Round-window delivery of neurotrophin 3 regenerates cochlear synapses after acoustic overexposure.
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ABSTRACT:
SUBMITTER: Suzuki J
PROVIDER: S-EPMC4842978 | biostudies-other | 2016 Apr
REPOSITORIES: biostudies-other
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Project description:ObjectiveTo determine anatomic relationships and variation of the round window membrane to bony surgical landmarks on computed tomography.Study designRetrospective imaging review.Methods100 temporal bone images were evaluated. Direct measurements were obtained for membrane position. Vector distances and angulation from umbo and bony annulus were calculated from image viewer software coordinates.ResultsThe angle of round window membrane at junction with cochlear basal turn was (42.1 ± 8.6)°. The membrane's position relative to plane of the facial nerve through facial recess was (14.7 ± 5.2)° posterior from a reference line drawn through facial recess to carotid canal. Regarding transtympanic drug delivery, the round window membrane was directed 4.1 mm superiorly from the inferior annulus and 5.4 mm anteriorly from the posterior annulus. The round window membrane on average was angled superiorly from the inferior annulus (77.1 ± 27.9)° and slightly anteriorly from the posterior annulus (19.1 ± 11.1°). The mean distance of round window membrane from umbo was 4 mm and posteriorly rotated 30° clockwise from a perpendicular drawn from umbo to inferior annulus towards posterior annulus. Together, these measurements approximate the round window membrane in the tympanic membrane's posteroinferior quadrant.ConclusionsThese radiologic measurements demonstrate normal variations seen in round window anatomy relative to facial recess approach and bony tympanic annulus, providing a baseline to assess round window insertion for cochlear implantation and outlines anatomic factors affecting transtympanic drug delivery.
| S-EPMC7801246 | biostudies-literature
Project description:Background: The development of less traumatic surgical techniques, such as the round window approach (RWA), as well as the use of flexible electrodes and post-operative steroid administration have enabled the preservation of residual hearing after cochlear implantation (CI) surgery. However, consideration must still be given to the complications that can accompany CI. One such potential complication is the impairment of vestibular function with resulting vertigo symptoms. The aim of our current study was to examine the changes in vestibular function after implantation in patients who received CI using less traumatic surgery, particularly the RWA technique. Methods: Sixty-six patients who received CI in our center were examined by caloric testing, cervical vestibular evoked myogenic potential (cVEMP) and ocular VEMP (oVEMP) before or after implantation, or both, to obtain data on semicircular canal, saccular and utricular function, respectively. Less traumatic CI surgery was performed by the use of the RWA and insertion of flexible electrodes such as MED-EL FLEX soft, FLEX 28, and FLEX 24 (Innsbruck, Austria). Results: Caloric response and the asymmetry ratio of cVEMP and oVEMP were examined before and after implantation using less traumatic surgical techniques. Compared with before implantation, 93.9, 82.4, and 92.5% of the patients showed preserved vestibular function after implantation based on caloric testing, cVEMP and oVEMP results, respectively. We also examined the results for vestibular function by a comparison of the 66 patients using the RWA and flexible electrodes, and 17 patients who underwent cochleostomy and insertion of conventional or hard electrodes. We measured responses using caloric testing, cVEMP and oVEMP in patients after CI. There were no differences in the frequencies of abnormal caloric and oVEMP results in the implanted ears between the RWA and cochleostomy. On the other hand, the frequency of abnormal cVEMP responses in the implanted ears in the patients who received implantation by cochleostomy was significantly higher than that in the patients undergoing surgery using the RWA. Conclusion: Patients receiving CI using less traumatic surgical techniques such as RWA and flexible electrodes have reduced risk of damage to vestibular function.
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Project description:Cochlear gene therapy holds promise for the treatment of genetic deafness. Assessing its impact in adult murine models of hearing loss, however, has been hampered by technical challenges that have made it difficult to establish a robust method to deliver transgenes to the mature murine inner ear. Here in we demonstrate the feasibility of a combined round window membrane injection and semi-circular canal fenestration technique in the adult cochlea. Injection of both AAV2/9 and AAV2/Anc80L65 via this approach in P15-16 and P56-60 mice permits robust eGFP transduction of virtually all inner hair cells throughout the cochlea with variable transduction of vestibular hair cells. Auditory thresholds are not compromised. Transduction rate and cell tropism is primarily influenced by viral titer and AAV serotype but not age at injection. This approach is safe, versatile and efficient. Its use will facilitate studies using cochlear gene therapy in murine models of hearing loss over a wide range of time points.
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Project description:Learning-induced trophic activity is thought to be critical for maintaining health of the aging brain. We report here that learning, acting through an unexpected pathway, activates synaptic receptors for one of the brain's primary trophic factors. Unsupervised learning, but not exploratory activity alone, robustly increased the number of postsynaptic densities associated with activated (phosphorylated) forms of BDNF's TrkB receptor in adult rat hippocampus; these increases were blocked by an NMDA receptor antagonist. Similarly, stimulation of hippocampal slices at the learning-related theta frequency increased synaptic TrkB phosphorylation in an NMDA receptor-dependent fashion. Theta burst stimulation, which was more effective in this regard than other stimulation patterns, preferentially engaged NMDA receptors that, in turn, activated Src kinases. Blocking the latter, or scavenging extracellular TrkB ligands, prevented theta-induced TrkB phosphorylation. Thus, synaptic TrkB activation was dependent upon both ligand presentation and postsynaptic signaling cascades. These results show that afferent activity patterns and cellular events involved in memory encoding initiate BDNF signaling through synaptic TrkB, thereby ensuring that learning will trigger neurotrophic support.
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Project description:OBJECTIVE:To establish whether the round window approach (RWA) leads to less vestibular dysfunction and dizziness than the standard cochleostomy approach (SCA) during cochlear implant (CI) surgery, as assessed using the video head impulse test (vHIT).Additionally, objective findings were compared with the subjective dizziness perceived by the patient. STUDY DESIGN:Double blinded, clinical randomized trial. SETTING:University Hospital. PATIENTS:Fifty-two ears from 46 patients were included. Inclusion criterion was a gain value more than 0.50. INTERVENTION:Patients were randomized to the RWA or the SCA. Evaluation with the vHIT was performed before surgery, 1 day after surgery, and 1 month after surgery. Subjective dizziness was measured using a visual analogue scale (VAS) and the dizziness handicap inventory (DHI). MAIN OUTCOME MEASURES:Gain values and the incidence of catch-up saccades. RESULTS:Three out of 23 patients in the SCA group experienced catch-up saccades compared with no patients in the RWA group, indicating the occurrence of objective vestibular dysfunction after CI surgery; the difference was not statistically significant. The VAS increased in both groups the day after surgery. The difference between the groups was not statistically significant. No statistically significant changes in the gain value or the DHI score could were observed between the two groups. CONCLUSION:No statistically significant difference between the cochleostomy approach and the round window approach using the vHIT and subjective dizziness perceived by the patient was found.
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Project description:Recent work shows that acoustic overexposures causing only transient threshold elevation, and no hair cell loss, nevertheless can cause irreversible loss of the synapses between inner hair cells and cochlear nerve fibers (Kujawa and Liberman 2009). This cochlear synaptopathy, which is selective for the subset of sensory fibers with high thresholds and low spontaneous rates (Furman et al. 2013), appeared fully developed at 24-h post-exposure and showed no recovery by 8 weeks. However, prior studies of this synaptopathy counted only pre-synaptic ribbons, did not examine post-exposure times less than 24 h, and did not analyze the spatial patterns of degeneration around the hair cell circumference. Here, we immunostained for pre-synaptic ribbons, post-synaptic terminals and glutamate receptor patches, as well as the hair cell cytoplasm in noise-exposed and control mice to address the dynamics and spatial organization of the synaptopathic process as a function of post-exposure time from 0 h to 2 weeks. Our analysis showed that the loss of synaptic elements is nearly complete immediately after the 2-h exposure, that there is a reversible downregulation of gluR expression in the peripheral terminals which may be part of a protective mechanism, that there may be reversible reorganization of synaptic locations immediately after exposure, and that the spatial patterns are consistent with the idea that low-SR fibers are mainly found on the modiolar face of the hair cell and are the most vulnerable to noise-induced degeneration.
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Project description:Most implantable hearing aids currently available were developed to compensate the sensorineural hearing loss by driving middle ear structures (e.g., the ossicles). These devices are successfully used in round window (RW) stimulation clinically, although this was initially not the intended use. Here, a novel microactuator, specifically designed for RW stimulation, was tested in human temporal bones to determine actuator performance and applicability.Stapes footplate response to RW stimulation was determined experimentally in human temporal bones and the obtained sound pressure output level was estimated.The actuator had a flat displacement response between 0.125 and 4?kHz, a resonance between 4 and 7?kHz, and a roll-off above. At increasing contact force, the stapes footplate displacement decreased by 5-10?dB re ?m for forces ? 2?mN. The equivalent sound pressure level between 0.125 and 4?kHz amounted to 87-97?eq?dB SPL and increased to 117?eq?dB SPL for frequencies of 4-7?kHz. The total harmonic distortion (THD) of the actuator ranged within 15-40% for static forces of 5?mN.The feasibility of an electromagnetic actuator that may be placed into the RW niche was demonstrated but requires further optimization in terms of THD and static force sensitivity.
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Project description:The use of small-interfering RNA (siRNA) has great potential for the development of drugs designed to knock down the expression of damage- or disease-causing genes. However, because of the high molecular weight and negative charge of siRNA, it is restricted from crossing the blood-cochlear barrier, which limits the concentration and size of molecules that are able to gain access to cells of the inner ear. Intratympanic approaches, which deliver siRNA to the middle ear, rely on permeation through the round window for access to the structures of the inner ear. We developed an innovative siRNA delivery recombination protein, TAT double-stranded RNA-binding domains (TAT-DRBDs), which can transfect Cy3-labeled siRNA into cells of the inner ear, including the inner and outer hair cells, crista ampullaris, macula utriculi and macula sacculi, through intact round-window permeation in the chinchilla in vivo, and there were no apparent morphological damages for the time of observation. We also found that Cy3-labeled siRNA could directly enter spiral ganglion neurons and the epithelium of the stria vascularis independently; however, the mechanism is unknown. Therefore, as a non-viral vector, TAT-DRBD is a good candidate for the delivery of double-stranded siRNAs for treating various inner ear ailments and preservation of hearing function.
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Project description:The application of ultrasound microbubbles (USMBs) enhances the permeability of the round window membrane (RWM) and improves drug delivery to the inner ear. In this study, we investigated the efficiency of USMB-aided delivery of chitosan-coated gold nanoparticles (CS-AuNPs) and the mechanism of USMB-mediated enhancement of RMW permeability. We exposed mouse inner ears to USMBs at an intensity of 2 W/cm2 and then filled the tympanic bulla with CS-AuNPs or fluorescein isothiocyanate-decorated CS-AuNPs (FITC-CS-AuNPs). The membrane uptake of FITC-CS-AuNPs and their depth of permeation into the three-layer structure of the RWM, with or without prior USMB treatment, were visualized by z-stack confocal laser scanning microscopy. Ultrastructural changes in the RWM due to USMB-mediated cavitation appeared as sunburn-like peeling and various degrees of depression in the RWM surface, with pore-like openings forming in the outer epithelium. This disruption of the outer epithelium was paralleled by a transient reduction in tight junction (TJ)-associated protein levels in the RWM and an enhanced delivery of FITC-CS-AuNPs into the RWM. Without prior USMB exposure, the treatment with CS-AuNPs also caused a noticeable reduction in TJ proteins of the RWM. Our findings indicated that the combined treatment with USMBs and CS-AuNPs represents a promising and efficient drug and gene delivery vehicle for a trans-RWM approach for inner ear therapy. The outer epithelial layer of the RWM plays a decisive role in controlling the transmembrane transport of substances such as CS-AuNPs following the administration of USMBs. Most importantly, the enhanced permeation of AuNPs involved the transient disruption of the TJ-created paracellular barrier in the outer epithelium of the RWM.
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