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.

Lateral Medullary Syndrome Following Injury of Lateral Vestibulospinal Tract: Diffusion Tensor Imaging Study.

BACKGROUND: Unilateral lesions of vestibular nucleus can cause lateral medullary syndrome. Little is known about injury of medial and lateral vestibulospinal tract (VST) after dorsolateral medullary infarct. We investigated injury of the lateral VST in patients with typical central vestibular disorder using diffusion tensor tractography (DTT). METHODS: Seven patients with lateral medullary syndrome and ten control subjects were recruited. For the medial VST, we determined seed region of interest (ROI) as medial vestibular nuclei of pons and target ROI on posteromedial medulla. For the lateral VST, the seed ROI was placed on lateral vestibular nuclei of pons, and the target ROI on posterolateral medulla. Fractional anisotropy (FA), mean diffusivity (MD), and tract volume were measured. RESULT: Reconstructed lateral VST on both sides had significantly lower FA values in patients than controls (p<0.05). Tract volume of lateral VST in affected side was significantly lower than unaffected side and control group (p<0.05). However, no DTI parameters of the medial VST differed between patients and controls (p>0.05). CONCLUSION: Injury of the lateral VST was demonstrated in patients with lateral vestibular syndrome following dorsolateral medullary infarct. Analysis of the lateral VST using DTT would be helpful in evaluation of patients with lateral medullary syndrome.

Vestibular nuclear infarction: Case series and review of the literature.

BACKGROUND AND PURPOSE: Acute vestibular syndrome (AVS) is a common cause of emergency admittance and has very rarely been reported due to a vestibular nucleus infarction. Initial magnetic resonance imaging studies (MRIs) including diffusion-weighted images may reveal normal results and even bedside examination tests like HINTS battery which involves head impulse test (HIT), nystagmus and test of skew can be challenging in differing a peripheral vestibulopathy from a central lesion. METHODS: Four patients seen in the emergency department with AVS and evaluated with HINTS battery, cervical vestibular-evoked myogenic potentials (cVEMP) and cranial MRI revealing infarcts restricted to vestibular nuclei were evaluated. RESULTS: In two patients spontaneous nystagmus beating towards the unaffected side was present. In one patient spontaneous nystagmus changed direction on looking to the affected side. In the fourth gaze evoked nystagmus was present without any spontaneous nystagmus. In all, HIT was positive to the affected side. In three cVEMPs was studied revealing delayed latency, reduced amplitude p13/n23 potentials on the lesioned side in two of them. Initial MRIs including diffusion-weighted images disclosed acute infarction in the area of the vestibular nuclei in two patients, with normal results in the other two. Follow-up MRI's performed 48 hours later revealed vestibular nuclear infarction. CONCLUSION: It is not always easy to differentiate small lesions restricted to central vestibular structures from peripheral vestibular lesions both on clinical and radiological grounds. Follow-up cranial MRI is necessary in patients with known vascular risk factors.

Terapia física en la hipofunción vestibular unilateral y bilateral / Physical therapy in unilateral and bilateral vestibular hypofunction

INTRODUCCIÓN: La rehabilitación vestibular (RV) basada en la terapia física, tiene el objetivo, en el caso de patología vestibular, de inducir la compensación del sistema nervioso central (SNC) a nivel de núcleos vestibulares y de otros niveles del SNC. Incluye ejercicios de habituación, adaptación y sustitución vestibular, ejercicios para mejorar el equilibrio y el control postural dinámico y ejercicios para el acondicionamiento general. En este capítulo discutimos los recientes avances sobre el adiestramiento del equilibrio y de la marcha, la estabilidad de la mirada y la habituación, en el contexto de los trastornos vestibulares uni y bilaterales. MÉTODO: Revisión narrativa. RESULTADOS: Los ejercicios se prescriben para mejorar la función; fortaleciendo, y favoreciendo la flexibilidad y la resistencia, a través de la adaptación del RVO, la habituación, la sustitución sensorial, la marcha y el equilibrio postural. Son más eficaces los programas personalizados que los genéricos. El cumplimiento mejora con la personalización y las visitas de seguimiento a un fisioterapeuta. Discusión/CONCLUSIONES: La RV permite mejorar el déficit funcional y los síntomas subjetivos derivados de la hipofunción vestibular periférica uni y bilateral, así como las alteraciones del equilibrio de origen central. Los objetivos de la RV consisten en reducir los síntomas para mejorar la estabilidad postural y de la mirada (particularmente durante los movimientos de la cabeza) y devolver al individuo a sus actividades normales, incluyendo la actividad física, la conducción y el trabajo habitual. Los médicos deben ofrecer la RV a quienes muestren limitaciones funcionales relacionadas con un déficit vestibular, pues actualmente se considera el tratamiento estándar en la disfunción vestibular periférica

INTRODUCTION: The vestibular rehabilitation is an exercise-based method, aiming to maximize central nervous system (CNS) compensation at vestibular nuclear and other CNS levels for vestibular pathology. Vestibular rehabilitation includes exercises to habituate symptoms, exercises to promote vestibular adaptation and substitution, exercises to improve balance and dynamic postural control, and exercises to improve general conditioning. Recent advances in balance and gait training, gaze stability training, habituation training, are discussed in this chapter in the context of unilateral and bilateral vestibular disorders. METHOD: Narrative review. RESULTS: Exercises are prescribed that address VOR adaptation, habituation, sensory substitution, gait and posture, strengthening, flexibility, and endurance to maximize functioning. Customized exercise programs have been shown to be more effective than providing a patient with a generic exercise program. It is thought that compliance is enhanced with customization and with follow-up visits with a physical therapist. Discussion/ conclusions: VR therapy is effective in improving functional deficits and subjective symptoms resulting from unilateral and bilateral peripheral vestibular hypo function, as well as from central balance disorders. The goals of vestibular rehabilitation are to reduce subjective symptoms, to improve gaze and postural stability (particularly during head movements), and to return the individual to normal activities, including regular physical activity, driving, and work. Clinicians should offer vestibular rehabilitation to persons with impairments and functional limitations related to the vestibular deficit. Vestibular rehabilitation is now considered the standard of care for persons with peripheral vestibular dysfunction

Self-motion perception is sensitized in vestibular migraine: pathophysiologic and clinical implications.

Vestibular migraine (VM) is the most common cause of spontaneous vertigo but remains poorly understood. We investigated the hypothesis that central vestibular pathways are sensitized in VM by measuring self-motion perceptual thresholds in patients and control subjects and by characterizing the vestibulo-ocular reflex (VOR) and vestibular and headache symptom severity. VM patients were abnormally sensitive to roll tilt, which co-modulates semicircular canal and otolith organ activity, but not to motions that activate the canals or otolith organs in isolation, implying sensitization of canal-otolith integration. When tilt thresholds were considered together with vestibular symptom severity or VOR dynamics, VM patients segregated into two clusters. Thresholds in one cluster correlated positively with symptoms and with the VOR time constant; thresholds in the second cluster were uniformly low and independent of symptoms and the time constant. The VM threshold abnormality showed a frequency-dependence that paralleled the brain stem velocity storage mechanism. These results support a pathogenic model where vestibular symptoms emanate from the vestibular nuclei, which are sensitized by migraine-related brainstem regions and simultaneously suppressed by inhibitory feedback from the cerebellar nodulus and uvula, the site of canal-otolith integration. This conceptual framework elucidates VM pathophysiology and could potentially facilitate its diagnosis and treatment.

The neural basis of motion sickness.

Although motion of the head and body has been suspected or known as the provocative cause for the production of motion sickness for centuries, it is only within the last 20 yr that the source of the signal generating motion sickness and its neural basis has been firmly established. Here, we briefly review the source of the conflicts that cause the body to generate the autonomic signs and symptoms that constitute motion sickness and provide a summary of the experimental data that have led to an understanding of how motion sickness is generated and can be controlled. Activity and structures that produce motion sickness include vestibular input through the semicircular canals, the otolith organs, and the velocity storage integrator in the vestibular nuclei. Velocity storage is produced through activity of vestibular-only (VO) neurons under control of neural structures in the nodulus of the vestibulo-cerebellum. Separate groups of nodular neurons sense orientation to gravity, roll/tilt, and translation, which provide strong inhibitory control of the VO neurons. Additionally, there are acetylcholinergic projections from the nodulus to the stomach, which along with other serotonergic inputs from the vestibular nuclei, could induce nausea and vomiting. Major inhibition is produced by the GABAB receptors, which modulate and suppress activity in the velocity storage integrator. Ingestion of the GABAB agonist baclofen causes suppression of motion sickness. Hopefully, a better understanding of the source of sensory conflict will lead to better ways to avoid and treat the autonomic signs and symptoms that constitute the syndrome.

Cooperation of the vestibular and cerebellar networks in anxiety disorders and depression.

The discipline of affective neuroscience is concerned with the neural bases of emotion and mood. The past decades have witnessed an explosion of research in affective neuroscience, increasing our knowledge of the brain areas involved in fear and anxiety. Besides the brain areas that are classically associated with emotional reactivity, accumulating evidence indicates that both the vestibular and cerebellar systems are involved not only in motor coordination but also influence both cognition and emotional regulation in humans and animal models. The cerebellar and the vestibular systems show the reciprocal connection with a myriad of anxiety and fear brain areas. Perception anticipation and action are also major centers of interest in cognitive neurosciences. The cerebellum is crucial for the development of an internal model of action and the vestibular system is relevant for perception, gravity-related balance, navigation and motor decision-making. Furthermore, there are close relationships between these two systems. With regard to the cooperation between the vestibular and cerebellar systems for the elaboration and the coordination of emotional cognitive and visceral responses, we propose that altering the function of one of the systems could provoke internal model disturbances and, as a result, anxiety disorders followed potentially with depressive states.

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.

Bipolar disorder in the balance.

Bipolar disorder (BD) is a severe mood disorder that lacks established electrophysiological, neuroimaging or biological markers to assist with both diagnosis and monitoring disease severity. This study's aim is to describe the potential of new neurophysiological features assistive in BD diagnosis and severity measurement utilizing the recording of electrical activity from the outer ear canal called Electrovestibulography (EVestG). From EVestG data sensory vestibulo-acoustic features were extracted from a single supine-vertical translation stimulus to distinguish 50 depressed and partly remitted/remitted bipolar disorder patients [18 symptomatic (BD-S, MADRS > 19), 32 reduced symptomatic (BD-R, MADRS ≤ 19)] and 31 age and gender matched healthy individuals (controls). Six features were extracted from the measured firing pattern interval histogram and the extracted shape of the average field potential response. Five of the six features had low but significant correlations (p < 0.05) with the MADRS assessment. Using leave-one-out-cross-validation, unbiased parametric and non-parametric classification routines resulted in 75-79%, 84-86%, 76-85% and 79-82% accuracy for separation of control from BD, BD-S and BD-R as well as BD-S from BD-R groups, respectively. The main limitation of this study was the inability to fully disentangle the impact of prescribed medication from the responses recorded. A mix of stationary and movement evoked EVestG features produced good discrimination between control and BD patients whether BD-S or BD-R. Moreover, BD-S and BD-R appear to have measurably different pathophysiological manifestations. The firing pattern features used were dissimilar to those observed in a prior major depressive disorder study.

Sensory overload and imbalance: Resting-state vestibular connectivity in PTSD and its dissociative subtype.

BACKGROUND: The vestibular system integrates multisensory information to monitor one's bodily orientation in space, and is influenced by interoceptive awareness. Post-traumatic stress disorder (PTSD) involves typically alterations in interoceptive and bodily self-awareness evidenced by symptoms of hyperarousal, as well as of emotional detachment, including emotional numbing, depersonalization, and derealization. These alterations may disrupt vestibular multisensory integration between the brainstem (vestibular nuclei) and key vestibular cortical regions (parieto-insular vestibular cortex, prefrontal cortex). Accordingly, this study examined functional connectivity of the vestibular system in PTSD and its dissociative subtype. METHODS: Using resting-state fMRI data in SPM12 and PickAtlas, a seed-based analysis was employed to examine vestibular nuclei functional connectivity differences among PTSD (n = 60), PTSD dissociative subtype (PTSD + DS, n = 41) and healthy controls (n = 40). RESULTS: Increased vestibular nuclei functional connectivity with the parieto-insular vestibular cortex and the dorsolateral prefrontal cortex (dlPFC) was observed in PTSD and in controls as compared to PTSD + DS, and greater connectivity with the posterior insula was observed in controls as compared to PTSD. Interestingly, whereas PTSD symptom severity correlated negatively with dlPFC connectivity, clinical measures of depersonalization/derealization correlated negatively with right supramarginal gyrus connectivity. DISCUSSION: Taken together, decreased vestibular nuclei functional connectivity with key cortical vestibular regions in the PTSD + DS as compared to PTSD group, and its negative correlations with PTSD and dissociative symptoms, suggest that dysregulation of vestibular multisensory integration may contribute to the unique symptom profiles of each group. Further research examining disruption of vestibular system neural circuitry in PTSD and its dissociative subtype will be critical in capturing the neurophenomenology of PTSD symptoms and in identifying psychotherapeutic techniques that target dysfunction related to the vestibular system.

Impact of a simulated gravity load for atmospheric reentry, 10 g for 2 min, on conscious mice.

The Japan Aerospace Exploration Agency recently performed a mouse experiment in the International Space Station in which mice were raised for 35 days, retrieved using the Dragon spacecraft, and then harvested for analysis 2 days after splashdown. However, the impact of the retrieval procedure, which exposed mice to 5-10 g for 2 min during atmospheric reentry and splashdown, was unknown. Therefore, the purpose of this study was to examine the impact of a 10 g load for 2 min (using a gondola-type centrifuge with a 1.5-m arm installed at Gifu University) on conscious mice. Plasma corticosterone increased at 30 min after load application and recovered at 90 min. Significant Fos expression was observed in the vestibular nuclei (VeN), paraventricular hypothalamic nucleus (PVN), and central nucleus of the amygdala (CeA). Rearing behavior and food intake were suppressed. Mice with vestibular lesions demonstrated increased corticosterone and Fos expression in the PVN, but neither suppression of food intake and rearing behavior nor increased Fos expression in the VeN and CeA. These results suggest that the simulated gravity load induced a transient stress response, hypoactivity, and a vestibular-mediated suppression of food intake.

Compensation of Vestibular Function and Plasticity of Vestibular Nucleus after Unilateral Cochleostomy.

Dizziness and vertigo frequently occur after cochlear implantation (CI) surgery, particularly during the early stages. It could recover over time but some of the patients suffered from delayed or sustained vestibular symptoms after CI. This study used rat animal models to investigate the effect of unilateral cochleostomy on the vestibular organs over time. Twenty-seven Sprague Dawley rats underwent cochleostomy to evaluate the postoperative changes in hearing threshold, gain and symmetry of the vestibular ocular response, overall balance function, number of hair cells in the crista, and the c-Fos activity in the brainstem vestibular nucleus. Loss of vestibular function was observed during the early stages, but function recovered partially over time. Histopathological findings demonstrated a mild decrease in vestibular hair cells numbers. Increased c-Fos immunoreactivity in the vestibular nucleus, observed in the early stages after cochleostomy, decreased over time. Cochleostomy is a risk factor for peripheral vestibular organ damage that can cause functional impairment in the peripheral vestibular organs. Altered vestibular nucleus activity may be associated with vestibular compensation and plasticity after unilateral cochleostomy.

Modulation of central nystagmus by vision, proprioception, and efference copy signals: a systematic evaluation.

Non-vestibular sensorimotor signals modulate the vestibular nucleus neuron to achieve current behavioral goals, and may generate or modulate nystagmus. In central lesions affecting the vestibular nuclei, non-vestibular signals such as mastication or swallowing may induce nystagmus. However, the influence of non-vestibular signals on these types of nystagmus has not been investigated in a systematic way and the underlying mechanisms of the modulation are poorly understood. In this study, several non-vestibular sensorimotor stimuli were applied to evaluate the patterns of nystagmus modulation in a patient with suspected rhombencephalitis or imaging negative small infarction, probably involving the left dorsolateral medulla. The nystagmus was induced or significantly modulated by (1) visual inputs, and (2) combined proprioceptive and efference copy signals (during voluntary motion) unrelated to body or head orientation. In contrast, isolated proprioceptive signal, mental set, or non-proprioceptive somatosensory inputs showed a negligible effect on the induction of nystagmus. Based on these modulations, we suggest that (1) the visually mediated nystagmus is due to a lesion-induced pursuit asymmetry, and (2) the nystagmus induced during voluntary motion is due to erroneous contribution of combined proprioceptive and efference copy signals during integration of non-vestibular signals for ocular motor control. Various non-vestibular sensorimotor stimulations may induce nystagmus due to dysfunction of the central vestibular neural circuity.

ACTION OF NEW 3-HYDROXYPYRIDINE DERIVATIVES WITH ANTI-NAUPATHIA PROPERTIES ON CENTRAL NEURONS.

Experiments with cats showed that microinjections into the lung of new 3-hydroxypyridine derivatives SK-119 and IBKhF-27 had a direct action on 50 and 84 % of medial vestibular nucleus (MVN) neurons respectively. The inhibitory response to the compounds was observed 6 and 25 times more frequently than exciting; inhibition by IBKhF-27 was observed 1.9 times more frequently than by SK-119. Also, microinjections of SK-1 19 and IBKhF-27 acted directly on 44 % and 81 % of cat's Purkinje cells, respectively. In case of Purkinje cells, the inhibitory reaction was seen 5.5 and 25 times oftener than exciting, respectively, and inhibition by IBKhF-27 occurred 2.1 times more frequently than by SK-119. Investigations of rat's cerebellum sections evidenced that 5 mM of IBKhF-27 inhibited population responses of Purkinje cells 95 1 3 %. In the presence of specific noncompetitive NMDA-receptor antagonist (MK-801, 100 pM) the depressive effect was annulled almost fully by 96 * 2 %. It follows that IBKhF-27 nearly entirely inhibits synaptic transmission from cerebellar parallel fibers to Purkinje cells, while MK-801 has a similarly strong anti-depression effect that testifies the involvement of the NMDA-receptor complex predominantly.

AVP modulation of the vestibular nucleus via V1b receptors potentially contributes to the development of motion sickness in rat.

BACKGROUND: Arginine vasopressin (AVP) is considered to be an etiologic hormone in motion sickness (MS). The present study was designed to investigate whether individual differences in AVP expression in the paraventricular nucleus (PVN) and in modulation on the vestibular nucleus (VN) are involved in MS. Systemic application or microinjection of AVP into rat VN and rotatory stimulus were used to induce conditioned taste aversion (CTA) to 0.15 % saccharin sodium solution as a model of MS. RESULTS: Intra-VN use of SSR149415, an antagonist of V1b receptors (V1bRs), blunted CTA. AVP inhibited Ca(2+) influxes through L-type Ca(2+) channels and NMDA receptor channels in cultured VN neurones, but antagonised by SSR149415. More AVP and V1bRs were expressed respectively in the PVN and VN after rotatory stimulus, especially in rats susceptible to MS. In the VN, AVP content was low, the AVP mRNA was less expressed, a few AVP-positive fibres were sparsely distributed, and fewer AVP/synaptophysin-positive terminals were identified. Almost no fluoro-ruby-labelled AVP-positive neurones in the PVN were found with retrograde tracing from the VN. SNP analysis of the reported 9 sites of the AVP gene showed significant difference between the groups susceptible and insusceptible to MS at the site rs105235842 in the allele frequencies and genotypes. However, there was not any difference between these two groups in the SNP of the reported 38 sites of V1bR gene. CONCLUSIONS: AVP, through its modulatory, possibly humoral action on the VN neurones via the mediation of V1bR, may contribute to the development of motion sickness in rats; AVP gene polymorphisms may contribute to the individual difference in the responsive expression of AVP in the PVN; and higher expressions of AVP in the PVN and V1bRs in the VN may contribute to the development of motion sickness in rats after vestibular stimulation.

Unilateral horizontal semicircular canal occlusion induces serotonin increase in medial vestibular nuclei: a study using microdialysis in vivo coupled with HPLC-ECD.

Unilateral single semicircular canal occlusion (USSCO) is an effective treatment for some cases of intractable vertigo. All patients suffer behavioural imbalance caused by surgery, and then recover with a resumption of vestibular function. However, the compensation mechanism has not been fully evaluated. Findings suggest that serotonin (5-HT) is released from nerve terminals, and plays a vital role in the plasticity of the central nervous system. In this study, we performed surgery of unilateral single semicircular canal occlusion (USSCO) on guinea pigs, and investigated the change of 5-HT by in vivo microdialysis of the medial vestibular nucleus (MVN) coupled with high-performance liquid chromatography and electrochemical detection (HPLC-ECD). A total of 12 guinea pigs were divided randomly into two groups, namely the USSCO group and the control group. Animals in the USSCO group underwent surgery of lateral horizontal semicircular canal occlusion, and those in the control group experienced the same operation but just to expose the horizontal semicircular canal without occlusion. Vestibular disturbance symptoms were observed in the case of the USSCO group, e.g. head tilting, and forced circular movements and spontaneous nystagmus at postoperative days 1 and 3. The basal level of 5-HT was determined to be 316.78 ± 16.62 nM. It elevated to 448.85 ± 24.56 nM at one day following occlusion (P = 0.001). The increase was completely abolished with the vestibular dysfunction recovery. The results showed that unilateral horizontal semicircular canal occlusion could increase the 5-HT level in MVN. 5-HT may play a significant role in the process of central vestibular compensation with residual vestibular function.

Vestibular Performance During High-Acceleration Stimuli Correlates with Clinical Decline in SCA6.

In spinocerebellar ataxia type 6 (SCA6), the vestibular dysfunction and its correlation with other clinical parameters require further exploration. We determined vestibular responses over a broad range of stimulus acceleration in 11 patients with SCA6 (six men, age range=33-72 years, mean age±SD=59±12 years) using bithermal caloric irrigations, rotary chair, and head impulse tests. Correlations were also pursued among disability scores, as measured using the International Cooperative Ataxia Rating Scale, disease duration, age at onset, cytosine-adenine-guanine (CAG) repeat length, and the gain of the vestibulo-ocular reflex (VOR). In response to relatively low-acceleration, low-frequency rotational and bithermal caloric stimuli, the VOR gains were normal or increased regardless of the severity of disease. On the other hand, with relatively high-acceleration, high-frequency head impulses, there was a relative increase in gain in the mildly affected patients and a decrease in gain in the more severely affected patients and gains were negatively correlated with the severity of disease (Spearman correlation, R=-0.927, p<0.001). Selective decrease of the vestibular responses during high-acceleration, high-frequency stimuli may be ascribed to degeneration of either the flocculus or vestibular nuclei. The performance of the VOR during high-acceleration, high-frequency head impulses may be a quantitative indicator of clinical decline in SCA6.

Decreased calcium-activated potassium channels by hypoxia causes abnormal firing in the spontaneous firing medial vestibular nuclei neurons.

Vertebrobasilar insufficiency (VBI) presents complex varied clinical symptoms, including vertigo and hearing loss. Little is known, however, about how Ca(2+)-activated K(+) channel attributes to the medial vestibular nucleus (MVN) neural activity in VBI. To address this issue, we performed whole-cell patch clamp and quantitative polymerase chain reaction (qPCR) to examine the effects of hypoxia on neural activity and the changes of the large conductance Ca(2+) activated K(+) channels (BKCa channels) in the MVN neurons in brain slices of male C57BL/6 mice. Brief hypoxic stimuli of the brain slices containing MVN were administrated by switching the normoxic artificial cerebrospinal fluid (ACSF) equilibrated with 21% O2/5% CO2 to hypoxic ACSF equilibrated with 5% O2/5% CO2 (balance N2). 3-min hypoxia caused a depolarization in the resting membrane potential (RM) in 8/11 non-spontaneous firing MVN neurons. 60/72 spontaneous firing MVN neurons showed a dramatic increase in firing frequency and a depolarization in the RM following brief hypoxia. The amplitude of the afterhyperpolarization (AHPA) was significantly decreased in both type A and type B spontaneous firing MVN neurons. Hypoxia-induced firing response was alleviated by pretreatment with NS1619, a selective BKCa activator. Furthermore, brief hypoxia caused a decrease in the amplitude of iberiotoxin-sensitive outward currents and mRNA level of BKCa in MVN neurons. These results suggest that BKCa channels protect against abnormal MVN neuronal activity induced by hypoxia, and might be a key target for treatment of vertigo and hearing loss in VBI.