Kathleen E. Cullen

The mammalian head direction (HD) system is thought to update its internal compass using angular head velocity (AHV) signals relayed from the brainstem. We tested this canonical interpretation by recording from the nucleus prepositus hypoglossi (NPH), a proposed AHV relay known to be important for accurate HD tracking, while simultaneously measuring eye and head movements in mice. Neurons classified as AHV-tuned instead predominantly encoded eye movements: most showed saccade-related bursts or pauses, and apparent AHV tuning was largely explained by eye rather than head motion. Optotagging showed that even NPH neurons projecting directly to the HD circuit predominantly encoded eye movements. Empirically constrained population models reconstructed eye position and gaze direction, but head-direction readouts failed when eye and head motion were dissociated. These findings overturn the canonical view of NPH as a dedicated AHV relay, revealing eye movements as a major, previously unmeasured component of the signals entering the mammalian HD circuit and thereby changing the computational problem that the HD system must solve to maintain a stable representation of heading.

Background: Vestibular schwannoma (VS) impairs balance and gait, often leading to substantial functional limitations that are incompletely captured by standard clinical assessments. While wearable inertial sensors and machine learning offer promise for objective gait analysis, clinical translation is limited by uncertainty regarding optimal sensor placement, task selection, and interpretability. Methods: We recorded six-dimensional kinematics from 32 individuals with unilateral vestibular schwannoma and 32 age-matched healthy controls as they performed the ten tasks of the Functional Gait Assessment (FGA). Adapting a previously developed deep learning framework, we systematically evaluated all combinations of ten gait tasks and six sensor locations, yielding 60 task–sensor models. Models were trained and tested using subject-level leave-one-out cross-validation. To support clinical interpretation, we derived a continuous kinematic score reflecting the similarity of an individual’s gait patterns to those observed in vestibular pathology. Results: Model performance depended strongly on task and sensor selection. Gait with eyes closed (FGA8) emerged as the most informative task, and wrist-mounted sensors consistently outperformed head and trunk sensors across tasks. A wrist-worn sensor during gait with eyes closed provided discrimination between VS and control participants with overall accuracies ranging from 60 to 83%, while substantially reducing instrumentation burden. The resulting kinematic score significantly differentiated groups, and model accuracies correlated with established clinical measures including the Dizziness Handicap Inventory. Conclusions: These findings demonstrate that machine learning can be used not only to classify gait pathology, but to identify a minimal, clinically deployable wearable configuration for objective gait assessment in vestibular schwannoma. The proposed wrist-based kinematic score offers a continuous, interpretable metric that complements existing clinical assessments and supports longitudinal monitoring across in-clinic and remote rehabilitation settings. This work advances the development of quantitative, scalable digital biomarkers for precision rehabilitation in vestibular disorders.

Visual motion is known to influence perceptions of tilt, verticality, and translation, suggesting that optic flow is combined with vestibular cues to estimate orientation relative to gravity. The cerebellar nodulus and ventral uvula (NU) are a prime candidate to perform this computation because this region uniquely receives convergent semicircular canal, otolith, and proprioceptive inputs, and in non-primate species full-field visual motion robustly modulates NU activity. Here, we tested whether visual roll motion, known to bias perceived orientation relative to gravity, alters the internal gravity-referenced transformation used by NU neurons to encode vestibular self-motion. To test this, we recorded single-unit activity from NU Purkinje cells in rhesus macaques during whole-body translations in darkness, either without visual stimulation or after prolonged full-field optokinetic roll motion. We hypothesized that visual motion simulating head tilt would bias the NU’s internal gravity estimate, leading to altered translation-evoked responses. Contrary to this prediction, visual motion had no effect on either baseline firing rates or vestibular responses. Moreover, a computational model predicting visually induced shifts in neural tuning was not supported by the data. These results show that visual roll motion, although known to influence perceived orientation, does not bias gravity-referenced vestibular coding in the primate NU. This specialization may preserve a fast, body-anchored gravity estimate for postural and reflexive motor control, delegating visual–vestibular integration for perception to downstream circuits.

Superior canal dehiscence syndrome (SCDS) is a peripheral vestibular disorder caused by a defect in the bony roof of the superior semicircular canal that alters inner-ear mechanics and produces abnormal vestibular stimulation and imbalance. Although postural instability is a prominent complaint in SCDS, how this disorder alters the kinematics of standing balance remains unclear. Here, we quantified how unilateral SCDS affects head and postural control during quiet standing using wearable inertial measurement units (IMUs). Angular velocities and linear accelerations were recorded from head and waist IMUs, enabling measurement of six-dimensional kinematics during seven standing balance tasks that systematically varied visual input and surface compliance. These measures revealed greater range and variability of head and waist motion in individuals with SCDS than in controls, indicating reduced stability during quiet standing. Group differences were greatest when visual and somatosensory feedback were degraded (e.g., standing on a foam surface with eyes closed), conditions that increase reliance on vestibular cues. Between-group differences were most consistently observed in pitch and roll kinematics, with increased yaw variability in several tasks. Variability in yaw head velocity correlated with oscillopsia and persistent postural-perceptual dizziness, whereas variability of waist vertical acceleration and yaw velocity mainly correlated with greater contra-lesional amplitude of cervical vestibular myogenic potential and impaired gait function, respectively. Global kinematic scores derived from IMU data significantly differentiated individuals with SCDS from healthy controls. Together, these findings demonstrate that unilateral SCDS produces multiplanar balance impairments, and that wearable kinematic analysis may provide a sensitive approach for quantifying postural instability and identifying underlying mechanisms of balance difficulties, complementing current standard functional balance assessments. In addition, our findings have the potential to inform future balance rehabilitation and fall prevention research in individuals with SCDS.

Accurate perception of self-motion requires that vestibular input be transformed into neural representations suitable for integrating multisensory cues to guide action. Here, we demonstrate that vestibular cortical neurons represent the self-motion stimuli encountered during everyday activities in a fundamentally different manner than the artificial self-motion stimuli typically used. Using stimuli whose waveforms reproduce the head dynamics encountered in natural behavior, we found that neural activity no longer tracked stimulus velocity through graded firing-rate changes, as observed during artificial sinusoidal stimulation, but instead reliably encoded distinct motion features through burst firing. At the population level, these bursts formed a distributed code that enhanced information transmission by reducing redundancy. This transformation emerged only during natural stimulation and was absent in the vestibular thalamus. Together, our results demonstrate that the vestibular cortex constructs a distributed, feature-based representation of natural self-motion, fundamentally reshaping our understanding of how cortical circuits encode vestibular signals to mediate perception.

Stable gaze is essential for effective navigation, yet during locomotion each stride generates phasic head movements that can destabilize the visual scene. The vestibular system is well positioned to counter these disturbances by sensing head motion and rapidly generating reflexive compensatory eye movements, but its specific contribution to gaze stabilization during locomotion is not well understood. To directly test the vestibular system's contribution during walking, we compared gait and gaze kinematics in male and female rhesus macaques with normal vestibular function and those with chronic bilateral vestibular loss (BVL) during treadmill walking at multiple speeds and during overground locomotion. We found that BVL animals showed systematic gait abnormalities, including markedly increased gait variability across conditions. Gaze stabilization deficits were equally pronounced: normal monkeys effectively stabilized gaze across conditions, whereas BVL animals exhibited reduced and more variable eye movements that failed to compensate for head motion. Vestibular loss increased the magnitude of reorienting eye movements, consistent with an increased tolerance for gaze position error. Extending established oculomotor models to incorporate intrinsic noise and elevated error thresholds reproduced these behavioral signatures, revealing that chronic vestibular loss drives a fundamental recalibration of gaze control strategies. Together, these findings demonstrate that vestibular input provides a central scaffold for stabilizing gaze and gait during natural locomotion and establish essential behavioral benchmarks for future neural, rehabilitative, and prosthetic interventions.

The vestibular system of the inner ear provides head motion and orientation information required for maintaining balance and spatial orientation. Each of the five vestibular sensory organs contains type I and type II hair cells (HCs). Type I HCs are particularly notable for their evolutionary adaptability and unique calyceal synapses, in which the vestibular afferent nerve ending envelopes the HC body. In vitro studies indicate that calyceal synapses can transduce signals from HCs to afferents via nonquantal transmission, a mechanism proposed to be faster than conventional bouton synaptic transmission. In specialized regions of vestibular organs—striolae and central zones—many afferents form calyces that encase multiple type I HC bodies, suggesting that nonquantal transmission could be especially important in these regions. Consistently, striolar/central zone afferents are thought to preferentially mediate rapid and high-frequency stimulations. However, the direct consequences of selectively losing these HCs remain unknown. Here, we investigated the role of type I HCs within striolar/central zones by genetically ablating these cells. Reduction of type I HCs in these regions led to a loss of calyces and a compensatory increase in striolar type II HCs. These mutants exhibit reduced vestibular-evoked potentials, a response driven predominantly by striolar activity. In contrast, the vestibulo-ocular reflex, which is thought not to require striolar/central zone function, remained intact. Furthermore, loss of striolar/central zone-specific type I HCs causes head tremor in pups and abnormal head motion in adults, indicating that these HCs are essential for mediating head stability and postural control.

In afoveate species such as mice, it is accepted that gaze is typically redirected by head movements with a saccade-and-fixate strategy, while the eyes primarily stabilize vision within a limited oculomotor range. This view suggests that the accompanying eye movements are primarily reflexive, driven by mechanisms like the vestibulo-ocular reflex (VOR). However, emerging evidence challenges this assumption, suggesting that eye movements during active head motion may not be purely reflex-driven. Here, we directly test whether eye movements in mice are actively coordinated as part of voluntary gaze redirection rather than being reflexive. By systematically monitoring head and pupil positions during goal-directed orienting in a cohort of male mice, we find that mice generated active saccadic eye movements whose onsets are tightly linked to head movements. Furthermore, these saccadic eye movements occur at markedly shorter latencies than reflexive quick-phase eye movements evoked by comparable passive head rotations. Importantly, the interplay between coordinated eye and head movements during voluntary orienting resemble the predictable, stereotyped gaze patterns seen in foveate animals, such as primates. Our results suggest that mice possess an evolutionarily conserved mechanism for gaze redirection, integrating voluntary eye-head coordination similar to that of foveate vertebrates. These findings reframe the prevailing view by demonstrating an actively coordinated eye-head component to gaze redirection under goal-directed conditions in mice, complementing established reflexive mechanisms.

In afoveate species such as mice, it is accepted that gaze is typically redirected by head movements with a saccade-and-fixate strategy, while the eyes primarily stabilize vision within a limited oculomotor range. This view suggests that the accompanying eye movements are primarily reflexive, driven by mechanisms like the vestibulo-ocular reflex (VOR). However, emerging evidence challenges this assumption, suggesting that eye movements during active head motion may not be purely reflex-driven. Here, we directly test whether eye movements in mice are actively coordinated as part of voluntary gaze redirection rather than being reflexive. By systematically monitoring head and pupil positions during goal-directed orienting in a cohort of male mice, we find that mice generated active saccadic eye movements whose onsets are tightly linked to head movements. Furthermore, these saccadic eye movements occur at markedly shorter latencies than reflexive quick-phase eye movements evoked by comparable passive head rotations. Importantly, the interplay between coordinated eye and head movements during voluntary orienting resemble the predictable, stereotyped gaze patterns seen in foveate animals, such as primates. Our results suggest that mice possess an evolutionarily conserved mechanism for gaze redirection, integrating voluntary eye-head coordination similar to that of foveate vertebrates. These findings reframe the prevailing view by demonstrating an actively coordinated eye-head component to gaze redirection under goal-directed conditions in mice, complementing established reflexive mechanisms.