Unilateral vestibular deafferentation impairs embodied spatial cognition.

A growing number of studies indicate that cognitive complaints are common in patients with peripheral vestibular disorders. A better understanding of how vestibular disorders influence cognition in these patients requires a clear delineation of the cognitive domains affected by vestibular disorders. Here, we compared the consequences of left and right vestibular neurectomy on third-person perspective taking-a visuo-spatial task requiring mainly own-body mental imagery, and on 3D objects mental rotation imagery-requiring object-based mental imagery, but no perspective taking. Patients tested 1 week after a unilateral vestibular neurectomy and a group of age- and gender-matched healthy participants played a virtual ball-tossing game from their own first-person perspective (1PP) and from the perspective of a distant avatar (third-person perspective, 3PP). Results showed larger response times in the patients with respect to their controls for the 3PP taking task, but not for the 1PP task and the 3D objects mental imagery. In addition, we found that only patients with left vestibular neurectomy presented altered 3PP taking abilities when compared to their controls. This study suggests that unilateral vestibular loss affects mainly own-body mental transformation and that only left vestibular loss seems to impair this cognitive process. Our study also brings further evidence that vestibular signals contribute to the sensorimotor bases of social cognition and strengthens the connections between the so far distinct fields of social neuroscience and human vestibular physiology.

Betahistine Treatment in a Cat Model of Vestibular Pathology: Pharmacokinetic and Pharmacodynamic Approaches.

This study is a pharmacokinetic (PK) and pharmacodynamics (PD) approach using betahistine doses levels in unilateral vestibular neurectomized cats (UVN) comparable to those used in humans for treating patients with Menière's disease. The aim is to investigate for the first time oral betahistine administration (0.2 and 2 mg/kg/day) with plasma concentrations of betahistine and its major metabolite 2-pyridylacetic acid (2-PAA) (N = 9 cats), the time course of posture recovery (N = 13 cats), and the regulation of the enzyme synthesizing histamine (histidine decarboxylase: HDC) in the tuberomammillary nuclei (TMN) of UVN treated animals (N = the same 13 cats plus 4 negative control cats). In addition the effect of co-administration of the lower betahistine dose (0.2 mg/kg/day) and selegiline (1 mg/kg/day), an inhibitor of the monamine oxidase B (MAOBi) implicated in betahistine catabolism was investigated. The PK parameters were the peak concentration (Cmax), the time when the maximum concentration is reached (Tmax) for both betahistine and 2-PAA and the area under the curve (AUC). The PD approach consisted at quantifying the surface support area, which is a good estimation of posture recovery. The plasma concentration-time-profiles of betahistine and 2-PAA in cats were characterized by early Cmax-values followed by a phase of rapid decrease of plasma concentrations and a final long lasting low level of plasma concentrations. Co administration of selegiline and betahistine increased values of Cmax and AUC up to 146- and 180-fold, respectively. The lowest dose of betahistine (0.2 mg/kg) has no effects on postural function recovery but induced an acute symptomatic effect characterized by a fast balance improvement (4-6 days). The higher dose (2 mg/kg) and the co-administration treatment induced both this acute effect plus a significant acceleration of the recovery process. The histaminergic activity of the neurons in the TMN was significantly increased under treatment with the 2 mg/kg betahistine daily dose, but not with the lower dose alone or in combination with selegiline. The results show for the first time that faster balance recovery in UVN treated cats is accompanied with high plasma concentrations of betahistine and 2-PAA, and upregulation of HDC immunopositive neurons in the TMN. The higher betahistine dose gives results similar to those obtained with the lower dose when co-administrated with an inhibitor of betahistine metabolism, selegiline. From a clinical point of view, the study provides new perspectives for Menière's disease treatment, regarding the daily betahistine dose that should be necessary for fast and slow metabolizers.

Comparative analysis of pharmacological treatments with N-acetyl-DL-leucine (Tanganil) and its two isomers (N-acetyl-L-leucine and N-acetyl-D-leucine) on vestibular compensation: Behavioral investigation in the cat.

Head roll tilt, postural imbalance and spontaneous nystagmus are the main static vestibular deficits observed after an acute unilateral vestibular loss (UVL). In the UVL cat model, these deficits are fully compensated over 6 weeks as the result of central vestibular compensation. N-Acetyl-dl-leucine is a drug prescribed in clinical practice for the symptomatic treatment of acute UVL patients. The present study investigated the effects of N-acetyl-dl-leucine on the behavioral recovery after unilateral vestibular neurectomy (UVN) in the cat, and compared the effects of each of its two isomers N-acetyl-L-leucine and N-acetyl-D-leucine. Efficacy of these three drug treatments has been evaluated with respect to a placebo group (UVN+saline water) on the global sensorimotor activity (observation grids), the posture control (support surface measurement), the locomotor balance (maximum performance at the rotating beam test), and the spontaneous vestibular nystagmus (recorded in the light). Whatever the parameters tested, the behavioral recovery was strongly and significantly accelerated under pharmacological treatments with N-acetyl-dl-leucine and N-acetyl-L-leucine. In contrast, the N-acetyl-D-leucine isomer had no effect at all on the behavioral recovery, and animals of this group showed the same recovery profile as those receiving a placebo. It is concluded that the N-acetyl-L-leucine isomer is the active part of the racemate component since it induces a significant acceleration of the vestibular compensation process similar (and even better) to that observed under treatment with the racemate component only.

Interaction between Vestibular Compensation Mechanisms and Vestibular Rehabilitation Therapy: 10 Recommendations for Optimal Functional Recovery.

This review questions the relationships between the plastic events responsible for the recovery of vestibular function after a unilateral vestibular loss (vestibular compensation), which has been well described in animal models in the last decades, and the vestibular rehabilitation (VR) therapy elaborated on a more empirical basis for vestibular loss patients. The main objective is not to propose a catalog of results but to provide clinicians with an understandable view on when and how to perform VR therapy, and why VR may benefit from basic knowledge and may influence the recovery process. With this perspective, 10 major recommendations are proposed as ways to identify an optimal functional recovery. Among them are the crucial role of active and early VR therapy, coincidental with a post-lesion sensitive period for neuronal network remodeling, the instructive role that VR therapy may play in this functional reorganization, the need for progression in the VR therapy protocol, which is based mainly on adaptation processes, the necessity to take into account the sensorimotor, cognitive, and emotional profile of the patient to propose individual or "à la carte" VR therapies, and the importance of motivational and ecologic contexts. More than 10 general principles are very likely, but these principles seem crucial for the fast recovery of vestibular loss patients to ensure good quality of life.

Where is straight ahead to a patient with unilateral vestibular loss?

The vestibular system is classically associated with postural control, oculomotor reflexes and self-motion perception. The patients with vestibular loss are primarily concerned with balance and gait problems including head and trunk tilt and walking trajectory deviation to the lesioned side. These long-lasting postural and locomotor biases are thought to originate from changes in spatial perception of self. Indeed, we show here that vestibular cues are necessary for an accurate representation of body orientation. Patients with right (RVN; n=11) or left vestibular neurotomy (LVN; 9) as a treatment for Menière's disease were compared with 10 healthy controls. The subjective straight ahead (SSA) was investigated using a method disentangling lateral shift and tilt components of error. In the horizontal plane, subjects were required to align a rod with their body midline. In the frontal plane, they were asked to align the rod with the midline of head or trunk. The analysis of SSA clearly showed distinct results according to the side of the lesion. The LVN patients had a contralesional lateral shift of SSA. In addition, they showed an ipsilesional tilt, more severe for the head than for the trunk. By contrast, in RVN patients, the representation of the body midline was fairly accurate in both the horizontal and frontal planes and did not differ from that of control subjects. The present study shows deviations in body orientation representation after unilateral vestibular loss. Deviations are observed in the horizontal as well as in the frontal planes. Interestingly, only patients with left vestibular loss were concerned with these changes in perception of self-orientation in space. These data support the hypothesis of an asymmetric vestibular function in healthy subjects and confirm the similarity of functional disorders in patients with vestibular deficits or spatial neglect. For the first time, this similarity is found at the level of body representation.

Static and dynamic posture control in postlingual cochlear implanted patients: effects of dual-tasking, visual and auditory inputs suppression.

Posture control is based on central integration of multisensory inputs, and on internal representation of body orientation in space. This multisensory feedback regulates posture control and continuously updates the internal model of body's position which in turn forwards motor commands adapted to the environmental context and constraints. The peripheral localization of the vestibular system, close to the cochlea, makes vestibular damage possible following cochlear implant (CI) surgery. Impaired vestibular function in CI patients, if any, may have a strong impact on posture stability. The simple postural task of quiet standing is generally paired with cognitive activity in most day life conditions, leading therefore to competition for attentional resources in dual-tasking, and increased risk of fall particularly in patients with impaired vestibular function. This study was aimed at evaluating the effects of postlingual cochlear implantation on posture control in adult deaf patients. Possible impairment of vestibular function was assessed by comparing the postural performance of patients to that of age-matched healthy subjects during a simple postural task performed in static (stable platform) and dynamic (platform in translation) conditions, and during dual-tasking with a visual or auditory memory task. Postural tests were done in eyes open (EO) and eyes closed (EC) conditions, with the CI activated (ON) or not (OFF). Results showed that the postural performance of the CI patients strongly differed from the controls, mainly in the EC condition. The CI patients showed significantly reduced limits of stability and increased postural instability in static conditions. In dynamic conditions, they spent considerably more energy to maintain equilibrium, and their head was stabilized neither in space nor on trunk: they behaved dynamically without vision like an inverted pendulum while the controls showed a whole body rigidification strategy. Hearing (prosthesis on) as well as dual-tasking did not really improve the dynamic postural performance of the CI patients. We conclude that CI patients become strongly visual dependent mainly in challenging postural conditions, a result they have to be awarded of particularly when getting older.

Postural performance of vestibular loss patients under increased postural threat.

The effects of increasing postural task difficulty on balance control was investigated in 9 compensated vestibular loss patients whose results were compared to 11 healthy adults. Subjects were tested in static (stable support) and dynamic (sinusoidal translation of the support) conditions, both at floor level and at height (62 cm above the floor), and with and without vision, to create an additional postural threat. Wavelet analysis of the center of foot pressure displacement and motion analysis of the body segments were used to evaluate the postural performance. Evaluation questionnaires were used to examine the compensation level of the patients (DHI test), their general anxiety level (SAST), fear of height (subjective scale), and workload (NASA TLX test). (Vestibular loss patients rely more on vision and spend more energy maintaining balance than controls, but they use the same postural strategy as normals in both static and dynamic conditions.) Questionnaire data all showed differences in behavior and perceptions between the controls and the patients. However, at height and without vision, a whole body strategy leading to rigid posture replaces the head stabilization strategy found for standing at floor level. The effects of height on postural control can be attributable to an increase in postural threat and attention changes resulting from modifications in perception.

Betahistine treatment improves the recovery of static symptoms in patients with unilateral vestibular loss.

Vestibular loss induces a combination of postural, oculomotor, and perceptive symptoms that are compensated over time. The aim of this study was to analyze the influence of betahistine dihydrochloride on vestibular compensation. A randomized, double-blind, placebo-controlled study was performed in Menière's disease patients who underwent a curative unilateral vestibular neurotomy (UVN). The effects of betahistine treatment were investigated on a broad spectrum of vestibular-induced changes resulting from vestibular loss: body sway, head orientation, ocular cyclotorsion, spontaneous nystagmus, verticality perception, and self-evaluation of the postural stability. The time course of the recovery was compared in 16 patients who received either a placebo or betahistine (24 mg b.i.d.) from 3 days up to 3 months after UVN. Patients were examined before (day -1) and after UVN (days 7, 30, and 90). Results indicate that betahistine reduces the time to recovery by 1 month or more depending on the tested functions. Betahistine was effective as soon as 4 days after treatment administration, and the effect remained during the whole compensation period (up to 3 months). The observed clinical effects may be attributed to an action of betahistine in rebalancing the neuronal activity between contralateral vestibular nuclei.

Age-related effects of a memorizing spatial task in the adults and elderly postural control.

The aim of this study was to evaluate the age-related changes in postural control during a simple quiet standing task and a dual-task paradigm (applying a memory-spatial task and quiet standing). Thirty-five subjects were divided in two age-related groups: both younger (Y: 20-26 years) and older (O: 60-77 years) groups performed a simple postural task (quiet standing) and a dual-task (a visual memory task combined with quiet standing). Measures of the center of pressure (CoP) were recorded and its two components, the center of gravity (CG) and the differential CoP-CG, were evaluated. An age-related effect was observed in static postural performance during dual-tasking. Postural stability led to improved performance in younger subjects during the dual-task and but not in the elderly. Of the results suggest there is a "cognition first" principle for the younger adults, that is, the mirror image of the "posture first" principle observed in older adults under dual-tasking situations.

Changes in TNFα, NFκB and MnSOD protein in the vestibular nuclei after unilateral vestibular deafferentation.

BACKGROUND: Unilateral vestibular deafferentation results in strong microglial and astroglial activation in the vestibular nuclei (VN) that could be due to an inflammatory response. This study was aimed at determining if markers of inflammation are upregulated in the VN after chemical unilateral labyrinthectomy (UL) in the rat, and if the inflammatory response, if any, induces the expression of neuroprotective factors that could promote the plasticity mechanisms involved in the vestibular compensation process. The expressions of inflammatory and neuroprotective factors after chemical or mechanical UL were also compared to verify that the inflammatory response was not due to the toxicity of sodium arsanilate. METHODS: Immunohistological investigations combined the labeling of tumor necrosis factor α (TNFα), as a marker of the VN inflammatory response, and of nuclear transcription factor κB (NFκB) and manganese superoxide dismutase (MnSOD), as markers of neuroprotection that could be expressed in the VN because of inflammation. Immunoreactivity (Ir) of the VN cells was quantified in the VN complex of rats. Behavioral investigations were performed to assess the functional recovery process, including both static (support surface) and dynamic (air-righting and landing reflexes) postural tests. RESULTS: Chemical UL (arsanilate transtympanic injection) induced a significant increase in the number of TNFα-Ir cells in the medial and inferior VN on both sides. These changes were detectable as early as 4 h after vestibular lesion, persisted at 1 day, and regained nearly normal values at 3 days. The early increase in TNFα expression was followed by a slightly delayed upregulation of NFκB 8 h after chemical UL, peaking at 1 day, and regaining control values 3 days later. By contrast, upregulation of MnSOD was more strongly delayed (1 day), with a peak at 3 days, and a return to control values at 15 days. Similar changes of TNFα, NFκB, and MnSOD expression were found in rats submitted to mechanical UL. Behavioral observations showed strong posturo-locomotor deficits early after chemical UL (1 day) and a complete functional recovery 6 weeks later. CONCLUSIONS: Our results suggest that the upregulation of inflammatory and neuroprotective factors after vestibular deafferentation in the VN may constitute a favorable neuronal environment for the vestibular compensation process.

Can tactile plantar stimulation improve postural control of persons with superficial plantar sensory deficit?

BACKGROUND AND AIMS: Complex interactions between visual, vestibular and somatosensory information and the cerebellar system are involved in the maintenance of upright posture. Previous studies have shown that normal aging and pathologies may lead to deterioration of the control of upright standing posture. METHODS: In order to investigate postural control during quiet standing in the elderly, the center of pressure (CoP) was analysed on two force platforms in three different groups. The first group was composed of 13 healthy older adults (O), the second consisted of 9 older adults with plantar sole deficit (OD), and the third (control) group was composed of 8 young healthy subjects (Y). All subjects were tested with eyes closed, before and after tactile plantar stimulation lasting ten minutes. Center of pressure displacements were analyzed in terms of sway area, mean velocity, and mean root mean square (RMS) along both mediolateral and antero-posterior axes. RESULTS: Results showed that, before tactile plantar stimulation, the sway area and mean RMS were greater in O and OD subjects compared with Y ones. After tactile plantar stimulation, a decrease in the mean RMS was observed in OD subjects, this effect being significant only for the medio-lateral axis. CONCLUSIONS: These results suggest that application of tactile plantar stimulation may compensate a loss of superficial plantar sensitivity.