Molecular profile of vestibular compensation in the medial vestibular nucleus after unilateral labyrinthectomy.

Long non-coding RNAs (lncRNAs) have emerged as crucial regulators in the central nervous system, yet their role in vestibular compensation remains elusive. To address this knowledge gap, we employed unilateral labyrinthectomy (UL) in rats to establish animal models of peripheral vestibular dysfunction. Utilizing ribonucleic acid sequencing (RNA-seq), we comprehensively analysed the expression profiles of genes dysregulated in the medial vestibular nucleus (MVN) of these rats at distinct time points: 4 h, 4 days, and 14 days post-UL. Through trans-target prediction analysis integrating differentially co-expressed messenger RNAs (mRNAs) and lncRNAs, we constructed lncRNA-mRNA regulatory networks. Validation of selected mRNAs and lncRNAs was performed using RT-qPCR. Our RNA-seq analysis revealed significant aberrant expression of 3054 lncRNAs and 1135 mRNAs compared to control samples. By applying weighted gene co-expression network analysis (WGCNA), we identified 11 co-expressed modules encompassing all genes. Notably, within the MEmagenta module, we observed an initial upregulation of differentially expressed genes (DEGs) at 4 h, followed by downregulation at 4- and 14-days post-UL. Our findings indicated that 3068 lncRNAs positively regulated 1259 DEGs, while 1482 lncRNAs negatively regulated 433 DEGs in the MVN. The RT-qPCR results corroborated the RNA-seq data, validating our findings. This study offers novel insights into the lncRNA-mRNA expression landscape during vestibular compensation, paving the way for further exploration of lncRNA functions in this context.

Compensatory strategies after an acute unilateral vestibulopathy: a prospective observational study.

PURPOSE: In case of an acute unilateral vestibulopathy (UVP), compensatory strategies such as restoration and adaptation will lead to a decrease in intensity of the symptoms. Although measurements of compensatory strategies are available, currently, an overview taking the different strategies into account is lacking. The objectives of this study are to explore compensatory strategies and to investigate the association between compensatory strategies and patient characteristics. METHODS: Restoration was objectified by the vestibulo-ocular reflex (VOR) gain on the video head impulse test, and adaptation-consisting of visual, multisensory, and behavioral substitution-was objectified by the Visual Vertigo Analog Scale (VVAS), Antwerp Vestibular Compensation Index (AVeCI), and Perez and Rey score (PR score), respectively. Adequate restoration and adaptation levels were interpreted as follows: VOR gain > 0.80, VVAS ≤ 40%, AVeCI > 0 and PR score ≤ 55. RESULTS: Sixty-two UVP patients, 34 men and 28 women, were included with an average age of 52.1 ± 17.3 years. At 10.5 ± 1.4 weeks after onset, 41.9% of the UVP patients reached adequate restoration levels and 58.1-86.9% reached adequate adaptation levels. Furthermore, significant associations were found between (1) restoration status and UVP etiology [Odds Ratio (OR) with 95% CI: 4.167 {1.353;12.828}] and balance performance (OR: 4.400 {1.258;15.386}), (2) visual sensory substitution status and perceived handicap (OR: 8.144 {1.644;40.395}), anxiety (OR: 10.000 {1.579;63.316}) and depression (OR: 16.667 {2.726;101.896}), and (3) behavioral substitution status and balance performance (OR: 4.143 {1.341;12.798}). CONCLUSION: UVP patients with adequate compensatory strategies presented with better balance performance, lower perceived handicap, and lower anxiety and depression scores.

The Vestibular Nuclei: A Cerebral Reservoir of Stem Cells Involved in Balance Function in Normal and Pathological Conditions.

In this review, we explore the intriguing realm of neurogenesis in the vestibular nuclei-a critical brainstem region governing balance and spatial orientation. We retrace almost 20 years of research into vestibular neurogenesis, from its discovery in the feline model in 2007 to the recent discovery of a vestibular neural stem cell niche. We explore the reasons why neurogenesis is important in the vestibular nuclei and the triggers for activating the vestibular neurogenic niche. We develop the symbiotic relationship between neurogenesis and gliogenesis to promote vestibular compensation. Finally, we examine the potential impact of reactive neurogenesis on vestibular compensation, highlighting its role in restoring balance through various mechanisms.

In vivo neuroplasticity in vestibular animal models.

An acute unilateral vestibulopathy leads to symptoms of vestibular tone imbalance, which gradually decrease over days to weeks due to central vestibular compensation. Animal models of acute peripheral vestibular lesions are optimally suited to investigate the mechanisms underlying this lesion-induced adaptive neuroplasticity. Previous studies applied ex vivo histochemical techniques or local in vivo electrophysiological recordings mostly in the vestibular nucleus complex to delineate the mechanisms involved. Recently, the use of imaging methods, such as positron emission tomography (PET) or magnetic resonance imaging (MRI), in vestibular animal models have opened a complementary perspective by depicting whole-brain structure and network changes of neuronal activity over time and in correlation to behaviour. Here, we review recent multimodal imaging studies in vestibular animal models with a focus on PET-based measurements of glucose metabolism, glial activation and synaptic plasticity. [18F]-FDG-PET studies indicate dynamic alterations of regional glucose metabolism in brainstem-cerebellar, thalamic, cortical sensory and motor, as well as limbic areas starting early after unilateral labyrinthectomy (UL) in the rat. Sequential whole-brain analysis of the metabolic connectome during vestibular compensation shows a significant increase of connections mostly in the contralesional hemisphere after UL, which reaches a maximum at day 3 and thereby parallels the course of vestibular recovery. Glial activation in the ipsilesional vestibular nerve and nucleus peak between days 7 and 15 after UL. Synaptic density in brainstem-cerebellar circuits decreases until 8 weeks after UL, while it increases in frontal, motor and sensory cortical areas. We finally report how pharmacological compounds modulate the functional and structural plasticity mechanisms during vestibular compensation.

Thyroid Axis and Vestibular Physiopathology: From Animal Model to Pathology.

A recent work of our group has shown the significant effects of thyroxine treatment on the restoration of postural balance function in a rodent model of acute peripheral vestibulopathy. Based on these findings, we attempt to shed light in this review on the interaction between the hypothalamic-pituitary-thyroid axis and the vestibular system in normal and pathological situations. Pubmed database and relevant websites were searched from inception through to 4 February 2023. All studies relevant to each subsection of this review have been included. After describing the role of thyroid hormones in the development of the inner ear, we investigated the possible link between the thyroid axis and the vestibular system in normal and pathological conditions. The mechanisms and cellular sites of action of thyroid hormones on animal models of vestibulopathy are postulated and therapeutic options are proposed. In view of their pleiotropic action, thyroid hormones represent a target of choice to promote vestibular compensation at different levels. However, very few studies have investigated the relationship between thyroid hormones and the vestibular system. It seems then important to more extensively investigate the link between the endocrine system and the vestibule in order to better understand the vestibular physiopathology and to find new therapeutic leads.

Oxytocin Disturbs Vestibular Compensation and Modifies Behavioral Strategies in a Rodent Model of Acute Vestibulopathy.

Unilateral inner ear injury is followed by behavioral recovery due to central vestibular compensation. The therapeutic effect of oxytocin (OT) on vestibular compensation was investigated by behavioral testing in a rat model of unilateral vestibular neurectomy (UVN). Animals in the oxytocin group (UVN-OT) exhibited delayed vestibular compensation on the qualitative scale of vestibular deficits and aggravated static postural deficits (bearing surface) compared to animals in the NaCl group (UVN-NaCl). Surprisingly, oxytocin-treated animals adopt a different postural strategy than untreated animals. Instead of shifting their weight to the ipsilesional paws (left front and hind paws), they shift their weight to the front paws (right and left) without modification along the lateral axis. Furthermore, some locomotor strategies of the animals to compensate for the vestibular loss are also altered by oxytocin treatment. UVN-OT animals do not induce an increase in the distance traveled, their mean velocity is lower than that in the control group, and the ipsilesional body rotations do not increase from 7 to 30 days after UVN. This study reveals that oxytocin treatment hinders the restoration of some postural and locomotor deficits while improving others following vestibular lesions. The mechanisms of the action of oxytocin that support these behavioral changes remain to be elucidated.

Dynamic whole-brain metabolic connectivity during vestibular compensation in the rat.

Unilateral damage to the inner ear results in an acute vestibular syndrome, which is compensated within days to weeks due to adaptive cerebral plasticity. This process, called central vestibular compensation (VC), involves a wide range of functional and structural mechanisms at the cellular and network level. The short-term dynamics of whole-brain functional network recruitment and recalibration during VC has not been depicted in vivo. The purpose of this study was to investigate the interplay of separate and distinct brain regions and in vivo networks in the course of VC by sequential [18F]-FDG-PET-based statistical and graph theoretical analysis with the aim of revealing the metabolic connectome before and 1, 3, 7, and 15 days post unilateral labyrinthectomy (UL) in the rat. Temporal changes in metabolic brain connectivity were determined by Pearson's correlation (|r| > 0.5, p < 0.001) of regional cerebral glucose metabolism (rCGM) in 57 segmented brain regions. Metabolic connectivity analysis was compared to univariate voxel-wise statistical analysis of rCGM over time and to behavioral scores of static and dynamic sensorimotor recovery. Univariate statistical analysis revealed an ipsilesional relative rCGM decrease (compared to baseline) and a contralesional rCGM increase in vestibular and limbic networks and an increase in bilateral cerebellar and sensorimotor networks. Quantitative analysis of the metabolic connections showed a maximal increase from baseline to day 3 post UL (interhemispheric: 2-fold, ipsilesional: 3-fold, contralesional: 12-fold) and a gradual decline until day 15 post UL, which paralleled the dynamics of vestibular symptoms. In graph theoretical analysis, an increase in connectivity occurred especially within brain regions associated with brainstem-cerebellar and thalamocortical vestibular networks and cortical sensorimotor networks. At the symptom peak (day 3 post UL), brain networks were found to be organized in large ensembles of distinct and highly connected hubs of brain regions, which separated again with progressing VC. Thus, we found rapid changes in network organization at the subcortical and cortical level and in both hemispheres, which may indicate an initial functional substitution of vestibular loss and subsequent recalibration and reorganization of sensorimotor networks during VC.

Breaking a dogma: acute anti-inflammatory treatment alters both post-lesional functional recovery and endogenous adaptive plasticity mechanisms in a rodent model of acute peripheral vestibulopathy.

BACKGROUND: Due to their anti-inflammatory action, corticosteroids are the reference treatment for brain injuries and many inflammatory diseases. However, the benefits of acute corticotherapy are now being questioned, particularly in the case of acute peripheral vestibulopathies (APV), characterized by a vestibular syndrome composed of sustained spinning vertigo, spontaneous ocular nystagmus and oscillopsia, perceptual-cognitive, posturo-locomotor, and vegetative disorders. We assessed the effectiveness of acute corticotherapy, and the functional role of acute inflammation observed after sudden unilateral vestibular loss. METHODS: We used the rodent model of unilateral vestibular neurectomy, mimicking the syndrome observed in patients with APV. We treated the animals during the acute phase of the vestibular syndrome, either with placebo or methylprednisolone, an anti-inflammatory corticosteroid. At the cellular level, impacts of methylprednisolone on endogenous plasticity mechanisms were assessed through analysis of cell proliferation and survival, glial reactions, neuron's membrane excitability, and stress marker. At the behavioral level, vestibular and posturo-locomotor functions' recovery were assessed with appropriate qualitative and quantitative evaluations. RESULTS: We observed that acute treatment with methylprednisolone significantly decreases glial reactions, cell proliferation and survival. In addition, stress and excitability markers were significantly impacted by the treatment. Besides, vestibular syndrome's intensity was enhanced, and vestibular compensation delayed under acute methylprednisolone treatment. CONCLUSIONS: We show here, for the first time, that acute anti-inflammatory treatment alters the expression of the adaptive plasticity mechanisms in the deafferented vestibular nuclei and generates enhanced and prolonged vestibular and postural deficits. These results strongly suggest a beneficial role for acute endogenous neuroinflammation in vestibular compensation. They open the way to a change in dogma for the treatment and therapeutic management of vestibular patients.

Different time course of compensation of subjective visual vertical and ocular torsion after acute unilateral vestibular lesion.

PURPOSE: Time course of the recovery of otolithic dis-function caused by superior vestibular neuritis has been examined in fifteen patients. METHODS: The subjective visual vertical (SVV) and the ocular cyclotorsion (OT) have been measured four times after the acute episode up to 1 year RESULTS: In most of the patients the SVV tilt returned to control values within few months (3-6 months) after the acute episode, while OT remained out of normal range in almost all patients a year later. CONCLUSION: The abnormal OT observed after 1 year from the acute episode of vestibular neuritis, suggests that the otolithic receptors remained altered for several months and the OT may be a good indicator of the entity of the residual peripheral otolithic lesion. Moreover, the dissociation between the SVV tilt recovery and that of OT supports the issue that the two signs of the otolithic disfunction are only partially linked each other with centrally or peripherally distinct re-balancing circuits.

Histamine H1 Receptor Contributes to Vestibular Compensation.

Vestibular compensation is responsible for the spontaneous recovery of postural, locomotor, and oculomotor dysfunctions in patients with peripheral vestibular lesion or posterior circulation stroke. Mechanism investigation of vestibular compensation is of great importance in both facilitating recovery of vestibular function and understanding the postlesion functional plasticity in the adult CNS. Here, we report that postsynaptic histamine H1 receptor contributes greatly to facilitating vestibular compensation. The expression of H1 receptor is restrictedly increased in the ipsilesional rather than contralesional GABAergic projection neurons in the medial vestibular nucleus (MVN), one of the most important centers for vestibular compensation, in unilateral labyrinthectomized male rats. Furthermore, H1 receptor mediates an asymmetric excitation of the commissural GABAergic but not glutamatergic neurons in the ipsilesional MVN, which may help to rebalance bilateral vestibular systems and promote vestibular compensation. Selective blockage of H1 receptor in the MVN significantly retards the recovery of both static and dynamic vestibular symptoms following unilateral labyrinthectomy, and remarkably attenuates the facilitation of betahistine, whose effect has traditionally been attributed to its antagonistic action on the presynaptic H3 receptor, on vestibular compensation. These results reveal a previously unknown role for histamine H1 receptor in vestibular compensation and amelioration of vestibular motor deficits, as well as an involvement of H1 receptor in potential therapeutic effects of betahistine. The findings provide not only a new insight into the postlesion neuronal circuit plasticity and functional recovery in the CNS, but also a novel potential therapeutic target for vestibular disorders.SIGNIFICANCE STATEMENT Vestibular disorders manifest postural imbalance, nystagmus, and vertigo. Vestibular compensation is critical for facilitating recovery from vestibular disorders, and of great importance in understanding the postlesion functional plasticity in the adult CNS. Here, we show that postsynaptic H1 receptor in the medial vestibular nucleus (MVN) contributes greatly to the recovery of both static and dynamic symptoms following unilateral vestibular lesion. H1 receptor selectively mediates the asymmetric activation of commissural inhibitory system in the ipsilesional MVN and actively promotes vestibular compensation. The findings provide not only a new insight into the postlesion neuronal circuit plasticity and functional recovery of CNS, but also a novel potential therapeutic target for promoting vestibular compensation and ameliorating vestibular disorders.

Suppression Head Impulse Paradigm (SHIMP) in evaluating the vestibulo-saccadic interaction in patients with vestibular neuritis.

PURPOSE: Evaluate the potential clinical application of the Suppression Head Impulse Paradigm (SHIMP) in evaluating the vestibulo-saccadic interaction in patients with vestibular neuritis (VN). METHODS: A retrospective study was performed. Fifteen patients diagnosed with unilateral VN were identified from a database of ENT vestibular clinic from January 2011 to February 2020. Medical records were reviewed to determine clinical presentation, vestibular testing results, treatment, and recovery. RESULTS: Fifteen patients (7 left ear, 8 right ear, mean age 58.73 ± 10.73, six female) met the inclusion criteria and were enrolled in the study. Significant differences were found in the within-subjects analysis at T1 in DHI score (p = 0.001), VOR gain (p < 0.005), and in the percentages of impulses containing a SHIMPs saccade when the head is passively turned toward the affected side (p = 0.001). CONCLUSIONS: SHIMPs paradigm provides useful information about the value of vestibulo-saccadic interaction as new recovery strategies in patients with VN.

BDNF Signaling Promotes Vestibular Compensation by Increasing Neurogenesis and Remodeling the Expression of Potassium-Chloride Cotransporter KCC2 and GABAA Receptor in the Vestibular Nuclei.

UNLABELLED: Reactive cell proliferation occurs rapidly in the cat vestibular nuclei (VN) after unilateral vestibular neurectomy (UVN) and has been reported to facilitate the recovery of posturo-locomotor functions. Interestingly, whereas animals experience impairments for several weeks, extraordinary plasticity mechanisms take place in the local microenvironment of the VN: newborn cells survive and acquire different phenotypes, such as microglia, astrocytes, or GABAergic neurons, whereas animals eventually recover completely from their lesion-induced deficits. Because brain-derived neurotrophic factor (BDNF) can modulate vestibular functional recovery and neurogenesis in mammals, in this study, we examined the effect of BDNF chronic intracerebroventricular infusion versus K252a (a Trk receptor antagonist) in our UVN model. Results showed that long-term intracerebroventricular infusion of BDNF accelerated the restoration of vestibular functions and significantly increased UVN-induced neurogenesis, whereas K252a blocked that effect and drastically delayed and prevented the complete restoration of vestibular functions. Further, because the level of excitability in the deafferented VN is correlated with behavioral recovery, we examined the state of neuronal excitability using two specific markers: the cation-chloride cotransporter KCC2 (which determines the hyperpolarizing action of GABA) and GABAA receptors. We report for the first time that, during an early time window after UVN, significant BDNF-dependent remodeling of excitability markers occurs in the brainstem. These data suggest that GABA acquires a transient depolarizing action during recovery from UVN, which potentiates the observed reactive neurogenesis and accelerates vestibular functional recovery. These findings suggest that BDNF and/or KCC2 could represent novel treatment strategies for vestibular pathologies. SIGNIFICANCE STATEMENT: In this study, we report for the first time that brain-derived neurotrophic factor potentiates vestibular neurogenesis and significantly accelerates functional recovery after unilateral vestibular injury. We also show that specific markers of excitability, the potassium-chloride cotransporter KCC2 and GABAA receptors, undergo remarkable fluctuations within vestibular nuclei (VN), strongly suggesting that GABA acquires a transient depolarizing action in the VN during the recovery period. This novel plasticity mechanism could explain in part how the system returns to electrophysiological homeostasis between the deafferented and intact VN, considered in the literature to be a key parameter of vestibular compensation. In this context, our results open new perspectives for the development of therapeutic approaches to alleviate the vestibular symptoms and favor vestibular function recovery.

The mammalian efferent vestibular system plays a crucial role in vestibulo-ocular reflex compensation after unilateral labyrinthectomy.

The α9-nicotinic acetylcholine receptor (α9-nAChR) subunit is expressed in the vestibular and auditory periphery, and its loss of function could compromise peripheral input from the predominantly cholinergic efferent vestibular system (EVS). A recent study has shown that α9-nAChRs play an important role in short-term vestibulo-ocular reflex (VOR) adaptation. We hypothesize that α9-nAChRs could also be important for other forms of vestibular plasticity, such as that needed for VOR recovery after vestibular organ injury. We measured the efficacy of VOR compensation in α9 knockout mice. These mice have deletion of most of the gene (chrna9) encoding the nAChR and thereby lack α9-nAChRs. We measured the VOR gain (eye velocity/head velocity) in 20 α9 knockout mice and 16 cba129 controls. We measured the sinusoidal (0.2-10 Hz, 20-100°/s) and transient (1,500-6,000°/s2) VOR in complete darkness before (baseline) unilateral labyrinthectomy (UL) and then 1, 5, and 28 days after UL. On day 1 after UL, cba129 mice retained ~50% of their initial function for contralesional rotations, whereas α9 knockout mice only retained ~20%. After 28 days, α9 knockout mice had ~50% lower gain for both ipsilesional and contralesional rotations compared with cba129 mice. Cba129 mice regained ~75% of their baseline function for ipsilesional and ~90% for contralesional rotations. In contrast, α9 knockout mice only regained ~30% and ~50% function, respectively, leaving the VOR severely impaired for rotations in both directions. Our results show that loss of α9-nAChRs severely affects VOR compensation, suggesting that complimentary central and peripheral EVS-mediated adaptive mechanisms might be affected by this loss.NEW & NOTEWORTHY Loss of the α9-nicotinic acetylcholine receptor (α9-nAChR) subunit utilized by the efferent vestibular system (EVS) has been shown to significantly affect vestibulo-ocular reflex (VOR) adaptation. In our present study we have shown that loss of α9-nAChRs also affects VOR compensation, suggesting that the mammalian EVS plays an important role in vestibular plasticity, in general, and that VOR compensation is a more distributed process than previously thought, relying on both central and peripheral changes.

Reduction of long-term potentiation at Schaffer collateral-CA1 synapses in the rat hippocampus at the acute stage of vestibular compensation.

Vestibular compensation is a recovery process from vestibular symptoms over time after unilateral loss of peripheral vestibular end organs. The aim of the present study was to observe time-dependent changes in long-term potentiation (LTP) at Schaffer collateral-CA1 synapses in the CA1 area of the hippocampus during vestibular compensation. The input-output (I/O) relationships of fEPSP amplitudes and LTP induced by theta burst stimulation to Schaffer's collateral commissural fibers were evaluated from the CA1 area of hippocampal slices at 1 day, 1 week, and 1 month after unilateral labyrinthectomy (UL). The I/O relationships of fEPSPs in the CA1 area was significantly reduced within 1 week post-op and then showed a non-significant reduction at 1 month after UL. Compared with sham-operated animals, there was a significant reduction of LTP induction in the hippocampus at 1 day and 1 week after UL. However, LTP induction levels in the CA1 area of the hippocampus also returned to those of sham-operated animals 1 month following UL. These data suggest that unilateral injury of the peripheral vestibular end organs results in a transient deficit in synaptic plasticity in the CA1 hippocampal area at acute stages of vestibular compensation.

Modeling eye-head gaze shifts in multiple contexts without motor planning.

During gaze shifts, the eyes and head collaborate to rapidly capture a target (saccade) and fixate it. Accordingly, models of gaze shift control should embed both saccadic and fixation modes and a mechanism for switching between them. We demonstrate a model in which the eye and head platforms are driven by a shared gaze error signal. To limit the number of free parameters, we implement a model reduction approach in which steady-state cerebellar effects at each of their projection sites are lumped with the parameter of that site. The model topology is consistent with anatomy and neurophysiology, and can replicate eye-head responses observed in multiple experimental contexts: 1) observed gaze characteristics across species and subjects can emerge from this structure with minor parametric changes; 2) gaze can move to a goal while in the fixation mode; 3) ocular compensation for head perturbations during saccades could rely on vestibular-only cells in the vestibular nuclei with postulated projections to burst neurons; 4) two nonlinearities suffice, i.e., the experimentally-determined mapping of tectoreticular cells onto brain stem targets and the increased recruitment of the head for larger target eccentricities; 5) the effects of initial conditions on eye/head trajectories are due to neural circuit dynamics, not planning; and 6) "compensatory" ocular slow phases exist even after semicircular canal plugging, because of interconnections linking eye-head circuits. Our model structure also simulates classical vestibulo-ocular reflex and pursuit nystagmus, and provides novel neural circuit and behavioral predictions, notably that both eye-head coordination and segmental limb coordination are possible without trajectory planning.

Vestibular compensation in cerebellar stroke patients.

BACKGROUND AND PURPOSE: There is little evidence about the site where compensatory vestibular mechanisms in patients with cerebellar strokes take place. METHODS: To determine whether the location of a cerebellar lesion might be a crucial variable in vestibular compensation a sample of 22 patients with cerebellar stroke were tested for graviceptive function in the acute and chronic stage. RESULTS: Our statistical anatomical lesion analysis indicated that mainly lesions of the cerebellar hemispheres (lobule V, VI, VIIa) hinder vestibular compensation and might lead to an overcompensation. CONCLUSIONS: Overcompensation-induced dysfunction can be explained by the absence of cerebellar inhibitory signals.

Responses of non-eye movement central vestibular neurons to sinusoidal horizontal translation in compensated macaques after unilateral labyrinthectomy.

After vestibular labyrinth injury, behavioral deficits partially recover through the process of vestibular compensation. The present study was performed to improve our understanding of the physiology of the macaque vestibular system in the compensated state (>7 wk) after unilateral labyrinthectomy (UL). Three groups of vestibular nucleus neurons were included: pre-UL control neurons, neurons ipsilateral to the lesion, and neurons contralateral to the lesion. The firing responses of neurons sensitive to linear acceleration in the horizontal plane were recorded during sinusoidal horizontal translation directed along six different orientations (30° apart) at 0.5 Hz and 0.2 g peak acceleration (196 cm/s(2)). This data defined the vector of best response for each neuron in the horizontal plane, along which sensitivity, symmetry, detection threshold, and variability of firing were determined. Additionally, the responses of the same cells to translation over a series of frequencies (0.25-5.0 Hz) either in the interaural or naso-occipital orientation were obtained to define the frequency response characteristics in each group. We found a decrease in sensitivity, increase in threshold, and alteration in orientation of best responses in the vestibular nuclei after UL. Additionally, the phase relationship of the best neural response to translational stimulation changed with UL. The symmetry of individual neuron responses in the excitatory and inhibitory directions was unchanged by UL. Bilateral central utricular neurons still demonstrated two-dimension tuning after UL, consistent with spatio-temporal convergence from a single vestibular end-organ. These neuronal data correlate with known behavioral deficits after unilateral vestibular compromise.

Middle fossa vestibular neurectomy for refractory vertigo: less is more.

OBJECTIVE: This study aimed to evaluate outcomes of the middle fossa (MF) superior vestibular neurectomy in unilateral Ménière's disease. PATIENTS AND METHODS: Case series with preoperative and postoperative analysis of the 1995 American Academy of Otolaryngology hearing stage and vertigo class, gait instability, and results of vestibular-evoked myogenic potentials (VEMP). RESULTS: Four out of the 5 patients had total vertigo control (class A) and 1 had near total control (class B) by the last visit (mean follow-up, 23.6 months). There were no changes in hearing thresholds and hearing stage. Four patients had resolution of their gait instability by 2 months after surgery. Postoperative VEMP responses were preserved in all 3 patients with positive VEMP preoperatively. CONCLUSION: This is the first report of the anatomical and functional preservation of the inferior vestibular nerve in vestibular neurectomy for the treatment of refractory vertigo in unilateral Ménière's disease, with VEMP testing before and after vestibular neurectomy. The modified technique limits the surgical dissection and may help avoid complications such as postoperative hearing loss and persistent gait instability. This approach is indicated when other more conservative measures have failed, and patient selection is paramount to avoid long-term complications.

Effects of high-dose betahistine on intractable dizziness in patients with uncompensated unilateral vestibulopathy.

OBJECTIVE: In the present study, we examined the effects of high-dose betahistine on dizziness handicap inventory (DHI) scores in patients with unilateral vestibulopathy. METHODS: An uncontrolled, open-label, multicenter clinical trial was conducted. Fifteen patients with unilateral vestibulopathy, such as vestibular neuritis, who complained of intractable dizziness for more than three months were enrolled. Initially, all patients were orally administered betahistine at a dose of 36 mg/day for four weeks, which is the standard dose and dosing period for the treatment of dizziness in Japan. The patients were then administered betahistine at a double dose of 72 mg/day for four weeks. Six patients who became aware of the benefits of high-dose betahistine were further administered betahistine at 72 mg/day for an additional 12 weeks (a total of 16 weeks). Perceived disability due to dizziness was assessed by DHI scores. RESULTS: In all 15 patients, short-term administration with high-dose (72 mg/day) betahistine for four weeks, but not low-dose betahistine (36 mg/day) for four weeks significantly decreased DHI scores. In particular, in six responding patients with self-reported benefits after short-term administration with high-dose betahistine, long-term administration with high-dose betahistine for 16 weeks further significantly decreased DHI scores. However, DHI scores of the remaining nine non-responding patients were not changed after short-term administration with high-dose betahistine for four weeks. CONCLUSION: Short-term administration with the standard dose and dosing period of betahistine did not improve DHI scores in the enrolled patients, indicating that they were not compensated for unilateral vestibulopathy with intractable dizziness. The present findings suggest that long-term administration with high-dose betahistine facilitates vestibular compensation to improve intractable dizziness in some, but not all patients with uncompensated unilateral vestibulopathy.

mGluR1/IP3/ERK signaling pathway regulates vestibular compensation in ON UBCs of the cerebellar flocculus.

AIMS: To investigate the role of mGluR1α in cerebellar unipolar brush cells (UBC) in mediating vestibular compensation (VC), using mGluR1α agonist and antagonist to modulate ON UBC neurons, and explore the mGluR1/IP3/extracellular signal-regulated kinase (ERK) signaling pathway. METHODS: First, AAV virus that knockdown ON UBC (mGluR1α) were injected into cerebellar UBC by stereotactic, and verified by immunofluorescence and western blot. The effect on VC was evaluated after unilateral labyrinthectomy (UL). Second, saline, (RS)-3,5-dihydroxyphenylglycine (DHPG), and LY367385 were injected into tubes implanted in rats at different time points after UL separately. The effect on ON UBC neuron activity was evaluated by immunofluorescence. Then, Phosphoinositide (PI) and p-ERK1/2 levels of mGluR1α were analyzed by ELISA after UL. The protein levels of p-ERK and total ERK were verified by western blot. In addition, the effect of mGluR1α activation or inhibition on VC-related behavior was observed. RESULTS: mGluR1α knockdown induced VC phenotypes. DHPG increased ON UBC activity, while LY367385 reduced ON UBC activity. DHPG group showed an increase in PI and p-ERK1/2 levels, while LY367385 group showed a decrease in PI and p-ERK1/2 levels in cerebellar UBC of rats. The western blot results of p-ERK and total ERK confirm and support the observations. DHPG alleviated VC-related behavior phenotypes, while LY367385 exacerbated vestibular decompensation-like behavior induced by UL. CONCLUSION: mGluR1α activity in cerebellar ON UBC is crucial for mediating VC through the mGluR1/IP3/ERK signaling pathway, which affects ON UBC neuron activity and contributes to the pathogenesis of VC.