Auditory Event-Related Potentials in Fetal Alcohol Syndrome and Down's Syndrome Children

0145-6008/96/2001-0035$03.00/0 ALCOHOLISM: CLINICAL AND EXPERIMENTAL RESEARCH

Vol. 20, No. 1 February 1996

Auditory Event-Related Potentials in Fetal Alcohol Syndrome and Down’s Syndrome Children

W. M. Kaneko. C. L. Ehlers.

Abnormal or borderline electroencephalograms are commonly ob- sewed in cases of gross mental retardation. However, fewer studies have focused on the use of event-related responses to aid in the differential diagnosis of developmental cognitive disorders. Fetal alcohol syndrome (FAS) and Down syndrome represent the most common known causes of mental retardation in the Western world. Al- though Down syndrome is easily diagnosed with a chromosome assay, FAS can be more difficult to diagnose since the diagnostic features are more subjectively based. The present study is the first to characterize auditory event-related potentials (ERPs) in children with FAS and contrast them to subjects with Down syndrome and controls. A passive auditory “oddball-plus-noise” paradigm was utilized to elicit ERPs. Parietal P300 latencies in response to the noise-burst stimuli for the FAS children were significantly longer, as were the P3OOs from all cortical sites in Down syndrome subjects in response to the both the infrequent tone and noise-burst stimuli when compared with the controls. Frontal P3OOs in Down syndrome children were significantly larger in amplitude compared to the controls and FAS children in response to the infrequent tone. A discriminant function analysis also revealed that these children could be correctly classified as being either Down syndrome, FAS, or normal controls using measures of latency and amplitude of the P300. These data suggest that an evaluation of ERP characteristics may provide a better understanding of the differences between FAS and Down syndrome children, and prove to be an aid in the early identification of children with FAS. These results demonstrate neurophysiological differences between FAS and Down syndrome, and suggest that P300 amplitude and latency data collected from a passive ERP task may be helpful in the discrimination of developmental cognitive disorders.

Key Words: FAS, Down syndrome, Event-Related Potentials, Dis- criminant Function Analysis.

ETAL ALCOHOL syndrome (FAS) was first identified F and described in 1973 by Jones and Smith.’,* Growth deficiency, dysmorphological characteristics, and central nervous system (CNS) manifestations are the three types of birth defects that define FAS.193 SoIfie birth defects observed in FAS children are also seen in children with other congenital disorders. For example, children with Down

From the Department of Neuropharmacology (W.M.R, C.L.E., E.L.P.), The Scripps Research Institute, La Jolla, California; and the Department of Psychology (E.P.R.), San Diego State Universiv, San Diego, California.

Received for publication September 29, 1994; accepted August 14, 1995 This study was supported by the National Institute on Alcohol Abuse and

Aleoholism Grant 00098 (to C.L.E.), the Alcohol Research Center of the National Institute on Alcohol Abuse and Alcoholism Grant 06420 and the General Clinical Research Center Grant 00833.

Reprint requests: W. M. Kaneko, Ph.D., Department of Neuropharmacol- 00, CW-14, The Scripps Research Institute, 10666 North Torrey Pines Road, La Jolla, CA 92037.

Copyright 0 1996 by The Research Society on Alcoholism.

Alcohol Clin Erp Res, Vol20, No 1, 1996 pp 3 5 4 2

E. L. Philips, and E. P. Riley

syndrome also show craniofacial dysmorphology, mental retardation, and behavioral problems. One difference between these two populations, however, is that Down syndrome children are easily distinguished from other cogni- tively impaired children by a simple chromosome test, whereas an objective and definitive clinical test that may identify children with FAS remains to be found. The recording of event-related potentials (ERPs) may po- tentially provide an objective measure by which to better characterize FAS and differentiate children with FAS from matched Down syndrome children and normal controls.

Long latency ERP components, such as the P300, appear to reflect the cognitive aspects of information processing (such as encoding, selecting, memorizing, decision making, etc.) and have been utilized as an index of cognitive processing under various conditions and between different study population^.^-^ Several studies have reported longer NlOO and P300 peak latencies in auditory ERP paradigms for adult Down syndrome patients.7-’’ Prolonged P3 latencies in response to visual stimuli have been reported in Down syndrome persons that may suggest slower neural processing.” Paradoxically, some studies have reported increased P300 amplitudes in Down syndrome patients, which, according to some theories, should suggest increased cognitive capacity.6 However, several other studies have found decreased P300 ,amplitudes in Down syn- dr~me.~-” To date, no reports of auditory ERPs have been published using FAS children for subjects. However, studies evaluating evoked potentials in human infants born to heavy drinking mothers have provided data suggesting that ethanol exposure in utero may alter the evaluation of sensory stimuli in these infantd3-” There is a need for more clinically discriminative indicators of FAS. If the ERPs of FAS children could be characterized distinctly from the ERP records of other patients with a congenital disorder that also consists of cognitive deficits, craniofacial dysmorphology, and growth retardation, then specific ERP variables may correctly categorize children into distinguished groups. The purpose of the present study was to: (1) determine whether ERPs can be obtained in FAS children; (2) characterize the wave morphology; (3) compare the ERP records to normal controls matched for age, gender, and ethnicity; and (4) compare the ERPs of FAS children with those of matched Down syndrome children.

35

36 KANEKO ET AL.

Table 1. Demographic Information for All Subjects Control Down syndrome FAS

Gender Age IQ Nonethnic match Medication IQ Nonethnic match Medication IQ Nonethnic match Medication F 4 111 <40 Caucasian 78 Hispanic/Caucasian F 6 112 45 73 Caucasian F 6 100 140 Caucasian 74 African-American F 7 94 140 Caucasian 56 African-American Mellaril M 7 109 39 96 Caucasian F 8 117 <40 Caucasian 69 African-American F 9 135 <40 74 Caucasian lmipramine F M 10 128 Caucasian <40 Caucasian Ritalin 78 Hispanic F 11 109 NA Caucasian Ritalin 52 African-American M 13 122 NA 51 Caucasian M 14 86 47 Caucasian 41 African-American Cylert M 14 103 <40 Caucasian 74 African-American M 15 101 43 87 Caucasian

9 116 43 Samoan 94 Caucasian

Mean = 11 0.21 SD = 13.15

SEM = 3.51

Mean = 71.21

SEM = 4.34 S D = 16.24

NA, not available. * Mellaril, phenobarbital, and Dalman.

METHODS

Subjects

Subjects were 18 triads of children who were carefully matched on gender, age, and, for the most part, ethnicity. The first group (n = 18) consisted of children diagnosed as having FAS by Dr. Kenneth Jones. Children diagnosed with FAS in this group had signs in each of the following categories: prenatal and/or postnatal growth retardation, CNS involvement, and characteristic facial features. This is in agreement with the guidelines for the diagnosis of FAS previously reported.16 Three of these children were currently on either Ritalin (methylphenidate) or Cylert, while three other children were on various drugs, such as mellaril, imipramine, phenobarbital, or dalmane (Table 1). Children in the second group (n = 18) were diagnosed as having Down syndrome by local physicians. Three children from this group were on comparable doses of methylphenidate. Children in the third group (n = 18) were normal controls with no family history of any neurological disorder and had not been exposed to alcohol or any other drug prenatally. None of these children were on any medication. The 54 children were between ages 4 to 15 years (average age of 9.1 2 3.2 years). The 10 females and 8 males recruited for the FAS group were from various ethnic backgrounds: 9 Caucasians, 7 African-Americans, 1 half Hispanic-half Caucasian, and 1 Hispanic.

Procedures

ERP recordings were conducted at the General Clinical Research Center in the Green Hospital of Scripps Clinic in La Jolla, CA. On test day, the parent or legal guardian of each subject completed questionnaires regarding their child’s demographics and medical history (e.g., hearing and visual complications, medications, handedness, etc.). Children with hearing problems were excluded from the study.

Full-Scale IQ, Verbal IQ, and Performance IQ were obtained using the Wechsler Intelligence Scale for Children-Revised or the Wechsler Pre- school and Primary Scale of Intelligence, depending on age and ability of the child, the results of which have been previously described.”

Electroencephalographic activity [electroencephalogram (EEG)] recordings were obtained from all subjects between 8:OO AM and 4:OO PM by a registered EEG technician. Individually gold-plated electrodes or tin electrodes set inside a tightly fitting electrode cap were used. The place- ment of the electrodes were based on the international 10-20 system.” Unipolar recordings from Fz, Cz, and Pz were referenced to linked earlobes. All electrode impedances were below 5 k0 .

Data were recorded on a Nihon-Kohden polygraph and transferred to a Macintosh computer for further analyses. Sensitivity was 7 pV, the time constant used was 0.1 sec, and the low pass was 35 Hz. Although these ERP recordings were not obtained blind to subject diagnosis, the ERP analyses were conducted by an automatic computer program that obvi- ously remained unbiased. Subjects were instructed to lie down comfortably on a bed and remain quiet, still, relaxed, and awake with their eyes closed during the entire recording.

Test Paradigm

An auditory ERP session was conducted, using headphones, through which the stimuli were presented. An acoustic “oddball-plus-noise” stimulus paradigm was utilized. The tones utilized were generated by a programmable multiple-tone generator, the characteristics of which have been previously de~cribed.’~

Due to of the common inability of several of the FAS and Down syndrome subjects to perfom an “active” discrimination task appropri- ately, this study incorporated a “passive” task paradigm. Each subject was required to listen to the three types of stimuli, but not required to respond behaviorally. This “passive” ERP paradigm has been found to elicit similar ERP morphology, comparable latency values, and scalp distributions comparable to the commonly used “active” ERP h a d i g m in which subjects are required to actively detect target tones.”

A total of 240 trials were presented to each subject. Acoustic param- eters were two square y v e tones (rise/fall times 4 0 msec): a standard tone (50 msec, 1 KHz, 70 dB SPL) presented on 84% of the trials and a rare tone (50 msec, 2 KHz, 80 dB SPL) presented on 10% of the trials. A noise burst (50 msec, noise, 100 dB SPL) was also presented on 6% of the trials to elicit an “automatic” P300.*’ Rare tones were interspersed with standards, such that no two rare tones occurred successively, and a noise burst was substituted for a rare tone every 12 trials.

Data Anafysis

ERP trials were digitized at a rate of 256 Hz and analyzed. Amplitudes of ERP components were measured peak-to-baseline, whereas latencies were calculated from the onset of the stimulus to the onset of the peak of the component. ERP recordings of Down syndrome children tended to have more movement artifact due to poor cooperation and, as a conse- quence, more trials were eliminated for this group. To eliminate individual trials in which the EEG exceeded 2 100 pV, an artifact rejection program

AUDITORY ERPs IN FAS 37

was utilized. The average percentage of trials eliminated was 3% for both the control and FAS groups and 16% for the Down syndrome group.

Latencies and amplitudes of the NlOO (i.e., the negative peak occurring -100 msec after stimulus onset) and the P300 (i.e., the positive peak occurring -300 msec after the onset of the stimulus) ERP components recorded from the three cortical areas (i.e., frontal, central, and parietal) were calculated and analyzed separately using two-way, between-subjects analyses of variance (ANOVAs), with two levels for gender (i.e., female and male) and three levels for group (Le., control, Down syndrome, and FAS). Tukey honestly significant difference tests were utilized for post- hoc analyses. Rather than use the traditional 0.05 level of significance, a more conservative 0.01 level was used because of the multiple compari- sons defined and tested in this study. In addition, a discriminant function analysis (DFA) was conducted using certain ERP variables to determine whether each of these children could be correctly categorized into one of the three study groups.

RESULTS

Group Characteristics The three groups were carefully matched and, therefore,

essentially identical in gender and age. IQ scores, however, were found to be significantly different between the FAS group and normal control group [F(1,26) = 48.78, p < 0.000051. FAS children had an average IQ of 71 ? 16.2, whereas normal controls had an average of 110 2 13.1. These averages were based on 14 matched subjects in each group. Three FAS subjects were excluded due to the failure of completing the ERP test session. One additional FAS child had an unmeasurable IQ and was subsequently excluded from this analysis. The Down syndrome group was excluded from this IQ analysis because only four Down syndrome children had measurable IQs which ranged from 43 to 47; the other Down syndrome children had IQ scores below 40. A summary of these data and detailed demographic information including medication of these children are provided in Table 1.

ERP Analyses Successful recordings on the "passive" ERP task were

obtained for 15 complete triads. Three of the original 18 Down syndrome children refused to complete the test session. In general, the ERP components examined in the Down syndrome children had larger aknplitudes than the control and FAS children, whereas the morphology of the waves seen in the ERPs of the FAS children were very poorly formed. There was no significant difference between the groups on number of "infrequent tone" trials eliminated ( p > 0.01). The average number of ERP responses to the infrequent tone used for the analyses for the FAS group was 24.4 2 2.2, the Down syndrome group averaged 22.1 2 3.0 trials, and the normal controls averaged 24.5 t 1.1 trials. The number of "noise-burst stimulus" trials eliminated from the children of the Down syndrome group was significantly greater than the other two groups [F(2,39) = 7.37, p < 0.0031. The average number of ERP responses to the noise-burst stimuli used for the analyses for the FAS group was 14.6 2 0.6, the Down syndrome group averaged

Infrequent Tone FRONTAL CORTEX

ERPS

0 200 400

-70%

Milliseconds

Noise Burst FRONTAL CORTEX

0 200 400

CE TRAL CORTEX 1 , P

-PAPIETAL CORTEX

0 200 400 Milliseconds

Fig. 1. Grand averages for ERPs recorded from each of the cortical regions in response to the infrequent tone and noise burst are plotted for 15 control children, 15 Down's syndrome children, and 15 FAS children. -, Control: - - -, Down syndrome; - -, FAS.

12.3 2 2.9 trials, and the normal controls averaged 14.6 2 1.3 trials.

Figure 1 shows a group comparison of the ERPs recorded from the three cortical areas in response to the infrequent tone and noise burst. In response to the stimuli, the frontal cortex first displayed an early negative wave (N100) which had a mean peak latency of 115-145 msec. The late positive wave, the P300, had a mean peak latency of 305-370 msec. In the central cortex, the NlOO had a mean latency of 100-115 msec, while the P300 had a mean latency of 285-345 msec. The parietal cortical area displayed an N100, with a mean latency that fell between 100-110 msec and a P300 having a mean latency of 290- 335 msec. No gender effects were seen at any of the cortical sites in response to any of the stimuli ( p > 0.01).

ERP Responses to the Infrequent Tone. Tables 2 and 3 show mean t SD latency and amplitude values, respectively, for the NlOO and P300 ERP components for each group in response to the infrequent tone. The Down syndrome children had significantly longer P300 latencies than FAS children and significantly larger P300 amplitudes com-

38 KANEKO ET AL.

Table 2. Latencies (Msec) for NlOO and P300 ERP Components in Response to the Infrequent Tone ~ . , Recording ERP Control Down syndrome FAS

site component (Mean -t SD) (Mean t SD) (Mean 5 SD) Statistics (Between subjects)

Frontal cortex N100 125.0 2 21.7 120.8 5 20.8 143.8 2 24.7 F(2.39) = 3.91, p < 0.028 P300 333.1 t 29.9 362.5 t 29.4 320.6 2 23.9 F(2.39) = 8.10, p < 0.00lt

F(2.39) = 0.28, p < 0.757 N100 P300 298.2 t 37.6 346.1 C 36.4 312.3 2 18.2 F(2,39) = 8.36, p < 0.001'

NlOO 104.7 t 17.9 111.5 t 10.8 99.5 2 22.5 F(2,39) = 1.79, p < 0.181 P300 298.2 t 28.5 331.5 t 30.2 309.1 2 25.5 F(2,39) = 7.33, p < 0.002'

Central cortex 109.9 2 13.9 113.3 t 13.9 108.3 2 21.2

Parietal cortex

Significant ANOVA (p < 0.01); post-hoc tests revealed a difference between the control and Down syndrome groups. t Significant ANOVA (p < 0.01); post-hoc tests revealed a difference between the control and FAS groups.

Table 3. Amplitudes (pv for NlOO and P300 ERP Components in Response to the Infrequent Tone

Recording ERP Control Down syndrome FAS

Frontal cortex

site component (Mean 2 SD) (Mean 2 SD) (Mean t SD) Statistics (Between subjects)

NlOO 8.5 t 5.6 6.7 t 7.3 5.9 2 4.9 F(2,39) = 0.75, p < 0.479 P300 4.8 t 4.6 11.5 t 5.4 4.0 2 4.4 F(2,36) = 11.09, p < 0.0005*,t

NlOO 7.5 t 5.0 7.1 2 7.8 4.5 2 4.1 F(2,39) = 1.59, p < 0.217 P300 7.4 C 5.9 10.7 2 7.3 4.8 2 4.9 F(2,39) = 3.61, p < 0.037

4.4 t 4.9 F(2,39) = 1.63, p < 0.210 NlOO P300 7.9 -+ 5.4 10.4 C 8.2 5.7 t 5.2 F(2,39) = 1.88, p < 0.166

Central cortex

Parietal cortex 4.6 ? 3.7 8.3 ? 11.0

Significant ANOVA (p < 0.01); post-hoc tests revealed a difference between the control and Down syndrome groups. t Significant ANOVA (p < 0.01); post-hoc tests revealed a difference between the Down syndrome and FAS groups.

Table 4. Latencies (Msec) for the NlOO and P300 ERP Components in Response to the Noise Burst

Recording ERP Control Down syndrome FAS

Frontal cortex

site component (Mean 5 SD) (Mean t SD) (Mean 5 SD) Statistics (Between subjects)

NlOO 118.8 2 16.5 118.2 5 13.6 135.5 t 18.5 F(2,36) = 3.86, p < 0.030 P300 307.4 t 20.0 370.7 t 44.4 319.1 2 21.3 F(2,36) = 13.29, p < 0.0005',$

NlOO 108.4 t 9.4 105.4 t 10.7 111.2 t 19.2 F(2,36) = 0.48, p < 0.624 P300 287.9 t 16.9 321.9 2 22.0 314.9 2 29.3 F(2,36) = 7.45, p < 0.002*

N l O O 109.7 t 13.8 104.0 t 10.8 102.8 2 21.3 F(2,33) = 0.54, p < 0.586 P300 291.9 2 17.3 317.1 C 16.5 310.5 ? 14.4 F(2,33) = 8.78, p < O.OOl*,t

Central cortex

Parietal cortex

' Significant ANOVA (p < 0.01); post-hoc tests revealed a difference between the control and Down syndrome groups. t Significant ANOVA (p < 0.01); post-hoc tests revealed a difference between the control and FAS groups. $Significant ANOVA (p < 0.01); post-hoc tests revealed a difference between the Down syndrome and FAS groups.

pared to both normal controls and FAS children in the frontal cortical region [F(2,39) = 8 . 1 0 , ~ < 0.001; F(2,39) = 11.09, p < 0.0005, respectively]. P300 latencies for the Down syndrome group were longer than those for the control group, but this difference did not quite reach significance (p < 0.017). No significant findings concerning the frontal NlOO component were found; however, FAS children tended to have delayed NlOO latencies compared to Down syndrome children in the frontal regions in response to the infrequent tone [F(2,39) = 3.91 ,~ < 0.0281. Although the controls had similar NlOO latency values as Down syndrome children, they were not significantly different from the FAS children.

In the central cortical areas, the latency of the P300, in response to the infrequent tone for the Down syndrome group, was significantly longer when compared to the normal control group [F(2,39) = 8.36, p < 0.001]. Down

syndrome children tended to have larger central cortical P300 amplitudes in response to the infrequent tone than the FAS children k8(2,39) = 3.61, p < 0.0271. Also, in response to the infrequent tone, the Down syndrome children had significantly longer latencies of the parietal P300 component than the normal controls [F(2,39) = 7.33, p <

ERP Responses to the Noise Burst. Tables 4 and 5 show the mean -f SD latency and amplitude values, respectively, for the NlOO and P300 ERP components in response to the noise-burst stimuli. For the frontal cortical area, Down syndrome children had significantly longer P300 latencies compared to control and FAS children [F(2,36) = 13.29,~ < 0.00051. The FAS group tended to have longer frontal NlOO latencies in response to the noise burst when compared with the Down syndrome group [F(2,36) = 3 . 8 6 , ~ <

0.0021.

0.031.


4 0 -

Table 5. Amplitudes (fiw for the NlOO and P300 ERP Components in Response to the Noise Burst

site component (Mean t SD) (Mean 2 SD) (Mean t SD) Statistics (Between subjects) Recording ERP Control Down syndrome FAS

Frontal cortex N100 5.2 rt 7.1 3.4 t 7.5 7.9 2 8.2 F(2,36) = 0.48, p < 0.624 P300 17.1 2 11.6 14.4 t 13.3 15.0 t 10.1 f(2.36) = 0.13, p < 0.877

22.6 t 12.7 7.5 t 9.9 14.7 t 11.8 F(2,36) = 4.38, p < 0.020 N100 31.9 ? 13.8 23.7 ? 14.6 18.5 t 14.7 F(2.36) = 1.80, p < 0.180 P300

NlOO 9.6 t 8.9 5.1 t 5.8 9.8 t 7.3 F(2,33) = 1.64, p < 0.209 P300 35.6 t 11.2 33.1 t 15.4 19.0 t 12.5 F(2,33) = 4.68, p < 0.016

Central cortex

Parietal cortex

30

w - o o D: ::: 20- c 1 "

10 -

The central cortical area also displayed significant P300 latency differences between the three groups in response to the noise burst [F(2,36) = 7 . 4 5 , ~ < 0.0021. Down syndrome children had longer P300 latencies compared to normal controls. Post-hoc Tukey tests also indicated that the FAS group tended to have a longer mean latency of the P300 component than the control group (p < 0.018). In the parietal cortex, P300 latencies seen in Down syndrome and FAS children were significantly longer than those seen in matched controls [F(2,36) = 8 . 7 8 , ~ < 0.0011. FAS children tended to have smaller parietal P300 amplitudes in response to the noise burst, compared with matched normal controls [F(2,33) = 4 . 6 8 , ~ < 0.0161.

Infrequent Tone Versus Noise Burst. Additional analyses were performed to determine whether the three study groups had similar NlOO and P300 amplitude changes when comparing the infrequent tone to the noise burst. NlOO amplitudes in response to the noise burst were significantly larger than those in response to the infrequent tone for both central and parietal areas [F(1,39) = 37.02, p < 0.0005; F(1,36) = 10.53, p < 0.003, respectively]. P300 amplitudes in response to the noise burst were also significantly larger than those in response to the infrequent tone for both central and parietal areas [F(1,39) = 5 2 . 3 1 , ~ < 0.0005; F(1,36) = 82.67, p < 0.0005, respectively]. ' A significant group X stimulus interaction effect was

found for the NlOO amplitude of the central cortex [F(2,39) = 6.42, p < 0.0041. Tlt& noise burst producg significantly larger NlOO amplitudes kor FAS children and normal con- troIs ,compared to the infreqhent tone. No significant differential NlOO amplitude effect in kesponse to the two stimuli for Down syndrome children was observed. For the parietal cortex, however, Down syndrome children and controls tended to have larger P300 amplitudes in response to the noise burst when compared with the P300s in response to the infrequent tone. A less apparent differential P300 amplitude response was observed in FAS children [F(2,39) = 3.69, p < 0.0351. NlOO and P300 amplitude changes in response to the infrequent tone and noise burst for all groups are demonstrated in Fig. 2.

DFA Fourteen matched triads, for a total of 42 subjects, were

used for the DFA. Each of the three variables-latency of

INFREQUENT TONE NOISE BURST

( p a r i e t a l P 3 0 0 cortex)

L

I

N O I S E BURST I N F R E Q U E N T TONE

Fig. 2. Mean t SEM amplitudes of the NlOO ERP component in response to the infrequent tons, compared with the nolse burst for the central cortical area (top). Mean t SEM amplitudes of the P300 ERP component in response to the infrequent tone, compared with the noise burst for the parietal cortex (bottom). 0, Control: A. Down syndrome: ., FAS: *p < 0.04; "p < 0.004.

the P300 in response to the infrequent tone, amplitude of the P300 in response to the infrequent tone, and latency of the P300 in response to the noise burst-significantly differentiated the three groups [F(6,74) = 8.89, p < 0.00051. DFA values are presented in Table 6. Forty-three percent (6 of 14) of the normal controls, 86% (12 of 14) of the Down syndrome children, and 79% (11 of 14) of the children with FAS were correctly classified by the DFA. These percentages are greater than the percentage of correct predictions expected on the basis of chance.

40 KANEKO ET AL.

Table 6. Values and Results from the DFA Using P300 Variables from the Frontal Cortical Sites (1 4 ControVDown SyndromeFAS-Matched Triads)

Canonical Proportion of Factor correlation variation

1 0.791 0.63 2 0.315 0.01

Wllks’ lambda = 0.338

Classification No. of cases (%)

Group Correct Incorrect

Control 6 (43) 8 (57)

FAS 11 (79) 3 (21) Down’s syndrome 12 (86) 2 (14)

Predictor variable df F P Infrequent tone 2,39 8.001 0.001

P300 latency

P300 amplitude

latency

Infrequent tone 2.39 16.91 5 0.0005

Noise burst P300 2,39 16.908 0.0005

Wilks’ lambda 6,74 8.880 0.0005

DISCUSSION

To date, there have been no studies that determine whether neurophysiological variables might distinguish Down syndrome from FAS. Our previous study reported significant reductions in mean power of the alpha-frequen- cies (7.5-12 Hz) in both FAS and Down syndrome children, although the distribution of this abnormality was distinct in each syndrome. l8 Alpha-Reductions in Down syndrome children were seen in posterior regions, whereas this type reduction was seen in the left hemisphere of the FAS subjects. Children with Down syndrome overall had diffuse EEG slowing, whereas children with FAS showed reduced alpha-power in the absence of significant slow activity.

The present study demonstrates that auditory ERPs can also differentiate FAS children from Down syndrome children. Children with Down syndrome in the present study had longer P300 latencies in response to both infrequent tones and noise bursts for all cortical sites. Our findings are consistent with previous reports of longer P300 latencies in response to unexpected auditory stimuli among adult Down syndrome patients.’-1° FAS children also showed longer P300 latencies in response to the noise burst, but only in the parietal cortical region. This suggests that FAS children may have more localized cerebral disturbances compared to Down syndrome children.

In the present study, a regression on IQ score and P300 latency would be informative; however, IQ scores from only 4 of the 15 Down syndrome children were obtainable, while the others were below clinical testing. Although there was a significant IQ difference between controls and FAS children, no significant correlation between Full-scale IQ and P300 latency was observed. It should be noted, however, there was a trend toward an association between shorter P300 latencies and higher Verbal IQ scores [F( 1,24) = 6.76, p < 0.021. More subjects are necessary to determine

whether the associations between IQ scores and P300 latency, which have been seen in previous studies:‘ would be enough to account for the differences seen between the FAS and control groups in the present study.

The difficulty in recording ERPs from Down syndrome children explains the paucity of studies among this population. Lincoln et a1.,I2 however, were able to record auditory ERPs from 12-year-old Down syndrome children and found increases in P300 amplitudes, in addition to delayed P300 latencies. Although our data further support their findings, increased amplitudes were only significant in frontal areas in the present study. In normal controls, greater frontal P300 amplitudes in response to novel stimuli have been However, after several exposures to the novel stimuli, the cortical distribution changed so that amplitudes are largest over posterior regions. Knight” found that the frontal P300 to novel auditory stimuli did not habituate in patients with frontal lobe lesions. Thus, if larger amplitudes reflect little or no habituation, the P300 amplitude findings in the frontal cortical area of Down syndrome children of the present study suggest possible neuropathological abnormalities in the frontal cortical region.

The present study offers a description of the differences in neurophysiological abnormalities between Down syndrome and FAS, which is a new finding considering that no published reports have appeared on ERPs in FAS children. However, studies that have evaluated visual and somato- sensory-evoked potentials in human infants born to heavy drinking mothers have provided data suggesting that ethanol exposure in utero may alter evaluation of sensory stimuli in these infants.13-15 Several studies suggest that evoked potential measures may be quite sensitive to the effects of fetal alcohol exposure and that neurophysiological abnormalities are long-lasting and perhaps

Stimulus probability has been shown to alter ERP com- p o n e n t ~ . * ~ , ~ ~ Decreases in the probability of a stimulus have been found to increase P3 In the present study, the noise-burst stimuli are presented less frequently and are louder than the infreyuenfYy presented tone. For control and Down syndrome children, a significant increase in P300 amplitude in response to the noise burst was found when compared with responses to the infrequent tone. However, FAS children showed only slight increases in P300 amplitude. This differential response between the Down syndrome and FAS children may reflect different deficits in cognitive processing.

There was no significant difference between the three study groups on number of trials of infrequent tones used for the analyses, and it was this variable that distinguished the groups. However, the Down syndrome group had a significantly greater number of noise-burst trials eliminated compared to the FAS group and normal controls, but the amplitude of this variable did not reliably discriminate between the groups. This difference in number of trials eliminated for the Down syndrome children may have


caused an increase in the variance within this group, thus leading to a lack of significance in this variable.

The NlOO amplitude, like the P300, was also found to increase in response to the more novel noise burst compared to the infrequent tone. This finding was observed in the controls and FAS children, but not for the Down syndrome children. The NlOO ERP component has been previously related to attention, and altered NlOOs have been reported in children with attention d e f i ~ i t s . ~ ~ - ~ ~ At- tention-related problems are commonly seen in both Down syndrome and FAS ~ h i l d r e n . ~ ~ , ~ ~ The finding that NlOO amplitudes seen in the FAS children increased similarly to the controls was surprising, considering that attention-related problems are common in FAS. Further research is necessary to evaluate various aspects of attention deficits involved in these two syndromes and to relate them to electrophysiological findings.

Because attention deficits are common in children with cognitive disorders, methylphenidate was the most commonly used medication in subjects of the present study. Three Down syndrome children were taking methylphenidate, three FAS children were taking methylphenidate or Cylert, and four other FAS subjects were on various drugs: two on anticonvulsants, one on phenothiazines, and one on a small dose of Imipramine at bedtime. A list of medication used by the subjects can be found in Table 1, as can individual subject descriptions. Although medications can have specific effects on electroencephalic a ~ t i v i t y , ~ ~ - ~ l a previous study provides evidence that methylphenidate may not have significant effects on the P300.42 Thus, our findings of altered P300s in FAS and Down syndrome children may not be related to psychostimulant usage. Few drugs besides methylphenidate were administered to the cogni- tively disabled children. These drugs may have had an effect on ERP waves; however, it is unlikely that these drugs would have influenced the group differences since there were only a few on medication.

In summary, the “passive” ERP paradigm used in the present study may provide a useful tool for assessing cog- nitively impaired or uncooperative subjects. These studies further suggest that children with FAS have different auditory ERP morphology from Down syndrome children. P300 latencies were delayed in all cortical sites in Down syndrome children, whereas FAS children had prolonged P300 latencies only in the parietal region compared to normal controls. In addition, Down syndrome children were found to have larger P300 amplitudes than FAS or control children in frontal sites. This study demonstrated that a combination of P300 component measures may be useful in assessing and diagnosing FAS children. Therefore, passive auditory ERPs may provide an objective measure to aid in the identification of prenatally alcohol-exposed indi- viduals with profound mental handicap and/or poor speech development.

ACKNOWLEDGMENTS

We thank Dr. Sarah Mattson for aiding in the estimation of IQs, Dr. Kenneth Lyons Jones for providing patients, and Dr. James Havstad for writing the computer programs.

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Auditory Event-Related Potentials in Fetal Alcohol Syndrome and Down's Syndrome Children