Bilateral Vestibular Weakness and its Management

Background and Objectives：The purpose of this study was to investigate the effects of low level laser for the prevention and treatment of aminoglycoside-induced vestibular ototoxicity. Materials and Method：An organotypic culture of 2 to 4 days old rat utricular maculae was established. Rats were divided into 6 groups according to the treadtment of the utricles：G (gentamicin-treated), L (laser-irradiated), LG (laser-irradiated and gentamicin-treated), GL (gentamicin-treated and laser-irradiated), LGL (gentamicin-treated during laser-irradiated) and C (control). After organotypic culture, the utricles of 6 groups were examined by confocal laser scanning electron microscope and scanning electron microscope. The results of each group were compared with each other by statistical methods. Results：The number of vestibular hair cells of the group G was smaller compared to that of the group C. The group L had no difference compared with the group C. The groups LG and GL showed more vestibular hair cells compared with the group G. The group LG showed more vestibular hair cells than the group GL. The group LGL showed most vestibular hair cells compared to that of the groups G, LG, and GL. Conclusion：The most effective treatment of aminoglycoside-induced vestibular otoxicity is the irradiation of low level laser before and after the insult of the aminoglycoside. Further clinical studies using low level laser were needed to prevent aminoglycoside-induced ototoxicity and to promote the regeneration of vestibular hair cells.

The vestibular system is a critical part of the human balance system, malfunction of this system will lead to balance disorders, such as vertigo. Mammalian vestibular hair cells, the mechanical receptors for vestibular function, are sensitive to ototoxic drugs and virus infection, and have a limited restorative capacity after damage. Considering that no artificial device can be used to replace vestibular hair cells, promoting vestibular hair cell regeneration is an ideal way for vestibular function recovery. In this manuscript, the development of human vestibular hair cells during the whole embryonic stage and the latest research on human vestibular hair cell regeneration is summarized. The limitations of current studies are emphasized and future directions are discussed.

Hair cell regeneration in the avian vestibular epithelium

Benign paroxysmal positional vertigo (BPPV) is a common cause of peripheral vestibular dysfunction, often resolving with canalith repositioning maneuvers (CRM). However, residual dizziness and imbalance may persist, impairing functional mobility. This case report describes a 55 year old female diagnosed with right posterior canal BPPV through a positive Dix Hallpike test. Following successful CRM, she reported residual postural instability and difficulty walking. A structured four week vestibular rehabilitation therapy (VRT) program was implemented, consisting of habituation (Brandt Daroff), adaptation (gaze stability, VOR x1, VOR x2), sensory substitution, and progressive balance training, delivered three times weekly for 45 minutes per session. Balance and mobility were assessed using the Berg Balance Scale (BBS) and Timed Up and Go (TUG) test at baseline and after the intervention. Results showed improvement in BBS from 42/56 to 53/56 (+11 points) and a reduction in TUG from 14.8 to 9.6 seconds (−5.2 seconds), both exceeding minimal detectable change values for older adults. The patient reported complete resolution of dizziness, increased walking confidence, and return to independent daily activities without adverse effects. This case suggests VRT as a valuable adjunct to CRM in BPPV patients with residual functional deficits, warranting further research in larger controlled studies.

Treatment of auditory and vestibular dysfunction has become increasingly dependent on inner ear drug delivery. Recent advances in molecular therapy and nanotechnology have pushed development of alternate delivery methodologies involving both transtympanic and direct intracochlear infusions. This review examines recent developments in the field relevant to both clinical and animal research environments. Transtympanic delivery of gentamicin and corticosteroids for the treatment of Meniere's disease and sudden sensorineural hearing loss continues to be clinically relevant, with understanding of pharmacokinetics becoming more closely studied. Stabilizing matrices placed on the round window membrane for sustained passive delivery of compounds offer more controlled dosing profiles than transtympanic injections. Nanoparticles are capable of traversing the round window membrane and cochlear membranous partitions, and may become useful gene delivery platforms. Cochlear and vestibular hair cell regeneration has been demonstrated by vector delivery to the inner ear, offering promise for future advanced therapies. Optimal methods of inner ear drug delivery will depend on toxicity, therapeutic dose range, and characteristics of the agent to be delivered. Advanced therapy development will likely require direct intracochlear delivery with detailed understanding of associated pharmacokinetics.

The Brn-3 subfamily of POU-domain transcription factor genes consists of three highly homologous members-Brn-3a, Brn-3b, and Brn-3c-that are expressed in sensory neurons and in a small number of brainstem nuclei. This paper describes the role of Brn-3c in auditory and vestibular system development. In the inner ear, the Brn-3c protein is found only in auditory and vestibular hair cells, and the Brn-3a and Brn-3b proteins are found only in subsets of spiral and vestibular ganglion neurons. Mice carrying a targeted deletion of the Brn-3c gene are deaf and have impaired balance. These defects reflect a complete loss of auditory and vestibular hair cells during the late embryonic and early postnatal period and a secondary loss of spiral and vestibular ganglion neurons. Together with earlier work demonstrating a loss of trigeminal ganglion neurons and retinal ganglion cells in mice carrying targeted disruptions in the Brn-3a and Brn-3b genes, respectively, the Brn-3c phenotype reported here demonstrates that each of the Brn-3 genes plays distinctive roles in the somatosensory, visual, and auditory/vestibular systems.

Gravity is a pervasive environmental stimulus, and accurate graviception is required for optimal spatial orientation and postural stability. The primary graviceptors are the vestibular organs, which include angular velocity (semicircular canals) and linear acceleration (otolith organs) sensors. Graviception is degraded in patients with vestibular damage, resulting in spatial misperception and imbalance. Since minimal therapy is available for these patients, substantial effort has focused on developing a vestibular prosthesis or vestibular implant (VI) that reproduces information normally provided by the canals (since reproducing otolith function is very challenging technically). Prior studies demonstrated that angular eye velocity responses could be driven by canal VI-mediated angular head velocity information, but it remains unknown whether a canal VI could improve spatial perception and posture since these behaviors require accurate estimates of angular head position in space relative to gravity. Here, we tested the hypothesis that a canal VI that transduces angular head velocity and provides this information to the brain via motion-modulated electrical stimulation of canal afferent nerves could improve the perception of angular head position relative to gravity in monkeys with severe vestibular damage. Using a subjective visual vertical task, we found that normal female monkeys accurately sensed the orientation of the head relative to gravity during dynamic tilts, that this ability was degraded following bilateral vestibular damage, and improved when the canal VI was used. These results demonstrate that a canal VI can improve graviception in vestibulopathic animals, suggesting that it could reduce the disabling perceptual and postural deficits experienced by patients with severe vestibular damage.SIGNIFICANCE STATEMENTPatients with vestibular damage experience impaired vision, spatial perception, and balance, symptoms that could potentially respond to a vestibular implant (VI). Anatomic features facilitate semicircular canal (angular velocity) prosthetics but inhibit approaches with the otolith (linear acceleration) organs, and canal VIs that sense angular head velocity can generate compensatory eye velocity responses in vestibulopathic subjects. Can the brain use canal VI head velocity information to improve estimates of head orientation (e.g., head position relative to gravity), which is a prerequisite for accurate spatial perception and posture? Here we show that a canal VI can improve the perception of head orientation in vestibulopathic monkeys, results that are highly significant because they suggest that VIs mimicking canal function can improve spatial orientation and balance in vestibulopathic patients.

Synaptic Transmission Between Hair Cells and Afferent Fibers

Subcellular immunolocalization of NMDA receptor subunit NR-1 in the chinchilla vestibular periphery

The expression patterns of the neurotrophin, brain-derived neurotrophic factor, BDNF, and the neurotrophic receptors—p75NTR and Trk receptors—in the developing human fetal inner ear between the gestational weeks (GW) 9 to 12 are examined via in situ hybridization and immunohistochemistry. BDNF mRNA expression was highest in the cochlea at GW 9 but declined in the course of development. In contrast to embryonic murine specimens, a decline in BDNF expression from the apical to the basal turn of the cochlea could not be observed. p75NTR immunostaining was most prominent in the nerve fibers that penetrate into the sensory epithelia of the cochlea, the urticule and the saccule as gestational age progresses. TrkB and TrkC expression intensified towards GW 12, at which point the BDNF mRNA localization was at its lowest. TrkA expression was limited to fiber subpopulations of the facial nerve at GW 10. In the adult human inner ear, we observed BDNF mRNA expression in the apical poles of the cochlear hair cells and supporting cells, while in the adult human utricle, the expression was localized in the vestibular hair cells. We demonstrate the highly specific staining patterns of BDNF mRNA and its putative receptors over a developmental period in which multiple hearing disorders are manifested. Our findings suggest that BDNF and neurotrophin receptors are important players during early human inner ear development. In particular, they seem to be important for the survival of the afferent sensory neurons.

The functional complementarity of the vestibulo-ocular reflex (VOR) and optokinetic reflex (OKR) allows for optimal combined gaze stabilization responses (CGR) in light. While sensory substitution has been reported following complete vestibular loss, the capacity of the central vestibular system to compensate for partial peripheral vestibular loss remains to be determined. Here, we first demonstrate the efficacy of a 6-week subchronic ototoxic protocol in inducing transient and partial vestibular loss which equally affects the canal- and otolith-dependent VORs. Immunostaining of hair cells in the vestibular sensory epithelia revealed that organ-specific alteration of type I, but not type II, hair cells correlates with functional impairments. The decrease in VOR performance is paralleled with an increase in the gain of the OKR occurring in a specific range of frequencies where VOR normally dominates gaze stabilization, compatible with a sensory substitution process. Comparison of unimodal OKR or VOR versus bimodal CGR revealed that visuo-vestibular interactions remain reduced despite a significant recovery in the VOR. Modeling and sweep-based analysis revealed that the differential capacity to optimally combine OKR and VOR correlates with the reproducibility of the VOR responses. Overall, these results shed light on the multisensory reweighting occurring in pathologies with fluctuating peripheral vestibular malfunction.

Rapid advances in neuroscience have sparked numerous efforts to study the neural correlate of consciousness. Prominent subjects include higher sensory area, distributed assemblies bound by synchronization of neuronal activity and neurons in specific cortical laminae. In contrast, it has been suggested that the quality of sensory awareness is determined by systematic change of afferent signals resulting from behaviour and knowledge thereof. Support for such skill-based theories of perception is provided by experiments on sensory substitution. Here, we pursue this line of thought and create new sensorimotor contingencies and, hence, a new quality of perception. Adult subjects received orientation information, obtained by a magnetic compass, via vibrotactile stimulation around the waist. After six weeks of training we evaluated integration of the new input by a battery of tests. The results indicate that the sensory information provided by the belt (1) is processed and boosts performance, (2) if inconsistent with other sensory signals leads to variable performance, (3) does interact with the vestibular nystagmus and (4) in half of the experimental subjects leads to qualitative changes of sensory experience. These data support the hypothesis that new sensorimotor contingencies can be learned and integrated into behaviour and affect perceptual experience.

In this study the functional role of afferent nerve calyx surrounding the type I vestibular hair cells was investigated. Synaptic microvesicles were present at the apex of the calyx in the vestibular epithelium of human foetuses at 9 weeks from gestation. Whole cell clamped type I hair cells isolated from guinea pig epithelium presented active movements as shortening of the neck and tilting of the cuticular plate at the cessation of the depolarising step. These movements were calcium dependent. With the aim of establishing the kinetics of calcium influx during the cell depolarisation, intracellular free calcium rate variations were investigated by coupling cytofluorimetry technique with whole cell patch clamp. An increase of intracellular calcium was only observed at the repolarisation of type I hair cells. Thus, a regulatory short-loop is thought to exist to control adaptation phenomena at the upper part of the type I hair cell. It is suggested that this occurs through the release of a neurotransmitter from the apex of the afferent calyx.

Differential subcellular immunolocalization of voltage-gated calcium channel α1 subunits in the chinchilla cristae ampullaris

Efferent circuits within the nervous system carry nerve impulses from the central nervous system to sensory end organs. Vestibular efferents originate in the brainstem and terminate on hair cells and primary afferent fibers in the semicircular canals and otolith organs within the inner ear. The function of this efferent vestibular system (EVS) in vestibular and motor coordination though, has proven difficult to determine, and remains under debate. We consider current literature that implicate corollary discharge from the spinal cord through the efferent vestibular nucleus (EVN), and hint at a potential role in overall vestibular plasticity and compensation. Hypotheses range from differentiating between passive and active movements at the level of vestibular afferents, to EVS activation under specific behavioral and environmental contexts such as arousal, predation, and locomotion. In this review, we summarize current knowledge of EVS circuitry, its effects on vestibular hair cell and primary afferent activity, and discuss its potential functional roles.