Rate and adaptation effects on the auditory evoked brainstem response in human newborns and adults

Hearing Research 111 (1997) 165^176

Rate and adaptation e¡ects on the auditory evoked brainstem response in human newborns and adults Robert E. Lasky * The University of Wisconsin-Madison Medical School, Department of Neurology, H6/528 Clinical Science Building, 600 Highland Avenue, Madison, WI 53792-5132, USA

Received 6 February 1997; revised 13 June 1997; accepted 17 June 1997

Abstract

Auditory evoked brainstem response (ABR) latencies increased and amplitudes decreased with increasing stimulus repetition rate for human newborns and adults. The wave V latency increases were larger for newborns than adults. The wave V amplitude decreases were smaller for newborns than adults. These differences could not be explained by developmental differences in frequency responsivity. The transition from the unadapted to the fully adapted response was less rapid in newborns than adults at short (= 10 ms) inter stimulus intervals (ISIs). At longer ISIs (= 20 ms) there were no developmental differences in the transition to the fully adapted response. The newborn transition occurred in a two stage process. The rapid initial stage observed in adults and newborns was complete by about 40 ms. A second slower stage was observed only in newborns although it has been observed in adults in other studies (Weatherby and Hecox, 1982; Lightfoot, 1991; Lasky et al., 1996). These effects were replicated at different stimulus intensities. After the termination of stimulation the return to the wave V unadapted response took nearly 500 ms in newborns. Neither the newborn nor the adult data can be explained by forward masking of one click on the next click. These results indicate human developmental differences in adaptation to repetitive auditory stimulation at the level of the brainstem. Keywords :

stimuli

Auditory brainstem evoked response; Human developmental di¡erence; Stimulus rate e¡ect; Adaptation to successive

1. Introduction

Auditory processing is a¡ected by prior and subsequent stimulation. Our knowledge of developmental di¡erences concerning temporal interactions among auditory stimuli is limited. Because auditory brainstem evoked responses (ABRs) are non-invasive and reliably measured, they can be used to investigate temporal interactions in the developing human. The rate paradigm has been the most frequently used evoked response paradigm to study human developmental di¡erences in temporal interactions. The same stimulus is presented repetitively at di¡erent rates. There are well documented developmental rate e¡ects on ABRs. Jewett and Romano (1972) in kittens and * Corresponding author. Tel.: +1 (608) 263-9061; Fax +1 (608) 263-0412.

rats and Despland and Galambos (1980) in humans report repetition rates to which ABRs cannot be recorded in an immature organism but can be recorded in a more mature organism. Other developmental rate e¡ects have also been reported (Jewett and Romano, 1972 ; Salamy et al., 1978 ; Mair et al., 1979 ; Despland and Galambos, 1980 ; Shipley et al., 1980; Lasky and Rupert, 1982; Lasky, 1984, 1991 ; Donaldson and Rubel, 1990; Cone-Wesson et al., 1995 ; see Hall, 1992 for a review of the human literature). ABR latencies increase with increasing stimulus repetition rate. Latency prolongation is greater for more centrally generated waves, suggesting central as well as peripheral rate effects. Amplitude reduction is also associated with increasing repetition rate. Latency prolongation and the di¡erences between central and peripheral rate e¡ects decrease with age. A second paradigm which has been used to study

0378-5955 / 97 / $17.00 ß 1997 Elsevier Science B.V. All rights reserved PII S 0 3 7 8 - 5 9 5 5 ( 9 7 ) 0 0 1 0 6 - 8

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166

rate

e¡ects

volves uses

on

evoked

maximum

responses

length

cross-correlation

sequence

techniques

developmentally (MLS) to

stimuli

recover

the

in-

These adaptation e¡ects are in the order of hundreds of

and

milliseconds and suggest that full recovery from prior

re-

stimulation takes a surprisingly long time. Developmental data concerning the transition to and

corded response (Lasky et al., 1992 ; Weber and Roush, 1993, 1995 ; Burkard et al., 1996a,b). MLSs di¡er from

recovery

stimuli conventionally used in rate studies in that the

present study investigated rate e¡ects and the transition

from

intervals between the stimuli (inter stimulus intervals,

from

ISIs) in the sequences are not constant but vary pseu-

newborns.

the

the

adapted

unadapted

to

the

ABR

are

adapted

lacking.

ABR

in

The

human

dorandomly. Thus, the response to a MLS re£ects this variation in ISIs, while the conventional response re£ects the adapted response to constant ISI stimulation.

2. Methodology

Nonlinear systems identi¢cation techniques can be used to quantify the e¡ect of these temporal variations in MLSs on the 1978 ;

response

Shi, 1990 ;

(Marmarelis

2.1. Subjects

and Marmarelis, Two

Shi and Hecox, 1991 ; Lasky et al.,

groups

of subjects were

assessed.

One group

1992, 1995a,b ; Eggermont, 1993). Another advantage

consisted of normal hearing adults (age range, 16^32

of using the MLS paradigm is the presentation of arbi-

years) with no history of audiologic or neurologic ab-

trarily short ISI stimuli. The ISIs presented convention-

normalities. Normal hearing was de¢ned by pure tone

ally are limited by the length of the recorded response.

audiometry. All subjects had no greater than a 10 dB

If the interval between successive stimuli is shorter than

hearing loss at octave intervals from 0.25 to 8 kHz. The other group was full term, healthy newborns.

the duration of the response, overlapping of responses will occur as a by-product of averaging making inter-

These

pretation

physical and neurologic examinations by the pediatric

di¤cult.

MLS

stimuli

and

cross-correlation

newborns

(1)

were

judged

healthy

by

routine

and

house sta¡, (2) were not given antibiotics, loop diu-

Schreiner, 1982). Thus, rate e¡ects can be studied at

retics, or other medications, (3) had 5 min Apgar scores

techniques

much

overcome

faster

rates

this

than

limitation

presented

(Eysholdt

conventionally.

s

7, (4) weighed

s

2.5 kg at birth, (5) were between 38

the e¡ects apparent at slower conventional

and 41 weeks post conception according to the pediatric

rates persist at higher MLS rates in human newborns

house sta¡'s estimate of gestational age, and (6) had no

and

family history of congenital hearing loss. All newborns

Many of

kittens

(Lasky

et

al.,

1992 ;

Weber

and

Roush,

were tested between 24 and 72 h after birth.

1993, 1995 ; Burkard et al., 1996a,b). Temporal masking paradigms have also been used to study

temporal

interactions

developmentally

(Lasky

2.2. Apparatus and stimuli

and Rupert, 1982 ; Lasky, 1991, 1993). Forward maskThree

ing increases human newborn ABR latencies (and also

Grass

gold-plated

cup

electrodes

were

at-

ABR thresholds) more than adult ABR latencies. There

tached at the vertex (+), mastoid ipsilateral to the stim-

may be a direct relationship between rate e¡ects and

ulus (

forward masking e¡ects ; the former are often explained

tween any two less than 10 000

3

), and forehead (ground) with impedances be-

6

.

Two di¡erent apparatuses were used in the di¡erent

in terms of the latter (Lasky and Rupert, 1982 ; Burkard

experiments. For experiments I, II, IV and V the re-

and Hecox, 1983).

5

Several researchers (Thornton and Coleman, 1975 ;

sponses were ampli¢ed (10 ) and ¢ltered by a Grass

Don et al., 1977 ; Weatherby and Hecox, 1982 ; Light-

AC preampli¢er (P511J). The 1/2 amplitude frequency

foot, 1991 ; Lasky et al., 1996) have presented trains of

for the low and high cuto¡s were 100 and 3000 Hz. The

stimuli in order to record the transition from the una-

roll-o¡

dapted to the adapted ABR. Don et al. (1977) presented

frequency cuto¡s. A Nicolet 171/4 Signal Digitizer con-

adults a train of 10 clicks with 10 ms between clicks and

verted the analog response to digital form and rejected

an interval of 500 ms between click trains. By the fourth

signals greater than 10

or ¢fth click Don et al. reported that the ABR was fully

signals were averaged by a Nicolet 1174 Signal Averag-

adapted, i.e. ABR latencies in response to the fourth or

er.

¢fth click were the same as to clicks presented at a rate

50 000 Hz, and for experiments IV and V it was 7143

of 100/s. ABR results are similar to the results of elec-

Hz. Two independently averaged waveforms were re-

trocochleographic studies using a similar paradigm (Eg-

corded in response to each stimulus (2048 responses)

germont

for experiments I, II, and V. The two replicate wave-

and

Weatherby

and

Odenthal, Hecox

1974 ;

(1982),

Eggermont,

Lightfoot

1985).

(1991),

For

was

12

dB/octave

experiments

I

WV

and

at

both

the

low

and

high

peak-to-peak voltage. The

II

the

sampling

rate

was

and

forms were averaged, and that waveform was used in all

Lasky et al. (1996) report that the transition from the

measurements. For experiment IV a single waveform of

unadapted to the adapted wave V response may extend

2048 responses was recorded.

beyond the ¢rst few clicks in a train in some conditions.

For experiments III, VI, and VII a Nicolet Path¢nd-

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167

er II was used to record the evoked responses. The ¢lter settings were 150^3000 Hz with a roll-o¡ of 12 dB/octave. The sampling rate was 51 200 Hz. Two independently averaged waveforms (2000 responses) were recorded to each stimulus. The latencies and amplitudes of waves I, III, and V were measured. The III-V complex was the most easily identi¢able portion of the ABR waveform (Lasky et al., 1987). The III-V complex was de¢ned by the rapid increment in amplitude to a peak (wave III) and the rapid decrement in amplitude following the last peak in the complex (wave V). Wave I was de¢ned as the highest peak prior to wave III. The amplitudes of waves I and III were measured from their peaks to the lowest trough between them. Using the trough after wave III to quantify wave III amplitude was less reliable. The amplitude of wave V was measured from its peak to the lowest trough after wave V. For experiments I, II, IV, and V the stimuli were generated by a WPI Anapulse Stimulator (model 302T). The intensity of the stimulus was controlled by Grason-Stadler ampli¢ers and attenuators. The stimuli were clicks, electronic pulses 100

Ws

in duration with instan-

taneous rise and fall times, which were fed into a shielded TDH-39 earphone. The intensity of the clicks was calibrated in dB nHL by calculating the mean threshold to the clicks for six adults who were assessed by pure tone audiometry to have no more than a 10 dB hearing loss at octave steps ranging from 0.25 to 8 kHz. The stimulus used to determine these adult thresholds was the 100

Ws

click at a rate of 10/s.

For experiments III, VI, and VII a Nicolet Path¢nder II was used to generate the stimuli, speci¢cally, the SM100 module in conjunction with the SM700 module. A TDH-50p earphone was used.

U

Fig. 1. Newborn and adult latency

rate functions for waves I, III,

and V. The error bars represent 1 S.D.

This study was reviewed by the Internal Review Boards at The University of Texas Health Science Cen-

long the latencies and reduce the amplitudes of new-

ter at Dallas and The University of Wisconsin-Madison

born ABRs may have little e¡ect on adult ABRs.

U

Figs. 1 and 2 present newborn and adult latency

Medical School. Informed consent was obtained from the adult subjects and the parents of the newborn sub-

rate and amplitude

jects prior to initiation of the testing.

V. 2 (developmental level)

U

U

U-

rate functions for waves I, III, and 3 (wave)

12 (rate) analy-

ses of variance were computed separately for latency and amplitude in order to investigate developmental di¡erences in rate e¡ects. As expected (see Hall, 1992,

3. Results

for a review), there were signi¢cant developmental level (F(1,18) = 64.11 ;

3.1. Experiment I

P

Although developmental rate e¡ects on the ABR

6

0.001),

and

P

6

0.001),

wave

rate

(F(11,198) = 41.09 ;

(F(2,36) = 2392.06 ;

U U

P

6

0.001)

main e¡ects for latency. Also as expected, there were

1992 for a review). In experiment I clicks at 12 di¡erent

rate (F(11,198) = 1.90 ; P = 0.042), developmental level wave (F(2,36) = 13.99 ; P 0.001), rate wave (F(22,396) = 5.15 ; P 0.001), and developmental level rate wave (F(22,396) = 2.13 ; P = 0.002) interactions for latency. Latency/rate

repetition rates were presented to 10 newborns and 10

e¡ects were similar for both developmental levels for

adults. Developmental di¡erences at slow repetition

wave I. For waves III and, especially, V latency/rate

rates were especially of interest. Slow rates which pro-

e¡ects were signi¢cantly greater for newborns. For am-

have been described in humans, only a relatively small number of repetition rates have been presented (Schulman-Galambos and Galambos, 1975 ; Salamy et al., 1978 ; Lasky and Rupert, 1982 ; Lasky, 1984 ; see Hall,

signi¢cant developmental level

6

HEARES 2861 11-11-97

U

U U

6

168

R.E. Lasky / Hearing Research 111 (1997) 165^176

Fig. 2. Newborn and adult amplitudeUrate functions for waves I, III, and V. The error bars represent 1 S.D.

plitude the results also replicated previous work (Lasky, 1984). There were signi¢cant rate (F(11,198) =11.86; P 6 0.001) and wave (F(2,36) = 51.03; P 6 0.001) main e¡ects. The developmental levelUwave (F(2,36) =15.35; P 6 0.001) and the developmental levelUrateUwave (F(22,396) = 2.20; P = 0.002) interactions were signi¢cant. Amplitudes decreased with increasing rate. Ampli-

tude reduction was greatest for wave V, and the reduction was signi¢cantly greater for adults than newborns. Rate e¡ects for the slow and fast stimulus repetition rates were investigated separately. Analyses of variance like those described above were computed for the six rates between 10 and 20/s and for the six rates between 25 and 100/s. For latency at both rate ranges signi¢cant developmental level, rate, wave, and developmental levelUwave e¡ects were observed. At the slow rates the rate main e¡ect was signi¢cant (F(5,90) = 2.39; P = 0.044) and the developmental levelUrate interaction approached signi¢cance (F(5,90) =2.12; P =0.070). At these slow rates the only obvious rate e¡ects seemed to be for newborn wave V latencies, however, the lack of su¤cient power in the design precluded a more de¢nitive statement. At the fast rates the rate e¡ects were signi¢cant for both developmental levels and all three waves. There were signi¢cant rateUwave (F(10,180) = 4.30; P 6 0.001) and developmental levelUrateUwave (F(10,180) =2.26; P = 0.016) interactions. The greatest rate e¡ects were observed for wave V, and those e¡ects were greater for newborns than adults. For amplitude there were signi¢cant rate, wave, and developmental levelUwave interactions at both rate ranges. Amplitude decreased with increasing rate for both rate ranges and developmental levels and all three waves. The only other signi¢cant e¡ect was a signi¢cant developmental levelUrateUwave interaction (F(10,180) = 3.28; P = 0.001) for the fast but not the slow rates. The decrement in amplitude was greatest for wave V and that decrement was greater for adults than newborns. In order to provide comparative data, for each subject least square linear regression functions were computed expressing the relationship between the 12 rates and the latencies and amplitudes of the three waves. For latency linear functions provided good ¢ts of the data for wave V and poorer ¢ts for waves I and III (see Table 1). These functions are similar to those previously reported for term newborns and adults (Lasky, 1984). The linear amplitudeUrate functions did not provide very adequate ¢ts of the data for either developmental level for any of the three waves (see Table 2). No non-

Table 1 Linear regressions characterizing the relationship between stimulus rate and ABR latency for newborns and adults Mean (S.D.) % of Mean (S.D.) Mean (S.D.) slope P-value of Age Wave No. of signi¢cant variance explainedb intercept (ms) (Ws/decade) t-testc regressions (out of 10)a Newborn I 4 31 (27) 3.0 (0.5) 62 (40) 6 0.001 III 6 40 (26) 5.4 (0.4) 47 (26) 6 0.001 V 10 85 (8) 7.6 (0.5) 139 (19) 6 0.001 Adult I 7 43 (25) 2.0 (0.3) 61 (57) 6 0.001 III 6 41 (32) 4.3 (0.2) 42 (23) 6 0.001 V 10 76 (19) 6.1 (0.2) 79 (33) 6 0.001 a Number of subjects whose stimulus rateUlatency linear regression function di¡ered signi¢cantly (P 6 0.05) from zero. b Mean (S.D.) percentage of the variance in latency of the ABR explained by stimulus rate. c Two tailed t-test that the slopes of the stimulus rateUlatency linear regression functions for the 10 subjects at each age were zero.

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169

linear functions consistently provided a better ¢t of the data. 3.2. Experiment II

Di¡erent latency and amplitude waveforms are elicited by di¡erent frequency stimuli (see Stapells et al., 1994 for a review). In normal hearing adults, ABRs to clicks at low stimulus rates re£ect stimulation of the 2^4 kHz region of the basilar membrane. At high rates of stimulation other frequencies may dominate the ABR. Thus, developmental di¡erences concerning the stimulus frequencies that generate the ABR at di¡erent rates could explain developmental rate e¡ects. A high pass masking paradigm (Teas et al., 1962) was used to restrict the stimuli eliciting the ABRs to explore this possibility. Ten healthy, term newborns were tested in experiment II. A 55 dB nHL, 100 Ws click was presented at four di¡erent rates, 20, 40, 70, and 100 clicks/s. A continuous broadband masker was presented simultaneously with the click. The masker was produced by a Grason-Stadler Noise Generator (model 455B) which was fed into two Krohn-Hite 48 dB/octave ¢lters (model 3700) in series. The output from the ¢lters was ampli¢ed, attenuated, and mixed with the click by a series of Grason-Stadler components. The intensity of the broadband masker was increased until an ABR was no longer elicited. That masker intensity was held constant for the remaining stimuli presented to that newborn. The four click rates were presented in the presence of one high pass masker with a low cut-o¡ frequency equal to 4 kHz. The di¡erence waveform resulting from subtracting the ABR in the presence of the masker containing frequencies s 4 kHz from the ABR in the presence of no masker yielded the ABR contributed by frequencies s 4 kHz. For the 10 newborns the slopes of the latencyUrate and amplitudeUrate functions were similar for the unmasked and the frequency restricted responses (see Fig. 3). The slopes did not signi¢cantly (P 6 0.05) di¡er from each other by 2 (frequency range)U4 (rate)U3 (wave) analysis of variance computed separately for la-

Fig. 3. Wave V latencies and amplitudes as a function of rate and frequency range (broadband or restricted). The error bars represent 1 S.D.

tency and amplitude (i.e. there were no signi¢cant frequency rangeUrate or frequency rangeUrateUwave interactions). However, the amplitudes of the unmasked responses were signi¢cantly greater than the amplitudes of the frequency restricted responses (i.e. there was a signi¢cant frequency range main e¡ect). 3.3. Experiment III

Experiment I described developmental di¡erences in rate e¡ects on the ABR. The response recorded to each rate represented the adapted response to that rate. In

Table 2 Linear regressions characterizing the relationship between stimulus rate and ABR amplitude for newborns and adults Mean (S.D.) % of Mean (S.D.) Mean (S.D.) P-value of Age Wave No. of signi¢cant variance explainedb intercept (WV) slope (WV/decade) t-testc regressions (out of 10)a Newborn I 6 40 (22) 0.20 (0.07) 30.012 (0.006) 6 0.001 III 3 26 (28) 0.24 (0.05) 30.007 (0.007) 0.007 V 3 23 (26) 0.26 (0.11) 30.006 (0.008) 0.034 Adult I 1 19 (17) 0.14 (0.05) 30.007 (0.006) 0.008 III 5 38 (30) 0.21 (0.05) 30.010 (0.006) 6 0.001 V 7 36 (20) 0.41 (0.08) 30.018 (0.011) 6 0.001 a Number of subjects whose stimulus rateUamplitude linear regression function di¡ered signi¢cantly (P 6 0.05) from zero. b Mean (S.D.) percentage of the variance in amplitude of the ABR explained by stimulus rate. c Two tailed t-test that the slopes of the stimulus rateUlatency linear regression functions for the 10 subjects at each age were zero.

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170

experiment III a train of stimuli was presented in order to investigate developmental di¡erences in the transition from the unadapted to the fully adapted response. Don et al. (1977) presented adults a train of 10 clicks with 10 ms between clicks and an interval of 500 ms between click trains. By the fourth or ¢fth click Don et al. reported that the ABR was fully adapted, i.e. the ABR in response to the fourth or ¢fth click was the same as to clicks presented at a rate of 100/s. Other researchers

have

reported

similar

results

(Thornton

and Coleman, 1975). These ABR results are similar to electrocochleographic

results

(Eggermont

and

Oden-

thal, 1974 ; Eggermont, 1985). Experiment III was conducted to investigate developmental di¡erences in the transition from the unadapted to the fully adapted ABR. The inter stimulus interval (ISI) between clicks in a train (10 or 20 ms) was varied. Nine healthy, term newborns and 11 normal hearing adults served as subjects in this experiment. Each subject was presented ¢ve di¡erent stimuli. The ¢rst stimulus was a 50 dB nHL, 100

Ws

click presented at a rate

of 10/s. The second and third stimuli were the same click at the same intensity but presented at rates of 50/s and 100/s. The ¢nal two stimuli were trains of twenty-three 50 dB nHL, 100

Ws

clicks. The clicks in

one of these click trains were separated by 10 ms ISIs. The clicks in the other click train were separated by 20 ms ISIs. There was a 250 ms inter train interval (ITI)

Fig. 4. Percentage of the wave V latency adapted response as a function of developmental level, number of click in the train, and the ISI characterizing the train. The error bars represent 1 S.D.

between click trains in both the 10 and 20 ms ISI stimuli. Describing developmental di¡erences in the transi-

sponse).

Responses

that

were

signi¢cantly

di¡erent

tion from the adapted to the unadapted response in

from neither the unadapted nor the adapted responses

terms of the change in

were too variable given the power in the design to in-

Ws or WV of the ABR is mislead-

ing because the dynamic range of the response in new-

terpret meaningfully. Similar analyses were conducted

borns and adults di¡ers. Consequently, changes in la-

to assess the transition in ABR amplitudes from the

tency

for

unadapted to the adapted response. Wave V latency

newborns and adults by the measured dynamic range.

measurements for both newborns and adults were inter-

For latency, dynamic range was de¢ned by the mean

pretable. The other measurements were not consistently

di¡erence in ABR latency to the 100/s or 50/s stimulus

interpretable and will not be reported.

and

amplitude

were

adjusted

separately

minus the ABR latency to the 10/s stimulus. For am-

Fig. 4 presents the percentage of the dynamic range

plitude, dynamic range was the mean di¡erence in am-

for wave V latency as a function of the number of the

plitude between the 10/s stimulus minus the 100/s or 50/

click in the train, the ISI de¢ning the train, and the

s stimulus. For latency, the dependent variable was the

developmental level of the subject. The adult wave V

percentage of the dynamic range accounted for by the

latency to the ¢rst click in the 20 ms ISI stimulus did

latency to the eliciting click minus the latency to the 10/

not signi¢cantly di¡er from the unadapted response.

s stimulus. For amplitude, the dependent variable was

The newborn and adult responses to all other clicks

the percentage of the dynamic range accounted for by

did. Thus, the ITI in this study (250 ms) was not su¤-

the amplitude to the 10/s click minus the amplitude to

ciently long for full recovery for the newborns in re-

the eliciting click.

sponse to either stimulus or for the adults when the

t-tests

determine

ISI was 10 ms. By the second click in the 20 ms ISI

whether the latency of the response to the click in ques-

stimulus newborn and adult responses did not signi¢-

tion was consistently longer than the response to the 10/

cantly di¡er from each other and were not signi¢cantly

t-tests

di¡erent from the fully adapted response. Thus, the

were also computed to determine whether the latency to

transition to the adapted response was achieved rapidly

the click in question was consistently shorter than to

and similarly at both developmental levels in response

the 100/s or the 50/s stimulus (the fully adapted re-

to the 20 ms ISI stimulus.

One

sample

were

computed

to

s stimulus (the unadapted response). One sample

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Fig. 5. Percentage of the newborn wave V latency adapted response as a function of number of click in a 25 click train. The error bars represent 1 S.D.

Although the response to the ¢rst click of the 10 ms ISI stimulus was signi¢cantly longer in latency than the unadapted response and did not di¡er between the two developmental levels, there was a signi¢cant developmental level e¡ect in the response to subsequent clicks. Newborn wave V latencies were generally signi¢cantly shorter than their adapted (100/s) wave V latencies. In contrast, that was only true for the ¢rst several clicks in the stimulus train for adults (replicating Don et al.'s results). The signi¢cant developmental level e¡ect was con¢rmed statistically by a 2 (developmental level)U23 (click) repeated measures analyses of variance (F(1,18) = 4.84; P 6 0.041). There was no signi¢cant developmental level e¡ect for the 20 ms ISI stimulus. 3.4. Experiment IV

Experiment III demonstrated that the transition from the unadapted to the fully adapted state was less rapid and less complete in newborns than adults in response to some stimuli. Experiment IV presented a 25 click train stimulus in an e¡ort to replicate this result in newborns. Furthermore, the ITI was increased to 500 ms since the ¢rst click in the 23 click train was not fully recovered after a 250 ms ITI (experiment III). A total of eight healthy, term newborns served as subjects in this study. Each subject was presented three stimuli. One stimulus was the 55 dB nHL, 100 Ws click presented at a rate of 10/s. A second stimulus was the same click at the same intensity but presented at a rate of 100/s. The ¢nal stimulus was a train of twenty-¢ve 55 dB nHL, 100 Ws clicks each separated by 10 ms of silence. There was a 500 ms ITI between click trains.

171

The ABR to the 10/s stimulus was used to estimate the unadapted response. The ABR to the 100/s stimulus was used to estimate the fully adapted response. The transition from the unadapted to the adapted response was de¢ned in terms of the percentage of the dynamic range explaining the di¡erence between the unadapted and adapted responses (see Fig. 5). Waves I and III latency and the amplitude data will not be presented due to the variability of the data. One sample t-tests were computed to determine whether the recorded latencies for wave V to each click signi¢cantly di¡ered from the wave V latencies to the unadapted (10/s) and the adapted (100/s) stimuli. Wave V to the ¢rst click was not signi¢cantly di¡erent from the unadapted response. By the third click and all clicks thereafter, it was. The transition from the unadapted response to 60% of the adapted response occurred by the ¢fth click. The remaining transition was quite gradual. It was not until the 20th click that the recorded wave V latency was no longer signi¢cantly di¡erent from the adapted response. Indeed, with a larger sample it is possible that the responses to even the 25th stimulus would not be fully adapted. 3.5. Experiment V

Experiments III and IV indicated that the fully adapted response in newborns to some stimuli (those of short ISI) takes a surprisingly long time to develop. Forward masking has been used to explain rate e¡ects (Lasky and Rupert, 1982; Burkard and Hecox, 1983). Experiment V was conducted to determine the relationship between forward masking and the rate and transition e¡ects reported in experiments I^IV. The vt between two clicks was systematically varied, and the vt at which forward masking e¡ects were no longer observed was determined. That vt de¢nes the length of time that a single click can in£uence the response to a subsequent click. If the auditory system were a second order nonlinear temporal system (i.e. one and only one stimulus a¡ects the response to a preceding or following stimulus), then that vt should de¢ne the maximum ISI (or the slowest rate) a¡ecting the ABR. It should also de¢ne the time between the ¢rst click in a train and the time the fully adapted response was ¢rst recorded. Experiment I indicated that for wave V latency, rate effects were observed at rates as slow as 25/s (ISI = 40 ms) for adults and slower than that for newborns. If the results of this two click paradigm fail to predict the results of experiments I^IV, those results are probably a consequence of higher order temporal nonlinearities (i.e. the interactions of three or more clicks). Eight adults and eight healthy, term newborns served as subjects. Five stimuli were presented to each subject. One stimulus was a 55 dB nHL, 100 Ws click presented at a rate of 10/s. A second stimulus was the same click

HEARES 2861 11-11-97

R.E. Lasky / Hearing Research 111 (1997) 165^176

172

the same click at the same intensity but presented at a rate of 100/s. The remaining two stimuli were trains of eight 50 dB nHL, 100

Ws clicks each separated by 10 ms

of silence. The only di¡erence in these two stimuli was the ITI between click trains (ITI = 304 or 475 ms). The ABR to the 10/s stimulus was used to estimate the unadapted response. The ABR to the 100/s stimulus was used to estimate the fully adapted response. As for experiments III and IV the transition from the unadapted to the adapted response was de¢ned in terms of the percentage of the di¡erence between the unadapted and adapted responses (see Fig. 6). t-tests were comFig. 6. Percentage of the wave V latency adapted response as a

puted to determine whether the recorded wave V laten-

function of click number and the ITI separating the click trains.

cies to each click were signi¢cantly di¡erent than the

The error bars represent 1 S.D.

latencies

to

the

unadapted

(10/s)

and

the

adapted

(100/s) stimuli. Wave V to the ¢rst click was not sigpresented at a rate of 100/s. The other three stimuli

ni¢cantly di¡erent (although longer in latency) than the

consisted of trains of two 55 dB nHL, 100

clicks

unadapted response at an ITI = 475 ms, however, it was

with 100 ms separating the o¡set of the second click

signi¢cantly longer in latency than the unadapted re-

of the train and the onset of the ¢rst click of the next

sponse at an ITI = 304 ms. The e¡ect of the shorter

train. The

between the two clicks of the trains dif-

ITI was to increase the latency of all clicks in the train

fered, they were 10, 20, and 30 ms for the three stimuli.

similar to the results reported by Lasky et al. (1996) for

vts

Ws

For both developmental levels all wave V latencies signi¢cantly (P

6

0.05) di¡ered from the 100/s response

t-test).

(by a one sample

Only wave V to the second

click of the pair separated by a

vt = 10

ms was signi¢-

cantly di¡erent from the 10/s response. There seemed to

adults. However, 2 (ITI)

U

8 (click) repeated measures

analysis of variance computed on the wave V latencies indicated that this di¡erence as a function of ITI was not statistically signi¢cant. The variability in the data prevented unquali¢ed interpretation of this di¡erence.

be little e¡ect of forward masking of one click on another at a no

vt = 30

ms. Furthermore, there seemed to be

developmental

di¡erences

as

a

function

vt

of

although the statistical power associated with this state-

U

ment warrants quali¢cation. These statements were sup-

U

ported by the results of a 2 (developmental level) (click

number)

of

variance.

P

0.001) and

6

fects

and

P = 0.007)

3

The

v

( t)

repeated

click

number

measures

2

analysis

(F(1,14) = 24.44 ;

vt (F(2,28) = 3.51 ; P = 0.044) main efthe click number vt (F(2,28) = 6.02 ;

U

3.7. Experiment VII Experiment VII was conducted to determine the effect of varying the intensity of the clicks on the transition from the unadapted to adapted wave V responses in human newborns. Seven healthy, term newborns served as subjects. Six stimuli were presented to each subject. One stimulus was a 60 dB nHL, 100

Ws

click presented at a rate of

interaction were signi¢cant. None of the ef-

10/s. A second stimulus was the same click at the same

fects involving developmental level were signi¢cant. The

intensity presented at a rate of 100/s. Two other stimuli

other ABR measurements will not be reported because of the variability associated with those measurements.

3.6. Experiment VI Experiment VI was conducted to investigate the effect of ITI on the recovery of the ABR to the unadapted state. Newborns were presented trains of 8 clicks. These trains of clicks were separated by two di¡erent ITIs (304 and 475 ms). In experiment III an ITI = 250 ms was insu¤cient for full recovery to the unadapted

state,

whereas

in

experiment

IV

an

ITI = 500 ms was su¤cient for full recovery. Nine healthy, term newborns served as subjects in this experiment. Each subject was presented four di¡erent stimuli. One stimulus was the 50 dB nHL, 100

Ws

click presented at a rate of 10/s. A second stimulus was

Fig. 7. Percentage of the wave V latency adapted response as a function of click number and the intensity of the click trains. The error bars represent 1 S.D.

HEARES 2861 11-11-97

R.E. Lasky / Hearing Research 111 (1997) 165^176

173

were identical to the ¢rst two stimuli except that they

sponses attenuate and lower frequency longer latency

were presented at 45 dB nHL. The ¢nal two stimuli

responses

were trains of sixteen 100

sponse.

Ws

clicks with an ISI = 10

One sample

t-tests

sition

were computed to compare the

characterize

the

recorded

re-

Experiments III, IV, VI, and VII concerned the tran-

ms and an ITI = 250 ms. One of these click trains was presented at 60 dB nHL, the other at 45 dB nHL.

increasingly

from

sponse.

the

The

unadapted

transition

to

from

the the

fully

adapted

unadapted

to

rethe

wave V latencies to each click to the unadapted (10/s)

adapted response (wave V latency) was more rapid in

and the adapted (50/s or the 100/s) wave V latencies.

adults than newborns at a short ISI (10 ms). Similarly,

The results were similar for the two intensities (see Fig.

in experiment I the range of rates which a¡ected wave

7). For the 60 dB nHL train, the 11th and 13th^16th

V

responses did not signi¢cantly di¡er from the response

Speci¢cally, newborn wave V latencies were prolonged

to the 100/s click. For the 45 dB nHL train, the eighth,

at ISIs which no longer a¡ected adult wave V latencies.

ninth and 11th^16th responses did not signi¢cantly dif-

At a longer ISI (20 ms) there were no developmental

fer from the response to the 100/s click. All other re-

di¡erences in the transition to the adapted response.

U

latencies

was

narrower

for

adults

than

newborns.

The results of experiment V indicate that a simple

sponses were signi¢cantly shorter latency than the wave 16 (click)

second order temporal nonlinearity cannot adequately

repeated measures analysis of variance was computed

account for rate and adaptation e¡ects in newborns and

for

adults. Speci¢cally, it was di¤cult to demonstrate an

V latency to the 100/s click. A 2 (intensity)

the

percentage

of

wave

V

latency

prolongation.

e¡ect of one click on another at a temporal separation

Only the click main e¡ect was signi¢cant.

(30 ms) that from rate studies there should be an e¡ect for both newborns and adults. Furthermore, there were no

4. Discussion

striking

developmental

di¡erences

in

the

forward

masking of one click on another click. Thus, di¡erences In experiment I developmental rate e¡ects reported

between newborn and adult rate results seem to be a

by a number of investigators were replicated (Jewett

consequence of temporal nonlinearities of greater than

and Romano, 1972 ; Schulman-Galambos and Galam-

second order (i.e. due to the interactions of three or

bos, 1975 ; Starr et al., 1977 ; Despland and Galambos,

more clicks).

1980 ; Lasky, 1984 ; see Hall, 1992 for a review). Two

For 10 ms ISI trains newborn transitions seemed to

results which have not been emphasized were noted.

occur in two stages, an initial rapid stage spanning the

The ¢rst is the likelihood that newborn ABR latencies

¢rst four or ¢ve stimuli and a slower second stage that

are

extended

a¡ected at

slow rates

which have

little

e¡ect on

for a considerable time. It is interesting to

adult ABR latencies. The data support this statement

note that in terms of milliseconds of wave V latency

although there was insu¤cient power in the study to be

prolongation (not percent of the adapted response as

de¢nitive. The second result concerns di¡erences in rate

presented

e¡ects on latencies and amplitudes. Amplitude reduc-

and the adult transition were similar, however, the sec-

tion was observed with increasing stimulus rate for all

ond stage was not observed in adults. The second stage

three waves and at both developmental levels. In con-

in newborns indicates that the responses to clicks in a

trast to the latency data, this e¡ect was signi¢cantly

train with 10 ms ISIs were a¡ected by clicks presented

greater for the wave Vs of adults than newborns. The

up to several hundred ms earlier. The temporal inter-

adult wave V was the largest amplitude measurement

actions responsible for the second stage in the transition

recorded which may explain this result. Greater ampli-

to the adapted response may distinguish newborns and

tude reduction is possible the larger the wave. The dif-

adults in terms of their responses to repetitive stimula-

ferences between the e¡ects of rate on latency and am-

tion.

plitude

underscore

interpreting duced

the

need

developmental

latency

rate

prolongation

and

to

exercise

care

in

di¡erences.

Rate

in-

amplitude

reduction

in

this

study)

the

¢rst

stage

of

newborns

Three studies (Weatherby and Hecox, 1982 ; Lightfoot, 1991 ;

Lasky et al., 1996) indicate that even in

adults the transition from the unadapted to the adapted

do

wave V response may be much less rapid in some con-

not necessarily imply more general developmental dif-

ditions than reported in this study and by Don et al.

ferences in rate e¡ects.

(1977). With a larger sample of subjects than used in

di¡er

with

developmental

level.

Those

di¡erences

Experiment II indicated that rate e¡ects in newborns

s

other studies, Lightfoot reported that none of the re-

and

sponses to clicks in eight click trains presented at an

broadband responses. Thus, it is unlikely that the great-

ISI = 11.1 ms were fully adapted. The greater statistical

er

power of Lightfoot's design may have allowed him to

were

similar

latency

for

frequency

prolongation

of

restricted

newborn

(

4

kHz)

responses

to

in-

creasing rate is a consequence of frequency e¡ects. Spe-

observe

ci¢cally, it does not seem to be the case that as rate in

Weatherby and Hecox replicated the results of Don et

newborns is increased high frequency short latency re-

al. (1977) with click stimuli but reported a much pro-

HEARES 2861 11-11-97

di¡erences

missed

by

other

investigators.

R.E. Lasky / Hearing Research 111 (1997) 165^176

174

longed two stage transition to the adapted response

click intensity while maintaining a constant click to

with noise burst stimuli. Lasky et al. (1996) recently

masker level (this result did not hold at the softest click

replicated the two stage transition to the adapted re-

levels presented) did not change the forward masking

sponse reported by Weatherby and Hecox and Light-

latency functions while changing masker level but main-

foot. These studies suggest that the transition from the

taining a constant click level did (experiment V, Lasky

unadapted to the adapted response may involve the

and Rupert, 1982 ; experiment II, Lasky, 1993). Among

same two stage function for newborns and adults and

other things, this result indicates that age related di¡er-

that stimulus parameters and developmental level a¡ect

ences in outer and middle ear resonances which do af-

the transition. The presence of the second stage of this

fect the level of the input to the cochlea probably do

function depends on whether the auditory system in

not account for the observed results.

question has su¤cient time to recover from prior stim-

Studies using a variety of paradigms consistently re-

ulation. In this study, for a 10 ms ISI the adult auditory

port di¡erences between human newborns and adults in

system seemed to be able to recover from prior stimu-

their brainstem responses to stimuli separated in time.

lation more rapidly than the newborn auditory system.

This study contributes to those results by indicating

For 20 ms trains both developmental levels seemed to

that the transition between the adapted and unadapted

be able recover so that their responses were only af-

response di¡ers in newborns and adults. Caution is warranted in interpreting the developmen-

fected by a few prior clicks. Another indication that long time constants de¢ne

tal di¡erences reported in this study. Statistical artifact

the limits of temporal interactions among clicks was

may explain some of those di¡erences. Because the la-

the

research

tency prolongation associated with adaptation is much

(Thornton and Coleman, 1975 ; Don et al., 1977 ; Lasky

greater in newborns than adults, the statistical power in

et al., 1996) on adults indicates that an ITI between 200

our experimental paradigms is greater for newborns

and 500 ms is needed in order to insure that the ¢rst

than adults. This di¡erence in statistical power does

response in a train is fully unadapted. Experiments III^

not seem to explain all of the results.

e¡ect

of

ITI

on

the

responses.

Other

VI indicate that the su¤cient ITI for full recovery of

Relating the results to neural mechanisms is specu-

the ABR is at least as long in newborns. In fact, experi-

lative. Single unit research at the level of the cochlear

ment III suggests that adults return to the unadapted

nerve suggests three adaptation stages to continuously

state more rapidly than newborns for the same ITI.

presented pure tones : the ¢rst lasting a few millisec-

Lasky and Rupert (1982) reported similar results con-

onds, the second lasting tens of milliseconds (Wester-

cerning forward masking with a broadband masker.

man and Smith, 1984 ; Yates et al., 1985 ; Rhode and

Thus, the memory of the auditory system at this level

Smith, 1985), and the third lasting in the order of tens

is such that the response to a click is altered depending

of seconds (Kiang et al., 1965 ; Young and Sachs, 1973).

on whether of not there was auditory input to the sys-

After stimulation, recovery of the spontaneous ¢ring

tem nearly 500 ms prior to the click.

rate takes up to 30 s (Kiang et al., 1965 ; Young and

The contrast between the two click results from ex-

Sachs, 1973).

periment V and the return to the unadapted response

How these processes are re£ected in volume con-

following a train of clicks from experiments III, IV, VI,

ducted potentials from many levels of the auditory

and VII indicate that a train of clicks has a larger and

pathway to repetitively presented transients is unclear.

longer lasting e¡ect on a subsequent click than a single

Relkin and Doucet (1991) demonstrated that low and

click. Similar results are reported from studies employ-

high spontaneous rate (SR) type I auditory neurons

ing temporal masking paradigms (Lasky and Rupert,

have di¡erent rates of recovery to a 80 dB SPL, 100

1982 ; Lasky, 1993). Long duration forward maskers

ms conditioning tone. Speci¢cally, low SR neurons re-

prolong

duration

cover 10 times slower than the 200 ms recovery time

maskers (experiment IV, Lasky and Rupert, 1982 ; ex-

characteristic of high SR neurons. The study of Relkin

periments I^III, Lasky, 1993) and that di¡erence re-

et al. (1995) demonstrated long term recovery of the

mains as the separation between masker and signal in-

compound action potential (CAP) on a time scale char-

creases (experiment IV, Lasky and Rupert, 1982). These

acteristic of low SR neurons. This suggests that the

studies also indicate that forward masking has a greater

CAP may be used to assess low SR neurons. The results

e¡ect on newborn than adult ABR latencies. Not sur-

of their study are similar to the CAP study in cats of

prisingly, there are similarities between adaptation and

Abbas and Gorga (1981). These results indicate that

forward masking e¡ects.

adaptation

ABR

latencies

more

than

short

and

recovery

involve

several

processes,

Varying the intensity of the train did not alter sig-

probably re£ecting di¡erent mechanisms and cell types,

ni¢cantly the transition from the unadapted to the

some of which last a surprisingly long time. Further-

adapted latency function (experiment VII). Again, Las-

more, the e¡ects of these processes can be observed in

ky and Rupert (1982 ; experiment VI) reported similar

compound action potentials. Similarly, the data from

results for forward masking latency functions. Varying

this study suggest that ABRs can be used to study sig-

HEARES 2861 11-11-97

R.E. Lasky / Hearing Research 111 (1997) 165^176

ni¢cant developments in adaptation time constants at the level of the brainstem in humans. Paradigms varying the temporal intervals between stimuli demonstrate that the auditory system is a time varying, nonlinear system with memory. The time constants de¢ning the memory of the auditory system change as a function of stimulation (e.g. the di¡erences between the responses to the 10 and 20 ms ISI trains in experiment III). Failing to address the time varying nature of the auditory system may contribute to the general lack of success of nonlinear systems identi¢cation approaches in modeling the auditory system (Eggermont, 1993; Lasky et al., 1995b). Furthermore, it suggests that time varying processes are fundamental to understanding how the auditory system processes sound. Consequently, they must be incorporated into models of the auditory system. Lasky et al. (1995b) have emphasized this point by demonstrating that temporal variations that di¡erentially a¡ect the ABR when presented separately (e.g. rate studies) fail to do so when presented one after the other (e.g. studies using stimuli with pseudorandomly varying ISIs). Those temporal variations may evoke similar responses due to the temporal inertia of the system. Some human newborn and adult auditory responses at the level of the brainstem di¡er. Volume conducted evoked responses to rate are one example. The experiments reported in this study begin to detail human developmental di¡erences in rate e¡ects at the level of the brainstem. Some auditory stimuli seem to a¡ect the newborn brainstem response to subsequent stimuli for a longer time than the adult response. Lasky and Spiro (1980) and Cowan et al. (1982) have reported that human infant behavioral responses are a¡ected by prior stimuli at inter stimulus intervals too long to a¡ect adult responses. Both studies investigated backward masking and one (Lasky and Spiro, 1980) vision. Like the present study, these studies indicate that stimuli may interact at temporally greater intervals with decreasing age of the subject. This may be a general developmental phenomenon across di¡erent sensory modalities and paradigms.

Acknowledgments This work was supported by NIH Grant #R01 NS2 0647-01A1.

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