More than 150 deafness-associated genes have been identified, but their expression across human cell types remains largely descriptive and incompletely mapped. Developmental pathways are well described in animal models, yet species differences may limit their translational relevance to humans. Moreover, no established framework existed for identifying the regulatory programs that control human inner ear cell fate. Single-cell RNA sequencing has transformed our understanding of human developmental biology in organs such as the skin, but in the inner ear field most single-cell studies have focused on the mouse cochlea, leaving human inner ear development, and the distinction between cochlear and vestibular regions, poorly defined. Human pluripotent stem cell-derived inner ear organoids are valuable tools for studying human-specific cell types, but they lack key cell types essential for normal function, particularly the secretory epithelia that maintain the ionic balance of the endolymph.

Now a team led by Wouter H. van der Valk, Shantha Devi Udayappan and Heiko Locher at Leiden University Medical Center, working with colleagues in Belgium and at Boston Children’s Hospital and Harvard Medical School, has addressed these gaps with a resource they call HIEDRA, the Human Inner Ear Development snRNA-seq Atlas. Published in Nature Neuroscience, the atlas is built from single-nucleus RNA sequencing of nine human fetal inner ear samples spanning fetal weeks 7 through 15, a window that captures the critical events of cell type specification, including cochlear elongation into its characteristic spiral shape, the onset of hair cell formation around fetal week 10, and the emergence of structures such as the tectorial membrane, the stria vascularis and Reissner’s membrane. After rigorous quality control, the datasets were integrated into an atlas of 42 annotated clusters containing cochlear and vestibular epithelia, hair cells, mesenchymal populations, neurons, Schwann cells, chondrocytes, melanocytes, endothelial cells, immune cells and cycling cells.

The technical power of HIEDRA lies in its ability to resolve transcriptional identities along known spatial domains. Cochlear epithelial cells segregated along the duct floor into medial, prosensory and lateral domains, destined to form the inner sulcus and interdental cells, the organ of Corti, and the outer sulcus respectively. A similar organization was observed in the cochlear roof, where a medial region gives rise to Reissner’s membrane and a lateral region forms the marginal cells of the stria vascularis. Notably, the gene ANOS1, mutations in which cause hearing loss of unknown mechanism, was highly expressed in this lateral roof region, suggesting that ANOS1 may contribute to pathways involved in stria vascularis development. In the vestibular epithelium, supporting cells separated into ampulla-associated and otolith-associated populations, corresponding to the cristae ampullaris and the utricle and saccule, with differential expression of genes such as NEGR1, KCNIP4 and MECOM reflecting their anatomical origins.

Cochlear and vestibular hair cells, though highly correlated, showed distinct transcriptional signatures. Cochlear hair cells enriched genes including UNC5B and ROBO2, the latter essential for cochlear hair cell innervation, while vestibular hair cells showed enrichment of XIRP2 and GALNTL6, genes also reported in developing mouse cochlear hair cells, suggesting that observed differences may partly reflect spatiotemporal variation in hair cell maturation rather than fully distinct developmental programs. Spiral ganglion-like neurons expressed markers such as PLXDC2, SEMA3A, NTNG1, ZFPM2 and ROR1, whereas vestibular ganglion-like neurons showed enriched expression of PCDH9, TAFA2 and RGS7, consistent with their distinct identities. The mesenchymal compartment revealed otic capsule-like clusters with osteoblast-like gene signatures, otic mesenchyme cell clusters expressing markers such as TBX18, CRYM and the hearing loss-associated genes OTOR, COCH and POU3F4, and shared populations of pericytes, endothelial cells, immune cells, melanocytes and Schwann cells, with melanocytes and endothelial cells increasing over time, consistent with inner ear development.

To validate the atlas, the team generated a separate dataset from a fetal week 12.4 inner ear in which the cochlea and vestibular system were manually separated before nuclei isolation. Jaccard similarity analysis quantified the overlap of gene expression between annotated cell types, and vestibular and cochlear epithelial clusters showed strong concordance. Reference-based mapping of HIEDRA hair cells to the validation dataset confirmed that cochlear hair cells mapped to cochlear hair cells and vestibular hair cells to vestibular hair cells. Cross-species comparisons with publicly available mouse single-cell data from the vestibular crista ampullaris and cochlea reinforced the accuracy of the annotations, and label transfer from a mouse cochlear reference spanning embryonic days 14, 16 and postnatal day 1 increased annotation granularity within the human cochlear epithelium, resolving finer subtypes such as inner and outer pillar cells, Deiters’ cells, inner phalangeal cells, Hensen’s cells and Claudius’ cells.

Beyond descriptive classification, the researchers reconstructed developmental trajectories to infer candidate transcriptional drivers of lineage formation. Applying trajectory inference to cochlear sensory differentiation across pseudotime, they identified three transcriptional states: prosensory, marked by ISL1 and JAG1; sensory, marked by GATA3, CDKN1B, SOX2 and LGR5; and hair cell, marked by INSM1, POU3F4, MYO7A, FGF8 and OTOF. Gene set enrichment analysis along the pseudotime trajectory revealed that PI3K-Akt, ERBB, Wnt, AMPK, Hippo and phospholipase D signaling were active across prosensory and sensory states, while TGF-β and Hippo signaling were suppressed in the hair cell state, indicating that their downregulation may be a necessary step for hair cell fate acquisition. Among the genes nominated by gene regulatory network analysis as candidates connected to the stereocilia program, ANKFN1 emerged as the most robust, showing a significant positive association with a stereocilia gene module score in both cochlear and vestibular hair cells, a finding consistent with the known disruption of Ankfn1 homologs in zebrafish causing vestibular defects.

Mapping disease-associated genes onto HIEDRA cell types revealed selective vulnerabilities. Genes linked to syndromic and nonsyndromic hearing loss, Ménière’s disease, presbycusis, vestibular schwannoma, ototoxicity and tinnitus were cross-referenced with cell populations, and the highest gene burden was observed in the cochlear and vestibular sensory units. However, disorder genes were also highly enriched in the secretory units, which include the cochlear lateral roof cells, vestibular dark cells and melanocytes, cell types that maintain endolymph ionic homeostasis, a critical process for normal inner ear function. The team also identified a potential mechanism linking RIPOR2 mutations, which cause adult-onset hearing loss, to otic mesenchyme cell dysfunction, as RIPOR2 was enriched in both vestibular and cochlear otic mesenchyme subtypes in addition to its known role in stereocilia function. These findings highlight that disorders may arise from dysfunction in both sensory and nonsensory lineages, and that so-called deafness genes may also impact vestibular function.

The most striking mechanistic insight came from the analysis of cochlear lateral roof cells and vestibular dark cells, two poorly characterized secretory populations that regulate potassium homeostasis in the endolymph. Trajectory inference identified early and late transcriptional states in both lineages, and pathway enrichment revealed Wnt, TGF-β and Hedgehog signaling among the pathways enriched in the early state that become less engaged in the late state. Hedgehog signaling stood out because of its central role in early inner ear morphogenesis and its limited prior association with secretory cell specification. Critically, both cell types expressed PTCH1, SMO, KIF7, GLI2 and GLI3 but showed little to no GLI1 expression, which implies the absence of ligand-induced activation, suggesting that repression of Hedgehog signaling may be required for secretory epithelial differentiation.

To test this prediction functionally, the team used human inner ear organoids derived from a GMP-compliant induced pluripotent stem cell line. Previous work had shown that these organoids contain vestibular sensory epithelium but that secretory dark cells do not spontaneously develop. Because sensory and secretory cells develop in parallel in the inner ear, the researchers inhibited Hedgehog signaling with cyclopamine from day 15 to day 30 of organoid differentiation, the window in which vestibular hair cells emerge transcriptionally by day 18 and are detectable by immunohistochemistry by day 30. At day 60, control organoids formed SOX2-positive sensory epithelium but lacked DACH1-positive, OTX2-negative dark cells, whereas cyclopamine-treated organoids developed both SOX2-positive sensory epithelium and DACH1-positive, OTX2-negative vestibular dark cell-like epithelium expressing early ion channel markers including SLC26A4, ATP1B2 and BSND. The treated organoids also showed integration of MLANA-positive melanocytes disrupting the LAM-positive basal membrane, all hallmarks of vestibular secretory function. Single-nucleus RNA sequencing of day 90 cyclopamine-treated organoids confirmed the emergence of dark cell-like populations comprising roughly 22 percent of the otic epithelial cells, compared with roughly 43 percent vestibular supporting cells. These results demonstrate that Hedgehog inhibition is critical for dark cell differentiation in human inner ear organoids, validating the developmental insights from HIEDRA and expanding the model’s capacity to capture the major functional cell types of the human inner ear. The atlas is publicly available through the gEAR portal and the UniApp Dataportal, positioning HIEDRA as both a reference atlas and a mechanistic framework for the developing human inner ear, and illustrating how human developmental atlases can directly inform improved experimental models for mechanistic and translational studies.

Subject of Research: Single-nucleus transcriptomic atlas of human inner ear development

Article Title: A single-nucleus transcriptomic atlas of human inner ear development

Article References: van der Valk, W. H., Udayappan, S. D., van Beelen, E. S. A., Goveia, J., Beatovic, A., Moisse, M., Menafra, R., de Groot, J. C. M. J., Koehler, K. R., van Benthem, P. P. G., & Locher, H. (2026). A single-nucleus transcriptomic atlas of human inner ear development. Nature Neuroscience. https://doi.org/10.1038/s41593-026-02432-8

Image Credits: AI Generated

DOI: 10.1038/s41593-026-02432-8

Keywords: inner ear, single-nucleus RNA sequencing, transcriptomic atlas, Hedgehog signaling, inner ear organoids, hearing loss, vestibular system, gene therapy, cell fate specification, stria vascularis, single-nucleus, transcriptomic

The researchers asked a deceptively simple question: what happens to walking balance when the eyes are fed misleading information about self-motion, and does aging make the consequences worse? Everyday life is full of such moments. When we glance at a stationary object while the scenery slides past a train window, or when we track a moving face in a crowd, the visual system generates signals that can be mistaken for movement of our own body. These illusions, known as visually induced self-motion perceptions, can trigger real postural responses even though the body has not actually moved. Younger adults appear to handle these conflicts reasonably well, but the researchers suspected that older adults, whose vestibular and proprioceptive systems degrade with age and who are known to lean more heavily on vision for balance, might be far more susceptible.

To test this, the team recruited fourteen healthy older adults with an average age of seventy-five and compared them with sixteen younger adults averaging twenty-three years old, using data from the younger group that the same laboratory had collected in a previous experiment. All participants walked on an instrumented treadmill at a fixed speed of 3.6 kilometers per hour while a large screen placed 1.60 meters in front of them displayed a background of black-and-white vertical stripes and a red target dot at eye level. Optical motion capture, sampling at fifty frames per second, tracked marker clusters on the heels, pelvis, trunk, and head, allowing the researchers to reconstruct the mediolateral trajectory of the center of mass, approximated from the pelvis markers, with millimeter precision.

The experiment imposed three distinct kinds of visual trickery. In the moving background condition, participants fixated the stationary red dot while the striped background swept forty-five degrees to the right over four seconds, held there for eight seconds, and returned. In the two target-tracking conditions, the background stayed still while the red dot itself moved to the right; in one version participants tracked it with combined head and eye movements, and in the other with eye movements alone while keeping the head stationary. Each five-minute trial contained roughly fourteen perturbations, triggered at right heel strikes and separated by six to eight randomly spaced steps. A normal walking trial without any perturbations served as the baseline against which all effects were measured.

The first major finding concerned overall gait variability. Across entire trials, both age groups showed significantly increased variability in the mediolateral position of the center of mass during all three perturbation conditions compared with normal walking, with large effect sizes. The older adults also showed greater overall center of mass variability than the younger adults regardless of condition, consistent with a general age-related decline in frontal plane balance control. Interestingly, however, the perturbations did not disproportionately inflate variability in the older group relative to the younger one, a result the authors attributed to the discrete, intermittent nature of the perturbations, which left unperturbed stretches of walking that diluted the age difference over the whole trial.

The real drama unfolded within the perturbation epochs themselves. When the background moved, younger adults consistently shifted their center of mass to the left, opposite to the rightward background motion, exactly as the self-motion illusion would predict: the brain interprets the moving background as evidence that the body is drifting left, and the nervous system responds by stepping to extend the base of support in that perceived direction. The older adults initially responded the same way, but something remarkable happened over repeated exposures: their deviation direction gradually reversed, drifting toward the direction of the background movement instead of away from it. This reversal, confirmed by a significant interaction between age and repetition in a linear mixed-effects model, may reflect either a loss of attentional fixation on the target, causing older participants to treat the moving background as the object of interest, or a strategic shift toward faster corrective moments generated by the stance leg rather than slower foot-placement adjustments.

The target-tracking conditions exposed an even sharper age divide. When participants tracked the moving target with head rotation, both groups deviated toward the target, but the older adults deviated earlier, starting at the very beginning of the target’s movement rather than after it had stopped, and their peak deviations were a staggering 8.5 times those of the younger adults during the moving phase and 3.8 times during the stationary phase. In the eye-movement-only condition, older adults again deviated earlier, though the peak magnitudes between groups were statistically similar. The researchers explain this pattern through the mechanics of sensory cancellation. When we actively rotate our head, an efference copy of the neck motor command allows the vestibular nuclei to suppress vestibular signals that are self-generated, a mechanism elegantly demonstrated in rhesus monkeys. If aging degrades the neck proprioceptive information needed to validate that prediction, the suppression fails, and the combined visual, vestibular, and proprioceptive conflict becomes far harder to resolve, which would explain why head rotation made the age effect so much larger.

The adaptation results carried perhaps the most hopeful message. In the eye-movement-only condition, the older adults’ center of mass deviations shrank significantly across the thirteen analyzed perturbation repetitions, while the younger adults, whose initial responses were small to begin with, showed no systematic change. This suggests that the aging nervous system retains a functional capacity for sensory reweighting, the process by which the brain dynamically adjusts the reliability it assigns to each sensory channel, gradually discounting visual information that proves unreliable. Crucially, however, this downweighting did not emerge in the head-rotation condition for either group, presumably because head movement simultaneously corrupted vestibular and somatosensory inputs, leaving no clean alternative channel for the brain to trust instead.

The practical stakes of these findings became vivid during testing itself. Three older participants deviated so far from the treadmill’s center during the tracking conditions, frequently glancing down at their feet for additional visual anchoring, that the measurements had to be terminated for safety. The authors also acknowledge important limitations: the treadmill belts provide proprioceptive and cutaneous cues that may constrain responses, the harness worn by older participants for safety may have supplied subtle sensory feedback, and the healthy, active volunteers who completed the protocol likely represent a fitter segment of the elderly population, meaning the true effects of aging in the general public may be even larger than measured. The study also cannot fully disentangle effects on balance control from effects on heading direction, since gaze and head orientation influence both.

Nevertheless, the conclusions carry real weight for fall prevention. Falls remain a leading cause of injury and loss of independence in older adults, and this work pinpoints a specific, everyday mechanism of vulnerability: when the visual scene moves or when the eyes chase a moving target, the aging brain struggles to correct the resulting self-motion illusion using vestibular and proprioceptive evidence, and the body’s walking path drifts accordingly. The encouraging corollary is that repeated exposure to such sensory conflicts appears to teach the older nervous system to discount misleading vision, at least when the head stays still. That plasticity opens a potential avenue for balance training programs that deliberately expose older adults to controlled visual perturbations, teaching the brain when to stop believing its eyes.

Subject of Research: Age-related differences in balance control during walking under repeated visual perturbations

Article Title: Balance control is more affected in older than younger adults by repeated visual perturbations during walking

Article References: Li, Y., Lambrecht, E., Bruijn, S. M., & van Dieën, J. H. (2026). Balance control is more affected in older than younger adults by repeated visual perturbations during walking. GeroScience. https://doi.org/10.1007/s11357-026-02573-5

Image Credits: AI Generated

DOI: 10.1007/s11357-026-02573-5

Keywords: balance control, aging, visual perturbation, gait, center of mass, sensory reweighting, vestibular system, proprioception, self-motion perception, treadmill walking, fall prevention, GeroScience

The study, led by Yuehua Geng and colleagues at Hebei University of Technology together with a collaborator at Tianjin Huanhu Hospital, rests on a growing body of evidence that the vestibular organs of the inner ear are exquisitely sensitive to magnetic fields. The dominant theory holds that the tiny crystals of calcium carbonate embedded in the vestibular system’s otoconia, which normally act as gravity sensors, behave faintly like magnets when exposed to strong, static or low-frequency magnetic fields. When a magnetic field is applied asymmetrically, these crystals experience forces that trick the brain into perceiving head movement that never happened. This is why patients emerging from high-field MRI scanners often report vertigo and involuntary eye movements called nystagmus. Rather than treating this effect as a nuisance, the researchers asked whether it could be harnessed deliberately, and in a controlled dose, to counteract the sensory conflict that gives rise to VIMS.

That conflict is thought to sit at the heart of motion sickness itself. When the eyes report swift, sweeping motion through a virtual landscape while the vestibular system reports a body sitting perfectly still, the brain receives mismatched signals about self-motion. The prevailing explanation, often framed through sensory conflict or postural instability theory, suggests that this discrepancy triggers the classic symptoms of nausea, dizziness, sweating, fatigue and headache. If magnetic vestibular stimulation can add a calibrated vestibular signal to the mix, the researchers reasoned, it might partially reconcile the conflicting streams of information, or at least shift the balance system’s set point in a way that reduces the perceived conflict. Conversely, an improperly tuned stimulation could add yet another discordant signal and make the sickness worse. The study was designed to test precisely this dose-dependence.

Twenty healthy young adults took part in a repeated-measures experiment in which each participant completed five separate sessions. One session served as a baseline control with no virtual reality exposure. In the remaining four, participants viewed VR videos known to provoke VIMS. During those VR sessions, magnetic vestibular stimulation was delivered at three different intensities, set at 90 percent, 100 percent and 110 percent of each individual’s resting motor threshold, a standard reference measure in brain stimulation research that personalizes the stimulation strength to the participant’s own nervous system. Anchoring the intensities to the resting motor threshold, typically measured by observing responses in hand muscles to transcranial magnetic stimulation, ensured that every participant received comparable relative doses despite natural variation in neural excitability between individuals.

To quantify how sick participants felt, the researchers used the Simulator Sickness Questionnaire, a widely adopted instrument that yields a total score along with subscores for nausea, oculomotor strain and disorientation. Questionnaires were administered before and after each session, allowing the team to compute symptom changes attributable to each experimental condition. In parallel, the researchers recorded resting-state electroencephalography after every session and analyzed the data using brain functional network analysis across multiple EEG frequency bands. This approach goes beyond simple power measurements, treating the brain as a network of interacting regions and computing parameters that describe how strongly and how efficiently those regions communicate at rest, from the slow delta and theta rhythms through alpha and beta up into the faster gamma range.

The symptom data told a strikingly non-linear story. Compared with VR exposure alone, stimulation at 110 percent of resting motor threshold was associated with a more favorable symptom profile on the Simulator Sickness Questionnaire, with participants reporting reduced sickness overall. Stimulation at 90 percent, however, showed the opposite pattern: it was associated with aggravated symptoms, leaving participants feeling worse than they did after VR alone. The intermediate 100 percent condition fell between these extremes. In other words, magnetic vestibular stimulation was not simply good or bad for motion sickness; its effect hinged critically on dose, with stronger stimulation appearing protective and weaker stimulation apparently compounding the sensory conflict rather than resolving it.

The EEG network analysis added a neurophysiological dimension to these behavioral findings. Although the authors describe these network results as exploratory, they observed session-related differences in functional network characteristics across multiple frequency bands. Notably, the patterns recorded after the 110 percent stimulation sessions generally resembled the baseline condition more closely than the patterns seen after VR exposure alone or with lower-intensity stimulation. This suggests that high-intensity magnetic stimulation may have helped the brain’s resting network organization recover toward its normal configuration after the disruptive VR experience, hinting that the subjective symptom relief tracked measurable changes in large-scale brain dynamics. Differences appeared in networks spanning several frequency ranges, consistent with the idea that vestibular input propagates widely through cortical and subcortical circuits that govern spatial orientation, autonomic responses and arousal.

The authors are careful to frame these conclusions within the limits of the study. The sample was small, consisting of twenty healthy young adults, and the network-level EEG findings are exploratory rather than definitive. The researchers explicitly state that their findings should be confirmed in larger studies before any clinical or consumer applications are pursued. Individual differences in inner-ear anatomy, the orientation of the labyrinth relative to the applied field, and personal susceptibility to motion sickness are all known to modulate responses to magnetic vestibular stimulation, and these variables would need systematic attention in follow-up work. The protocol also involved repeated sessions, and the authors’ funding came from the CAS Superconducting Research Project and the Hebei Natural Science Foundation, reflecting the superconducting magnet technology underlying the stimulation approach.

Even with those caveats, the implications are considerable. If the dose-dependence holds up in larger trials, the study points toward a design principle rather than a single fix: vestibular stimulation for motion sickness must be calibrated individually, and getting the dose wrong could actively harm the user experience. A future VR headset or clinical device might one day pair with a magnetic stimulation module that tunes intensity to a user’s resting motor threshold, offering a drug-free, non-invasive way to extend comfortable session times for training simulators, rehabilitation programs, telemedicine and entertainment. Beyond VR, the same principle could benefit passengers prone to seasickness or simulator sickness in aviation and driving simulation. The work also strengthens the scientific case that the vestibular system is a legitimate and tractable target for magnetic neuromodulation, a field that has matured from the serendipitous observation of MRI-induced dizziness into a quantitative discipline with dosing frameworks, personalized thresholds and objective neuroimaging endpoints. For the millions of would-be VR users who currently abandon headsets within minutes, that progression carries real promise: the sensory conflict behind their discomfort may soon be something engineers can measure, model and magnetically quiet.

Subject of Research: The dose-dependent regulatory effect of magnetic vestibular stimulation on visually induced motion sickness and resting-state EEG networks in virtual reality users

Article Title: Study on the regulatory effect of magnetic vestibular stimulation on visually induced motion sickness

Article References: Geng, Y., Li, X., Li, Y., Zhai, X., & Xu, G. (2026). Study on the regulatory effect of magnetic vestibular stimulation on visually induced motion sickness. Medical & Biological Engineering & Computing. https://doi.org/10.1007/s11517-026-03666-1

Image Credits: AI Generated

DOI: 10.1007/s11517-026-03666-1

Keywords: magnetic vestibular stimulation, visually induced motion sickness, virtual reality, EEG functional networks, Simulator Sickness Questionnaire, resting motor threshold, vestibular system, brain stimulation, cybersickness, neuromodulation, regulatory, effect