Brainstem auditory-evoked responses with and without sedation in Autism and Down's syndrome

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Brainstem Auditory-Evoked Responses With and Without Sedation in Autism and Down's Syndrome E.A. Sersen, G. Heaney, J. Clausen, R. Belser, and S. Rainbow

Brainstem auditory-evoked responses (BAER) were obtained from 46 control, 16 Down's syndrome, and 48 autistic ma!e s,~b]ects. Six Down's syndrome and 37 autistic subjects were tested with sedation. Sedated and unsedated Down's syndrome subjects displayed shorter absolute and interpeak latencies for early components of the BAER whereas the sedated autistic group showed longer latencies for the middle and late components. The prolongation of latencies in the sedated autistic group was unrelated to age or intellectual level. Although individuals requiring sedation may have a higher probability of neurological impairment, an effect of sedation on the BAER cannot be ruled out.

Introduction The brainstem auditory-evoked response waveform (BAER) consists of several waveform components reflecting the activity of the auditory pathway from the acoustic nerve to higher midbrain structures. It has been regarded as a useful indicator of auditory sensory processing in some groups nf developmentally disabled individuals. The speculation that autistic behaviors result from distortions in the sensation or perception of environmental stimuli has led investigators (e.g., Tanguay and Edwards 1982) to search for evidence of BAER abnormalities. The BAER feature most commonly reported is a prolonged latency of Wave Ill, suggesting that autism may be associated with pathology at midbrainstem levels of the auditory pathway. In addition, several studies have found prolonged BAER Wave I latencies in many autistic subjects (Sohmer and Student 1978; Student and Sohmer 1978, 1979; Skoff et al. 1980; Tanguay and Edwards 1982; Tanguay et al. 1982; Ross 1982; Arick 1982; Gillberg et al. 1983) implying peripheral hearing impairment. Prolonged latencies between components have also.been reported for Wave V relative to Wave llI (Skoff et al. 1980), or Wave I (Taylor et al. 1982; Afick 1982), indicating increased brainstem transmission time. Other studies raise the possibility of only unilateral pathology, suggested by increased interwave latencies for left, but not fight, ear stimulation (Skoff et al. 1980; Arick 1982). From the N.Y.S. Office of Mental Retardationand DevelopmentalDisibilities, Institute for Basic Research in Developmental Disabilities, Staten Island, NY. Address reprint requests to Eugene A. Sersen, Ph.D., Institute for Basic Research in D.D., 1050 Forest Hill Road, Staten Island, NY 10314. Received November 14, 1987; revised April 22, 1989. This research was supported in part by Grant NS 19403 from the National Institute of Neurological and Communicative Disorders and Stroke. © 1990 Society of BiologicalPsychiatry

0006-3223/90/$03.50

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In contrast to these earlier studies, Rumsey et al. (1984) reported shorter Wave [ ] and shorter interpeak latencies ( I - [ ] and I-IV) in subjects with pervasive developmental disorders, including autism. The authors suggested their findings may have resulted from exclusion of children with identifiable neurological syndromes and gross neurological disorders. Courchesne et al. (1985) also failed to find BAER abnormalities in a group of high functioning autistic individuals who were not retarded, suggesting that auditory brainstem pathology is not a necessary condition for autism. It is also clear, however, that prolonged latencies are not simply a consequence of mental retardation in that shorter latencies have been reported in cases with Down's syndrome (Widen et al. 1987). One problem with respect to BAER testing in the developmentally disabled is the frequent necessity for sedation. Although the initial summaries suggested a minimal effect of sedation on latencies (Stockard et al. 1980), there have been sporadic reports of small but statistically significant latency prolongations with a variety of agents in rats (Church and Gritzke 1987), cats (Sims and Horohov 1986), and humans (Drummond et al. 1987; Manninen et al. 1985). In a previous study, we also found small latency increases in drowsiness as opposed to active wakefullness in normal individuals (Sersen et al. 1984). Such small differences may not be clinically significant, but they could result in significant differences in group comparisons. The present study is part of an extensive project examining sensory and perceptual dysfunction in a large group of autistic individuals by means of brainstem and corticalevoked potentials, autonomic reactivity, and behavioral preference for selected visual stimuli. This study compares the BAERs of sedated and unsedated groups of infantile autistic and Down's syndrome individuals with normal controls. In contrast to many previous studies~ only individuals with BAER thresholds within normal limits were examined, and a number of other aspects of the BAER were analyzed. Because recent evidence suggests that abnormal BAERs may occar only on contralateral recordings (Furune et al. 1985), and that positive and negative components reflect different underlying neural mechanisms (Hughes et al. 1985), recordings were made of both ipsilateral and contralateral activity, and latencies were obtained for negative as well as positive deflections in response to left and right ear stimulation.

Method

Subjects All subjects were male; their characteristics are summarized in Table 1. All Down's syndrome and 32% of the autistic subjects were outpatients of the Ip.stitute's Diagnostic Clinic and had received complete medical and neurological evaluations. The medical records of the remaining autistic subjects were reviewed by the lnstitute's clinical staff and fulfilPd DSM-[] (American Psychiatric Association, 1980) criteria for infantile autism. Children in whom autism was associated with a gross neurological disorder or systemic disea~ were excluded. The normal controls were paid volunteers recruited from family and friends of Institute staff, and all had no unusual history of medical, neurological, or psychiatric problems. The study was limited to subjects with BAER thresholds within 11 dB (2 SDS) of the laboratory mean in order to rule out latenCy differences resulting from hearing deficits.

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Table 1. Subject Characteristics Control Sedative N Mean age Age range Median M R Lowest level Highest level

46 13 7-18 --

Down's 10 11 7-18 Moderate Moderate Mild

Autism + 6 8 2-14 Moderate Moderate Mild

11 13 7-21 Mild Moderate Borderline

+ 37 10 3-24 Moderate Profound Borderline

Procedure For the most part, the autistic and Down's .~yndrom¢ subjects were familiarized with laboratory personnel and aspects of the proce~iures (e.g., electro,de application) prior to formal testing. When required, sedation involuting orally admini~tered chloral hydrate or intravenous sedation monitored by a qualifiec~l anesthesiologist ~ as used to enable evaluation. Sedation sufficient to suppress gross movement was ac~omplished using one or more of the following agents: thiopental, fentanyl citrate (Sublimate), diazepam (Valium), or droperidol. The duration of sedation was usually less than 1 hr. Testing took place in a sound attenuated, ~emperature and h~midity controlled, electrostatically shielded room (2.4 x 2.3 × 2.0 ra). Recording were obtained from Beckman electrodes applied to forehead and left and right mastoids, with a ground electrode applied to the forearm. Electrode resistance was below 5 kohms. Stimuli consisted of 0.1 ms square-wave rarefaction clicks, and averages were based on 1500 responses. The brain electrical activity was amplified with a gain of 500,000 and frequency band pass of 0.1 kHz-3 kHz. Signals were digitized for 12.8 ms at a rate of 10 kHz per channel with 12 bit resolution. An artifact rejection algorithm was used to eliminate overload conditions. White noise, 30 dB below click intensity, was presented contralaterally as a masking stimulus. Each ear was tested separately, recording both ipsilateral and contralateral responses. Testing of each subject required approximately 40 rain. BAER threshold was defined as the lowest intensity at which Wave V was discernible, as determined by presenting a descending series of intensities from 110 dB (peak equivalent SPL), in 20 dB steps followed by an ascending series in 10 dB steps. Such a procedure has been shown to yield BAER thresholds within 6 dB of behavioral thresholds (Pratt and Sohmer 1978). To reduce testing time, thresholds were obtained using a click rate of 29/sec. After the thresholds had been determined, latency values were obtained by testing each ear at an intensity of 50 dB above threshold with a click rate of 10.3/sec. Latencies were scored both on-line, and by a second experimenter from the printed output, scoring blindly with respect to group membership. When the difference exceeded 0.2 ms, a third experimenter also determined the pa~ticul~ latencies blindly. The score was then based on the average of the two closest measures. Initial agreement ranged from 70.1% (Wave VII) to 94.7% (Wave III), with a mean of 85.3%. The measures obtained for each ear included threshold intensity and absolute latencies of the successive maximum positive and negative deflections of Waves I through VII (referred to as I-P, I-N, etc.).

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Table 2. Means and Standard Deviations of the Ipsilateral Latencies Control

l-P I-N II-P I1-N llI-P III-N IV-P IV-N V-P V-N VI-P VI-N VII-P

1.79(0.18) 2.39 (0.21) 2.95 (0.21) 3.33 (0.19) 3.89 (0.18) 4.45 (0.20) 5.12 (0.26) 5.44 (0.26) 5.75 (0.21) 6.53 (0.25) 7.50(0.43) 8.07(0.41) 9.30 (0.45) 9.89(0.61) 46

VII-N n °p < t,p < Cp < ~p <

Down's unsedated

1.76 2.27 ~ 2.70 te 3.20 ~ 3.82 4.36 4.89 ~ 5.24 ° 5.68 6.50 7.38 7.96 9.36 10.08

10

(0.17) (0.18) (0.16) (0.16) (0.24) (0.27) (0.36) (0.37) (0.38) (0.50) (0.54) (0.55) (0.56)

(0.74)

Down's sedated

1.72 2.38 2.82 ° 3.07 ~ 3.83 4.38 4.85" 5.24 5.75 6.50 7.62 8.16 9.41 9.99 6

(0.21) (0.25) (0.33) (0.24) (0.18) (0.31) (0.39) (0.26) ¢O.!9~(0.26) (0.43) (0.44) (0.34)

(0.42)

Autistic unsedated 1.73 2.34 2.91 3.32 3.88 4.49 5.05 5.39 ~5.72

(o.2o)

(0.22) (0.20) (0.19) (0.20) (0.33) (0.35) (0.36) (0.32) 6.59 (0.39) 7.44 (0.37)

8.03 (0.45) 9.32 (0 5O) 9.85 (0.6O) 11

Autistic sedated

1.86 2.44 3.01 3.43

(0.17) (0.22) (0.20) (0.20)

4.03 b (0.21)

4.68 b (0.26) 5.38 ~ (0.29) 5.67 ~ (0.31) 6.00 ~ (0.25) 6.79 ~ (0.30) 7.73 ~ (0.34) 8.33 ~ (0.36) 9.55 b't (0.51) 10.17a (0.61) 37

0.05 versus control (absolute latency). 0.01 versus control (absolute latency). 0.05 versus control (interpeak latency). 0.01 versus conlml (inteq~eak latency).

Results The data were analyzed by multivariate analysis of variance, using program P4V of the BMDP statistical analysis package (Dixon 1983). Group membership was a betweensubject factor, and side of stimulation (right versus left ear) and electrode placement (ipsilateral versus contralateral) were within-subject variables. Thresholds and latencies were separately analyzed as sets of dependent variables. For left and right ear thxeshoJds, significant group differences were present (F(4, 104) = 4.02, p < 0.01). Mean threshold intensities were 50.7 dB for the control group, 55.5 and 55.8 dB for the unsedated and sedated Down's groups, and 50.5 and 54.0 dB for the unsedated and sedated autistic groups. All but the unsedated autistic groups had somewhat higher hearing thresholds than the controls. Analysis of the latencies revealed a significant group effect (F(56, 360) = 1.87, p < 0.001). Planned contrasts with the control group showed significant differences from the unsedated Down's group (F(14,92) = 1.99 p < 0.03), the sedated Down's group (F(14, 92) = 2.05, p < 0.02), and the sedated autistic groups (F(14,92) = 2.44, p <

O.Ol). Table 2 presents the means and standard deviations of the ipsilateral latencies for the combined ears and the peaks identified as differing significantly from the controls in the analysis of group contrasts. As can be seen, bo~h Down's groups display shorter latencies for aspects of Waves g and IV. The sedated autistic group, on the other hand, shows longer latencies for all components following Wave HI. The unsedated autistic group does not differ from the control and, in fact, has somewhat shorter latencies for most

ccm nents. The overall analysis has revealed a significant group × laterality interaction (F(56, 360) = 1.68, p < 0.01) which resulted from differences between the control and unsedated

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Down's group. Contralateral differences exceeded ipsilateral for peak I-N and H-N, whereas the reverse was true for VI-N. Interpeak latencies were examined by subtracting the ipsilateral I-P latency for each side from subsequent ipsilateral and contralateral latencies. The main effect of group was again significant (F (52, 362) = 1.59, p < 0.01). As before, the control group differed from the unsedated Down's (F(13, 93) = 2.06, p < 0.95), the sedated Down's (F(13, 93) = 1.86, p < 0.05), and the sedated autistic (F(13, 93) = 1.95, p < 0.05) groups. Table 2 also indicates significant interpeak differences~ demonstrating shorter transmission times for the Down's in the early components and longer for the sedated autistic in components III-N through VI-N. The group × laterality interaction was also again significant (F(52, 36) = 1.83, p < 0.001), involving the unsedated Down's (F(13, 93) = 2.53, p < 0.01) and the sedated autistic (F(13,93) =- 1.83, p < 0.05) groups relative to the controls. The Down's group indicated contralateral interpeak latency differences which were shorter than the ipsilateral for peaks I-N and H-N, and a reverse pattern for VI-N. For the sedated autistic group, ipsilateral differences exceeded the contralateral for HI-N and VH-N. Relative to the unsedated individuals, those who were sedated were somewhat younger and of lower levels of functioning. To determine whether these characteristics were contributing to the group differences, the sedated and unsedated Down's and autistic groups were separately compared, covarying for age and functional level. Covariates consisted of age, the square of age, and dummy-coded variables which were used to represent the levels of intellectual functioning. For the Down's group, neither the set of variables nor any individual variable was significantly related to latency nor did the sedated and unsedated groups differ flora each other. For the w.tis~ic groug.~, ',h~ entire set of variables failed to account for a significant proportion of vari~".ce in latency (F(7,39) = 1.89, p < 0.05) although the severe (F(1,39) = 4.25, p < 0.05) and moderate (F(1,39) = 4.87, p < 0.05) groups differed individually from the borderline group. Nevertheless, significant group differences (F(1,39) = 18.37, p < 0.001) were obtained after covarying for these factors. Examination of the adjusted measures, in fact, revealed an increase in the differences between the sedated and unsedated groups.

Discussion Our results indicate shorter latencies in the early components of the BAER in Down's subjects with and without sedation and a prolongation of middle and late latencies in a sedated autistic group. The latencies of the unsedated autistic group were indistinguishable from those of the control. These data appear to support the contention of Courchesne et al. (1985) that brainstem pathology is not a necessary concomitant of autism. As our group included subjects who were mentally retarded, it is also evident that normal brainstem function is not restricted only to the higher functioning autistic subjects. Like Rumsey et al. (1984), we excluded those with gross neurological disorders, although we did not find shorter latencies in this group. Our exclusion of subjects ~ abnormal bralns:em thresholds may also have contributed to the lack of deviation from the controls. The key question regarding the sedated autistic group is whether the prolonged latencies resulted from the sedation or were a consequence of the characteristics that made the sedation necessary. The sedated and unsedated Down's groups did not differ significantly from each other, but the sedated group demonstrated fewer differences from the control

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group and had mean latencies for the early components which were somewhat longer than those of the unsedated subjects. In addition, the majority of the sedated Down's subjects had received chloral hydrate, the milder form of sedation. Examination of type of agent and dosage in the autistic group was more difficult. Combinations of agents were frequently used and duration of sedation was variable. Brainstem testing often followed clinical EEG or CT scan examinations which also required sedation, making the active dose at time of testing difficult to calculate. In addition, because sedation was used to maintain a constant state of quiet restfulness, dose-response effects might not be evident. As temperature was not monitored, we cannot rule out the presence of hypothermia; however, total duration of sedation tended to be short. The most obvious difference between the sedated and unsedated groups, age and intellectual level, did not appear to account for the latency differences as demonstrated by the covariance analysis. The decision to administer sedation was based on parental expectations of the individual's ability to sit quietly for the duration of the test, and on behavioral observations suggesting likelihood of cooperation. It is possible that the less tractable individuals have subtle neurological dysfunction including abnorn,~ities of the brainstem. The present data cannot provide a decisive answer. They do suggest, however, that studies involving BAER comparisons of clinical populations should not assume an absence of sedative effects. We gratefully thank Dr. David Holmes of the Eden Institute, Princeton, NJ, and Dr. Steven Krapes of the Forum School, Waldwick, NJ for providing access to their students. We also thank Dr. Andre Smessaert and Dr. Bernadette Giblin who administered and monitored the sedation.

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