The middle ear muscle reflex: Current and future role in assessing noise-induced cochlear damage.

The middle ear muscle reflex (MEMR) in humans is a bilateral contraction of the middle ear stapedial muscle in response to moderate-to-high intensity acoustic stimuli. Clinically, MEMR thresholds have been used for differential diagnosis of otopathologies for decades. More recently, changes in MEMR amplitude or threshold have been proposed as an assessment for noise-induced synaptopathy, a subclinical form of cochlear damage characterized by suprathreshold hearing problems that occur as a function of inner hair cell (IHC) synaptic loss, including hearing-in-noise deficits, tinnitus, and hyperacusis. In animal models, changes in wideband MEMR immittance have been correlated with noise-induced synaptopathy; however, studies in humans have shown more varied results. The discrepancies observed across studies could reflect the heterogeneity of synaptopathy in humans more than the effects of parametric differences or relative sensitivity of the measurement. Whereas the etiology and degree of synaptopathy can be carefully controlled in animal models, synaptopathy in humans likely stems from multiple etiologies and thus can vary greatly across the population. Here, we explore the evolving research evidence of the MEMR response in relation to subclinical noise-induced cochlear damage and the MEMR as an early correlate of suprathreshold deficits.

Evidence of "hidden hearing loss" following noise exposures that produce robust TTS and ABR wave-I amplitude reductions.

In animals, noise exposures that produce robust temporary threshold shifts (TTS) can produce immediate damage to afferent synapses and long-term degeneration of low spontaneous rate auditory nerve fibers. This synaptopathic damage has been shown to correlate with reduced auditory brainstem response (ABR) wave-I amplitudes at suprathreshold levels. The perceptual consequences of this "synaptopathy" remain unknown but have been suggested to include compromised hearing performance in competing background noise. Here, we used a modified startle inhibition paradigm to evaluate whether noise exposures that produce robust TTS and ABR wave-I reduction but not permanent threshold shift (PTS) reduced hearing-in-noise performance. Animals exposed to 109 dB SPL octave band noise showed TTS >30 dB 24-h post noise and modest but persistent ABR wave-I reduction 2 weeks post noise despite full recovery of ABR thresholds. Hearing-in-noise performance was negatively affected by the noise exposure. However, the effect was observed only at the poorest signal to noise ratio and was frequency specific. Although TTS >30 dB 24-h post noise was a predictor of functional deficits, there was no relationship between the degree of ABR wave-I reduction and degree of functional impairment.

Selective Inner Hair Cell Dysfunction in Chinchillas Impairs Hearing-in-Noise in the Absence of Outer Hair Cell Loss.

Poorer hearing in the presence of background noise is a significant problem for the hearing impaired. Ototoxic drugs, ageing, and noise exposure can damage the sensory hair cells of the inner ear that are essential for normal hearing sensitivity. The relationship between outer hair cell (OHC) loss and progressively poorer hearing sensitivity in quiet or in competing background noise is supported by a number of human and animal studies. In contrast, the effect of moderate inner hair cell (IHC) loss or dysfunction shows almost no impact on behavioral measures of hearing sensitivity in quiet, when OHCs remain intact, but the relationship between selective IHC loss and hearing in noise remains relatively unknown. Here, a moderately high dose of carboplatin (75 mg/kg) that produced IHC loss in chinchillas ranging from 40 to 80 % had little effect on thresholds in quiet. However, when tested in the presence of competing broadband (BBN) or narrowband noise (NBN), thresholds increased significantly. IHC loss >60 % increased signal-to-noise ratios (SNRs) for tones (500-11,300 Hz) in competing BBN by 5-10 dB and broadened the masking function under NBN. These data suggest that IHC loss or dysfunction may play a significant role in listening in noise independent of OHC integrity and that these deficits may be present even when thresholds in quiet are within normal limits.

Assessment of thermal treatment via irrigation of external ear to reduce cisplatin-induced hearing loss.

Systemic and local changes in body temperature can have a profound effect on traumatic injuries including those to the inner ear. Therefore, we investigated the effects of acutely increasing or decreasing the temperature of the external ear canal on cisplatin-induced hearing loss. The external auditory canals of male guinea pigs were acutely irrigated with warm (44 °C), euthermic (37 °C), or cool (30 °C) water and subsequently injected with cisplatin (12 mg/kg, i.p.). Hearing was assessed by the auditory brainstem response and cochleograms were prepared to determine loss of hair cells. Ear canal irrigation with warm water potentiated cisplatin-induced hearing loss and outer hair cell loss whereas cool ear canal irrigation showed significant protection from cisplatin-induced hearing loss and outer hair cell loss. These results suggest that non-invasive cool water ear canal irrigation may be highly effective clinical procedure for protecting against cisplatin-induced hearing loss.

Insensitivity of the audiogram to carboplatin induced inner hair cell loss in chinchillas.

Noise trauma, aging, and ototoxicity preferentially damage the outer hair cells of the inner ear, leading to increased hearing thresholds and poorer frequency resolution. Whereas outer hair cells make synaptic connections with less than 10% of afferent auditory nerve fibers (type-II), inner hair cells make connections with over 90% of afferents (type-I). Despite these extensive connections, little is known about how selective inner hair cell loss impacts hearing. In chinchillas, moderate to high doses of the anticancer compound carboplatin produce selective inner hair cell and type-I afferent loss with little to no effect on outer hair cells. To determine the effects of carboplatin-induced inner hair cell loss on the most widely used clinical measure of hearing, the audiogram, pure-tone thresholds were determined behaviorally before and after 75 mg/kg carboplatin. Following carboplatin treatment, small effects on audiometric thresholds were observed even with extensive inner hair cell losses that exceed 80%. These results suggest that conventional audiometry is insensitive to inner hair cell loss and that only small populations of inner hair cells appear to be necessary for detecting tonal stimuli in a quiet background.

The gap-startle paradigm for tinnitus screening in animal models: limitations and optimization.

In 2006, Turner and colleagues (Behav. Neurosci., 120:188-195) introduced the gap-startle paradigm as a high-throughput method for tinnitus screening in rats. Under this paradigm, gap detection ability was assessed by determining the level of inhibition of the acoustic startle reflex produced by a short silent gap inserted in an otherwise continuous background sound prior to a loud startling stimulus. Animals with tinnitus were expected to show impaired gap detection ability (i.e., lack of inhibition of the acoustic startle reflex) if the background sound containing the gap was qualitatively similar to the tinnitus pitch. Thus, for the gap-startle paradigm to be a valid tool to screen for tinnitus, a robust startle response from which to inhibit must be present. Because recent studies have demonstrated that the acoustic startle reflex could be dramatically reduced following noise exposure, we endeavored to 1) modify the gap-startle paradigm to be more resilient in the presence of hearing loss, and 2) evaluate whether a reduction in startle reactivity could confound the interpretation of gap prepulse inhibition and lead to errors in screening for tinnitus. In the first experiment, the traditional broadband noise (BBN) startle stimulus was replaced by a bandpass noise in which the sound energy was concentrated in the lower frequencies (5-10 kHz) in order to maintain audibility of the startle stimulus after unilateral high-frequency noise exposure (16 kHz). However, rats still showed a 57% reduction in startle amplitude to the bandpass noise post-noise exposure. A follow-up experiment on a separate group of rats with transiently-induced conductive hearing loss revealed that startle reactivity was better preserved when the BBN startle stimulus was replaced by a rapid airpuff to the back of the rat's neck. Furthermore, it was found that transient unilateral conductive hearing loss, which was not likely to induce tinnitus, caused an impairment in gap prepulse inhibition as assessed with the traditional BBN gap-startle paradigm, resulting in a false-positive screening for tinnitus. Thus, the present study identifies significant caveats of the traditional gap-startle paradigm, and describes experimental parameters using an airpuff startle stimulus which may help to limit the negative consequences of reduced startle reactivity following noise exposure, thereby allowing researchers to better screen for tinnitus in animals with hearing loss.

Altered neuronal intrinsic properties and reduced synaptic transmission of the rat's medial geniculate body in salicylate-induced tinnitus.

Sodium salicylate (NaSal), an aspirin metabolite, can cause tinnitus in animals and human subjects. To explore neural mechanisms underlying salicylate-induced tinnitus, we examined effects of NaSal on neural activities of the medial geniculate body (MGB), an auditory thalamic nucleus that provides the primary and immediate inputs to the auditory cortex, by using the whole-cell patch-clamp recording technique in MGB slices. Rats treated with NaSal (350 mg/kg) showed tinnitus-like behavior as revealed by the gap prepulse inhibition of acoustic startle (GPIAS) paradigm. NaSal (1.4 mM) decreased the membrane input resistance, hyperpolarized the resting membrane potential, suppressed current-evoked firing, changed the action potential, and depressed rebound depolarization in MGB neurons. NaSal also reduced the excitatory and inhibitory postsynaptic response in the MGB evoked by stimulating the brachium of the inferior colliculus. Our results demonstrate that NaSal alters neuronal intrinsic properties and reduces the synaptic transmission of the MGB, which may cause abnormal thalamic outputs to the auditory cortex and contribute to NaSal-induced tinnitus.