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.

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 perceptual testing from lab to clinic: a review.

Not all dizziness presents as vertigo, suggesting other perceptual symptoms for individuals with vestibular disease. These non-specific perceptual complaints of dizziness have led to a recent resurgence in literature examining vestibular perceptual testing with the aim to enhance clinical diagnostics and therapeutics. Recent evidence supports incorporating rehabilitation methods to retrain vestibular perception. This review describes the current field of vestibular perceptual testing from scientific laboratory techniques that may not be clinic friendly to some low-tech options that may be more clinic friendly. Limitations are highlighted suggesting directions for additional research.

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.

Influence of Visual Feedback on Roll Tilt Perceptual Training.

HYPOTHESIS: We hypothesized that the addition of visual feedback during roll tilt perceptual training would yield a significant reduction in vestibular perceptual thresholds relative to a control group. BACKGROUND: We previously showed that roll tilt vestibular thresholds could be improved through a perceptual training protocol that used a simple auditory cue. Variability in training outcomes within the treatment group suggested that an auditory cue alone may be suboptimal for improving self-motion perception. METHODS: In 10 healthy adults, roll tilt vestibular thresholds, quantifying the smallest motion that can be reliably perceived, were measured before ("pretraining") and after ("posttraining") a training protocol designed to improve roll tilt perception. The protocol included 1,300 trials of 0.5 Hz whole-body roll tilt over 5 days, with participants being given both an auditory cue ("correct' vs. "incorrect') and visual feedback (viewing a stationary visual scene) after indicating their perceived direction of tilt. A control group (N = 10) underwent only the "pretraining" and "posttraining" assessments. RESULTS: The training group showed an average decrease in roll tilt vestibular thresholds of 1.7% ± 56%, with training outcomes varying widely. Three individuals showed an average increase in roll tilt thresholds of 69.7%, whereas the remaining seven adults showed an average decrease in thresholds of 32.3%. CONCLUSION: These data show that visual feedback during roll tilt perceptual training leads to heterogenous outcomes, but in a subset of individuals, it may lead to improvements in perceptual precision. Additional work is needed to define the optimal training parameters, including feedback schema, before investigating potential clinical applications.

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.

A modified two-dimensional sensory organization test that assesses both anteroposterior and mediolateral postural control.

Background: The Sensory Organization Test (SOT) was designed to measure changes in postural control in response to unreliable visual and/or proprioceptive feedback. However, secondary to the manipulation of sensory cues in only the sagittal plane, the SOT is capable of only describing postural control in a single direction. The present study aimed to characterize postural responses to a modified SOT designed to concurrently challenge both anteroposterior and mediolateral postural control. Methods: Twenty-one healthy adult volunteers (30.6 ± 10.2 years) completed the standard anteroposterior one-dimensional (1D) SOT, in addition to a modified SOT with the support surface sway-referenced to both anteroposterior and mediolateral postural sway (two-dimensional, 2D). Our primary analysis concerned a comparison of mediolateral, as well as anteroposterior postural sway measured during the standard one-dimensional (i.e., pitch tilt) and the novel two-dimensional (i.e., roll and pitch tilt) sway-referenced paradigms. Here, postural sway was quantified by calculating the root mean square distance (RMSD) of the center of pressure (CoP) during each trial. Results: Our data showed that the 2D sway-referenced conditions yielded a selective increase in mediolateral postural sway relative to the standard 1D conditions for both wide (η2 = 0.66) and narrow (η2 = 0.78) stance conditions, with anteroposterior postural sway being largely unaffected (η2 = 0.001 to 0.103, respectively). The ratio between mediolateral postural sway in the sway-referenced conditions and postural sway in the corresponding stable support surface conditions was greater for the 2D (2.99 to 6.26 times greater) compared to 1D paradigms (1.25 to 1.84 times greater), consistent with a superior degradation of viable proprioceptive feedback in the 2D paradigm. Conclusion: A modified 2D version of the SOT was shown to provide a greater challenge to mediolateral postural control relative to the standard 1D SOT protocol, putatively as a result of a superior capacity to degrade proprioceptive feedback in the mediolateral direction. Given these positive findings, future studies should investigate the clinical utility of this modified SOT as a means by which to better characterize sensory contributions to postural control in the presence of various sensorimotor pathologies, including vestibular hypofunction.

Compensatory saccades differ between those with vestibular hypofunction and multiple sclerosis pointing to unique roles for peripheral and central vestibular inputs.

Individuals with peripheral or central vestibular dysfunction recruit compensatory saccades (CSs) in response to high acceleration, yaw head impulses. Although CSs have been shown to be an effective strategy for reducing gaze position error (GPE) in individuals with peripheral hypofunction, for individuals with central vestibular dysfunction, the effectiveness of CS is unknown. The purpose of our study was to compare the effectiveness of CS, defined as the ability to compensate for head velocity and eye position errors, between persons with central and peripheral vestibular dysfunction. We compared oculomotor responses during video head impulse testing between individuals with unilateral peripheral vestibular deafferentation, a disorder of the peripheral vestibular afferents, and individuals with multiple sclerosis, a condition affecting the central vestibular pathways. We hypothesized that relative to individuals with peripheral lesions, individuals with central dysfunction would recruit CSs that were delayed and inappropriately scaled to head velocity and GPE. We show that CSs recruited by persons with central vestibular pathology were not uniformly deficient but instead were of a sufficient velocity to compensate for reductions in VOR gain. Compared to those with peripheral vestibular lesions, individuals with central pathology also recruited earlier covert CS with amplitudes that were better corrected for GPE. Conversely, those with central lesions showed greater variability in the amplitude of overt CS relative to GPE. These data point to a unique role for peripheral and central vestibular inputs in the recruitment of CS and suggest that covert CSs are an effective oculomotor strategy for individuals with multiple sclerosis.NEW & NOTEWORTHY Compensatory saccades (CSs) are recruited by individuals with unilateral vestibular deafferentation (UVD) to compensate for an impaired vestibulo-ocular reflex (VOR). The effectiveness of CS in multiple sclerosis (MS), a central vestibular impairment, is unknown. We show that in UVD and in MS, covert CSs compensate for reduced VOR gain and minimize gaze position error (GPE), yet in >50% of individuals with MS, overt CS worsened GPE, suggesting unique roles for peripheral and central vestibular inputs.

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.

Analysis of functional surfaces on the actin nucleation promoting factor Dip1 required for Arp2/3 complex activation and endocytic actin network assembly.

Arp2/3 complex nucleates branched actin filaments that drive processes like endocytosis and lamellipodial protrusion. WISH/DIP/SPIN90 (WDS) proteins form a class of Arp2/3 complex activators or nucleation promoting factors (NPFs) that, unlike WASP family NPFs, activate Arp2/3 complex without requiring preformed actin filaments. Therefore, activation of Arp2/3 complex by WDS proteins is thought to produce the initial actin filaments that seed branching nucleation by WASP-bound Arp2/3 complexes. However, whether activation of Arp2/3 complex by WDS proteins is important for the initiation of branched actin assembly in cells has not been directly tested. Here, we used structure-based point mutations of the Schizosaccharomyces pombe WDS protein Dip1 to test the importance of its Arp2/3-activating activity in cells. Six of thirteen Dip1 mutants caused severe defects in Arp2/3 complex activation in vitro, and we found a strong correlation between the ability of mutants to activate Arp2/3 complex and to rescue endocytic actin assembly defects caused by deleting Dip1. These data support a model in which Dip1 activates Arp2/3 complex to produce actin filaments that initiate branched actin assembly at endocytic sites. Dip1 mutants that synergized with WASP in activating Arp2/3 complex in vitro showed milder defects in cells compared to those that did not, suggesting that in cells the two NPFs may coactivate Arp2/3 complex to initiate actin assembly. Finally, the mutational data reveal important complementary electrostatic contacts at the Dip1-Arp2/3 complex interface and corroborate the previously proposed wedge model, which describes how Dip1 binding triggers structural changes that activate Arp2/3 complex.

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.

Measuring Vestibular Contributions to Age-Related Balance Impairment: A Review.

Aging is associated with progressive declines in both the vestibular and human balance systems. While vestibular lesions certainly contribute to imbalance, the specific contributions of age-related vestibular declines to age-related balance impairment is poorly understood. This gap in knowledge results from the absence of a standardized method for measuring age-related changes to the vestibular balance pathways. The purpose of this manuscript is to provide an overview of the existing body of literature as it pertains to the methods currently used to infer vestibular contributions to age-related imbalance.

Might Vestibular "Noise" Cause Subclinical Balance Impairment and Falls?

Falls are the leading causes of accidental injury in older adults and directly contribute to more than 600,000 deaths each year worldwide. Although the issue of falls is complex, balance dysfunction is one the principal contributors to the heightened incidence of falls in older adults. A nationally representative survey of older adults in the United States showed that an inability to stand on a foam pad with the eyes closed was associated with more than a six-fold increase in the odds of reporting "difficulty with falls." As stability in the "eyes closed, on foam" condition is reliant upon intact vestibular cues, these data implicate age-related vestibular loss as a potential contributor to falls, yet, the specific causal mechanism explaining the link between age-related vestibular loss and imbalance/falls was not known. Here we review recent data showing that, vestibular perceptual thresholds, an assay of vestibular sensory noise, were found to, (1) account for nearly half of subclinical balance impairment in healthy older adults and (2) correlate with postural sway in healthy young adults. Based upon the identified links between balance dysfunction and vestibular noise in healthy adults, we posit the following causal chain: (a) increased "noise" in vestibular feedback - yielding a reduced signal-to-noise ratio in vestibular feedback-increases sway, (b) excessive sway leads to imbalance, and (c) imbalance contributes to falls. Identifying the "cause" of age-related balance dysfunction will inform the development of interventions tailored to prevent falls, and fall-related injuries, in the growing population of older adults.

Evidence a shared mechanism mediates ipsi- and contralesional compensatory saccades and gait after unilateral vestibular deafferentation.

The study objective was to understand how the contralesional labyrinth contributes to gaze and gait stability after unilateral vestibular deafferentation (UVD). Head impulse testing (vHIT) was completed in 37 individuals [22 women (59%); age 52.13 ± 11.59 yr, mean ± SD] with UVD from vestibular schwannoma resection. Compensatory saccades (CS) and vestibulo-ocular reflex (VOR) gain were analyzed for both ipsilesional and contralesional impulses. Gait speed (10-m walk test) and endurance (2-min walk test) were collected for 35 individuals. CS were recruited during contralesional head rotation regardless of VOR gain on either the ipsilesional [ρ = 0.21 (-0.14, 0.57); Spearman rank (95% confidence interval)] or contralesional side [ρ = -0.04 (-0.42, 0.35)]. Additionally, the latency of these CS (151.19 ± 52.41 ms) was similar to that of CS generated during ipsilesional rotation (165.65 ± 21.62 ms; P = 0.159). CS recruited during ipsilesional vHIT were of a higher velocity (P < 0.001) and greater frequency (P < 0.001) compared with contralesional CS. VOR gain asymmetry was significantly correlated with gait speed [ρ = -0.37 (-0.73, -0.01)], yet individual VOR gain was not correlated [ipsilesional: ρ = 0.17 (-0.20, 0.55); contralesional: ρ = -0.18 (-0.52, 0.15)]. Our data reveal CS are recruited at similar latencies without correlation to VOR gain or direction of head rotation, and that the central integration of ipsilesional and contralesional vestibular afference correlates with gait. Together, our data suggest the brain considers vestibular afference from both sides when generating related behavioral output after UVD.NEW & NOTEWORTHY After unilateral vestibular deafferentation, compensatory saccades (CS) have similar latencies regardless of the direction of head rotation, and those CS generated during contralesional head rotation are unrelated to extent of vestibular loss. Additionally, the extent of asymmetry in residual vestibular function, not the extent of vestibular loss, correlates with gait speed. Our data suggest a common mechanism is responsible for the generation of CS and restoration of gait speed in vestibular compensation.

Single-Turnover Activation of Arp2/3 Complex by Dip1 May Balance Nucleation of Linear versus Branched Actin Filaments.

Arp2/3 complex nucleates branched actin filaments important for cellular motility, endocytosis, meiosis, and cellular differentiation [1-4]. Wiskott-Aldrich syndrome proteins (WASPs), the prototypical Arp2/3 complex activators, activate Arp2/3 complex only once it is bound to the side of an actin filament [5, 6]. This ensures WASP-activated Arp2/3 complex only nucleates branched actin filaments but means branched actin networks must be seeded with an initial preformed filament. Dip1 and other WISH/DIP/SPIN90 family proteins activate Arp2/3 complex without preformed filaments [7], creating seed filaments that activate WASP-bound Arp2/3 complex [8]. Importantly, Dip1-mediated activation of Arp2/3 complex creates linear filaments instead of branches [7]. Cells may therefore need to limit Dip1 activity relative to WASP to preserve the dendritic nature of actin networks, although it is unclear whether such regulatory mechanisms exist. Here, we use total internal reflection fluorescence (TIRF) microscopy to show that Dip1 causes actin assembled with WASP and Arp2/3 complex to form disconnected networks with many linear filaments rather than highly branched arrays. We discover a key biochemical difference between Dip1 and WASP that may limit linear filament nucleation in cells; although WASP must be released for nucleation, Dip1 stays associated with Arp2/3 complex on the pointed ends of nucleated actin filaments, so Dip1 is consumed in the reaction. Using live-cell imaging of fission yeast, we provide evidence that Dip1 is a single-turnover activator of Arp2/3 complex in vivo, revealing a mechanism by which Dip1 can initiate branched actin networks at endocytic sites without disrupting their branched architectures.

Dip1 Co-opts Features of Branching Nucleation to Create Linear Actin Filaments that Activate WASP-Bound Arp2/3 Complex.

When activated by Wiskott-Aldrich syndrome proteins (WASP), Arp2/3 complex nucleates branched actin filaments important for processes like cellular motility and endocytosis [1]. WASP-mediated activation of Arp2/3 complex requires a preformed actin filament, ensuring that activation by WASP creates branched instead of linear filaments. However, this biochemical requirement also means that assembly of branched actin networks must be primed with an initial seed filament [2-4]. We recently described a class of activators called WISH/DIP/SPIN90 (WDS) proteins, which, unlike WASP, activate Arp2/3 complex without a preformed filament [4]. Although this property may allow WDS proteins to serve as seed filament generators, it is unknown whether actin filaments nucleated by WDS-activated Arp2/3 complex can activate WASP-bound Arp2/3 complex. Further, despite their potential importance as branched actin network initiators, little is known about how WDS proteins turn on Arp2/3 complex. Here, we use two-color single-molecule total internal reflection fluorescence (TIRF) microscopy to show that Dip1, the S. pombe WDS protein [5], co-opts features of branching nucleation to activate Arp2/3 complex. Specifically, it activates Arp2/3 complex to nucleate linear filaments analogous to the branch created by WASP-mediated activation. The barbed ends of Dip1-Arp2/3 nucleated filaments are free to elongate, and their pointed ends remain anchored to Dip1-bound Arp2/3 complex. The linear filaments nucleated by Dip1-bound Arp2/3 complex activate WASP-bound Arp2/3 complex as potently as spontaneously nucleated or branched actin filaments. These observations provide important insights into the regulation of Arp2/3 complex by its activators and the molecular basis for initiation of branched actin networks.