Characterization of Vestibular Perception in Patients with Persistent Postural-Perceptual Dizziness.

OBJECTIVE: To assess vestibular (i.e., passive self-motion) perception in patients diagnosed with persistent postural-perceptual dizziness (PPPD). STUDY DESIGN: Case-controlled, cross-sectional, observational investigation. SETTING: Single-center laboratory-based study. PATIENTS: Thirteen patients with PPPD, 13 age-matched healthy control volunteers. Of those with PPPD, eight had co-occurring vestibular migraine (VM). INTERVENTIONS: All participants completed a vestibular threshold test battery reflecting perception with predominant inputs from ( a ) the otoliths (1-Hz interaural y -axis translation, 1-Hz superior-inferior z -axis translation), ( b ) the semicircular canals (2-Hz yaw rotation, 2-Hz tilts in the planes of the vertical canal pairs), and ( c ) and canal-otolith integration (0.5-Hz roll tilt). MAIN OUTCOME MEASURES: Direction-recognition thresholds for each vestibular threshold test condition. RESULTS: Across all patients with PPPD, higher thresholds for superior-inferior z -translations thresholds in comparison to age-matched healthy control participants were identified ( p < 0.001). Those patients with co-occurring VM and PPPD (PPPD/+VM) displayed significantly higher z -translation thresholds ( p = 0.006), whereas patients with PPPD without VM (PPPD/-VM) displayed significantly higher roll tilt thresholds ( p = 0.029). CONCLUSIONS: Patients with PPPD did not display a global worsening of passive self-motion perception as quantified by vestibular perceptual thresholds. Instead, patients with PPPD displayed elevated thresholds for only roll tilt and z -translation thresholds, with the relative change in each threshold impacted by the co-occurrence of VM. Because both z -translation and roll tilt motions are reliant on accurate gravity perception, our data suggest that patients with PPPD may exhibit impaired processing of graviceptive cues.

Vestibular contributions to linear motion perception.

Vestibular contributions to linear motion (i.e., translation) perception mediated by the otoliths have yet to be fully characterized. To quantify the maximal extent that non-vestibular cues can contribute to translation perception, we assessed vestibular perceptual thresholds in two patients with complete bilateral vestibular ablation to compare to our data in 12 young (< 40 years), healthy controls. Vestibular thresholds were assessed for naso-occipital ("x-translation"), inter-aural ("y-translation"), and superior-inferior ("z-translation") translations in three body orientations (upright, supine, side-lying). Overall, in our patients with bilateral complete vestibular loss, thresholds were elevated ~ 2-45 times relative to healthy controls. No systematic differences in vestibular perceptual thresholds were noted between motions that differed only with respect to their orientation relative to the head (i.e., otoliths) in patients with bilateral vestibular loss. In addition, bilateral loss patients tended to show a larger impairment in the perception of earth-vertical translations (i.e., motion parallel to gravity) relative to earth-horizontal translations, which suggests increased contribution of the vestibular system for earth-vertical motions. However, differences were also noted between the two patients. Finally, with the exception of side-lying x-translations, no consistent effects of body orientation in our bilateral loss patients were seen independent from those resulting from changes in the plane of translation relative to gravity. Overall, our data confirm predominant vestibular contributions to whole-body direction-recognition translation tasks and provide fundamental insights into vestibular contributions to translation motion perception.

Joint Contributions of Auditory, Proprioceptive and Visual Cues on Human Balance.

One's ability to maintain their center of mass within their base of support (i.e., balance) is believed to be the result of multisensory integration. Much of the research in this literature has focused on integration of visual, vestibular, and proprioceptive cues. However, several recent studies have found evidence that auditory cues can impact balance control metrics. In the present study, we sought to better characterize the impact of auditory cues on narrow stance balance task performance with different combinations of visual stimuli (virtual and real world) and support surfaces (firm and compliant). In line with past results, we found that reducing the reliability of proprioceptive cues and visual cues yielded consistent increases in center-of-pressure (CoP) sway metrics, indicating more imbalance. Masking ambient auditory cues with broadband noise led to less consistent findings; however, when effects were observed they were substantially smaller for auditory cues than for proprioceptive and visual cues - and in the opposite direction (i.e., masking ambient auditory cues with broadband noise reduced sway in some situations). Additionally, trials that used virtual and real-world visual stimuli did not differ unless participants were standing on a surface that disrupted proprioceptive cues; disruption of proprioception led to increased CoP sway metrics in the virtual visual condition. This is the first manuscript to report the effect size of different perturbations in this context, and the first to study the impact of acoustically complex environments on balance in comparison to visual and proprioceptive contributions. Future research is needed to better characterize the impact of different acoustic environments on balance.

Increased roll tilt thresholds are associated with subclinical postural instability in asymptomatic adults aged 21 to 84 years.

Background: Balance assessments that intentionally alter the reliability of visual and proprioceptive feedback (e.g., standing on foam with eyes closed) have become a standard approach for identifying vestibular mediated balance dysfunction in older adults. However, such assessments cannot discern which specific element of the vestibular system (e.g., semicircular canal, otolith, or combined canal-otolith) underlies the observed age-related changes in balance performance. The present study was designed to determine the associations between specific sources of vestibular noise and quantitative measures of quiet stance postural control measured during standard "vestibular" balance conditions. Methods: A group of 52 asymptomatic adults (53.21 ± 19.7, 21 to 84 years) without a history of vestibular or neurologic disorders volunteered for this study. We measured a battery of five vestibular perceptual thresholds that assay vestibular noise with predominant contributions from the vertical canals, lateral canals, utricles, saccules, and the centrally integrated canal-otolith signal. In addition, participants completed two standard balance assessments that were each designed to prioritize the use of vestibular cues for quiet stance postural control-eyes closed on foam (Condition 4 of the Modified Romberg Balance Test) and eyes closed, on a sway referenced support surface (Condition 5 of the Sensory Organization Test). Results: In age adjusted models, we found strong positive associations between roll tilt vestibular thresholds, a measure of noise in the centrally integrated canal-otolith signal, and the root mean square distance (RMSD) of the anteroposterior and mediolateral center of pressure (CoP) captured during eyes closed stance on a sway referenced support surface. The strength of the association between roll tilt thresholds and the RMSD of the CoP was between 3-times and 30-times larger than the association between postural sway and each of the other vestibular thresholds measured. Conclusion: We posit that noise in the centrally estimated canal-otolith "tilt" signal may be the primary driver of the subclinical postural instability experienced by older adults during the "vestibular" conditions of balance assessments. Additional testing in adults with clinical balance impairment are needed to identify if roll tilt thresholds may also serve as a surrogate metric by which to detect vestibular mediated balance dysfunction and/or fall risk.

Recurrence quantification analysis of postural sway in patients with persistent postural perceptual dizziness.

Background: Persistent postural perceptual dizziness (PPPD) is a common cause of chronic dizziness and imbalance. Emerging evidence suggests that changes in quantitative measures of postural control may help identify individuals with PPPD, however, traditional linear metrics of sway have yielded inconsistent results. Methodologies to examine the temporal structure of sway, including recurrent quantification analysis (RQA), have identified unique changes in dynamic structure of postural control in other patient populations. This study aimed to determine if adults with PPPD exhibit changes in the dynamic structure of sway and whether this change is modulated on the basis of available sensory cues. Methods: Twelve adults diagnosed with PPPD and twelve age-matched controls, completed a standard battery of quiet stance balance tasks that involved the manipulation of visual and/or proprioceptive feedback. For each group, the regularity and complexity of the CoP signal was assessed using RQA and the magnitude and variability of the CoP signal was quantified using traditional linear measures. Results: An overall effect of participant group (i.e., healthy controls vs. PPPD) was seen for non-linear measures of temporal complexity quantified using RQA. Changes in determinism (i.e., regularity) were also modulated on the basis of availability of sensory cues in patients with PPPD. No between-group difference was identified for linear measures assessing amount and variability of sway. Conclusions: Participants with PPPD on average exhibited sway that was similar in magnitude to, but significantly more repeatable and less complex than, healthy controls. These data show that non-linear measures provide unique information regarding the effect of PPPD on postural control, and as a result, may serve as potential rehabilitation outcome measures.

Evaluating vestibular contributions to rotation and tilt perception.

Vestibular perceptual thresholds provide insights into sensory function and have shown clinical and functional relevance. However, specific sensory contributions to tilt and rotation thresholds have been incompletely characterized. To address this limitation, tilt thresholds (i.e., rotations about earth-horizontal axes) were quantified to assess canal-otolith integration, and rotation thresholds (i.e., rotations about earth-vertical axes) were quantified to assess perception mediated predominantly by the canals. To determine the maximal extent to which non-vestibular sensory cues (e.g., tactile) can contribute to tilt and rotation thresholds, we tested two patients with completely absent vestibular function and compared their data to those obtained from two separate cohorts of young (≤ 40 years), healthy adults. As one primary finding, thresholds for all motions were elevated by approximately 2-35 times in the absence of vestibular function, thus, confirming predominant vestibular contributions to both rotation and tilt self-motion perception. For patients without vestibular function, rotation thresholds showed larger increases relative to healthy adults than tilt thresholds. This suggests that increased extra-vestibular (e.g., tactile or interoceptive) sensory cues may contribute more to the perception of tilt than rotation. In addition, an impact of stimulus frequency was noted, suggesting increased vestibular contributions relative to other sensory systems can be targeted on the basis of stimulus frequency.

Improving self-motion perception and balance through roll tilt perceptual training.

The present study aimed to determine if a vestibular perceptual learning intervention could improve roll tilt self-motion perception and balance performance. Two intervention groups (n = 10 each) performed 1,300 trials of roll tilt at either 0.5 Hz (2 s/motion) or 0.2 Hz (5 s/motion) distributed over 5 days; each intervention group was provided feedback (correct/incorrect) after each trial. Roll tilt perceptual thresholds, measured using 0.2-, 0.5-, and 1-Hz stimuli, as well as quiet stance postural sway, were measured on day 1 and day 6 of the study. The control group (n = 10) who performed no perceptual training, showed stable 0.2-Hz (+1.48%, P > 0.99), 0.5-Hz (-4.0%, P > 0.99), and 1-Hz (-17.48%, P = 0.20) roll tilt thresholds. The 0.2-Hz training group demonstrated significant improvements in both 0.2-Hz (-23.77%, P = 0.003) and 0.5-Hz (-22.2%, P = 0.03) thresholds. The 0.5-Hz training group showed a significant improvement in 0.2-Hz thresholds (-19.13%, P = 0.029), but not 0.5-Hz thresholds (-17.68%, P = 0.052). Neither training group improved significantly at the untrained 1-Hz frequency (P > 0.05). In addition to improvements in perceptual precision, the 0.5-Hz training group showed a decrease in sway when measured during "eyes open, on foam" (dz = 0.57, P = 0.032) and "eyes closed, on foam" (dz = 2.05, P < 0.001) quiet stance balance tasks. These initial data suggest that roll tilt perception can be improved with less than 5 h of training and that vestibular perceptual training may contribute to a reduction in subclinical postural instability.NEW & NOTEWORTHY Roll tilt vestibular perceptual thresholds, an assay of vestibular noise, were recently found to correlate with postural sway. We therefore hypothesized that roll tilt perceptual training would yield improvements in both perceptual precision and balance. Our data show that roll tilt perceptual thresholds and quiet stance postural sway can be significantly improved after less than 5 h of roll tilt perceptual training, supporting the hypothesis that vestibular noise contributes to increased postural sway.

Impacts of Rotation Axis and Frequency on Vestibular Perceptual Thresholds.

In an effort to characterize the factors influencing the perception of self-motion rotational cues, vestibular self-motion perceptual thresholds were measured in 14 subjects for rotations in the roll and pitch planes, as well as in the planes aligned with the anatomic orientation of the vertical semicircular canals (i.e., left anterior, right posterior; LARP, and right anterior, left posterior; RALP). To determine the multisensory influence of concurrent otolith cues, within each plane of motion, thresholds were measured at four discrete frequencies for rotations about earth-horizontal (i.e., tilts; EH) and earth-vertical axes (i.e., head positioned in the plane of the rotation; EV). We found that the perception of rotations, stimulating primarily the vertical canals, was consistent with the behavior of a high-pass filter for all planes of motion, with velocity thresholds increasing at lower frequencies of rotation. In contrast, tilt (i.e, EH rotation) velocity thresholds, stimulating both the canals and otoliths (i.e., multisensory integration), decreased at lower frequencies and were significantly lower than earth-vertical rotation thresholds at each frequency below 2 Hz. These data suggest that multisensory integration of otolithic gravity cues with semicircular canal rotation cues enhances perceptual precision for tilt motions at frequencies below 2 Hz. We also showed that rotation thresholds, at least partially, were dependent on the orientation of the rotation plane relative to the anatomical alignment of the vertical canals. Collectively these data provide the first comprehensive report of how frequency and axis of rotation influence perception of rotational self-motion cues stimulating the vertical canals.

Impact of Canal-Otolith Integration on Postural Control.

Roll tilt vestibular perceptual thresholds, an assay of vestibular noise, have recently been shown to be associated with suboptimal balance performance in healthy older adults. However, despite the strength of this correlation, the use of a categorical (i.e., pass/fail) balance assessment limits insight into the impacts of vestibular noise on postural sway. As a result, an explanation for this correlation has yet to be determined. We hypothesized that the correlation between roll tilt vestibular thresholds and postural control reflects a shared influence of sensory noise. To address this hypothesis, we measured roll tilt perceptual thresholds at multiple frequencies (0.2 Hz, 0.5 Hz, 1 Hz) and compared each threshold to quantitative measures of quiet stance postural control in 33 healthy young adults (mean = 24.9 years, SD = 3.67). Our data showed a significant linear association between 0.5 Hz roll tilt thresholds and the root mean square distance (RMSD) of the center of pressure in the mediolateral (ML; ß = 5.31, p = 0.002, 95% CI = 2.1-8.5) but not anteroposterior (AP; ß = 5.13, p = 0.016, 95% CI = 1.03-9.23) direction (Bonferroni corrected α of 0.006). In contrast, vestibular thresholds measured at 0.2 Hz and 1 Hz did not show a significant correlation with ML or AP RMSD. In a multivariable regression model, controlling for both 0.2 Hz and 1 Hz thresholds, the significant effect of 0.5 Hz roll tilt thresholds persisted (ß = 5.44, p = 0.029, CI = 0.60-10.28), suggesting that the effect cannot be explained by elements shared by vestibular thresholds measured at the three frequencies. These data suggest that vestibular noise is significantly associated with the temporospatial control of quiet stance in the mediolateral plane when visual and proprioceptive cues are degraded (i.e., eyes closed, standing on foam). Furthermore, the selective association of quiet-stance sway with 0.5 Hz roll tilt thresholds, but not thresholds measured at lower (0.2 Hz) or higher (1.0 Hz) frequencies, may reflect the influence of noise that results from the temporal integration of noisy canal and otolith cues.

Impact of gravity on the perception of linear motion.

Accurate perception of gravity and translation is fundamental for balance, navigation, and motor control. Previous studies have reported that perceptual thresholds for earth-vertical (i.e., parallel to gravity) and earth-horizontal (i.e., perpendicular to gravity) translations are equivalent in healthy adults, suggesting that the nervous system compensates for the presence of gravity. However, past study designs were not able to fully separate the effect of gravity from the potential effects of motion direction and body orientation. To quantify the effect of gravity on translation perception relative to these alternative factors, we measured vestibular perceptual thresholds for three motion directions (inter-aural, naso-occipital, and superior-inferior) and three body orientations (upright, supine, and ear-down). In contrast to prior reports, our data suggest that the nervous system does not universally compensate for the effects of gravity during translation, instead, we show that the colinear effect of gravity significantly decreases the sensitivity to stimuli for motions sensed by the utricles (inter-aural and naso-occipital translation), but this effect was not significant for motions sensed by the saccules (superior-inferior translations). We also identified increased thresholds for superior-inferior translation, suggesting decreased sensitivity of motions sensed predominantly by the saccule. An overall effect of body orientation on perception was seen; however, post hoc analyses suggest that this orientation effect may reflect the impact of gravity on self-motion perception. Overall, our data provide fundamental insights into the manner by which the nervous system processes vestibular self-motion cues, showing that the effect of gravity on translation perception is impacted by the direction of motion.NEW & NOTEWORTHY Perception of gravity and translation are fundamental for self-motion perception, balance, and motor control. The central nervous system must accurately disambiguate peripheral otolith signals encoding both linear acceleration and gravity. In contrast to past reports, we show that perception of translation depends on both motion relative to gravity and motion relative to the head. These results provide fundamental insights into otolith-mediated perception and suggest that the nervous system must compensate for the presence of gravity.

Vestibular Thresholds: A Review of Advances and Challenges in Clinical Applications.

Vestibular disorders pose a substantial burden on the healthcare system due to a high prevalence and the severity of symptoms. Currently, a large portion of patients experiencing vestibular symptoms receive an ambiguous diagnosis or one that is based solely on history, unconfirmed by any objective measures. As patients primarily experience perceptual symptoms (e.g., dizziness), recent studies have investigated the use of vestibular perceptual thresholds, a quantitative measure of vestibular perception, in clinical populations. This review provides an overview of vestibular perceptual thresholds and the current literature assessing use in clinical populations as a potential diagnostic tool. Patients with peripheral and central vestibular pathologies, including bilateral vestibulopathy and vestibular migraine, show characteristic changes in vestibular thresholds. Vestibular perceptual thresholds have also been found to detect subtle, sub-clinical declines in vestibular function in asymptomatic older adults, suggesting a potential use of vestibular thresholds to augment or complement existing diagnostic methods in multiple populations. Vestibular thresholds are a reliable, sensitive, and specific assay of vestibular precision, however, continued research is needed to better understand the possible applications and limitations, especially with regard to the diagnosis of vestibular disorders.

Advances and Challenges in Pharmaceutical Therapies to Prevent and Repair Cochlear Injuries From Noise.

Noise induces a broad spectrum of pathological injuries to the cochlea, reflecting both mechanical damage to the delicate architecture of the structures of the organ of Corti and metabolic damage within the organ of Corti and lateral wall tissues. Unlike ototoxic medications, the blood-labyrinth barrier does not offer protection against noise injury. The blood-labyrinth barrier is a target of noise injury, and can be weakened as part of the metabolic pathologies in the cochlea. However, it also offers a potential for therapeutic intervention with oto-protective compounds. Because the blood-labyrinth barrier is weakened by noise, penetration of blood-borne oto-protective compounds could be higher. However, systemic dosing for cochlear protection from noise offers other significant challenges. An alternative option to systemic dosing is local administration to the cochlea through the round window membrane using a variety of drug delivery techniques. The review will discuss noise-induced cochlear pathology, including alterations to the blood-labyrinth barrier, and then transition into discussing approaches for delivery of oto-protective compounds to reduce cochlear injury from noise.

Noise-induced cochlear synaptopathy: Past findings and future studies.

For decades, we have presumed the death of hair cells and spiral ganglion neurons are the main cause of hearing loss and difficulties understanding speech in noise, but new findings suggest synapse loss may be the key contributor. Specifically, recent preclinical studies suggest that the synapses between inner hair cells and spiral ganglion neurons with low spontaneous rates and high thresholds are the most vulnerable subcellular structures, with respect to insults during aging and noise exposure. This cochlear synaptopathy can be "hidden" because this synaptic loss can occur without permanent hearing threshold shifts. This new discovery of synaptic loss opens doors to new research directions. Here, we review a number of recent studies and make suggestions in two critical future research directions. First, based on solid evidence of cochlear synaptopathy in animal models, it is time to apply molecular approaches to identify the underlying molecular mechanisms; improved understanding is necessary for developing rational, effective therapies against this cochlear synaptopathy. Second, in human studies, the data supporting cochlear synaptopathy are indirect although rapid progress has been made. To fully identify changes in function that are directly related this hidden synaptic damage, we argue that a battery of tests including both electrophysiological and behavior tests should be combined for diagnosis of "hidden hearing loss" in clinical studies. This new approach may provide a direct link between cochlear synaptopathy and perceptual difficulties.

Canertinib induces ototoxicity in three preclinical models.

Neuregulin-1 (NRG1) ligand and its epidermal growth factor receptor (EGFR)/ERBB family regulate normal cellular proliferation and differentiation in many tissues including the cochlea. Aberrant NRG1 and ERBB signaling cause significant hearing impairment in mice. Dysregulation of the same signaling pathway in humans is involved in certain types of cancers such as breast cancer or non-small cell lung cancer (NSCLC). A new irreversible pan-ERBB inhibitor, canertinib, has been tested in clinical trials for the treatment of refractory NSCLC. Its possible ototoxicity was unknown. In this study, a significant dose-dependent canertinib ototoxicity was observed in a zebrafish model. Canertinib ototoxicity was further confirmed in two mouse models with different genetic backgrounds. The data strongly suggested an evolutionally preserved ERBB molecular mechanism underlying canertinib ototoxicity. Thus, these results imply that clinical monitoring of hearing loss should be considered for clinical testing of canertinib or other pan-ERBB inhibitors.