Electrical vestibular stimulation in humans. A narrative review

Background: In patients with bilateral vestibulopathy, the regular treatment options, such as medication, surgery, and/ or vestibular rehabilitation, do not always suffice. Therefore, the focus in this field of vestibular research shifted to electri- cal vestibular stimulation (EVS) and the development of a system capable of artificially restoring the vestibular func- tion. Key Message: Currently, three approaches are being investigated: vestibular co-stimulation with a cochlear im- plant (CI), EVS with a vestibular implant (VI), and galvanic vestibular stimulation (GVS). All three applications show promising results but due to conceptual differences and the experimental state, a consensus on which application is the most ideal for which type of patient is still missing. Summa- ry: Vestibular co-stimulation with a CI is based on “spread of excitation,” which is a phenomenon that occurs when the currents from the CI spread to the surrounding structures and stimulate them. It has been shown that CI activation can indeed result in stimulation of the vestibular structures. Therefore, the question was raised whether vestibular co- stimulation can be functionally used in patients with bilat- eral vestibulopathy. A more direct vestibular stimulation method can be accomplished by implantation and activa- tion of a VI. The concept of the VI is based on the technology and principles of the CI. Different VI prototypes are currently being evaluated regarding feasibility and functionality. So far, all of them were capable of activating different types of vestibular reflexes. A third stimulation method is GVS, which requires the use of surface electrodes instead of an implant- ed electrode array. However, as the currents are sent through the skull from one mastoid to the other, GVS is rather unspe- cific. It should be mentioned though, that the reported spread of excitation in both CI and VI use also seems to in- duce a more unspecific stimulation. Although all three ap- plications of EVS were shown to be effective, it has yet to be defined which option is more desirable based on applicabil- ity and efficiency. It is possible and even likely that there is a place for all three approaches, given the diversity of the pa- tient population who serves to gain from such technologies

Stimulation from Cochlear Implant Electrodes Assists with Recovery from Asymmetric Perceptual Tilt: Evidence from the Subjective Visual Vertical Test

Vestibular end organ impairment is highly prevalent in children who have sensorineural hearing loss (SNHL) rehabilitated with cochlear implants (CIs). As a result, spatial perception is likely to be impacted in this population. Of particular interest is the perception of visual vertical because it reflects a perceptual tilt in the roll axis and is sensitive to an imbalance in otolith function. The objectives of the present study were thus to identify abnormalities in perception of the vertical plane in children with SNHL and determine whether such abnormalities could be resolved with stimulation from the CI. Participants included 53 children (15.2 ± 4.0 years of age) with SNHL and vestibular loss, confirmed with vestibular evoked myogenic potential (VEMP) testing. Testing protocol was validated in a sample of nine young adults with normal hearing (28.8 ± 7.7 years). Perception of visual vertical was assessed using the static Subjective Visual Vertical (SVV) test performed with and without stimulation in the participants with cochleovestibular loss. Trains of electrical pulses were delivered by an electrode in the left and/or right ear. Asymmetric spatial orientation deficits were found in nearly half of the participants with CIs (24/53 [45%]). The abnormal perception in this cohort was exacerbated by visual tilts in the direction of their deficit. Electric pulse trains delivered using the CI shifted this abnormal perception towards center (i.e., normal; p = 0.007). Importantly, this benefit was realized regardless of which ear was stimulated. These results suggest a role for CI stimulation beyond the auditory system, in particular, for improving vestibular/balance function

Novel variants in GNAI3 associated with auriculocondylar syndrome strengthen a common dominant negative effect

Auriculocondylar syndrome is a rare craniofacial disorder comprising core features of micrognathia, condyle dysplasia and question mark ear. Causative variants have been identified in PLCB4, GNAI3 and EDN1, which are predicted to function within the EDN1-EDNRA pathway during early pharyngeal arch patterning. To date, two GNAI3 variants in three families have been reported. Here we report three novel GNAI3 variants, one segregating with affected members in a family previously linked to 1p21.1-q23.3 and two de novo variants in simplex cases. Two variants occur in known functional motifs, the G1 and G4 boxes, and the third variant is one amino acid outside of the G1 box. Structural modeling shows that all five altered GNAI3 residues identified to date cluster in a region involved in GDP/GTP binding. We hypothesize that all GNAI3 variants lead to dominant negative effects.CRANIRAREUniversite Paris Descartes-Sorbonne Paris Cite Pole de Recherche et d'Enseignement SuperieurAgence Nationale de la Recherche (project EvoDevoMut)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)National Health and Medical Research Council of AustraliaUniv São Paulo, Inst Biociencias, Dept Genet & Biol Evolut, Ctr Pesquisas Genoma Humano & Celulas Tronco, BR-05508090 São Paulo, BrazilUniv Paris 05, Sorbonne Paris Cite, INSERM, U1163, Paris, FranceUniv São Paulo, HRCA, Dept Clin Genet, Bauru, BrazilUniv Melbourne, Royal Childrens Hosp, Murdoch Childrens Res Inst, Victorian Clin Genet Serv, Melbourne, Vic, AustraliaUniv Melbourne, Dept Paediat, Melbourne, Vic, AustraliaRoyal Childrens Hosp, Dept Plast & Maxillofacial Surg, Melbourne, Vic, AustraliaHosp Sick Children, Dept Otolaryngol Head & Neck Surg, Toronto, ON M5G 1X8, CanadaUniv São Paulo, Inst Biosci, BR-05508090 São Paulo, BrazilLeiden Univ, Med Ctr, Leiden Genome Technol Ctr, Leiden, NetherlandsUniversidade Federal de São Paulo, Inst Ciencia & Tecnol, Sao Jose Dos Campos, BrazilHop Necker Enfants Malad, AP HP, Dept Genet, Paris, FranceUniversidade Federal de São Paulo, Inst Ciencia & Tecnol, Sao Jose Dos Campos, BrazilUniversite Paris Descartes-Sorbonne Paris Cite Pole de Recherche et d'Enseignement Superieur: SPC/JFG/2013-031National Health and Medical Research Council of Australia: 607431Web of Scienc

Olfactory testing in children using objective tools: comparison of Sniffin’ Sticks and University of Pennsylvania Smell Identification Test (UPSIT)

BACKGROUND: Detection of olfactory dysfunction is important for fire and food safety. Clinical tests of olfaction have been developed for adults but their use in children has been limited because they were felt to be unreliable in children under six years of age. We therefore administered two olfactory tests to children and compared results across tests. METHODS: Two olfactory tests (Sniffin’ Sticks and University of Pennsylvania Smell Identification Test (UPSIT)) were administered to 78 healthy children ages 3 to 12 years. Children were randomized to one of two groups: Group 1 performed the UPSIT first and Sniffin’ Sticks second, and Group 2 performed Sniffin’ Sticks first and UPSIT second. RESULTS: All children were able to complete both olfactory tests. Performance on both tests was similar for children 5 and 6 years of age. There was an age-dependent increase in score on both tests (p < .01). Children performed better on the Sniffin’ Sticks than the UPSIT (65.3% versus 59.7%, p < .01). There was no difference in performance due to order of test presentation. CONCLUSIONS: The Sniffin’ Sticks and UPSIT olfactory tests can both be completed by children as young as 5 years of age. Performance on both tests increased with increasing age. Better performance on the Sniffin’ Sticks than the UPSIT may be due to a decreased number of test items, better ability to maintain attention, or decreased olfactory fatigue. The ability to reuse Sniffin’ Sticks on multiple children may make it more practical for clinical use

Misfolding diverts CFTR from recycling to degradation: quality control at early endosomes

To investigate the degradation mechanism of misfolded membrane proteins from the cell surface, we used mutant cystic fibrosis transmembrane conductance regulators (CFTRs) exhibiting conformational defects in post-Golgi compartments. Here, we show that the folding state of CFTR determines the post-endocytic trafficking of the channel. Although native CFTR recycled from early endosomes back to the cell surface, misfolding prevented recycling and facilitated lysosomal targeting by promoting the ubiquitination of the channel. Rescuing the folding defect or down-regulating the E1 ubiquitin (Ub)-activating enzyme stabilized the mutant CFTR without interfering with its internalization. These observations with the preferential association of mutant CFTRs with Hrs, STAM-2, TSG101, hVps25, and hVps32, components of the Ub-dependent endosomal sorting machinery, establish a functional link between Ub modification and lysosomal degradation of misfolded CFTR from the cell surface. Our data provide evidence for a novel cellular mechanism of CF pathogenesis and suggest a paradigm for the quality control of plasma membrane proteins involving the coordinated function of ubiquitination and the Ub-dependent endosomal sorting machinery

Electrical vestibular stimulation in humans: a narrative review

Background: In patients with bilateral vestibulopathy, the regular treatment options, such as medication, surgery, and/ or vestibular rehabilitation, do not always suffice. Therefore, the focus in this field of vestibular research shifted to electrical vestibular stimulation (EVS) and the development of a system capable of artificially restoring the vestibular function. Key Message: Currently, three approaches are being investigated: vestibular co-stimulation with a cochlear implant (CI), EVS with a vestibular implant (VI), and galvanic vestibular stimulation (GVS). All three applications show promising results but due to conceptual differences and the experimental state, a consensus on which application is the most ideal for which type of patient is still missing. Summary: Vestibular co-stimulation with a CI is based on “spread of excitation,” which is a phenomenon that occurs when the currents from the CI spread to the surrounding structures and stimulate them. It has been shown that CI activation can indeed result in stimulation of the vestibular structures. Therefore, the question was raised whether vestibular costimulation can be functionally used in patients with bilateral vestibulopathy. A more direct vestibular stimulation method can be accomplished by implantation and activation of a VI. The concept of the VI is based on the technology and principles of the CI. Different VI prototypes are currently being evaluated regarding feasibility and functionality. So far, all of them were capable of activating different types of vestibular reflexes. A third stimulation method is GVS, which requires the use of surface electrodes instead of an implanted electrode array. However, as the currents are sent through the skull from one mastoid to the other, GVS is rather unspecific. It should be mentioned though, that the reported spread of excitation in both CI and VI use also seems to induce a more unspecific stimulation. Although all three applications of EVS were shown to be effective, it has yet to be defined which option is more desirable based on applicability and efficiency. It is possible and even likely that there is a place for all three approaches, given the diversity of the patient population who serves to gain from such technologies

CHD7 Mutational Analysis and Clinical Considerations for Auditory Rehabilitation in Deaf Patients with CHARGE Syndrome

BACKGROUND: Otologic manifestations are one of the most consistent findings of CHARGE syndrome found in more than 90%. Since genetic analysis of the CHD7 gene has rarely been performed in previous reports dealing with ear abnormalities, the genotypic spectrum of CHD7 mutations was analyzed in deaf patients with CHARGE syndrome, and the clinical considerations concerning auditory rehabilitation were investigated. METHODS: Nine Korean patients with CHARGE syndrome showing profound hearing loss and semicircular canal aplasia were included. All 38 exons of CHD7 were analyzed by direct sequencing. For splice site variations, in silico and exon-trapping analyses were performed to verify the pathogenicity of nucleotide variations. Clinical features and the outcome of auditory rehabilitation were also analyzed. RESULTS: Eight of 9 patients revealed alterations of the CHD7 gene including 3 frameshift, 2 nonsense, 2 splice site, and 1 missense mutations. Five of 9 patients were clinically diagnosed as atypical CHARGE syndrome but demonstrated various mutations of the CHD7 gene. One familial case showed intra-familial variability. Radiologic findings suggesting cochleovestibular nerve deficiency were identified in most of the patients. Of the 8 patients who underwent cochlear implantation, 5 patients demonstrated favorable outcome. Larger diameter of the cochleovestibular nerve on imaging and absence of severe mental retardation were factors related to better outcome after cochlear implantation rather than the type of CHD7 mutations. Auditory brainstem implantation was performed in two patients who did not benefit from cochlear implantation. CONCLUSIONS: Genetic analysis of the CHD7 gene should be performed in cases with semicircular canal aplasia even when other typical features of CHARGE syndrome are absent. For auditory rehabilitation in CHARGE syndrome, cochlear implantation should be strongly recommended in selected cases with favorable prognostic factors. Auditory brainstem implantation may be a viable option in patients with CHARGE syndrome who have failed to benefit from cochlear implantation