Temporal Variability of Somatosensory, Visual, and Auditory Evoked Potentials in Schizophrenia Charles

Shagass, MD;

Richard A.

Roemer, MD; John J. Straumanis, MD; Marco Amadeo, MD

\s=b\ Previous findings in chronic schizophrenics showed greater than normal somatosensory evoked potential (SEP) waveshape stability before 100-ms after stimulus and reduced stability after 100 ms. To confirm and extend these findings, EPs to left and right median nerve stimuli, visual pattern flashes (VEPs), and auditory clicks (AEPs) were recorded from 14 locations in 86 patients and 33 controls. Three sets of analyses compared different patient groups with age- and sex-matched controls. The results confirmed previous SEP findings in chronic schizophrenics; no other subject group displayed the combination of high early and low late SEP stability. The SEP results did not generalize to VEPs and AEPs. Lead location was important for group differences. In overt schizophrenics, late epoch stability was low in all EPs. The results suggest certain limitations to the hypothesis of an impaired subcortical filtering mechanism in chronic schizophrenics. (Arch Gen Psychiatry 36:1341-1351, 1979)

number of investigators have compared psychiatric and control populations with respect to the variability in time of evoked potential (EP) waveshape. Evoked potential (EP) waveshape variability measures have consistently discriminated between controls and psychotic patient groups, including schizophrenics, psy¬ chotic depressives, and Korsakoff's psychotics.111 Most of the reported studies have dealt with auditory evoked potentials (AEPs) or visual evoked potentials (VEPs); variability of somatosensory evoked potentials (SEPs) appears to have been investigated only in this laborato¬ ry."12 jn generai; EP variability has been found to be greater than normal in the psychotics. Attempts to specify

A patient

Accepted

for publication Sept 5, 1978. Department of Psychiatry, Temple University, and the Eastern Pennsylvania Psychiatric Institute, Philadelphia. Read in part before the annual meeting of the Society of Biological Psychiatry, Atlanta, May 5, 1978. Reprint requests to Eastern Pennsylvania Psychiatric Institute, Henry Avenue and Abbottsford Road, Philadelphia, PA 19129 (Dr Shagass). From the

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which aspects of psychopathology correlate with increased EP variability in psychosis suggest that the symptoms of thought disorder may be the most closely related clinical manifestations313; these findings led Callaway14 to propose that cognitive variability is the relevant psychological process. Other workers have considered EP variability to reflect perceptual variability.13 The conclusion that EP variability is increased in psycho¬ sis may be valid only for the later portions of the EP. In SEP studies, we measured variability separately for epochs before and after 100 ms poststimulus. We found early variability was less in chronic schizophrenics than in nonpatients, nonpsychotic patients, or patients with acute and latent subtypes of schizophrenia.!l Within a heteroge¬

schizophrenic population, early SEP variability was relatively nondepressed patients with high ratings on overt psychotic symptoms, eg, hallucinatory activity, than in more depressed and less psychotic patients.12 On the other hand, later SEP variability was greater in the more overtly psychotic patients. This contrast between clinical correlates of early and late SEP variability provided important support for a hypothesis that proposed that the relatively stable, high-amplitude early EPs found in chronic schizophrenics reflect an impaired filtering or gating mechanism, resulting from underactivation of subcortical modulating structures.1" The finding of reduced early SEP variability in chronic schizophrenics is also of methodological importance; while increased variability neous

less in

could result from artifactual factors, such as increased muscle tension, which might be more frequent in psychosis, reduced variability cannot readily be attributed to such artifacts. A study to confirm the SEP waveshape variability findings in schizophrenia appeared to be desirable, in view of their theoretical and methodological implications. In

addition, it seemed important to determine whether the SEP results would generalize to EPs of other sensory modalities. Specifically, would the diagnostic correlates of

early- and late-epoch AEP and VEP waveshape variability measures be different as they were for SEP measures? To accomplish the purposes of confirming previous SEP find¬ ings and extending them to EPs of other sensory modali¬ ties, we recorded EPs evoked by means of several types of sensory stimuli in one experimental session. By recording from many locations, we were also able to obtain informa¬ tion about the spatial distribution of the EP measures."17 In

addition,

we

used two forms of EP

averaging, which

permitted us to compute measures of waveshape variabili¬ ty over shorter and longer time periods. We report here the results obtained by comparing waveshape variability measures obtained with this EP recording procedure in age- and sex-matched groups of

schizophrenics of several subtypes, psychotic depressives, nonpsychotic patients (neuroses, personality disorders), and nonpatient con¬

trols. We have previously presented some other aspects of the data obtained with this procedure in the same subjects. In an analysis that compared the group mean EPs, it was demonstrated that, compared to nonpatients or patients without overt psychoses, later EP events were markedly attenuated in overtly psychotic patients.18 Also, a negative peak occurring 60 ms poststimulus in the SEP was more posteriorly distributed in chronic schizophrenics than in any other group of subjects. In other reports,"19 the measures of waveshape variability were analyzed with respect to hemispheric lateralization, the main question being whether diagnostic groups differed in degree of asymmetry between the hemispheres. With the VEP measures, the main finding was that, although waveshape variability was generally greater than normal in schizo¬ phrenics, it was particularly high in VEPs of the left hemisphere." This asymmetry was taken to support the view that the left hemisphere is involved in schizophrenic dysfunction. Although the VEP stability measures of psychotic depressives were also greater in the left than in the right hemisphere, the left hemisphere values of depres¬ sives were like those of normal subjects. The principal result of the analyses dealing with hemispheric lateraliza¬ tion of AEP waveshape variability measures was that left hemisphere AEPs (early epoch) were more variable than normal in overtly psychotic schizophrenics.1" The AEP data thus augmented the VEP evidence implicating the left hemisphere in schizophrenic dysfunction. However, the SEP results did not yield lateralization results like those obtained with VEP and AEP measures.1" Although the data to be presented here were drawn from the same source that provided the previously reported findings concerning hemispheric lateralization of EP waveshape variability,'" the material differs from that described elsewhere" because a different set of questions was addressed. These questions can be stated as follows: (1) Are the previous findings concerning relatively reduced early and increased later SEP waveshape variability in chronic schizophrenia replicable? (2) Does the use of monopolar derivations, instead of the bipolar recordings used in previous work, make a difference in the SEP results? (3) If one compares two kinds of EP variability measures, one of which reflects changes in waveshape over short time intervals, and the other over longer intervals, how will they

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differ from one another? (4) Will the clinical correlates obtained with SEP variability measures be paralleled in VEP and AEP measures? In particular, will early VEP and AEP variability be relatively low and later variability be

relatively high in chronic schizophrenia? (5) How does recording electrode location influence discriminations between clinical groups by EP variability measures? (6) To what extent is EP variability a generalized individual characteristic and to what extent is it specific to a sensory modality? SUBJECTS AND METHODS

Subjects Data from a total of 86 psychiatric inpatients and 33 nonpatient volunteers were used in the analyses reported here. All subjects consented to be studied after the nature of the procedures had been fully explained; nonpatients were paid. The subjects used for data analysis were selected from a larger tested population of patients and nonpatients to form appropriate comparison groups, matched for sex and age, within four years. Three comparison groups were formed: (1) chronic schizophrenics (chronic paranoid, chronic undifferentiated, and simple) vs nonpsychotics (neuroses and personality disorders) vs controls (N 25 each); (2) latent schizophrenics vs "other" schizophrenics (catatonic, schizo-alfective, and acute) vs controls (N 12 each); (3) psychotic depressives 12 each). Differences in age and sex composition vs controls (N resulted in insufficient numbers to permit direct comparisons between all patient groups. Several nonpatients were included in more than one of the comparison groups. Diagnostic classification of patients was based on final hospital diagnosis, made independently by at least two senior psychia¬ trists. In addition, the extent to which the relevant Research Diagnostic Criteria (RDC) of Feighner et al2" were met was evaluated. Table 1 gives descriptive data about the patient groups, including diagnostic subtype, sex, age, number definitely or probably conforming to RDC, and duration of illness. No patients were receiving medication at time of testing; Table 1 also shows the median number of days elapsed since psychoactive drugs were last given. Of the 12 psychotic depressives, ten met RDC for primary, and two for secondary, depression. Of the 37 patients with overt schizophrenic syndromes (other than latent), 25 met definite and five met probable RDC criteria for schizophrenia; it should be noted that three of the remaining seven patients had schizophrenia of the acute type. The latent schizophrenic patients were mainly of pseudoneurotic type; 11 had symptoms of two or more neuroses, six had experienced a transitory overt psychotic episode, and eight had major problems with sexual identity or =

=

=

adjustment.

Procedures

recording, and for administering chlorided silver disks affixed with collodion. The selection of lead placements was determined by the need to include, in a single array, optimal sites for recording EPs in several modalities. The recording leads were, with exceptions, placed according to the 10-20 International System (Fig 1). The standard leads included T3, T4, T5, T6, 02, 01, Oz, Cz, Al and A2. The leads designated F3X, F4X, C3X, C4X were placed 2 cm posterior and 1 cm lateral to the standard F3, F4, C3, and C4 positions to replicate placements previously used for somatosenso¬ ry EP recording." The leads designated 03 and 04 were placed halfway between 01 and T5 and 02 and T6, respectively. The lead designated E was placed in the middle of the forehead to monitor the electro-oculogram (EOG). All scalp leads were referenced to the ear leads (Al and A2) linked through a 22-kohm resistor. Stimulating leads were placed 3 cm apart over the right and left Electrodes.-Electrodes for

somatosensory stimuli,

were

Table

1.—Description

of Patient

Days Drug-Free Testing1'

Age, yr Psychotic depression Nonpsychotics Neurotic depression Other

Total No. 12

No. M

neuroses

Personality disorders

14

14

Total Chronic schizophrenias Chronic undifferentiated

25

19

Chronic

Range

Median 38

Range

21-42 28-41 17-33 21-42

32

4-N

33 24 29

5-N 4-N

31

Median

7-21

Total

25

schizophrenia "Other" schizophrenias

no

Median 9.5

by RDCf 12

2-16 2-17 2-19

11 22

7-60

3-13

12

3-30

1-15

10

1-22

22

15 20

10

19-44

10

3-60

12

17-39

25

6-N

27 24 21

12

21-35 20-37 19-23 19-37

7-9 6-50 7-10 -6-50

Catatonic Schizo-affective

Acute Total

19

No. Definite or Probable

0.5-19

29

Latent

Range 0.2-33

14

19-44

paranoid

Duration of Illness, yr

Before

16-61

Simple

"N indicates

Groups

24

drug history.

2-27 3-8 1-20 0.2-0.3 2-20

10

0.2

tRDC indicates Research Diagnostic Criteria.

median

nerves at the wrist, with the cathode closer to the body. Stimuli.—Somatosensory stimuli consisted of 0.1-ms electrical pulses, generated by a constant current source, delivered to the right or left median nerves. Because one stimulator served for both wrists, the intensity used was 10 mamp above the mean of the two thresholds, if the thresholds were within 1 mamp. If threshold difference was greater than 1 mamp, the stimulating leads were replaced until this 1-mamp difference criterion was met. Visual stimuli consisted of the 8-ms presentation of a checker¬ board pattern on a television monitor screen, 120 cm from the subject's eyes. The checkerboard pattern was composed of two 19 x 19-cm squares separated by an 0.7-cm vertical dark strip, the center of which contained a fixation point. Each square contained 128 black and 128 white checks; one check subtended a visual angle of 33'. The mean intensity of the checkerboard was 1.2 foot-

lambert. 0.1-ms clicks, presented to both ears To minimize the effects of ambient room noise, a constant level of white noise at 75 dB was introduced into the earphones; the click level was 125 dB, ie, 50 dB above the white noise level. The subject sat in a comfortable chair in a dark room with earphones in place, and was asked to look continually at the constantly illuminated fixation point on the television screen.

Auditory stimuli through earphones.

were

Recording.—Eight polygraph amplifiers (upper frequency cutoff, constant) were used. Stimulus timing was performed by a minicomputer (PDP12). The order of stimuli was pseudorandomized, the constraints being that no two identical 3 kHz and 0.45 time

stimuli should be delivered in succession, and that an equal number of each kind should be delivered within any block of 192 stimuli. The interval between successive stimuli was randomized between 1.5 and 2.0 s, with a mean of 1.75 s. Evoked potential averaging was performed on line by the computer (512-ms analysis time, 1-ms sampling interval). The stimulus was delayed by 10% of the trace, and a 10-juV calibration signal was entered in series with the recording electrodes in the middle portion of this 10%.21 Because only eight amplifying channels were available, two lead montages were employed, each consisting of seven scalp leads and the EOG lead; leads in homologous locations on the two sides of the

head

were recorded together in one montage. Stimulation was accomplished in four runs, with rest periods of two to four minutes intervening.

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O

100

200

300

400

ms

Fig 1 .—Group sum somatosensory evoked potentials for 16 normal subjects (right median nerve stimuli). Linked ear reference, scalp posltivlty up. Note contralateral early response in lead C3X. El and Ell designate recordings from E lead in two separate runs.

needed to assess the extent to which stability findings were independent of amplitude. The EP amplitude measures were obtained by the method of average deviation,2-' which reflects the area under the curve for the relevant epochs. Covariance Adjustment Procedures.—To evaluate waveshape stability, independent of EP amplitude and of EOG contamina¬

LOW

tion, mean Zr values were adjusted for their covariance with mean amplitude of the EPs contributing to the Zr in the relevant epochs and also with mean EOG amplitude. We used analysis of multiple covariance, with a pooled within-group multiple regression derived from Winer.-'3 Adjusted mean Zr values were obtained for each epoch, lead, and subject. These covariance-adjusted Zr values, which will be designated Zr', were then subjected to multivariate profile analysis.24 RESULTS

Bipolar SEP Data 151-450

.20

Fig 2.—Examples of high and low stability of visual evoked potential (VEP) waveshapes at lead 03; four VEPs from each of two subjects. Two time periods used to calculate early (51 to 150 ms) and late (151 to 450 ms) stability indices are indicated by vertical lines on each record.

Treatment of Data Serial and Intermittent Averaging.—Averaging was carried out in two ways; the EPs so generated will be designated here as serial and intermittent. Four serial EPs were obtained by averaging four consecutive sets of 48 sequential stimuli, ie, stimuli 1 to 48 yielded the first serial EP; stimuli 49 to 96, the second serial EP, etc. Intermittent averaging was designed to minimize the longterm, or "drift," effects, that may contribute to variability in

serial averages, by summing interlaced responses over the entire recording session. Four intermittent averages were obtained as follows: the first intermittent EP resulted from stimuli 1, 5, 9, 13, etc, to 189; the second from stimuli 2, 6,10,14, etc, to 190; the third from stimuli 3, 7,11, etc, to 191; and the fourth from stimuli 4, 8,12, etc, to 192. For each type, this provided four EPs obtained at about the same time over the entire recording session.

Computation of Waveform Stability.—Waveform stability was assessed by computing the product-moment correlation coefficient between corresponding data points in the respective averages. Because such correlations are inversely related to variability, and are directly related to stability, we shall use the term "stability" henceforth. All coefficients were converted to Zr by Fisher's r to transform before further computation. The four serial and the four intermittent averages each yielded six Zr values for each lead; the mean of these six was taken as the stability index. For both types of averages, separate Zrs were calculated for two poststimulus epochs: 15 to 100 and 101 to 450 ms for SEP and AEP; and 51 to 150 and 151 to 450 ms for VEP (because of the later onset of this potential). The VEPs and corresponding Zr values are shown in Fig 2 for two subjects selected to demonstrate high and low stability.

Derivation of Bipolar EPs.—To confirm previous SEP findings," it necessary to derive bipolar EPs from the monopolar F3X and C3X recordings with right median nerve stimuli. This was done by subtracting the F3X from the C3X tracing after they had been equated for amplification with reference to the calibration signal. The C4X-F4X bipolare with left median nerve stimuli were also obtained. Only serial bipolar averages were derived. Amplitude Measurements.-Since the stability index tends to be correlated with EP amplitude," amplitude measurements were was

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The reason for deriving the bipolar SEPs was to deter¬ mine whether present data would replicate previous results in chronic schizophrenics. Those results were based on SEPs from C3X-F3X to right nerve stimuli.0 Table 2 summarizes the findings obtained by comparing the contralateral bipolar SEPs of chronic schizophrenics, nonpsychotics, and nonpatient controls with respect to adjusted Zr (Zr') and amplitude measures. Trends were similar for right and left nerve stimuli. For the early epoch, mean Zr' and mean amplitude values were higher in both patient groups than in controls, but statistically significant differences across groups were obtained only with the C3X-F3X amplitude measure. For the late epoch, the mean Zr' and amplitude values were both lower in the chronic schizophrenics than in the nonpsychotics or controls, but only the Zr' differences across groups achieved the .05 confidence level. In a separate analysis, the data for only the chronic schizophrenics and controls were compared. The results are displayed in Fig 3. The values are for a one-tailed test because definite predictions were being tested. With right nerve SEPs, the early-epoch Zr' and amplitude values were higher in the patients. The late Zr' values were also as predicted, being lower in the patients, but the late-epoch amplitude difference was not significant. The trends with left nerve SEPs were similar to those for right nerve, but only the late-epoch Zr' values were significantly different. It seems reasonable, however, to view the core result, for which confirmation was being sought, as the contrast between early and late Zr' and amplitude findings in patients and controls. From this point of view, the impor¬ tant prediction to be verified was that there would be interactions between early- and late-epoch values, ie, high¬ er than normal values in chronic schizophrenics in the early epoch and lower ones in the late epoch. As Fig 3 shows, all four interactions were significant in the predicted direc¬ tion. Figure 4 shows the Zr' results for the individual leads contributing to the bipolar recordings (P values here reflect a two-tailed test). It is evident that both leads involved in the bipolar contributed to group differences, the central lead to a greater extent than the frontal. Also, comparing the Zr' values for the 101 to 450-ms epoch in Fig 3 and 4, the bipolar values were much lower than the monopolar. This can be attributed in part to the reduction

Table 2.—Mean

Stability

Amplitude Values From Bipolar Somatosensory Evoked Potentials 25 Each) Nonpsychotics, and Nonpatients (N

and

in Chronic

Schizophrenics,

=

Right Median Nerve (C3X-F3X)

Left Median Nerve

(C4X-F4X) fV

15-100

ms

101-450

1.16

schizophrenics Nonpsychotics

1.17

0.28 0.40

Controls

1.03

0.40

Chronic

.174

"By analysis

15-100 ms 3.29 3.44 2.54 .033

ms

.031

,.V

Zr' 101-450 ms 1.99 2.60 2.29 .078

15-100 ms 1.06 1.05 0.96 .305

15-100 ms 3.18 3.21 2.64 .292

101-450 ms 0.25 0.41 0.38 .005

101-450 1.92

ms

2.49 2.16 .120

of variance.

STABILITY

AMPLITUDE

RIGHT .

LEFT .

RIGHT N.

LEFT N.

C3X-F3X

C4X-F4X

C3X-F3X

C4X-F4X

>

a.

UJ

1.0

O-O -

I

Q en

CHRONIC SCHIZ CONTROLS

(N=25EACH)

4.0

-
< UJ

|UJ

3.0 x-—

2.0

.01

.001

.08

INTERACTION

.01

101-450

.19

.008

J_

15-100

.05

.001

101-450

15-100

.17

.09

INTERACTION

LU

>

Temporal variability of somatosensory, visual, and auditory evoked potentials in schizophrenia.

Temporal Variability of Somatosensory, Visual, and Auditory Evoked Potentials in Schizophrenia Charles Shagass, MD; Richard A. Roemer, MD; John J...
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