Hearing Research. 53 (1991) 41-48 ~3 1991 Elsevier Science Publishers
41 B.V. 0378-5955/91/$03.50
Binaural effects in brainstem
auditory evoked potentials Gunn rats *
Steven M. Shapiro Waisman Center on Mental Retardation and Human Development, Departments of Neurology and Pediatrrcs. Unioersiiy of Wisconsin-Madison, Madison. Wisconsin U.S.A. (Received
31 July 1989: accepted
Bilirubin toxicity causes encephalopathy associated with lesions of the central auditory nervous system. Abnormal brainstem auditory evoked potentials (BAEPs) in jaundiced Gunn rats made acutely bilirubin toxic suggest abnormal input into the superior olivary complex, which might result in abnormal binaural interaction. Binaural difference waves (BDWs), obtained by subtracting the sum of two monaural BAEPs from a binaural BAEP. were obtained in 16- to 20-day-old jaundiced Gunn rats before and after injection of sulfadimethoxine. which produces bilirubin neurotoxicity by promoting net transfer of bilirubin out of the circulation into brain tissue. Reliable BDWs were recorded with onset 4.5 ms after the stimulus. followed by a large, often bimodal, positive peak occurring at about 6 ms. Following injection of sulfadimethoxine to produce bilirubin neurotoxicity, there was loss of BDW amplitude (21% i 14% of baseline. P < 0.0001) and increase in latency (0.62 * 0.42 ms, P = 0.03) in bihrubin-toxic jaundiced rats compared to baseline. but no significant changes in nonjaundiced controls treated similarly. This documents abnormal BDWs in acute bilirubin encephalopathy suggesting that abnormalities of functions dependent on binaural processing of auditory information may be found as neurologic sequelae to bilirubin toxicity. BAEP BDWs may be a sensitive method for detecting neurophysiological abnormalities due to bilirubin toxicity.
Bilirubin toxicity causes encephalopathy associated with lesions of the central auditory nervous system. Brainstem auditory nuclei and fiber tracts, including the cochlear nucleus, trapezoid body, lateral lemniscus, superior olivary complex, inferior colliculus, and medial geniculate, are damaged in bilirubin encephalopathy in humans (AhdabBarmada and Moossy, 1984) and in animal models (Blanc and Johnson, 1959; Jew and Williams, 1977: Johnson et al., 1959).
Correspondence to: Steven M. Shapiro (Presenf address) Division of Child Neurology. Departments of Neurology and Pediatrics. Medical College of Virginia, Virginia Commonwealth University. P.O. Box 211. MCV Station, Richmond. VA, 23298-0211. U.S.A. * This research was presented in part at the Association for Research in Otolaryngology Mid-Winter Meeting, February 1989.
The homozygote jaundiced (ii) Gunn rat has been used as a model for human bilirubin encephalopathy (Johnson et al., 1959). These rats cannot conjugate bilirubin due to an autosomal recessive absence of hepatic glucuronyl transferase enzyme activity (Strebel and Odell, 1971). and exhibit lifelong unconjugated hyperbilirubinernia, which peaks at about 17 days of age (Johnson et al., 1959; Schutta and Johnson, 1969). Since bilirubin is bound to albumin in blood, injecting an albumin-binding drug displaces bilirubin from blood into brain tissue (Odell, 1959). Injecting sulfadimethoxine, a long-acting sulfonamide, into young jj Gunn rats reliably produces electrophysiological abnormalities and neuropathological lesions resembling those in human bilirubin encephalopathy (Rose and Wisnewski, 1979; Shapiro, 1988). Brainstem auditory evoked potentials (BAEPs) recorded from jj Gunn rats made acutely bilirubin toxic by injecting sulfonamide indicate abnormal
central auditory system functioning, and suggest the possibility of abnormal binaural functioning. BAEPs in humans and in Gunn rats show delayed latencies and reduced amplitudes in waves most likely generated by second-order neurons at the level of, and rostra1 to the cochlear nucleus (Shapiro and Hecox, 1988; Shapiro and Hecox, 1989). Young jj rats injected with sulfadimethoxine develop prolongations of wave II and the I-II and I-III interwave intervals, and decreased amplitude of waves II and III (Shapiro, 1988). Electron microscopy of the cochlear nucleus of jaundiced animals with abnormal BAEPs shows degeneration in second-order postsynaptic neurons in ventral cochlear nucleus (Brugge et al., 1987). Since BAEP waves are generated by synchronous discharges of neurons time-locked to the stimulus, delayed firing of these neurons may contribute to the delayed conventional BAEP wave II in rats with bilirubin toxicity. In bilirubin encephalopathy. abnormal binaural interaction might result from abnormal input into the superior olivary complex (SOC). The SOC. with neurons which compare inputs from the two sides. is one of the first sites of binaural interaction in the ascending auditory nervous system. Cells in the SOC. by comparing interaural differences in time, intensity or phase. provide information important for sound localization. Binaural interaction can be detected with BAEP recordings in normal animals and humans (Ainslie, 1980; Dobie, 1979; Dobie, 1980; HosfordDunn et al.. 1981; Wrege, 1981). In the usual paradigm, a click is presented separately to each ear monaurally. and binaurally. Binaural difference waves (BDWs) are the sum of the two monaural BAEP waves digitally subtracted from the binaural BAEP. Binaural difference waves (BDWs) were obtained in 16620 day old jaundiced and nonjaundiced Gunn rats before and after injection of sulfadimethoxine, which is used to promote the net transfer of bilirubin from blood into brain tissue (Diamond and Schmid, 1966), to test the hypothesis that binaural interaction becomes abnormal in acute bilirubin encephalopathy. This report provides the initial description of abnormalities of BDWs in this model of acute bilirubin encephalopathy.
Methods and Materials Animuls Gunn rats were obtained from our breeding colony at the Waisman Center of the University of Wisconsin-Madison. Two of the homozygous jaundiced Gunn rats (jj’s) had nonjaundiced heterozygous (Nj) mothers: the rest had jj mothers. Four littermate Nj control rats, two with jj and two with Nj mothers. were matched to jj’s by weight. Each animal was anesthetized with intraperitoneal injection of ketamine 60 mg/kg and acepromazine 6 mg/kg. Supplemental doses of one quarter to one half the initial dose were given for any movement, or any increase of muscle activity on the continuously monitored scalp EEG recording. Stimuli The stimuli, 100 ps square wave clicks (Grass Model S88. Grass Instruments. Inc., Quincy. MA), were used to drive a Sony Walkman 4LIS speaker centered 3.4 cm in front of the infant rats head. This distance produces a delay of 0.1 ms (34 cm/ms sound velocity). BAEP wave latencies were obtained with a digital cursor according to objective criteria (Shapiro and Hecox. 1988). The sound system was calibrated with a l/2 inch prepolarized condenser microphone (Brtiel and Kjaer Type 4155) placed in a position midway between the two ears and attached to a Briiel and Kjaer Precision Integrating Sound Level Meter (Type 2233) set at impulse weighting, peak detecting, linear scale. Sound levels are expressed in dB SPL re. 0.0002 dynes/cm’. All recordings were done in a sound attenuated booth (Industrial Acoustic Company Model AC-3). With the speaker centered in front of the head, occluding one ear created monaural stimulation of the other ear. This method has the advantage of using the same sound generator. amplifier and speaker to deliver the stimulus to each ear, and the sound passes naturally through the external ear canals. Since the external ears contribute significant binaural cues to the auditory system (Blauert. 1983: Butler, 1975; Butler and Belendiuk, 1977; Butler and Planert, 1976; Fisher and Freedman. 1968: Wightman and Kistler. 1989a: Wightman
and Kistler, 1989b), this method may present interaural differences that closed systems do not. Care was taken to move neither the speaker nor the head of the rat during collection of the data. At the start, the rat’s jaw was embedded in earmold impression material (Micro-sil, Microsonic, Ambridge, PA) to insure immobilization during the experiment. EEG recording Electrical activity was amplified (lo’), filtered (30-3000 Hz), and averaged with a Nicolet 1170 Evoked Potential system (Nicolet Instrument Corp., Madison, WI). Each response waveform was derived from the average of 2048 stimulus presentations, and was replicated. Three orthogonal electrode pairings (montages) were recorded simultaneously from platinum needle electrodes (Grass Instruments, Inc.. Quincy, MA) inserted in the scalp. The pairings were 1) nose to inion (FPz-In), 2) vertex to chin (Cz-Chin), and 3) left mastoid to right mastoid prominence (LM-RM). The largest responses were obtained from the first recording montage (FPz-In).
For each animal, control BAEPs were obtained to compare function of the two ears, and insure minimal acoustic cross-talk. Under each monaural condition, BAEPs were obtained at a series of intensities: 75, 65, 55 and 45 dB SPL. Parallel curves with < 10 dB difference between ears were required for all animals studied. In order to determine the degree to which ear plugging was effective, both ears were plugged with earmold impression material (Audalin, Esschem Co., Essington, PA) and a BAEP threshold to the stimulus was obtained to within i: 5 dB. A response was classified as absent only after there were no replicable BAEPs on at least two replications to 8192 clicks, with no significant muscle artifact on the scalp EEG, which was monitored continuously. The click intensity for determination of BDWs (75 dB SPL) was 10 dB above the mean threshold with the ears plugged, 65 dB, and was never more than 15 dB above this threshold for any individual animal. Thus. stimulation was never more than 15 dB above the BAEP threshold of the contralateral ear in the monaural condition.
Data were collected under three conditions: right monaural (RE open, LE plugged); left monaural (LE open, RE plugged); and binaural (both ears open). The order of stimulus presentation was: 1) binaural, 2) 1”’ ear monaural, 3) both ears plugged (threshold determination), and 4) 2”d ear monaural to obtain data to derive the first BDW. This was then followed immediately by the reverse order of presentation to obtain a second BDW and to control for order of presentation: 5) 2”d ear monaural, 6) 1” ear monaural, and 7) binaural to obtain a second BDW. The ear to be stimulated first was randomly chosen. BA EP binaural difference waues Binaural interaction in BAEPs was defined as any deviation from the predictions of a model that assumes two independent populations of neurons (monaural BAEP generators) whose outputs are additive (Dobie, 1979). That is, if there is no interaction between ears in the binaural condition, the BAEP response from stimulating both ears simultaneously should be identical to the combination of the responses from stimulating one ear at a time. Any differences between the binaural and the summed monaural responses must be due
Left Monaural --+U
Right Monaural 4
Binaural Difference (Binaural-Sum) -*
Fig. 1. Derivation of a BAEP binaural difference wave (BDW) is illustrated in a nonjaundiced, 19 day old Gunn rat in the nasion-inion electrode montage (nasion positivity displayed upwards). The replicated responses to left (A) and right (B) monaural stimulation are obtained and digitally summed in C (dashed line). The response to binaural stimulation is obtained (C, solid line). Finally. the sum of the monaural responses is subtracted from the binaural to give a BDW (D).
(jj) Gunn rat 4 hrs post sulfa
Bin (---) Sum (___-__-)
Fig. 2. Binaural dlfference waves obtained before and after injection of sulfadimethoxine (sulfa) to produce acute bilirubin encephalopathy in a 19 day old jaundiced Gunn rat. The BDW disappears 4 h after sulfa, whereas wave I of the BAEP remains. The reduced amplitude of wave I in this animal is not representative of the entire group.
to some binaural interaction, e.g.. more (or less) neuronal activity in the binaural condition. A representative BDW is illustrated in Fig. 1 from a nonjaundiced (Nj) Gunn rat. BAEPs are obtained to left and right monaural stimulation separately. The sum of these two monaural BAEPs is then digitally subtracted from the BAEP obtained to binaural stimulation to obtain the BDW.
Ana~,ws The latency of the largest positive wave was chosen, and amplitude was measured from this peak to the subsequent trough in the FPz-Inion montage. Conventional BAEP wave latencies and amplitudes of waves I, II, III, III- (the negative trough after III) and IV were measured in the Cz-Chin montage, since this montage most closely approximated traditional vertex recordings. Changes in latency and amplitude from baseline were analyzed with one sample, two-tailed t-tests of change in latency (ms) and amplitude (percent of baseline). Two sample, two-tailed z-tests were used for unpaired comparisons. Results
Reliable BDWs were recorded in 16- to 20-dayold Gunn rats (Fig. 1) with mean onset of 4.5 + 0.3 ms (mean + SD) after the stimulus and a large, often bimodal positive peak occurring at 5.9 _t 0.4 ms. There were no statistically significant dif-
ferences between jj and Nj groups before sulfadimethoxine injection. There was a gradual loss of BDW amplitude and increase in latency after injection of sulfadimethoxine in jj rats (Fig. 2) but not Nj controls. In more extreme cases the BDWs disappeared altogether, despite persistence of the earliest wave (wave I) of the BAEP (Fig. 3. and see below). Amplitude of the BDWs decreased to 21%’ f 14% of pre-injection baseline in jj’s four hours after injection of sulfadimethoxine (P < 0.0001 L
4 hrs Fig. 3. Gradual change and disappearance of the BDW in one jaundiced rat with acute bilirubin encephalopathy. Note the increase in latency and decrease in amplitude at one hour. The residual BDW remaining at four hours is possibly from a different source than the original. since their latencies and morphologies differ suhstantially.
Time after sulfadimethoxine
of 90% + 11% at 4 hours of the largest positive peak at four hours increased 0.62 k 0.42 ms compared to baseline (P = 0.03) and compared to controls of 0.08 + 0.17 ms at four hours (P = 0.049) (Fig. 5). In Nj controls injected with
Fig. 5. Change in BDW latency of the largest. positive wave in the FPz-Inion montage plotted as change in milliseconds compared to baseline in jaundiced (solid lines and circles) and nonjaundiced (shaded lines. open circles) Gunn rats after acute bihrubin toxicity produced by giving sulfadimethoxine, 100 mg/kg ip. On the right. means (x) and k 1 SEM are given for the change in latencies of the largest, nasion-positive wave of the two groups at 4 h.
(P -c0.001) (Fig. 4). The latency
Time after sulfadimethoxine
Fig. 4. Change in BDW amplitude of the largest. positive wave in the FPz-Inion montage in jaundiced (solid lines and circles) and nonjaundiced (shaded lines. open circles) Gunn rats after acute bilirubin toxicity produced by giving sulfadimethoxine. 100 mg/kg ip. On the right, means (x) and f 1 SEM are given for the change in amplitudes of the two groups at 4 h.
sulfadimethoxine, BDW latency not change from baseline. Conventional BAEP waves hours after sulfadimethoxine in waves I, II and IV decreased
also changed four jj’s: amplitudes of to about 60% of
BAEP Wave h
II III IIIIV
2.81 3.52 4.15 4.95
1.56 f 0.07 2.84kO.19 3.55 50.21 4.23 k 0.29 5.01 * 0.35
0.05 * 0.04 0.30*0.09 ** t -0.4OkO.23 * -0.09*0.17
kO.20 + 0.24 f 0.27 f 0.36
- 0.01 &-0.03 0.18+0.12 *
1.2kO.5 0.7 kO.3 0.8 f 0.3 0.7 + 0.2 0.5 +0.2
1.1 kO.4 0.6kO.3 0.7 + 0.2 0.6 f 0.3 0.5 f 0.2
65*23 * 56+_20 ** o* 0 *** 61k7 *** 58+29 ***
68+24 * 61517 ** Ok o*** 94*43 54i27 ***
i -0.59kO.23 -0.18+0.11
a Values and means & 1 SD; ‘See text for definitions of waves; ’ Not corrected different from baseline values at * P i 0.05. delay); d Changes significantly t Unable to calculate value due to disappearance of wave III.
for the 3.5 cm distance from speaker to ear (a 0.1 ms * * P c 0.01. or * * * P < 0.001 by two-tailed t-test;
baseline. and wave 111 disappeared: the latency of wave II increased. and wave III- latency decreased (Table I). In Nj controls there were no significant changes of conventional BAEP waves from baseline except for a reduced amplitude of wave IV (P = 0.016). and an increased latency of I (P = 0.042). only on stimulation of the left ear. Discussion
This is the first report of abnormal binaural interaction waves in bilirubin encephalopathy to the author’s knowledge. The results suggest that abnormalities of functions dependant on binaural processing of auditory information may be found as neurologic sequelae to bilirubin toxicity. Integration of precisely timed binaural information in units in the SOC is an essential ingredient of binaural processing. Fast conducting pathways in the ascending auditory system are important both in binaural processing. and in the generation of BAEPs. Lesions in the brainstem auditory nuclei in humans and Gunn rats with bilirubin encephalopathy include areas important in comparing information from both ears (responding to binaural cues). The endbulbs of Held, synapses with multisynaptic contacts of one ple. glomerulus-like primary onto one second-order neuron in the ascending auditory nervous system, are specialized for rapid and accurate transmission. Synaptic delay is very short. and the electron microscopic morphology is distinctive. The output of these synapses projects bilaterally to the SOC, where neurons integrate the input from both ears. Neurons in the medial superior olivary nucleus then project to the inferior colliculus. The circuit, from endbulb to SOC to lateral lemniscus to inferior colliculua. may contribute to some of the early waves of conventional BAEPs, which are predominantly generated by large. fast-conducting neurons in ascending auditory pathways. The clinical literature of central auditory dysfunction in humans with bilirubin encephalopathy is largely anecdotal, but does contain a report of patients with decreased binaural fusion (Matkin and Carhart. 1966). There is also BAEP evidence of central auditory dysfunction with bilirubin toxicity in humans (Perlman et al.. 1983: Lenhardt
et al., 1984: Nakamura et al.. 1985; Nwaesei et al., 1984). and the localization of the initial brainstem abnormality in the ascending auditory nervous system is the same as in rats-namely generators in the cochlear nucleus. This produces an increased I-II interwave interval in rats (Shapiro and Hecox. 1988) corresponding to an increased I-III interwave interval in humans. since both wave II in rats and wave III in humans appear to be generated by the cochlear nucleus (Moller et al.. 1981). The sound delivery system here differs from the sealed, in-the-ear-canal sound delivery system typically used in other studies. The open system used in these experiments has the advantage of using the same stimulus generator. amplifier and speaker to deliver sound to each ear. Furthermore, the sound passes naturally through the external ear canals. Since the external ear canals contribute significant binaural cues (Blauert. 1983: Butler. 1975: Butler and Belendiuk. 1977: Butler and Planert, 1976: Fisher and Freedman. 1968: Wightman and Kistler. 1989a: Wightman and Kistler. 1989b). this method of stimulus presentation includes additional, potentially important binaural cues that may not he present with in-the-ear-canal stimulation. The disadvantage of the free-field stimulation used herein is that sound is more likely to stimulate the opposite ear during the monaural condition. This is controlled to some degree by the requirement of BAEP thresholds with the ears plugged. However, these methodological concerns in no way invalidate the results of this study. since contralateral stimulation in the monaural condition would make it more difficult to detect binaural differences. and would only have been of concern had the results of this experiment been negative. Furthermore, baseline and nonjaundiced controls insure that the abnormalities seen after sulfadimethoxine injection are not a result of inadvertent contralateral ear stimulation. since the controls were stimulated identically. This study found large differences in binaural BAEPs in a model of acute bilirubin toxicity. It is possible that smaller differences exist with lesser degrees of hiliruhin toxicity. For example. jaundiced rats not given sulfonamides may have BDWs that are prolonged and diminished in amplitude. Studies comparing littermate Nj and jj pairs not given sulfonamide would examine bi-
lirubin encephalopathy less severe than the acute encephalopathy produced by giving sulfonamide to jj Gunn rats. The differences in BDWs would be expected to be less striking, and statistical analyses of well controlled experiments might be necessary to discern differences. Significant amplitude reductions and latency increases of conventional BAEP waves were found. Wave III, previously shown to be a sensitive indicator of bilirubin toxicity, disappeared altogether. The abnormalities of BDWs may result from the loss of input into BDW generators. Alternatively, significant input may reach binaural units, if generators other than those responsible for wave III supply afferent input to BDW generators. This study did not attempt to compare the sensitivity of BDWs to conventional BAEPs as indices of bilirubin toxicity. Systematic studies comparing conventional BAEP and BDW changes may help clarify these uncertainties and determine which is a more sensitive technique for detecting subtle bilirubin encephalopathy. This study predicts abnormal binaural interaction in humans with acute and/or chronic bilirubin encephalopathy. BAEP BDWs have been obtained in humans (Dobie, 1980; Wrege, 1981) including newborns (Hosford-Dunn et al., 1981) and may be a sensitive method for detecting physiological abnormalities due to bilirubin toxicity. In addition, sound localization tasks and other tests of binaural function may be abnormal in older children and adults with the sequelae of bilirubin toxicity.
The author thanks Drs. Frederic Wightman, John Brugge and Kurt Hecox, and Ms. Prudence Allen for helpful discussions of these experiments. This research was supported by N.I.H. Teacher Investigator Development Award NS00829, N.I.H. ROl-NS23895, and awards from the University of Wisconsin-Madison Medical and Graduate School Research Committees. References Ahdab-Barmada, M. and Moossy, J. (1984) The neuropathology of kernicterus in the premature neonate: diagnostic problems. J. Neuropath. Exp. Neurol. 43, 45-56.
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