Effect of vestibular loss on head-on-trunk stability in individuals with vestibular schwannoma.

The vestibulo-collic reflex generates neck motor commands to produce head-on-trunk movements that are essential for stabilizing the head relative to space. Here we examined the effects of vestibular loss on head-on-trunk kinematics during voluntary behavior. Head and trunk movements were measured in individuals with vestibular schwannoma before and then 6 weeks after unilateral vestibular deafferentation via surgical resection of the tumor. Movements were recorded in 6 dimensions (i.e., 3 axes of rotation and 3 axes of translation) using small light-weight inertial measurement units while participants performed balance and gait tasks. Kinematic measures differed between individuals with vestibular schwannoma (at both time points) and healthy controls for the more challenging exercises, namely those performed in tandem position or on an unstable surface without visual input. Quantitative assessment of the vestibulo-ocular reflex (VOR) revealed a reduction in VOR gain for individuals with vestibular schwannoma compared to control subjects, that was further reduced following surgery. These findings indicated that the impairment caused by either the tumor or subsequent surgical tumor resection altered head-on-trunk kinematics in a manner that is not normalized by central compensation. In contrast, we further found that head-on-trunk kinematics in individuals with vestibular schwannoma were actually comparable before and after surgery. Thus, taken together, our results indicate that vestibular loss impacts head-on-trunk kinematics during voluntary balance and gait behaviors, and suggest that the neural mechanisms mediating adaptation alter the motion strategies even before surgery in a manner that may be maladaptive for long-term compensation.

Head movement kinematics are differentially altered for extended versus short duration gait exercises in individuals with vestibular loss.

Head kinematics are altered in individuals with vestibular schwannoma (VS) during short duration gait tasks [i.e., Functional Gait Assessment (FGA)], both before and after surgery, yet whether these differences extend to longer duration gait exercises is currently unknown. Here we examined the effects of vestibular loss and subsequent compensation on head kinematics in individuals with VS during gait exercises of relatively extended versus short duration (< 10 versus 30 s), compared to age-matched controls. Six-dimensional head movements were recorded during extended and short duration gait exercises before and then 6 weeks after sectioning of the involved vestibular nerve (vestibular neurectomy). Standard functional, physiological, and subjective clinical assessments were also performed at each time point. Kinematics were differentially altered in individuals with vestibular loss at both time points during extended versus short duration exercises. Range of motion was significantly reduced in extended tasks. In contrast, movement variability predominately differed for the short duration exercises. Overall, our results indicate that quantifying head kinematics during longer duration gait tasks can provide novel information about how VS individuals compensate for vestibular loss, and suggest that measurements of range of motion versus variability can provide information regarding the different strategies deployed to maintain functional locomotion.

Complexes of vertebrate TMC1/2 and CIB2/3 proteins form hair-cell mechanotransduction cation channels.

Calcium and integrin-binding protein 2 (CIB2) and CIB3 bind to transmembrane channel-like 1 (TMC1) and TMC2, the pore-forming subunits of the inner-ear mechanoelectrical transduction (MET) apparatus. Whether these interactions are functionally relevant across mechanosensory organs and vertebrate species is unclear. Here we show that both CIB2 and CIB3 can form heteromeric complexes with TMC1 and TMC2 and are integral for MET function in mouse cochlea and vestibular end organs as well as in zebrafish inner ear and lateral line. Our AlphaFold 2 models suggest that vertebrate CIB proteins can simultaneously interact with at least two cytoplasmic domains of TMC1 and TMC2 as validated using nuclear magnetic resonance spectroscopy of TMC1 fragments interacting with CIB2 and CIB3. Molecular dynamics simulations of TMC1/2 complexes with CIB2/3 predict that TMCs are structurally stabilized by CIB proteins to form cation channels. Overall, our work demonstrates that intact CIB2/3 and TMC1/2 complexes are integral to hair-cell MET function in vertebrate mechanosensory epithelia.

Head movement kinematics are altered during balance stability exercises in individuals with vestibular schwannoma.

BACKGROUND: Balance stabilization exercises are often prescribed to facilitate compensation in individuals with vestibular schwannoma (VS). However, both the assessment and prescription of these exercises are reliant on clinical observations and expert opinion rather than on quantitative evidence. The aim of this study was to quantify head motion kinematics in individuals with vestibular loss while they performed commonly prescribed balance stability exercises. METHODS: Using inertial measurement units, head movements of individuals with vestibular schwannoma were measured before and after surgical deafferentation and compared with age-matched controls. RESULTS: We found that individuals with vestibular schwannoma experienced more variable head motion compared to healthy controls both pre- and postoperatively, particularly in absence of visual input, but that there was little difference between preoperative and postoperative kinematic measurements for our vestibular schwannoma group. We further found correlations between head motion kinematic measures during balance exercises, performed in the absence of visual input, and multiple clinical measurements for preoperative VS subjects. Subjects with higher head motion variability also had worse DVA scores, moved more slowly during the Timed up and Go and gait speed tests, and had lower scores on the functional gait assessment. In contrast, we did not find strong correlations between clinical measures and postoperative head kinematics for the same VS subjects. CONCLUSIONS: Our data suggest that further development of such metrics based on the quantification of head motion has merit for the assessment and prescription of balance exercises, as demonstrated by the calculation of a "kinematic score" for identifying the most informative balance exercise (i.e., "Standing on foam eyes closed").

Distinct representations of body and head motion are dynamically encoded by Purkinje cell populations in the macaque cerebellum.

The ability to accurately control our posture and perceive our spatial orientation during self-motion requires knowledge of the motion of both the head and body. However, while the vestibular sensors and nuclei directly encode head motion, no sensors directly encode body motion. Instead, the integration of vestibular and neck proprioceptive inputs is necessary to transform vestibular information into the body-centric reference frame required for postural control. The anterior vermis of the cerebellum is thought to play a key role in this transformation, yet how its Purkinje cells transform multiple streams of sensory information into an estimate of body motion remains unknown. Here, we recorded the activity of individual anterior vermis Purkinje cells in alert monkeys during passively applied whole-body, body-under-head, and head-on-body rotations. Most Purkinje cells dynamically encoded an intermediate representation of self-motion between head and body motion. Notably, Purkinje cells responded to both vestibular and neck proprioceptive stimulation with considerable heterogeneity in their response dynamics. Furthermore, their vestibular responses were tuned to head-on-body position. In contrast, targeted neurons in the deep cerebellar nuclei are known to unambiguously encode either head or body motion across conditions. Using a simple population model, we established that combining responses of~40-50 Purkinje cells could explain the responses of these deep cerebellar nuclei neurons across all self-motion conditions. We propose that the observed heterogeneity in Purkinje cell response dynamics underlies the cerebellum's capacity to compute the dynamic representation of body motion required to ensure accurate postural control and perceptual stability in our daily lives.

Continuous Head Motion is a Greater Motor Control Challenge than Transient Head Motion in Patients with Loss of Vestibular Function.

Background. The vestibular system is vital for gaze stability via the vestibulo-ocular reflex, which generates compensatory eye motion in the direction opposite to head motion. Consequently, individuals with peripheral vestibular loss demonstrate impaired gaze stability that reduces functional capacity and quality of life. To facilitate patients' compensatory strategies, two classes of gaze stabilization exercises are often prescribed: (i) transient (eg, ballistic) and (ii) continuous. However, the relative benefits of these two classes of exercises are not well understood. Objective. To quantify head motion kinematics in patients with vestibular loss while they performed both classes of exercises. Methods. Using inertial measurement units, head movements of 18 vestibular schwannoma patients were measured before and after surgical deafferentation and compared with age-matched controls. Results. We found that the head movement during both classes of exercises paralleled those of natural head movement recorded during daily activities. However, head movement patterns were more informative for continuous than transient exercises in distinguishing patients from healthy controls. Specifically, we observed coupling between kinematic measures in control subjects that was absent in patients for continuous but not transient head motion exercises. In addition, kinematic measures (eg, cycle duration) were predictive of standard clinical measures for continuous but not transient head motion exercises. Conclusions. Our data suggest that performing continuous head motion is a greater motor control challenge than transient head motion in patients with less reliable vestibular feedback during the sub-acute stage of recovery, which may also prove to be a reliable measure of progression in vestibular rehabilitation protocols.

Proprioception and the predictive sensing of active self-motion.

As we actively explore the environment, our motion relative to the world stimulates numerous sensory systems. Notably, proprioceptors provide feedback about body and limb position, while the vestibular system detects and encodes head motion. When the vestibular system is functioning normally, we are unaware of a distinct sensation because vestibular information is integrated with proprioceptive and other sensory inputs to generate our sense of motion. However, patients with vestibular sensory loss experience impairments that provide important insights into the function of this essential sensory system. For these patients, everyday activities such as walking become difficult because even small head movements can produce postural and perceptual instability. This review describes recent research demonstrating how the proprioceptive and vestibular systems effectively work together to provide us with our "6th sense" during everyday activities, and in particular considers the neural computations underlying the brain's predictive sensing of head movement during voluntary self-motion.

Head movement kinematics are altered during gaze stability exercises in vestibular schwannoma patients.

Gaze stability is the ability of the eyes to fixate a stable point when the head is moving in space. Because gaze stability is impaired in peripheral vestibular loss patients, gaze stabilization exercises are often prescribed to facilitate compensation. However, both the assessment and prescription of these exercises are subjective. Accordingly, here we quantified head motion kinematics in patients with vestibular loss while they performed the standard of care gaze stability exercises, both before and after surgical deafferentation. We also correlate the head kinematic data with standard clinical outcome measures. Using inertial measurement units, we quantified head movements in patients as they transitioned through these two vestibular states characterized by different levels of peripheral damage. Comparison with age-matched healthy control subjects revealed that the same kinematic measurements were significantly abnormal in patients both pre- and post-surgery. Regardless of direction, patients took a longer time to move their heads during the exercises. Interestingly, these changes in kinematics suggest a strategy that existed preoperatively and remained symmetric after surgery although the patients then had complete unilateral vestibular loss. Further, we found that this kinematic assessment was a good predictor of clinical outcomes, and that pre-surgery clinical measures could predict post-surgery head kinematics. Thus, together, our results provide the first experimental evidence that patients show significant changes in head kinematics during gaze stability exercises, even prior to surgery. This suggests that early changes in head kinematic strategy due to significant but incomplete vestibular loss are already maladaptive as compared to controls.

Loss of peripheral vestibular input alters the statistics of head movement experienced during natural self-motion.

KEY POINTS: Sensory systems are adapted to the statistical structure of natural stimuli, thereby optimizing neural coding. Head motion during natural activities is first sensed and then processed by central vestibulo-motor pathways to influence subsequent behaviour, thereby establishing a feedback loop. To investigate the role of this vestibular feedback on the statistical structure of the head movements, we compared head movements in patients with unilateral vestibular loss and healthy controls. We show that the loss of vestibular feedback substantially alters the statistical structure of head motion for activities that require rapid online feedback control and predict this change by modelling the effects of increased movement variability. Our findings suggest that, following peripheral vestibular loss, changes in the reliability of the sensory input to central pathways impact the statistical structure of head motion during voluntary behaviours. ABSTRACT: It is widely believed that sensory systems are adapted to optimize neural coding of their natural stimuli. Recent evidence suggests that this is the case for the vestibular system, which senses head movement and contributes to essential functions ranging from the most automatic reflexes to voluntary motor control. During everyday behaviours, head motion is sensed by the vestibular system. In turn, this sensory feedback influences subsequent behaviour, raising the questions of whether and how real-time feedback provided by the vestibular system alters the statistical structure of head movements. We predicted that a reduction in vestibular feedback would alter head movement statistics, particularly for tasks reliant on rapid vestibular feedback. To test this proposal, we recorded six-dimensional head motion in patients with variable degrees of unilateral vestibular loss during standard balance and gait tasks, as well as dynamic self-paced activities. While distributions of linear accelerations and rotational velocities were comparable for patients and age-matched healthy controls, comparison of power spectra revealed significant differences during more dynamic and challenging activities. Specifically, consistent with our prediction, head movement power spectra were significantly altered in patients during two tasks that required rapid online vestibular feedback: active repetitive jumping and walking on foam. Using computational methods, we analysed concurrently measured torso motion and identified increases in head-torso movement variability. Taken together, our results demonstrate that vestibular loss significantly alters head movement statistics and further suggest that increased variability and impaired feedback to internal models required for accurate motor control contribute to the observed changes.

Effects of vestibular neurectomy and neural compensation on head movements in patients undergoing vestibular schwannoma resection.

The vestibular system is vital for maintaining balance and stabilizing gaze and vestibular damage causes impaired postural and gaze control. Here we examined the effects of vestibular loss and subsequent compensation on head motion kinematics during voluntary behavior. Head movements were measured in vestibular schwannoma patients before, and then 6 weeks and 6 months after surgical tumor removal, requiring sectioning of the involved vestibular nerve (vestibular neurectomy). Head movements were recorded in six dimensions using a small head-mounted sensor while patients performed the Functional Gait Assessment (FGA). Kinematic measures differed between patients (at all three time points) and normal subjects on several challenging FGA tasks, indicating that vestibular damage (caused by the tumor or neurectomy) alters head movements in a manner that is not normalized by central compensation. Kinematics measured at different time points relative to vestibular neurectomy differed substantially between pre-operative and 6-week post-operative states but changed little between 6-week and > 6-month post-operative states, demonstrating that compensation affecting head kinematics is relatively rapid. Our results indicate that quantifying head kinematics during self-generated gait tasks provides valuable information about vestibular damage and compensation, suggesting that early changes in patient head motion strategy may be maladaptive for long-term vestibular compensation.

Retinoic acid degradation shapes zonal development of vestibular organs and sensitivity to transient linear accelerations.

Each vestibular sensory epithelium in the inner ear is divided morphologically and physiologically into two zones, called the striola and extrastriola in otolith organ maculae, and the central and peripheral zones in semicircular canal cristae. We found that formation of striolar/central zones during embryogenesis requires Cytochrome P450 26b1 (Cyp26b1)-mediated degradation of retinoic acid (RA). In Cyp26b1 conditional knockout mice, formation of striolar/central zones is compromised, such that they resemble extrastriolar/peripheral zones in multiple features. Mutants have deficient vestibular evoked potential (VsEP) responses to jerk stimuli, head tremor and deficits in balance beam tests that are consistent with abnormal vestibular input, but normal vestibulo-ocular reflexes and apparently normal motor performance during swimming. Thus, degradation of RA during embryogenesis is required for formation of highly specialized regions of the vestibular sensory epithelia with specific functions in detecting head motions.