Case Report: Vestibular cortex morphometry in Usher Syndrome: a case-based study

1 Introduction

The vestibular cortex constitutes a complex, distributed network involved in multiple functions, including spatial orientation, balance, and multisensory integration (Bottini et al., 2001; zu Eulenburg et al., 2013). The vestibular system integrates three functional domains: a reflexive sensorimotor control (mediated by brainstem and cerebellum), perception of movement and control of voluntary movement (involving the cortex and subcortex), and higher-order vestibular functions, including cognitive processing (cortex) (Dieterich and Brandt, 2015). Recent neuroimaging evidence suggests that the vestibular cortex comprises at least 10 separate cortical areas, primarily located in the depth of the lateral sulcus and perisylvian cortex, integrating the posterior insula, parietal operculum, and temporoparietal junction (Lopez, 2015). Additional vestibular-responsive areas have been identified in the primary somatosensory cortex, posterior parietal cortex, frontal cortex, extrastriate cortex, cingulate cortex, and hippocampus (Lopez, 2015; Arvaniti et al., 2024). Importantly, lateralization of the vestibular cortex has been observed, typically favoring the non-dominant (right) hemisphere, matched with the handedness (Dieterich et al., 2003; Dieterich and Brandt, 2018).

Usher Syndrome, a rare genetic cause of deaf blindness, provides a unique model for studying the impact of multisensory deficits on cortical organization, including vestibular dysfunction. Patients with Usher Syndrome types 1 and 2 exhibit congenital severe-to-profound hearing loss and retinitis pigmentosa, together with vestibular dysfunction that is typically severe and clinically apparent in infancy in USH1, leading to delayed motor milestones, whereas vestibular deficits in USH2 are generally milder, centrally compensated, and not functionally apparent during early childhood (Nisenbaum et al., 2022; Amorim et al., 2025a). This vestibular dysfunction significantly increases the fall risk in patients (Agrawal et al., 2009). However, despite its clinical relevance and potentially disabling effects, imbalance in USH remains poorly understood, particularly with regard to its morphometric features and functional correlates (Amorim et al., 2025a).

While cross-modal cortical plasticity following sensory loss has been extensively studied in the visual and auditory domains, research on vestibular loss-induced neuroplasticity remains limited (Grégoire et al., 2022). Several voxel-based morphometric (VBM) studies in retinitis pigmentosa have demonstrated reduced GMV in visual cortical areas, suggesting early neurodegenerative changes, even before complete blindness develops. These findings have important functional restoration prognosis, as they relate to the minimal integrity of the visual pathways (Rita Machado et al., 2017).

Few studies have related VBM vestibular cortex changes with vestibular loss, including cognitive and perceptual functions, such as spatial navigation, memory, vertical perception, internal models of gravity, bodily awareness and self-consciousness (Lopez, 2015; Brandt et al., 2005; Hüfner et al., 2009; Jacob et al., 2020).

We hypothesize that USH patients might exhibit significant volume changes in vestibular cortical areas, reflecting both primary sensory deficits and putative compensatory neuroplastic phenomena. To date, no studies have characterized the GMV in the vestibular cortex of Usher Syndrome patients, a condition marked by multisensory deficits. Conducting morphometric analysis of the vestibular cortex in Usher Syndrome may yield significant insights applicable to a wide range of vestibular disorders, potentially informing both diagnostic approaches and therapeutic interventions.

In this study, we explore the morphometry of the vestibular cortex in two USH patients with contrasting degrees of vestibular impairment, further associating these findings with vestibular function assessment, and exploring potential mechanisms of vestibular compensation.

2 Materials and methods

Two male patients with genetically confirmed USH, aged 21 years (USH1) and 48 years (USH2) underwent a comprehensive evaluation. Clinical assessments included a structured interview focusing on hearing and vestibular symptoms, administration of the Dizziness Handicap Inventory and Hospital Anxiety and Depression Scales, and a complete otoneurologic examination. Audiovestibular testing comprised audiogram, caloric test, video head impulse test, vestibular evoked myogenic potentials and posturography and have been described in detail elsewhere (Amorim et al., 2025b). Genotypes and best-corrected visual acuity were retrieved from clinical records. A 6-min T1-weighted magnetization-prepared rapid acquisition with gradient echo (MPRAGE) sequence,1 mm³ isotropic resolution, was performed in a 3T scanner (Magneton TrioTim, Siemens AG, Germany), using a 12-channel birdcage head coil. Fully automated volumetric analysis was conducted using the validated VolBrain platform (https://volbrain.net), specifically the vol2Brain pipeline for supratentorial gray matter and the CERES pipeline for cerebellum. The vol2Brain pipeline provides segmentation of 135 different brain tissues and structures, at different anatomical scales, based on 3D convolution neural networks, with high accuracy even in lesioned brains (for technical details please see references Manjón et al., 2022 and Coupé et al., 2020). The pipeline estimates total intracranial volume (ICV) and used it to normalize volumetric data, presented as both absolute values (cm³) and relative values (% of total intracranial volume). The report highlights out-of-normal-range findings, considering expected limits (95%) of normalized volume in function of sex and age for each measure, extracted from several open-access imaging repositories. We focused on primary GMV regions of interest (ROIs), previously identified as components of the vestibular cortex and segmented in VolBrain including: the insula (anterior insula) (Lopez and Blanke, 2011), posterior insula (Brandt and Dieterich, 1999; Bense et al., 2004), and parietal operculum (Eickhoff et al., 2006; zu Eulenburg et al., 2012; Ibitoye et al., 2023; Kahane et al., 2003). Two additional important vestibular-related cortical areas, clearly segmented by Vol2Brain, were also considered GMV regions of interest: precuneus (Kahane et al., 2003; Lopez et al., 2012; Wiest et al., 2004) and hippocampus (Brandt et al., 2005; Göttlich et al., 2016). Finally, we included ROIs based on anatomic structures previously described to be associated with vestibular disorders and that are involved in central vestibular processing and compensation with subsequent GMV changes: parts of the visual cortex (lingual gyrus, medial and inferior occipital gyri) (Hong et al., 2014) and the cerebellum (Brandt et al., 2002; Della-Justina et al., 2015; Wurthmann et al., 2017). VolBrain has been validated in previous studies for its reliability and accuracy in neuroanatomical segmentation and volumetry (Manjósn and Coupé, 2016). The volumetric data related to the cerebellum was obtained using CERES pipeline, a package that produces reliable results for cerebellar lobule segmentation, based on Optimized PatchMatch Label fusion method, and for volume calculation (Romero et al., 2017). Our area of special interest in CERES was GMV of Cerebellum Lobule X as it corresponds to flocculo-nodular lobe, also known as vestibulocerebellum (Roostaei et al., 2014). We performed a descriptive analysis of clinical and paraclinical findings.

Written informed consent was obtained from the participants according to the Declaration of Helsinki, and the study protocol was approved by the Institutional Review Board (OBS.SF.75-2021).

3 Results

3.1 Case 1

The USH1 patient was a right-handed, deaf-mute male who communicated using sign language. He reported hearing loss since age of 2 years old and progressive vision loss since adolescence. No other relevant medical history was noted. Audiometry showed profound hearing loss; vestibular tests indicated bilateral vestibular loss. Posturography revealed high instability with a sensory organization score of 100% for vestibular/proprioceptive inputs and 0% for visual input (see Table 1).

Table 1. Patients‘ characteristics.

DHI, Dizziness handicap inventory; HADS, Hospital anxiety and depression scale.

^*Corrected visual acuity of the better eye converted to a decimal scale; SPV, slow phase velocity; vHIT, video Head Impulse test; VOR, vestibulo-ocular reflex; cVEMP, cervical Vestibular evoked myogenic potential; oVEMP, ocular Vestibular evoked myogenic potential; SOT, sensory organization test.

Compared to the reference values of a normal dataset, MRI analysis found increased GMV in the left precuneus [16.65 cm³ [1.0 % (0.7, 0.1)]] and significant asymmetry in the posterior insula [29.8% (−11.9, 22.1)] (see Table 2). The occipital cortex showed right dominance in the superior gyrus [47.2% (−18.4, 46.0)] and left dominance in the inferior gyrus [−31.1% (−27.6, 26.5)]. Reduced volumes were noted in cerebellar lobule X [0.78 cm³ [0.05% (0.2, 0.4)] right; 0.67 cm³ [0.04% (0.2, 0.4) left]], with significant rightward asymmetry [15.3% (−11.2, 14.7)]. No significant differences were found in hippocampal GM volume (Table 3).

Table 2. Gray Matter Volume (GMV) of regions of interest within the vestibular cortex in two patients with Usher Syndrome type1 (USH1) and type 2 (USH2), measured using the VolBrain pipeline.

All the volumes are presented in absolute value (measured in cm³) and in relative value (measured in relation to the intracranial volume). The asymmetry index is calculated as the difference between right and left volumes divided by their mean (in percent). Segmentation images are located in the Montreal Neurological Institute (MNI) space (neurological orientation). Values between brackets show expected limits (95%) of normalized volume in function of sex and age for each measure for reference purpose. Values outside the limits are highlighted (Manjósn and Coupé, 2016).

Table 3. Gray Matter Volume of the hippocampus, cerebellar lobule X and visual cortex in two patients with Usher Syndrome type1 (USH1) and type 2 (USH2), measured with VolBrain pipeline (including CERES).

All the volumes are presented in absolute value (measured in cm³) and in relative value (measured in relation to the intracranial volume). The asymmetry index is calculated as the difference between right and left volumes divided by their mean (in percent). Segmentation images are located in the Montreal Neurological Institute (MNI) space (neurological orientation). Values between brackets show expected limits (95%) of normalized volume in function of sex and age for each measure for reference purpose. Values outside the limits are highlighted (Manjósn and Coupé, 2016).

^aData from CERES.

A graphical comparison of cerebellar, occipital, and vestibular ROI volumes between cases is provided in Supplementary Figure S1.

3.2 Case 2

The USH2 patient was a right-handed male. He reported bilateral hearing loss since childhood, partially corrected with hearing aids from the age of 11 years old. He also mentioned instability, dizziness and one recent fall. Medical history included multiple myeloma diagnosed 8 years before, for which he underwent autologous medullary auto-transplant 2 years before, and he was currently on lenalidomide. Audiometry showed bilateral severe hearing loss. Vestibular tests revealed normal caloric responses and horizontal vHIT gains, but slightly decreased vertical canal gains without corrective saccades. Cervical and ocular VEMP were symmetric and considered to be normal. Posturography indicated low instability with normal sensory organization (100%) (see Table 1).

MRI-based VolBrain analysis revealed no significant deviations in the GMV of the vestibular cortex (Table 2), considering the expected volume based on a normal dataset. There was notable asymmetry in the inferior occipital gyrus, with a right-dominant index of 44.4% [−30.4, 23.1] and a volume difference of 6.37 cm³ [0.531% (0.3, 0.5) of ICV] was noted. Reduced volume in cerebellar Lobule X was observed, totaling 0.89 cm³ [0.0729% (0.4, 0.7) of ICV], with approximately 0.45 cm³ [0.04% (0.2, 0.4)] decrease on the right and 0.43 cm³[0.04% (0.2, 0.4)] on the left. No significant differences were found in hippocampal GM volume (see Table 3).

4 Discussion

This exploratory study thoroughly assessed two patients (USH1 and USH2) with contrasting vestibular profiles and their associated vestibular cortex morphometry. USH1, with congenital bilateral areflexia, exhibited increased GMV in the left precuneus and greater right volume asymmetry index in the posterior insula. In contrast, USH2, with minimal vestibular dysfunction, showed no relevant abnormalities in these regions. Both patients exhibited reduced GMV in cerebellar lobule X. Additionally, visual cortex asymmetries were also observed: USH1 showed a rightward asymmetry index in the superior occipital gyrus and a leftward asymmetry index in the inferior occipital gyrus, while USH2 had right-dominant asymmetry index in the inferior occipital gyrus.

In a typical USH1 patient, the increased GMV in the vestibular cortex may reflect compensatory neuroplasticity. Indeed, increases in GMV in the posterior insula and precuneus has been linked to vestibular compensation and spatial processing (Helmchen et al., 2011; Müller et al., 2018). These findings align with posturography results and prior studies on vestibular compensation (Amorim et al., 2025a; Helmchen et al., 2009).

Sensory loss leads to extensive adaptation of brain circuits to allow human navigation with its remaining senses, this is known as cross-modal plasticity. This plasticity involves two processes: cross-modal recruitment (the deprived cortex is recruited for processing remaining senses) and compensatory plasticity (spared sensory cortices enhance their own processing) (Lee and Whitt, 2015). In retinitis pigmentosa, progressive vision loss leads to tactile-evoked activation of the primary visual cortex (V1), this cross-model response has been purposed to account as a biomarker for potential individual differences in visual performance following sight recovery treatments (Cunningham et al., 2015). It is also known that brain plasticity across sensory modalities during deafness is associated with individual cochlear implant outcomes through the degree and nature of cross-modal reorganization in auditory and visual cortices (Anderson et al., 2017). The sensory substitution theory defends that when the brain experiences a severe absence of vestibular input, as seen in UHS1, it reallocates cortical resources to enhance processing of other sensory modalities, particularly proprioception and visual inputs, to compensate for the loss of vestibular function (Curthoys and Halmagyi, 1995). Psychophysical and neurophysiological tests have provided various examples of sensory loss in one modality being substituted by increased functional sensitivity in other modalities (Dieterich et al., 2007; Fabre et al., 2023; Jamali et al., 2014). Functional imaging studies in patients with vestibular loss indicated increased activation in the visual or somatosensory cortex reflecting this compensatory reorganization (Curthoys and Halmagyi, 1995; Jamali et al., 2014). This remodeling activity is also observed in other vestibular diseases. In acute vestibular neuritis, for example, PET imaging shows heightened metabolic activity in multisensory vestibular areas (posterior insula/parietoinsular vestibular cortex (PIVC), posterolateral thalamus, anterior cingulate, hippocampus) alongside reduced activity in visual and somatosensory cortices, reflecting reciprocal interactions between visual and vestibular systems (Bense et al., 2004). Persistent Postural-Perceptual Dizziness is associated with reduced gray matter volume and decreased functional connectivity within multisensory vestibular cortices, particularly the PIVC and posterior insula. This is accompanied by increased connectivity between the prefrontal cortex and visual and motor regions, suggesting maladaptive sensory reweighting with excessive visual dependence (Teh et al., 2022). Similarly, BVL demonstrates reduced functional connectivity in the posterior insula and parietal operculum. However, BVL additionally shows increased connectivity in the posterior cerebellum, consistent with compensatory reorganization (Lee et al., 2023). Structural alterations include reduced gray matter in the parahippocampal gyri, anterior cingulate cortex, and middle temporal gyrus, along with disrupted anatomical connectivity in the corpus callosum and fornix. Hippocampal atrophy is a consistent finding and correlates with spatial memory and navigation deficits (Bosmans et al., 2022).

Despite congenital vestibular loss, USH1 patient showed no hippocampal volume reduction, suggesting early-onset compensatory mechanisms. Previous research report mixed hippocampal changes in individuals with congenital bilateral vestibular loss or progressive peripheral vision loss, with spatial deficits linked to anterior hippocampal atrophy (Rita Machado et al., 2017; Brandt et al., 2005; Göttlich et al., 2016; Hüfner et al., 2011; Dobbels et al., 2019; Kremmyda et al., 2016; Helmchen et al., 2020). Our study did not reveal any significant difference in the hippocampal GMV, which highlights the importance of timing and chronicity of vestibular loss when interpreting structural brain changes. The absence of hippocampal atrophy in this young USH patient may indicate an early disease stage, where hippocampal neurodegeneration has not yet reached a detectable threshold, possibly buffered by compensatory mechanisms established since birth, given the congenital nature of the condition.

Vestibular rehabilitation (VR) accelerates recovery by activating central neuroplastic mechanisms. At the cellular level, VR promotes microgliogenesis and cell proliferation in the medial vestibular nucleus, facilitating compensation (Wu et al., 2025). Neuroimaging studies show that VR increases functional connectivity between the parietal operculum and frontal regions, and these connectivity changes correlate with improvements in anxiety and dizziness handicap (Chen et al., 2025). Balance training in healthy adults increases cortical thickness in visual and vestibular cortical regions (superior temporal cortex, visual association cortices), demonstrating that exercise-induced neuroplasticity can enhance vestibular processing (Rogge et al., 2018). Functional improvements are consistently observed across peripheral and central vestibular disorders, with significant reductions in dizziness handicap and increased balance confidence following individualized vestibular rehabilitation programs (Millar et al., 2020). These improvements are not always explained by changes in objective vestibular function (e.g., VOR gain), but are associated with enhanced behavioral performance and subjective recovery, indicating central compensation and sensory reweighting.

The dissociation between auditory and vestibular function is not unique to Usher Syndrome. For instance, in Ménière's disease—another inner ear disorder—audiometric loss does not correlate with caloric response, underscoring the independence of cochlear and vestibular pathways (Maihoub et al., 2022). In USH, this dissociation is further compounded by progressive visual loss, creating a triad of sensory deficits that may drive distinct patterns of cortical reorganization.

Vestibular disorders are linked to cognitive deficits, including impaired attention, visuospatial perception, spatial memory, and executive function (Danneels et al., 2020; Smith et al., 2024). While underlying mechanisms remain unclear, the vestibular system projects to cortical areas involved in cognition, sleep, autonomic functions and emotional responses—potentially explaining the symptoms reported by patients (Danneels et al., 2020; Smith et al., 2024). Despite congenital BVL, our USH1 patient reported minimal cognitive complaints—although not formally assessed—possibly due to early-age compensatory adaptation. The low DHI score in this patient further supports this interpretation and was somewhat unexpected, as patients with BVL typically report higher DHI scores, with a moderate correlation observed between objective vestibular deficits (e.g., vHIT gain) and DHI outcomes, such that lower vestibular function is generally associated with greater self-perceived handicap (Surmeli et al., 2026). Both brain neuroplasticity and the fact that objective and subjective measures frequently fail to correlate in patients with vestibular disease can explain this disparity (Helmchen et al., 2011, 2009; Yip and Strupp, 2018). Both USH patients scored high on the HADS, consistent with known associations between sensory loss, and psychiatric disorders (Blazer and Tucci, 2019; Lahmann et al., 2024; van Stiphout et al., 2023; Kiely et al., 2024; Molnár et al., 2022). Although available evidence suggests that HADS anxiety and depression scores in BVL, including in conditions such as USH1, are generally within the normal to mildly elevated range—indicating a lower prevalence and severity of psychiatric comorbidity compared with episodic vertigo or dizziness (Lahmann et al., 2024)—hearing loss, as observed in our two patients, appears to negatively affect quality of life (Jorissen et al., 2025). Furthermore, in BVL, clinically meaningful improvement over time is uncommon, supporting the rationale for early intervention—such as vestibular implantation—to prevent prolonged vestibular deprivation, which may reduce the efficacy of neural stimulation over time, similar to what has been observed with cochlear implantation (Loos et al., 2025).

Disparate observations in visual cortex areas of both patients should be further analyzed. Sensory substitution through vision has been described as part of vestibular compensation processes following vestibular loss (Lacour et al., 2016; Lacour and Tighilet, 2010). However, previous VBM studies have reported conflicting results, with some showing increased GMV in the visual cortex (Helmchen et al., 2009; zu Eulenburg et al., 2010), while others have found decreases (Hüfner et al., 2009). Additionally, studies in patients with retinitis pigmentosa have shown significantly reduced GMV (Rita Machado et al., 2017), which may add the effects related to vestibular dysfunction.

Both patients exhibited decreased GMV in lobule X, underscoring the cerebellum's role in balance and vestibular processing. The cerebellum integrates vestibular and sensorimotor inputs for balance, with lobule X (flocculus and nodulus) specifically processing vestibular signals (Roostaei et al., 2014). Vestibular dysfunction can induce neuroplastic changes in the cerebellum, potentially resulting in atrophy due to reduced afferent input. Cerebellar atrophy was noted in both USH1 and USH2 (Schaefer et al., 1998; Koizumi et al., 1988; Tamayo et al., 1996). While the underlying cause remains unclear—particularly in the USH2 case with minimal vestibular impairment—reduced multisensory input due to auditory and visual deficits may contribute to this finding, suggesting that decreased afferent stimulation could play a role in cerebellar structural changes (Baumann and Mattingley, 2010; Sens and de Almeida, 2007).

Importantly, variability in cortical GMV findings seems to depend on several factors, including differences in vestibular loss type (acquired or congenital), severity of phenotype, compensatory strategies, and individual factors such as age, sex, education, additional sensory deficits, mobility, and psychiatric comorbidities (Göttlich et al., 2016; zu Eulenburg et al., 2010; Smith, 2022). Additionally, hearing loss present in both USH1 and USH2 may also contribute to cortical changes.

All these factors may have contributed to the morphometric differences observed in our two patients.

This work has several limitations. VolBrain primarily focuses on large anatomical structures and lacks resolution for finer regions such as the gracile nucleus, limiting our ability to assess proprioceptive pathways involved in body orientation. Additionally, as VolBrain is based on anatomical rather than functional segmentation, key vestibular-related areas, such as MT/V5 and the frontal eye fields are not distinctly mapped, restricting analysis of potential compensatory changes in these areas.

The case-based, cross-sectional design limits generalizability and precludes assessment of longitudinal neuroplastic changes. The comorbid conditions of the USH2 patient, as well as the age differences between the patients, may have influenced the observed cortical volumes. Furthermore, the absence of a control group or patients with isolated sensory impairments (i.e., hearing or vision loss alone) limits the ability to distinguish and interpret the specific contribution of vestibular dysfunction to the observed brain changes. Future studies involving larger cohorts across USH subtypes are necessary to validate the conclusions drawn from this exploratory investigation. Including matched control groups comprising neurotypical individuals, as well as individuals with isolated hearing loss or visual loss, will help disentangle the specific contributions of each sensory deficit to the observed brain changes.

5 Conclusions

Vestibular cortex morphometry seems to be associated with vestibular function in Usher Syndrome, apparently distinguishing USH1 and USH2 despite their shared hearing loss. The lack of hippocampal atrophy in USH1, despite congenital bilateral vestibular loss, suggests that early-onset deprivation may promote compensatory neuroplasticity. This may help mitigate cognitive deficits through adaptive strategies developed during critical periods of brain maturation. On the other hand, cerebellar lobule X atrophy in both patients, seems to reflect lack of multisensory input, reinforcing its role in vestibular, auditory and visual integration. Finally, heterogeneous visual cortex findings and preserved hippocampal volume in USH1 most likely highlight the complex interplay between sensory loss, cortical reorganization and compensation. Our study highlights the need for a comprehensive multimodal assessment to better understand how multisensory deprivation shapes vestibular cortical architecture. Advancing our mapping of the vestibular network in conditions like USH may inform more targeted interventions and ultimately improve vestibular patients' quality of life.

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Supplementary material

The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fauot.2026.1767944/full#supplementary-material

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Footnotes

Edited by: András Molnár, Protone Audio Kft., Hungary

Reviewed by: Susann Michanski, South Westphalia University of Applied Sciences, Germany

Stefani Maihoub, Maihoub ENT Center, Cyprus

Reem Elbeltagy, Princess Nourah Bint Abdulrahman University, Saudi Arabia

Footnotes

BVL, Bilateral vestibular loss; DHI, Dizziness handicap inventory; HADS, Hospital anxiety and depression scale; ICV, Intracranial volume; GMV, Gray matter volume; MRI, Magnetic resonance imaging; PIVC, Parietoinsular vestibular cortex; ROI, Region of interest; VBM, Voxel brain morphometric; VEMP, Vestibular evoked myogenic potential; cVEMP, Cervical-Vestibular evoked myogenic potential; oVEMP, Ocular-Vestibular evoked myogenic potential; vHIT, Video Head impulse test; VOR, Vestibulo-ocular reflex; VR, Vestibular rehabilitation; SOT, Sensorial organization test; SPV, Slow phase velocity; USH, Usher Syndrome; USH1, Usher Syndrome type1; USH2, Usher Syndrome type2.