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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Vestibular nucleus neurons respond to hindlimb movement in the decerebrate cat.

The vestibular nuclei integrate information from vestibular and proprioceptive afferents, which presumably facilitates the maintenance of stable balance and posture. However, little is currently known about the processing of sensory signals from the limbs by vestibular nucleus neurons. This study tested the hypothesis that limb movement is encoded by vestibular nucleus neurons and described the changes in activity of these neurons elicited by limb extension and flexion. In decerebrate cats, we recorded the activity of 70 vestibular nucleus neurons whose activity was modulated by limb movements. Most of these neurons (57/70, 81.4%) encoded information about the direction of hindlimb movement, while the remaining neurons (13/70, 18.6%) encoded the presence of hindlimb movement without signaling the direction of movement. The activity of many vestibular nucleus neurons that responded to limb movement was also modulated by rotating the animal's body in vertical planes, suggesting that the neurons integrated hindlimb and labyrinthine inputs. Neurons whose firing rate increased during ipsilateral ear-down roll rotations tended to be excited by hindlimb flexion, whereas neurons whose firing rate increased during contralateral ear-down tilts were excited by hindlimb extension. These observations suggest that there is a purposeful mapping of hindlimb inputs onto vestibular nucleus neurons, such that integration of hindlimb and labyrinthine inputs to the neurons is functionally relevant.

A dynamic model for eye-position-dependence of spontaneous nystagmus in acute unilateral vestibular deficit (Alexander's Law).

Spontaneous nystagmus (SN) is a symptom of acute vestibular tone asymmetry. Alexander's Law (AL) states that slow-phase velocity of SN is higher when looking in the direction of fast-phases of nystagmus and lower in the slow-phase direction. Earlier explanations for AL predict that during SN, slow-phase eye velocity is a linear function of eye position, increasing linearly as eye deviates towards the fast-phase direction. Recent observations, however, show that this is often not the case; eye velocity does not vary linearly with eye position. Such new findings necessitate a re-evaluation of our understanding of AL. As AL may be an adaptive response of the vestibular system to peripheral lesions, understanding its mechanism could shed light on early adaptation strategies of the brain. Here, we propose a physiologically plausible mechanism for AL that explains recent experimental data. We use a dynamic control system model to simulate this mechanism and make testable predictions. This mechanism is based on the known effects of unilateral vestibular deficit on the response of the ipsi- and contralesional vestibular nuclei (VN) of the brainstem. This hypothesis is based on the silencing of the majority of ipsilesional VN units, which creates an asymmetry between the responses of the ipsi- and contralesional VN. Unlike former explanations, the new hypothesis does not rely on lesion detection strategies or signals originating in higher brain structures. The proposed model demonstrates possible consequences of acute peripheral deficits for the function of the velocity-to-position neural integrator of the ocular motor system and the vestibulo-ocular reflex.

Gene profiles during vestibular compensation in rats after unilateral labyrinthectomy.

OBJECTIVES: The aims of this study were to determine changes in gene expression in the chronic state of vestibular compensation by microarray analysis and to validate the asymmetrical levels of gene expression in the ipsilateral and contralateral vestibular nucleus complexes (VNCs). METHODS: Microarray analysis was used to examine the expression of genes up-regulated or down-regulated in the ipsilateral VNC at 1 and 7 days after unilateral labyrinthectomy. Up-regulated or down-regulated gene expression in the ipsilateral and contralateral VNCs was then validated by reverse transcriptase polymerase chain reaction at 1, 7, 14, and 28 days after labyrinthectomy. RESULTS: The genes down-regulated at 1 day after labyrinthectomy and up-regulated at 7 days after labyrinthectomy as determined by microarray analysis and reverse transcriptase polymerase chain reaction were zinc finger protein 307, zinc metallopeptidase, P34, calcitonin receptor, insulin-like growth factor binding protein 5, GATA binding protein 3, and CD151. Expression of zinc finger protein 307, zinc metallopeptidase, P34, and calcitonin receptor was up-regulated even after 7 days in the contralateral VNC of rats that had labyrinthectomy. CONCLUSIONS: This study demonstrated changes in gene expression in rats during the chronic phase of vestibular compensation after unilateral labyrinthectomy and provided profiles of these changes in gene expression.

[On the mechanism of antimotion sickness effects of mexidol].

The path-clamp method used within the whole-cell configuration in experiments with convoluted medullar oblongata sections obtained from white mongrel male rats aged 13 to 17 days evidenced that 5 mV of mexidol caused 96 +/- 2% inhibition of the excitation postsynaptic current in neurons of the medial vestibular nucleus generated by the depolarization step of 10 mV (holding potential = -70 my). This means that the antimotion sickness effect of mexidol has its origin in the ion mechanisms with involvement of the glutamate- and GABAergic components, primarily inhibition of ion currents through channels of the NMDA-receptor complex.

An ipsilateral vestibulothalamic tract adjacent to the medial lemniscus in humans.

We examined 14 patients with acute anteromedial pontomesencephalic infarctions for signs of vestibular and ocular motor dysfunction. In all cases, an isolated ipsilateral deviation of the subjective visual vertical (mean: 4.1, range: 2.7- 6.6) was found without any further signs of vestibular or eye movement disorders like ocular torsion or skew deviation. Distinct lesions in thin-slice brainstem MRI showed an overlap zone in the medial portion of the medial lemniscus. The finding of putative ipsilateral vestibular projections running adjacent to or within the medial lemniscus was subsequently confirmed by a reanalysis of an anterograde tracer labelling study in the primate after tracer injection in the vestibular nucleus complex. The major conclusions of this study are as follows: (i) there is evidence for an ipsilateral graviceptive pathway running from the vestibular nuclei close to and within the medial lemniscus to the posterolateral thalamus [ipsilateral vestibulothalamic tract (IVTT)], (ii) this pathway might be the human homologue of the three-neuron sensory vestibulocortical tract described in primates and (iii) unilateral lesions of this pathway cause only vestibulo-perceptive dysfunction in the roll plane in contrast to lesions of the crossed graviceptive pathways (in the medial longitudinal fascicle), which were described earlier and which manifest as a combination of tilt of the subjective visual vertical, ocular torsion and skew deviation.

Ten-year longitudinal study of the effect of impulse noise exposure from gunshot on inner ear function.

This longitudinal study investigated how chronic gunshot noise exposure affects cochlear and saccular function in police officers who engaged in regular target shooting practice using dual protection (ear plugs plus earmuffs) for >10 years. In 1997, 20 male police officers underwent audiometry before and two weeks after shooting. Twelve of the original subjects were re-examined by audiometry coupled with vestibular evoked myogenic potential (VEMP) test in 2007. Significant deterioration of mean hearing thresholds at frequencies of 500 Hz through 4000 Hz was noted ten years later, affecting both ears. However, only the frequencies of 4000 and 6000 Hz on the left ear revealed significant difference in mean hearing thresholds compared with healthy controls. Abnormal VEMP responses were evident in nine police officers (75%), including absent VEMPs 7 and delayed VEMPs 2. In conclusion, deterioration to hearing may occur after long term exposure to gunshots, even when double hearing protection is used. Further study is in progress regarding how to preserve both cochlear and saccular function during long term gunshot exposure.

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.

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.

Synaptic protein expression in the medial temporal lobe and frontal cortex following chronic bilateral vestibular loss.

Several studies have reported that bilateral vestibular deafferentation (BVD) results in the disruption of place cell function and theta activity in the hippocampus. Recent magnetic resonance imaging (MRI) studies in humans demonstrated that bilateral but not unilateral vestibular loss is associated with a bilateral atrophy of the hippocampus. In this study we investigated whether BVD in rats resulted in changes in the expression of four proteins related to neuronal plasticity, synaptophysin, SNAP-25, drebrin and neurofilament-L, in the hippocampal subregions (CA1, CA2/3, the DG) and the entorhinal (EC), perirhinal (PRC) and frontal cortices (FC), using western blotting. At 6 months following BVD, there were no significant differences in the expression of synaptophysin in any region. There were also no significant differences in SNAP-25 expression in CA1, CA2/3, EC, PRC, or the FC; however, there was a significant increase in SNAP-25 expression in the DG compared to sham controls. Drebrin A and E expression was significantly reduced in the EC and drebrin A was significantly reduced in the FC of BVD animals. NF-L expression was not significantly different in CA1, CA2/3, DG, EC, or the PRC. However, its expression was significantly reduced in the FC of BVD animals. These data suggest that circumscribed neurochemical changes in SNAP-25, drebrin and NF-L expression occur in the DG, EC, and the FC over 6 months following BVD.