visible EPs (35) and auditory EPs (36, 37) are well-described and EP approaches are used worldwide in scientific routine. Relating to the vestibular system, the EP method is well-developed to evaluate vestibulo-ocular and vestibulocollic reflex pathways (38) by way of electromyographic recordings above the oculomotor and neck muscular tissues, respectively (Determine 1). Vestibular stimulation by air-conducted sounds and bone-conducted vibrations (43) are actually generally used to evaluate the latency and amplitude of cervical vestibular-evoked myogenic potentials (cVEMPs, recorded above neck muscular tissues) and ocular vestibular-evoked myogenic potentials (oVEMPs, recorded above oculomotor muscular tissues). Nonetheless, we notice that cerebral vestibular-EPs [referred to as Vestibular-Evoked Potentials (VestEPs) in line with (44) and (33)] recorded over the scalp utilizing EEG or magnetoencephalography (MEG) have been explored since many years however should not but a part of the scientific vestibular evaluation.

This text critiques findings from electrophysiological investigations of VestEPs in people. We define the benefits and limitations of various vestibular stimulation strategies for EPs approaches. We then describe the spatiotemporal traits of VestEPs, distinguishing between these of possible brainstem, cerebellar, and cortical origins. Lastly, we current potential functions of the VestEPs to otoneurology and to cognitive neuroscience.

Vestibular Stimulation for Neuroimaging Research and Their Utility to Vestibular-Evoked Potentials

The shortage in VestEPs research is essentially as a consequence of technical challenges to stimulate the vestibular system in a well-controlled and reproducible manner. Quite a lot of methods has been used to activate the vestibular receptors or vestibular nerve in people. These methods fall into two foremost teams. One group includes pure vestibular stimulation utilizing whole-body rotations or translations on motorized gadgets. These methods are suitable with EEG recordings and EPs approaches, however they’re to this point not suitable with “on-line” fMRI and PET recordings. The opposite group of methods includes synthetic stimulation of the vestibular finish organs in individuals maintaining their head fastened in area. Chilly and heat CVS with air or water, binaural or monaural GVS and sound-induced vestibular stimulation (SVS) are the most typical methods. These stimulation methods are totally suitable with neuroimaging and electrophysiological recordings. Nonetheless, though they’ve been largely utilized in fMRI and PET research, they haven’t usually been utilized in EEG research. This part briefly presents the principle methods for vestibular stimulation [for detailed reviews see (15, 45, 46)] with their benefits and limitations to measure VestEPs utilizing EEG.

Rotatory Chairs and Complete-Physique Movement Platforms

Passive whole-body movement has been used to research VestEPs, largely utilizing rotatory chairs mixed with EEG recordings (44, 47–54). To our information, the primary examine presenting outcomes from EEG recordings in individuals sitting on a rotating chair was carried out by Greiner et al. (47). Chairs rotating round an earth-vertical axis stimulate the horizontal semicircular canals in individuals sitting upright, and stimulate the vertical canals in individuals mendacity supine or mendacity on their facet (55). Rotations will also be utilized solely to the top, for instance in mendacity individuals with their head inserted and firmly held in a rotating drum (56). As summarized in a literature evaluation by Ertl and Boegle (46), “most research used clean movement profiles like raised-cosine velocity profiles with peak velocities above 100°/s” or “used transient stimuli with length shorter than 100 ms and peak accelerations as much as 12,500°/s²” (32, 51, 57). Such managed stimuli permit to review vestibular-evoked responses time-locked to totally different movement parameters (i.e., onset, offset, peak velocity). Voluntary, lively head rotations with accelerations as much as 12,000°/s² have additionally been used (58, 59).

Linear movement platforms and tilting gadgets ship pure stimulation to the otolithic receptors (the utricule and the saccule) (60). When in comparison with the processing of semicircular canal alerts, there may be solely scarce description of how the vestibulo-thalamo-cortical system processes otolithic alerts (61). Units permitting whole-body translations are much less frequent than rotating chairs in primary science laboratories and hospitals, which can have hampered the outline of otolithic responses.

New movement platforms with exact management of the amplitude, acceleration, and velocity of passively utilized actions now permit to review responses to complicated pure vestibular stimulation. Six-degree-of-freedom movement platforms, such because the Moog^® 6DOF2000E (Determine 2A), present comparisons with research in macaques which have used the identical platform to document single cell responses to whole-body rotations and translations (24, 64).

Rotatory chairs and whole-body movement platforms are incompatible with fMRI and PET, as a result of head actions are precluded in scanners. To bypass this concern, passive whole-body rotations and translations adopted by offline PET recordings have been utilized in a current examine (65). Though this examine is authentic in that it reviews predominant bilateral activation within the deep a part of the Heschl’s gyrus, overlapping with the posterior insula, in response to pure whole-body movement, the response was recorded offline, and doesn’t replicate the spatiotemporal sample of vestibular data processing. Few research have used blood-oxygen-level-dependent (BOLD) recordings after voluntary lively head rotations to research vestibular responses (25–27). A foremost limitation of this method is that vestibular responses are lowered within the brainstem and cerebellum throughout lively in comparison with passive actions, as proven in animal research (66–68). As well as, intraparietal neurons reply to totally different instructions of motion relying on whether or not the motion is lively or passive (69, 70). These variations in vestibular processing restrict a direct comparability of neuroimaging information utilizing lively head movement with research utilizing passive physique movement.

Utility to VestEPs

Electroencephalography stays one of the best and most direct technique to investigate the spatiotemporal dynamics of mind responses to pure vestibular stimuli, given its excessive temporal decision under the milliseconds and its compatibility with recordings throughout pure, passive whole-body movement. One should, nonetheless, contemplate that rotatory chairs and movement platforms for physique translations can induce mechanical and electromagnetic artifacts within the EEG sign, in addition to artifacts as a consequence of reflexive eye actions (i.e., vestibulo-ocular reflex) and muscular tissues contractions (i.e., vestibulocollic and vestibulospinal reflexes). Rotatory chairs and movement platforms additionally generate auditory noise that must be managed for. Lastly, it must be famous that physique rotations and translations activate the somatosensory and interoceptive programs, respectively, because of the stress of the physique towards the chair or to the motion of bodily fluids, which might hardly be diminished.

Caloric Vestibular Stimulation

Caloric vestibular stimulation (CVS) is the most typical approach to guage the semicircular canals features (see Determine 2B). It consists in making use of heat (≥44°C) or chilly ( ≤ 30°C) water (or gasoline) within the auditory canal of individuals mendacity supine, with their head tilted 30° ahead. The fluid creates a temperature gradient within the semicircular canals, which induces an endolymphatic movement activating the hair cells within the crista ampullaris. The firing charge within the vestibular afferents will increase or decreases accordingly to the rise or lower in temperature within the inside ear. Caloric vestibular stimulation largely prompts the horizontal semicircular canal, with a weaker contribution of the anterior and posterior canals (71). This stimulation induces a nystagmus towards the stimulated ear with sizzling water or gasoline and induces a nystagmus towards the other ear with chilly water or gasoline. These oculomotor responses are accompanied by complicated sensations of rotation, floating, and tilting. These manifestations happen solely after a number of seconds of stimulation and a transparent onset is usually troublesome to find out. They’ll additionally final a number of minutes after the top of the stimulation. Caloric vestibular stimulation is totally suitable with fMRI, PET, EEG, and MEG and has been used within the pioneer vestibular neuroimaging research about 40 years in the past (72, 73). Current neuroimaging research confirmed that CVS prompts a number of cortical areas, such because the inferior parietal lobule, superior temporal gyrus, insula, frontal cortex, and frontal eye fields in addition to hippocampal, parahippocampal, and thalamic areas [(74–80); for a detailed review see (15)].

Utility to VestEPs

Caloric vestibular stimulation has been utilized in early research of VestEPs, particularly in epileptic sufferers (81–85). These research confirmed that CVS modulates mind rhythms (e.g., alpha rhythm desynchronization) and might set off seizures in predisposed sufferers. Nonetheless, CVS doesn’t appear acceptable for EPs approaches for a number of causes. First, the nystagmus evoked by CVS can create essential artifacts to the EEG recordings. Second, as the precise onset of the consequences of caloric stimulation on vestibular receptors is troublesome to find out, this precludes EP approaches. Third, CVS can’t be repeated many occasions in a brief time period, which is required to calculate EPs. Lastly, CVS prompts the somatosensory, thermoceptive and nociceptive sensory programs, resulting in unspecific activations of extravestibular pathways.

Galvanic Vestibular Stimulation

In distinction to CVS, galvanic vestibular stimulation (GVS) prompts the vestibular finish organs with a temporal precision beneath the microsecond. Galvanic vestibular stimulation consists within the software of a small transcutaneous electrical present (usually as much as 5 mA) by way of a cathode and an anode positioned on the pores and skin over the mastoid processes (see Determine 2C). Galvanic vestibular stimulation will be utilized monaurally (electrodes are on the identical ear) or binaurally (electrodes are positioned on the other ears), with steady electrical stimulation, single square-wave pulse, or trains of pulses. Galvanic vestibular stimulation is believed to instantly modulate the firing charge of the vestibular afferents (86), though a GVS might also stimulate the vestibular hair cells (87). The cathode will increase the firing charge within the vestibular afferents, whereas the anode decreases it [reviewed in (88)]. Galvanic vestibular stimulation is a synthetic vestibular stimulation in that it bypasses the mechanoelectrical transduction within the hair cells and prompts afferent fibers from receptors that will by no means be activated collectively throughout naturalistic head actions. Steady GVS induces, nearly instantaneously, complicated sensations of mixed translation and rotation, which orientation and depth will be modulated by the route and depth of the utilized present. As early because the Nineties, neuroimaging research have used GVS to localize the vestibular cortex. They recognized areas such because the supramarginal gyrus, precuneus, posterior cingulum, superior and center temporal gyrus, insula, frontal areas and frontal eye fields, inferior and superior occipital gyrus in addition to hippocampal, parahippocampal, and thalamic areas [(89–93); for a detailed review see (15)].

Utility to VestEPs

Trains of quick electrical pulses, corresponding to these used to evoke cVEMPs [e.g., 2-ms pulses at 5 Hz; (94)], typically don’t evoke self-motion notion and are theoretically splendid to measure VestEPs. Nonetheless, GVS can evoke muscular responses corresponding to cVEMPs (94) additionally time-locked to the stimulation, which might contaminate VestEPs recordings utilizing EEG. Galvanic vestibular stimulation is a transcutaneous stimulation that prompts the somatosensory—and typically the nociceptive—system. Extra importantly, GVS generates electromagnetic artifacts that have an effect on EEG recordings and is probably not suppressed, stopping the statement of quick latency VestEPs. One early examine mixed steady GVS with EEG to research lengthy latency VestEPs and described a collection of constructive and unfavorable parts with an onset latency round 60–80 ms which might last as long as 500 ms after the stimulation (95). To our information, just one EEG examine has just lately recognized VestEPs of center and lengthy latency evoked by 3 ms square-wave pulses (96).

Sound-Induced Vestibular Stimulation

Sound-induced vestibular stimulation (SVS) gives the exact timing of GVS with out electromagnetic artifacts and appears subsequently notably acceptable for event-related EEG research (see Determine 2D). Brief sounds are extremely reproducible and repeatable stimuli whose onset and offset will be managed with a millisecond precision. Brief excessive sound stress clicks at intensities round 100 dB-SPL and quick tone-bursts at 500 Hz pressurize and activate otolithic receptors (43, 97, 98). Sound-induced vestibular stimulation is broadly utilized in otoneurology to match the latency and amplitude of cVEMPs and oVEMPs after stimulation of the appropriate and left ear individually (38, 99, 100). Sound-induced vestibular stimulation doesn’t appear to induce any vestibular notion though this has by no means been totally investigated. Sound-induced vestibular stimulation has been utilized in neuroimaging research of the vestibular system and revealed otolithic projections to frontal, parietal, and cingulate areas, just like areas revealed utilizing semicircular canal stimulation (101–103).

Utility to VestEPs

Sound-induced vestibular stimulation allowed to determine VestEPs and to explain parts of quick (40, 104–109), center (42, 108, 110, 111), and late latency (42, 110, 112). As described under, quick, center, and late VestEPs evoked by SVS have been related to totally different turbines alongside the vestibulo-thalamo-cortical pathways, in order that SVS possible permits to review the spatiotemporal processing of vestibular data from the periphery to the cortex.

Vestibular-evoked potentials and auditory EPs present comparable latencies and a few responses to SVS seem to comprise each auditory and vestibular contributions. Totally different methods can then be used to disentangle them. As SVS de facto prompts the auditory system, research have used management auditory stimuli, modulating both the depth or the frequency of sounds to separate vestibular and auditory responses (108, 111, 113). Most research of VestEPs utilizing SVS have used sounds under and above the vestibular threshold, decided because the depth above which sounds evoke VEMPs for a given ear in a given particular person (42, 107, 108, 110, 113–115). This permits to determine VestEPs, which solely seem for SVS above the vestibular threshold, from auditory parts showing for SVS under and above the vestibular threshold. The validity of this method has been confirmed in current fMRI research. An unbiased element evaluation revealed a selected enhance in BOLD response for SVS above the vestibular threshold in areas such because the insula, precuneus, inferior parietal lobule, center cingulate cortex, and cerebellar uvula (116). Subsequent parametric analyses revealed vestibular-auditory integration within the caudal a part of the superior temporal gyrus and posterior insula (117). Nonetheless, some authors argued that in EEG research it may be troublesome to disambiguate between auditory and vestibular parts as a result of the time course of VestEPs throughout whole-body translation and the time course of auditory EPs overlap (33). In conclusion, SVS appears to be a helpful and handy approach to evoke VestEPs and examine their cerebral origin utilizing supply evaluation, offered that related controls and analyses are used to disentangle them from auditory parts.

Impulsive Acceleration Stimulation

Impulsive acceleration stimulation [IAS; (46)] additionally known as “bone-conducted” stimulation (41), will be utilized utilizing a minishaker positioned over one of many mastoids or on the brow, on the hairline (Fz), perpendicular to the cranium floor (see Determine 2E). 5 hundred Hz vibrations stimulate the otolithic receptors and induce ocular and cervical VEMPs (43, 118, 119). These can be utilized to research unilateral vestibular loss, for instance by evaluating responses under each eyes (63).

Utility to VestEPs

Impulsive acceleration stimulation has been utilized in just a few research to evoke VestEPs, because it creates speedy and extremely reproducible translational accelerations as much as 0.2 g (108, 120). Nonetheless, IAS prompts the somatosensory and auditory programs and might trigger small head actions creating artifacts in fMRI and EEG research. For these causes, IAS stays not often used for the examine of central vestibular projections.

Magnetic Vestibular Stimulation

Magnetic vestibular stimulation (MVS) just lately emerged as a brand new technique to stimulate vestibular receptors (see Determine 2F). Magnetic fields over 1 T can induce a nystagmus in wholesome individuals that’s absent in sufferers with a bilateral vestibular failure (121–123). Primarily based on the evaluation of the nystagmus it evokes, MVS is believed to activate the horizontal and superior semicircular canals (124). Magnetic vestibular stimulation interacts with ionic currents within the endolymph, inducing Lorentz forces pushing on the cupula. It gives a option to produce long-duration vestibular stimulation, equal to a continuing angular acceleration on a rotatory chair. Accordingly, MVS over 3 T can induce sensations of rotation. Magnetic vestibular stimulation has been proven to modulate the BOLD response in vestibular and oculomotor areas, together with the anterior cingulum, cerebellar vermis, and calcarine sulcus (125). Magnetic vestibular stimulation can be utilized as vestibular stimulation along with resting-state fMRI or fMRI research of cognitive processes.

Utility to VestEPs

Electrophysiological recordings can now be organized in an MRI bore and several other research confirmed that EEG, with event-related potential approaches, will be recorded concurrently as fMRI (126–128). Nonetheless, MVS has a number of main caveats for EP approaches, which have been reviewed in Ertl and Boegle (46). Largely, MVS precludes the applying of repeated stimuli with a transparent onset: because the magnetic area of the scanner is fixed, MVS doesn’t permit to match modifications in mind exercise as a consequence of MVS with respect to a baseline (with out MVS) with an event-related potential method. Magnetic vestibular stimulation additionally induces a nystagmus, that must be managed for or inhibited to keep away from muscular artifacts within the EEG alerts. Of notice, the magnetic area interferes with electrophysiological recordings and cautious artifact removing is required [e.g., (129, 130)].

Intraoperative Vestibular Nerve Stimulation

Direct electrical stimulation of the vestibular nerve will be mixed with EEG recordings in sufferers present process vestibulocochlear nerve surgical procedure. This was carried out in uncommon research throughout unilateral vestibular neurectomy for intractable Menière’s illness and through neuroma resection (131–133).

Utility to VestEPs

Intraoperative vestibular nerve stimulation is near early electrophysiological investigations of the vestibular cortex in cats and monkeys (134, 135) or to current research in rodents (136), which utilized electrical stimulation to the vestibular nerve. Early human research, utilizing montages with solely few electrodes, didn’t present data relating to the turbines of the VestEPs (131, 132). Electrical stimulation could unfold to the facial nerve or the acoustic nerve and basic anesthesia could alter vestibular data processing.

Conclusion

Main shortcomings have been emphasised for pure and synthetic vestibular stimulations when neuroimaging the vestibular system is anxious (15, 46). So far, pure vestibular stimulation isn’t suitable with neuroimaging methods with excessive spatial decision corresponding to fMRI. Most neuroimaging research to this point have used synthetic stimulation to review the vestibular system with a excessive spatial decision however a poor temporal decision. In contrast, EEG has a excessive temporal decision and is suitable with each pure and a few synthetic vestibular stimulations. Nonetheless, EEG is thought for its comparatively low spatial decision and the issue to precisely determine subcortical turbines of alerts recorded on the scalp. Along with these problems with compatibility between stimulation and recording methods, most synthetic vestibular stimulation (and pure vestibular stimulation to a lesser extent) co-activate different sensory receptors. This consists of largely activation of auditory, somatosensory, interoceptive, in addition to typically nociceptive programs, that are troublesome to manage for in neuroimaging research. Furthermore, synthetic vestibular stimulation can induce sensory conflicts between vestibular data and different senses, opposite to pure vestibular stimulation.

With these limitations in thoughts, it appears possible to research the spatiotemporal dynamics of vestibular data processing within the human central nervous system by rigorously adapting the vestibular stimulation to every recording approach and utilizing the required management situations. The subsequent part focuses on how VestEPs assist perceive the spatiotemporal dynamics of vestibular data processing.

Vestibular-Evoked Potentials

Pioneering work described VestEPs in people as early because the Sixties (47, 137, 138). Apparently, VestEPs had been additionally described in a number of animal species through the Sixties or the next decade utilizing comparable approaches [see for example studies in guinea pigs: (139); cats: (48, 140); non-human primates: (141)]. Early analysis centered on the affect of rotatory vestibular stimulation on EEG alerts in epileptic sufferers. These research confirmed that vestibular stimulation might activate temporal epileptic foci and typically set off seizures (47, 85, 142–144). One other line of research in contrast scalp responses between wholesome individuals and sufferers with a bilateral vestibulopathy or between the 2 sides in sufferers with a unilateral vestibular loss. They confirmed the existence of a vestibular response beneath scalp electrodes. Probably the most constant discovering was a suppression of alpha rhythm over the temporo-parietal junction (47, 82, 143). Lastly, early research utilizing CVS reported comparable results on EEG alerts, displaying that cerebral responses may be evoked by synthetic vestibular stimulation (82–85).

On the grounds of those pioneering research and after enchancment in recording methods, VestEPs had been described extra exactly. Supplementary Desk 1 summarizes the research thought of on this evaluation, along with the latencies and scalp location of the principle VestEPs, in addition to the electrode montages used to document them. To facilitate the literature evaluation, we now have categorised VestEPs as quick (<20 ms), center (20–50 ms), and late (> 50 ms) relying on their peak latencies and their most possible turbines, equally to the classification of auditory EPs (145). Within the textual content and within the figures, we selected to homogenize the report of the VestEPs parts by indicating their constructive (p) or unfavorable (n) polarity adopted by their reported peak latency (or common latency) expressed in ms post-stimulation onset. We subsequently keep away from the usage of basic labels relative to the order of look of the parts, corresponding to P1, N1, P2, and N2, which confer with very totally different latencies in several research utilizing totally different paradigms and stimulation parameters. The aim of this isn’t to redefine frequent element names however to assist the reader evaluate parts latency and polarity in a easy manner and keep away from confusion.

Brief Latency Vestibular-Evoked Potentials

Vestibular-evoked potentials with a latency under 10 ms have been associated to sign conduction within the vestibular nerve and vestibular data processing within the vestibular nuclei (40, 56, 57, 104–106, 109, 132, 133, 146, 147). Vestibular-evoked potentials with a peak latency between 10 and 20 ms have been attributed to myogenic, cerebellar or cortical sources (41, 42, 56, 57, 107, 108, 110, 113–115, 120, 133, 148–150). On this part, we describe the quick latency parts that emerge throughout the research and briefly focus on their origin.

Brief Latency Responses Below 10 ms

Responses with the shortest latency have been noticed throughout perioperative stimulation of the vestibular nerve. An early examine utilizing direct electrical vestibular nerve stimulation in 9 sufferers operated on for intractable Menière’s illness revealed a unfavorable potential with a latency of two ms and an amplitude of 0.5 μV (132). This response was suppressed after vestibular neurectomy, indicating its vestibular origin. In a later examine, the same stimulation elicited VestEPs with an onset of three.5–5 ms and peak latency of 9.5 ms in 11 sufferers with 30 electrodes on the scalp (133). These responses had been recorded bilaterally, however the bigger responses had been noticed beneath ipsilateral electrodes on the decrease a part of the temporal scalp area.

A collection of research utilizing speedy and passive head rotations within the yaw airplane, consisting of impulses at 10,000°/s², report comparable responses. Some research recognized a brow constructive peak at 3.5 ms, a unfavorable peak at 6 ms, and a constructive peak at 8.4 ms (56, 57). One other examine recorded a response onset round 2.2 ms, adopted by a constructive peak at 2.9 ms, and different parts with peak latencies at 5.1, 7.0, and eight.6 ms (147). The responses amplitude ranged from 0.3 to 0.6 μV. Horizontal lateral translations additionally triggered responses with 3 and 6 ms peak latencies (146). Impulsive acceleration stimulation additionally evoked parts with latencies of 1.9, 2.4, and 4.5 ms (151). Of notice, pores and skin floor recordings and intracranial recordings within the cat vestibular nuclei with the identical acceleration impulses revealed that irregular neurons responded with a 3.5 ms latency to the onset of the top acceleration (152, 153). The authors proposed that the element with an onset round 2 ms displays vestibular nerve exercise, whereas the next parts are of vestibular nuclei origin (152, 153).

More moderen research in search of vestibular parts within the brainstem auditory-evoked potentials (BAEPs) have confirmed and prolonged such outcomes. Brainstem auditory-evoked potentials are a normal for the scientific analysis of listening to and brainstem auditory pathways (37). They consist of 5 to 6 vertex constructive waves and certain current vestibular parts of saccular origin. This was first instructed by research in guinea pigs displaying preserved quick latency far area parts after cochlear hair cells destruction (154, 155). In people, the same 3 ms latency unfavorable peak, known as the n3, was recognized utilizing a classical BAEPs montage with loud clicks (40, 104, 109). Air-conducted tones pips, which delay BAEPs, induced a response just like the n3, however with a 5 ms latency, known as the n5 (105, 106). The n3 and n5 are possible of vestibular origin, as they’re present in deaf sufferers (104), however are absent in vestibular-defective sufferers, even after they present preserved listening to and a residual caloric nystagmus (109).

The n3 will be recorded on the vertex and the n5 is greatest noticed ipsilaterally to the acoustic stimulation, over parietal areas. The quick latency of the n3 and n5 parts counsel that they’re far-field potentials originating from the vestibular nuclei (104). Their absence in a number of sclerosis sufferers with demyelination within the decrease pons confirms this origin (40, 105). As well as, an n6 element, additionally evoked by SVS however unbiased of the n5, was maximally recorded over the parieto-occipital space (106). As a result of it seems roughly 1 ms after the n5, this element has been proposed to originate within the rostral pons or the midbrain (106).

Brief Latency Responses Above 10 ms

Vestibular-evoked potentials between 10 and 20 ms are probably the most investigated, and several other parts have been recognized. These parts are sometimes thought of as a part of a biphasic wave (such because the p10–n15 and n15–p21 waves) or have been described as particular person parts with a given peak latency (such because the p10 and p21). We summarize under the principle particular person parts reported within the literature (Supplementary Desk 1).

Part p10

A number of research have described a constructive element with an onset latency of 6–7 ms and a peak latency round 10 ms after whole-body rotations (56, 57), SVS (42, 107, 108, 110, 114, 115, 149), and direct electrical nerve stimulation (133). A number of VestEPs appear to look at this latency as a result of they’re recorded beneath totally different electrode areas. Utilizing SVS, it was potential to indicate that the p10 (in addition to subsequent parts: n15, n17, and p21; see under) was of vestibular origin. The p10 (in addition to n15, n17, and p21) was current in a affected person with listening to loss and preserved vestibular perform, however was abolished in a affected person with impaired vestibular perform and preserved listening to (107). As well as, it was absent for SVS under the vestibular threshold (i.e., the depth at which VEMPs seem) and was noticed above this threshold (42, 107, 108, 110).

Vestibular-evoked potentials with a latency close to 10 ms had been first confirmed frontally (56, 57, 133) or maximal at central electrode Cz with a small ipsilateral lateralization (107). De Waele et al. (133) proposed that such VestEPs replicate activation of a number of cortical areas. A dipole supply evaluation confirmed, inside 6 ms, parallel activation of the ipsilateral temporo-parietal cortex, prefrontal, and/or frontal lobe, supplementary motor space, and contralateral parietal cortex [(133); Figure 3A]. These findings are in keeping with the statement that the posterior a part of the postcentral gyrus (space 2) is activated inside 5–6 ms after electrical vestibular nerve stimulation within the rhesus monkey (135).

A p10 element, adopted by an n17 element, has additionally been noticed at parietal electrode Pz [(108); Figure 3B] or on the inion (115). A number of turbines have been proposed for the p10 and n17 parts. Because the p10/n17 is concomitant to the oVEMP biphasic wave n10/p17, a myogenic or cerebral generator has been proposed (108, 113). Subsequent research discovered that the p10 mirrors a frontal or infra-ocular n10 response (110) and supported the concept that they’re two distinct responses (115).

A line of analysis means that the p10 could originate from the cerebellum (108, 110, 115, 149). Sound-induced vestibular stimulation evoked a p10/n17 response at occipital electrodes (PO7 and PO8) contralateral to the stimulated ear and on the inion (Iz), along with a n10/p17 complicated beneath electrodes positioned over the splenius muscular tissues to document cerebellar exercise (115). A supply evaluation discovered the contralateral cerebellum because the most certainly origin of those responses (115). The truth that, as for the oVEMP n10/p17, the p10/n17 will depend on gaze route (115) signifies both a myogenic origin or the recording of cerebellar or cerebral mechanisms to manage ocular responses to vestibular stimulation. To additional examine the cerebellar origin of those VestEPs, current research used prolonged EEG montages to document the electrocerebellogram, with electrodes over, laterally to and under the posterior fossa, thus over the inferior cerebellum (41, 120, 150, 156). With such montages, IAS revealed a p12/n17 biphasic wave (41, 120, 150). A supply evaluation confirmed the cerebellar origin of the p12/n17 (150). It was argued that the response couldn’t be myogenic as a result of neck muscular tissues had been relaxed throughout recordings, the response was lateralized, and the waveforms differed from these of cVEMPs (41). Though these current outcomes are very promising, one can’t exclude that neck muscle leisure doesn’t totally abolish a possible muscular contribution to the noticed responses.

The above-mentioned outcomes should not solely encouraging for the electrophysiological investigation of the spatiotemporal dynamics of vestibular data processing, but in addition for the non-invasive electrophysiological examine of cerebellar features usually. The examine of the cerebellum utilizing EEG is certainly controversial because of the construction of the cerebellum, historically low EEG spatial sampling over the cerebellum, and non-realistic spherical head fashions for supply analyses [reviewed in (157)]. Nonetheless, increasingly more proof helps the feasibility of EEG and MEG research of cerebellar exercise, offered that enhancements are made to the same old EEG and MEG methods (157). Todd and colleagues of their collection of EEG research have taken a primary step towards these enhancements by putting EEG electrodes extra posteriorly with the intention to enhance the possibilities to document cerebellar exercise. Nonetheless, warning ought to nonetheless be taken relating to the outcomes of supply localization, as enhancements are nonetheless wanted to adapt the present fashions which contemplate the top as a sphere and poorly combine the cerebellum.

Part n15

A number of SVS research report a unfavorable element with an onset latency round 8 ms and a peak latency of 15 ms. The n15 was greatest recorded beneath frontal [(107, 113, 148), Figure 3B] or prefrontal electrodes (42, 110). The vestibular origin of the n15 was confirmed by its presence in a affected person with profound listening to loss however preserved vestibular perform, and its absence in a affected person with hypovestibular perform however preserved listening to (107). The n15 amplitude elevated within the case of superior canal dehiscence, supporting its vestibular origin (148).

The n15 was first considered pure myogenic origin (107, 148, 158). Certainly, the n15 recorded frontally was comparable in measurement and morphology to responses recorded across the eyes, and it was modulated by modifications in gaze route. As well as, a affected person with superior canal dehiscence confirmed a really massive n15 amplitude (as much as 11.8 μV) for SVS at 42 dB above vestibular threshold, which is uncommon for neurogenic potentials (107). Nonetheless, left SVS appeared to induce a extra asymmetrical n15 with an earlier contralateral onset (107) or bigger responses for left in comparison with proper SVS (114), which means that there could also be a central origin to this element. In contrast, supply localization instructed that the frontal n15 could have a cerebellar and cortical origin (108, 113). Specifically, a Mind Electrical Supply Evaluation (BESA) localized the turbines within the contralateral cerebellum or the precentral sulcus (108). A Low Decision Electromagnetic Tomography Evaluation (LORETA) localized the n15 turbines in the appropriate precuneus and cuneus (113). Altogether, these outcomes point out that the n15 could signify concomitant vestibular-induced extraocular, cerebellar, and cortical activations round 15 ms. The cerebellar origin of a element higher recorded on the frontal degree stays nonetheless to be confirmed with the event of electrocerebellogram methods.

Part p20

Elements with a latency round 20 ms typically comply with these detected close to 10 or 15 ms with an inversed polarity beneath the identical or carefully situated electrodes. An n20 element follows the p15 throughout whole-body rotations (56, 57, 147, 159) or SVS (137, 138). Likewise, in newer research, a constructive element with a peak latency of 20–21 ms follows the n15 after SVS (107, 108, 113, 114). A p21 element has been reported beneath frontal electrodes (107, 108) or beneath posterior occipital electrodes and proper temporal electrodes (113). Making use of LORETA localized the p21 turbines in the appropriate precentral gyrus, with contributions of the appropriate medial and superior temporal gyri (113).

Conclusion

Electroencephalography and averaging methods have confirmed to be efficient to review and assess the spatiotemporal dynamics of vestibular data processing throughout the first milliseconds after stimulation onset. Brief-latency responses with a peak latency beneath 10 ms have been associated to exercise within the vestibular nerve or vestibular nuclei. That is in accordance with outcomes from early research in cats and monkeys the place the vestibular nerve was instantly stimulated and responses recorded within the animal mind (135, 160, 161). Potentials round 2 ms are prone to replicate vestibular nerve response whereas parts with onsets close to 2–3 ms and peak latencies noticed inside 10 ms after the stimulation are attributed to vestibular nuclei exercise. Far-field parts greatest recorded on the vertex, such because the n3 and n5, or recorded over parieto-occipital areas, such because the n6, could replicate vestibular data processing alongside the brainstem, from the decrease pons to the rostral pons or midbrain, respectively.

Responses with a peak latency of 10–20 ms could also be myogenic, but in addition reveal a speedy spreading of vestibular data to the cerebellum and cerebral cortex. To our information, just one group documented cerebellar VestEPs in people (41, 108, 110, 115, 120, 149, 150). Of notice, quick latency VestEPs had been evoked by SVS or IAS on the mastoids, each methods focusing on the otolithic receptors, in order that we lack details about the potential cerebellar evoked responses to semicircular canal stimulation. Extra systematic research utilizing stimulation methods corresponding to rotations are wanted to raised determine the origin of those responses in people.

A number of research additionally counsel that vestibular data reaches the cerebral cortex inside 6 to fifteen ms after stimulation (107, 108, 113, 133). de Waele et al. (133) argued for simultaneous activation of a number of trisynaptic vestibulo-thalamo-cortical pathways, indicating that vestibular data quickly spreads to totally different areas within the cortex. Nonetheless, the speculation of a parallel processing in these areas isn’t in keeping with current electrophysiological research in monkeys. Parieto-insular vestibular cortex responses to translations had shorter latency in comparison with responses within the ventral intraparietal (VIP) space and space MST, supporting the concept that the PIVC is “nearer” to the periphery (23).

Center Latency Vestibular-Evoked Potentials

Solely few research recognized VestEPs with a latency between 20 and 50 ms. Right here, we are going to give attention to two biphasic VestEPs that appear to persistently emerge from EEG research: a primary VestEP with peak latencies round 20 and 30 ms and a second VestEP with peak latencies round 42 and 52 ms. Some research additionally described particular person peaks with comparable latencies individually.

The “20–30 ms Advanced”

A 20–30 ms complicated was reported after SVS (111, 162), GVS (96), and cranium vibration on the nasion (112). Sound-induced vestibular stimulation evoked a constructive peak at 20 ms and a unfavorable peak at 30 ms beneath fronto-central and centroparietal electrodes of a 32-channel EEG [(111); Figure 4A]. This 20–30 complicated was additionally noticed utilizing a simplified Laplacian montage that could possibly be used for scientific functions (111). One other SVS examine reported the p23, n24, and n32 parts individually (108). Galvanic vestibular stimulation elicited a counterpart of the 20–30 ms complicated with latencies of 25 and 35 ms (96). A BESA supply evaluation and outcomes from an epileptic affected person implanted with deep mind electrodes revealed that this complicated originated from the bilateral anterior insula and posterior operculum (111). Nonetheless, the comparability of supply analyses revealed dipoles oriented in a different way in area in these areas for identical latencies after SVS and GVS (96).

Cranium vibration induced biphasic n26–p30 or p26–n35 responses for constructive and unfavorable stimulation polarity, respectively (112). Supply localization revealed deep midline sources plausibly representing exercise from the cingulate cortex, medial thalamus or basal ganglia, in addition to bilateral frontal sources (112). Comparable unbiased parts had been recognized close to 30 ms utilizing whole-body rotations (147) and translations (163).

The “42–52 ms Advanced”

A number of current research recognized a frontocentral n42–p52 complicated utilizing SVS (42, 108, 110) and IAS on the nasion (112). The n42–p52 complicated was additionally known as the N^*/P^* response because it seems amongst auditory EPs. Nonetheless, it was argued that the n42–p52 (N^*/P^*) complicated represents a extra particular vestibular response as its peak-to-peak slope elevated linearly for SVS above the vestibular threshold, and it was not noticed in a affected person with an unilateral vestibular loss stimulated within the broken ear [(42); Figure 4B]. Mind Electrical Supply Evaluation revealed that the n42/p52 was greatest defined by a mid-cingulate supply, along with bilateral sources within the superior temporal cortex (42, 110). That is in keeping with fMRI research displaying exercise within the cingulate cortex following CVS (75, 164, 165) and GVS (89). Different research reported constructive particular person parts round 40 ms following whole-body rotations [(163); 38.9 ms] and translations [(33, 166, 167); p38.2 ms under parietal electrodes]. Extra just lately, IAS on the left mastoid was additionally discovered to evoke n25, p40, and n53 parts beneath Bz, an electrode positioned over the cerebellum, two rows under Iz on the midline [(150); following a nomenclature proposed by Heine et al. (168)].

Conclusion

4 peaks are most persistently reported as VestEPs of center latencies: they represent the 20–30 complicated and the 42–52 complicated. These parts offered little variability of their latencies and their amplitude elevated with stimulation depth, main the authors to suggest them as dependable markers of cortical vestibular data processing (112).

Research of center latency VestEPs localize turbines within the operculo-insular complicated and cingulate cortex, two key areas of the vestibular cortical community. The insular and cingulate contributions to vestibular processing is well-supported by anatomical proof in non-human primates (20), meta-analyses of neuroimaging information (15, 16), and intracranial electrical stimulation in epileptic sufferers (169, 170).

Late Latency Vestibular-Evoked Potentials

Responses with a latency above 50 ms had been already recognized in VestEPs investigations from the Sixties (47, 49, 50, 95, 137, 138). Nonetheless, these early research didn’t report the latency of all noticed parts or talked about collection of parts inside a time vary. Research utilizing whole-body rotations recognized 5 to seven waves with latencies starting from 70 to 850 ms (44, 171–176). Responses with latencies as much as 3,000 ms have been reported (47). We summarize under a few of the most persistently reported responses with latencies above 50 ms (see Supplementary Desk 1).

Responses at 60–70 ms

Sound-induced vestibular stimulation has been proven to evoke a constructive element with a peak latency of 60 ms beneath temporal electrodes, adopted by a frontal element with a peak latency of 70 ms (111). The authors hypothesized that the 70 ms element could replicate crosstalk exercise between vestibular areas 2v, 3nv, and the frontal eye fields (111). Galvanic vestibular stimulation additionally evoked responses at 50 and 80 ms beneath the identical electrodes (96). Supply evaluation in addition to information from an epileptic affected person implanted with deep electrodes confirmed that the anterior insula and posterior opercular cortex responded to SVS [(111); Figure 5A]. Comparable sources had been noticed for the response to GVS [(96); Figure 5A]. Impulsive acceleration stimulation evoked VestEPs with comparable latencies beneath electrode FCz (112). These VestEPs consisted in a unfavorable peak at 65 ms after constructive polarity stimulation and a constructive peak at 60 ms adopted by a unfavorable peak at 78 ms after unfavorable polarity stimulation (112). Supply evaluation instructed a posterior cingulate contribution.

Responses at 80 ms

Complete-body translation evoked the n80, a unfavorable element with a peak latency of 80 ms [(33, 166, 167); Figure 5B]. The n80 was most outstanding beneath frontal electrodes, however a weaker occipital positivity was additionally noticed with the identical latency. The n80 amplitude elevated with linear acceleration depth (33, 166). This was defined by elevated exercise within the cingulate sulcus visible space, an space concerned in self-motion processing (177).

Response at 110 ms

A constructive element with a peak latency at 110 ms was reported after each SVS and acoustic management stimulation (111), in addition to after GVS (96). This means a vestibular contribution to the late auditory EPs, round 100 ms.

Responses at 200 ms

An early examine used a vertex referred to mastoid montage and confirmed a constructive potential with a peak latency of 220 ms after the sudden cease of a rotation (178). This VestEPs was current in 30 wholesome individuals, but it surely was absent in two sufferers after labyrinthectomy. A subsequent examine in contrast the p220 in 159 sufferers with infarct on the center cerebral artery to these of 130 controls (179). Hundred and twelve sufferers confirmed delayed, decreased, or no evoked response in any respect, suggesting that vestibular evoked responses to rotations concerned the temporo-parietal cortex. Hofferberth [(179), p. 125] concluded that there’s a “major pathway of vestibular evoked potentials […] from the vestibular nuclei by way of the midbrain to the thalamus and from the thalamus to the temporo-parietal cortex.” That is very near some descriptions of vestibular pathways, highlighting a foremost contribution of the temporo-parietal cortex (65, 89, 180, 181).

More moderen research utilizing physique translations revealed a constructive element with a peak latency of 199 ms, greatest noticed beneath electrode Cz [(33, 166, 167); Figure 5B]. As for the n80, the p199 amplitude elevated with physique acceleration and this enhance was greatest defined by elevated exercise within the cingulate sulcus visible space.

Lastly, we notice that different EEG investigations utilizing whole-body rotations have recognized unbiased parts with peak latencies at 200 ms (50, 182), or biphasic waves with peak latencies from 200 to 350 or 400 ms, maximally recorded on the vertex (49, 52, 178, 179, 183, 184).

Responses at 300–500 ms

Varied responses have been described throughout the 300–500 ms time window after lively (58, 59) and passive physique rotations (32, 44, 47–49, 51, 52, 171, 174, 176, 185), in addition to after physique translation (33, 166, 167, 186). A seminal examine in contrast human responses to animal responses that had been already accepted as vestibular in origin (48). The authors used the sudden cease of yaw rotations as a stimulus each in cats with implanted electrodes and in people who underwent scalp EEG recordings. They noticed late diffuse responses with peak latencies of 300–600 ms in each species, which had been prevalent within the preoccipital (space 19) and/or parastriate (space 18) areas in people. Vestibular-evoked potentials with such late latencies possible replicate the processing of the acceleration profile, with peak amplitudes at peak accelerations (186) or motion inversion (32, 47).

Though their actual latency differ between research, VestEPs round 300 ms have persistently been reported after passive whole-body rotations (32, 185) and translations (33). For instance, whole-body rotations within the yaw airplane evoked a vertex unfavorable element with a peak latency close to 300 ms (32, 185).

Equally, whole-body translations evoked a unfavorable element at 340 ms beneath parietal electrodes, accompanied by a weak negativity beneath electrode FCz, in addition to a constructive element at 461 ms which was greatest noticed in centroparietal areas [(33); Figure 5B].

Conclusion

Late VestEPs are much less effectively characterised than quick and center latency responses and so they seem throughout a big time window after the stimulation onset. Primarily based on two current research utilizing physique translations, Ertl et al. (166) proposed that responses with a latency beneath 220 ms could replicate bodily properties of the stimulus, whereas later responses could replicate larger degree perceptual and cognitive processes. Such transition from a sensory processing to a higher-level perceptual evaluation has been proposed for the auditory system (187).

Conclusions and Views

We’ve reviewed outcomes from pioneering electrophysiological research and newer research utilizing state-of-the-art EEG indicating that VestEPs can now be thought of significant electrophysiological signatures of vestibular data processing from the vestibular nerve to the cerebral cortex, owing to the excessive temporal decision of EEG. After summarizing the principle findings relating to VestEPs with parts of quick (<20 ms), center (20–50 ms), and late (> 50 ms) latency, we focus on how VestEPs research are informative relating to the parallel vs. hierarchical processing of vestibular alerts within the cerebral cortex, and relating to hemispheric dominance of vestibular data processing. Whereas underlining points with replicability and variability of VestEPs throughout research, we focus on the principle limitations of VestEPs research and spotlight the issue to isolate parts of vestibular origin whereas controlling for extravestibular sensory contributions. Lastly, we open views relating to the contributions of VestEPs research to the fields of neurology, otoneurology, cognitive neuroscience, and programs neuroscience.

Major Findings and Their Hyperlink With Vestibular Processing Alongside Ascending Pathways

Vestibular-evoked potentials with quick, center and late latency mark the totally different steps and the spatiotemporal group of vestibular data processing. Vestibular-evoked potentials with a brief latency beneath 20 ms are probably the most investigated, however unbiased potentials or biphasic waves additionally emerge from the literature within the center and late latency ranges.

In step with electrophysiological outcomes from animal research (152, 153), the primary potentials round 2 ms possible replicate vestibular nerve exercise, whereas following potentials round 3 ms point out data processing within the vestibular nuclei (40, 56, 57, 104, 109, 132, 133, 146, 147). It has been proposed that parts discovered at 5 and 6 ms could replicate the transmission of vestibular data alongside the brainstem (105, 106). Others proposed that vestibular alerts attain the cortex as early as 6 ms after stimulation onset (133), that’s with a latency equal to that essential to set off vestibulo-ocular and vestibulocollic reflexes. Reaching the cortex with such quick latency could contain vestibular data in an alarm or preattentional system, along with top-down management of vestibulo-ocular and vestibulocollic reflexes.

A number of parts with peak latencies between 10 and 20 ms seem to replicate parallel spreading of vestibular data to the cerebellum (41, 108, 110, 115, 120, 149) and to a number of cortical areas, together with the precentral sulcus, the precuneus, and cuneus, in addition to a number of frontal areas (108, 113, 133). The precise origin and differentiation of those potentials stay to be clarified, and their cerebellar and cortical turbines should be disentangled from myogenic contributions (41, 108, 115). Alternatively, VestEPs with such latency might replicate the descending management of vestibular oculomotor reflexes.

Center latency VestEPs (20–50 ms) have been related to exercise within the insular, posterior opercular and cingulate cortex in a collection of current EEG research utilizing SVS and GVS (42, 96, 111). These areas kind the core area of the cortical vestibular community (11, 15, 16, 18, 188) and present sturdy useful connectivity with different cortical vestibular areas (189).

Outcomes regarding VestEPs with late latencies (>50 ms) are extra disparate. The heterogeneity of outcomes from early research could also be as a consequence of variations in stimulation methods, stimulation parameters for a similar methods, totally different ranges of high quality for management situations and limitations of the recording programs/montages (placement and variety of electrodes). Current research have recognized extra persistently a number of VestEPs parts with late latency, that are informative concerning the later steps of vestibular data processing. A serious discovering about VestEPs with late latency is that parts beneath 220 ms could replicate low-level sensory processing whereas parts above 200 ms could replicate larger degree perceptual and cognitive processes, and the acutely aware processing of vestibular data (166).

Parallel vs. Sequential Vestibular Data Processing within the Cerebral Cortex

One essential query in vestibular neuroscience was to find out whether or not vestibular alerts are transmitted to cortical areas by way of a number of parallel pathways with comparable latencies, or whether or not vestibular alerts attain a core vestibular space (activated earlier) earlier than being distributed to secondary areas (activated later). The flexibility to reply this query will depend on the temporal and spatial decision of the recording approach.

Outcomes from VestEPs research reported above point out that vestibular alerts quickly attain the cerebral cortex. The statement that a number of cortical areas could obtain vestibular data in <10 ms after direct electrical stimulation of the vestibular nerve has been used to help the concept that there isn’t any major vestibular cortex, however quite parallel processing of vestibular alerts in a minimum of 5 cortical areas (133). This appears in keeping with native area potentials recorded with overlapping latencies in a number of mind areas after electrical stimulation of the vestibular nerve in rats (136).

Our evaluation of the literature reveals that quick, center and late VestEPs have been discovered to originate from numerous cortical areas at comparable or shut latencies, corresponding to each frontal and occipital activations at 10 ms, or later at 80 ms, for instance. The research out there to this point counsel that VestEPs with latencies between 10 and 20 ms could have a cerebellar origin (41, 108, 110, 115, 120, 149, 150), and/or a cerebral origin with a number of turbines within the precentral sulcus (108) or the precuneus and cuneus (113) for the n15. Vestibular-evoked potentials with latencies from 20 to 30 ms have been related to exercise within the bilateral anterior insula and posterior operculum (111) whereas parts with latencies from 40 to 50 ms have been related to a mid-cingulate supply with contributions of the bilateral superior temporal cortex (42, 110). Vestibular-evoked potentials with late latencies have been related to numerous sources in all lobes. Altogether, these research point out a speedy diffusion of vestibular data in several areas of the cortex, distributed processing, and crosstalk mechanisms with recurrent processing lasting a number of a whole bunch of milliseconds after the stimulation.

The floor EEG and the event-related method could lack the decision to totally describe the spatiotemporal sample of vestibular data processing because it replicate exercise of too massive assemblies of neurons. Native area potentials and single neurons recordings have a extra acceptable spatiotemporal decision. To our information, native area potentials from intracranial electrodes had been recorded in just one epileptic affected person throughout SVS, offering comparable findings as recordings from scalp electrodes in wholesome individuals (111). Apparently, single neuron recordings in non-human primates have been in contrast in a number of cortical areas throughout pure whole-body displacements. A notable examine in macaque by Chen et al. (23) in contrast the spatiotemporal tuning of neurons from the PIVC, space MSTd (dorsal a part of space MST), and VIP throughout animal translations. On the idea of the response latency of the neurons, the authors suggest that there’s a “hierarchy in cortical vestibular processing, with PIVC being most proximal to the vestibular periphery and MSTd being most distal.” Accordingly, vestibular alerts could be first processed within the PIVC earlier than being transmitted to space VIP and MSTd. Though this appears in contradiction with outcomes from most VestEPs research summarized right here, it could simply replicate the lack of EEG to know totally different patterns of responses of various cortical areas to acceleration, velocity, and place of whole-body movement as can do single neuron recordings (24).

Lastly, we notice it’s troublesome to match the spatiotemporal dynamics of vestibular data processing as revealed by EEG analyses with information from fMRI and PET research of the vestibular cortex. Given the low temporal decision of those neuroimaging methods, they haven’t been in a position to exactly describe the responses of vestibular cortical areas as a perform of time, and by no means with the time decision of the VestEPs summarized above. A examine by Klingner et al. (190) analyzed the temporal sample of a number of cortical responses measured with fMRI throughout 30 s of CVS utilizing unbiased element evaluation. The authors recognized seven unbiased parts representing cortical responses with totally different temporal profiles. Though the time course of those parts differed considerably, with a pattern for extra lasting response for the element originating from the insula, retroinsular cortex, and superior temporal gyrus, there was no distinction within the latency of the height of the response for all parts. One other examine combining repeated quick pulses of CVS and fMRI confirmed that through the 40 s following CVS there was an extended and stronger activation within the brainstem in comparison with activation within the cerebellum, thalamus, and proper insula (78). The latency of the height of the response and the response length (>10 s) in these two research can under no circumstances be in contrast with the electrophysiological findings reported in our evaluation of the literature. Altogether, this means the complementarity of EEG and fMRI approaches to raised characterize the time course and site of vestibular data processing within the human mind.

Laterality of Vestibular Projections and Hemispheric Dominance within the Vestibulo-Thalamo-Cortical System

One other essential query for vestibular neuroscience issues the laterality of vestibular projections from one labyrinth to the cortex, and whether or not there may be an total hemispheric dominance for vestibular data processing, as proven by earlier neuroimaging and anatomical research (77, 102, 191).

Vestibular-evoked potentials with latencies beneath 10 ms will be recorded bilaterally, however bigger amplitudes have been noticed ipsilaterally to the perioperative stimulation of the vestibular nerve (133). That is in keeping with the projection of major vestibular afferents to the ipsilateral vestibular nuclei, and the inhibition of contralateral vestibular nuclei by way of wealthy commissural pathways (192).

Research of VestEPs with latencies between 10 and 20 ms have reported contradictory outcomes as to the lateralization of the responses. Regarding the p10 evoked by SVS, some research instructed bigger ipsilateral responses with a proper hemisphere dominance (107), in keeping with earlier neuroimaging findings utilizing the identical kind of SVS (102). Different research discovered a contralateral dominance of a deep supply, doubtlessly cerebellar, for a similar element (108, 110, 115). Utilizing IAS, Todd et al. (120) reported an ipsilateral p12/n17 and a contralateral p19/n23, however solely reported a contralateral p12/n17 in a subsequent examine (150). They discovered that these EPs of potential cerebellar origin had been bigger on the appropriate facet for bone carried out sounds (108), an statement not confirmed with stronger vestibular stimulation (41). Secondary vestibular fibers challenge bilaterally to the cerebellum in each animals and people (17, 192, 193). Nonetheless, in contrast to in people, animal research converge on bigger contralateral responses to vestibular stimulation within the vermis and flocculus (194). Neuroimaging research have additionally instructed a contralateral activation of the cerebellum (78).

The few research which have related quick latency VestEPs with cerebral sources appear to corroborate neuroimaging findings of bilateral responses, with bigger responses within the ipsilateral and within the non-dominant hemisphere (77, 102). de Waele et al. (133) reported a bigger p10 beneath ipsilateral in comparison with contralateral frontal electrodes. As anticipated, BESA revealed bilateral sources, with ipsilateral sources within the superior frontal gyrus and precentral gyrus, and contralateral sources within the anterior supplementary motor space close to the frontal eye fields and within the superior occipital gyrus in addition to a transverse prefrontal supply (133). The n15 and p20 evoked by proper ear SVS had been discovered to originate from the appropriate precuneus and cuneus and from the appropriate precentral gyrus, medial and superior temporal gyri, respectively (113).

There are scarce information on the center latency VestEPs. Relating to the 20–30 complicated, bigger amplitudes had been noticed within the anterior insula for left SVS in comparison with proper SVS in right-handed individuals (111). Nonetheless, such lateralization results weren’t reproduced with GVS (96) and IAS (112). Relating to the n42/p52 VestEPs, a weak proper ear benefit has been reported for the peak-to-peak amplitude measured at electrode FCz, whereas a contralateral left ear benefit has been discovered for the n42 element when thought of alone (110).

Current research on late VestEPs report no hemispheric dominance or contradictory outcomes. Contralateral SVS evoked larger VestEPs amplitudes within the non-dominant hemisphere (111) however these outcomes weren’t reproduced utilizing GVS (96). Ertl et al. (166) discovered an impact of the route of lateral passive translation on two parts, the n80 and a constructive element with a peak between 240 and 352 ms. Each VestEPs confirmed bigger amplitudes beneath C3 (left to Cz) or C4 (proper to Cz) relying on whether or not the individuals had been moved to the left or to the appropriate, respectively. The results had been mentioned by way of lateralized somatosensory stimulation throughout physique movement.

Altogether, outcomes from the VestEPs research point out that parts with totally different latencies have bilateral mind sources, thus data originating from one ear is processed in each cerebral hemispheres. The evaluation of VestEPs amplitudes and their turbines, nonetheless, is much less conclusive relating to the determinants of hemispheric dominance within the vestibulo-thalamo-cortical system, when in comparison with the clear sample that arises from PET and fMRI research: (1) bilateral however bigger activations within the hemisphere ipsilateral to the activated ear and (2) bigger response within the non-dominant hemisphere, that’s in the appropriate cerebral hemisphere for the right-handed individuals (77, 195, 196). We agree with Kammermeier et al. (111) in that this distinction could partially be because of the “modalities of short-termed electrical exercise [for EEG studies] vs. long-term vascular or metabolic modifications [for fMRI and PET studies].” Extra work is required to research how VestEPs are influenced by the facet of stimulation and the individuals’ handedness.

Replicability and Variability of Findings in VestEPs Research

It could appear {that a} lack of replicability and enormous variability of VestEPs emerges from the gathering of research on the subject to this point. First, we notice that there are few out there research on VestEPs in comparison with the wealth of research present for well-defined visible, somatosensory, and auditory EPs (31). Second, a significant impediment to replicating outcomes from one examine to a different is the big variability within the stimulation and recording procedures. Among the many many sources of variability within the recorded vestibular responses, two classes appear notably essential.

Methodology of Vestibular Stimulation

The tactic of vestibular stimulation (see Determine 1) offers a significant supply of variation within the noticed responses. As famous earlier, synthetic stimulation of the vestibular system (GVS, CVS, SVS, IAS, MVS) differ from pure vestibular stimulation (rotatory chair, movement platform) in lots of elements, together with the kind of vestibular receptor (otolithic, canalar) stimulated, the bodily nature of the stimulation resulting in activation of hair cells or the vestibular nerve, the co-activation of different sensory programs (corresponding to listening to for SVS and interoception for physique rotations), the length of the stimulation, and so on. Probably the most generally used synthetic vestibular stimulation for VestEPs research (SVS and IAS) are transient stimuli lasting usually a few milliseconds, whereas passive whole-body translations and rotations have a completely totally different temporal sample, lasting usually greater than 1 s [e.g., (32, 60)]. It’s subsequently troublesome to instantly evaluate the spatiotemporal dynamics of vestibular data processing for transient synthetic vestibular stimulation and pure physique motions (see under).

The Spatial Density of Recording Electrodes and the Montage

Very various electrode montages have been used to document VestEPs with a big variability within the spatial density of electrodes, as proven in Supplementary Desk 1. Early research have used montages near these used for BAEP recordings, with a spatial density of electrodes inadequate to explain the spatiotemporal dynamics of vestibular data processing. As research have used totally different references for the evaluation of VestEPs (ear lobes, mastoid, common reference…), it’s troublesome to instantly evaluate the form and polarity of VestEPs parts throughout research. A consensus about commonplace electrode montage and reference ought to subsequently be established with the intention to enhance replicability of the leads to future EEG research of the vestibular system, as completed for cVEMPs and oVEMPs recordings (43, 100), or for somatosensory (34), visible (35), and auditory (36, 37) EPs recordings.

The most important variability within the VestEPs waveforms arises from research that investigated vestibular responses throughout pure whole-body translations and rotations. For instance, research of rotatory VestEPs recognized solely quick or center latency parts (56, 57, 147), whereas others solely recognized late parts (32, 44, 171, 173, 174, 176). That is very possible associated to totally different stimulation parameters. Within the case of quick and center VestEPs, the rotations utilized to the top solely had been speedy horizontal (56, 57) or vertical (159) rotational acceleration impulses as much as 12,000°/s² that could possibly be utilized at frequencies from 0.5 to 2 Hz. Within the case of late VestEPs, whole-body rotations might consist in ramps with acceleration phases of 250 or 500 ms to succeed in an angular velocity of 60°/s maintained for 400 ms (171), step-wise accelerations of 53°/s² (173, 174) lasting 1 s, or accelerations of 15°/s² lasting 1 s (44) or 2 s (176), or transient “raised-cosine” rotations with a peak velocity of 110°/s for 1.3 s (32). Shorter and extra intense rotations would subsequently make it potential to watch quick or center latency VestEPs whereas longer rotations would permit to document later responses, probably time-locked to modifications within the acceleration profile.

Extra constant outcomes have been obtained with stimulation strategies that use standardized stimuli corresponding to quick excessive sound stress clicks at intensities round 100 dB-SPL. There may be certainly a consensus concerning the parameters of the sounds (frequency, length, depth, variety of stimulation) that are optimum to activate the otolithic receptors, and are generally used for scientific investigations of cVEMPs and oVEMPs (38). Vestibular-evoked potentials have been persistently recognized utilizing very comparable stimulation or recording methods. For instance, the identical group has repeatedly reproduced the p10, n15, p21 parts in addition to the n42/p52 complicated utilizing bone carried out or air carried out tone bursts of 500 Hz lasting 6 ms (107, 114) or tone pips of 500 Hz lasting 2 ms (42, 108, 110). Totally different outcomes had been obtained utilizing totally different parameters of SVS. They in contrast air-conducted and bone-conducted SVS, displaying that they permit to document reproducible parts such because the p10 and n15 whereas noting that bone carried out stimulation induces bigger responses (108). Additionally they in contrast left vs. proper SVS (110), totally different references such because the linked earlobes or frequent common reference (42), and totally different inter-stimulus intervals (149). This reveals how essential the stimulation methods and their parameters are to raised characterize VestEPs.

Major Limits of VestEPs Research

The examine of the spatiotemporal dynamics of vestibular sign processing within the mind is restricted by the truth that the vestibular system is multisensory in nature (197). Vestibular afferents challenge to the vestibular nuclei and cerebellum, the place vestibular alerts are processed and built-in with visible and somatosensory data (198). Vestibular alerts are additionally built-in with visible and somatosensory alerts in a number of thalamic nuclei and in a number of cortical areas, together with the PIVC (199). This multisensory convergence will be evidenced by the modulation of the p12/n17 biphasic wave by optic movement (120).

As vestibular alerts are blended with different sensory data as early because the second synapse within the brainstem, most VestEPs recorded to this point possible signify a multisensory response owing to the shortage of specificity of the strategies to stimulate the vestibular receptors (Determine 2). Pure and synthetic vestibular stimulation usually stimulates one or a number of extravestibular sensory programs, such because the auditory (for SVS, CVS, IAS, rotating chairs, and movement platforms), tactile (for GVS, CVS, IAS, rotating chairs, and movement platforms), nociceptive (for GVS and CVS), thermoceptive (for GVS and CVS), and interoceptive programs (for physique rotations and translations). Thus, vestibular responses recorded over the scalp are blended with time-locked responses from these sensory programs. Throughout passive whole-body translations and rotations, a significant sensory affect on VestEPs comes from the interoceptive system, because the physique fluids transfer in a time-locked method with the rotatory chair or movement platform. The interoceptive and vestibular programs are largely interconnected at each anatomical and useful ranges. Interoceptive alerts from visceral receptors can modulate vestibular alerts as early as within the vestibular nuclei (200). Vestibular data can also be built-in with interoceptive alerts within the insula (80). Though visible, auditory, tactile, and nociceptive controls can be utilized, it’s not possible to manage for the interoceptive contributions to VestEPs, which can’t be switched off and are hardly manipulated. For instance, late VestEPs responses are actually not purely vestibular as they will also be noticed in sufferers with a bilateral vestibular failure (32, 182).

Potential Functions of VestEPs in Neurology and Otoneurology

Regardless of these limitations, VestEPs signify a promising software for the scientific investigation of the vestibular system. First, there appears to be little interindividual variations in VestEPs onset and peak latencies for electrical stimulations of the vestibular nerve (133) and for SVS (42, 110, 149). Second, VestEPs amplitude will increase with the depth of {the electrical} present utilized to the vestibular nerve (131, 133), the depth of SVS (42, 107), the impulsive acceleration in IAS (112) or the acceleration of the physique rotation (44, 173, 184) or physique translation (33, 60). The consistency of those traits makes VestEPs measurement acceptable for primary analysis and scientific investigations. Research in massive populations ought to first be carried out to determine normative values of latency and amplitude in wholesome individuals as a perform of age, as completed for VEMPs [i.e., tests of the otolithic function; (201, 202)] and for the video head impulse take a look at [i.e., tests of the semicircular canals; (203)].

Sound-induced vestibular stimulation seems a handy and dependable approach to standardize VestEPs as completed for cVEMPs and oVEMPs, for which SVS is already routinely utilized in scientific testing. With many managed repetitions potential in a comparatively quick time period, SVS evokes quick, center, and lengthy latency VestEPs which possible replicate the successive processing of vestibular data alongside the vestibulo-thalamo-cortical pathways (see Determine 1). Sound-induced vestibular stimulation permits to check every ear individually. Simplified montages could possibly be used, corresponding to Laplacian montages (111), or particular vertex-mastoid or parieto-frontal derivations for instance (106). Apparently, recordings with 32- and 64-channel EEG programs allowed to watch a discount of the n42/p54 response in few sufferers with a bilateral (114) or unilateral (42) vestibular loss. A primary step towards scientific functions of VestEPs could be to make use of SVS (and the suitable auditory management situations) to check bigger samples of sufferers with numerous vestibular issues and evaluate their responses to these from wholesome individuals.

Brainstem auditory evoked potentials have been proposed as a complement to cVEMPs to guage vestibular schwannoma (204), although their cost-effectiveness could also be decrease than that of MRI (205). In comparison with cVEMPs, far-field vestibular potentials have the benefit to be recorded even in sufferers who can’t correctly contract their neck muscular tissues, a situation for cVEMPs recording. It has been proposed that the n5 could also be appropriate to evaluate vestibular projections in scientific observe. First, the n3 element could solely seem when BAEPs auditory parts are drastically lowered. Second, the n5 will be noticed with sounds of decrease depth, round 80 dB nHL, and permits for shorter testing occasions in comparison with the n3, which is greatest obtained utilizing clicks over 100 dB nHL (105).

To document center and late latency VestEPs in scientific observe, Kammermeier et al. (111) have proposed a simplified EEG setup with round Laplacian montages round electrodes FC5/6 (over proper and left anterior insula) and CP5/6 (proper and left posterior opercula). They discovered reproducible n20, p30, and p60 responses, indicating that VestEPs of quick, center, and late latency will be recorded utilizing simplified montages in scientific settings.

Vestibular-evoked potentials must be altered in sufferers with lesions in vestibular areas, offering a quicker, less complicated and cheaper equal to fMRI or PET for demonstrating lowered or altered exercise in vestibular areas (206, 207). Vestibular-evoked potentials might assist assess central vestibular processing in sufferers who report vestibular sensations however present no obvious vestibular finish organs or nerve alterations and assist determine the underlying pathology. Vestibular-evoked potentials could possibly be an essential diagnostic help within the investigation of central vestibular syndromes (21). Amongst these, the incidence of vestibular epilepsy might be underestimated and pose essential differential diagnostic issues with vestibular migraine and psychogenic types of paroxysmal vertiginous manifestations (208, 209). It’s potential that, as in different epilepsies, particular alterations of sure cerebral areas could also be investigated by VestEPs sooner or later and that these alterations will likely be totally different in migraine and psychogenic issues. One the one hand, there may be proof that sufferers with vestibular migraine have a special vestibular threshold and sensitivity to movement than wholesome controls (210, 211). Then again, there may be proof that sufferers with persistent postural-perceptual dizziness (PPPD), a useful vestibular dysfunction (212) confirmed altered exercise and connectivity within the vestibular cortical community, together with areas processing visuo-vestibular integration and feelings (213–215). In an fMRI examine, SVS evoked lowered activation and connectivity of key vestibular areas such because the posterior and anterior insula, hippocampus and anterior cingulate cortex in persistent subjective dizziness in comparison with wholesome controls (213). We suggest that VestEPs could present extra data on the temporal traits of vestibular processing linked with nervousness on this type of useful vestibular dysfunction.

Perspective of VestEPs for Cognitive and Programs Neuroscience

We suggest that VestEPs evaluation is a technique to research the spatiotemporal traits of multisensory mechanisms underlying numerous pre-reflexive and cognitive features. To fulfill such goals, research want to mix vestibular stimulation with cognitive duties, because it has already been efficiently completed. A self-motion oddball detection activity mixed with VestEPs recording revealed a vestibular-evoked P3 element, a marker of rare change detection recognized for different sensory modalities (216, 217). A perceptual resolution making examine (166) confirmed a constructive element with latencies starting from 240 to 352 ms, that will replicate expectation and decision-making processes involving self-motion alerts (166), because it was not noticed in earlier recordings in individuals not engaged in any activity (33). Research of the modulation of recognized EPs throughout vestibular stimulation, as effectively research of the variations of VestEPs based on totally different multisensory stimuli or cognitive duties are subsequently possible and will yield essential insights into the vestibular contribution to notion and cognition.

Vestibular-evoked potentials might also supply the likelihood to review extra exactly the spatiotemporal dynamics of attentional and cognitive results reported utilizing different neuroimaging methods. An fMRI examine confirmed that attentional load in a visible monitoring activity decreased exercise within the PIVC (218), probably as a consequence of a downregulation of excitatory neurotransmitters and upkeep of inhibitory transmitters to cut back PIVC responses to thalamic inputs (219). Vestibular-evoked potentials could assist to refine the timing of such phenomena in addition to to review them in a number of areas concurrently.

Though it’s past the scope of the current evaluation article to explain event-related synchronizations and desynchronizations throughout vestibular stimulation, response evaluation within the time-frequency area might additionally serve the identical goals as VestEPs evaluation and supply further details about the spatiotemporal dynamics of vestibular data processing in wholesome individuals and in sufferers. Certainly, EPs and event-related synchronizations/desynchronizations replicate totally different electrophysiological occasions. Evoked potentials are phase-locked occasions originating from post-synaptic responses of cortical neurons (220). In contrast, event-related synchronizations/desynchronizations are time-locked occasions, however not phase-locked occasions, reflecting extra neuronal and synaptic traits, community connectivity, and modulation on kind of prolonged neuronal assemblies (220). A couple of research investigated each VestEPs and responses within the time-frequency area (32, 111, 166, 167, 171). Rotations had been discovered to induce alpha rhythm desynchronization in central and parietal scalp areas (32, 171). This desynchronization was considerably lowered in sufferers with a bilateral vestibular failure when in comparison with wholesome individuals, indicating it’s partially associated to vestibular data processing (32). A newer examine discovered that physique translations induced a delta and theta synchronization within the bilateral operculo-insular area, mid-orbital gyrus, and medial frontal gyrus, with further contribution to the theta synchronization from cingulate sulcus visible space and anterior cingulate gyrus (167). Physique translations and SVS had been each related to low beta synchronizations, noticed at Cz 67.5 ms after most acceleration for translations (33), and localized in the appropriate anterior insula and posterior operculum 20–80 ms after SVS (111). Delta, theta, mu, or gamma synchronizations and desynchronizations had been additionally reported following passive physique rotations (32, 171), translations (166, 167), and SVS (111). Right here, once more research in bigger populations, utilizing standardized stimulation and recording methods, or time-frequency or microstates (166) analyses could be wanted to enrich VestEPs findings.

Lastly, MEG may be used to review VestEPs and vestibular-related synchronizations and desynchronizations. Magnetoencephalography gives higher supply localization than EEG and would subsequently be a great complement to the spatial localization of vestibular data processing, particularly for investigations of deep sources such because the cerebellum (157). Nonetheless, EEG stays the one recording approach totally suitable with extra ecologically legitimate vestibular stimulation.

Conclusion

Vestibular-evoked potentials of quick, center, and late latency reveal the spatiotemporal properties of vestibular processing from the vestibular nerve to cortical areas. They signify promising instruments for the scientific and experimental investigation of the vestibular system, its issues and its relation to cognition.

Writer Contributions

EN and CL wrote the draft and revised the ultimate manuscript. FB revised the ultimate manuscript. All authors contributed to the article and accepted the submitted model.

Funding

This work was supported by the ANR VESTISELF challenge, grant ANR-19-CE37-0027 of the French Agence Nationale de la Recherche to CL and FB.

Battle of Curiosity

The authors declare that the analysis was carried out within the absence of any industrial or monetary relationships that could possibly be construed as a possible battle of curiosity.

Writer’s Notice

All claims expressed on this article are solely these of the authors and don’t essentially signify these of their affiliated organizations, or these of the writer, the editors and the reviewers. Any product that could be evaluated on this article, or declare that could be made by its producer, isn’t assured or endorsed by the writer.

Supplementary Materials

The Supplementary Materials for this text will be discovered on-line at: https://www.frontiersin.org/articles/10.3389/fneur.2021.674100/full#supplementary-material

References

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