Electrophysiological assessment and pharmacological treatment of blast-induced tinnitus.

Tinnitus, the phantom perception of sound, often occurs as a clinical sequela of auditory traumas. In an effort to develop an objective test and therapeutic approach for tinnitus, the present study was performed in blast-exposed rats and focused on measurements of auditory brainstem responses (ABRs), prepulse inhibition of the acoustic startle response, and presynaptic ribbon densities on cochlear inner hair cells (IHCs). Although the exact mechanism is unknown, the "central gain theory" posits that tinnitus is a perceptual indicator of abnormal increases in the gain (or neural amplification) of the central auditory system to compensate for peripheral loss of sensory input from the cochlea. Our data from vehicle-treated rats supports this rationale; namely, blast-induced cochlear synaptopathy correlated with imbalanced elevations in the ratio of centrally-derived ABR wave V amplitudes to peripherally-derived wave I amplitudes, resulting in behavioral evidence of tinnitus. Logistic regression modeling demonstrated that the ABR wave V/I amplitude ratio served as a reliable metric for objectively identifying tinnitus. Furthermore, histopathological examinations in blast-exposed rats revealed tinnitus-related changes in the expression patterns of key plasticity factors in the central auditory pathway, including chronic loss of Arc/Arg3.1 mobilization. Using a formulation of N-acetylcysteine (NAC) and disodium 2,4-disulfophenyl-N-tert-butylnitrone (HPN-07) as a therapeutic for addressing blast-induced neurodegeneration, we measured a significant treatment effect on preservation or restoration of IHC ribbon synapses, normalization of ABR wave V/I amplitude ratios, and reduced behavioral evidence of tinnitus in blast-exposed rats, all of which accorded with mitigated histopathological evidence of tinnitus-related neuropathy and maladaptive neuroplasticity.

Investigating the Geometry and Mechanical Properties of Human Round Window Membranes Using Micro-Fringe Projection.

HYPOTHESIS: The geometry and the mechanical property of the round window membrane (RWM) have a fundamental impact on the function of cochlea. BACKGROUND: Understanding the mechanical behavior of RWM is important for cochlear surgery and design for the cochlear implant. Although the anatomy of RWM has been widely studied and described in the literature, argument remains regarding the true shape of RWM. The mechanical properties of RWM are also scarcely reported due to the difficulty of the measurement of the small size RWM. METHODS: In this paper, micro-fringe projection was used to reconstruct the 3-dimensional geometries of 14 RWMs. Mechanical properties of the RWMs were subsequently measured using finite element (FE) model and an inverse method. The three-dimensional surface topographies and the curvatures of the two major directions reconstructed from the micro-fringe projection both demonstrated wide variations among samples. RESULTS: The diameters of the RWMs vary from 1.65 to 2.2 mm and the curvatures vary from -0.97 to 3.76 mm-1. The nonlinear elasticity parameters in the Ogden model for each sample was measured and the average effective Young's modulus is approximately 1.98 MPa. CONCLUSION: The geometries and mechanical properties of the human RWM measured in the work could potentially be applied to surgery design and on modeling analysis for the cochlea.

Mapping the Young's modulus distribution of the human tympanic membrane by microindentation.

The human tympanic membrane (TM, or eardrum) is composed primarily of layers of collagen fibers oriented in the radial and circumferential directions, as well as epidermal and mucosal layers at the lateral and medial surfaces. The mechanical properties of the TM depend on the microstructures of the collagen fibers, which vary with location, resulting in a spatial variation of Young's modulus. In this study, the Young's modulus of the human TM is measured using microindentation. A 10 µm diameter spherical nanoindenter tip is used to indent the TM at different locations in the lateral and medial surfaces. Through a viscoelastic contact analysis, the steady state out-of-plane (through thickness) Young's modulus at a constant strain rate for the TM is determined from the uniaxial relaxation modulus. The measured spatial distribution of Young's modulus is reported for the entire TM pars tensa on both lateral and medial surfaces. The Young's modulus, for the four TM quadrants, is analyzed statistically using a normal quantile-quantile (Q-Q) plot. The obtained S-shaped curve indicates a bi-modal Gaussian distribution in the Q-Q plot. The spatial distribution of the Young's modulus is modeled by a bivariate Gaussian function in the polar coordinates over the entire TM on both the lateral and medial surfaces. It is shown that the anterior-superior quadrant has the smallest value of Young's modulus. Differences are observed in the spatial distribution of the Young's modulus for both the lateral and medial surfaces. For the medial surface, Young's modulus varies mainly along the radial direction following a small-large-small trend, emanating from the umbo. For the lateral surface, the modulus at the anterior-superior quadrant shows the smallest modulus; the modulus decreases gradually along the radial directions. The quantitative results presented in this paper will help improve future simulation models of the middle ear by using spatial dependence of Young's modulus over the entire TM.

Regeneration of Cochlear Hair Cells and Hearing Recovery through Hes1 Modulation with siRNA Nanoparticles in Adult Guinea Pigs.

Deafness is commonly caused by the irreversible loss of mammalian cochlear hair cells (HCs) due to noise trauma, toxins, or infections. We previously demonstrated that small interfering RNAs (siRNAs) directed against the Notch pathway gene, hairy and enhancer of split 1 (Hes1), encapsulated within biocompatible poly(lactic-co-glycolic acid) nanoparticles (PLGA NPs) could regenerate HCs within ototoxin-ablated murine organotypic cultures. In the present study, we delivered this sustained-release formulation of Hes1 siRNA (siHes1) into the cochleae of noise-injured adult guinea pigs. Auditory functional recovery was measured by serial auditory brainstem responses over a nine-week follow-up period, and HC regeneration was evaluated by immunohistological evaluations and scanning electron microscopy. Significant HC restoration and hearing recovery were observed across a broad tonotopic range in ears treated with siHes1 NPs, beginning at three weeks and extending out to nine weeks post-treatment. Moreover, both ectopic and immature HCs were uniquely observed in noise-injured cochleae treated with siHes1 NPs, consistent with de novo HC production. Our results indicate that durable cochlear HCs were regenerated and promoted significant hearing recovery in adult guinea pigs through reversible modulation of Hes1 expression. Therefore, PLGA-NP-mediated delivery of siHes1 to the cochlea represents a promising pharmacologic approach to regenerate functional and sustainable mammalian HCs in vivo.

Biomechanical Measurement and Modeling of Human Eardrum Injury in Relation to Blast Wave Direction.

Rupture of the eardrum or tympanic membrane (TM) is one of the most frequent injuries of the ear after blast exposure. To understand how the TM damage is related to blast wave direction, human cadaver ears were exposed to blast waves along three directions: vertical, horizontal, and front with respect to the head. Blast overpressure waveforms were recorded at the ear canal entrance (P0), near the TM (P1), and inside the middle ear (P2). Thirteen to fourteen cadaver ears were tested in each wave direction and the TM rupture thresholds were identified. Results show that blast wave direction affected the peak P1/P0 ratio, TM rupture threshold, and energy flux distribution over frequencies. The front wave resulted in lowest TM rupture threshold and the horizontal wave resulted in highest P1/P0 ratio. To investigate the mechanisms of TM injury in relation to blast wave direction, the recorded P1 waveforms were applied onto the surface of the TM in a three-dimensional finite element model of the human ear and distributions of the stress in TM were calculated. Modeling results indicate that the sensitivity of TM stress change with respect to P1 pressure (dσ/dP1) may characterize mechanical damage of the TM in relation to blast waves.

Computational Modeling of Blast Wave Transmission Through Human Ear.

Hearing loss has become the most common disability among veterans. Understanding how blast waves propagate through the human ear is a necessary step in the development of effective hearing protection devices (HPDs). This article presents the first 3D finite element (FE) model of the human ear to simulate blast wave transmission through the ear. The 3D FE model of the human ear consisting of the ear canal, tympanic membrane, ossicular chain, and middle ear cavity was imported into ANSYS Workbench for coupled fluid-structure interaction analysis in the time domain. Blast pressure waveforms recorded external to the ear in human cadaver temporal bone tests were applied at the entrance of the ear canal in the model. The pressure waveforms near the tympanic membrane (TM) in the canal (P1) and behind the TM in the middle ear cavity (P2) were calculated. The model-predicted results were then compared with measured P1 and P2 waveforms recorded in human cadaver ears during blast tests. Results show that the model-derived P1 waveforms were in an agreement with the experimentally recorded waveforms with statistic Kurtosis analysis. The FE model will be used for the evaluation of HPDs in future studies.

Characterization of the nonlinear elastic behavior of chinchilla tympanic membrane using micro-fringe projection.

The mechanical properties of an intact, full tympanic membrane (TM) inside the bulla of a fresh chinchilla were measured under quasi-static pressure from -1.0 kPa to 1.0 kPa applied on the TM lateral side. Images of the fringes projected onto the TM were acquired by a digital camera connected to a surgical microscope and analyzed using a phase-shift method to reconstruct the surface topography. The relationship between the applied pressure and the resulting volume displacement was determined and analyzed using a finite element model implementing a hyperelastic 2(nd)-order Ogden model. Through an inverse method, the best-fit model parameters for the TM were determined to allow the simulation results to agree with the experimental data. The nonlinear stress-strain relationship for the TM of a chinchilla was determined up to an equibiaxial tensile strain of 31% experienced by the TM in the experiments. The average Young's modulus of the chinchilla TM from ten bullas was determined as approximately 19 MPa.

Mechanical damage of tympanic membrane in relation to impulse pressure waveform - A study in chinchillas.

Mechanical damage to middle ear components in blast exposure directly causes hearing loss, and the rupture of the tympanic membrane (TM) is the most frequent injury of the ear. However, it is unclear how the severity of injury graded by different patterns of TM rupture is related to the overpressure waveforms induced by blast waves. In the present study, the relationship between the TM rupture threshold and the impulse or overpressure waveform has been investigated in chinchillas. Two groups of animals were exposed to blast overpressure simulated in our lab under two conditions: open field and shielded with a stainless steel cup covering the animal head. Auditory brainstem response (ABR) and wideband tympanometry were measured before and after exposure to check the hearing threshold and middle ear function. Results show that waveforms recorded in the shielded case were different from those in the open field and the TM rupture threshold in the shielded case was lower than that in the open field (3.4 ± 0.7 vs. 9.1 ± 1.7 psi or 181 ± 1.6 vs. 190 ± 1.9 dB SPL). The impulse pressure energy spectra analysis of waveforms demonstrates that the shielded waveforms include greater energy at high frequencies than that of the open field waves. Finally, a 3D finite element (FE) model of the chinchilla ear was used to compute the distributions of stress in the TM and the TM displacement with impulse pressure waves. The FE model-derived change of stress in response to pressure loading in the shielded case was substantially faster than that in the open case. This finding provides the biomechanical mechanisms for blast induced TM damage in relation to overpressure waveforms. The TM rupture threshold difference between the open and shielded cases suggests that an acoustic role of helmets may exist, intensifying ear injury during blast exposure.

Experimental and modeling study of human tympanic membrane motion in the presence of middle ear liquid.

Vibration of the tympanic membrane (TM) has been measured at the umbo using laser Doppler vibrometry and analyzed with finite element (FE) models of the human ear. Recently, full-field TM surface motion has been reported using scanning laser Doppler vibrometry, holographic interferometry, and optical coherence tomography. Technologies for imaging human TM motion have the potential to lead to using a dedicated clinical diagnosis tool for identification of middle ear diseases. However, the effect of middle ear fluid (liquid) on TM surface motion is still not clear. In this study, a scanning laser Doppler vibrometer was used to measure the full-field surface motion of the TM from four human temporal bones. TM displacements were measured under normal and disease-mimicking conditions with different middle ear liquid levels over frequencies ranging from 0.2 to 8 kHz. An FE model of the human ear, including the ear canal, middle ear, and spiral cochlea was used to simulate the motion of the TM in normal and disease-mimicking conditions. The results from both experiments and FE model show that a simple deflection shape with one or two major displacement peak regions of the TM in normal ear was observed at low frequencies (1 kHz and below) while complicated ring-like pattern of the deflection shapes appeared at higher frequencies (4 kHz and above). The liquid in middle ear mainly affected TM deflection shapes at the frequencies higher than 1 kHz.

Dynamic properties of round window membrane in guinea pig otitis media model measured with electromagnetic stimulation.

The round window, one of two openings into the cochlea from the middle ear, plays an important role in hearing and is known to be structurally altered during otitis media. However, there have been no published studies systematically describing the changes in biomechanical properties of the round window membrane (RWM) that accompany bacterial otitis media. Here we describe the occurrence of significant changes in the dynamic properties of the RWM between normal guinea pigs and those with acute otitis media (AOM) that are detectable by electromagnetic force stimulation and laser Doppler vibrometry (LDV) measurements. AOM was induced by transbullar injection of streptococcus pneumoniae into the middle ear, and RWM specimens were prepared three days after challenge. Vibration of the RWM induced by coil-magnet coupling was measured by LDV over frequencies of 0.2-40 kHz. The experiment was then simulated in a finite element model, and the inverse-problem solving method was used to determine the complex modulus in the frequency domain and the relaxation modulus in the time domain. Results from 18 ears (9 control ears and 9 AOM ears) established that both the storage modulus and loss modulus of the RWM from ears with AOM were significantly lower than those of RWM from uninfected ears. The average decrease of the storage modulus in AOM ears ranged from 1.5 to 2.2 MPa and the average decrease of the loss modulus was 0.025-0.48 MPa. Our findings suggest that middle ear infection primarily affects the stiffness of the RWM due to the morphological changes that occur in AOM ears. We also conclude that the coil-magnet coupling method for assessment of RWM function may provide a valuable new approach to characterizing the mechanical response of the RWM when reverse driving is selected for middle ear implantable devices. This article is part of a special issue entitled "MEMRO 2012".

Mechanical properties of stapedial annular ligament.

Stapedial annular ligament (SAL) provides a sealed but mobile boundary between the stapes footplate and oval window bony wall. Mechanical properties of the SAL affect the transmission of ossicular movement into the cochlea in sound conduction. However, the mechanical properties of this tissue have never been investigated due to its complexity. In this paper, we report measurement of the viscoelastic properties of SAL on human cadaver temporal bones using a micro-material testing system with digital image correlation analysis. The measured load-deformation relations of SAL samples were converted into shear stress-shear strain relationship, stress relaxation function, and ultimate shear stress and shear strain of the SAL. The hyperelastic Ogden model was used to describe constitutive behavior of the SAL and a 3D finite element model of the experimental setup with SAL was created for assessing the effects of loading variation and measurement errors on results. The study demonstrates that the human SAL is a typical viscoelastic material with hysteresis, nonlinear stress-strain relationship and stress relaxation function. The shear modulus changes from 3.6 to 220 kPa when the shear stress increases from 2 to 140 kPa. These results provide useful information on quasi-static behavior of the SAL.

A totally implantable hearing system--design and function characterization in 3D computational model and temporal bones.

Implantable middle ear hearing devices are emerging as an effective technology for patients with mild to moderately severe sensorineural hearing loss. Several devices with electromagnetic or piezoelectric transducers have been investigated or developed in the US and Europe since 1990. This paper reports a totally implantable hearing system (TIHS) currently under investigation in Oklahoma. The TIHS consists of implant transducer (magnet), implantable coil and microphone, DSP-audio signal processor, rechargeable battery, and remote control unit. The design of TIHS is based on a 3D finite element model of the human ear and the analysis of electromagnetic coupling of the transducer. Function of the TIHS is characterized over the auditory frequency range in three aspects: (1) mass loading effect on residual hearing with a passive implant, (2) efficiency of electromagnetic coupling between the implanted coil and magnet, and (3) functional gain of whole unit in response to acoustic input across the human skin. This paper focuses on mass loading effect and the efficiency of electromagnetic coupling of TIHS determined from the FE model of the human ear and the cadaver ears or temporal bones. Some preliminary data of whole unit function are also presented in the paper.

Magnetic resonance imaging compatibility and safety of the SOUNDTEC Direct System.

OBJECTIVE/HYPOTHESIS: The purpose of this study was to evaluate magnetic resonance imaging (MRI) compatibility and safety of an electromagnetic implanted hearing device (the SOUNDTEC Direct System; SOUNDTEC, Inc., Oklahoma City, OK) implant during a 0.3-Tesla open MRI imaging examination of the head and neck and to develop an MRI protocol that maximizes patient safety while minimizing the need for implant removal. The current literature regarding MRI compatibility of implantable hearing devices was reviewed. STUDY DESIGN: Linear and torsional forces, heating, and implant magnetization were evaluated in vitro. Implanted fresh-frozen human temporal bones were used to evaluate image distortion. A prospective study of 11 volunteers previously implanted with the SOUNDTEC Direct System was conducted to evaluate MRI compatibility and safety. A MEDLINE search of the literature between 1980 and July 2005 was reviewed to summarize MRI compatibility testing of implantable hearing devices. METHODS: Torsional and linear forces experienced by eight implant magnets were measured using calibrated neurologic Von Frey Hairs and compared with finite element analysis predictions as well as forces required to separate the incudostapedial joints of 12 fresh-frozen human temporal bones. Implant heating was determined by measuring the temperature change of eight implant vials compared with saline controls immediately after a head MRI scan. Implant magnetization was evaluated after repeated exposure to a 0.3-Tesla magnetic field. An 11-patient prospective study was performed to evaluate MRI compatibility in a 0.3-Tesla open MRI environment using adult volunteers previously implanted with the SOUNDTEC Direct System. A modified MRI protocol was developed to maximize patient safety. Each individual underwent an audiometric and otologic examination immediately before and after MRI. RESULTS: Peak linear force at the MRI entry measured 0.5 g +/- 0.2 standard deviation (SD). Maximum torque occurred at isocenter and measured 11.4 g-cm +/- 1.2 SD. The mean torque required to separate the incudostapedial joint was 33.8 g-cm +/- 20.4 SD. The average increase in temperature of the eight implant vials was 0.45 degrees C +/- 0.11 SD, whereas the increase in temperature of the three saline controls measured 0.47 degrees C +/- 0.11 SD. The average change in magnetic flux density of the 14 implant magnets tested was 22.0 gauss. Maximum image distortion occurred during the gradient echo sequence and measured 8.6 cm in diameter with a volume of 5,096 mm. Eleven patients completed a total of 12 head, one shoulder, and three lumbar 0.3-Tesla open MRI scans without patient- or device-related complications other than degradation of the MR image. There was no report of discomfort, tinnitus, dizziness, change in hearing, or change in device performance. All post-MRI changes in pure-tone thresholds, speech discrimination, soundfield thresholds, and aided soundfield thresholds were within the range of test-retest variability. CONCLUSION: When considering MRI of implantable ferromagnetic hearing devices, issues related to mechanical forces, implant heating, current induction, implant demagnetization, image degradation, and acoustic trauma must be considered. The SOUNDTEC Direct System is both MRI-compatible and safe in a 0.3-Tesla open MRI environment when a modified protocol is used. Degradation of the head MRI image may impair visualization of the ipsilateral temporal bone and adjacent structures within a 2.5- to 4.3-cm radius of the implant and is minimized by using a fast spin echo sequence.