comparison of abr stimuli for the early detection of ototoxicity

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Abstract

Effective objective testing methodology is needed for early detection of theeffects of ototoxicity on hearing in patients. The requirements for such testinginclude responses that are: 1) reliable across test sessions; 2) sensitive to oto-toxic change ( > 8 kHz), and 3) recordable in a time-efficient manner. Auditorybrainstem responses (ABR) appear well suited to this task however, conven-tional clicks stimulate primarily mid-frequencies (1-4 kHz) and high frequencytonebursts require too much time. We hypothesized that delivery of a band ofhigh frequencies (a high frequency “click”), would elicit reliable and usefulABRs. In the current study, flat and sloped HF (high frequency) clicks with abandwidth of 8-14 kHz were used. The purpose was to compare brainstemresponses elicited by tonebursts, two HF clicks and conventional clicks. Theresults show that the reliability of responses to the HF clicks were compara-ble to the tonebursts and further, both HF clicks produced responses slightlylarger than tonebursts.

Key Words: Auditory brainstem responses, clicks, ototoxicity, tonebursts

Abbreviations: ABR = auditory brainstem response, ANOVA = analysis ofvariance, ARO = Association for Research in Otolaryngology, HF = high fre-quency, kHz = kilohertz, ms = millisecond, PC = personal computer, SD =standard deviation

Sumario: Se necesita una metodología eficiente y objetiva para la deteccióntemprana de los efectos de la ototoxicidad en la audición. Los requisitos paratales pruebas incluyen respuestas que sean: 1) confiables durante todas lassesiones de evaluación, 2) sensibles al cambio ototóxico (> 8 kHz), y 3) reg-istrables de una manera tiempo-eficiente. Las respuestas auditivas del tallocerebral (ABR) parecen ser apropiadas para esa tarea, y sin embargo, loschasquidos o “clicks” convencionales estimulan primariamente las frecuen-

Comparison of ABR Stimuli for the Early Detection of Ototoxicity: Conventional ClicksCompared with High Frequency Clicks andSingle Frequency ToneburstsStephen A. Fausti*Christopher L. Flick*Alison M. Bobal*Roger M. Ellingson*James A. Henry*Curtin R. Mitchell*

*National Center for Rehabilitative Auditory Research, 3710 SW US Veterans Hospital Road (R&D-NCRAR), Portland, Oregon 97207

Reprint requests: Stephen A. Fausti, Ph.D., 3710 SW US Veterans Hospital Road (R&D-NCRAR), Portland, Oregon 97207,Phone: 503-220-8262, ext. 57535, Fax: 503-220-3439, Email: [email protected]

A portion of this study was presented as, Fausti, SA, Mitchell, CR, Henry, JA, Flick, CL, Pandya, PK (1998) A comparison of audito-ry brainstem responses evoked by a sloped and a flat high frequency “click” Assoc Res Otol 21st Midwinter Meeting.

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Aprimary focus of this laboratory hasbeen to introduce objective method-ology that can be applied to the early

detection of ototoxic hearing loss in patientsunable to provide reliable behavioral thresh-olds (Fausti et al. 1993a). Conventional clicksevoke robust (i.e. large and easily detected)auditory brainstem responses (ABR) frommost individuals and are often used as anobjective test of auditory sensitivity. Thesebrainstem responses have a comparativelylarge amplitude and good response mor-phology and thus are easily identified.Because click evoked responses are robustthey usually have a high signal to noise ratioand as such are resistant to degradation bybackground physiological noise. Theseresponses to conventional clicks, however,are dominated by neural activity in the 1-4kHz frequency region of the cochlea (Hall,1992; Fausti et al., 1992).This mid-frequencyregion is usually affected late in the ototoxicprocess because ototoxic hearing loss typicallybegins at the highest audible frequenciesand progresses to the middle and lower fre-quencies (Brummett et al. 1972; Huizing etal. 1987; Fausti et al. 1992, Blakley & Myers1993). Thus, conventional clicks are not wellsuited for the early detection of hearing lossdue to ototoxicity.

Previous investigations by the staff ofthe laboratory have shown that ABRs elicitedby high-frequency tonebursts (8 to 14 kHz)

are reliable and effective for early detectionof the effects of ototoxicity (Fausti et al. 1995).However, responses to high-frequency tone-bursts are less robust than those elicited byconventional clicks because, they stimulatenerve fibers in restricted regions of thecochlea, i.e. fewer nerve fibers than wide-band click stimuli. Further, the time requiredto obtain responses from tonebursts, whichoften require 2000 sweeps/average, at severaldifferent frequencies and intensities preventstheir routine clinical use (Fjermedal & Laukli,1989; Beattie, Garcia & Johnson, 1996, Henryet al. 2000).

These practical deficiencies of ABR stim-uli have prompted us to develop improvedABR stimuli for the early detection and mon-itoring of ototoxicity. One alternative to con-ventional wide-band clicks is filtered clicks.Filtered clicks have been successfully used tostimulate more limited areas of the cochlea(Brama & Sohmer, 1977; Coats, Martin &Kidder, 1979; Kinarti & Sohmer, 1982; Folsom,1984). These studies suggest that band-lim-ited clicks, could provide stimulation of adesired area of the cochlea, e.g. a high fre-quency area. It was hypothesized that deliv-ery of a stimulus containing a band of high-frequencies would stimulate more nerve fibersin the high frequency portion of the cochleathan a single high frequency toneburst. Thusa high frequency (HF) click stimulus wouldhave the advantages of stimulating several

cias medias (1-4 kHz) y los bursts tonales demandan mucho tiempo. Establecimos lahipótesis de que la presentación de una banda de alta frecuencia (un “click” de alta fre-cuencia), generaría registros de ABR confiables y útiles. En el presente estudio se utilizaronclicks planos y con pendientes hacia las alta frecuencias (HF), con un ancho de bandade 8-14 kHz. El propósito fue comparar las respuestas del tallo cerebral con bursts tonales,dos clicks de alta frecuencia (HF) y clicks convencionales. Los resultados mostraron quela confiabilidad de las respuestas con clicks HF fue comparable a los bursts tonales, ymás aún, ambos clicks HF produjeron respuestas un poco más amplias que los burststonales.

Palabras Clave: Respuestas auditivas del tallo cerebral, ototoxicidad, chasquidos o clicks,bursts tonales.

Abreviaturas: ABR = respuestas auditivas del tallo cerebral, ANOVA = análisis de vari-ancia, ARO = Asociación de Investigación en ORL, HF = alta frecuencia, kHz = kilohertz,ms = milisegundo, PC = computadora personal, SD = desviación estándar

frequencies simultaneously thereby reduc-ing testing time, and possibly yielding morerobust responses than tonebursts. ThereforeHF clicks were digitally synthesized usingmultiple tonebursts in the desired frequencyrange rather than by filtering a conventionalclick. Two different HF clicks were synthe-sized to stimulate the frequency region suit-able for the early detection of ototoxicity, (8- 14 kHz).

The purpose of the current study was todevelop and evaluate the reliability of the HFclick stimuli for the early detection and serialABR monitoring of ototoxic changes. Auditorybrainstem responses elicited by the two differ-ent HF click stimuli were compared to responseselicited by four high frequency tonebursts (8,10,12 & 14 kHz) as well as to responses from a con-ventional click stimulus. These two narrow-band HF clicks are referred to as ‘flat’ and‘sloped’ HF clicks according to their acousticspectral content in the 8-14kHz region.

METHODS

Subjects

Twenty adult human subjects (15Females and 5 Males) ranging in age from 21to 43 years, mean age of 27, participated inthis study. Acceptance criteria for subjectswere, 1) no history of ear disease, 2) normalimmittance results, and 3) hearing sensitiv-ity < 15 dB HL between 0.25 and 8 kHz.Thresholds at and above 8 kHz were obtainedusing Koss Pro/4X Plus earphones and werewithin 1 standard deviation of laboratorynorms as described in Fausti et al. (1979).

Equipment

All stimuli were digitally synthesizedand controlled by a custom built, PC based,signal generation and data acquisition sys-tem (Advanced Logic Research, 90 MHz Pen-tium). A National Instruments DSP 2200was used for precision signal generation.Synthesized electrical signals were routedthrough Tucker-Davis Technologies precisionmodular instrumentation for attenuationand headphone buffering.

Calibration

The acoustic spectra of the tonebursts, theconventional click and HF clicks wererecorded with a 1/2 inch Bruel & Kjaer con-denser microphone mounted in a flat-platecoupler (Fausti et al. 1979) using a HewlettPackard spectrum analyzer (model #35660A).The acoustic spectra of these stimuli areshown in Figure 1A-G. The intensity cali-bration was accomplished using this samemicrophone and coupler.

Stimuli

The high-frequency tonebursts were pre-sented with alternating phase, at 8, 10, 12 &14 kHz. Tonebursts had Cos2 rise/fall timesof 1 ms with no plateau. They were deliveredmonaurally through a Koss Pro 4/X Plusheadphone.

Conventional clicks were produced bydelivering a 100 us electrical square wave toa TDH-50 earphone transducer. The acousticspectrum of this standard or conventionalclick is shown in Figure 1A.This click has con-siderable energy up to 6 kHz and little energyin the 8-14kHz region.

The flat HF click consisted of a flatacoustic spectrum across the frequency range8-14 kHz, see Figure 1B.The amplitude of theacoustic spectrum of the flat HF click had lessthan a 3 dB ripple from 8 to 14 kHz. Due tothe audiometric threshold configuration ofmost subjects when the flat HF click is pre-sented the energy at 8 kHz would be expectedto be at a greater sensation level than thehigher frequencies (up to 14 kHz).This poten-tially biases the evoked response to 8kHz. Forthis reason a sloped HF click was also used.

The spectrum of the sloped HF click isshown in Figure 1C and was designed tomore closely match the slope of the subjectsaudiometric threshold (Schechter et al., 1986).The acoustic spectrum of the sloped HF clickhad approximately +3 dB/kHz slope, (18 dBtotal) between 8 k and 14 kHz. Thus thesloped HF click had the potential to stimu-late at more nearly equal sensation levelsacross the 8 to 14 kHz range.

Both the flat and sloped HF clicks weresynthesized by digitally adding seven tone-bursts to produce the click waveforms withthe desired level, rise-time, duration andbandwidth. The frequencies of the tone-

Comparison of ABR Stimuli/Fausti et al.

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bursts were 8, 9, 10, 11, 12, 13 and 14 kHz.The amplitude of each toneburst componentwas adjusted to achieve the desired flat orsloped HF click spectra. The waveform ofboth HF clicks had a Cos2 rise/fall times of 1ms, 2 ms duration with no plateau. Bothwere delivered with alternating polarity (tominimize stimulus artifact), monaurallythrough Koss Pro 4/X Plus headphones.

Procedures

Subjects reclined comfortably in anacoustically and electrically shielded booth(Acoustic Systems, Model RE-245S). ABRswere recorded with gold cup electrodes, simul-taneously from vertex-ipsilateral mastoidand vertex-contralateral mastoid using acommon forehead ground. Single electrodeimpedances were maintained below 1000


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Figure 1A-G. The spectra of the click and toneburst stim-uli are shown in the upper panels. The auditory brainstem responses (duplicates in each session) to eachstimulus, from one subject, are shown in the lower panels


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ohms, with interelectrode impedances nogreater than 2000 ohms. Vertex-ipsilateralrecordings were scored for Wave V latency(peak) and amplitude (peak to trough). Ver-tex-contralateral recordings provided betterIV-V separation and assisted in Wave V iden-tification.

Electrode outputs were routinely ampli-fied with a gain of 500,000, however, when therejected sweeps exceeded 15%, the amplifi-cation was reduced to 200,000. The electricalsignal was bandpass filtered from 100 to 3000Hz using Astromed-Grass (Model P511K) bio-logical amplifier/filters. A PC based, 12 bitdata acquisition board (EISA A2000, NationalInstruments Corp.) was used to digitize thebioamplifier analog outputs. Responses to2048 stimulus presentations were digitallyaveraged for each ABR waveform in a 10 msanalysis window using an acquisition sam-pling rate of 50 k samples/s on each channel.

ABR Protocol

Behavioral threshold to each of the stim-uli was determined prior to data acquisition ineach session. ABR data for each subject werecollected in two sessions (S1 and S2). Duringeach session duplicate averages (R1 and R2)were obtained for each stimulus. The stimuliwere: 1) tonebursts at 8, 10, 12 and 14 kHz; 2)a conventional click; 3) the flat HF click and 4)the sloped HF click.All stimuli were presentedmonaurally at 50 dB SL at a rate of 22.3/sec-ond. Responses to 2048 stimuli were summed

to obtain each averaged response. Each ABRaverage was scored by two investigators.

RESULTS

The acoustic frequency spectrum of eachstimulus is shown in Figure 1 A-G. Cor-

responding examples of the ABRs recordedfrom the ipsilateral-mastoid position, usedthroughout the data analysis, for one subjectare shown in this same Figure.

Conventional clicks produced largeramplitudes and more defined waveforms ascompared to tonebursts. Visual inspection ofthe ABRs to the single toneburst stimulireveals a trend for decreased response ampli-tude as a function of increasing frequency.These were the findings in most subjects andare reflected in the mean amplitudes shownin Table 1.

The latencies and amplitudes of ipsilat-eral Wave V responses for each stimulus wereanalyzed with a three-way ANOVA (Scorers,Sessions, Runs). No significant differences(< 0.05) in latencies or amplitudes were founddue to the run, session or the investigator whoscored the responses. A repeated measuresANOVA determined that the mean ampli-tudes of the conventional click were signifi-cantly greater (p < 0.0001) than for the otherstimuli. Scheffe tests determined that themean amplitudes for both HF clicks weregreater (p < 0.01) than responses to 12 and14 kHz tonebursts, but not different thanresponses to the 8 and 10 kHz tonebursts.

Amplitude (uV) Latency (ms)Stimulus S1 S2 S1 S2

Conv. Click 0.38 0.37 6.06 6.03

Flat HFC 0.22 0.23 6.76 6.77

Sloped HFC 0.22 0.21 6.87 6.94

8 kHz 0.19 0.19 6.55 6.56

10 kHz 0.16 0.17 6.59 6.64

12 kHz 0.13 0.13 6.77 6.78

14 kHz 0.12 0.12 6.80 6.83

Table 1. Mean amplitudes and latencies for each stimulus in the two sessions (S1 and S2).


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Within Session Reliability

To determine the within session variabil-ity the latency differences between repeatedruns (R1-R2) in each session were calculatedfor each subject and averaged. Means andstandard deviation (SD) of these differencesfor each stimulus are shown in Table 2.Repeated measures ANOVAs determined thatthere were no significant differences (p > 0.01)across the sessions. In Table 2, the relative (+and -) rather than absolute differences areshown.The SD, also shown Table 2, is a gaugeof absolute differences and a comparison of theSD among the stimuli indicates no difference.

Amplitude differences were calculatedbetween repeated runs (R1-R2) in each sessionand for each subject. The means and SDs ofthese differences for each stimulus are shownin Table 3. Repeated measures ANOVA deter-mined that there were no significant differ-ences (p > 0.01) between session one and two.

Mean differences give an indication of thewithin-session variability, however, the stan-dard deviations of the differences can be a bet-ter indicator of the response reliability.Tables2 and 3 show only small differences in thestandard deviations among the different stim-uli. From the mean differences and the SD weconclude that the within-session reliability ofthe response amplitudes and latencies to theHFC clicks were no different than the tone-bursts or the conventional click.

Between Session or Test-Retest Reliability

The test retest variability of the stimuliused in this study were of considerable inter-est.The brainstem responses for each subjectwere obtained on two different days, in ses-sion 1 and 2, the test retest differencesbetween the two different days was calculatedas follows. The latencies and amplitudes ofduplicate ABRs in each session (R1 & R2)were averaged and the difference between

Session One Session TwoStimulus Mean (R1-R2) SD Mean (R1-R2) SD

Conv. Click 0.01 0.09 0.01 0.09

Flat HFC 0.00 0.11 -0.01 0.12

Sloped HFC -0.03 0.09 -0.03 0.10

8 kHz -0.02 0.11 -0.01 0.09

10 kHz 0.01 0.12 0.01 0.13

12 kHz -0.04 0.09 -0.04 0.10

14 kHz -0.01 0.12 0.01 0.12

Table 2. Within-session Wave V latency differences (ms), means and standarddeviations (SD). R1 and R2 are the first and second runs during a session.

Session One Session Two

Stimulus Mean (R1-R2) SD Mean (R1-R2) SD

Conv. Click -0.01 0.05 0.01 0.06

Flat HFC -0.02 0.04 0.02 0.05

Sloped HFC 0.02 0.04 -0.01 0.05

8 kHz 0.01 0.05 0.00 0.04

10 kHz -0.01 0.05 0.00 0.05

12 kHz 0.01 0.03 0.00 0.02

14 kHz 0.01 0.03 0.01 0.04

Table 3. Within-session Wave V amplitude differences (uv), means and standard deviations.


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session 1 and session 2 were computed foreach subject and then averaged.The betweensession or test-retest latency differences areshown in Table 4. A repeated measuresANOVA differences showed no significantdifference between the stimuli (p > 0.01).Although the conventional click had a smallerstandard deviation than the other stimuli, anF-test found no significant difference betweenthe standard deviations (p > 0.01).

The test-retest amplitude differencesbetween sessions are also shown in Table 4.A repeated measures ANOVA showed nosignificant difference (p > 0.01 level) betweenstimuli. As previously mentioned, mean dif-ferences provide an indication of reliability,however, standard deviations of the differ-ences are a more sensitive indicator ofresponse reliability. Table 4 shows similarstandard deviations among the different stim-uli. Specifically, the between-session relia-bility (mean and SD) of the responses to the

HF clicks are similar to those of the toneb-ursts.

Absent or Missing Responses

For an ABR procedure to be useful thestimuli must yield scorable responses. Ifresponses cannot be obtained a high per-centage of the time, it can render the proce-dure useless. Table 5 is a summary of thepercent of absent or unscorable responsesfrom the various stimuli. Absent or missingresponses from both ipsilateral and con-tralateral electrode positions are shown inthis Table. Each stimulus was presented at 50dB SL, four times to each subject (two runsin each of two sessions). The fewest missingresponses were observed when the conven-tional click and the sloped HF click were pre-sented and the highest missing when the 12k and 14 kHz tonebursts were presented.

Latency Amplitude

Stimulus Mean (S2-S1) SD Mean (S2-S1) SD

Conv. Click 0.03 0.14 0.01 0.05

Flat HFC -0.03 0.18 -0.01 0.03

Sloped HFC -0.07 0.23 0.00 0.04

8 kHz -0.02 0.22 0.00 0.05

10 kHz -0.05 0.22 -0.01 0.04

12kHz -0.03 0.24 0.00 0.03

14 kHz 0.01 0.25 0.01 0.03

Table 4. Between-session Wave V latency and amplitude differences, means and standard deviations.

Missing Responses (%)Stimulus IP CO

Conv. Click 0 0

Flat HFC 2 5

Sloped HFC 0 0

8 kHz 8 5

10 kHz 2 9

12 kHz 14 25

14 kHz 25 30

Table 5. Single Trial Missing (%) Ipsilateral (IP) and Contralateral (CO) wave V responses from different stimuli.


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DISCUSSION

There is a need for a test to detect hear-ing loss due to ototoxicity which does not

rely on patient active attention and coop-eration. The reason for this is that 30 to 40%hospitalized patients who are administeredpotentially ototoxic medications are too illto give reliable behavioral audiometricthresholds. Because ABR is a method whichdoes not rely upon behavioral responses todetermine auditory sensitivity, it can beused in very ill or even comatose patients.An effective test for the early detection ofototoxicity requires that reliable responsescan be obtained in a time efficient mannerand that the responses are sensitive to oto-toxicity (that is, changes in auditory sensi-tivity at the highest frequencies possible).The present study compared the reliabilityof auditory brainstem responses elicited bydifferent stimuli and determined thatresponses to HF click stimuli have reliabilitycomparable to those elicited by toneburstsand conventional click stimuli (see Tables2 - 4). HF clicks also have the advantage ofshorter testing time when compared withtonebursts. The response to a HF click(spanning 8k-14kHz) can be obtained inone-fourth the time as four tonebursts (8k,10k, 12k & 14kHz).

The use of stimuli at 50 dB SL levels forcomparing responses in the current studydeserves some comment. As far as ABR test-ing is concerned, obtaining responses tothreshold is perhaps the most ideal meas-ure for the early detection of hearing lossfrom ototoxic agents. The uncertainty ofobtaining reliable responses near thresholdcoupled with the extensive time necessaryfor testing precluded the use of low levelstimuli. Further, in a previous study,wherehearing changes and ABR changes werecompared, it was determined that the sin-gle most reliable ABR measure for ototoxicchange was a change from response to noresponse (Fausti et al, 1992). Given theseconsiderations we felt justified in usingsuprathreshold stimuli in order to compareresponses elicited by different stimuli forthis study.

Traditionally, clicks are produced bydelivering short duration electrical squarewaves (e.g., 100 microseconds) to a speakeror headphone, effectively ringing the trans-ducer. While the acoustic spectrum result-

ing from the such an electrical square waveis relatively flat across a wide frequencyrange (such as 1k to 6 kHz), the acoustic out-put reflects the frequency response of theparticular transducer and is further shapedby ear canal resonance. Thus, acousticallythe click from a TDH-50 earphone arrivingat the tympanic membrane has neither aflat spectrum nor appreciable high fre-quency energy (> 6 kHz). The responseamplitude elicited by the conventional clickis larger than responses from the otherstimuli used in this study, as shown in Table1. There are two reasons for this, firstbecause the rise-time is faster (<0.25 vs 1ms) producing more synchronous firing ofthe nerve fibers (Goldstein and Kiang, 1958)and secondly because the band-width iswider and more neurons are activated.Since the HF clicks and tonebursts havethe same rise-time, the larger amplitudeof the HF clicks relative to the toneburstsmay be explained by the wider bandwidthof the HF clicks (Table 1). The smallestamplitude was exhibited by the response to14 kHz perhaps because this frequency islocated at the extreme basal end of the basi-lar membrane where very few nerve fibersmay be available for stimulation.

The latency differences amongresponses to the various stimuli (Table 1)were also due primarily to rise-time differ-ences. The 1 ms rise-time for the HF clicksand the tonebursts introduced an electricaland consequently acoustic delay relative tothe conventional click (0.25 ms rise).Latency differences are also a function ofstimulus intensity and travel time in thecochlea. When considering tonebursts atdifferent frequencies, it would be expectedthat the cochlear travel time or delay wouldbe least for the highest frequency burst (14kHz), and responses to it would have theshortest latency with progressively longerlatencies at lower freqencies. The latencytrend among the tonebursts, shown in Table1, is the reverse of what would be expected.It is difficult to reconcile these data with thetheoretic latencies. However, ABR laten-cies are well known to vary with intensityand in the current study ABRs were onlyobtained at one level (50 dB SL). Further-more, the time differences between fre-quencies were very small. (An analysis offemale and male subjects separately didnot eliminate this trend.) High frequency


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latency-intensity functions which have beenreported by Gorga et al. (1987) and Faustiet al. (1993b) have similar latency reversals.Explanations for these reversals include,(1) the middle ear transfer function beingfrequency-dependent, (2) the frequenciesbeing represented in a small portion of thebasal cochlea, (3) response variabilityobscuring real differences as well as, (4)the reduction in hearing sensitivity withincreasing frequency. Further, when testingwith tonebursts at higher intensities it ispossible that lower frequency areas of thecochlea could be stimulated by low fre-quency sidebands of the tonebursts. Thismay explain the unexpected long latenciesfor the higher frequency tonebursts (14kHz) as compared to the lower frequencytonebursts (8 kHz), however, the latenciesat the highest frequencies did not convergeon those of the lower frequencies. It shouldbe noted that evoked response latencies arethe result of a combination of severalprocesses and the latency change with inten-sity has not been completely explained.

The usefulness of stimulus, alsodepends upon the ability to obtain a scorableresponse on a high percentage of trials whenthe stimulus is presented. The ipsilateralelectrode position usually had fewer absentor missing responses than the contralat-eral position (8k being an exception) asshown in Table 5. Inspection of the datafrom individual subjects found that the ipsi-lateral response was often present and thecontralateral was missing. When the ipsi-lateral response was absent, the contralat-eral response was usually also absent. Thus,when the ipsilateral response was absent ormissing, the contralateral response couldonly rarely be used to determine Wave V.The smallest number of missing responseswas found when click stimuli were used, asshown in Table 5. The findings of importanceare that the usefulness of the HF clicks, interms of % absent, are better than thetonebursts. The data in Table 5 demon-strates that clicks (conventional and HF)yielded the fewest missing or unscorableresponses and thus clicks would be prefer-able to tonebursts for obtaining responsesmost consistently.

As previously mentioned, the conven-tional click is not suitable for ototoxic mon-itoring because click ABRs are not sensitiveto changes in the high frequencies (above 6

kHz). On the other hand, even thoughresponses to high frequency tonebursts maybe sensitive to changes in high frequencyhearing they are not preferred for routinemonitoring because of the extended test-ing time required. HF clicks, on the otherhand, are robust, reliable, time efficient,and should be sensitive to changes in thehigh frequencies. These features of the HFclick stimuli indicate that they meet thedesired criteria for the early detection of oto-toxicity.

It will be the subject of future investi-gations as to whether the Flat or Sloped HFclick is the most sensitive to ototoxic change.This may depend upon the population beingmonitored, for example, in a younger pop-ulation, with good hearing above 8 kHz,the responses to both HF clicks may be verysimilar. In an older population where manypersons have hearing losses above 4 kHz asloped HF click may be the most appropri-ate, steepening the slope to 25 dB/octave ormore would perhaps increase its useful-ness. Another important application wouldbe to use conventional clicks along with HFclicks to test infants in both the mid- andhigh frequency ranges.

The HF clicks can also be designed tohave faster rise times and thereby improvetheir usefulness. Also, other band-limitedclicks, such as, 2k – 6kHz, 4k – 8 kHz, etc.with different slopes could be used in thefuture. Further, we also expect to use trainsof clicks to reduce testing time even further(Mitchell, et al. 1996; 1999; Henry et al.2000). The possibilities of digital stimulusdesigns exceed the current research andclinical needs. We expect however, as theinformation desired from evoked potentialsbecomes more specific new custom stimulican be synthesized to meet the needs.

There is a trade-off between frequencyspecificity, obtained with single frequencytonebursts and shorter testing times, usingHF clicks. The primary goal is to detecthearing loss from ototoxicity in the fre-quencies at or above 8 kHz, that is, beforespeech frequencies are affected. Ideally, ahigh frequency audiogram would beobtained and monitored. However, giventhe constraints of the patient populationthat is in need of monitoring, neither abehavioral audiogram nor toneburst ABRtesting are feasible at this time. ABR test-ing with HF clicks, while not ideal, is fea-


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sible and may fulfill the primary goal ofearly detection of sensitivity changes atand above 8 kHz.

Another method which has promise formonitoring ototoxic changes is otoacousticemissions at high-frequencies (> 8 kHz).Currently obtaining otoacoustic emissionsat these high frequencies in humans is prob-lematic and their interpretation is a subjectof considerable controversy. The placementof probe tubes, transducer distortion andstanding waves are persistent problemswhich have not been sufficiently resolved toallow the use of this method with confi-dence. Overcoming these problems may bepossible in the future and there are inves-tigations currently underway in our labo-ratory to explore this possibility.

CONCLUSIONS

The aim of this study was to comparethe suitability of different ABR stimuli

for the early identification of ototoxicity.ABRs elicited by toneburst stimuli werecompared with ABRs to conventional andhigh frequency clicks. What prompted thisstudy was that tonebursts have been showneffective in eliciting reliable ABRs, how-ever the response amplitude is small and totest multiple frequencies and intensitiesrequires considerable time.

All stimuli tested produced reliableresponses both within and between ses-sions. Conventional and high frequencyclicks elicited more robust responses thantonebursts. Responses to these clicks areeasily identifiable and highly reproduciblewithin individuals. Conventional clicks,however, do not stimulate high frequencyregions of the cochlea, which are suitable fordetecting ototoxicity. HF clicks elicit robustABRs suited to the early detection of oto-toxicity as their spectra are limited to thehigh frequency region (8k to 14 kHz). HFclicks also offer the advantage of time-effi-ciency as compared with tonebursts.

Acknowledgment. Support of this project was pro-vided by a grant from the U. S. Department of VeteransAffairs, Medical Research Service.

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comparison of abr stimuli for the early detection of ototoxicity

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