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.

In humans, the acoustic reflex, also known as the middle ear muscle reflex (MEMR), is a sound-evoked involuntary bilateral contraction of the middle ear stapedial muscle that is triggered by moderate to relatively intense acoustic stimuli. Activation of the MEMR stiffens the middle ear ossicular chain and limits sound transmission for sounds approximately below 1000 Hz (Liden , 1964). Originally thought to serve as a protective function to limit intense sound exposure, the proposed role of the MEMR is best described by the desensitization, interference, and injury protection (DIIP) theory (Borg, 1984). The DIIP theory outlines a potential multifunctional role for the MEMR in humans. The desensitization function of the MEMR response could explain the involuntary contraction of the reflex during auto-stimulation such as chewing, swallowing, and vocalization. Studies using bats (Henson, 1965) and humans (Salomon and Starr, 1963; Borg and Zakrisson, 1975) suggest that the desensitization that occurs during auto-stimulation may help maintain environmental alertness. Similarly, given that primarily low-frequency sounds are attenuated by the MEMR (Borg, 1971; Moller, 1974b; Borg, 1984), the DIIP theory suggests that the reflex may reduce the interference caused by vocalization so that external sounds may be perceived more clearly. The final proposed function of the MEMR per the DIIP theory is the prevention of noise-induced injury, as moderate-to-loud transient external sounds can also elicit the MEMR. Studies in cats (Lawrence, 1960; Sokolovski, 1973) and rabbits (Borg, 1977, 1982) have demonstrated that lesioning the stapedial muscle, and thereby preventing the MEMR response, results in significantly more noise-induced hearing loss (NIHL) relative to animals with intact stapedial muscles.

The external sound protective feature of the MEMR has generated some debate, given that there are few instances of intense impulse sounds that occur in nature that would support evolutionary pressure for such a function to be present (Katz , 2002). Beyond the DIIP theory, it has been suggested that MEMR activation may serve as a high pass filter to enhance hearing and improve signal to noise ratio (SNR) by limiting low frequency sound transmission (Simmons, 1964). This theory also proposes a multifunctional role, where the contraction of the stapedial muscle modulates the sound environment, provides information regarding sound origin (i.e., internal or external), and decreases the perception of low-frequency sounds for improved environmental sound sensitivity (Simmons, 1964).

The majority of theories regarding the evolutionary function of the MEMR response have not changed, even as our understanding of the reflex pathway and the potential diagnostic utility of the MEMR has improved. MEMR response is currently used as an objective component of comprehensive clinical assessment of auditory function. For example, conductive hearing loss due to middle ear problems often suppresses or abolishes the MEMR response (Hong , 2016; Keefe , 2017). The MEMR can also be used as a potential indicator of retrocochlear pathology (Olsen , 1975). Because of the bilateral nature of the MEMR response, brainstem pathology can prevent the contralateral activation of the reflex by interfering with neural transmission in the descending pathway of the reflex arc (Rouiller , 1989). In cases of cochlear hearing loss, reflexes are typically present and have normal thresholds as long as hearing thresholds are under 60 dB hearing level (HL) and tonal stimuli are used to elicit the MEMR (Jerger , 1972). Across the lifespan, studies have shown that the MEMR response may improve towards adulthood but then decline in old age, suggesting that MEMR threshold or amplitude measurement may be able to detect early signs of aging in the cochlea (Katz , 2002), though this has not yet been well-investigated.

More recently, the MEMR has been studied as a potential measure to detect early signs of cochlear damage in animals (Valero , 2016; Valero , 2018) and humans (Wojtczak , 2017; Guest , 2019a). This new application of the MEMR response is partly the result of technological developments that have allowed additional assessment of the MEMR response with wideband acoustic probes. The use of wideband probe stimuli allows for simultaneous assessment of the MEMR response across a broad range of frequencies, an application that has been suggested to be more sensitive to early cochlear damage than single frequency probes (Bharadwaj , 2019; Bramhall , 2022). In the sections below, we will discuss both current and emerging uses of the MEMR with a specific focus on detection of cochlear damage that occurs before threshold elevation.

The neural pathway of the MEMR has been studied across multiple species (Borg, 1973; Lyon, 1978; Lyon and Malmgren, 1982). The validity and reproducibility of the MEMR as it relates to various lesions along the auditory pathway was initially assessed in rabbits (Borg, 1973, 1977). Subsequent studies found that the neuronal organization of the reflex pathway in rats (Rouiller , 1989) and cats (Lyon, 1978; Lyon and Malmgren, 1982) were comparable to the findings in rabbits. These studies, as well as others, led to the current understanding of the MEMR pathway. The pathway begins when sound energy progresses through the external ear canal and transfers to the middle ear via vibration of the tympanic membrane. The middle ear ossicles then transmit the vibrational energy to the fluid-filled cochlea, where sensory cells that communicate with the auditory nerve are stimulated to send signals to the central auditory nervous system. The MEMR pathway extends from the auditory periphery to the central auditory nervous system by ascending to the ventral cochlear nucleus and then progressing through two sets of neural fibers (Moller, 1974a; Mukerji , 2010). The first neural fiber track activates the ipsilateral facial nerve motor neuron. The second set of neural fibers travel from the ventral cochlear nucleus through the brainstem and then descend to the contralateral facial nerve motor neuron. The facial nerve neuron traverses back through the internal auditory meatus and out to the middle ear, where a branch of the facial nerve is sent to the stapedius muscle (Mukerji , 2010). This ipsilateral and contralateral pathway activation results in bilateral contraction of the stapedius muscle that “stiffens” the tympanic membrane and preferentially attenuates low frequency sounds (Borg and Zakrisson, 1974; Moller, 1974a; Mukerji , 2010). Any disruption along this pathway can eliminate or elevate the reflex response. The threshold and amplitude of the MEMR, as elicited by an external sound, is dependent on both the intensity and frequency content of the incoming acoustic signal as well as the acoustic parameters of the MEMR response probe (Olsen , 1975; Stach, 1987; Margolis, 1993).

The MEMR response is used extensively in clinical audiology as an objective cross-check test to identify various pathologies along the auditory pathway. The MEMR response encompasses both a threshold and amplitude measure. The MEMR response can be effective in identifying the possible presence of middle ear, cochlear, or retrocochlear pathologies (Borg, 1977). Studies have shown that there is a reduced or absent MEMR response in individuals with conductive hearing loss from medical conditions such as otosclerosis or third window disorders (Keefe , 2017). The MEMR, in conjunction with tympanometry and behavioral audiometry, is often used to screen and identify conductive hearing loss (Hong , 2016; Keefe , 2017). The MEMR has also been used in the assessment of cochlear hearing loss. In individuals with mild sensorineural hearing loss (20–40 dB HL thresholds), the MEMR can be elicited by stimulus levels of ∼90 dB HL. However, as hearing thresholds increase beyond ∼40 dB HL, MEMR thresholds increase (Margolis, 1993). For example, in individuals with moderate hearing loss (50–60 dB HL thresholds), the MEMR can be elicited at 35–45 dB sensation level (SL), or at approximately 95 dB HL (Katz , 2002). With severe-profound sensorineural hearing loss (>80 dB HL thresholds), the MEMR response is either absent or present at the highest presentation levels (95–105 dB HL). Consequently, the presence or absence of the MEMR response largely depends on the degree and configuration of hearing loss.

In addition to its use in standard clinical hearing assessments, the MEMR response is also used as part of test batteries for the diagnosis of retrocochlear pathology. Studies have found that the MEMR amplitudes can be reduced or absent in cases of acoustic neuromas (>15 mm in size), although the sensitivity and specificity can be quite variable and is affected by the location and size of the tumor (Mangham and Miller, 1979; Mangham , 1980; Bergenius , 1983; Hunter , 1999). Abnormalities in the MEMR response are also found in patients with facial nerve palsy. Inflammation and swelling of the CNVII results in temporary MEMR amplitude weakness or paralysis (Kopala and Kukwa, 2016). The complex anatomy and physiology of the MEMR increases its susceptibility to multiple pathologies, including middle ear problems, cochlear damage, and neural pathway disruption. For these reasons, the MEMR response is often tested as part of wider battery of tests, and MEMR response interpretation can be challenging in the absence of established evidence-based protocols. For research purposes related to hearing loss, the MEMR response should be used in conjunction with other tests of cochlear or auditory function.

The ipsilateral MEMR response is assessed using a multifunction probe that creates a hermetic seal in the ear canal, presents an acoustic elicitor stimulus, and records the resulting change in tympanic membrane compliance to a separate acoustic probe stimulus. Of these functions, both the elicitor stimuli and probe parameters have the potential to impact the results of the test. For example, elicitor stimulus type and frequency content can affect the MEMR response. Pure tone stimuli at 0.5, 1, and 2 kHz are commonly used in clinic and reliably elicit the MEMR response. In contrast, MEMR responses to 4 kHz pure tones can be elevated or absent in some individuals with normal hearing. It has been speculated that this elevation or absence of the MEMR response at 4 kHz may be due to more rapid onset latencies (Jerger , 1986) and subsequently more rapid adaptation rates observed in higher frequency stimuli (Wilson , 1978). In a study that compared multiple different elicitor stimuli on the MEMR response, the lowest proportion of MEMR responses was elicited using brief (100 ms) 4 kHz pure tones in a population of normal hearing, adult participants; conversely, brief 1 kHz pure tones elicited the highest proportion of MEMR responses (Deiters , 2019). In addition to pure tone stimuli, broadband noise (BBN) and filtered noise have also been used as elicitors. Noise elicitors have been shown to produce overall lower MEMR thresholds than pure tone stimuli in adults (Silman, 1979; Thompson , 1980; Margolis, 1993) as noise stimuli simultaneously activates a broader frequency region of the cochlea relative to single frequency elicitors (Peterson and Liden, 1972; Wilson and McBride, 1978). Taken together, the type and frequency spectra of MEMR elicitor stimuli have clear implications for the resulting response.

Studies have also shown that elicitor duration can have a significant effect on the MEMR response (Woodford , 1975; Barry and Resnick, 1976; Korabic and Cudahy, 1984; Cacace , 1991). These studies suggest that MEMR threshold and amplitude measures adhere to the temporal integration effects observed in psychoacoustic studies (Barry and Resnick, 1976). For example, a study that varied elicitor duration (10, 20, 50, 100, 200, 500 ms) using multiple pure tone stimuli (0.5, 1, 2, 3, 4 kHz) found that as elicitor duration decreased, MEMR threshold increased in normal hearing adults (Woodford , 1975). In a similar study, MEMR threshold increased as elicitor duration decreased, and short duration stimuli (20 ms) produced overall higher contralateral MEMR thresholds (Cacace , 1991). In adults with sensorineural hearing loss, increasing stimulus duration produced MEMR threshold temporal integration functions that were relatively steeper than normal hearing adult participants, suggesting that elicitor duration parameters may be useful for assessing differences among individuals (Korabic and Cudahy, 1984).

In Sec. II B, the effects of elicitor parameters on the MEMR response were discussed, including elicitor type, frequency content, and duration. However, the frequency of the probe tone can also influence the MEMR response. In adults, the MEMR is typically measured using a low frequency (e.g., 220 or 226 Hz) probe tone. A low frequency, low intensity probe tone was originally selected because it did not risk activating the reflex, while allowing MEMR response assessment by the probe microphone to elicitor stimuli (Terkildsen and Nielsen, 1960; Silman, 1984). In contrast, higher frequency probes are used in pediatric assessment. Higher frequency probe tones such as 660 or 1000 Hz have been shown to be more effective at measuring the MEMR response in this population (Sprague , 1985; Yang and Liu, 2020). This is in part due to smaller ear canal volumes and overall higher compliance in infant ears (Holte , 1991; Hunter and Margolis, 1992; Swanepoel , 2007). Although both low and high single-frequency probe tones are used in research and in the clinic, studies have shown that the probe frequency capable of measuring maximal changes in compliance can differ across individuals (Bharadwaj , 2019). For that reason, probe measurements that are capable of assessing changes in compliance across a range of frequencies, such as wideband probe stimuli, are emerging diagnostic and clinical research tools.

Wideband probe measures can be used in conjunction with different elicitor stimuli to measure changes in admittance across multiple frequencies simultaneously. These wideband probe measurements have been suggested to be more sensitive to compliance differences among individuals and may be more sensitive to changes in the MEMR response overall (Feeney , 2003). In humans, the use of wideband probes yields thresholds that can be 20–24 dB lower than those measured using single frequency probes (Feeney and Keefe, 2001; Schairer , 2007). Although single frequency probes produce higher thresholds, it is important to note that even with the standard 226 Hz probe, MEMR thresholds in humans are considered reliable and repeatable when using a minimum amplitude criteria of 0.02 ml or greater reduction in compliance and a 10 dB down, 2 dB up stair wise threshold procedure (Guest , 2019b). MEMR assessment with wideband click probes has also been shown to have high test-retest reliably when elicitor stimuli presentation levels are between 70 and 90 dB SPL. However, when the presentation level of the elicitor stimuli is reduced to 60–65 dB SPL, reliability becomes moderate and at 45–50 dB SPL, reliability becomes low (Kamerer , 2019). As such, MEMR elicitor presentation levels for both single frequency and wideband probes are an important consideration for both clinical and research purposes. In order to briefly summarize the MEMR parameters of the references cited in this paper, a table has been provided (Table I).

TABLE I.

MEMR parameters of the references cited in this manuscript.

Study No. Subjects Probe parameters Elicitor parameters
HUMAN  Jerger , 1986   26  24 normal hearing adults; 2 adults with abnormal reflex patterns  Single frequency, 270 Hz, 85 dB SPL  0.5 and 2 kHz pure tone; broadband noise
80–110 dB SPL, 10 dB steps
ipsilateral & contralateral 
Wilson , 1978   Adults with normal hearing  Single frequency, 220 Hz  0.5, 1, 2, 4 kHz pure tones
threshold, 1 dB steps
contralateral 
Silman, 1979   40  20 young normal hearing adult ears 20 elderly normal hearing adult ears  Single frequency, 220 Hz  0.5, 1, 2 kHz pure tones; broadband noise threshold, 1 dB step 
Peterson and Liden, 1972   99  67 normal hearing adults
32 adults with sensorineural hearing loss 
Single frequency, 220 Hz, 625 Hz, 800 Hz
70 dB SPL 
0.25, 0.5, 1, 2, 4 kHz pure tones; narrowband noise centered at 0.5, 1, 2, 4 kHz
threshold, growth function 
Wilson and McBride, 1978   Adults with normal hearing  Single frequency, 220 Hz, 660 Hz  0.25, 0.5, 1, 2, 4 kHz pure tones; broadband noise
Thresholds 2 dB steps, growth function, 4 dB steps up to 116 dB SPL 
Deiters , 2019   190  Adults with normal hearing  Single frequency, 226 Hz  0.5, 1, 2, 4, 8 kHz; white noise; firearm stimuli (0.22, 5.56, and 0.50 caliber gunshots)
threshold, 80–100 dB HL
ipsilateral & contralateral 
Woodford , 1975   10  Adults with normal hearing  Single frequency, 220 Hz  0.5, 1, 2, 3, and 4 kHz with durations of 500, 200, 100, 50, 20 and 10 ms
Threshold, ascending 2 dB steps
contralateral 
Barry and Resnick, 1976   Adults with normal hearing  Single frequency  0.5, 1, 2, and 4 kHz with durations of 10, 30, 100, 300 and 1000 ms
threshold, 1 dB steps 
Korabic and Cudahy, 1984   3 adults with normal hearing
3 adults with sensorineural hearing loss 
Single frequency  1 and 3 kHz and broadband noise with durations of 500, 200, 100, 50, and 20 ms
threshold, 1 dB steps
contralateral 
Cacace , 1991   Adults with normal hearing  Single frequency, 300 Hz, 80 dB SPL  1 kHz with durations of 200, 50, 100, and 500 ms
ipsilateral and contralateral 
Sprague , 1985   53  Neonates  Single frequency, 220 Hz, 660 Hz  1 kHz pure tone; broadband noise
threshold, 5-10 dB steps
ipsilateral & contralateral 
Jacob–Corteletti , 2015   36  20 newborn and 16 neonates who passed hearing screener  Single frequency, 226 Hz, 1000 Hz  0.5, 1, 2, and 4 kHz
threshold
ipsilateral 
Bharadwaj , 2019   Adults  Wideband, click  76 dB SPL broadband noise 
Feeney , 2003   34  Adults with normal hearing  Single frequency, 226 Hz  1 and 2 kHz pure tone
thresholds, 2 dB steps
contralateral 
Wideband, chirp, 65 dB SPL  1 and 2 kHz pure tone
contralateral 
Feeney and Keefe, 2001   Adults  Single frequency, 226 Hz  Broadband noise
threshold, 2 dB steps
contralateral 
Wideband, chirp  Broadband noise
contralateral 
Schairer , 2007   38  22 adults
16 children 
Single frequency, 226 Hz  1, 2 kHz and broadband noise
threshold, 95 dB, 5–10 dB steps 
Wideband, click  Broadband noise
threshold, 90 dB 4 dB steps 
Feeney , 2017   33  Adults with normal hearing  Single frequency, 226 Hz  Broadband noise
threshold starting at 65 dB, 5–10 dB steps
ipsilateral 
Wideband, click  Broadband noise, low pass filter of 8 kHz 45–90 dB, 5 dB steps 
Guest , 2019b   30  Adults with normal hearing  Single frequency, 226 Hz  1, 2, and 4 kHz
threshold, 2–10 dB steps
ipsilateral 
Kamerer , 2019   17  Adults with normal hearing  Wideband, click, 95 dB peSPL  Broadband noise
45–90 dB SPL in 5 dB steps 
Lindgren , 1983   100  Adults with noise induced hearing loss  Single frequency, 220 Hz  Tone burst 0.5, 1, 2 kHz
threshold
contralateral 
Causon , 2020   48  Adults with normal hearing  Single frequency, 226 Hz  0.5, 2, 4 kHz and broadband noise
growth function and threshold, 65–75 dB, 5 dB steps
ipsilateral & contralateral 
Shehorn , 2020   43  Adults with normal hearing (20) and adults with hearing loss (21)  Wideband, click  Broadband noise burst (0.1–4 kHz)
75-, 90-, and 105-dB SPL
ipsilateral & contralateral 
Wojtczak , 2017   18  Adults with normal hearing and tinnitus  Wideband, clicks, 95 dB peSPL  Gaussian noise (0.5–10 kHz) growth function, 63 dB SPL, 5 dB steps contralateral 
Guest , 2019a   38  Adults with normal hearing  Single frequency, 226 Hz  1, 2, 4 kHz
threshold, 75 dB, 2 dB steps
ipsilateral 
Saiz-Alia , 2019   43  Adults with normal hearing and difficulty in background noise  Single frequency, 226 Hz  1 and 4 kHz
threshold, 75 dB, 2 dB steps
ipsilateral 
Mepani , 2020   165  Adults with normal hearing  Single frequency, 226 Hz and  0.5, 1,2, and 4 kHz
Threshold, 65–95 dB, 1 dB steps
ipsilateral 
Wideband, click (2 different pieces of equipment)  White noise
threshold, 60-95 dB, 5 dB steps
contralateral 
Bharadwaj , 2022   53  Adults with normal hearing, at risk for cochlear synaptopathy  Wideband, click, 90 dB peSPL  Broadband noise
34–94 dB SPL, 6 dB steps
ipsilateral 
ANIMAL  Noise exposed chinchillas 
Valero , 2016   Noise exposed mice  Wideband, chirp train  Frozen noise, high pass (16-45.2 kHz)
72 to 100 dB, 2 dB steps
contralateral 
Valero , 2018   16  Noise exposed mice  Wideband, chirp train (70-80 dB SPL)  Frozen noise
threshold, 75 dB in 5 dB steps
contralateral 
Trevino , 2022   Carboplatin-treated chinchillas  Single frequency, 226 Hz  Low bandpass noise, high bandpass noise, broadband noise
95 dB HL
ipsilateral 
Study No. Subjects Probe parameters Elicitor parameters
HUMAN  Jerger , 1986   26  24 normal hearing adults; 2 adults with abnormal reflex patterns  Single frequency, 270 Hz, 85 dB SPL  0.5 and 2 kHz pure tone; broadband noise
80–110 dB SPL, 10 dB steps
ipsilateral & contralateral 
Wilson , 1978   Adults with normal hearing  Single frequency, 220 Hz  0.5, 1, 2, 4 kHz pure tones
threshold, 1 dB steps
contralateral 
Silman, 1979   40  20 young normal hearing adult ears 20 elderly normal hearing adult ears  Single frequency, 220 Hz  0.5, 1, 2 kHz pure tones; broadband noise threshold, 1 dB step 
Peterson and Liden, 1972   99  67 normal hearing adults
32 adults with sensorineural hearing loss 
Single frequency, 220 Hz, 625 Hz, 800 Hz
70 dB SPL 
0.25, 0.5, 1, 2, 4 kHz pure tones; narrowband noise centered at 0.5, 1, 2, 4 kHz
threshold, growth function 
Wilson and McBride, 1978   Adults with normal hearing  Single frequency, 220 Hz, 660 Hz  0.25, 0.5, 1, 2, 4 kHz pure tones; broadband noise
Thresholds 2 dB steps, growth function, 4 dB steps up to 116 dB SPL 
Deiters , 2019   190  Adults with normal hearing  Single frequency, 226 Hz  0.5, 1, 2, 4, 8 kHz; white noise; firearm stimuli (0.22, 5.56, and 0.50 caliber gunshots)
threshold, 80–100 dB HL
ipsilateral & contralateral 
Woodford , 1975   10  Adults with normal hearing  Single frequency, 220 Hz  0.5, 1, 2, 3, and 4 kHz with durations of 500, 200, 100, 50, 20 and 10 ms
Threshold, ascending 2 dB steps
contralateral 
Barry and Resnick, 1976   Adults with normal hearing  Single frequency  0.5, 1, 2, and 4 kHz with durations of 10, 30, 100, 300 and 1000 ms
threshold, 1 dB steps 
Korabic and Cudahy, 1984   3 adults with normal hearing
3 adults with sensorineural hearing loss 
Single frequency  1 and 3 kHz and broadband noise with durations of 500, 200, 100, 50, and 20 ms
threshold, 1 dB steps
contralateral 
Cacace , 1991   Adults with normal hearing  Single frequency, 300 Hz, 80 dB SPL  1 kHz with durations of 200, 50, 100, and 500 ms
ipsilateral and contralateral 
Sprague , 1985   53  Neonates  Single frequency, 220 Hz, 660 Hz  1 kHz pure tone; broadband noise
threshold, 5-10 dB steps
ipsilateral & contralateral 
Jacob–Corteletti , 2015   36  20 newborn and 16 neonates who passed hearing screener  Single frequency, 226 Hz, 1000 Hz  0.5, 1, 2, and 4 kHz
threshold
ipsilateral 
Bharadwaj , 2019   Adults  Wideband, click  76 dB SPL broadband noise 
Feeney , 2003   34  Adults with normal hearing  Single frequency, 226 Hz  1 and 2 kHz pure tone
thresholds, 2 dB steps
contralateral 
Wideband, chirp, 65 dB SPL  1 and 2 kHz pure tone
contralateral 
Feeney and Keefe, 2001   Adults  Single frequency, 226 Hz  Broadband noise
threshold, 2 dB steps
contralateral 
Wideband, chirp  Broadband noise
contralateral 
Schairer , 2007   38  22 adults
16 children 
Single frequency, 226 Hz  1, 2 kHz and broadband noise
threshold, 95 dB, 5–10 dB steps 
Wideband, click  Broadband noise
threshold, 90 dB 4 dB steps 
Feeney , 2017   33  Adults with normal hearing  Single frequency, 226 Hz  Broadband noise
threshold starting at 65 dB, 5–10 dB steps
ipsilateral 
Wideband, click  Broadband noise, low pass filter of 8 kHz 45–90 dB, 5 dB steps 
Guest , 2019b   30  Adults with normal hearing  Single frequency, 226 Hz  1, 2, and 4 kHz
threshold, 2–10 dB steps
ipsilateral 
Kamerer , 2019   17  Adults with normal hearing  Wideband, click, 95 dB peSPL  Broadband noise
45–90 dB SPL in 5 dB steps 
Lindgren , 1983   100  Adults with noise induced hearing loss  Single frequency, 220 Hz  Tone burst 0.5, 1, 2 kHz
threshold
contralateral 
Causon , 2020   48  Adults with normal hearing  Single frequency, 226 Hz  0.5, 2, 4 kHz and broadband noise
growth function and threshold, 65–75 dB, 5 dB steps
ipsilateral & contralateral 
Shehorn , 2020   43  Adults with normal hearing (20) and adults with hearing loss (21)  Wideband, click  Broadband noise burst (0.1–4 kHz)
75-, 90-, and 105-dB SPL
ipsilateral & contralateral 
Wojtczak , 2017   18  Adults with normal hearing and tinnitus  Wideband, clicks, 95 dB peSPL  Gaussian noise (0.5–10 kHz) growth function, 63 dB SPL, 5 dB steps contralateral 
Guest , 2019a   38  Adults with normal hearing  Single frequency, 226 Hz  1, 2, 4 kHz
threshold, 75 dB, 2 dB steps
ipsilateral 
Saiz-Alia , 2019   43  Adults with normal hearing and difficulty in background noise  Single frequency, 226 Hz  1 and 4 kHz
threshold, 75 dB, 2 dB steps
ipsilateral 
Mepani , 2020   165  Adults with normal hearing  Single frequency, 226 Hz and  0.5, 1,2, and 4 kHz
Threshold, 65–95 dB, 1 dB steps
ipsilateral 
Wideband, click (2 different pieces of equipment)  White noise
threshold, 60-95 dB, 5 dB steps
contralateral 
Bharadwaj , 2022   53  Adults with normal hearing, at risk for cochlear synaptopathy  Wideband, click, 90 dB peSPL  Broadband noise
34–94 dB SPL, 6 dB steps
ipsilateral 
ANIMAL  Noise exposed chinchillas 
Valero , 2016   Noise exposed mice  Wideband, chirp train  Frozen noise, high pass (16-45.2 kHz)
72 to 100 dB, 2 dB steps
contralateral 
Valero , 2018   16  Noise exposed mice  Wideband, chirp train (70-80 dB SPL)  Frozen noise
threshold, 75 dB in 5 dB steps
contralateral 
Trevino , 2022   Carboplatin-treated chinchillas  Single frequency, 226 Hz  Low bandpass noise, high bandpass noise, broadband noise
95 dB HL
ipsilateral 

Given the ensuing impact on the MEMR response and the reliability of the MEMR, it is critical to consider both elicitor and measurement probe parameters. When these factors are considered, emerging research suggests that the clinical utility of the MEMR response could expand and may provide an objective and reliable proxy measure of cochlear health.

Noise-induced hearing loss (NIHL) is a well-documented consequence that occurs as a result of exposure to hazardous noise levels. Numerous animal studies have shown that within the cochlea, high levels of noise produce metabolic and mechanical stress that can permanently damage the sensory cells of the inner ear (Kurabi , 2017; Ding , 2019; Frye , 2019). For example, noise-induced cochlear damage is correlated with permanent audiometric threshold shifts (PTS), tinnitus, and hyperacusis (Eggermont and Roberts, 2015; Turner and Larsen, 2016; Ding , 2019). In general, when hearing thresholds are elevated, whether due to aging, noise exposure, or other cochlear pathologies, MEMR thresholds are also elevated (Katz , 2015). In many cases, NIHL is differentiated from other causes of hearing loss by a “notch” in the audiogram, where hearing thresholds are elevated at the frequencies that appear to be most susceptible to noise exposure (3–6 kHz) (Coles , 2000; McBride and Williams, 2001; Kirchner , 2012). However, notched audiograms can occur in individuals without corresponding noise exposure history (Nondahl , 2009), and NIHL may be present in audiograms that are otherwise not distinguishable from traditional sensorineural hearing loss (Lie , 2017). Thus, it has been suggested that the MEMR response may have the potential to differentiate between sensorineural hearing loss and NIHL (Lindgren , 1983).

Early research that investigated the MEMR response in relation to NIHL suggested that the MEMR response could be used to differentiate NIHL from other sensorineural pathologies in instances where the audiometric “noise notch” is unclear. In two studies the MEMR response was elicited with 4000 Hz pure tone stimuli in individuals with 60 dB HL or higher pure tone thresholds at 4000 Hz. One of the studies measured MEMR thresholds in individuals with NIHL and found that the MEMR was reliably elicited in 90% of the participants despite high audiometric thresholds at that frequency (60–80 dB HL) (Lindgren , 1983). In contrast, the second study assessed the MEMR response in individuals with other cochlear pathologies and similar 60 dB HL pure tone thresholds at 4000 Hz, but found that the MEMR response could not be elicited with 4000 Hz pure tone stimuli (Jerger , 1972). The differences observed between studies suggest that pure-tone thresholds alone may fail to account for differences in the underlying cochlear pathology across patients. While studies that assess the MEMR response as a tool to differentially diagnose cochlear hearing loss are limited, some studies support the possibility of using the MEMR response in conjunction with other clinical measures to distinguish between NIHL and other causes of cochlear hearing loss.

The discovery that noise exposure can substantially damage cochlear IHC synapses before there is evidence of permanent threshold elevation has significantly altered how we think about NIHL, NIHL risk, and NIHL assessment (Kujawa and Liberman, 2009; Furman , 2013). Studies in multiple species, including mice, guinea pigs, chinchillas, and rhesus monkeys (Song , 2016; Hickox , 2017; Valero , 2017), have shown that noise-induced loss of IHC synaptic terminals is correlated with permanent reductions in auditory brainstem response (ABR) wave-1 amplitudes at suprathreshold levels (Kujawa and Liberman, 2009). The pattern of synaptic damage preferentially affects low spontaneous rate (SR) auditory nerve fibers that are activated at high intensity sound levels, but has little effect on high SR fibers activated at lower intensity sound levels (Furman , 2013; Marmel , 2015), though this effect may be species-dependent (Suthakar and Liberman, 2021). Consequently, impaired afferent communication between low SR fibers and IHC does not produce threshold elevation but is believed to compromise suprathreshold hearing (Chen , 2021b; Cildir , 2022; Shehabi , 2022).

Cochlear synaptopathy is believed to produce a number of suprathreshold deficits including poorer temporal resolution, poorer word recognition in competing background noise, tinnitus, and hyperacusis (Hickox and Liberman, 2014; Chen , 2021a). The proposed deficits associated with synaptopathy have been labeled as “hidden hearing loss” (Schaette and McAlpine, 2011; Bajin , 2022; Valderrama , 2022), or threshold-independent (Kamerer , 2019; Trevino and Lobarinas, 2022), due to the lack of changes in auditory thresholds. Thus far, the most reliable physiological correlate of synaptopathy in animals has been the reduction of ABR wave-1 amplitude (Kujawa and Liberman, 2006, 2009; Furman , 2013; Kujawa and Liberman, 2015). In humans, however, ABR wave-I amplitudes alone can have significant variability across individuals. For example, head size and distance to early ABR wave generators can affect wave-I amplitude (Bramhall , 2019; Bramhall, 2021). In addition, unlike animal studies, there is typically no baseline assessment prior to noise exposure, precluding measurement of potential noise-induced changes in MEMR threshold or amplitude. To mitigate this limitation, other electrophysiological measures have been suggested as objective markers of noise-induced synaptopathy. These include ABR wave I/V ratios (Grose , 2017), SP/AP ratios (Liberman , 2016), and envelope following response measures (Mepani , 2021). The reliability and specificity of these measures are currently under investigations across a number of laboratories with promising results in both human and animal studies (Bramhall , 2021; Bharadwaj , 2022). Regardless of which evoked potential metric is selected, there is no agreed upon definition for clinically significant change (if a baseline is available) or clinically significant deficit (if no baseline is available).

One of the key advantages of the MEMR response is that it is a rapid, objective assessment that is elicited at higher external sound levels. The higher-level activation may reflect the afferent cochlear activity that constitutes the initial portion of the reflex circuit that is postulated to be highly dependent on low SR fibers (Kobler , 1992; Valero , 2018). If the MEMR response is dependent on low SR fibers [as suggested by Kobler (1992) and Valero (2018)] and if synaptopathy degrades low SR fibers [either preferentially or in combination of degradation of medium or high SR fibers as shown in Furman (2013), Marmel (2015), and Suthakar and Liberman (2021)], then loss of low SR fibers could reduce the amplitude of the MEMR. This hypothesis may be supported by studies in mice with evidence of noise-induced synaptopathy, where it has been reported that synaptopathic noise exposures can significantly reduce the amplitude of the MEMR (Valero , 2016; Valero , 2018). Importantly, the MEMR amplitude was only reduced in frequency regions with moderate IHC synapse loss, but not in regions with minimal synaptic loss. Additionally, the reduced MEMR amplitudes were observed when using wideband probe measurements, but not with single frequency probes that are often used clinically. It has been suggested that individuals that have similar MEMR thresholds and amplitudes to single frequency probes (e.g., 226 Hz) could have significant differences at other frequencies (Feeney , 2017; Bharadwaj , 2019).

The lack of sensitivity of the 226 Hz probe to noise exposure history, noise-induced synaptopathy or IHC damage have been discussed across multiple studies. In humans, MEMR response assessment using the 226 Hz probe tone did not correlate with lifetime noise exposure (Causon , 2020) or tinnitus and speech-in-noise perception (Guest , 2019a). Interestingly, 226 Hz MEMR threshold and amplitude growth were related to middle ear compliance, where higher compliance yielded lower thresholds and steeper growth functions (Causon , 2020). Thus, middle ear compliance could play a greater role in MEMR reflexes and thresholds among individuals with normal or near normal thresholds regardless of their noise exposure history. An additional study in humans also failed to find a correlation between hearing-in-noise ability and the 226 Hz probe MEMR response, and instead suggested that poorer hearing-in-noise ability was likely the result of reduced top-down processes, rather than peripheral bottom up deficits (Saiz-Alia , 2019). More recently, an animal study destroyed 50%–80% of IHC pharmacologically, a level of deafferentation much greater than that produced by noise exposure, found no effect on the 226 Hz probe MEMR response (Trevino , 2022). Collectively, the human and animal studies to date suggest limitations of the commonly used 226 Hz probe in MEMR measurement as an assay of IHC synapse and cochlear damage.

In contrast to the aforementioned results from 226 Hz probe MEMR response studies, more recent studies using wideband MEMR probes suggest that these may be more sensitive to cochlear damage. For example, in one human study, reduced MEMR amplitudes elicited with wideband probes were shown to correlate with both increased estimates of lifetime noise-exposure and poorer word recognition in competing noise as a function of increasing presentation level (74–104 dBA) (Shehorn , 2020). In another study, elevated MEMR thresholds assessed with wideband probes were related to poorer word recognition in noise in some, but not all tasks, and were also correlated with poorer performance for time compressed speech (Mepani , 2020). Reduced MEMR amplitude strength using wideband probes has also been found in individuals with tinnitus and otherwise normal or near normal hearing. Evidence of weakened MEMR response, when assessed using click probe stimuli with a flat spectrum (0.25–12 kHz) and broadband noise elicitor stimuli, were found in individuals with tinnitus suspected of having synaptopathy (Wojtczak , 2017). Taken together, these studies suggest a potential research and clinical role of the wideband MEMR response with respect to cochlear synaptopathy and suprathreshold deficits; however, additional research is warranted.

NIHL is widespread across active military and veteran populations (Yankaskas, 2013; Theodoroff , 2015; Moore , 2019) as well as workers in industries with hazardous noise levels (Nelson , 2005; Engdahl and Tambs, 2010). In these environments, hearing protection devices may not be used due to safety concerns, but also due to lack of compliance to safety regulations (Casali , 2009; Green , 2021). For this reason, there has been substantial effort towards investigating potential pharmaceutical interventions that could minimize risk and improve compliance (Le Prell, 2022). An ideal otoprotective drug would minimize the damaging effects of noise and preserve hearing, either by prevention (prior to exposure) or by rescue (after exposure).

Currently, the efficacy of otoprotectants is often evaluated by typical markers of NIHL, such as changes or shifts in distortion product otoacoustic emissions (DPOAE), ABR thresholds, or behavioral audiometric thresholds. Given the growing body of data suggesting that noise exposure may also produce suprathreshold deficits (Hickox and Liberman, 2014; Lobarinas , 2017; Le Prell, 2022), otoprotective drug studies lack reliable and sensitive objective measures to detect these changes. MEMR responses have been posited as a potential measure of synaptopathic damage, NIHL, and the resulting suprathreshold symptoms that is both noninvasive and objective; however, additional validation and agreed on definitions for clinically significant change are needed if MEMR is to be used in clinical trials as a measure of otoprotectant efficacy. It is important to note that the MEMR responses can be temporarily reduced or eliminated by muscle relaxants, sedatives, and general anesthetics (Borg and Moller, 1975; Uhles , 2000; Arslan , 2017).

Moreover, although the presence of the MEMR is common, it fails to meet the criteria of being pervasive, as defined by 95% confidence of being observed in at least 95% of the people. An analysis of data from the National Health and Nutrition Examination Survey (NHANES) in 2017 found that in over 15 000 participants, the MEMR failed to be pervasive with prevalence of 86.9% in adults 18–30 with normal hearing, 85.3% in all adults 18–30, and 74/6% across all participants (McGregor , 2018). These findings suggest that the MEMR is unlikely to be effective as a singular metric for any clinical study. For studies evaluating experimental medicines, the FDA stipulates that the outcome of the treatment yields clinically significant results (Le Prell, 2021, 2022). The lack of prevalence and criteria for clinical significance of the MEMR at this time present a significant limitation for the use of the MEMR as a singular metric for intervention studies for hearing loss. However, despite these limitations, the MEMR may prove useful as an objective measure and correlate of clinically significant suprathreshold auditory deficits. In individuals with normal hearing sensitivity but reported suprathreshold auditory problems, widely accepted objective correlates of these deficits have yet to be established. The emerging studies appear to suggest that in a subset of these patients, the MEMR may provide measurable and reliable changes that can be used to evaluate intervention among specific clinical populations.

The MEMR pathway and physiological processes have been studied extensively and provide significant diagnostic utility in audiological evaluation. However, our understanding of the relationship between the MEMR responses and cochlear hearing loss is still developing, and results from both animal and human studies vary. Nevertheless, the search for objective measures to assess subclinical hearing loss has renewed investigation of the potential utility of the MEMR. Data from both human and animal studies suggest that the MEMR response has good test-retest reliability, is non-invasive, and is relatively easy to obtain using existing audiological protocols. Human studies suggest that wideband probes may be more sensitive to cochlear synaptopathy than single frequency probe tones or ABR wave-I amplitudes. If the MEMR is indeed sensitive to cochlear synaptopathy, it could prove to be an extremely valuable and readily deployable tool for the early detection of NIHL. MEMR response testing may also provide an objective measure of suprathreshold cochlear function. Its use for large-scale pharmacological studies on otoprotectants could provide an essential pre- and post-treatment marker to assess relative efficacy for threshold independent changes. Perhaps most importantly, the MEMR response could serve a critical diagnostic role in early identification of potential cochlear damage across the human lifespan.

Preparation of this paper was partially supported by National Institutes of Heath grants from the National Institute on Deafness and Other Communication Disorders (NIDCD, Grant No. R01-DC014088). Its contents are solely the responsibility of the authors and do not necessarily represent the official views of NIDCD.

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