Auditory neuropathy spectrum disorder (ANSD): a distortion product otoacoustic emissions (DPOAEs) study
The Egyptian Journal of Otolaryngology volume 39, Article number: 35 (2023)
Auditory neuropathy spectrum disorder (ANSD) is characterized by normal OHCs function as shown by intact cochlear microphonics (CMs) and/or otoacoustic emissions (OAEs); absent or grossly abnormal auditory brainstem responses (ABRs) and absent middle ear muscle reflexes. This study is designed to address whether the input/output function of distortion product OAEs (DPOAEs I/O) in ANSD patients is similar or different from normal hearing subjects. This work included 2 groups: control group (GI) composed of 20 normal hearing subjects and study group (GII) consisted of 20 patients with ANSD. All cases were subjected to basic audiological evaluation, DPOAEs I/O function recorded at four frequencies of 2f1-f2 and 5 intensity levels of L1 and L2.
DPOAEs amplitudes were significantly higher in ANSD group when compared with control. The pattern of DPOAEs I/O function was different in ANSD and it was dependent on the frequency and intensity of the stimulus.
Despite normal DPOAEs recordings in ANSD patients, their amplitudes and DP I/O function are different from that of normal hearing subjects. This finding suggested different OHC pattern of activity in ANSD patients.
Distortion-product otoacoustic emissions (DPOAEs) are byproducts of the outer hair cells (OHCs) nonlinearity when two tones interact within the cochlea. This nonlinearity is essential for normal auditory function including auditory sensitivity, sharp frequency resolution, and wide dynamic range of sounds received by the ear [1, 2].
DPOAEs are used for identifying normal or impaired OHCs function. In such a condition, a distortion product-gram (DP-gram) is recorded in response to single intensity moderate sounds along with a wide range of different frequencies (e.g., 500–8000 Hz). DPOAE amplitudes and signal-to-noise ratio (SNR) are measured, that are judged whether they are normal or not . DPOAEs also give information about the rate of growth of cochlear response as a function of increasing stimulus level and this is called DPOAE input/output (DPOAE-I/O) functions. Normal DPOAE-I/O function show a linear growth in response to low stimulus levels when the basilar membrane is driven at its characteristic frequencies (CF) followed by nonlinear growth (compression) at moderate levels, and a linear response to stimuli presented at high levels . Damage of the OHCs causes elevation of the lowest stimulus level required for detection of the basilar membrane motion, compression reduction, and more steepened slope of the I/O function .
Auditory neuropathy spectrum disorder (ANSD) is a unique type of hearing disorder characterized by normal OHCs function as indicated by the presence of cochlear microphonics (CMs) and/or otoacoustic emissions (OAEs) and absent or severely abnormal auditory brainstem responses (ABRs), absent middle ear muscle reflexes (MEMRs) and abnormal olivocochlear bundle function . The exact pathophysiology is still ambiguous, but, damaged cochlear inner hair cells (IHC), abnormal IHC/auditory nerve synapse , disorder of the spiral ganglion , reduced neuronal populations in the auditory brainstem , and demyelination of the auditory nerve  are possible mechanisms. Clinically, patients with ANSD have difficulty of hearing in noise, fluctuating hearing sensitivity, and show speech perception abilities that are disproportionately poor in relation to their degree of hearing loss as measured by pure tone audiometry in addition to the delayed speech and language development in children . Otoacoustic emissions including the DPOAEs have been studied extensively in ANSD and are known to be normal in many patients with such disorders, but little is known about the input/output function of DP used to evaluate the cochlear response growth with stimulus level.
Many researchers studied DP-gram in ANSD; however, no study (to the author's knowledge) had studied DPOAEs-I/O function in this group of patients. In the present study, DPOAE I/O function in ANSD patients compared with that recorded in normal-hearing young adults.
The aim of the work
The objective of this work is to assess the possibility of the presence of different DPOAE amplitude growth function (DPOAEs-I/O) in ANSD in comparison to normal ears as a function of frequency. These comparisons might help to describe different changes in response growth that occur as a consequence of ANSD.
We examined the hypothesis that DPOAEs-I/O have different pattern from normal hearing cases. To this end, forty adults (15–25 years of age; mean age 18.3 ± 2.3 years) were recruited to participate in this study. They were divided into two groups: a control group (GI) 20 normal hearing subjects (12 females and 8 males), and a study group (GII) of 20 subjects (13 females and 7 males) who were previously diagnosed as ANSD patients at childhood (through basic evaluation, OAEs, and ABR).
Inclusion criteria of the control group included subjects with bilateral normal peripheral hearing thresholds (≤ 25 dBHL at all frequencies). None of the participants had a history of otological disorders or surgery, a history of noise exposure, systemic diseases, or psychological problems. Inclusion criteria of the study group included subjects diagnosed with ANSD with various degree of hearing thresholds and normal middle ear function.
Exclusion criteria included subjects with hearing impairment (in control group only) or previous ear surgery, history of ototoxic medication, cervical spondylosis, a history of head injury or cerebrovascular accident, chronic systemic diseases (e.g., diabetes mellitus or hypertension), psychological disorders, or endocrinal diseases. In the study group, cases with history of HA use were excluded from this study.
Participants were recruited from cases attending the Audiovestibular Unit, Otolaryngology Department, XXX University Hospitals, Egypt. Written consent was obtained from all participants in the study after explaining the test procedure. The study was approved by the Ethics committee of the Faculty of Medicine, XXX University Hospitals (20–190-615) and in accordance with the Code of Ethics of the World Medical Association .
All participants were submitted to thorough history taking, otoscopic examination, pure tone audiometry (PTA) throughout the frequency range of 250–8000 Hz and, speech audiometry. Both tests were performed using AD629 audiometer (Interacoustic, Middelfart, Denmark), tympanometry and acoustic reflexes (ipsilateral and contralateral) were performed using an AT235 (Interacoustic) and DPOAEs-I/O (using Interacoutic-Eclipse EP25; Middelfart, Denmark). The I/O function was measured at four DP-frequencies (2f1-f2) of 500, 1000, 2000, and 4000 Hz where the f1/f2 ratio was 1.22 (Table 1). At each DP-frequency, both DP amplitude and signal to noise ratio (SNR) were measured at 5 intensities of L1/L2. L1 was higher than L2 by 10 dB in the following order: 75/65, 65/55, 55/45, 45/35, and 35/25dBSPL. At each level of L1/L2, three recordings were done with accepted SNR > 3 dB, then the average amplitude of the 3 trials was calculated (Table 1). Otoacoustic emissions recordings were performed in a quiet room with total session time of 30–45 min for each subject. The sound was delivered to the ear by an insert-earphone that included two separate sound sources and a calibrated microphone ER-10C (Etymōtic Research).
The collected data were statistically analyzed using the Statistical Package for the Social Studies (SPSS) version 19. Qualitative data are presented as number and percentage. Quantitative data are described using means (minimum and maximum), and standard deviations. The level of significance was adopted at p < 0.05. Student t test was used for normally distributed quantitative variables to compare between the two groups. The Mann–Whitney test was used for abnormally distributed quantitative variables to compare between the two groups. Friedman’s two-way analysis of variance for repeated measurements was used to compare DP amplitudes at different intensities at each frequency.
This study was conducted between October 2019 to October 2020 and included 40 participants: the control group (n = 20), mean age 26.1 ± 4 years and the study group (n = 20), mean age 24 ± 2.4 years with no significant difference between both groups as regard age (P > 0.005).
In the current study, DPOAEs-I/O function we assessed in ANSD cases in both ears (study group, GII) in comparison to the normal hearing subjects (control group, GI).
Results in the study group showed a significant hearing loss at all tested frequency range (250–8000 Hz) mainly at the lower frequencies when compared to the control (Table 2; Fig. 1). The same group showed a significantly elevated speech reception threshold (SRT) and their speech discrimination scores (SD%) ranged from 0 to 64% with the mean of 29.20 ± 20.67% (Table 2).
The DPOAEs-I/O amplitude growth function was measured in both groups. At 500 Hz, the control group showed gradual increase in the amplitude till reaching 65/55 dB followed by an abrupt significant increased amplitude at 75/65 dB when compared with the amplitudes recorded at other intensities. At 1000 Hz and 2000 Hz, the control group showed a gradual significant increase in DP amplitudes with increasing stimulus intensity till reaching 65/55 and 75/65 dB where both intensities showed similar and significantly higher amplitudes than that recorded at other intensities. At 4000 Hz, the control group showed a gradual non-significant increase in amplitude till 65/55 dB followed by an abrupt significant increase at 75/65 dB (Table 3; Fig. 2).
The study group showed different patterns of amplitude growth function at different frequencies. For example, at 500 Hz, there were similar DP amplitudes at lower intensities (35/25 and 45/35 dB) followed by significant amplitude increase at 55/45 dB then a plateau at higher intensities. At 1000 Hz, there was a gradual linear growth till reaching the highest amplitude at 75/65 dB. At 2000 Hz, there was a gradual increase in amplitude then abrupt significant increase at 65/55 dB and 75/65 dB. As regards 4000 Hz, there was a plateau response from 35/25 dB up to 65/55 dB, and then abrupt significant increased amplitude at 75/65 dB (Figs. 2 and 3).
The comparison between the control and study groups as regard DPOAEs-I/O showed higher amplitudes in ANSD group at all tested intensities and frequencies except at 75/65 dB at 4000 Hz where the control group showed significantly higher amplitude than the study group. The pattern of amplitude growth function was also different between both groups as a function of frequency. At 500 Hz, there was an abrupt increased amplitudes at 55/45 dB in study group followed by a plateau at higher intensities, while the control group showed a sudden increase at 75/65 dB). At 1000 Hz, there was more smooth growth in the study group, while the control group showed linear growth with 2 abrupt increases at 45/35 and 65/55 dB. At 2000 Hz, there was a similar linear growth in both groups. Finally, at 4000 Hz there a flat response in the study group and gradual increase in the control group till 65/55 followed by a significant amplitude increase at 75/65 dB (Table 3; Figs. 2 and 3).
The OHCs play an essential role in sound amplification as they are able to contract or elongate as a result of changes in the intracellular potential. This unique property of OHCs is known as electromotility. This movement is responsible for generation of mechanical forces that amplify the sound-induced vibrations within the organ of Corti perceived by IHCs . Clinically, OHCs function can be assessed using OAEs and CM. Normal OHCs function is the main feature in ANSD which has a controversy about the site of the lesion, however, it is essentially beyond OHCs .
This work included 20 patients with bilateral ANSD which was more prevalent in females (65%). Similar female prevalence was reported by Penido and Isaac  and Narne, et al. . At the contrary, Kumar and Jayaram  and Berlin, et al.  reported a greater prevalence of this problem in males than females. There was no significant difference between both groups as regard age (26 ± 4 years and 24 ± 9 years in control and study groups respectively).
Results of PTA showed significant hearing loss at all tested frequencies (250-8000 Hz) in the study group in comparison to the control. The pattern of hearing loss was reverse slop configuration mainly affecting the lower frequencies. This configuration of hearing loss was reported by many authors ex: [15, 18, 19] (Table 2; Fig. 1). As regards speech audiometry, there was a significantly elevated speech reception threshold (SRT). Speech recognition scores (SRS%) ranged from 0 to 64% with a mean of 29.20 ± 20.67% in the study group and was not proportionate to the hearing thresholds. This discrepancy could be related to disruption of the neural firing as a result of dys-synchronization (the main pathological feature in ANSD) and results in impaired capacity to discriminate complex or rapidly changing sounds (such as speech) as a result of presence of temporal deficits. This will be followed by decreased ability to detect/discriminate signals in the presence of background noise .
Patients with ANSD have normal OHCs function with normal cochlear processing of frequency and intensity parameters [20, 21]. In this disorder, the major pathology is the disruption of neural firing patterns (dys-synchronization) along the ascending auditory pathway. This neural dys-synchronization is accompanied by abnormal percepts that depend on the available auditory temporal cues. Normally, neural encoding of the temporal features of sounds depends on synchronization of their firing (phase locking) to both the fine structure of the acoustic waveform and the signal envelope. This temporal coding is preserved in cochlear sensory loss; however, in ANSD it is severely impaired where dys-synchrony in the neural firing of the order of fractions of a millisecond  is sufficient to disrupt the response with perceptual consequences including poor sound localization, poor speech discrimination, and impaired identification of signals in background noise .
Outer hair cells in ANSD are normal; however, their role in enhancing auditory sensitivity and sharpening frequency resolution is not addressed in such disease. In this work, DPOAE-I/O functions were measured at 4 DP-frequencies in both groups. At each frequency, I/O function was elicited at 5 intensity levels of L1/L2. Results in the control group showed general increased DP-amplitude with increasing stimulus intensity. The pattern of amplitude-growth function showed either gradual or abrupt pattern with increasing the stimulus levels up to 65/55 or 75/65 dB and sometimes at both intensity levels. This might be related to using of higher stimulus intensities providing better detectability of OAEs and providing evidence of residual OHCs activity .
However, the study group showed increased DP amplitude with different patterns at different frequencies. At 500 Hz, there were similar DP amplitudes at lower intensities followed by abrupt significant amplitude increase at 55/45 dB, followed by a plateau at higher intensities. Both 1000 Hz and 2000 Hz showed a gradual linear growth with increasing intensities while at 4000 Hz. Then, there was a plateau response till reaching 65/55 dB and then an abrupt increased amplitude at 75/65 dB.
Comparison between both groups showed that DP-amplitudes were higher in the ANSD group at all tested intensities and frequencies except at 75/65 dB at 4000 Hz. The pattern of amplitude growth function was also different between both groups. This indicated that despite normal OHCs function in ANSD, the pattern of their activity is different from normal hearing subjects. Some speculations might be used to explain such different OHC function in ANSD.
First, the possibility of change in the OHCs resting membrane potential. This is consistent with the finding of Starr et al., [25, 26] who recorded higher CM amplitude in patients with ANSD that persists several milliseconds after a transient click stimulus. Second, the role of the efferent system that is disrupted in ANSD. Those patients characteristically show an abnormal olivocochlear bundle reflex that is measured by absent contralateral suppression of OAEs [5, 27]. This abnormality might be relate to the disruption of the auditory nerve as the afferent pathway of the reflex arc alone or a combination of both the efferent and afferent parts of the arc . Alternatively, OCB might be activated in ANSD causing hyperpolarization of OHCs associated with an accompanying increase in receptor potentials and a reduction in the auditory nerve neural activity. This action was observed in experimental animals and if the same pattern of activity took place in humans, CMs would be of large amplitude than normal [26, 29,30,31]. Third, the role of the neurotransmitter acetyl choline (ACh) that is an efferent neurotransmitter. ACh evokes an increase of the electromotile responses of OHCs through decreasing their axial stiffness with later reduction of the overall mechanical load of the OHC motors aggregate. AC mediates its action on OHCs through Ca 2+ dependent phosphorylation of some components of the OHCs cortical cytoskeleton [32, 33]. Finally, the effect of middle ear muscle contractions in response to non-acoustic stimuli, even in the absence of an acoustically activated contraction [34, 35]. This contraction might be graded and can selectively enhance transmission of certain tonal frequencies. This effect had been noticed during CM recording in some ANSD patients and caused an increase in CM amplitude [9, 36].
Despite normal DPOAEs recordings in ANSD patients as a result of normal OHCs function, their amplitudes and DPOAEs-I/O function are different from that of normal hearing subjects. The presence of detectable OAEs with good signal to noise ratio is of clinical importance, however, this work provides evidence that the strength of the response is also important. Although those patients have normal OHCs function, the activity pattern is different from normal hearing subjects and this, in turn, provides a new concept for OAEs recording in ANSD. Future studies are required to address this point using other types of OAEs in ANSD patients with different ages and etiologies.
Availability of data and materials
Data and material of this work is available upon request.
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Ethics approval and consent to participate
This work was approved from the Ethical committee at Faculty of Medicine, Kafrelsheikh University (Approval number: 20-190-615). Informed written consents were taken from all participants after explaining the research procedure (or their parent or legal guardian in the case of children under 16) to participate in this study.
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Gabr, T., Elakkad, M.A. Auditory neuropathy spectrum disorder (ANSD): a distortion product otoacoustic emissions (DPOAEs) study. Egypt J Otolaryngol 39, 35 (2023). https://doi.org/10.1186/s43163-023-00395-2