J Am Acad Audiol 26:299-310 (2015)
Reliability in Hearing Threshold Prediction in Normal-Hearing and Hearing-Impaired Participants Using Mixed Multiple ASSR DOI: 10.3766/jaaa.26.3.9 Kjell-Erik Israelsson* Renata Bogof Erik Berningeri
Abstract Background and Purpose: The rapidly evolving field of hearing aid fitting in infants requires rapid, objec tive, and highly reliable methods for diagnosing hearing impairment. The aim was to determine test-retest reliability in hearing thresholds predicted by multiple auditory steady-state response (ASSRthr) among normal-hearing (NH) and hearing-impaired (HI) adults, and to study differences between ASSRthr and pure-tone threshold (PTT) as a function of frequency in each participant. ASSR amplitude versus stim ulus level was analyzed to study ASSR growth rate in NH and HI participants, especially at ASSRthr. Research Design and Study Sample: Mixed multiple ASSR (100% AM, 20% FM), using long-time aver aging at a wide range of stimulus levels, and PTT were recorded in 10 NH and 14 HI adults. ASSRthr was obtained in 10 dB steps simultaneously in both ears using a test-retest protocol (center frequencies = 500, 1000, 2000, and 4000 Hz; modulation frequencies = 80-96 Hz). The growth rate at ASSRthr was calculated as the slope (nV/dB) of the ASSR amplitudes obtained at, and 10 dB above, ASSRthr. PTT was obtained in both ears in 1 dB steps using a fixed-frequency Bekesy technique. All of the NH par ticipants showed PTTs better than 20 dB HL (125-8000 Hz), and mean pure-tone average (PTA; 5004000 Hz) was 1.8 dB HL. The HI participants exhibited quite symmetrical sensorineural hearing losses, as revealed by a mean interaural PTA difference of 6.5 dB. Their mean PTA in the better ear was 38.7 dB HL. Results: High ASSRthr reproducibility (independent of PTT) was found in both NH and HI participants (test-retest interquartile range = 10 dB). The prediction error was numerically higher in NH participants (f >1000 Hz), although only a significant difference existed at 1000 Hz. The median difference between ASSRthr (dB HL) and PTT (dB HL) was approximately 10 dB in the HI group at frequencies of 1000 Hz or greater, and 20 dB at 500 Hz. In general, the prediction error decreased ( p < 0.001) with increasing hearing threshold, although large intersubject variability existed. Regression analysis (PTT versus ASSRthr) in HI participants revealed correlation coefficients between 0.72-0.88 (500-4000 Hz) and slopes at approximately 1.0. Large variability in ASSRthr-PTT versus frequency was demonstrated across HI participants (interquartile range approximately 20 dB). The maximum across-frequency differ ence (ASSRthr-PTT) in an individual participant was 50 dB. HI participants showed overall significantly higher amplitudes and slopes at ASSRthr than did NH participants (p < 0.02). The amplitude-intensity function revealed monotonically increasing ASSRs in NH participants (slope 2 nV/dB), whereas HI par ticipants exhibited heterogeneous and mostly nonmonotonically increasing ASSRs. Conclusions: Long-time averaging of ASSR revealed high ASSRthr reproducibility and systematic decrease in prediction error with increasing hearing threshold, albeit large intersubject variability in pre diction error existed. A plausible explanation for the systematic difference in ASSRthr between NH and HI
*ENT-clinic, Malarsjukhuset, Eskilstuna, Sweden; tDepartment of Clinical Sciences, Intervention and Technology Section of Audiology, Karolinska Institutet, Stockholm, Sweden; tDepartment of Audiology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden Kjell-Erik Israelsson, ENT-clinic, Malarsjukhuset, SE-631 88 Eskilstuna, Sweden; Telephone: +4616166231; Cell phone: +46 76 7200197; Fax: +46 16 105065; E-mail: [email protected] The study was approved by the local ethics committee of Karolinska University Hospital, Huddinge, Sweden. Part of this study was presented as posters during A Sound Foundation Through Early Amplification, Chicago, IL, USA, 2004, and European Federation of Audiology Sciences (EFAS) 2005, Gothenburg, Sweden, and at Newborn Hearing Screening (NHS) 2006, Villa Erba, Lake Como, Italy. This study was supported by the Eskilstuna-Huddinge Research Fund, Tysta Skolan Foundation, the regional agreement on medical training and clinical research (ALF) between the Stockholm County Council and Karolinska Institutet, and Karolinska University Hospital, Sweden.
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adults might be significantly higher ASSR amplitudes and higher overall growth rates at ASSRthr among HI participants. Across-frequency comparison of PTT and ASSRthr in an individual HI participant dem onstrated large variation; thus, ASSR may not be optimal for, e.g., reliable threshold prediction in infants and subsequent fine-tuning of hearing aids.
Key Words: Auditory steady-state response, reliability, objective audiometry, evoked potential Abbreviations: ABR = auditory brainstem response; AM = amplitude modulation; ASSR = auditory steady-state response; ASSRthr = ASSR threshold; c-ABR attenuator level; FM = frequency modulation; HA = hearing normal hearing; PTA = pure-tone average; PTT = pure-tone SNR = signal-to-noise ratio; SNHL = sensorineural hearing tb-ABR = tone-burst ABR
IN T R O D U C T IO N
earing aid (HA) fitting after universal newborn hearing screening is highly dependent on the rapid and reliable prediction of hearing thresh olds. Infants need higher sound pressure levels (SPLs) th an adults for the identification of speech sounds (/ba/vs/ga/) in quiet (25 dB) (Nozza, Rossman, et al, 1991), and in noise (6-7 dB) (Nozza et al, 1990; Nozza, Miller, et al, 1991). It is also necessary to identify infants with slight or mild, hearing impairments (16-30 dB HL), as these have adverse consequences for speech and language development (Olusanya and Newton 2007). Conse quently, a presumed hearing loss has to be precisely quantified for fine-tuning of acoustic amplification in order to allow high acoustic gain for soft sounds. Outer ear canal acoustics change a great deal during the first two years (Kruger 1987) and thereafter asymp totically toward adult-like behavior (e.g., Dempster and Mackenzie, 1990). In an electrophysiological study, young infants a t age 1 wk (n = 81) dem onstrated a 16 dB higher m ean click-evoked auditory brainstem response (c-ABR) threshold than normal-hearing (NH) adults when the stimulus level was measured as a sound pressure level at the tympanic membrane (Sininger and Abdala 1996). Moreover, corresponding infant-adult differences in tone-burst ABR (tb-ABR) thresholds increased monotonically with frequencies up to 4000 Hz (26 dB), possibly reflecting frequency-dependent neu ral maturation and differences in the conductive mech anism. Frequency-dependent maturation has also been demonstrated psychoacoustically in children younger than age 12 mo (Olsho et al, 1988). In comparison with adults, pure-tone thresholds (PTTs) were 15-30 dB higher (2508000 Hz) at age 3 mo (the greatest difference at 8000 Hz), and 10-15 dB higher at age 6-12 mo (Olsho et al, 1988). Clinically, different earphone types (circumaural, supraaural, and insert) are used. The sound pressure generated by all of these earphones is dependent on ear canal dimen sions and differences in impedance at the tympanic mem brane. Average sound pressure levels generated by insert earphones are, for example, 5-8 dB larger in infant ears than in adult ears across frequency, whereas the difference
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= click-evoked ABR; dB(att) = dB aid; HI = hearing impaired; NH = threshold; SD = standard deviation; loss; SPL = sound pressure level;
using circumaural or supra-aural earphones is within 2 dB below 2000 Hz and 2-7 dB smaller above 2000 Hz (Voss and Herrm ann 2005). Correction factors could, in part, compensate for these systematic age-related differen ces (e.g., infants versus adults) but could not correct for the large intersubject variability among infants and small children. Hence, obtaining thresholds in infants, with a minimum of interindividual variability, should be based on stim ulus level recordings at the tympanic membrane. New auditory electrophysiological techniques mainly aiming at threshold prediction in infants should be thor oughly evaluated before clinical use. Although highly precise psychophysical correlates could be attained in adults (Berninger et al, 2014), this is not possible in infants or young children. Additionally, it is important to consider nonsensory differences (e.g., attention and response criteria) comparing infant versus adult behav ioral thresholds. Approximately 4 dB is supposed to be a nonsensory contribution to the behavioral threshold dif ference between infants and adults (Nozza and Henson 1999). Various electrophysiological methods have been used for the prediction of hearing thresholds. Sininger (1993) found a 1:1 relationship between pure-tone aver age (PTA) (500-2000 Hz) and c-ABR thresholds (correla tion = 0.98), using the F sp technique (Elberling and Don 1984). Although c-ABR cannot per se be used for frequency-specific threshold estimation, some qualitative information on the frequency shape of hearing thresholds could be obtained by using c-ABR latency-intensity infor mation (Gorga et al, 1985), whereas the degree of recruit m ent m ight be reflected by the am plitude-intensity function (Eggermont 1977; Karlsson et al, 1995). Frequency-specific thresholds can be obtained by toneburst ABR (tb-ABR). A high correlation (>0.94) between tb-ABR thresholds in notched noise and PTTs in the 5004000 Hz frequency range has been shown in NH and hearing-impaired (HI) children (Stapells et al, 1995). Although 98% of the tb-ABR thresholds were within 30 dB of the psychoacoustical thresholds, differences up to approximately 50 dB occurred, thereby highlighting the clinical challenge in the diagnosing and fine-timing
R eliability in H earing Threshold P rediction U sing ASSR/Israelsson et al
of nonlinear HAs for the audibility of soft sounds. Al though tb-ABR is widely used in clinical practice and predicts hearing thresholds quite accurately in both NH (typically 10-20 dB higher than PTT) and HI partic ipants (typically 5-15 dB higher than PTT) (Stapells, 2000a), it requires training and skill for clinicians to be able to interpret tb-ABR waveforms (Stapells, 2000b; Vidler and Parkert, 2004). Auditory steady-state response (ASSR) technique allows objective simultaneous testing at several fre quency regions in both ears, at the same time, by using differential amplitude modulation (AM) in combination with frequency modulation (FM) to enhance response amplitudes (John et al, 2004). The reported mean recording time for the prediction of hearing thresholds in one ear at four frequencies, in sleeping or relaxed adults, is 47 min (78% within 60 min) and is somewhat longer when testing both ears (Herdman and Stapells, 2003). Hearing thresholds can be predicted relatively reliably in sleeping adults and children using AM of more than 70 Hz (250-4000 Hz) (Ranee et al, 1995), albeit the need for more research is emphasized in a recent article (Korczak et al, 2012). Reported correla tion coefficients for the relationship between behavioral and ASSR thresholds are 0.75-0.89 (500-4000 Hz) for multiple AM stimulation (Herdman and Stapells, 2003) and are somewhat higher for AM+FM stimuli (0.85-0.95) (Dimitrijevic et al, 2002). Prediction error is largest at low frequencies and in NH participants (Cone-Wesson et al, 2002; Ranee et al, 1995). Further more, the possibility of identifying minor hearing loss is highly dependent on the ASSR detection algorithm (Luts and Wouters, 2005). Low ASSR amplitudes and interindividual variability in amplitude growth make threshold estimation using suprathreshold levels chal lenging (Vander Werff and Brown, 2005). Clinically, objective and precise estimation of hearing thresholds versus frequency is of the utmost importance for the characterization of hearing impairment and the subsequent fine-tuning of HA param eters in young infants. High reliability in ASSRthr measurements is param ount for precise prediction of hearing thresholds. The reliability can, for example, be studied as the differ ence between repeated tests (test-retest) or by correla tion analyses. However, correlation analyses measure the strength of the relation between two tests, not the agreement between them (Bland and Altman, 1986). Correlation also depends on the range of the sample. If the range is wide, the correlation will be greater than if it is narrow. Previously, poor to moder ately strong test-retest reliability in NH participants (D’Haenens et al, 2008) and in participants with simulated sensorineural hearing loss (SNHL) have been reported (Kaf et al, 2006). A study using suprathreshold stimu lation found high variability in ASSR amplitudes between test sessions in both NH and HI participants
and th at it could be a possible cause of test-retest differ ences in ASSRthr measurements (Wilding et al, 2012). Furthermore, ASSR might be used for the recording of loudness recruitment. Therefore, ASSR amplitudeintensity function and amplitude growth ratio, espe cially close to ASSRthr, should be studied. Moreover, to our knowledge, the interindividual variability in the difference between predicted hearing thresholds by ASSR compared with PTT across-frequency has not been studied. The aim of this study was to determine test-retest reliability in hearing thresholds predicted by m ulti ple ASSR (ASSRthr) among NH as well as HI adults, and to study differences between ASSRthr and PTT as a function of frequency in each participant. The test-retest reliability and prediction error were also studied as a function of the precisely recorded hearing threshold. Long-time averaging was used in order to enhance signal-to-noise ratio (SNR). ASSR amplitude versus stimulus level was analyzed to study ASSR growth rate in NH and HI participants, especially close to ASSRthr.
PARTICIPANTS AND METHODS Participants A total of 24 healthy adults participated in this study. They were recruited from personnel, students, and vol unteers from Karolinska University Hospital. There were 10 NH participants (age range = 29-52 yr, mean age = 36 yr, 1 male and 9 females). All of the NH par ticipants showed PTTs better than 20 dB HL (125-8000 Hz), and their mean PTA for both ears (500,1000,2000, and 4000 Hz) was 1.8 dB HL (n = 20). A total of 14 HI participants (age range = 31-83 yr, mean age = 58 yr, 9 males and 5 females) also participated in the study. Their mean PTA in the better ear was 38.7 dB HL (stand ard deviation [SD] = 23.1 dB HL, median = 42.1 dB HL, range = 3.5-77.5 dB HL, n = 14). Corresponding mean PTA for both ears together was 41.3 dB HL (SD = 25.0 dB HL, median = 47.5 dB HL, range = -2 to 94 dB HL, n = 28). The HI participants exhibited quite symmetrical SNHLs, as revealed by a mean interaural PTA difference of 6.5 dB (SD = 4.5 dB, median = 4.8 dB, range = 1.3— 18.8 dB, n = 14). Similar variety of SNHLs was demon strated in the left ears (Fig. 1) and right ears (not shown).
Study Design All participants underwent otomicroscopic examination, tympanometry, acoustic reflex testing (Grason Stadler 33 middle ear analyzer, stimulus frequency = 1000 Hz), and recordings of PTT and ASSR. During the ASSR recording, the participants relaxed or slept in the supine position. All audiological tests were performed
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Electrodes were placed on the forehead (active), neck (reference), and chest (ground). The electrode impedan ces were 3 kOhm or less, as measured at 33 Hz using an Interacoustics EP25 preamplifier (Interacoustics, Assens, Denm ark). The artifact rejection level was 80 p.V.
Figure 1. PTT versus frequency in HI participants (left ears, n = 14; 500-4000 Hz). Median PTT was 29, 43, 49, and 55 at 500, 1000,2000, and 4000 Hz, respectively. (The participant with the low est PTT had PTT >20 dB HL at 8000 Hz, hence categorized as a HI participant.)
in an audiometric test room allowing PTT determina tions down to -20 dB HL (ISO 8253-1, 2010). All of the tests were completed within 4 hr (i.e., approxi mately 3 hr test time for ASSR). The study was approved by the local ethics committee of Karolinska University Hospital, Huddinge, Sweden.
PTT PTTs were measured in both ears using ER 3A in sert earphones (Etymotic Research, USA), at standard audiometric frequencies between 125-8000 Hz, using a computerized fixed-frequency Bekesy technique (Madsen OB822) in steps of 1 dB and three turningpoint pairs for the calculation of hearing thresholds (Karlsson et al, 1995). The relationship between PTT (ISO, 389-2, 1994) and the corresponding threshold obtained by ASSR was studied at 500, 1000, 2000, and 4000 Hz in NH and HI participants. A PTT retest was obtained at 1000 Hz.
ASSR Mixed multiple ASSR (100% AM, 20% FM) was re corded at a wide range of stimulus levels, using the Rotman MASTER portable amplifier system (MPAS1) (John and Picton, 2000), connected to a battery power-driven port able computer. Acoustic stimuli were presented binaurally via ER 3A insert earphones (Etymotic Research, USA), using modulation frequencies of 80.078, 84.961, 89.844, and 93.750 Hz in the left ear and 82.031, 86.914, 91.797, and 95.703 Hz in the right ear at stimu lus center frequencies of 500, 1000, 2000, and 4000 Hz, respectively. Each sweep lasted for 16.384 sec (16 epochs of 1.024 sec each). Approximately 50 sweeps were ob tained at each stimulus level.
3QS
All ASSRs were recorded using factory-calibrated lev els expressed in dB attenuator level (dB[att]), which were supposed to reflect dB SPL. During data analysis, the used stimulus levels were converted from dB(att) to dB HL according to (IEC 60318-4, 2010) (B&K 2636, Bruel & Kjaer, Denmark) using correction levels of -1.0, +1.5, -6.0, and -4.0 dB at the center frequencies of 500, 1000, 2000, and 4000 Hz, respectively (e.g., at 500 Hz, 50 dB(att) corresponded to a stimulus level of 49 dB HL). A S S R T hreshold Differential ASSR stimulus protocols were used for NH and HI participants. The start level was 50 dB (att) for all NH participants and 80 dB(att) for HI par ticipants with two exceptions. One participant, who had a severe hearing loss, accepted stimulus levels of 100 dB (att) and another participant who had a mild highfrequency hearing loss did not accept a start level higher than 50 dB(att). In the NH participants, the stimulus level was decreased in 10 dB steps down to 0 dB(att), followed by a retest at 0 dB(att). The stimulus level was then increased to 50 dB(att) in 10 dB steps. In the HI participants, the stimulus level was decreased in 10 dB steps from the start level until no significant response existed at any center frequency or ear (signifi cant response,/; < 0.05, see John and Picton, 2000). The stimulus level was then increased in 10 dB steps upwards to the start level. The reproducibility of ASSRthr was calculated as the difference (in dB) between the thresholds obtained in the descending procedure (test), and those obtained in the ascending procedure (retest), in order to achieve test-and-retest ASSRthrs during a period with similar noise levels (ASSR recorded at a specific stimulus level is independent of ASSRs obtained at adjacent stimulus levels). ASSRthr for both test and retest was defined as the lowest level th at demonstrated a significant response (p < 0.05) at each center frequency and ear, as defined by the MASTER system (John and Picton, 2000 ).
To achieve a high SNR, long-term averaging was used and data acquisition was completed either when signifi cant responses were achieved at all frequencies at the same stimulus level or when the maximum test time was reached (maximum 15 min test time at each stimu lus level). The ASSRthr, as obtained in the descending procedure (test), was used when the relationship was studied between PTT and ASSRthr.
R e lia b ility in H ea rin g T h resh o ld P r e d ic tio n U sin g A SSR /Israelsson e t al
ASSR A m plitude-Intensity Function a n d ASSR G rowth R ate Close to A SSR thr All statistically significant ASSRs (test-and-retest recordings) were included in the analysis of amplitudeintensity functions and amplitude reproducibility. In NH participants, amplitude-intensity function was studied by median ASSR amplitudes versus stimulus level in the range of 0-50 dB HL and at frequencies between 500-4000 Hz. As the HI participants demon strated a variety of hearing losses, the amplitudeintensity function was studied using dB SL, i.e., stimulus level (dB HL)-PTT (dB HL) (n >3 participants at each stimulus level, grouped ±5 dB). The ASSR growth rate close to ASSRthr was calcu lated as the slope (nV/dB) of the ASSR amplitudes obtained at, and 10 dB above, ASSRthr. Statistical A nalysis Comparisons of ASSRthr (test-retest) and differences between ASSRthr and PTT were performed in both NH and HI participants by boxplots and scatterplots (see Bland and Altman, 1986). Regression analysis was used to study the relationship between PTT and ASSRthr and prediction error (ASSRthr-PTT) as a function of PTT. Regression and variance analyses were performed with Statistica AX version 7 (StatSoft Inc., Tulsa, USA). Correlation analysis (Pearson’s correlation coefficient, r) of test versus retest ASSR amplitudes and boxplots was performed with SPSS version 19 (SPSS, Chicago, USA). Outliers and extreme values (defined as values >1.5 and 3 box-lengths above/below quartiles) are shown in the boxplots as ( • ) and (★ ), respectively. RESULTS R eproducibility of PTT PTT was precisely recorded in both NH and HI partic ipants, as reflected by a median test-retest difference of 0.5 dB (1000 Hz), in combination with an interquartile range of 3 dB (maximum difference = 5 dB, n = 48; NH and HI participants, left and right ears). R eproducibility o f ASSRthr High reproducibility of ASSRthr (recorded in 10 dB steps) was found in both NH and HI participants (Fig. 2A). The overall median test-retest difference was 0 dB, and the interquartile range was 10 dB (n = 161; NH and HI participants and four frequencies), that is, within the used step-size. Furthermore, 44% (70/161) of the ASSRthr test-retest differences were zero, whereas 80% (128/161) were within 10 dB (Fig. 2B). The reprodu-
F ig u r e 2. (A) Test-retest difference of ASSRthr versus center fre quency in NH (left bar) and H I (right bar) participants, respectively. Median, quartiles, range, outliers (•), and extreme values (★ ) are shown [left and right ears in NH (HI) participants, n = 15 (28), 20 (25), 20 (14), and 19 (20) at 500,1000,2000, and 4000 Hz], (B) Test-retest difference of ASSRthr as a function of hearing threshold in NH and HI participants. An estimated 44% (70/161) of the ASSRthr test-retest dif ferences were 0 dB deft and right ears in NH (HI) participants, n = 15 (28), 20 (25), 20 (14), and 19 (20) at 500, 1000, 2000, and 4000 Hz],
cibility of ASSRthr did not depend on PTT (Fig. 2B). No effect of frequency on the reproducibility of ASSRthr was demonstrated (Fig. 2A).
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Although the maximum stimulus level was 50 dB(att) in NH participants and 80 dB(att) in HI participants, some ASSRthrs were absent (i.e., they did not reach the response criterion despite use of long-term averag ing to achieve a high SNR ratio). Among the NH partic ipants, eight ASSRthrs were absent (seven at 500 Hz and one at 4000 Hz). Among the HI participants, all ASSRthrs were recorded at 500 Hz, whereas 4, 20, and 13 ASSRthrs were absent at 1000, 2000, and 4000 Hz, respectively. Overall, 95% (152/160) of the ASSRthrs and 93% (74/80) of the pairwise (test-and-retest) ASSRthrs were obtained in NH participants, whereas the cor responding figures in HI participants were 84% (187/ 224) and 78% (87/112), respectively. D ifference betw een ASSRthr and PTT on Group Level Although the median difference between ASSRthr (test) and PTT for NH participants was approximately 20 dB at all frequencies, the median difference for HI par ticipants was approximately 10 dB at frequencies of 1000 Hz and higher and was somewhat larger at 500 Hz, that is, approximately 20 dB (Fig. 3A). The NH participants showed a slightly larger median difference between ASSRthr and PTT than did the HI participants, but only at 1000 Hz did a significant difference exist between the groups [F(i,45)=4.03, p = 0.05] (Fig. 3A). The overall variability expressed as interquartile range was 17 dB (n = 177 NH and HI participants). P rediction Error as a F unction o f PTT Prediction error (ASSRthr-PTT) decreased in a sys tematic way with increasing PTT, although high varia bility was demonstrated (Fig. 3B). Regression analysis for the entire material revealed a regression line with an intercept of 24 dB and a slope of -0.30 (r = 0.54, p ^ 0.001, n = 177). Systematic effects were demonstra ted at all the four test frequencies (Table 1). Correlation coefficients for the prediction error versus frequency var ied between 0.48-0.61 for the entire material (p < 0.001). Corresponding correlation coefficients were somewhat higher in the HI group, between 0.64 (1000 Hz) and 0.74 (500 Hz) (p < 0.000), whereas also the NH group dem onstrated p levels
Reliability in Hearing Threshold Prediction in Normal-Hearing and Hearing-Impaired Participants Using Mixed Multiple ASSR DOI: 10.3766/jaaa.26.3.9 Kjell-Erik Israelsson* Renata Bogof Erik Berningeri
Abstract Background and Purpose: The rapidly evolving field of hearing aid fitting in infants requires rapid, objec tive, and highly reliable methods for diagnosing hearing impairment. The aim was to determine test-retest reliability in hearing thresholds predicted by multiple auditory steady-state response (ASSRthr) among normal-hearing (NH) and hearing-impaired (HI) adults, and to study differences between ASSRthr and pure-tone threshold (PTT) as a function of frequency in each participant. ASSR amplitude versus stim ulus level was analyzed to study ASSR growth rate in NH and HI participants, especially at ASSRthr. Research Design and Study Sample: Mixed multiple ASSR (100% AM, 20% FM), using long-time aver aging at a wide range of stimulus levels, and PTT were recorded in 10 NH and 14 HI adults. ASSRthr was obtained in 10 dB steps simultaneously in both ears using a test-retest protocol (center frequencies = 500, 1000, 2000, and 4000 Hz; modulation frequencies = 80-96 Hz). The growth rate at ASSRthr was calculated as the slope (nV/dB) of the ASSR amplitudes obtained at, and 10 dB above, ASSRthr. PTT was obtained in both ears in 1 dB steps using a fixed-frequency Bekesy technique. All of the NH par ticipants showed PTTs better than 20 dB HL (125-8000 Hz), and mean pure-tone average (PTA; 5004000 Hz) was 1.8 dB HL. The HI participants exhibited quite symmetrical sensorineural hearing losses, as revealed by a mean interaural PTA difference of 6.5 dB. Their mean PTA in the better ear was 38.7 dB HL. Results: High ASSRthr reproducibility (independent of PTT) was found in both NH and HI participants (test-retest interquartile range = 10 dB). The prediction error was numerically higher in NH participants (f >1000 Hz), although only a significant difference existed at 1000 Hz. The median difference between ASSRthr (dB HL) and PTT (dB HL) was approximately 10 dB in the HI group at frequencies of 1000 Hz or greater, and 20 dB at 500 Hz. In general, the prediction error decreased ( p < 0.001) with increasing hearing threshold, although large intersubject variability existed. Regression analysis (PTT versus ASSRthr) in HI participants revealed correlation coefficients between 0.72-0.88 (500-4000 Hz) and slopes at approximately 1.0. Large variability in ASSRthr-PTT versus frequency was demonstrated across HI participants (interquartile range approximately 20 dB). The maximum across-frequency differ ence (ASSRthr-PTT) in an individual participant was 50 dB. HI participants showed overall significantly higher amplitudes and slopes at ASSRthr than did NH participants (p < 0.02). The amplitude-intensity function revealed monotonically increasing ASSRs in NH participants (slope 2 nV/dB), whereas HI par ticipants exhibited heterogeneous and mostly nonmonotonically increasing ASSRs. Conclusions: Long-time averaging of ASSR revealed high ASSRthr reproducibility and systematic decrease in prediction error with increasing hearing threshold, albeit large intersubject variability in pre diction error existed. A plausible explanation for the systematic difference in ASSRthr between NH and HI
*ENT-clinic, Malarsjukhuset, Eskilstuna, Sweden; tDepartment of Clinical Sciences, Intervention and Technology Section of Audiology, Karolinska Institutet, Stockholm, Sweden; tDepartment of Audiology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden Kjell-Erik Israelsson, ENT-clinic, Malarsjukhuset, SE-631 88 Eskilstuna, Sweden; Telephone: +4616166231; Cell phone: +46 76 7200197; Fax: +46 16 105065; E-mail: [email protected] The study was approved by the local ethics committee of Karolinska University Hospital, Huddinge, Sweden. Part of this study was presented as posters during A Sound Foundation Through Early Amplification, Chicago, IL, USA, 2004, and European Federation of Audiology Sciences (EFAS) 2005, Gothenburg, Sweden, and at Newborn Hearing Screening (NHS) 2006, Villa Erba, Lake Como, Italy. This study was supported by the Eskilstuna-Huddinge Research Fund, Tysta Skolan Foundation, the regional agreement on medical training and clinical research (ALF) between the Stockholm County Council and Karolinska Institutet, and Karolinska University Hospital, Sweden.
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adults might be significantly higher ASSR amplitudes and higher overall growth rates at ASSRthr among HI participants. Across-frequency comparison of PTT and ASSRthr in an individual HI participant dem onstrated large variation; thus, ASSR may not be optimal for, e.g., reliable threshold prediction in infants and subsequent fine-tuning of hearing aids.
Key Words: Auditory steady-state response, reliability, objective audiometry, evoked potential Abbreviations: ABR = auditory brainstem response; AM = amplitude modulation; ASSR = auditory steady-state response; ASSRthr = ASSR threshold; c-ABR attenuator level; FM = frequency modulation; HA = hearing normal hearing; PTA = pure-tone average; PTT = pure-tone SNR = signal-to-noise ratio; SNHL = sensorineural hearing tb-ABR = tone-burst ABR
IN T R O D U C T IO N
earing aid (HA) fitting after universal newborn hearing screening is highly dependent on the rapid and reliable prediction of hearing thresh olds. Infants need higher sound pressure levels (SPLs) th an adults for the identification of speech sounds (/ba/vs/ga/) in quiet (25 dB) (Nozza, Rossman, et al, 1991), and in noise (6-7 dB) (Nozza et al, 1990; Nozza, Miller, et al, 1991). It is also necessary to identify infants with slight or mild, hearing impairments (16-30 dB HL), as these have adverse consequences for speech and language development (Olusanya and Newton 2007). Conse quently, a presumed hearing loss has to be precisely quantified for fine-tuning of acoustic amplification in order to allow high acoustic gain for soft sounds. Outer ear canal acoustics change a great deal during the first two years (Kruger 1987) and thereafter asymp totically toward adult-like behavior (e.g., Dempster and Mackenzie, 1990). In an electrophysiological study, young infants a t age 1 wk (n = 81) dem onstrated a 16 dB higher m ean click-evoked auditory brainstem response (c-ABR) threshold than normal-hearing (NH) adults when the stimulus level was measured as a sound pressure level at the tympanic membrane (Sininger and Abdala 1996). Moreover, corresponding infant-adult differences in tone-burst ABR (tb-ABR) thresholds increased monotonically with frequencies up to 4000 Hz (26 dB), possibly reflecting frequency-dependent neu ral maturation and differences in the conductive mech anism. Frequency-dependent maturation has also been demonstrated psychoacoustically in children younger than age 12 mo (Olsho et al, 1988). In comparison with adults, pure-tone thresholds (PTTs) were 15-30 dB higher (2508000 Hz) at age 3 mo (the greatest difference at 8000 Hz), and 10-15 dB higher at age 6-12 mo (Olsho et al, 1988). Clinically, different earphone types (circumaural, supraaural, and insert) are used. The sound pressure generated by all of these earphones is dependent on ear canal dimen sions and differences in impedance at the tympanic mem brane. Average sound pressure levels generated by insert earphones are, for example, 5-8 dB larger in infant ears than in adult ears across frequency, whereas the difference
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= click-evoked ABR; dB(att) = dB aid; HI = hearing impaired; NH = threshold; SD = standard deviation; loss; SPL = sound pressure level;
using circumaural or supra-aural earphones is within 2 dB below 2000 Hz and 2-7 dB smaller above 2000 Hz (Voss and Herrm ann 2005). Correction factors could, in part, compensate for these systematic age-related differen ces (e.g., infants versus adults) but could not correct for the large intersubject variability among infants and small children. Hence, obtaining thresholds in infants, with a minimum of interindividual variability, should be based on stim ulus level recordings at the tympanic membrane. New auditory electrophysiological techniques mainly aiming at threshold prediction in infants should be thor oughly evaluated before clinical use. Although highly precise psychophysical correlates could be attained in adults (Berninger et al, 2014), this is not possible in infants or young children. Additionally, it is important to consider nonsensory differences (e.g., attention and response criteria) comparing infant versus adult behav ioral thresholds. Approximately 4 dB is supposed to be a nonsensory contribution to the behavioral threshold dif ference between infants and adults (Nozza and Henson 1999). Various electrophysiological methods have been used for the prediction of hearing thresholds. Sininger (1993) found a 1:1 relationship between pure-tone aver age (PTA) (500-2000 Hz) and c-ABR thresholds (correla tion = 0.98), using the F sp technique (Elberling and Don 1984). Although c-ABR cannot per se be used for frequency-specific threshold estimation, some qualitative information on the frequency shape of hearing thresholds could be obtained by using c-ABR latency-intensity infor mation (Gorga et al, 1985), whereas the degree of recruit m ent m ight be reflected by the am plitude-intensity function (Eggermont 1977; Karlsson et al, 1995). Frequency-specific thresholds can be obtained by toneburst ABR (tb-ABR). A high correlation (>0.94) between tb-ABR thresholds in notched noise and PTTs in the 5004000 Hz frequency range has been shown in NH and hearing-impaired (HI) children (Stapells et al, 1995). Although 98% of the tb-ABR thresholds were within 30 dB of the psychoacoustical thresholds, differences up to approximately 50 dB occurred, thereby highlighting the clinical challenge in the diagnosing and fine-timing
R eliability in H earing Threshold P rediction U sing ASSR/Israelsson et al
of nonlinear HAs for the audibility of soft sounds. Al though tb-ABR is widely used in clinical practice and predicts hearing thresholds quite accurately in both NH (typically 10-20 dB higher than PTT) and HI partic ipants (typically 5-15 dB higher than PTT) (Stapells, 2000a), it requires training and skill for clinicians to be able to interpret tb-ABR waveforms (Stapells, 2000b; Vidler and Parkert, 2004). Auditory steady-state response (ASSR) technique allows objective simultaneous testing at several fre quency regions in both ears, at the same time, by using differential amplitude modulation (AM) in combination with frequency modulation (FM) to enhance response amplitudes (John et al, 2004). The reported mean recording time for the prediction of hearing thresholds in one ear at four frequencies, in sleeping or relaxed adults, is 47 min (78% within 60 min) and is somewhat longer when testing both ears (Herdman and Stapells, 2003). Hearing thresholds can be predicted relatively reliably in sleeping adults and children using AM of more than 70 Hz (250-4000 Hz) (Ranee et al, 1995), albeit the need for more research is emphasized in a recent article (Korczak et al, 2012). Reported correla tion coefficients for the relationship between behavioral and ASSR thresholds are 0.75-0.89 (500-4000 Hz) for multiple AM stimulation (Herdman and Stapells, 2003) and are somewhat higher for AM+FM stimuli (0.85-0.95) (Dimitrijevic et al, 2002). Prediction error is largest at low frequencies and in NH participants (Cone-Wesson et al, 2002; Ranee et al, 1995). Further more, the possibility of identifying minor hearing loss is highly dependent on the ASSR detection algorithm (Luts and Wouters, 2005). Low ASSR amplitudes and interindividual variability in amplitude growth make threshold estimation using suprathreshold levels chal lenging (Vander Werff and Brown, 2005). Clinically, objective and precise estimation of hearing thresholds versus frequency is of the utmost importance for the characterization of hearing impairment and the subsequent fine-tuning of HA param eters in young infants. High reliability in ASSRthr measurements is param ount for precise prediction of hearing thresholds. The reliability can, for example, be studied as the differ ence between repeated tests (test-retest) or by correla tion analyses. However, correlation analyses measure the strength of the relation between two tests, not the agreement between them (Bland and Altman, 1986). Correlation also depends on the range of the sample. If the range is wide, the correlation will be greater than if it is narrow. Previously, poor to moder ately strong test-retest reliability in NH participants (D’Haenens et al, 2008) and in participants with simulated sensorineural hearing loss (SNHL) have been reported (Kaf et al, 2006). A study using suprathreshold stimu lation found high variability in ASSR amplitudes between test sessions in both NH and HI participants
and th at it could be a possible cause of test-retest differ ences in ASSRthr measurements (Wilding et al, 2012). Furthermore, ASSR might be used for the recording of loudness recruitment. Therefore, ASSR amplitudeintensity function and amplitude growth ratio, espe cially close to ASSRthr, should be studied. Moreover, to our knowledge, the interindividual variability in the difference between predicted hearing thresholds by ASSR compared with PTT across-frequency has not been studied. The aim of this study was to determine test-retest reliability in hearing thresholds predicted by m ulti ple ASSR (ASSRthr) among NH as well as HI adults, and to study differences between ASSRthr and PTT as a function of frequency in each participant. The test-retest reliability and prediction error were also studied as a function of the precisely recorded hearing threshold. Long-time averaging was used in order to enhance signal-to-noise ratio (SNR). ASSR amplitude versus stimulus level was analyzed to study ASSR growth rate in NH and HI participants, especially close to ASSRthr.
PARTICIPANTS AND METHODS Participants A total of 24 healthy adults participated in this study. They were recruited from personnel, students, and vol unteers from Karolinska University Hospital. There were 10 NH participants (age range = 29-52 yr, mean age = 36 yr, 1 male and 9 females). All of the NH par ticipants showed PTTs better than 20 dB HL (125-8000 Hz), and their mean PTA for both ears (500,1000,2000, and 4000 Hz) was 1.8 dB HL (n = 20). A total of 14 HI participants (age range = 31-83 yr, mean age = 58 yr, 9 males and 5 females) also participated in the study. Their mean PTA in the better ear was 38.7 dB HL (stand ard deviation [SD] = 23.1 dB HL, median = 42.1 dB HL, range = 3.5-77.5 dB HL, n = 14). Corresponding mean PTA for both ears together was 41.3 dB HL (SD = 25.0 dB HL, median = 47.5 dB HL, range = -2 to 94 dB HL, n = 28). The HI participants exhibited quite symmetrical SNHLs, as revealed by a mean interaural PTA difference of 6.5 dB (SD = 4.5 dB, median = 4.8 dB, range = 1.3— 18.8 dB, n = 14). Similar variety of SNHLs was demon strated in the left ears (Fig. 1) and right ears (not shown).
Study Design All participants underwent otomicroscopic examination, tympanometry, acoustic reflex testing (Grason Stadler 33 middle ear analyzer, stimulus frequency = 1000 Hz), and recordings of PTT and ASSR. During the ASSR recording, the participants relaxed or slept in the supine position. All audiological tests were performed
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Frequency (Hz) 500
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Electrodes were placed on the forehead (active), neck (reference), and chest (ground). The electrode impedan ces were 3 kOhm or less, as measured at 33 Hz using an Interacoustics EP25 preamplifier (Interacoustics, Assens, Denm ark). The artifact rejection level was 80 p.V.
Figure 1. PTT versus frequency in HI participants (left ears, n = 14; 500-4000 Hz). Median PTT was 29, 43, 49, and 55 at 500, 1000,2000, and 4000 Hz, respectively. (The participant with the low est PTT had PTT >20 dB HL at 8000 Hz, hence categorized as a HI participant.)
in an audiometric test room allowing PTT determina tions down to -20 dB HL (ISO 8253-1, 2010). All of the tests were completed within 4 hr (i.e., approxi mately 3 hr test time for ASSR). The study was approved by the local ethics committee of Karolinska University Hospital, Huddinge, Sweden.
PTT PTTs were measured in both ears using ER 3A in sert earphones (Etymotic Research, USA), at standard audiometric frequencies between 125-8000 Hz, using a computerized fixed-frequency Bekesy technique (Madsen OB822) in steps of 1 dB and three turningpoint pairs for the calculation of hearing thresholds (Karlsson et al, 1995). The relationship between PTT (ISO, 389-2, 1994) and the corresponding threshold obtained by ASSR was studied at 500, 1000, 2000, and 4000 Hz in NH and HI participants. A PTT retest was obtained at 1000 Hz.
ASSR Mixed multiple ASSR (100% AM, 20% FM) was re corded at a wide range of stimulus levels, using the Rotman MASTER portable amplifier system (MPAS1) (John and Picton, 2000), connected to a battery power-driven port able computer. Acoustic stimuli were presented binaurally via ER 3A insert earphones (Etymotic Research, USA), using modulation frequencies of 80.078, 84.961, 89.844, and 93.750 Hz in the left ear and 82.031, 86.914, 91.797, and 95.703 Hz in the right ear at stimu lus center frequencies of 500, 1000, 2000, and 4000 Hz, respectively. Each sweep lasted for 16.384 sec (16 epochs of 1.024 sec each). Approximately 50 sweeps were ob tained at each stimulus level.
3QS
All ASSRs were recorded using factory-calibrated lev els expressed in dB attenuator level (dB[att]), which were supposed to reflect dB SPL. During data analysis, the used stimulus levels were converted from dB(att) to dB HL according to (IEC 60318-4, 2010) (B&K 2636, Bruel & Kjaer, Denmark) using correction levels of -1.0, +1.5, -6.0, and -4.0 dB at the center frequencies of 500, 1000, 2000, and 4000 Hz, respectively (e.g., at 500 Hz, 50 dB(att) corresponded to a stimulus level of 49 dB HL). A S S R T hreshold Differential ASSR stimulus protocols were used for NH and HI participants. The start level was 50 dB (att) for all NH participants and 80 dB(att) for HI par ticipants with two exceptions. One participant, who had a severe hearing loss, accepted stimulus levels of 100 dB (att) and another participant who had a mild highfrequency hearing loss did not accept a start level higher than 50 dB(att). In the NH participants, the stimulus level was decreased in 10 dB steps down to 0 dB(att), followed by a retest at 0 dB(att). The stimulus level was then increased to 50 dB(att) in 10 dB steps. In the HI participants, the stimulus level was decreased in 10 dB steps from the start level until no significant response existed at any center frequency or ear (signifi cant response,/; < 0.05, see John and Picton, 2000). The stimulus level was then increased in 10 dB steps upwards to the start level. The reproducibility of ASSRthr was calculated as the difference (in dB) between the thresholds obtained in the descending procedure (test), and those obtained in the ascending procedure (retest), in order to achieve test-and-retest ASSRthrs during a period with similar noise levels (ASSR recorded at a specific stimulus level is independent of ASSRs obtained at adjacent stimulus levels). ASSRthr for both test and retest was defined as the lowest level th at demonstrated a significant response (p < 0.05) at each center frequency and ear, as defined by the MASTER system (John and Picton, 2000 ).
To achieve a high SNR, long-term averaging was used and data acquisition was completed either when signifi cant responses were achieved at all frequencies at the same stimulus level or when the maximum test time was reached (maximum 15 min test time at each stimu lus level). The ASSRthr, as obtained in the descending procedure (test), was used when the relationship was studied between PTT and ASSRthr.
R e lia b ility in H ea rin g T h resh o ld P r e d ic tio n U sin g A SSR /Israelsson e t al
ASSR A m plitude-Intensity Function a n d ASSR G rowth R ate Close to A SSR thr All statistically significant ASSRs (test-and-retest recordings) were included in the analysis of amplitudeintensity functions and amplitude reproducibility. In NH participants, amplitude-intensity function was studied by median ASSR amplitudes versus stimulus level in the range of 0-50 dB HL and at frequencies between 500-4000 Hz. As the HI participants demon strated a variety of hearing losses, the amplitudeintensity function was studied using dB SL, i.e., stimulus level (dB HL)-PTT (dB HL) (n >3 participants at each stimulus level, grouped ±5 dB). The ASSR growth rate close to ASSRthr was calcu lated as the slope (nV/dB) of the ASSR amplitudes obtained at, and 10 dB above, ASSRthr. Statistical A nalysis Comparisons of ASSRthr (test-retest) and differences between ASSRthr and PTT were performed in both NH and HI participants by boxplots and scatterplots (see Bland and Altman, 1986). Regression analysis was used to study the relationship between PTT and ASSRthr and prediction error (ASSRthr-PTT) as a function of PTT. Regression and variance analyses were performed with Statistica AX version 7 (StatSoft Inc., Tulsa, USA). Correlation analysis (Pearson’s correlation coefficient, r) of test versus retest ASSR amplitudes and boxplots was performed with SPSS version 19 (SPSS, Chicago, USA). Outliers and extreme values (defined as values >1.5 and 3 box-lengths above/below quartiles) are shown in the boxplots as ( • ) and (★ ), respectively. RESULTS R eproducibility of PTT PTT was precisely recorded in both NH and HI partic ipants, as reflected by a median test-retest difference of 0.5 dB (1000 Hz), in combination with an interquartile range of 3 dB (maximum difference = 5 dB, n = 48; NH and HI participants, left and right ears). R eproducibility o f ASSRthr High reproducibility of ASSRthr (recorded in 10 dB steps) was found in both NH and HI participants (Fig. 2A). The overall median test-retest difference was 0 dB, and the interquartile range was 10 dB (n = 161; NH and HI participants and four frequencies), that is, within the used step-size. Furthermore, 44% (70/161) of the ASSRthr test-retest differences were zero, whereas 80% (128/161) were within 10 dB (Fig. 2B). The reprodu-
F ig u r e 2. (A) Test-retest difference of ASSRthr versus center fre quency in NH (left bar) and H I (right bar) participants, respectively. Median, quartiles, range, outliers (•), and extreme values (★ ) are shown [left and right ears in NH (HI) participants, n = 15 (28), 20 (25), 20 (14), and 19 (20) at 500,1000,2000, and 4000 Hz], (B) Test-retest difference of ASSRthr as a function of hearing threshold in NH and HI participants. An estimated 44% (70/161) of the ASSRthr test-retest dif ferences were 0 dB deft and right ears in NH (HI) participants, n = 15 (28), 20 (25), 20 (14), and 19 (20) at 500, 1000, 2000, and 4000 Hz],
cibility of ASSRthr did not depend on PTT (Fig. 2B). No effect of frequency on the reproducibility of ASSRthr was demonstrated (Fig. 2A).
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Although the maximum stimulus level was 50 dB(att) in NH participants and 80 dB(att) in HI participants, some ASSRthrs were absent (i.e., they did not reach the response criterion despite use of long-term averag ing to achieve a high SNR ratio). Among the NH partic ipants, eight ASSRthrs were absent (seven at 500 Hz and one at 4000 Hz). Among the HI participants, all ASSRthrs were recorded at 500 Hz, whereas 4, 20, and 13 ASSRthrs were absent at 1000, 2000, and 4000 Hz, respectively. Overall, 95% (152/160) of the ASSRthrs and 93% (74/80) of the pairwise (test-and-retest) ASSRthrs were obtained in NH participants, whereas the cor responding figures in HI participants were 84% (187/ 224) and 78% (87/112), respectively. D ifference betw een ASSRthr and PTT on Group Level Although the median difference between ASSRthr (test) and PTT for NH participants was approximately 20 dB at all frequencies, the median difference for HI par ticipants was approximately 10 dB at frequencies of 1000 Hz and higher and was somewhat larger at 500 Hz, that is, approximately 20 dB (Fig. 3A). The NH participants showed a slightly larger median difference between ASSRthr and PTT than did the HI participants, but only at 1000 Hz did a significant difference exist between the groups [F(i,45)=4.03, p = 0.05] (Fig. 3A). The overall variability expressed as interquartile range was 17 dB (n = 177 NH and HI participants). P rediction Error as a F unction o f PTT Prediction error (ASSRthr-PTT) decreased in a sys tematic way with increasing PTT, although high varia bility was demonstrated (Fig. 3B). Regression analysis for the entire material revealed a regression line with an intercept of 24 dB and a slope of -0.30 (r = 0.54, p ^ 0.001, n = 177). Systematic effects were demonstra ted at all the four test frequencies (Table 1). Correlation coefficients for the prediction error versus frequency var ied between 0.48-0.61 for the entire material (p < 0.001). Corresponding correlation coefficients were somewhat higher in the HI group, between 0.64 (1000 Hz) and 0.74 (500 Hz) (p < 0.000), whereas also the NH group dem onstrated p levels
