Course Of Vestibular Compensation Research Articles

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.

Vestibular Compensation after Vestibular Dysfunction Induced by Arsanilic Acid in Mice.

When vestibular function is lost, vestibular compensation works for the reacquisition of body balance. For the study of vestibular dysfunction and vestibular compensation, surgical or chemical labyrinthectomy has been performed in various animal species. In the present study, we performed chemical labyrinthectomy using arsanilic acid in mice and investigated the time course of vestibular compensation through behavioral observations and histological studies. The surgical procedures required only paracentesis and storage of 50 µL of p-arsanilic acid sodium salt solution in the tympanic cavity for 5 min. From behavioral observations, vestibular functions were worst at 2 days and recovered by 7 days after surgery. Spontaneous nystagmus appeared at 1 day after surgery with arsanilic acid and disappeared by 2 days. Histological studies revealed specific damage to the vestibular endorgans. In the ipsilateral spinal vestibular nucleus, the medial vestibular nucleus, and the contralateral prepositus hypoglossal nucleus, a substantial number of c-Fos-immunoreactive cells appeared by 1 day after surgery with arsanilic acid, with a maximum increase in number by 2 days and complete disappearance by 7 days. Taken together, these findings indicate that chemical labyrinthectomy with arsanilic acid and the subsequent observation of vestibular compensation is a useful strategy for elucidation of the molecular mechanisms underlying vestibular pathophysiologies.

EPV 20. Vascular encephalopathy is a major risk factor for poor vestibular compensation

Background and aim Acute unilateral vestibular loss leads to vertigo sensation, nystagmus and postural imbalance. As a rule, a behavioral recovery of the signs and symptoms follows over days to months due to central vestibular compensation (VC). The present study aimed to investigate the influence of cerebral vascular lesions on VC by following a large cohort of patients after vestibular neuritis. Methods 235 patients (mean age: 54.2 ± 15.2, 53.4% men) with the clinical picture or history of an acute unilateral vestibulopathy, who were seen at the Department of Neurology and the German Center for Vertigo and Balance Disorders over the last 10 years, were included in the study. All patients underwent a detailed neuro-ophthalmological and neurological examination, including measures of the subjective visual vertical (SVV), ocular torsion (OT), head impulse test (HIT), provocation nystagmus (PN), visual acuity and postural control and were followed along their course of VC (mean number of visits 3.5 ± 1.2, mean time of follow-up 217 ± 625 days). In all patients a cranial MRI was available at onset of vestibular failure. The MRI was assessed by a two senior neuro-radiologist. Extent of supra- and infratentorial vascular white matter lesions was classified by the ARWMC scale (0–3 points). Strategic lesions in the vestibular network (medulla, vestibulocerebellum, thalamus) were registered separately. Patients were indicated as poorly compensated, if deviation of SVV (>2.5°), PN and postural asymmetry persisted for longer than 3 months after vestibular failure. Results 13.3% of patients were classified as poorly compensated at 3 months (PN: 55%, SVV deviation: 36%, postural asymmetry: 22%), 12.8% at 6 months and 10.6% at 12 months after acute unilateral vestibulopathy. These patients had significantly higher ARWMC scales as compared to patients with regular VC ( p Conclusions About 10% of patients have an impeded course of VC after acute unilateral vestibulopathy. Supratentorial vascular encephalopathy is a major risk factor for poor VC and should be considered to guide the intensity of physical treatment following acute unilateral vestibulopathy.

Contribution of vestibular efferent system alpha-9 nicotinic receptors to vestibulo-oculomotor interaction and short-term vestibular compensation after unilateral labyrinthectomy in mice

Sudden unilateral loss of vestibular afferent input causes nystagmus, ocular misalignment, postural instability and vertigo, all of which improve significantly over the first few days after injury through a process called vestibular compensation (VC). Efferent neuronal signals to the labyrinth are thought to be required for VC. To better understand efferent contributions to VC, we compared the time course of VC in wild-type (WT) mice and α9 knockout (α9−/−) mice, the latter lacking the α9 subunit of nicotinic acetylcholine receptors (nAChRs), which is thought to represent one signaling arm activated by the efferent vestibular system (EVS). Specifically, we investigated the time course of changes in the fast/direct and slow/indirect components of the angular vestibulo-ocular reflex (VOR) before and after unilateral labyrinthectomy (UL). Eye movements were recorded using infrared video oculography in darkness with the animal stationary and during sinusoidal (50 and 100°/s, 0.5–5Hz) and velocity step (150°/s for 7–10s, peak acceleration 3000°/s2) passive whole-body rotations about an Earth-vertical axis. Eye movements were measured before and 0.5, 2, 4, 6 and 9 days after UL. Before UL, we found frequency- and velocity-dependent differences between WT and α9−/− mice in generation of VOR quick phases. The VOR slow phase time constant (TC) during velocity steps, which quantifies contributions of the indirect component of the VOR, was longer in α9−/− mutants relative to WT mice. After UL, spontaneous nystagmus (SN) was suppressed significantly earlier in WT mice than in α9−/− mice, but mutants achieved greater recovery of TC symmetry and VOR quick phases. These data suggest (1) there are significant differences in vestibular and oculomotor functions between these two types of mice, and (2) efferent signals mediated by α9 nicotinic AChRs play a role during VC after UL.

Neural substrates underlying vestibular compensation: Contribution of peripheral versus central processing

The vestibulo-ocular reflex (VOR), which functions to stabilize gaze and ensure clear vision during everyday activities, shows impressive adaptation in response to environmental requirements. In particular, the VOR exhibits remarkable recovery following the loss of unilateral labyrinthine input as a result of injury or disease. The relative simplicity of the pathways that mediate the VOR, make it an excellent model system for understanding the changes (learning) that occur in the brain following peripheral vestibular loss to yield adaptive changes. This mini review considers the findings of behavioral, single unit recording and lesion studies of VOR compensation. Recent experiments have provided evidence that the brain makes use of multiple plasticity mechanisms (i.e., changes in peripheral as well as central processing) during the course of vestibular compensation to accomplish the sensory-motor transformations required to accurately guide behavior.

Oculomotor Plasticity During Vestibular Compensation Does Not Depend on Cerebellar LTD

Vestibular paradigms are widely used for investigating mechanisms underlying cerebellar motor learning. These include adaptation of the vestibuloocular reflex (VOR) after visual-vestibular mismatch training and vestibular compensation after unilateral damage to the vestibular apparatus. To date, various studies have shown that VOR adaptation may be supported by long-term depression (LTD) at the parallel fiber to Purkinje cell synapse. Yet it is unknown to what extent vestibular compensation may depend on this cellular process. Here we investigated adaptive gain changes in the VOR and optokinetic reflex during vestibular compensation in transgenic mice in which LTD is specifically blocked in Purkinje cells via expression of a peptide inhibitor of protein kinase C (L7-PKCi mutants). The results demonstrate that neither the strength nor the time course of vestibular compensation are affected by the absence of LTD. In contrast, analysis of vestibular compensation in spontaneous mutants that lack a functional olivo-cerebellar circuit (lurchers) shows that this form of motor learning is severely impaired. We conclude that oculomotor plasticity during vestibular compensation depends critically on intact cerebellar circuitry but not on the occurrence of cerebellar LTD.

Rapid vestibular compensation in guinea pig even with prolonged anesthesia

The results of previous studies have suggested that prolonged anesthesia following unilateral labyrinthectomy (UL) results in a retardation of vestibular compensation, the process of behavioral recovery that occurs following the lesion. In this study we investigated the effects of short-term (25 min) and long-term (4 h) anesthesia with isoflurane on the time course of vestibular compensation following UL in guinea pig. Although there were significant differences in the frequency of spontaneous nystagmus (SN) ( p < 0.05) and its rate of compensation ( p < 0.05) between the 25 min and 4 h isoflurane groups, these differences appeared to be due largely to the 5, 9 and 13 h time points. There was also a significant difference in the rate of yaw head tilt (YHT) compensation, largely due to the 5 h time point. When exponential regression analysis was performed to evaluate the overall pattern of compensation, there was no significant difference in the time required to reach 100% SN or YHT compensation between the 25 min and 4 h isoflurane groups. Furthermore, there were no significant differences in roll head tilt (RHT) compensation between the two groups. These results suggest that the time course of vestibular compensation is largely independent of the duration of the anesthesia used for UL surgery.

Idiosyncratic compensation of the subjective visual horizontal and vertical in 60 patients after unilateral vestibular deafferentation

ObjectiveTo investigate long-term compensation mechanisms of utricular function after translabyrinthine surgery for vestibular schwannoma. Correlations between the subjective visual horizontal (SVH) and subjective visual vertical (SVV) and other parameters of vestibular compensation were studied. The correlation between the SVH and SVV was also investigated to see whether these measurements are compatible for patients.Material and MethodsSixty consecutive patients were investigated 3 months before and 6 months after surgery by means of electronystagmography and SVH and SVV tests. Tumor size was measured using MRI.ResultsThe SVH and SVV increased significantly towards the ipsilesional side postoperatively. Preoperative tilt correlated with age. Postoperative tilt correlated weakly with preoperative caloric sensitivity and inversely with tumor size. The correlation between the SVH and SVV was high both before and after surgery (rs>0.74; p<0.001).ConclusionsThe long-term compensation of static tilt perception was dependent on age and not on dynamic canal functions. We propose an idiosyncrasy in the SVH and SVV compensation after unilateral vestibular deafferentation, incongruous with the general course of vestibular compensation. The results suggest a probable dependence on non-vestibular information, i.e. proprioception, in facilitating compensation of static vestibular deficits. The similarity between the SVH and SVV measurements confirms that either test can be used clinically for patients with vestibular lesions.

Plasticity of GABA(a) system during ageing: focus on vestibular compensation and possible pharmacological intervention

The lesion of the vestibular end organ evokes static and dynamic symptoms, which spontaneously regress during a complex process known as ‘vestibular compensation’. Vestibular compensation is age-dependent and involves several transmitter-identified pathways in the central nervous system. In this paper we studied the time course of vestibular compensation in adult (3 months) and old (24 months) rats and correlated behavioral recovery with modifications of glutamic acid decarboxylase (GAD) mRNA expression and benzodiazepine receptor density in different brain areas. Compensation in adult rats was complete 28 days after hemilabyrinthectomy, whereas old rats still showed significant behavioral impairment. A higher GABAergic tone was found in old rats, as indicated by higher benzodiazepine receptor density in lateral vestibular nucleus and higher mRNA level for glutamic acid decarboxylase in cerebral cortex and medial vestibular nucleus. In adult, compensated rats, benzodiazepine receptor density in the vestibular nuclei was normal 28 days after lesion, whereas GAD mRNA level was higher in anterior cingulate cortex, only. On the contrary, these parameters were still altered in anterior cingulate and somatosensory cortex, basal ganglia, vestibular nuclei and cerebellum in old rats 28 days after vestibular lesion. We also evaluated the effect of the ergoline derivative nicergoline on behavioral and neurochemical correlates of vestibular compensation in old rats. Nicergoline treatment attenuated the severity of oculomotor and postural symptoms after vestibular lesion and reversed most of these age- and lesion-induced alterations in GAD mRNA expression. Thus, lesion-related alterations of the GABAergic transmission and behavioral profile after vestibular lesion are age-dependent.

Temporal changes of cFos-like protein expression in medial vestibular nuclei following arsanilate-induced unilateral labyrinthectomy in rats

The compensation of spontaneous nystagmus and head deviation following chemical unilateral labyrinthectomy (UL) induced by arsanilate was delayed compared with surgical UL. Surgical UL produced two phases of significant asymmetry of cFos-like (cFL) protein expression between the bilateral medial vestibular nuclei, with more expression in the contralateral medial vestibular nuclei to the injured side than in the ipsilateral medial vestibular nuclei 2 h after UL; the pattern reversed after 6 h and expression disappeared after 72 h. Chemical UL produced three phases of asymmetric expression, with more cFL protein expression in the contralateral medial vestibular nuclei than in the ipsilateral medial vestibular nuclei 6 h after UL and a reversed pattern after 12 h. Asymmetric expression 72 h after UL followed increased expression in the contralateral medial vestibular nuclei. These results suggest that the course of vestibular compensation and the temporal expression of cFL protein in the medial vestibular nuclei following UL differed between surgical and chemical labyrinthectomy.

VESTIBULAR COMPENSATION IN AGED RATS WITH UNILATERAL LABYRINTHECTOMY TREATED WITH DOPAMINERGIC DRUGS

Drugs acting as agonists (SKF38393 and quinpirol) or antagonists (SCH23390 and sulpiride) on dopamine receptors were administered at various doses (1, 2 or 4mgkg −1day −1) to aged male rats of the Sprague–Dawley strain subjected to labyrinth unilateral lesion. The time course of vestibular compensation was evaluated by recording spontaneous eye nystagmus and by scoring ambulation and rearing with the open field test and motor ability and coordination with the rotorod test. Treatment started 3 days prior to surgery and continued until day 7 after surgery. The vestibular compensation of untreated young male rats was also studied with the same methods. The decline of spontaneous nystagmus in aged animals was slower than that of young rats and was facilitated by the large doses of quinpirol (D2 receptor agonist) and inhibited by sulpiride (D2 receptor antagonist) 4mgkg −1day −1, while the other drugs did not affect this parameter. After operation, ambulation and rearing of aged rats increased more slowly as compared to that of young animals. Moreover, motor performance and coordination in aged rats improved less rapidly than those of young controls. Dopamine receptor agonists increased ambulation and improved motor performance and coordination in aged rats, while dopamine receptor antagonists exerted opposite effects. Rearing was not affected by any kind of drug treatment. These results suggest that dopamine neurotransmission plays a role in vestibular compensation process following unilateral labyrinthectomy in aged animals, and this may have clinical relevance in vestibular pathologies of peripheral origin that are associated to brain ageing.

Effects of flunarizine on ocular motor and postural compensation following peripheral vestibular deafferentation in the guinea pig

The aim of the present study was to determine if the calcium channel antagonist flunarizine would affect the time course of vestibular compensation for unilateral labyrinthectomy (UL) in guinea pigs. Animals received either a single IP injection of flunarizine 1 h pre-UL or a series of IP injections every 6 h for 24 h post-UL, starting at 6 h post-UL. Flunarizine was dissolved in 50−100% DMSO or suspended in 10% Tween-80 and administered at a dose of 10 mg/kg in the pre-UL condition.and 10 or 20 mg/kg in the post-UL condition. All injections were 1 ml/kg in volume. Spontaneous nystagmus (SN), yaw head tilt (YHT), and roll head tilt (RHT) were measured using video analysis. When dissolved in DMSO and administered 1 h prr-UL, 10 mg/kg flunarizine had a small but significant effect on the rate of RHT compensation; otherwise, flunarizine had no significant effects on SN, YHT, or RHT when dissolved in DMSO. When suspended in Tween-80, 10 mg/kg flunarizine pre-UL resulted in a significant decrease in SN frequency and YHT relative to the control group, although the magnitude of the differences was small. When 20 mg/kg was given post-UL, both SN and YHT showed a small but significant change in the rate of compensation. No significant differences in RHT were observed. These results demonstrate that IP administration of flunarizine at a dose o 10−20 mg/kg IP has little effect on vestibular compensation compared to the effects obtained with low IM doses (0.8 mg/kg) of verapamil given 1 h pre-UL.

Neurochemical changes in the cholinergic system of the rat lateral vestibular nucleus following hemilabyrinthectomy

The neurochemistry of the cholinergic system in the lateral vestibular nucleus (LVN) of the hemilabyrinthectomized rat was studied in view of the previous findings of other research showing that the process of vestibular compensation (VC) following hemilabyrinthectomy can be influenced by the administration of cholinergic agents. At 15 min, 2 h, and 7 days after right hemilabyrinthectomy, animals were killed and the LVNs were removed from sections of the brain stem for various neurochemical measurements. The content of acetylcholine (ACh) and the activity of acetylcholinesterase in the LVN showed no significant changes at any time interval. In contrast, choline acetyltransferase activity decreased slightly in the nucleus on the unoperated side 15 min after the operation. These findings possibly implicate alterations in ACh synthesis in the LVN at an early stage of VC. However, there was no significant alteration in either high-affinity choline transport into the LVN or ACh release from the LVN 15 min after the operation. Furthermore, muscarinic ACh-receptor binding also showed no significant changes. These results suggest that the possible alterations in the function of cholinergic synapses in the course of VC indicated by previous pharmacological studies may take place in regions of the brain other than the LVN.

Dynamic characteristics of vestibular nuclear neurons responses to vestibular and optokinetic stimulation during vestibular compensation in the rat.

In albino rats and pigmented rats, neurons were recorded extracellularly in the vestibular nuclei during the first 2 weeks after unilateral labyrinthectomy in order to study the neuronal events occurring during vestibular compensation and the effect of unilateral vestibular lesion on the optokinetic responses of neurons in the vestibular nuclei. It was found in albino rats that a re-equilibration took place in the gains of type I neurons between both lesioned and intact sides. The gain of the rare type I neurons on the deafferented side, which was low just after the lesion (t less than 48 h) subsequently increased (48 h less than t less than 14 d) while on the intact side the gain was greater just after the lesion, and then decreased. This re-equilibration of the gains of type I neurons is considered to be the neuronal equivalent of behavioural effects which occur after hemilabyrinthectomy. In pigmented rats, most type I and II VN neurons recorded on both sides 24 to 96 h after the lesion did not respond to pure horizontal OKS, while in controls almost all of them responded. It seems evident that the tonic activation of VN neurons by vestibular afferences is necessary for their responsiveness to pure OKS. However, when comparing the gain/phase of their responses to pure, vestibular and combined optokinetic-vestibular stimulations, it was found that optokinetic inputs improved the performance of type I and II VN neurons on both lesioned and intact sides. Finally, the time course of vestibular compensation is shorter in pigmented rats than in albino rats, since the re-equilibration in gains between the two sides was already reached 4 days after the lesion in the former.