Novel ways to modulate the vestibular system: Magnetic vestibular stimulation, deep brain stimulation and transcranial magnetic stimulation / transcranial direct current stimulation.

BACKGROUND: Advances in neurotechnologies are revolutionizing our understanding of complex neural circuits and enabling new treatments for disorders of the human brain. In the vestibular system, electromagnetic stimuli can now modulate vestibular reflexes and sensations of self-motion by artificially stimulating the labyrinth, cerebellum, cerebral cortex, and their connections. OBJECTIVE: In this narrative review, we describe evolving neuromodulatory techniques including magnetic vestibular stimulation (MVS), deep brain stimulation (DBS), transcranial magnetic stimulation (TMS), and transcranial direct-current stimulation (tDCS) and discuss current and potential future application in the field of neuro-otology. RESULTS: MVS triggers both vestibular nystagmic (persistent) and perceptual (lasting ∼1 min) responses that may serve as a model to study central adaptational mechanisms and pathomechanisms of hemispatial neglect. By systematically mapping DBS electrodes, targeted stimulation of central vestibular pathways allowed modulating eye movements, vestibular heading perception, spatial attention and graviception, resulting in reduced anti-saccade error rates and hypometria, improved heading discrimination, shifts in verticality perception and transiently decreased spatial attention. For TMS/tDCS treatment trials have demonstrated amelioration of vestibular symptoms in various neuro-otological conditions, including chronic vestibular insufficiency, Mal-de-Debarquement and cerebellar ataxia. CONCLUSION: Neuromodulation has a bright future as a potential treatment of vestibular dysfunction. MVS, DBS and TMS may provide new and sophisticated, customizable, and specific treatment options of vestibular symptoms in humans. While promising treatment responses have been reported for TMS/tDCS, treatment trials for vestibular disorders using MVS or DBS have yet to be defined and performed.

Pharmacological characterization and differential expression of NMDA receptor subunits in the chicken vestibular system during development.

Previous studies demonstrated that in vitro preparations of the isolated vestibular system of diverse animal species still exhibit stable resting electrical activity and mechanically evoked synaptic transmission between hair cells and primary afferent endings. However, there are no reports related to their neurodevelopment. Therefore, this research aimed to examine whether NMDA receptors mediate these electrical signals in an isolated preparation of the chicken vestibular system at three developmental stages, E15, E18, and E21. We found that the spontaneous and mechanically evoked discharges from primary afferents of the posterior semicircular canal were modulated by agonists NMDA and glycine, but not by the agonist d-serine applied near the synapses. Moreover, the individually applied by bath perfusion of three NMDA receptor antagonists (MK-801, ifenprodil, and 2-naphthoic acid) or high Mg2+ decreased the resting discharge rate, the NMDA response, and the discharge rate of mechanically evoked activity from these primary afferents. Furthermore, we found that the vestibular ganglion shows a stage-dependent increase in the expression of NMDA receptor subunits GluN1, GluN2 (A-C), and GluN3 (A-B), being greater at E21, except for GluN2D, which was inversely related to the developmental stage. However, in the crista ampullaris, the expression pattern remained constant throughout development. This could suggest the possible existence of presynaptic NMDA receptors. Our results highlight that although the NMDA receptors are functionally active at the early embryonic stages of the vestibular system, NMDA and glycine reach their mature functionality to increase NMDA responses close to hatching (E21).

Recent advancements in bioelectronic devices to interface with the peripheral vestibular system.

Balance disorders affect approximately 30% of the population throughout their lives and result in debilitating symptoms, such as spontaneous vertigo, nystagmus, and oscillopsia. The main cause of balance disorders is peripheral vestibular dysfunction, which may occur as a result of hair cell loss, neural dysfunction, or mechanical (and morphological) abnormality. The most common cause of vestibular dysfunction is arguably vestibular hair cell damage, which can result from an array of factors, such as ototoxicity, trauma, genetics, and ageing. One promising therapy is the vestibular prosthesis, which leverages the success of the cochlear implant, and endeavours to electrically integrate the primary vestibular afferents with the vestibular scene. Other translational approaches of interest include stem cell regeneration and gene therapies, which aim to restore or modify inner ear receptor function. However, both of these techniques are in their infancy and are currently undergoing further characterization and development in the laboratory, using animal models. Another promising translational avenue to treating vestibular hair cell dysfunction is the potential development of artificial biocompatible hair cell sensors, aiming to replicate functional hair cells and generate synthetic 'receptor potentials' for sensory coding of vestibular stimuli to the brain. Recently, artificial hair cell sensors have demonstrated significant promise, with improvements in their output, such as sensitivity and frequency selectivity. This article reviews the history and current state of bioelectronic devices to interface with the labyrinth, spanning the vestibular implant and artificial hair cell sensors.

Purinergic signaling in the peripheral vestibular system.

The inner ear comprises the cochlea and vestibular system, which detect sound and acceleration stimulation, respectively. The function of the inner ear is regulated by ion transport activity among sensory epithelial cells, neuronal cells, non-sensory epithelial cells, and luminal fluid with a unique ionic composition of high [K+] and low [Na+], which enables normal hearing and balance maintenance. One of the important mechanisms regulating ion transport in the inner ear is purinergic signaling. Various purinergic receptors are distributed throughout inner ear epithelial cells and neuronal cells. To date, most studies have focused on the role of purinergic receptors in the cochlea, and few studies have examined these receptors in the vestibular system. As purinergic receptors play an important role in the cochlea, they would likely do the same in the vestibular system, which is fairly similar to the cochlea in cellular structure and function. Based on available studies performed to date, purinergic signaling is postulated to be involved in the regulation of ion homeostasis, protection of hair cells, otoconia formation, and regulation of electrical signaling from the sensory epithelium to vestibular neurons. In this review, the distribution and roles of purinergic receptors in the peripheral vestibular system are summarized and discussed.

Effects of primary Sjögren's syndrome on hearing and vestibular systems.

OBJECTIVE: This study aimed to evaluate primary Sjögren's syndrome patients in terms of hearing and vestibular functions. METHODS: The patient group consisted of 35 individuals diagnosed with primary Sjögren's syndrome and a control group of 35 healthy individuals similar in terms of age and gender. RESULTS: The rate of hearing loss in the patient group was significantly higher than in the control group (p = 0.021). The N1 latency value for the ocular vestibular-evoked myogenic potentials test was significantly longer in the patient group than in the control group (p = 0.037). Additionally, the posterior semicircular canal and lateral semicircular canal vestibulo-ocular reflex gain values were significantly lower than in the control group (p = 0.022 and p < 0.001, respectively). CONCLUSION: These results indicate subclinical vestibular involvement and hearing loss in primary Sjögren's syndrome patients. Vestibular-evoked myogenic potentials and video head impulse tests can be used to detect vestibular involvement in primary Sjögren's syndrome patients.

Pulsed infrared stimulation evoked electrical potential in mouse vestibular system.

To improve accuracy of VsEP and avoid the inherent limitation of mechanical vibration, we designed an infrared optical stimulation approach to stimulate mouse vestibular system and measured the evoked potential. IR pulses (1871 nm, 30 pps and 100 µs pulse width) were delivered to mice with different vestibular dysfunction levels and the evoked potential was recorded. The result suggests that the amplitude and latency of the IR-evoked potential (IR-VsEP) were significantly associated with vestibular function integrity. Immunofluorescence staining confirmed that magnitude of IR-VsEP decreased was consistent with the loss of HCs. Micro-CT imaging revealed that the optical fiber was orientating towards the vestibular system. Taken together, we found that: 1) IR stimulation can generate VsEP evoked potential in vestibular system (IR-VsEP), which can be potentially used for vestibular function evaluation; 2) intact HCs and fully functional synaptic transmission are crucial for efficient IR-induced vestibular system stimulation.

Neurotransmitter and neurotransmitter receptor expression in the saccule of the human vestibular system.

The saccule is one of the vestibular sensory organs of the inner ear. It detects head movements and provides information to maintain balance and orient in space. Despite its critical role, very little is known about its neurotransmission and regulation. Multiple disease entities and medications affect balance, which is why information on neurotransmission in the vestibular end organs including the saccule could have important pharmacological implications. To the best of our knowledge, this is the first paper to describe immunohistochemical expression of a large panel of neurotransmitters and receptors in the human saccule. Saccular tissue was sampled freshly during surgery. Based partly on previous findings in non-humans and partly on potential biological relevance, the neurotransmitters cholecystokinin, dopamine, GABA, glutamate, histamine and serotonin as well as receptors for these were selected for the tested panel. The neuroepithelium expressed glutamate receptor 1 (GluR1), metabotropic glutamate receptor (mGluR), GABA A receptor α (GABAARα), GABA B receptor 2 and cholecystokinin receptor B (CCKBR), whereas l-glutamate, GluR1, CCKBR, GABAARα, dopamine and serotonin receptor 1D were expressed in the subepithelial stroma. The non-sensory epithelium expressed GluR1, mGluR, histamine receptor 3, CCKAR and dopamine transporter. These findings provide a basis for pharmacological research and potential drug development.

Pigeon as a model to study peripheral projections from the horizontal semicircular canal vestibular apparatus to a brainstem target immunoreactive for AMPA.

PURPOSE: To evaluate whether the pigeon (Columba livia) is a good model for evaluating the vestibular system involved with postural maintenance during movement. METHODS: This study maps the brainstem targets of the horizontal ampullary inputs from the vestibular periphery of the pigeon. We used biotin dextran amine (BDA) injection in horizontal semicircular canal (HSCC), immunohistochemistry for GluR2/3 and GluR4 AMPA and computerized histomorphology reconstruction. RESULTS: Our results show the same distribution pattern with ipsilateral projections to vestibular nuclear complex (VNC) from the HSCC, with the majority of labeled fibers being, long, thin, with few varicosities and many ramifications. Horizontal semicircular canal projections achieve neurons belonging to all nuclei of the VNC with exception of dorsal portion of lateral vestibular nucleus and this area express GluR2/3 and GluR4 AMPA receptors reinforcing the idea of glutamate participation in these connections. CONCLUSIONS: Pigeon is an appropriated experimental model to study of projections of HSCC and reinforcing the information that the vestibular system has strong relation with the fast responses necessary for postural control. Moreover, its phylogenetic organization apparently conservation, also seems to be a fundamental characteristic for vertebrates.

Kinematic Analysis of 360° Turning in Stroke Survivors Using Wearable Motion Sensors.

BACKGROUND: A stroke often bequeaths surviving patients with impaired neuromusculoskeletal systems subjecting them to increased risk of injury (e.g., due to falls) even during activities of daily living. The risk of injuries to such individuals can be related to alterations in their movement. Using inertial sensors to record the digital biomarkers during turning could reveal the relevant turning alterations. OBJECTIVES: In this study, movement alterations in stroke survivors (SS) were studied and compared to healthy individuals (HI) in the entire turning task due to its requirement of synergistic application of multiple bodily systems. METHODS: The motion of 28 participants (14 SS, 14 HI) during turning was captured using a set of four Inertial Measurement Units, placed on their sternum, sacrum, and both shanks. The motion signals were segmented using the temporal and spatial segmentation of the data from the leading and trailing shanks. Several kinematic parameters, including the range of motion and angular velocity of the four body segments, turning time, the number of cycles involved in the turning task, and portion of the stance phase while turning, were extracted for each participant. RESULTS: The results of temporal processing of the data and comparison between the SS and HI showed that SS had more cycles involved in turning, turn duration, stance phase, range of motion in flexion-extension, and lateral bending for sternum and sacrum (p-value < 0.035). However, HI exhibited larger angular velocity in flexion-extension for all four segments. The results of the spatial processing, in agreement with the prior method, showed no difference between the range of motion in flexion-extension of both shanks (p-value > 0.08). However, it revealed that the angular velocity of the shanks of leading and trailing legs in the direction of turn was more extensive in the HI (p-value < 0.01). CONCLUSIONS: The changes in upper/lower body segments of SS could be adequately identified and quantified by IMU sensors. The identified kinematic changes in SS, such as the lower flexion-extension angular velocity of the four body segments and larger lateral bending range of motion in sternum and sacrum compared to HI in turning, could be due to the lack of proper core stability and effect of turning on vestibular system of the participants. This research could facilitate the development of a targeted and efficient rehabilitation program focusing on the affected aspects of turning movement for the stroke community.

Hearing loss versus vestibular loss as contributors to cognitive dysfunction.

In the last 5 years, there has been a surge in evidence that hearing loss (HL) may be a risk factor for cognitive dysfunction, including dementia. At the same time, there has been an increase in the number of studies implicating vestibular loss in cognitive dysfunction. Due to the fact that vestibular disorders often present with HL and other auditory disorders such as tinnitus, it has been suggested that, in many cases, what appears to be vestibular-related cognitive dysfunction may be due to HL (e.g., Dobbels et al. Front Neurol 11:710, 2020). This review analyses the studies of vestibular-related cognitive dysfunction which have controlled HL. It is suggested that despite the fact that many studies in the area have not controlled HL, many other studies have (~ 19/44 studies or 43%). Therefore, although there is certainly a need for further studies controlling HL, there is evidence to suggest that vestibular loss is associated with cognitive dysfunction, especially related to spatial memory. This is consistent with the overwhelming evidence from animal studies that the vestibular system transmits specific types of information about self-motion to structures such as the hippocampus.

Health Care Resource Utilization and Costs for Adults With Mild Traumatic Brain Injury With Chronic Vestibular Impairment.

OBJECTIVE: To quantify the economic burden of all-cause health care resource utilization (HCRU) among adults with and without chronic vestibular impairment (CVI) after a mild traumatic brain injury (mTBI). DESIGN: Retrospective matched cohort study. SETTING: IQVIA Integrated Data Warehouse. PARTICIPANTS: People with mTBI+CVI (n=20,441) matched on baseline age, sex, year of mTBI event, and Charlson Comorbidity Index (CCI) score to people with mTBI only (n=20,441) (N=40,882). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: All-cause health HCRU and costs at 12 and 24 months post mTBI diagnosis. RESULTS: People with mTBI+CVI had significantly higher all-cause HCRU and costs at both time points than those with mTBI only. Multivariable regression analysis showed that, when controlling for baseline variables, costs of care were 1.5 times higher for mTBI+CVI than mTBI only. CONCLUSIONS: People who developed CVI after mTBI had greater overall HCRU and costs for up to 2 years after the injury event compared with people who did not develop CVI after controlling for age, sex, region, and CCI score. Further research on access to follow-up services and effectiveness of interventions to address CVI is warranted.

Cerebellar ataxia, neuropathy and vestibular areflexia syndrome (CANVAS): genetic and clinical aspects.

Cerebellar ataxia, neuropathy and vestibular areflexia syndrome (CANVAS) typically presents in middle life with a combination of neuropathy, ataxia and vestibular disease, with patients reporting progressive imbalance, oscillopsia, sensory disturbance and a dry cough. Examination identifies a sensory neuropathy or neuronopathy and bilaterally impaired vestibulo-ocular reflex. The underlying genetic basis is of biallelic AAGGG expansions in the second intron of replication factor complex subunit 1 (RFC1). The frequency and phenotype spectrum of RFC1 disease is expanding, ranging from typical CANVAS to site-restricted variants affecting the sensory nerves, cerebellum and/or the vestibular system. Given the wide phenotype spectrum of RFC1, the differential diagnosis is broad. RFC1 disease due to biallelic AAGGG expansions is probably the most common cause of recessive ataxia. The key to suspecting the disease (and prompt genetic testing) is a thorough clinical examination assessing the three affected systems and noting the presence of chronic cough.

Ontogenetic variation in the crocodylian vestibular system.

Crocodylians today live in tropical to subtropical environments, occupying mostly shallow waters. Their body size changes drastically during ontogeny, as do their skull dimensions and bite forces, which are associated with changes in prey preferences. Endocranial neurosensory structures have also shown to change ontogenetically, but less is known about the vestibular system of the inner ear. Here we use 30 high-resolution computed tomography (CT) scans and three-dimensional geometric morphometrics to investigate the size and shape changes of crocodylian endosseous labyrinths throughout ontogeny, across four stages (hatchling, juvenile, subadult and adult). We find two major patterns of ontogenetic change. First, the labyrinth increases in size during ontogeny, with negative allometry in relation to skull size. Second, labyrinth shape changes significantly, with hatchlings having shorter semicircular canal radii, with thicker diameters and an overall dorsoventrally shorter labyrinth than those of more mature individuals. We argue that the modification of the labyrinth during crocodylian ontogeny is related to constraints imposed by skull growth, due to fundamental changes in the crocodylian braincase during ontogeny (e.g. verticalisation of the basicranium), rather than changes in locomotion, diet, or other biological functions or behaviours.

A comprehensive review of the effects of caffeine on the auditory and vestibular systems.

Coffee, of which caffeine is a critical component, is probably the most frequently used psychoactive stimulant in the world. The effects of caffeine on the auditory and vestibular system have been investigated under normal and pathological conditions, such as acoustic trauma, ototoxicity, auditory neuropathy, and vestibular disorders, using various tests. Lower incidences of hearing loss and tinnitus have been reported in coffee consumers. The stimulatory effect of caffeine is represented by either a shorter latency or enhanced amplitude in electrophysiological tests of the auditory system. Furthermore, in the vestibular system, oculomotor testing revealed significant effects of caffeine, while other tests did not reveal any significant caffeine effects. It could be that caffeine improves transmission in the auditory and vestibular systems' central pathways. Importantly, the effects of caffeine seem to be dose-dependent. Also, inconsistent findings have been observed regarding caffeine's effects on the auditory and vestibular systems and related disorders. Overall, these findings suggest that caffeine does not strongly influence the peripheral auditory and vestibular systems. Instead, caffeine's effects seem to occur almost solely at the level of the central nervous system.

Galvanic Vestibular Stimulation Headset balancing robust and simple administration with subject comfort: A Usability Analysis.

The vestibular system is responsible for spatial orientation and stability. It can be stimulated with a weak electric current, a mechanism known as Galvanic Vestibular Stimulation (GVS). Typical GVS administration involves holding down electrodes on the mastoids either with a strap (or bandage) wrapped around the head or by positioning a self-adhesive electrode at the mastoid location. While the latter approach is simple to administer, it is limited to exposed skin application as hair impedes adhesion. The reduced access area limits total current delivery allowable due to increased skin sensation. Accordingly the former approach is more typically employed but leads to inconsistent and inaccurate electrode placement. As current flow pattern is directly influenced by electrode position, this results in inconsistent stimulation and replicability issues. The primary goal of this study was to test usability and comfort while developing a GVS-specific headset named "Mastoid Adjustable Robust Stimulation (MARS)" compared to a conventional elastic strap. We recruited 10 subjects, 5 operators and 5 wearers, and tested usability using the System Usability Scale (SUS) as well as comfort levels over a typical 20 minute stimulation session. Additional questions were answered by the operators and wearers on visual appeal, interference, slippage, and electrode placement. The results of this testing guided the development of a final version meeting our requirements of robustness, simple to administer, and subject comfort.Clinical Relevance-This study introduces a headset for routine Bilateral-Bipolar GVS administration that is highly usable and ensures both flexible and consistent electrode application over typical approaches.

Postural Sway Characteristics Are Affected by Alzheimer's Disease.

The vestibular system, responsible for balance, is affected by Alzheimer's disease (AD). In this paper, linear and non-linear balance features were used to assess the postural stability of 13 AD individuals at mild stages in comparison with 16 healthy controls. Utilizing two accelerometers, the anterior-posterior (AP) and medial-lateral (ML) sways were recorded from the T2 vertebrae and lateral malleolus of participants standing on a solid and soft foam surface under both eyes-open and eyes-closed conditions. From the recorded signals, four features were extracted and used for statistical analysis: Number of Position Changes (NPC), Number of Non-Zero Accelerations (NNZA), Katz, and Higuchi fractal dimensions (KFD and HFD, respectively). The results show: 1) postural stability is significantly worse for the eyes-closed compared to eyes-open condition (P<0.05 for all features except HFD) as well as whilst standing on soft foam compared to the solid surface (P<0.05 for all features) in both groups; 2) balance perturbations were larger for AP sway than ML on both solid and foam surfaces in both groups (P<0.05 for NPC and NNZA); and 3) stationary balance is significantly poorer for AD individuals compared to controls (P<0.05 for all features). These observations show that both linear and non-linear characteristics of postural stability data have the potentials to be used as objective diagnostic aids for the detection of AD.

Incremental Velocity Error as a New Treatment in Vestibular Rehabilitation (INVENT VPT) Trial: study protocol for a randomized controlled crossover trial.

BACKGROUND: A clinical pattern of damage to the auditory, visual, and vestibular sensorimotor systems, known as multi-sensory impairment, affects roughly 2% of the US population each year. Within the population of US military service members exposed to mild traumatic brain injury (mTBI), 15-44% will develop multi-sensory impairment following a mild traumatic brain injury. In the US civilian population, multi-sensory impairment-related symptoms are also a common sequela of damage to the vestibular system and affect ~ 300-500/100,000 population. Vestibular rehabilitation is recognized as a critical component of the management of multi-sensory impairment. Unfortunately, the current clinical practice guidelines for the delivery of vestibular rehabilitation are not evidence-based and primarily rely on expert opinion. The focus of this trial is gaze stability training, which represents the unique component of vestibular rehabilitation. The aim of the Incremental Velocity Error as a New Treatment in Vestibular Rehabilitation (INVENT VPT) trial is to assess the efficacy of a non-invasive, incremental vestibular adaptation training device for normalizing the response of the vestibulo-ocular reflex. METHODS: The INVENT VPT Trial is a multi-center randomized controlled crossover trial in which military service members with mTBI and civilian patients with vestibular hypofunction are randomized to begin traditional vestibular rehabilitation or incremental vestibular adaptation and then cross over to the alternate intervention after a prescribed washout period. Vestibulo-ocular reflex function and other functional outcomes are measured to identify the best means to improve the delivery of vestibular rehabilitation. We incorporate ecologically valid outcome measures that address the common symptoms experienced in those with vestibular pathology and multi-sensory impairment. DISCUSSION: The INVENT VPT Trial will directly impact the health care delivery of vestibular rehabilitation in patients suffering from multi-sensory impairment in three critical ways: (1) compare optimized traditional methods of vestibular rehabilitation to a novel device that is hypothesized to improve vestibulo-ocular reflex performance, (2) isolate the ideal dosing of vestibular rehabilitation considering patient burden and compliance rates, and (3) examine whether recovery of the vestibulo-ocular reflex can be predicted in participants with vestibular symptoms. TRIAL REGISTRATION: ClinicalTrials.gov NCT03846830 . Registered on 20 February 2019.

[Effects of cochlear implantation on vestibular function]. / Vozdeistvie kokhlearnoi implantatsii na vestibulyarnuyu funktsiyu.

The literature review is devoted to the effects arising from the effect of a cochlear implant on the vestibular system. Due to the pronounced anatomical proximity and physiological interaction of vestibular receptors with the cochlea, the installation of a cochlear implant and its electrical activity are associated with an effect on the vestibular system. The analysis of the works of foreign and domestic researchers who carried out monitoring of vestibular function in patients after cochlear implantation using modern objective methods was carried out.

[Dizziness in Parkinson's disease]. / Golovokruzhenie pri bolezni Parkinsona.

OBJECTIVE: To study clinical features of vestibular disorders in patients with Parkinson's disease (PD) and to develop methods of their treatment. MATERIAL AND METHODS: The study included 90 patients with PD who were divided into two groups: the main group (60 patients with PD and vestibular symptoms (VS)) and the control group (30 patients with PD without VS). All patients underwent clinical neurological examination, assessment of cognitive functions, affective and autonomic disorders as well as neurovestibular examination. RESULTS: In some cases, dizziness was due to concomitant diseases of the vestibular system. Among the rest of the patients of the main group, signs of disorders of the central mechanisms of gaze control, otolith dysfunction, anxiety disorder and visuospatial dysfunction were recorded significantly more often than in the control group. The addition of vestibular rehabilitation to the complex treatment of patients of the main group helped to reduce postural instability and decreased the risk of falls. CONCLUSION: Vestibular disorders are significantly more common in patients with PD who complain of dizziness. An early detection of these disorders is feasible with the help of neurovestibular research. It is reasonable to add individually selected vestibular exercises to the complex treatment of these disorders.