David Bakhos

Les enfants sourds congénitaux ne peuvent pas acquérir le langage oral. L'acquisition du langage après réhabilitation montre des différences individuelles qui peuvent être liées à la réorganisation corticale consécutive à la surdité. Le fonctionnement auditif cortical peut être exploré par les méthodes électrophysiologiques. Notre première étude a permis de montrer une relation entre les réponses auditives temporales (onde N1c) et les capacités langagières chez des enfants avec une réhabilitation audioprothétique. Dans une seconde étude, nous avons mis en évidence une réponse spécifique à la voix humaine chez les enfants implantés cochléaires ayant un bon niveau de langage. La distribution de cette réponse est cependant différente de celle obtenue chez les enfants normo-entendants. La réduction de l'artefact dû à l'implant cochléaire a été une étape préliminaire indispensable à l'analyse des potentiels évoqués auditifs corticaux. L’identification de tels marqueurs permettra de définir des facteurs pronostics et de mieux repérer les enfants nécessitant une adaptation précoce de la rééducation.

To date, no treatment has been developed for targeted delivery to the inner ear (IE). Sonoporation, a promising drug delivery method, increases the permeability of round window membranes (RWMs), enhancing drug diffusion to the IE. A dedicated ultrasound protocol is essential to treat IE pathologies in combination with sonoporation. In situ acoustic pressure (AP) measurements cannot be used for RWM sonoporation because of the heterogeneous anatomy of the temporal bone. This study aimed to model ultrasound propagation in the IE to ensure adequate AP for RWM sonoporation. The impact of the position of the ultrasound probe relative to the RWM on AP as well as potential temperature increases caused by tissue/ultrasound interaction were investigated. Using MATLAB®, a surgical procedure was simulated based on the computed tomography scans of sheep heads (14 IEs). An ultrasound probe (12.7 mm in diameter, 1 MHz) with a degassed water-filled adapter was placed in front of the RWM. Mechanical properties, such as tissue density, sound speed, and ultrasound attenuation, were computed. Ultrasound propagation was simulated using k-wave. Standing waves can double the AP locally; however, the final AP is comparable to a free water field map when accounting for microbubble-induced attenuation. The angle and distance of the probe relative to the RWM have minimal effect on the AP; the main effect is caused by centering the probe on the RWM. No significant thermal elevation was observed. The developed computational model paves the way for designing an optimal and safe ultrasound protocol for sonoporation-mediated drug delivery into the IE.

Sonoporation using microbubble-assisted ultrasound increases the permeability of a biological barrier to therapeutic molecules. Application of this method to the round window membrane could improve the delivery of therapeutics to the inner ear. The aim of this study was to assess the safety of sonoporation of the round window membrane in a sheep model. To achieve this objective, we assessed auditory function and cochlear heating, and analysed the metabolomics profiles of perilymph collected after sonoporation, comparing them with those of the control ear in the same animal. Six normal-hearing ewes were studied, with one sonoporation ear and one control ear for each. A mastoidectomy was performed on both ears. On the sonoporation side, Vevo MicroMarker^® microbubbles (MBs; VisualSonics—Fujifilm, Amsterdam, The Netherlands) at a concentration of 2 × 10⁸ MB/mL were locally injected into the middle ear and exposed to 1.1 MHz sinusoidal ultrasonic waves at 0.3 MPa negative peak pressure with 40% duty cycle and 100 μs interpulse period for 1 min; this was repeated three times with 1 min between applications. The sonoporation protocol did not induce any hearing impairment or toxic overheating compared with the control condition. The metabolomic analysis did not reveal any significant metabolic difference between perilymph samples from the sonoporation and control ears. The results suggest that sonoporation of the round window membrane does not cause damage to the inner ear in a sheep model.

The pathophysiological mechanisms of noise-induced hearing loss remain unknown. Identifying biomarkers of noise-induced hearing loss may increase the understanding of pathophysiological mechanisms of deafness, allow for a more precise diagnosis, and inform personalized treatment. Emerging techniques such as metabolomics can help to identify these biomarkers. The objective of the present study was to investigate immediate-early changes in the perilymph metabolome following acoustic trauma. Metabolomic analysis was performed using liquid chromatography coupled to mass spectrophotometry to analyze metabolic changes in perilymph associated with noise-induced hearing loss. Sheep (n = 6) were exposed to a noise designed to induce substantial hearing loss. Perilymph was collected before and after acoustic trauma. Data were analyzed using univariate analysis and a supervised multivariate analysis based on partial least squares discriminant analysis. A metabolomic analysis showed an abundance of 213 metabolites. Four metabolites were significantly changed following acoustic trauma (Urocanate (p = 0.004, FC = 0.48), S-(5’-Adenosyl)-L-Homocysteine (p = 0.06, FC = 2.32), Trigonelline (p = 0.06, FC = 0.46) and N-Acetyl-L-Leucine (p = 0.09, FC = 2.02)). The approach allowed for the identification of new metabolites and metabolic pathways involved with acoustic trauma that were associated with auditory impairment (nerve damage, mechanical destruction, and oxidative stress). The results suggest that metabolomics provides a powerful approach to characterize inner ear metabolites which may lead to identification of new therapies and therapeutic targets.