Insights into Inner Ear Function and Disease Through Novel Visualization of the Ductus Reuniens, a Seminal Communication Between Hearing and Balance Mechanisms.

The sensory end-organs responsible for hearing and balance in the mammalian inner ear are connected via a small membranous duct known as the ductus reuniens (also known as the reuniting duct (DR)). The DR serves as a vital nexus linking the hearing and balance systems by providing the only endolymphatic connection between the cochlea and vestibular labyrinth. Recent studies have hypothesized new roles of the DR in inner ear function and disease, but a lack of knowledge regarding its 3D morphology and spatial configuration precludes testing of such hypotheses. We reconstructed the 3D morphology of the DR and surrounding anatomy using osmium tetroxide micro-computed tomography and digital visualizations of three human inner ear specimens. This provides a detailed, quantitative description of the DR's morphology, spatial relationships to surrounding structures, and an estimation of its orientation relative to head position. Univariate measurements of the DR, inner ear, and cranial planes were taken using the software packages 3D Slicer and Zbrush. The DR forms a narrow, curved, flattened tube varying in lumen size, shape, and wall thickness, with its middle third being the narrowest. The DR runs in a shallow bony sulcus superior to the osseus spiral lamina and adjacent to a ridge of bone that we term the "crista reuniens" oriented posteromedially within the cranium. The DR's morphology and structural configuration relative to surrounding anatomy has important implications for understanding aspects of inner ear function and disease, particularly after surgical alteration of the labyrinth and potential causative factors for Ménière's disease.

Context-independent encoding of passive and active self-motion in vestibular afferent fibers during locomotion in primates.

The vestibular system detects head motion to coordinate vital reflexes and provide our sense of balance and spatial orientation. A long-standing hypothesis has been that projections from the central vestibular system back to the vestibular sensory organs (i.e., the efferent vestibular system) mediate adaptive sensory coding during voluntary locomotion. However, direct proof for this idea has been lacking. Here we recorded from individual semicircular canal and otolith afferents during walking and running in monkeys. Using a combination of mathematical modeling and nonlinear analysis, we show that afferent encoding is actually identical across passive and active conditions, irrespective of context. Thus, taken together our results are instead consistent with the view that the vestibular periphery relays robust information to the brain during primate locomotion, suggesting that context-dependent modulation instead occurs centrally to ensure that coding is consistent with behavioral goals during locomotion.

Three-dimensional visualization of the human membranous labyrinth: The membrana limitans and its role in vestibular form.

The inner ear contains the end organs for balance (vestibular labyrinth) and hearing (cochlea). The vestibular labyrinth is comprised of the semicircular canals (detecting angular acceleration) and otolith organs (utricle and saccule, which detect linear acceleration and head tilt relative to gravity). Lying just inferior to the utricle is the membranous membrana limitans (ML). Acting as a keystone to vestibular geometry, the ML provides support for the utricular macula and acts as a structural boundary between the superior (pars superior) and inferior (pars inferior) portions of the vestibular labyrinth. Given its importance in vestibular form, understanding ML morphology is valuable in establishing the spatial organization of other vestibular structures, particularly the utricular macula. Knowledge of the 3D structure and variation of the ML, however, remain elusive. Our study addresses this knowledge gap by visualizing, in 3D, the ML and surrounding structures using micro-CT data. By doing so, we attempt to clarify: (a) the variation of ML shape; (b) the reliability of ML attachment sites; and (c) the spatial relationship of the ML to the stapes footplate using landmark-based Generalized Procrustes, Principal Component and covariance analyses. Results indicate a consistent configuration of three distinct bony ML attachments including an anterolateral, medial, and posterior attachment which all covary with bony structure. Our results set the stage for further understanding into vestibular and more specifically, utricular macula spatial configuration within the human head, offering the potential to aid in clinical and evolutionary studies which rely on a 3D understanding of vestibular spatial configuration.

Reassessment of the phylogenetic relationships of the late Miocene apes Hispanopithecus and Rudapithecus based on vestibular morphology.

Late Miocene great apes are key to reconstructing the ancestral morphotype from which earliest hominins evolved. Despite consensus that the late Miocene dryopith great apes Hispanopithecus laietanus (Spain) and Rudapithecus hungaricus (Hungary) are closely related (Hominidae), ongoing debate on their phylogenetic relationships with extant apes (stem hominids, hominines, or pongines) complicates our understanding of great ape and human evolution. To clarify this question, we rely on the morphology of the inner ear semicircular canals, which has been shown to be phylogenetically informative. Based on microcomputed tomography scans, we describe the vestibular morphology of Hispanopithecus and Rudapithecus, and compare them with extant hominoids using landmark-free deformation-based three-dimensional geometric morphometric analyses. We also provide critical evidence about the evolutionary patterns of the vestibular apparatus in living and fossil hominoids under different phylogenetic assumptions for dryopiths. Our results are consistent with the distinction of Rudapithecus and Hispanopithecus at the genus rank, and further support their allocation to the Hominidae based on their derived semicircular canal volumetric proportions. Compared with extant hominids, the vestibular morphology of Hispanopithecus and Rudapithecus most closely resembles that of African apes, and differs from the derived condition of orangutans. However, the vestibular morphologies reconstructed for the last common ancestors of dryopiths, crown hominines, and crown hominids are very similar, indicating that hominines are plesiomorphic in this regard. Therefore, our results do not conclusively favor a hominine or stem hominid status for the investigated dryopiths.

A comparative analysis of the vestibular apparatus in Epipliopithecus vindobonensis: Phylogenetic implications.

Pliopithecoids are an extinct group of catarrhine primates from the Miocene of Eurasia. More than 50 years ago, they were linked to hylobatids due to some morphological similarities, but most subsequent studies have supported a stem catarrhine status, due to the retention of multiple plesiomorphic features (e.g., the ectotympanic morphology) relative to crown catarrhines. More recently, some morphological similarities to hominoids have been noted, raising the question of whether they could be stem members of this clade. To re-evaluate these competing hypotheses, we examine the morphology of the semicircular canals of the bony labyrinth of the middle Miocene pliopithecid Epipliopithecus vindobonensis. The semicircular canals are suitable to test between these hypotheses because (1) they have been shown to embed strong phylogenetic signal and reliably discriminate among major clades; (2) several potential hominoid synapomorphies have been identified previously in the semicircular canals; and (3) semicircular canal morphology has not been previously described for any pliopithecoid. We use a deformation-based (landmark-free) three-dimensional geometric morphometric approach to compare Epipliopithecus with a broad primate sample of extant and extinct anthropoids. We quantify similarities in semicircular canal morphology using multivariate analyses, reconstruct ancestral morphotypes by means of a phylomorphospace approach, and identify catarrhine and hominoid synapomorphies based on discrete characters. Epipliopithecus semicircular canal morphology most closely resembles that of platyrrhines and Aegyptopithecus due to the retention of multiple anthropoid symplesiomorphies. However, Epipliopithecus is most parsimoniously interpreted as a stem catarrhine more derived than Aegyptopithecus due to the possession of a crown catarrhine synapomorphy (i.e., the rounded anterior canal), combined with the lack of other catarrhine and any hominoid synapomorphies. Some similarities with hylobatids and atelids are interpreted as homoplasies likely related to positional behavior. The semicircular canal morphology of Epipliopithecus thus supports the common view that pliopithecoids are stem catarrhines.

Alterations to vestibular morphology in highly bred domestic dogs may affect balance.

The modern domestic dog (Canis lupus familiaris) provides an excellent model to examine the effects of cranial modification. Extreme variation in skull length among dog breeds due to high levels of selective breeding is known to be linked to disorders of the head and neck. Such alteration may also influence sensory organs including those of the vestibular system (VS), one of the most fundamental sense organs, essential in maintaining balance. Studies in mammals have shown that orientation of ipsilateral semicircular canals (SCCs) of the VS at right angles (orthogonality) is related to angular acceleration sensitivity. Due to their considerable variation in craniofacial form while exhibiting similar locomotion, domestic dogs provide an excellent natural experiment to examine if cranial alteration influences VS functional morphology. Our methods examine how change in cranial base length across dog breeds relates to SCC orthogonality using linear modeling and analyses of variance. The sample studied (29 bony labyrinths of 17 dog breeds) was obtained from a previous study on canid inner ear metrics. Results support the hypothesis that orthogonality between the anterior and posterior SCC + ampulla significantly correlates with cranial base length. This suggests a close relationship between the orientations of SCCs with their ampullae and cranial structure among dog breeds. Specifically, highly derived breeds, such as the brachycephalic pug, have anterior and posterior SCCs and ampullae that deviate the most from orthogonality. Therefore, such highly bred domestic dogs may also have altered vestibular function due to compressed cranial form.

The real identity and sensory overlap mechanism of special vestibular afferent neurons that sense both rotation and linear force.

AIMS: Although the vestibular system has been widely investigated over the past 50 years, there is still an unsolved mystery. Some special vestibular afferent (SVA) neurons responding to both rotation and linear force were found through neurophysiological techniques, however, the sensory overlap mechanism of SVA neurons is still unclear, which may be closely related to vestibular-related diseases. MATERIALS AND METHODS: To address the above-mentioned problem, a cupula buoyancy theory was established in the present study, where SVA neurons were considered semicircular canal afferent (SCCA) neurons. Then labyrinth anatomy and neural response dynamics of vestibular afferent neurons in chinchilla were investigated through vestibular labyrinth reconstruction and single unit recording technique, respectively. KEY FINDINGS: We analyzed the deflections of cupulae under multiple conditions with the help of Amira Software and predicted the neural response law of SCCA neurons to linear force based on the cupula buoyancy theory. Data analysis confirmed that the basic response characteristic of SVA neurons had no significant difference to those of SCCA neurons, but were significantly different from those of otolith afferent neurons. Further, the actual responses of SVA neurons to linear force are completely consistent with our predictions. These results strongly suggest that SVA neurons actually are SCCA neurons, and the cupula buoyancy theory is the key to the sensory overlap mechanism of SCCA neurons. SIGNIFICANCE: Our study revealed the real identity of SVA neurons and provided a reasonable mechanism for sensory overlap of rotation and linear force, which improved our understanding about the vestibular system.

Structural connectome and connectivity lateralization of the multimodal vestibular cortical network.

Unlike other sensory systems, the structural connectivity patterns of the human vestibular cortex remain a matter of debate. Based on their functional properties and hypothesized centrality within the vestibular network, the 'core' cortical regions of this network are thought to be areas in the posterior peri-sylvian cortex, in particular the retro-insula (previously named the posterior insular cortex-PIC), and the subregion OP2 of the parietal operculum. To study the vestibular network, structural connectivity matrices from n=974 healthy individuals drawn from the public Human Connectome Project (HCP) repository were estimated using multi-shell diffusion-weighted data followed by probabilistic tractography and spherical-deconvolution informed filtering of tractograms in combination with subject-specific grey-matter parcellations. Weighted graph-theoretical measures, modularity, and 'hubness' of the multimodal vestibular network were then estimated, and a structural lateralization index was defined in order to assess the difference in fiber density of homonym regions in the right and left hemisphere. Differences in connectivity patterns between OP2 and PIC were also estimated. We found that the bilateral intraparietal sulcus, PIC, and to a lesser degree OP2, are key 'hub' regions within the multimodal vestibular network. PIC and OP2 structural connectivity patterns were lateralized to the left hemisphere, while structural connectivity patterns of the posterior peri-sylvian supramarginal and superior temporal gyri were lateralized to the right hemisphere. These lateralization patterns were independent of handedness. We also found that the structural connectivity pattern of PIC is consistent with a key role of PIC in visuo-vestibular processing and that the structural connectivity pattern of OP2 is consistent with integration of mainly vestibular somato-sensory and motor information. These results suggest an analogy between PIC and the simian visual posterior sylvian (VPS) area and OP2 and the simian parieto-insular vestibular cortex (PIVC). Overall, these findings may provide novel insights to the current models of vestibular function, as well as to the understanding of the complexity and lateralized signs of vestibular syndromes.

Inner ear sensory system changes as extinct crocodylomorphs transitioned from land to water.

Major evolutionary transitions, in which animals develop new body plans and adapt to dramatically new habitats and lifestyles, have punctuated the history of life. The origin of cetaceans from land-living mammals is among the most famous of these events. Much earlier, during the Mesozoic Era, many reptile groups also moved from land to water, but these transitions are more poorly understood. We use computed tomography to study changes in the inner ear vestibular system, involved in sensing balance and equilibrium, as one of these groups, extinct crocodile relatives called thalattosuchians, transitioned from terrestrial ancestors into pelagic (open ocean) swimmers. We find that the morphology of the vestibular system corresponds to habitat, with pelagic thalattosuchians exhibiting a more compact labyrinth with wider semicircular canal diameters and an enlarged vestibule, reminiscent of modified and miniaturized labyrinths of other marine reptiles and cetaceans. Pelagic thalattosuchians with modified inner ears were the culmination of an evolutionary trend with a long semiaquatic phase, and their pelagic vestibular systems appeared after the first changes to the postcranial skeleton that enhanced their ability to swim. This is strikingly different from cetaceans, which miniaturized their labyrinths soon after entering the water, without a prolonged semiaquatic stage. Thus, thalattosuchians and cetaceans became secondarily aquatic in different ways and at different paces, showing that there are different routes for the same type of transition.

Vestibular cognition: State-of-the-art and future directions.

Vestibular information has been traditionally considered as a specialized input for basic orienting behaviours, such as oculo-motor adjustments, postural control and gaze orientation. However, in the past two decades a widespread vestibular network in the human brain has been identified, that goes far beyond the low-level reflex circuits emphasized by earlier work. Because this vestibular cortical network is so widely distributed, it could, in principle, impact multiple neurocognitive functions in health and disease. This paper focuses on the relations between vestibular input, vestibular networks, and vestibular interventions by providing the authors' personal viewpoint on the state-of-the-art of vestibular cognitive neuropsychology, and its potential relevance for neurorehabilitation.

The evolution of the vestibular apparatus in apes and humans.

Phylogenetic relationships among extinct hominoids (apes and humans) are controversial due to pervasive homoplasy and the incompleteness of the fossil record. The bony labyrinth might contribute to this debate, as it displays strong phylogenetic signal among other mammals. However, the potential of the vestibular apparatus for phylogenetic reconstruction among fossil apes remains understudied. Here we test and quantify the phylogenetic signal embedded in the vestibular morphology of extant anthropoids (monkeys, apes and humans) and two extinct apes (Oreopithecus and Australopithecus) as captured by a deformation-based 3D geometric morphometric analysis. We also reconstruct the ancestral morphology of various hominoid clades based on phylogenetically-informed maximum likelihood methods. Besides revealing strong phylogenetic signal in the vestibule and enabling the proposal of potential synapomorphies for various hominoid clades, our results confirm the relevance of vestibular morphology for addressing the controversial phylogenetic relationships of fossil apes.

Humans, gorillas, chimpanzees, orangutans and gibbons all belong to a group known as the hominoids. This 'superfamily' also includes the immediate ancestors and close relatives of these species, however in many instances the evolutionary relationships between these extinct ape species remain controversial. While DNA can help evolutionary biologists to work out how living species are related to one another, fossils are typically the principle source of information for extinct species. Inferring evolutionary relationships from fossils must be done with caution, but the bony cavity that houses the inner ear ­ which is involved in balance and hearing and fairly common in the fossil record ­ has proven useful for tracing the evolution of certain groups of mammals. However, no one had previously looked to see if this structure could give insights into the evolutionary relatedness among living and extinct hominoids. Urciuoli et al. have now used a 3D imaging technique to capture the complex shapes of the inner ear cavities of 27 species of monkeys and apes, including humans and two extinct apes (Oreopithecus and Australopithecus). The results confirmed that the shape of these structures most closely reflected the evolutionary relationships between the species and not, for example, how the animals moved. Urciuoli et al. went on to identify features of these bony chambers that were shared within several hominoid groups, and to estimate what the inner ears of the ancestors of these groups might have looked like. The results for Australopithecus, for example, were consistent with it being most closely related to modern humans than other apes, while those for the enigmatic Oreopithecus supported the view that it was a much older species of ape that converged in some respects with other apes still alive today. The findings highlight the potential of the inner ear for reconstructing the early branches of our family tree. They also offer the prospect of refining the controversial evolutionary relationships within the impressive diversity of extinct ape species.

Asociaciones entre función vestibular y habilidades cognitivas: un enfoque básico-clínico / Associations between vestibular function and cognitive abilities: from basic to clinical approach

RESUMEN El sistema vestibular tiene un rol fundamental en funciones sensorio-motoras, control del equilibrio y estabilidad de la mirada. En las últimas décadas un amplio número de trabajos ha descrito la importancia de las aferencias vestibulares en el funcionamiento de diversas áreas del cerebro relacionadas con funciones cognitivas tales como la atención, memoria, navegación y otras habilidades visuo-espaciales. Estudios en pacientes con vestibulopatía han demostrado que estos individuos presentan disminución de su rendimiento en algunas pruebas neuropsicológicas; y, a su vez, que personas con patología cognitiva como deterioro cognitivo leve y demencia por enfermedad de Alzheimer tienen mayor probabilidad de presentar pruebas vestibulares alteradas. Esta revisión se enfoca en el papel que cumple el sistema vestibular y su asociación con habilidades cognitivas; basándose en estudios básicos y clínicos que describen una red vestibular cerebral y que han llevado a proponer modelos teóricos que relacionan la función vestibular con la cognición.

ABSTRACT The vestibular system is widely known for its role in sensory-motor functions, balance control and gaze stability. In recent decades, several research articles have described the importance of vestibular afferents in the functioning of brain areas related to cognitive skills such as attention, spatial memory, spatial navigation and other visuospatial abilities. Studies involving subjects with vestibulopathy reveal that these individuals show decreased performance on neuropsychological tests; and that patients with neurocognitive pathologies, such as mild cognitive impairment and dementia due to Alzheimer's disease, have a greater probability of producing diminished or absent responses in clinical vestibular electrophysiological tests. This literature review focuses on the role played by the vestibular system and its association with cognitive abilities. The review incorporates a description of basic and clinical research that describe the cortical vestibular network and emerging theoretical models linking vestibular function to cognition.

A probabilistic atlas of the human inner ear's bony labyrinth enables reliable atlas-based segmentation of the total fluid space.

Intravenous contrast agent-enhanced magnetic resonance imaging of the endolymphatic space (ELS) of the inner ear permits direct, in-vivo, non-invasive visualization of labyrinthine structures and thus verification of endolymphatic hydrops (ELH). However, current volumetric assessment approaches lack normalization. The aim of this study was to develop a probabilistic atlas of the inner ear's bony labyrinth as a first step towards an automated and reproducible volume-based quantification of the ELS. The study included three different datasets: a source dataset (D1) to build the probabilistic atlas and two testing sets (D2, D3). D1 included 24 right-handed patients (12 females; mean age 51.5 ± 3.9 years) and D2 5 patients (3 female; mean age 48.8 ± 5.01 years) with vestibular migraine without ELH or any measurable vestibular deficits. D3 consisted of five patients (one female; mean age 46 ± 5.2 years) suffering from unilateral Menière's disease and ELH. Data processing comprised three steps: preprocessing using an affine and deformable fusion registration pipeline, computation of an atlas for the left and right inner ear using a label-assisted approach, and validation of the atlas based on localizing and segmenting previously unseen ears. The three-dimensional probabilistic atlas of the inner ear's bony labyrinth consisted of the internal acoustic meatus and inner ears (including cochlea, otoliths, and semicircular canals) for both sides separately. The analyses showed a high level of agreement between the atlas-based segmentation and the manual gold standard with an overlap of 89% for the right ear and 86% for the left ear (measured by dice scores). This probabilistic in vivo atlas of the human inner ear's bony labyrinth and thus of the inner ear's total fluid space for both ears represents a necessary step towards a normalized, easily reproducible and reliable volumetric quantification of the perilymphatic and endolymphatic space in view of MR volumetric assessment of ELH. The proposed atlas lays the groundwork for state-of-the-art approaches (e.g., deep learning) and will be provided to the scientific community.

Sexual dimorphism in vestibular function and dysfunction.

It has been recognized for some time that females appear to be overrepresented in the incidence of many vestibular disorders, and recent epidemiological studies further support this idea. While it is possible that this is due to a reporting bias, another possibility is that there are actual differences in the incidence of vestibular dysfunction between males and females. If this is true, it could be due to a sexual dimorphism in vestibular function and therefore dysfunction, possibly related to the hormonal differences between females and males, although the higher incidence of vestibular dysfunction in females appears to last long after menopause. Many other neurochemical differences exist between males and females, however, that could be implicated in sexual dimorphism. This review critically explores the possibility of sexual dimorphism in vestibular function and dysfunction, and the implications it may have for the treatment of vestibular disorders.

Vestibular Neuroscience for the Headache Specialist.

BACKGROUND: The vestibular system is a multifaceted, integrative sensory system that is often referred to as the "multi-sensory" sense. There is an extensive literature about the vestibular sensory organs and afferent nerve pathways; however, this rich resource is often unknown to the headache specialist. AIMS: In this review, we highlight the significance of vestibular sensory processing beyond its role in the maintenance of balance. The role of the vestibular system in migraine pathophysiology is emphasized, not just in how it impacts dizziness or nausea, but also in its higher order effects on mood and cognition. How the vestibular system responds to current and new migraine therapies, such as anti-CGRP (calcitonin gene-related peptide) antibodies, is also discussed. CONCLUSIONS: The vestibular system is not just about balance; this should be taken into account by clinicians as they assess their patients' associated non-headache symptoms. There is a co-occurrence of migraine and vestibular-based problems and a confluence of disciplines relevant to vestibular migraine.

Habitat use and vestibular system's dimensions in lacertid lizards.

The vestibular system is crucial for movement control during locomotion. As the dimensions of the vestibular system determine the fluid dynamics of the endolymph and, as such, the system's function, we investigate the interaction between vestibular system size, head size and microhabitat use in lizards. We grouped 24 lacertid species in three microhabitat types, we acquired three-dimensional models of the bony vestibular systems using micro-computer tomography scanning, and we performed linear and surface measurements. All vestibular measurements scale with a negative allometry with head size, suggesting that smaller heads house disproportionally large ears. As the sensitivity of the vestibular system is positively related to size, a sufficiently large vestibular system in small-headed animals may meet the sensitivity demands during challenged locomotion. We also found that the microhabitat affects the locomotor dynamics: lizards inhabiting open microhabitats run at higher dimensionless speeds. On the other hand, no statistical relationship exists between dimensionless speed and the vestibular system dimensions. Hence, if the vestibular size would differ between microhabitats, this would be a direct effect (i.e. imposed, for instance, by requirements for manoeuvring, balance control, etc.), rather than depending on the lizards' intrinsic running speed. However, we found no effect of the microhabitat on the allometric relationship between head and vestibular system size. The finding that microhabitat is not reflected in the vestibular system size (hence sensitivity) of the lacertids in this study is possibly due to spatial constraints of the skull.

Three-dimensional study of vestibular anatomy as it relates to the stapes footplate and its clinical implications: an augmented reality development.

BACKGROUND: The anatomy of the membranous labyrinth within the vestibule has direct implications for surgical intervention. The anatomy of the otoliths has been studied, but there is limited information regarding their supporting connective tissue structures such as the membrana limitans in humans. METHODS: One guinea pig and 17 cadaveric human temporal bones were scanned using micro computed tomography, after staining with 2 per cent osmium tetroxide and preservation with Karnovsky's solution, with a resolution from 1 µm to 55 µm. The data were analysed using VGStudio Max software, rendered in three-dimensions and published in augmented reality. RESULTS: In 50 per cent of ears, the membrana limitans attached directly to the postero-superior part of the stapes footplate. If attachments were present in one ear, they were present bilaterally in 100 per cent of cases. CONCLUSION: Micro computed tomography imaging allowed three-dimensional assessment of the inner ear. Such assessments are important as they influence the surgical intervention and the evolution of future innovations.

Segmental Analysis of the Vestibular Nerve and the Efferents of the Vestibular Complex.

Use of a segmental approach in the study of vestibular centers in the hindbrain improves morphological and functional understanding of this region controlled by Hox genes, among other molecular determinants. Here, we review accrued data about segmental organization of vestibular afferents and efferents. Inner ear-originated vestibular fibers enter the hindbrain, together with auditory ones, through the alar plate of rhombomere 4, then branch into descending and ascending branches to reach appropriate vestibular nuclei along the vestibular column. Classical vestibular nuclei (superior, lateral, medial, and inferior) originate in eight successive rhombomeric segments, which suggests internal subdivisions correlated with distinct connections and functions. The vestibular projection neurons identified for various targets aggregate in discrete groups, which correlate topographically either with rhombomeric units, or with internal subdivisions within them. Each vestibular projection system (e.g., vestibulo-spinal, vestibulo-ocular, vestibulocerebellar) has a characteristic ipsilateral/contralateral organization. Comparing them as a connective mosaic in different species shows that various aspects of this segmental connective organization are conserved throughout evolution in vertebrates. Furthermore, certain genes that control the development of the rhombomeric units in the hindbrain may determine, among other aspects, the specific properties of the different neuronal subpopulations related to their axonal navigation and synaptogenesis. Anat Rec, 302:472-484, 2019. © 2018 Wiley Periodicals, Inc.

Neurod1 Is Essential for the Primary Tonotopic Organization and Related Auditory Information Processing in the Midbrain.

Hearing depends on extracting frequency, intensity, and temporal properties from sound to generate an auditory map for acoustical signal processing. How physiology intersects with molecular specification to fine tune the developing properties of the auditory system that enable these aspects remains unclear. We made a novel conditional deletion model that eliminates the transcription factor NEUROD1 exclusively in the ear. These mice (both sexes) develop a truncated frequency range with no neuroanatomically recognizable mapping of spiral ganglion neurons onto distinct locations in the cochlea nor a cochleotopic map presenting topographically discrete projections to the cochlear nuclei. The disorganized primary cochleotopic map alters tuning properties of the inferior colliculus units, which display abnormal frequency, intensity, and temporal sound coding. At the behavioral level, animals show alterations in the acoustic startle response, consistent with altered neuroanatomical and physiological properties. We demonstrate that absence of the primary afferent topology during embryonic development leads to dysfunctional tonotopy of the auditory system. Such effects have never been investigated in other sensory systems because of the lack of comparable single gene mutation models.SIGNIFICANCE STATEMENT All sensory systems form a topographical map of neuronal projections from peripheral sensory organs to the brain. Neuronal projections in the auditory pathway are cochleotopically organized, providing a tonotopic map of sound frequencies. Primary sensory maps typically arise by molecular cues, requiring physiological refinements. Past work has demonstrated physiologic plasticity in many senses without ever molecularly undoing the specific mapping of an entire primary sensory projection. We genetically manipulated primary auditory neurons to generate a scrambled cochleotopic projection. Eliminating tonotopic representation to auditory nuclei demonstrates the inability of physiological processes to restore a tonotopic presentation of sound in the midbrain. Our data provide the first insights into the limits of physiology-mediated brainstem plasticity during the development of the auditory system.

Influence of patient-specific anatomy on medical computed tomography and risk evaluation of minimally invasive surgery at the otobasis.

PURPOSE: With the increasing use of new minimally invasive approaches in temporal bone surgery, the need arises for evaluation of the risk of injury to sensitive anatomical structures. The factors that influence the measurement uncertainty (variation in representation of position and shape of anatomical structures) of imaging are of relevance. We investigate the effect of patients' anatomy on the measurement uncertainty of medical CT. METHODS: Six formalin-fixed temporal bones were used, fiducial markers were bone-implanted, and 20 CT scans of each temporal bone were generated. Surgically threatened anatomical structures of importance were defined. Manual segmentation was performed to create 3D surface models, and different Gaussian filters were applied. Analysis points were established along the border of the superior semicircular canal to determine the deviation between the 3D images of the labyrinth. The standard uncertainty was calculated, and one-way analysis of variance was performed (significance level = 5%) to evaluate the effect of certain factors (patient, side, Gaussian filter) on the measurement uncertainty. RESULTS: The influence of patient-specific anatomy on the measurement uncertainty of medical CT (p = 0.049) was demonstrated for the first time. The applied Gaussian filter (p = 0.622) and the patient's side (p = 0.341) showed no significant effect. CONCLUSION: The applied method and the results of the statistical analysis suggest that the patient's individual anatomical conditions affect the measurement uncertainty of medical CT. Thus, the patient's anatomy must be considered as an important influencing factor during risk evaluation concerning minimally invasive and image-guided surgery.