Genetic interactions support an inhibitory relationship between bone morphogenetic protein 2 and netrin 1 during semicircular canal formation.

The semicircular canals of the mammalian inner ear are derived from epithelial pouches in which epithelial cells in the central region of each pouch undergo resorption, leaving behind the region at the rim to form a tube-shaped canal. Lack of proliferation at the rim and/or over-clearing of epithelial cells in the center of the pouch can obliterate canal formation. Otic-specific knockout of bone morphogenetic protein 2 (Bmp2) results in absence of all three semicircular canals; however, the common crus and ampullae housing the sensory tissue (crista) are intact. The lack of Bmp2 causes Ntn1 (which encodes netrin 1), which is required for canal resorption, to be ectopically expressed at the canal rim. Ectopic Ntn1 results in reduction of Dlx5 and Lmo4, which are required for rim formation. These phenotypes can be partially rescued by removing one allele of Ntn1 in the Bmp2 mutants, indicating that Bmp2 normally negatively regulates Ntn1 for canal formation. Additionally, non-resorption of the canal pouch in Ntn1-/- mutants is partially rescued by removing one allele of Bmp2 Thus, reciprocal inhibition between Bmp2 and netrin 1 is involved in canal formation of the vestibule.

Auditory ganglion source of Sonic hedgehog regulates timing of cell cycle exit and differentiation of mammalian cochlear hair cells.

Neural precursor cells of the central nervous system undergo successive temporal waves of terminal division, each of which is soon followed by the onset of cell differentiation. The organ of Corti in the mammalian cochlea develops differently, such that precursors at the apex are the first to exit from the cell cycle but the last to begin differentiating as mechanosensory hair cells. Using a tissue-specific knockout approach in mice, we show that this unique temporal pattern of sensory cell development requires that the adjacent auditory (spiral) ganglion serve as a source of the signaling molecule Sonic hedgehog (Shh). In the absence of this signaling, the cochlear duct is shortened, sensory hair cell precursors exit from the cell cycle prematurely, and hair cell differentiation closely follows cell cycle exit in a similar apical-to-basal direction. The dynamic relationship between the restriction of Shh expression in the developing spiral ganglion and its proximity to regions of the growing cochlear duct dictates the timing of terminal mitosis of hair cell precursors and their subsequent differentiation.

Role of bone morphogenetic proteins on cochlear hair cell formation: analyses of Noggin and Bmp2 mutant mice.

The mammalian organ of Corti of the inner ear is a highly sophisticated sensory end organ responsible for detecting sound. Noggin is a secreted glycoprotein, which antagonizes bone morphogenetic proteins 2 and 4 (Bmp2 and Bmp4). The lack of this antagonist causes increased rows of inner and outer hair cells in the organ of Corti. In mice, Bmp2 is expressed transiently in nascent cochlear hair cells. To investigate whether Noggin normally modulates the levels of Bmp2 for hair cell formation, we deleted Bmp2 in the cochlear hair cells using two cre strains, Foxg1(cre/+) and Gfi1(cre/+). Bmp2 conditional knockout cochleae generated using these two cre strains show normal hair cells. Furthermore, Gfi1(cre/+);Bmp2(lox/-) mice are viable and have largely normal hearing. The combined results of Noggin and Bmp2 mutants suggest that Noggin is likely to regulate other Bmps in the cochlea such as Bmp4.

Foxg1 is required for proper separation and formation of sensory cristae during inner ear development.

The vestibular portion of the inner ear, the three semicircular canals and their sensory cristae, is responsible for detecting angular head movements. It was proposed that sensory cristae induce formation of their non-sensory components, the semicircular canals. Here, we analyzed the inner ears of Foxg1(-/-) mouse mutants, which display vestibular defects that are in conflict with the above model. In Foxg1(-/-) ears, the lateral canal is present without the lateral ampulla, which houses the lateral crista. Our gene expression analyses indicate that at the time when canal specification is thought to occur, the prospective lateral crista is present, which could have induced lateral canal formation prior to its demise. Our genetic fate-mapping analyses indicate an improper separation between anterior and lateral cristae in Foxg1(-/-) mutants. Our data further suggest that a function of Foxg1 in the inner ear is to restrict sensory fate.

Lmx1a maintains proper neurogenic, sensory, and non-sensory domains in the mammalian inner ear.

Lmx1a is a LIM homeodomain-containing transcription factor, which is required for the formation of multiple organs. Lmx1a is broadly expressed in early stages of the developing inner ear, but its expression is soon restricted to the non-sensory regions of the developing ear. In an Lmx1a functional null mutant, dreher (dr(J)/dr(J)), the inner ears lack a non-sensory structure, the endolymphatic duct, and the membranous labyrinth is poorly developed. These phenotypes are consistent with Lmx1a's role as a selector gene. More importantly, while all three primary fates of the inner ear - neural, sensory, and non-sensory - are specified in dr(J)/dr(J), normal boundaries among these tissues are often violated. For example, the neurogenic domain of the ear epithelium, from which cells delaminate to form the cochleovestibular ganglion, is expanded. Within the neurogenic domain, the demarcation between the vestibular and auditory neurogenic domains is most likely disrupted as well, based on the increased numbers of vestibular neuroblasts and ectopic expression of Fgf3, which normally is associated specifically with the vestibular neurogenic region. Furthermore, aberrant and ectopic sensory organs are observed; most striking among these is vestibular-like hair cells located in the cochlear duct.

Noggin heterozygous mice: an animal model for congenital conductive hearing loss in humans.

Conductive hearing loss occurs when sound waves are not relayed efficiently to the inner ear. Mutations of the NOGGIN (NOG) gene in humans are associated with several autosomal dominant disorders such as proximal symphalangism and multiple synostoses. These syndromes are characterized by skeletal defects and synostoses, which include conductive hearing loss. Noggin is an antagonist of bone morphogenetic proteins (BMPs), and balanced levels of BMPs and Noggin are required for proper skeletal formation. Depending on the genetic background, some of the Nog(+/-) mice display mild hearing loss, that is, conductive in nature. Since Noggin is a single exon gene, this data strongly suggest that the autosomal dominant disorders associated with NOG mutations are due to haploinsufficiency of NOGGIN. The conductive hearing loss in Nog(+/-) mice is caused by an ectopic bone bridge located between the stapes and the posterior wall of the tympanum, which affects the normal mobility of the ossicle. Our analyses suggest that the ectopic bone formation is caused by a failure of the stapes and styloid process to separate completely during development. This failure of bone separation in the Nog(+/-) mice reveals another consequence of chondrocyte hyperplasia due to unopposed Bmp activities in these mutants such as Bmp4 and Bmp14 (Gdf5). More importantly, these results establish Nog(+/-) mice as the first animal model for the study of conductive rather than neurosensory hearing loss that has direct relevance to human genetic disorders.

Age-related changes on the morphology of the otoconia.

OBJECTIVES/HYPOTHESIS: Although there are numerous reports on otoconial morphology using field-emission scanning electron microscopy (FESEM), there are few reports regarding the changes of otoconial morphology with aging. The aim of the current study was to investigate changes in otoconial morphology in rats according to age, using FESEM. STUDY DESIGN: Laboratory study using experimental animals. METHODS: We investigated age-related changes in otoconial morphology using FESEM in three groups of rats: young (1 wk old), middle-aged (6 mo old), and aged (23 mo old). RESULTS: There was great size variation in utricular otoconia in the young and aged rats, but we found no clear regional separation of saccular otoconia in all groups based on size. In the oldest rats, the bodies of many otoconia in both maculae were pitted, fissured, penetrated, and eventually broken into several fragments. However, the terminal facets were smooth and the lines of intersection of facets were sharp, despite the degenerated bodies of the otoconia in this group. Giant otoconia were discovered frequently on the outer margin of the utricular maculae in aged rats. We directly observed weakened or broken linking filaments and otoconial fragments in the aged group. CONCLUSION: The oldest rats showed the most degeneration of otoconia and linking filaments with otoconial fragments. This study of age-related morphologic changes in otoconia might help us understand the origin of idiopathic benign paroxysmal positional vertigo.

The neural correlates of cross-modal interaction in speech perception during a semantic decision task on sentences: a PET study.

Speech perception in face-to-face conversation involves processing of speech sounds (auditory) and speech-associated mouth/lip movements (visual) from a speaker. Using PET where no scanner noise was present, brain regions involved in speech cue processing were investigated with the normal hearing subjects with no previous lip-reading training (N = 17) carrying out a semantic plausibility decision on spoken sentences delivered in a movie file. Multimodality was ensured at the sensory level in all four conditions. Sensory-specific speech cue of one sensory modality, i.e., auditory speech (A condition) or mouth movement (V condition), was delivered with a control stimulus of the other modality whereas speech cues of both sensory modalities (AV condition) were delivered during bimodal condition. In comparison to the control condition, extensive activations in the superior temporal regions were observed bilaterally during the A condition but these activations were reduced in extent and left lateralized during the AV condition. Polymodal region such as left posterior superior temporal sulcus (pSTS) involved in cross-modal interaction/integration of audiovisual speech was found to be activated during the A and more so during the AV conditions but not during the V condition. Activations were observed in Broca's (BA 44), medial frontal (BA 8), and anterior ventrolateral prefrontal (BA 47) regions in the left during the V condition, where lip-reading performance was less successful. Results indicated that the speech-associated lip movements (visual speech cue) rendered suppression on the activity in the right auditory temporal regions. Overadditivity (AV > A + V) observed in the right postcentral region during the bimodal condition relative to the sum of unimodal speech conditions was also associated with reduced activity during the V condition. These findings suggested that visual speech cue could exert an inhibitory modulatory effect on the brain activities in the right hemisphere during the cross-modal interaction of audiovisual speech perception.

PET evidence of neuroplasticity in adult auditory cortex of postlingual deafness.

UNLABELLED: Controversy regarding functional reorganization in the adult brain remains. To investigate whether neuroplasticity is present in adults with postlingual deafness, we examined the pattern of cerebral glucose metabolism on (18)F-FDG brain PET images of postlingually deaf patients by comparing the auditory cortical activation pattern with those of age- and sex-matched healthy control subjects. We also correlated the cerebral glucose metabolism in deaf patients with the duration of deafness using statistical parametric mapping. METHODS: In the resting state (eye closed, ears unoccluded in a dark and quiet environment), (18)F-FDG brain PET scans were performed on 9 postlingually deaf patients and 9 age- and sex-matched healthy volunteers. Significant increases and decreases of regional cerebral metabolism in the patient group were estimated by comparing their PET images with those of the healthy volunteers using t statistics at every voxel. To reveal regions in which metabolism was significantly correlated with the duration of deafness, the general linear model with the duration of deafness as a covariate was tested at each voxel. RESULTS: When we compared (18)F-FDG brain PET images of postlingually deaf patients with those of age- and sex-matched healthy control subjects by performing a t test at every voxel, the glucose metabolism of deaf patients was significantly (P < 0.001) lower than that of the control subjects in both anterior cingulate gyri (Brodmann area 24 [BA24]) and superior temporal cortices (BA41, BA42) and in the right parahippocampal gyrus. No area showed a significant increase of metabolism in deaf patients with the same threshold. When we correlated glucose metabolism of deaf patients with the duration of deafness after total deprivation of hearing capability using a general linear model with the duration of deafness as a covariate at every voxel, metabolism in both anterior cingulate gyri (BA24) and superior temporal cortices (BA41, BA42) showed a significant (P < 0.005) positive correlation with the duration of deafness. CONCLUSION: This study suggests that plasticity is present in adult brains of postlingually deaf patients. In the mature brain, auditory deprivation decreased neuronal activity transiently in primary auditory and auditory-related cortices, and, over time, functional reorganization likely takes place in the auditory cortex. Plasticity was prominent in superior temporal and anterior cingulate gyri in the sensory-deprived mature brain and militated against postimplantation improvement in patients with cochlear implants.

Speech perception after cochlear implantation over a 4-year time period.

OBJECTIVE: To evaluate the long-term speech perception of cochlear implantees and to compare the developing auditory performance patterns of prelingual children and postlingual deaf adults. MATERIAL AND METHODS: Twenty-nine prelingually deaf children and 17 postlingually deaf adults who had been followed up for 4 years were included in the study. Speech perception ability was assessed by means of vowel and consonant confusion tests and the Korean version of the Central Institute of Deafness (K-CID) test (performed without visual cues). The test results were analyzed at 3 and 6 months after implantation and then annually. RESULTS: In the prelingually deaf children, the average results continuously improved over the 4-year period. In the postlingually deaf adults, the average results did not improve further after the first 2 years. Individuals with < 5 years of deafness had a faster rate of recovery of speech perception than those who had been deaf for > 5 years. The K-CID scores were negatively correlated with age at implantation for the prelingually deaf group and with the duration of deafness in the postlingually deaf group. Children fitted with implants at a younger age showed better speech perception ability than those fitted with implants at an older age. Interestingly, prelingually deaf children aged 5-7 years at implantation showed the widest variation in individual outcomes. Amongst this group of children with highly variable outcomes, the metabolic status of brain cortices determined by means of 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) was available for three patients. The individual with the widest hypometabolic area had the best speech perception ability. CONCLUSION: The extent of hypometabolism as assessed by FDG-PET seemed to be one of the major factors predicting the outcome of cochlear implantation.

Management of intratemporal facial nerve schwannoma.

OBJECTIVE: The aim of this study was to report a series of 18 facial nerve schwannomas, including 2 infantile cases. STUDY DESIGN: Retrospective case review. SETTING: Tertiary referral center. PATIENTS: Eighteen patients with facial nerve schwannoma, operated on between 1980 and 2000. INTERVENTION: Surgical treatments were performed in all cases. MAIN OUTCOME MEASURES: The presenting symptoms and facial nerve function were graded using the House-Brackmann scale and eye closure. RESULTS Facial nerve paralysis was the most common symptom, presenting in 94% of cases, followed by hearing loss and mass lesion. In one case, the tumor was shaved, leaving the facial nerve intact. In the other cases, the facial nerve reconstruction with hypoglossal-facial anastomosis or interposition graft was performed. The postoperative facial function was House-Brackmann grade IV in most cases (88.2%). In terms of the functional recovery classified by complete or incomplete eye closure, the moderate preoperative facial nerve palsy group showed a better functional outcome than severe group. CONCLUSION: In cases with good facial nerve function, it would be better to consider an alternative method for preserving the facial nerve. Furthermore, when facial nerve paralysis has developed to more than House-Brackmann grade III, an immediate operation is recommended to obtain a good postoperative facial functional recovery.