BRAIN STEM AUDITORY-EVOKED RESPONSES IN PREMATURE INFANTS CAROL SCHULMAN-GALAMBOSand ROBERT GALAMBOS
University o~ California, San Diego, La 1olla, California Brain stem auditory-evoked responses were recorded in 24 infants ranging in age from six-weeks premature to term. At a given age, the latency of the response increased with decreasing stimulus intensity. Further, as age increased, there was a systematic decrease in latency of the response at each sound intensity level. The response was shown not to be susceptible to fatigue or sleep stage. It may, therefore, be of use for evaluating auditory function in high-risk newborn infants. The existence of very early potentials, occurring during the first 10 msec following stimulus onset, in the electrical response recorded from the scalp of human subjects has recently been described. In adults and children a characteristic series of waves have been identified (Jewett, Romano, and Williston, 1970; Jewett and Williston, 1971; Lev and Sohmer, 1972; Lieberman, Sohmer, and Szabo, 1973; Amadeo and Shagass, 1973; Hecox and Galambos, 1974). The individual components of this series are named Wave I, II, . . . , VII, in the order of their appearance in the adult record, and the sequence is thought to reflect progressive activation of the auditory nerve and the brain stem auditory tracts and nuclei. Figures 1 and 3 show adult and infant examples of this type of response. Several special properties of one of the waves in this series, Wave V, have been demonstrated: 1. The latency of Wave V, when measured for a stimulus with a level of 60 dB (re: normal adult perceptual thresholds), decreases systematically as a function of maturational age from birth through somewhere around 12 to 18 months of age (Hecox and Galambos, 1974); 2. Variability in latency of Wave V across subjects and within a given age group is small (Hecox and Galambos, 1974); 3. Within a given subject, latency increases systematically as the sound Pressure level of a stimulus is decreased (Lev and Sohmer, 1972; Lieberman, et al., 1973); and 4. The response can be obtained from unconscious as well as conscious subjects and is therefore apparently independent of behavioral state or level of arousal (Starr and Achor, 1975; Amadeo and Shagass, 1973). 456
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ii
m
Fictrea~ 1. Brain stem evoked-responses with waves labeled according to the convention of Jewett and Williston (1971). Normal adult: clicks at 10 per second, 60 dB SL; sum of 2048 responses.
, I "25/~; I msec
All these characteristics of this response of the auditory system qualify it as a highly interesting and useful one for studying the properties of the brain stem auditory system in the developing infant and in the infant who may have peripheral auditory impairment. We have previously reported data on this brain stem auditory response in infants from term birth and in children and adults (Hecox and Galambos, 1974). The purpose of the present paper is to extend these data backward to premature infants from 34 weeks gestational age through term. METHOD
Subiects Subjects were 24 infants ranging in age from 34 to 42 weeks gestational age at the time responses were recorded. There were six subjects in each of the age groups 34-35, 36-37, 38-39, and 40-42 weeks gestational age. Gestational age is technically defined as the number of weeks from day of onset of the mother's last menstrual period to the date of reference (term = 40 weeks). However, since the last menstrual date is often uncertain, gestational age in our nursery is estimated from multiple criteria, including mother's menstrual history, and physical development and neurological examination of the infant (see Sweet, 1973, for technique). Our four groups are homogeneous with respect to true gestational age only to the extent these estimates are correct. All subjects had been confined to an intensive care unit for varying periods of time, but were healthy, breathing room air, and ready for discharge at the time of testing. Table 1 provides pertinent medical information about each. Every infant selected was tested successfully; each test lasted one to two hours. SCHULMAN-GALAMBOS,GALAMBOS:Auditory-Evoked Responses 457
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TABLE 1. Pertinent medical information on each subject.
Sub/ect No. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
Gestational Age (Weeks) At Birth At Test 32 32 33 30 32 33 32 33 29 34 36 31 36 36 36 36 36 38 28 37 36 39 40 39
34 34 35 34 34 35 36 36 36 37 37 37 39 39 38 39 39 39 41 40 40 41 41 42
Diagnosis
mild RDS mild RDS prematurity mild RDS prematurity prematurity mild RDS mild RDS severe RDS moderate RDS transient tachypnea jaundice severe RDS Twin A Twin B persistent bradycardia aseptic meningitis mild RDS sepsis, hypocalcemia -severe RDS, chronic lung disease Twin B, renal problems moderate RDS aseptic meningitis aspiration pneumonia diabetic mother, mild RDS
Procedures All testing was conducted in a double-walled, sound-treated, and temperature-eontrolled chamber. The instrumentation, except for the first amplification stage, was located outside the chamber To record brain waves from the infants, electrode sites at the vertex and both mastoids were prepared by scouring the skin gently with alcohol-soaked gauze. Gold-cup electrodes with electrode paste on all surfaces were applied to these sites and held in place with surgical tape. Electrode impedance was 12 k ohms or less at the start of the recording session and usually decreased to 5 k ohms by the end of the first run. The mastoid on the stimulated side served as reference, and the opposite mastoid served as ground. A positive deflection at the vertex, the active lead, was up in the recordings. The electrical response was amplified in two stages using a preamplifier (Grass P-15) for the first stage and an amplifier (Tektronix FM-122) for the second stage. Amplifier band pass was set at 100-3000 Hz. The amplified signal was monitored on an oscilloscope and fed to a small averaging computer (Nicolet Model 1070). All subjects were in natural sleep during testing. The monitor was observed continuously, and averaging was interrupted whenever movement artifact contaminated the response signal. 458 1ournal of Speech and Hearing Research
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18 456-465
1975
The auditory signal was a click generated by a square wave generator and associated timing equipment (Grason-Stadler, 1200 series) and controlled for level by an attenuator (Hewlett-Packard Model 350D). Square waves of 0.1 msec duration delivered to a TDH-39 earphone generated the dicks, which were presented monaurally at an interstimulus interval of 30 msec (33.3 clicks per second). The earphone was placed over the baby's ear and taped to the head. In most cases each ear was separately tested. Click levels are here expressed in decibels relative to the average subiective threshold of normal-hearing adult observers in our laboratory. Such dicks, at 33.3 per second and 60 dB above this reference, yielded an SPL reading of 64-66 dB on a sound level meter (Bruel and Kiaer Model 2203, linear scale, "slow" setting) when delivered through a 6-cc coupler and associated condenser microphone (Bruel and Kiaer 4144). The reading for a 1 k Hz sine wave at the same peak-to-peak voltage as the click was 94-96 dB SPL.
Data Analysis During the averaging process the computer sampled 256 points of the response with a dwell time of 40/zsec per point (10.24 msec). The pulse used to produce the click initiated the averaging process, and this trigger was also continuously monitored on .the oscilloscope. An averaged response consisted of samples from 4096 stimuli. The averaged responses were written out on an X-Y plotter (Hewlett-Packard Model 2000). Sometimes two but usually four separate sums of 4096 responses were obtained at each click intensity level. The peak of Wave V in each of these replications was estimated by using the cursor (a light spot) built into the computer; this cursor was moved manually to the appropriate point and the bin number of this point was retrieved from the computer memory and converted to milliseconds. Repeated determinations made in this way on the same record by the same and by different observers usually agreed to within ___40/~sec. Variability, as used in this paper, refers to the microsecond differences in such Wave V estimates obtained in the separate replications. Mean latencies were usually obtained as just described after all responses stored in the computer memory (either 8192 or 16,384) had been summed. RESULTS
Latency as a Function of Signal Level and Gestational Age Table 2 presents the latencies to the peak of Wave V for each subject at each click level and tabulated subject group means. The latter values are also plotted in Figure 2. Figure 3 shows actual data obtained on one subject, an infant of 39 weeks gestational age. The data reveal that for these premature infants Wave V increases in latency at a rate of about 0.4 msec with each SCHULMAN,GALAMBOS,GALAMBOS:Auditory-Evoked Responses 459
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TABLE 2. Time in msec to Wave V as a function of age and stimulus level.
Stimulus Level (dB SL) 50 dB 40 dB
Age
Subject No.
60 dB
30 dB
34-35 weeks
1 2 3 4 5 6 Mean
8.88 9.12 7.68 8.80 8.16 8.76 8.57
9.20 7.84 9.28 8.96 9.20 8.90
9.64 8.56 9.16 9.48 9.21
9.92 9.92
36-37 weeks
1 2 3 4 5 6 Mean
7.96 8.44 7.76 7.52 8.00 8.68 8.06
8.16 8.68 8.00 7.80 8.32 8.96 8.32
8.72 9.04 8.48 8.40 8.64 9.48 8.79
9.48 9.20 9.04 8.68 9.72 9.22
38-39 weeks
1 2 3 4 5 6 Mean
7.36 7.88 7.32 7.84 8.48 8.32 7.87
7.76 8.12 7.76 8.60 8.84 8.68 8.29
7.92 8.68 8.04 9.08 8.92 8.68 8.55
8.44 9.16 8.28 9.52 8.85
40-42 weeks
1 2 3 4 5 6 Mean
7.36 7.36 7.44 7.08 7.28 7.28 7.30
7.84 7.80 7.80 7.40 7.52 7.68 7.67
8.36 8.08 8.40 7.76 8.24 8.28 8.19
8.40 8.36 9.04 8.92 8.80 8.76 8.71
10-dB attenuation in stimulus level, a generalization that also holds for adults (for example, see Hecox and Galambos, 1974). Furthermore, this latency at a given stimulus level decreases systematically with increasing gestational age. Thus, the mean latencies obtained for infants in a given age group do not overlap those of the next older or younger group (see Figure 2), and no individual in the youngest group produced a response with shorter latency (at any sound intensity level) than an individual in the 40-42 week group (see Table 2). Additional evidence for this regular decrease in latency with increasing age comes from three infants who were reexamined at w e e k l y intervals. These infants are included only once in Table 2. In all cases, the latencies recorded on the second test were shorter than those obtained on the first. For the one infant studied on three successive weeks, the Wave V latencies (to the 60-dB click) were 9.28 msec (34 weeks), 8.84 msec, and 8.24 msec. According to all our observations, therefore, the latency of Wave V shortens at a rate of around 0.3-0.5 msec per week during the period of life under study. 460 lournal of Speech and Hearing Research
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18 456-465 1975
10.0 - 3 4 - 35 WKS g. a.
9.6 - 3 6 - 37 WKS g.a. 9.2
X
8.8
0
8.4
40- 42
..
E
8.0
7.6
7.2
6.6
"
i
i
I
30
40
50
,,
I
60
dB - S PL
FxctraE 2. Changes in latency of Wave V as a function of signal level in premature infants grouped according to gestational age at the time of recording (term equals 40 weeks). Each point corresponds to the grouF, mean shown in Table 2. Reliability
One of the major methodological problems in studying responses in newborn infants has been that of obtaining consistent responses. The newborn fluctuates in his level of arousal, and these fluctuations affect responsiveness markedly (Prechtl, 1969). Another problem has been the habituation or fatiguing of the response itself (Schulman, 1970). Because at least two, and usually four, replications of a given response were obtained for each subject at each stimulus level, the reliability of the Wave V latency measure can be estimated by comparing the values obtained in the different replications. A difference of 320 btsec between such replications was the maximum noted, and the mean of all such differences (each subject, each level) was 156 fcsec. The amount of this intrasubject variability was SCHULMAN-GALAMBOS,GALAMBOS:A u d i t o r y - E v o k e d
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Responses
461
40 dB 60dB
.25/~V
30dB I
Imsec
50 dB
FxGom~ 3. Brain stem evoked-responses obtained from one 39-week infant. Waves labeled as in Figure 1; infants do not generate certain waves apparent in adults. Each trace sums the response of 4096 clicks presented at 33,~ per second; superirnposed traces are replications.
not systematically related to gestational age or stimulus intensity. Thus the Wave V estimate for a given subject and signal level is accurate to within about __+0.15msec, regardless of age. The possibility that Wave V latency might change systematically over a prolonged recording session was specifically assessed. Twenty-eight successive averages were recorded in one 39-week gestational age infant, who during a 90-minute period cycled naturally through quiet sleep, active sleep, and back through quiet sleep while 60-dB clicks were continuously delivered through the earphone taped to his head. (Sleep stage was judged by observation of the EEG and of behavior-presence or absence of eye movements, small body movements, sucking, and so forth.) Figure 4 shows responses to Blocks 1-4 and 25-28 in this subject. The maximum difference in Wave V latency among the 28 measurements of this series was 280/zsec, and there was no systematic change as a function of sleep stage. Since Wave V latency remained essentially stable over this time period, it can be said not to habituate or be subject to fatigue effects. Some small changes in the earlier portion of the response may require further study in this regard. DISCUSSION
AND CONCLUSIONS
Several conclusions can be drawn from these data. First, the brain stem responses described here are reliably recorded from premature infants; the responses are not importantly subject to fatigue or habituation under continued stimulation, and they are uninfluenced by stage of sleep. This method of evaluation therefore gives promise of being highly useful in detecting 462 ]ournal o[ Speech and Hearing Research
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18 456-465 1975
1
.25/~V
I
I msec
FIG~Jla~.4. Stability of the brain stem response during quiet and active sleep. Subject is the same infant whose responses are shown in Figure 3. Clicks were presented continuously at 60 dB SL for 90 minutes. Each trace sums 4096 responses, the top four from the beginning of the session, the bottom four from the end. Because of a technical error the voltage calibration must be considered as only approximate. impaired peripheral auditory function in the high-risk newborn infant. The infants in this study, for instance, would not appear to have had such functional problems at the time of test. Second, the threshold for auditory responsivity obtained by this method is considerably lower than that obtained by recording heart rate change as a response measure (Schulman, 1973). Furthermore, the brain stem measures suggest that this threshold is dropping during the period here under study. Figure 3, for example, demonstrates that a click which is only 30 dB above the adult threshold evokes a consistent, easily recognized response from the auditory nerve and brain stem of a 39-week infant. Such a click must, therefore, have been above the threshold of hearing for the child. As Table 2 shows, however, only one of the six youngest subjects produced a response at this stimulus level, and two of them were unresponsive to the click of 10 dB SCttULMAN-GALAMBOS, GALAMBOS:Auditory-Evoked Responses 463
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greater magnitude. Because the probability of obtaining responses to these weak stimuli increases with age (Table 2), it can be argued that the threshold for the clicks must be dropping during this period of development. An attempt to test this idea by establishing the actual response thresholds in this age group is presently under study. Third, the drop in latency of the brain stem response with age (Figure 2, Table 2) is undoubtedly related to maturational changes occurring in the peripheral auditory system during this period. Neurological maturation proceeds, as is well known (St. Anne Dargassies, 1966), on a predictable time table that is not altered in any important way by premature delivery. The main difficulty in the attempt to relate our response measure to brain development in prematures is the problem of accurately establishing a given infant's gestational age. If its determination were in error by ___ 1 week, which is not unreasonable to assume, each of our subjects would move into the group either older or younger that the one in which he has been placed. Despite the misclassifications of this sort, which undoubtedly occurred, the data of Figure 2 and Table 2 clearly support the conclusion that latency decreases systematically with neurologic maturation. This trend continues beyond birth to 12-18 months, as we have previously reported (Hecox and Galambos, 1974). As a technical point, it should be noted that the latencies to Wave V reported here are about 0.5 msec shorter than those given in our earlier report for term and immediately postterm infants. We are at present unable to explain this discrepancy. It may be important that the two studies in question were conducted in different facilities with different equipment. The norms developed in other laboratories undertaking similar studies will be helpful in resolving this problem. ACKNOWLEDGMENT We wish to thank Don Jewett, who suggested in 1969 that this research should be done; Kurt Heeox, for many informative diseussions; the Naval Electronics Laboratory, Point Loma, for providing some of the equipment; Donald Krebs at the San Diego Speech and Hearing Center, who provided space and equipment and the staff and parents at Children's Health Center, who cooperated in this study. This research was supported by NIH Grants HD08694 and NS 10482. REFERENCES A.NIADI~.O,M., and SHAGASS, C., Brief latency click-evoked potentials during waking and sleep in man. Psychophysiology, 10, 244-250 (1973). Hr,cox, K., and GALAMBOS,R., Brain stem auditory evoked responses in human infants and adults. Archs. Otolar., 99, 30-33 (1974). Jr.wEar, D., Volume conducted potentials in response to auditory stimuli as detected by averaging in the cat. Electroenceph. clin. Neurophysiol, 28, 609-618 (1970). Jr,w~ar, D., ROMANO,H. N., and WILtaSTON, J. S., Human auditory evoked responses: Possible brain stem components detected on the scalp. Science, 167, 1517-1518 (1970). Jr,WETT, D., and WILLISTON,J. S., Auditory-evoked far fields averaged from the scalp of humans. Brain, 94, 681-696 (1971). 464 1ournal of Speech and Hearing Research
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18 456-465 1975
LEv, A., and SOHMEa, H., Sources of averaged neural responses recorded in animal and human subiects during cochlear audiometry. Arch. klin. exp. Ohr.-, Nas.-, KehlHeilk., 301, 79-90 (1972). LmBEaMAN, A., SOHMm~, H., and SZ,~BO, G., Cochlear audiometry (electrocochleography) during the neonatal period. Dev. Med. child Neurol, 15, 8-13 (1973). P~crrrL, H. F. R., Brain and behavioral mechanisms in the human newborn infant. In R. J. Robinson (Ed.), Brain and Early Behavior. London: Academic (1969). SCHtrLMAN, C. A., Heart rate response habituation in high risk premature infants. Psychophysiology, 6, 690-694 (1970). SCHtrUMAN, C. A., Heart rate audiometry. Part I. An evaluation of heart rate response to auditory stimuli in newborn hearing screening. Neuropadiatrie, 4, 362-374 (1973). STXXart,A., and AcaoR, L. J., Auditory brain stem responses in neurological disease. Neurology, in press (1975). SWEET, A. Y., Classification of the low-birth-weight infant. In M. H. Klaus and A. A. Fanaroff (Eds.), Care of the High-Risk Neonate. Philadelphia: W. B. Saunders (1973). ST.-ANN~- DAaGASSmS, S., Neurological maturation of the premature infant of 28 to 41 weeks' gestational age. In F. Falkner (Ed.), Human Development. Philadelphia: W. B. Saunders, 306-325 (1966). Received December 1, 1974. Accepted April 4, 1975.
SCHULMAN-GALA.MBOS,GALAMBOS: Auditory-Evoked Responses 465
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University o~ California, San Diego, La 1olla, California Brain stem auditory-evoked responses were recorded in 24 infants ranging in age from six-weeks premature to term. At a given age, the latency of the response increased with decreasing stimulus intensity. Further, as age increased, there was a systematic decrease in latency of the response at each sound intensity level. The response was shown not to be susceptible to fatigue or sleep stage. It may, therefore, be of use for evaluating auditory function in high-risk newborn infants. The existence of very early potentials, occurring during the first 10 msec following stimulus onset, in the electrical response recorded from the scalp of human subjects has recently been described. In adults and children a characteristic series of waves have been identified (Jewett, Romano, and Williston, 1970; Jewett and Williston, 1971; Lev and Sohmer, 1972; Lieberman, Sohmer, and Szabo, 1973; Amadeo and Shagass, 1973; Hecox and Galambos, 1974). The individual components of this series are named Wave I, II, . . . , VII, in the order of their appearance in the adult record, and the sequence is thought to reflect progressive activation of the auditory nerve and the brain stem auditory tracts and nuclei. Figures 1 and 3 show adult and infant examples of this type of response. Several special properties of one of the waves in this series, Wave V, have been demonstrated: 1. The latency of Wave V, when measured for a stimulus with a level of 60 dB (re: normal adult perceptual thresholds), decreases systematically as a function of maturational age from birth through somewhere around 12 to 18 months of age (Hecox and Galambos, 1974); 2. Variability in latency of Wave V across subjects and within a given age group is small (Hecox and Galambos, 1974); 3. Within a given subject, latency increases systematically as the sound Pressure level of a stimulus is decreased (Lev and Sohmer, 1972; Lieberman, et al., 1973); and 4. The response can be obtained from unconscious as well as conscious subjects and is therefore apparently independent of behavioral state or level of arousal (Starr and Achor, 1975; Amadeo and Shagass, 1973). 456
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ii
m
Fictrea~ 1. Brain stem evoked-responses with waves labeled according to the convention of Jewett and Williston (1971). Normal adult: clicks at 10 per second, 60 dB SL; sum of 2048 responses.
, I "25/~; I msec
All these characteristics of this response of the auditory system qualify it as a highly interesting and useful one for studying the properties of the brain stem auditory system in the developing infant and in the infant who may have peripheral auditory impairment. We have previously reported data on this brain stem auditory response in infants from term birth and in children and adults (Hecox and Galambos, 1974). The purpose of the present paper is to extend these data backward to premature infants from 34 weeks gestational age through term. METHOD
Subiects Subjects were 24 infants ranging in age from 34 to 42 weeks gestational age at the time responses were recorded. There were six subjects in each of the age groups 34-35, 36-37, 38-39, and 40-42 weeks gestational age. Gestational age is technically defined as the number of weeks from day of onset of the mother's last menstrual period to the date of reference (term = 40 weeks). However, since the last menstrual date is often uncertain, gestational age in our nursery is estimated from multiple criteria, including mother's menstrual history, and physical development and neurological examination of the infant (see Sweet, 1973, for technique). Our four groups are homogeneous with respect to true gestational age only to the extent these estimates are correct. All subjects had been confined to an intensive care unit for varying periods of time, but were healthy, breathing room air, and ready for discharge at the time of testing. Table 1 provides pertinent medical information about each. Every infant selected was tested successfully; each test lasted one to two hours. SCHULMAN-GALAMBOS,GALAMBOS:Auditory-Evoked Responses 457
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TABLE 1. Pertinent medical information on each subject.
Sub/ect No. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
Gestational Age (Weeks) At Birth At Test 32 32 33 30 32 33 32 33 29 34 36 31 36 36 36 36 36 38 28 37 36 39 40 39
34 34 35 34 34 35 36 36 36 37 37 37 39 39 38 39 39 39 41 40 40 41 41 42
Diagnosis
mild RDS mild RDS prematurity mild RDS prematurity prematurity mild RDS mild RDS severe RDS moderate RDS transient tachypnea jaundice severe RDS Twin A Twin B persistent bradycardia aseptic meningitis mild RDS sepsis, hypocalcemia -severe RDS, chronic lung disease Twin B, renal problems moderate RDS aseptic meningitis aspiration pneumonia diabetic mother, mild RDS
Procedures All testing was conducted in a double-walled, sound-treated, and temperature-eontrolled chamber. The instrumentation, except for the first amplification stage, was located outside the chamber To record brain waves from the infants, electrode sites at the vertex and both mastoids were prepared by scouring the skin gently with alcohol-soaked gauze. Gold-cup electrodes with electrode paste on all surfaces were applied to these sites and held in place with surgical tape. Electrode impedance was 12 k ohms or less at the start of the recording session and usually decreased to 5 k ohms by the end of the first run. The mastoid on the stimulated side served as reference, and the opposite mastoid served as ground. A positive deflection at the vertex, the active lead, was up in the recordings. The electrical response was amplified in two stages using a preamplifier (Grass P-15) for the first stage and an amplifier (Tektronix FM-122) for the second stage. Amplifier band pass was set at 100-3000 Hz. The amplified signal was monitored on an oscilloscope and fed to a small averaging computer (Nicolet Model 1070). All subjects were in natural sleep during testing. The monitor was observed continuously, and averaging was interrupted whenever movement artifact contaminated the response signal. 458 1ournal of Speech and Hearing Research
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18 456-465
1975
The auditory signal was a click generated by a square wave generator and associated timing equipment (Grason-Stadler, 1200 series) and controlled for level by an attenuator (Hewlett-Packard Model 350D). Square waves of 0.1 msec duration delivered to a TDH-39 earphone generated the dicks, which were presented monaurally at an interstimulus interval of 30 msec (33.3 clicks per second). The earphone was placed over the baby's ear and taped to the head. In most cases each ear was separately tested. Click levels are here expressed in decibels relative to the average subiective threshold of normal-hearing adult observers in our laboratory. Such dicks, at 33.3 per second and 60 dB above this reference, yielded an SPL reading of 64-66 dB on a sound level meter (Bruel and Kiaer Model 2203, linear scale, "slow" setting) when delivered through a 6-cc coupler and associated condenser microphone (Bruel and Kiaer 4144). The reading for a 1 k Hz sine wave at the same peak-to-peak voltage as the click was 94-96 dB SPL.
Data Analysis During the averaging process the computer sampled 256 points of the response with a dwell time of 40/zsec per point (10.24 msec). The pulse used to produce the click initiated the averaging process, and this trigger was also continuously monitored on .the oscilloscope. An averaged response consisted of samples from 4096 stimuli. The averaged responses were written out on an X-Y plotter (Hewlett-Packard Model 2000). Sometimes two but usually four separate sums of 4096 responses were obtained at each click intensity level. The peak of Wave V in each of these replications was estimated by using the cursor (a light spot) built into the computer; this cursor was moved manually to the appropriate point and the bin number of this point was retrieved from the computer memory and converted to milliseconds. Repeated determinations made in this way on the same record by the same and by different observers usually agreed to within ___40/~sec. Variability, as used in this paper, refers to the microsecond differences in such Wave V estimates obtained in the separate replications. Mean latencies were usually obtained as just described after all responses stored in the computer memory (either 8192 or 16,384) had been summed. RESULTS
Latency as a Function of Signal Level and Gestational Age Table 2 presents the latencies to the peak of Wave V for each subject at each click level and tabulated subject group means. The latter values are also plotted in Figure 2. Figure 3 shows actual data obtained on one subject, an infant of 39 weeks gestational age. The data reveal that for these premature infants Wave V increases in latency at a rate of about 0.4 msec with each SCHULMAN,GALAMBOS,GALAMBOS:Auditory-Evoked Responses 459
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TABLE 2. Time in msec to Wave V as a function of age and stimulus level.
Stimulus Level (dB SL) 50 dB 40 dB
Age
Subject No.
60 dB
30 dB
34-35 weeks
1 2 3 4 5 6 Mean
8.88 9.12 7.68 8.80 8.16 8.76 8.57
9.20 7.84 9.28 8.96 9.20 8.90
9.64 8.56 9.16 9.48 9.21
9.92 9.92
36-37 weeks
1 2 3 4 5 6 Mean
7.96 8.44 7.76 7.52 8.00 8.68 8.06
8.16 8.68 8.00 7.80 8.32 8.96 8.32
8.72 9.04 8.48 8.40 8.64 9.48 8.79
9.48 9.20 9.04 8.68 9.72 9.22
38-39 weeks
1 2 3 4 5 6 Mean
7.36 7.88 7.32 7.84 8.48 8.32 7.87
7.76 8.12 7.76 8.60 8.84 8.68 8.29
7.92 8.68 8.04 9.08 8.92 8.68 8.55
8.44 9.16 8.28 9.52 8.85
40-42 weeks
1 2 3 4 5 6 Mean
7.36 7.36 7.44 7.08 7.28 7.28 7.30
7.84 7.80 7.80 7.40 7.52 7.68 7.67
8.36 8.08 8.40 7.76 8.24 8.28 8.19
8.40 8.36 9.04 8.92 8.80 8.76 8.71
10-dB attenuation in stimulus level, a generalization that also holds for adults (for example, see Hecox and Galambos, 1974). Furthermore, this latency at a given stimulus level decreases systematically with increasing gestational age. Thus, the mean latencies obtained for infants in a given age group do not overlap those of the next older or younger group (see Figure 2), and no individual in the youngest group produced a response with shorter latency (at any sound intensity level) than an individual in the 40-42 week group (see Table 2). Additional evidence for this regular decrease in latency with increasing age comes from three infants who were reexamined at w e e k l y intervals. These infants are included only once in Table 2. In all cases, the latencies recorded on the second test were shorter than those obtained on the first. For the one infant studied on three successive weeks, the Wave V latencies (to the 60-dB click) were 9.28 msec (34 weeks), 8.84 msec, and 8.24 msec. According to all our observations, therefore, the latency of Wave V shortens at a rate of around 0.3-0.5 msec per week during the period of life under study. 460 lournal of Speech and Hearing Research
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18 456-465 1975
10.0 - 3 4 - 35 WKS g. a.
9.6 - 3 6 - 37 WKS g.a. 9.2
X
8.8
0
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FxctraE 2. Changes in latency of Wave V as a function of signal level in premature infants grouped according to gestational age at the time of recording (term equals 40 weeks). Each point corresponds to the grouF, mean shown in Table 2. Reliability
One of the major methodological problems in studying responses in newborn infants has been that of obtaining consistent responses. The newborn fluctuates in his level of arousal, and these fluctuations affect responsiveness markedly (Prechtl, 1969). Another problem has been the habituation or fatiguing of the response itself (Schulman, 1970). Because at least two, and usually four, replications of a given response were obtained for each subject at each stimulus level, the reliability of the Wave V latency measure can be estimated by comparing the values obtained in the different replications. A difference of 320 btsec between such replications was the maximum noted, and the mean of all such differences (each subject, each level) was 156 fcsec. The amount of this intrasubject variability was SCHULMAN-GALAMBOS,GALAMBOS:A u d i t o r y - E v o k e d
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Responses
461
40 dB 60dB
.25/~V
30dB I
Imsec
50 dB
FxGom~ 3. Brain stem evoked-responses obtained from one 39-week infant. Waves labeled as in Figure 1; infants do not generate certain waves apparent in adults. Each trace sums the response of 4096 clicks presented at 33,~ per second; superirnposed traces are replications.
not systematically related to gestational age or stimulus intensity. Thus the Wave V estimate for a given subject and signal level is accurate to within about __+0.15msec, regardless of age. The possibility that Wave V latency might change systematically over a prolonged recording session was specifically assessed. Twenty-eight successive averages were recorded in one 39-week gestational age infant, who during a 90-minute period cycled naturally through quiet sleep, active sleep, and back through quiet sleep while 60-dB clicks were continuously delivered through the earphone taped to his head. (Sleep stage was judged by observation of the EEG and of behavior-presence or absence of eye movements, small body movements, sucking, and so forth.) Figure 4 shows responses to Blocks 1-4 and 25-28 in this subject. The maximum difference in Wave V latency among the 28 measurements of this series was 280/zsec, and there was no systematic change as a function of sleep stage. Since Wave V latency remained essentially stable over this time period, it can be said not to habituate or be subject to fatigue effects. Some small changes in the earlier portion of the response may require further study in this regard. DISCUSSION
AND CONCLUSIONS
Several conclusions can be drawn from these data. First, the brain stem responses described here are reliably recorded from premature infants; the responses are not importantly subject to fatigue or habituation under continued stimulation, and they are uninfluenced by stage of sleep. This method of evaluation therefore gives promise of being highly useful in detecting 462 ]ournal o[ Speech and Hearing Research
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18 456-465 1975
1
.25/~V
I
I msec
FIG~Jla~.4. Stability of the brain stem response during quiet and active sleep. Subject is the same infant whose responses are shown in Figure 3. Clicks were presented continuously at 60 dB SL for 90 minutes. Each trace sums 4096 responses, the top four from the beginning of the session, the bottom four from the end. Because of a technical error the voltage calibration must be considered as only approximate. impaired peripheral auditory function in the high-risk newborn infant. The infants in this study, for instance, would not appear to have had such functional problems at the time of test. Second, the threshold for auditory responsivity obtained by this method is considerably lower than that obtained by recording heart rate change as a response measure (Schulman, 1973). Furthermore, the brain stem measures suggest that this threshold is dropping during the period here under study. Figure 3, for example, demonstrates that a click which is only 30 dB above the adult threshold evokes a consistent, easily recognized response from the auditory nerve and brain stem of a 39-week infant. Such a click must, therefore, have been above the threshold of hearing for the child. As Table 2 shows, however, only one of the six youngest subjects produced a response at this stimulus level, and two of them were unresponsive to the click of 10 dB SCttULMAN-GALAMBOS, GALAMBOS:Auditory-Evoked Responses 463
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greater magnitude. Because the probability of obtaining responses to these weak stimuli increases with age (Table 2), it can be argued that the threshold for the clicks must be dropping during this period of development. An attempt to test this idea by establishing the actual response thresholds in this age group is presently under study. Third, the drop in latency of the brain stem response with age (Figure 2, Table 2) is undoubtedly related to maturational changes occurring in the peripheral auditory system during this period. Neurological maturation proceeds, as is well known (St. Anne Dargassies, 1966), on a predictable time table that is not altered in any important way by premature delivery. The main difficulty in the attempt to relate our response measure to brain development in prematures is the problem of accurately establishing a given infant's gestational age. If its determination were in error by ___ 1 week, which is not unreasonable to assume, each of our subjects would move into the group either older or younger that the one in which he has been placed. Despite the misclassifications of this sort, which undoubtedly occurred, the data of Figure 2 and Table 2 clearly support the conclusion that latency decreases systematically with neurologic maturation. This trend continues beyond birth to 12-18 months, as we have previously reported (Hecox and Galambos, 1974). As a technical point, it should be noted that the latencies to Wave V reported here are about 0.5 msec shorter than those given in our earlier report for term and immediately postterm infants. We are at present unable to explain this discrepancy. It may be important that the two studies in question were conducted in different facilities with different equipment. The norms developed in other laboratories undertaking similar studies will be helpful in resolving this problem. ACKNOWLEDGMENT We wish to thank Don Jewett, who suggested in 1969 that this research should be done; Kurt Heeox, for many informative diseussions; the Naval Electronics Laboratory, Point Loma, for providing some of the equipment; Donald Krebs at the San Diego Speech and Hearing Center, who provided space and equipment and the staff and parents at Children's Health Center, who cooperated in this study. This research was supported by NIH Grants HD08694 and NS 10482. REFERENCES A.NIADI~.O,M., and SHAGASS, C., Brief latency click-evoked potentials during waking and sleep in man. Psychophysiology, 10, 244-250 (1973). Hr,cox, K., and GALAMBOS,R., Brain stem auditory evoked responses in human infants and adults. Archs. Otolar., 99, 30-33 (1974). Jr.wEar, D., Volume conducted potentials in response to auditory stimuli as detected by averaging in the cat. Electroenceph. clin. Neurophysiol, 28, 609-618 (1970). Jr,w~ar, D., ROMANO,H. N., and WILtaSTON, J. S., Human auditory evoked responses: Possible brain stem components detected on the scalp. Science, 167, 1517-1518 (1970). Jr,WETT, D., and WILLISTON,J. S., Auditory-evoked far fields averaged from the scalp of humans. Brain, 94, 681-696 (1971). 464 1ournal of Speech and Hearing Research
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18 456-465 1975
LEv, A., and SOHMEa, H., Sources of averaged neural responses recorded in animal and human subiects during cochlear audiometry. Arch. klin. exp. Ohr.-, Nas.-, KehlHeilk., 301, 79-90 (1972). LmBEaMAN, A., SOHMm~, H., and SZ,~BO, G., Cochlear audiometry (electrocochleography) during the neonatal period. Dev. Med. child Neurol, 15, 8-13 (1973). P~crrrL, H. F. R., Brain and behavioral mechanisms in the human newborn infant. In R. J. Robinson (Ed.), Brain and Early Behavior. London: Academic (1969). SCHtrLMAN, C. A., Heart rate response habituation in high risk premature infants. Psychophysiology, 6, 690-694 (1970). SCHtrUMAN, C. A., Heart rate audiometry. Part I. An evaluation of heart rate response to auditory stimuli in newborn hearing screening. Neuropadiatrie, 4, 362-374 (1973). STXXart,A., and AcaoR, L. J., Auditory brain stem responses in neurological disease. Neurology, in press (1975). SWEET, A. Y., Classification of the low-birth-weight infant. In M. H. Klaus and A. A. Fanaroff (Eds.), Care of the High-Risk Neonate. Philadelphia: W. B. Saunders (1973). ST.-ANN~- DAaGASSmS, S., Neurological maturation of the premature infant of 28 to 41 weeks' gestational age. In F. Falkner (Ed.), Human Development. Philadelphia: W. B. Saunders, 306-325 (1966). Received December 1, 1974. Accepted April 4, 1975.
SCHULMAN-GALA.MBOS,GALAMBOS: Auditory-Evoked Responses 465
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