P300 topographic asymmetries are present in unmedicated schizophrenics
Steven F. Faux a , , Robert W. McCarley a Paul G. Nestor a Martha E. Shenton a, Seth D. Pollak a Virginia Penhune a Erik Mondrow a Brian Marcy a
A n n Peterson b, Thomas Horvath b and Kenneth L. Davis b a Department o f Psychiatry, Harvard Medical School, Brockton VA Medical Center and Massachusetts Mental Health Center,
Brockton, MA (USA), and ~ Department of Psychiatry, Bronx VA Medical Center and Mount Sinai School of Medicine, Bronx, N Y (USA)
(Accepted for publication: 24 August 1992)
Summary Our laboratory has repeatedly found a left < right auditory P300 temporal lobe topographic asymmetry in right-handed, medicated schizophrenics. To determine whether this asymmetry was attributable to the effects of antipsychotic medications, we collected auditory "odd-ball" P300 event-related potentials from 14 right-handed, unmedicated schizophrenics (withdrawn from medication for an average of 21 days) and 14 right-handed, normal controls. Analysis of normalized P300 amplitudes showed a statistically significant difference in the voltage distributions between groups (a group by temporal electrode site interaction) that was consistent with a left < right temporal voltage asymmetry in schizophrenics but not in the normal controls. We conclude that P300 topographic asymmetries are present in unmedicated schizophrenics. These data are compatible with the growing body of data suggesting left temporal lobe structural abnormalities in schizophrenia.
Three previous studies from this laboratory of the topography of the auditory P300 event-related poten- tial (ERP) have found a left- greater than right-sided attenuation in right-handed schizophrenics compared with normal controls. Moreover, statistical discrimina- tion between groups was consistently greatest in the left temporal scalp region (Morstyn et al. 1983; Faux et al. 1988, 1990; for review, see McCarley et al. 1991a). All of these studies used patients being treated with neuroleptic medication. The present study addresses the question of whether P300 amplitude asymmetries are attributable to the disease state or to the effects of medication.
Neuroleptics may have important effects on various electrophysiological measures, including both spectral analyses of the E E G (e.g., Karson et al. 1987, 1988) and the amplitude, latency, and variability of ERP components (e.g., Shagass 1977; Shagass et al. 1982; Kahn et al. 1988; Roemer et al. 1990). Previous P300
Correspondence to: Dr. Robert W. McCarley, Dept. of Psychiatry l16A, 940 Belmont St., Brockton, MA 02401 (USA). Tel.: (508) 583-4500, x367; Fax: (508) 580-0059.
* Present address: Department of Psychology, Drake University, Des Moines, IA 50311, USA.
studies of unmedicated schizophrenics using central electrode measurements have found profound ampli- tude decrements compared to normal controls, even in patients without medication for extended periods (e.g., Blackwood et al. 1987; Brecher et al. 1987). However, since these studies did not employ lateral electrodes the important question of whether the lateral P300 amplitude asymmetry observed by us was a product of medication is unresolved.
The question of medication effects on P300 ampli- tude asymmetries in lateral electrodes has been even more forcefully raised by a recent study by Pfeffer- baum et al. (1990). In an auditory reaction time paradigm they found that P300 in unmedicated pa- tients produced a midline parietal (Pz) amplitude maxi- mum, but produced a midline central (Cz) maximum in medicated patients, suggesting that medication might have influenced scalp voltage distributions in their particular experimental paradigm. However, Pfeffer- baum et al. failed to find lateralized alterations of P300 in group means of 18 off-medication and 10 medicated schizophrenics. Important methodological and sample differences between the Pfefferbaum et al. study and those used by our laboratory unfortunately leave open the question as to whether the previous P300 asymme- try findings from this laboratory could have been the
result of medication. These differences have been de- scribed in some detail elsewhere (McCarley et al. 1991b). 1 Also a recent study (Radwan et al. 1991), although not using an auditory oddball paradigm and not recording at lateral electrodes, did not find an asymmetry in P3-P4 P300 latency wave forms in non- medicated schizophrenics, further raising the issue of medication effects.
Other studies have suggested that attention to infor- mation about asymmetries in lateral electrodes may prove to be important for evoked potential correlates of lateralized temporal lobe structural abnormalities in schizophrenia (Daruna et al. 1989; McCarley et al. 1989). Our earlier CT study (McCarley et al. 1989) provided evidence of a 3-way association of temporal lobe size reduction in schizophrenics with left temporal scalp region P300 abnormality and positive symptoms. In this study the left lateral temporal region electrodes showed the highest correlations with left sylvian fissure enlargement. This enlargement might have, in turn, reflected the specific left-lateralized temporal lobe vol- ume reductions demonstrated by M R I studies; these include superior temporal gyrus (Barta et al. 1990) and medial limbic structures (Suddath et al. 1990). Prelimi- nary data have suggested lateral electrodes may be most sensitive to abnormalities in medial temporal lobe P300 generators (McCarthy et al. 1987) and the later- ally located superior temporal gyrus has also been implicated in P300 generation (Knight et al. 1989). Also, our own recent data show a strong correlation in medicated schizophrenics between quantitative volu- metric magnetic resonance imaging measurements of left superior temporal gyrus volume and P300 ampli- tude at T3 (McCarley et al. 1992). These data further underline the importance of P300 measurements and controlling for medication factors.
In this study we employ the measurement and
i Briefly, the methodological differences included: (1) a reaction time paradigm versus our silent count paradigm; (2) their use of fewer rare tones for averaging; (3) different physical characteristics of stimuli, including loudness and the lack of a white noise back- ground; (4) our computation of grand mean values by integration rather than "peak picking"; and (5) our taking into account differing variances of individual electrode sites (MANOVA) versus using the assumption of homogeneity (repeated-measures ANOVA) in compu- tation of statistical significance. Additionally, recent data from our laboratory (Holinger et al. (1992) indicate that left-handed schizophrenics have a reversed P300 asymmetry (i.e., right < left T3 amplitude) compared to right-handed schizophrenics. Since Pfeffer- baum et al. (1989) combined left- and right-handed schizophrenic subjects for their grand means (J. Ford, personal communication), it is possible that their grand means may not reflect existing asymme- tries within individuals. Finally, it has been suggested by Pfefferbaum et al. (1989) that our use of a linked-ears reference electrode might induce topographic asymmetries. Our recent systematic study (Faux et al. 1990) has ruled out use of linked-ear electrodes as a cause of the P300 left temporal asymmetry.
recording technology previously used by Us to compare off-medication right-handed schizophrenic subjects with age-matched, right-handed normal controls on an auditory oddball P300 task. We confirm: (1) a left < right lateral scalp electrode topographic asymmetry in schizophrenics, (2) maximal statistical differentiation of schizophrenics versus normal controls at a left lat- eral temporal scalp region electrode, and (3) the cor- rect identification of a high percentage of normals (93%) and schizophrenics (79%) by a previously de- fined 2/~V threshold criterion at T3.
Methods and procedures
Subjects This study utilized 14 neuroleptic-withdrawn male
subjects with schizophrenia and 14 healthy male con- trols. Twelve schizophrenic subjects were drawn from an on-going off-medication study at the Clinical Re- search Center of the Bronx (NY) Veterans Administra- tion Medical Center. All subjects from the Bronx site were interviewed with the SADS (Spitzer and Endicott 1978). Patients were interviewed by two raters, both present during the same interview and who indepen- dently assigned DSM-I I I -R (American Psychiatric Ass. 1987) and R D C (Spitzer et al. 1978) diagnoses. The ratings and diagnoses were presented at a consensus meeting with a supervising diagnostician who obtained a consensus on the final diagnosis. The inter-rater reliability (kappa) for the initial independent diagnoses was 0.86. Two additional subjects were drawn from the outpatient population of the Brockton (MA) Veterans Administration Medical Center. These subjects also met DSM-I I I -R and RDC criteria for schizophrenia as determined by SADS administration by a trained inter- viewer and by chart reviews and video-taped inter- views. All diagnostic information for the Bronx site patients was independently reviewed by the Brockton diagnostic team and in all cases there was agreement on a diagnosis of schizophrenia.
The following additional criteria for subject selec- tion- were used: age range of 20-55; right-handed; no history of ECT, neurological illness, drug abuse, or alcohol abuse (DSM-II I -R criteria); and no medica- tions which would grossly affect the E E G (e.g., reser- pine or barbiturates). Subjects with hearing impair- ments or projected verbal IQs (based on the WAIS information sub-scale) below 85 were not selected. Patient subjects were paid with VA Canteen coupons ($10.00 equivalence) for their participation. Five re- cruited schizophrenic subjects were excluded from the present analysis: two because of marked hearing loss, two for whom diagnostic consensus was not achieved by the Bronx raters, and one due to inability to com- plete the task.
All schizophrenic patients were drug-free for a mini- mum of 14 days; one subject was neuroleptic-naive. The range of days off-medication for non-naive pa- tients was 14-71 days (mean = 21.2). We note that a minimum of 14 days off medication is the conventional standard for off-medication studies. Further, although relapse studies indicate that therapeutic effects of neu- roleptics persist up to 6 months after withdrawal (Hogarty and Ulrich: 1977), measures of D2 receptor binding may return to near normal after 2 weeks with- drawal (Sedvall et al. 1986).
Normal control subjects were drawn from hospital staff and the community; they met the same exclusion criteria as the patient group, and had no personal or family history of psychiatric illness. Control subjects were paid $10.00/h for their participation. Nine con- trol volunteers are excluded from the present analysis: screening interviews raised a question of personal or family history of mental illness in 3 subjects; 3 subjects showed excessive E M G or E O G artifact; one subject's data were unusable due to equipment malfunction; and two recruited subjects were dropped in the process of age matching, leaving a total of 14 normal controls. All subjects were given detailed information concerning the study protocol and all gave informed consent.
The normal and schizophrenic groups did not differ statistically on age, WAIS-R Information sub-scale, or the Mini-Mental-State exam scores (Folstein et al. 1975). The mean age (S.D.) of the schizophrenic group was 39.5 (6.25) years and that of the normal group was 40.5 (8.27) years. The mean score of the schizophrenic subjects on the WAIS-R Information sub-scale was 12.29 (4.83) and the normal group 10.64 (3.15). The mean score of the schizophrenic subjects on the Mini- Mental-State exam was 26.93 (3.17) and the control group was 28.64 (1.15). The groups did differ, however, on mean years of education (t (26) = 2.90, P < 0.008). The schizophrenic group completed an average of 12.5 (1.74) years of schooling and the control group 14.71 (2.37).
Recording procedures Event-related potentials (ERPs) were recorded us-
ing the linked-ear reference in an auditory "odd-ball" paradigm. ERPs were elicited by tone pips of 40 msec duration (10 msec r ise / fa l l times) using fixed 1.2 sec interstimulus intervals and presented by Etymotic in- sert headphones. The infrequent (15%) high-pitch tones (1500 Hz, 97 dB SPL) were presented pseudorandomly, interspersed between frequent low-pitched tones (1000 Hz, 97 dB SPL). There was a continuous background of 70 dB binaural white noise.
ERPs were recorded during two experimental con- ditions; in each condition 600 tones were presented, yielding between 70 and 100 infrequent tones:
(1) "Inattentit,e" condition. The subject performed a distractor task (reading a novel) and was told he might hear some sounds but was not given instructions for processing the sounds. Subjects were told they would be asked questions about the content of the reading and upon completion of the inattentive condition were able to describe the content of what they had read, confirming their attention to the distractor task. Al- though we do not report results in the "inattentive" condition, we performed statistical analyses of the ERP data to insure that this condition did not interact with groups or the "attentive" condition (discussed next).
(2) "Attenti~e" condition. Subjects were asked to stare at a central fixation point and to indicate the presence of infrequent high-pitched tones by a button press. (Prior to testing, subjects received 5 min of practice.) The hand used for the button press was partially counterbalanced among subjects; 10 subjects in each group used the right hand and 4 subjects in each group used the left. Analyses showed no group differences on any of the study parameters between the 4 subjects with left-hand button press and the subjects with right-hand button press; moreover, schizophrenics using the left-hand press showed scalp voltage trends similar to those present in schizophrenics using the right-hand press. An investigator monitored the sub- jects for compliance with the oddball detection task and coached subjects to minimize muscle movement. Schizophrenic subjects were able to perform the detec- tion task with a median accuracy of 0.99; no subject scored lower than 0.92. 2 Normal controls performed the task with a median accuracy of 1.00; no subject scored lower than 0.99.
Subjects were first tested on the inattentive, fol- lowed by the attentive condition. ERPs were recorded from 28 tin plate scalp electrodes using an Electro-Cap International, Inc. electrode cap. Scalp electrode placements included all electrodes in the international 10-20 system with 8 additional interpolated electrodes. The Fpl , Fp2 and Cz sites were located by precise international 10-20 measurements, and all other elec- trodes were positioned automatically at standard rela- tive distances. The cap contained the following interpo- lated electrodes: FTC1/2 , TCP1/2 , CP1/2 , PO1/2 . FTC1 was placed at the intersection between F3-T3 and C3-F7; TCP1 was placed between C3-T5 and P3- T3; CP1 and PO1 were placed at the midpoints of the diagonals formed by Cz-P3 and Pz-O1, respectively. Electrodes were placed at homologous sites on the contralateral side. Vertical E O G was recorded using right eye supra- and infra-orbital electrodes. Horizon-
2 Accuracy was defined by the formula: c = (1.0 - [ I P - a f/a]), where c equals the proportion correct (overall accuracy), p equals the subject's count, and a equals the actual count.
tal E O G was recorded from electrodes at the right and left external canthi. Electrode impedance was main- tained at less than 4 kO. The E E G was filtered using a bandpass of 0.15-40 Hz (NeuroScience, Inc. E E G aria- plifiers: 36 dB/oc tave rolloff for low-pass and 6 dB/oc tave for high-pass). Single trial epochs were digi- tized and stored on a hard disk, with archival storage on tape. ERP averages for each channel were con- structed from 256 msec samples over a 700 msec time interval. Sampling began 100 msec prior to stimulus presentation, and the average of this prestimulus inter- val established the baseline. Single trial epochs from any channel which had voltages in excess of ___ 50 /xV were excluded. Also, single trial epochs with vertical E O G contamination were corrected using regression- based and subject-unique weighting coefficients based on the Semlitsch et al. (1986) procedure. These strict artifact removal procedures resulted in 54 mean ac- cepted trials for schizophrenics and 59 mean accepted trials for normal controls. No subject had less than 40 accepted trials.
In order to minimize the possible effects of "t ime- locked" alpha activity all subjects were tested with their eyes open. Bursts of alpha activity, nevertheless, were occasionally present but were often eliminated using the voltage-based artifact criteria. Routine FFT analyses of the raw E E G revealed no statistically signif- icant le f t / r ight asymmetries in the alpha band, either within subjects or between groups. Therefore, group comparisons of P300 amplitude are not likely to be have been confounded by " t ime-locked" alpha.
The P300 peak component latency was defined as the data point at the Cz electrode (in the "at tent ive" condition) with the largest positive voltage between 270 and 600 msec. There were no statistical differences between latencies established with this procedure and those using an adaptation of the Woody filtering tech- nique, as used by us previously (Faux et al. 1990). For statistical comparisons, P300 mean amplitude was measured as the mean voltage between 300 and 400 msec in the attentive condition. This time window captures the rising phase and peak of the P300 compo- nent in most normal subjects, and was the same as used in previous studies (Morstyn et al. 1983; Faux et al. 1990) In addition to the 300-400 msec measure- ment, we also computed the mean voltage after adjust- ing for latency delays in schizophrenics so as to capture the same portions of the wave form being analyzed in normals, a measure we term the "latency adjusted" P300 mean amplitude.
The first step in analysis was to examine the voltage topography using color-coded maps (Duffy et al. 1981; Duffy 1982) of the voltages at the 28 scalp electrodes. We then examined group mean differences as a func- tion of the variance at each site using a t statistic significance probability map (t-SPM) to determine the
area of maximal t statistic separation between schizophrenics and normal controls (Duffy et al. 1981). SPM analysis was used to insure that the planned subsets of electrodes for hypothesis-testing were suffi- cient to describe group differences measured at all 28 electrodes.
The topographic pattern of left temporal P300 deficits in previous studies was the basis for selecting, prior to data collection, a subset of electrodes for MANOVA. Specifically, in the attentive condition we examined the mean P300 integrated voltages following the target tones at electrodes T3, Tcpl , Cz, Tcp2, and T4. 3 The set of analyses used paralleled our previous studies. The M A N O V A focused on "be tween" group differences, where Hotelling's T e test provided infor- mation on 3 kinds of differences: (1) overall group amplitude differences; (2) group amplitude differences at each scalp electrode site ("pro tec ted" t contrasts); and (3) group topographic differences based on a test of a group-by-electrode site interaction (profile analysis of parallelism; see Faux and McCarley 1990 for compu- tational details). Profile analysis of parallelism is the multivariate equivalent of an A N O V A test of the inter- action between group and electrode site. It essentially tests for parallelism of the lines connecting the elec- trode site voltage values and thus is useful for deter- mining differences in scalp voltage topography between groups. We also used McCarthy and Wood's (1985) algorithm for normalizing the data to eliminate ampli- tude differences which might be misinterpreted by M A N O V A as an interaction (see formula in Fig. 3 caption).
In a previous study (Faux et al. 1990) a P300 voltage criterion of 2 ~V at the T3 electrode correctly catego- rized 18/20 normals and 18/20 schizophrenics. The same 2 tzV criterion level at T3 was used to determine the degree of differentiation of unmedicated schizo- phrenic and control subjects.
Results
(1) P300 grand-averaged wave forms and latency mea- surements
Grand-averaged wave forms for schizophrenics and normal controls are displayed for frontal (Fpl , Fp2, F7, F8), lateral (T3, T4, Tcpl , Tcp2), and midline (Cz) electrode s i tes ' in Fig. 1. Examination of the wave forms from normal controls shows that P300 compo-
3 An important methodological point is that, in the present study as in the Faux et al. (1990) study, our analyses focus on the P300 component derived from the rare stimulus in the attentive condition, e.g., the wave form associated with the target stimulus; we will refer to this simply as the "P300." This is the same wave form used by Pfefferbaum et al. (1989) and is in contrast to the "P300g," a subtraction wave form previously used by us (Faux et al. 1988).
ERP T O P O G R A P H Y IN S C H I Z O P H R E N I A 37
nent amplitude (300--400 msec) was largest at the mid- line, with symmetrically reduced amplitudes at lateral sites. Compared to normal controls, schizophrenics showed P300 component amplitude reductions at all sites, with greater right- than left-sided P300 compo- nent amplitudes. This pattern was visible in both peak values and integrated values.
Scoring of P300 peak component latency for each subject's P300 wave form revealed statistical differ- ences between the normal control and schizophrenic groups at the Cz electrode site. Latency was 382.7 msec (S.D. = 28.9) for controls and was 435.6 msec (S.D. = 78.7) for schizophrenics (t = 2.36, df = 26, P < 0.05).
To insure that this 53 msec latency delay in schizophrenics did not bias subsequent amplitude anal- yses, we analyzed schizophrenic P300 amplitudes using 2 different time windows: (1) our previously used time window of 300-400 msec, and (2) a shifted time win- dow of 353-453 msec (in order to capture, on average, the same wave form component in both groups). This
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Fig. 2. Mean integrated P300 ampli tude compared by groups, scalp recording region, and time window of integration. Note that normal control ampli tudes were symmetrical about the midline (Cz), but that schizophrenics showed a L < R ampli tude profile in both time win- dows (300-400 msec and 353-454 msec, "latency adjusted" time window). Statistical analysis of between group amplitude differences by electrode site was performed by "protected t contrasts." In the compar isons of the normal controls versus latency-adjusted schizophrenics (triangles, 353-453 msec integration window), the t values were 4.30", 4.45", 3.21, 3.83, 3.30 respectively, where * indicates P < 0.05. In the comparisons of the normal controls versus the non-latency-adjusted schizophrenics (circles, 300-400 msec inte- gration window), the values were: T 3 = 5.15 +, Tcpl = 5.68 +, C z = 3.47, Tcp2 = 4.76 +, T4 = 3.79, where + indicates P < 0.05. Error bars are +s t anda rd errors of the mean (S.E.M.). We note that, al though the differences between means of normals and schizophren- ics were greatest at central electrodes, t values were highest at T3 and Tcpl because of lower variances at these sites (pooled variance (300-400 msec): T 3 = 2 . 7 3 ; Tcpl = 7.05; Cz=17 .35 ; Top2=4 .31 ; T 4 = 2.87; pooled variance (with latency adjustment): T 3 = 2.84; Tcpl = 6.97; Cz = 14.18; Tcp2 = 4.03; T4 = 2.81), a finding confirm- ing our previous reports on medicated patients (Faux et al. 1988,
1990).
shifted time window will be henceforth referred to as the "latency adjusted" time window.
(2) P300 topographic distribution and t-SPM analyses We next computed t-SPMs to compare schizophrenic
vs. control group difference topography for all scalp electrode sites. Comparing integrated amplitudes be- tween 300 and 400 msec for both groups, the largest t values were in the left temporal region (in descending order of t values [values listed in brackets]: Tcpl [5.68], P3 [5.47], T3 [5.19], FTC1 [5.00]). Comparison of latency adjusted amplitudes in schizophrenics with nor- mal control amplitudes (300-400 msec) showed slightly reduced statistical discrimination between groups, but did not significantly alter the topographic pattern; t values in descending order were: Tcpl [4.45], Ftcl [4.36], T3 [4.30], P3 [4.17]. In both time windows, left- temporal electrodes showed larger t values than did midline or right-sided electrodes. Thus the exploratory t statistic analyses were, as predicted and as in previ- ous studies, consistent with left vs. right differences in voltages between groups, and did not show any fea- tures different from previous studies. We were thus able to reduce the number of variables without exclud- ing possible areas of difference between schizophrenic vs normals. Our planned multivariate statistical com- parisons used the band of electrodes beginning at T3 and progressing contralaterally to include Tcpl, Cz, Tcp2 and T4. Although our previous studies have in- cluded C3 and C4 in statistical analyses, we used Tcpl and its homologue, Tcp2 in this study, since Tcpl showed the largest statistical between-group discrimi- nation of any electrode site. Actually the first study from our laboratory to use interpolated Tcpl electrode also showed maximal separation at this site in the nose reference condition (Faux et al. 1990). We think it important in our continuing studies of the topography of P300 alterations in schizophrenia to use the tempo- ral region electrode with the strongest statistical ef- fects.
(3) P300 multivariate between-group analyses using Hotelling's T 2 test
The MANOVA consisted of a "between-groups" analysis to test for (1) group amplitude differences over all electrode sites (using non-normalized, raw data); (2) amplitude differences specific to electrode sites (pro- tected contrasts); and (3) topographic difference or group by electrode interaction using the profile analy- sis of parallelism with normalized data.
(i) Overall group differences. Fig. 2 plots the mean amplitude values (by group, electrode site, and time window of analysis) which were used in the "between- groups" MANOVA analyses. Overall P300 amplitude differences comparing schizophrenics (300-400 msec) and normal controls (300-400 msec) were statistically significant (Hotelling's T 2 equivalent F(5, 22)= 7.34,
P < 0.05). Comparison of latency adjusted values (353- 453 msec) in schizophrenics versus normal controls (300-400 msec) does not alter statistical significance (F(5, 22)= 5.37, P < 0.05). Normal controls showed a relatively symmetrical voltage distribution, with a slight L > R predominance, while, as shown in Fig. 2, schizophrenics showed a distinct L < R pattern in both time windows of analysis. The group voltage distribu- tions in Fig. 2 suggest the presence of a group-by-scalp electrode site interaction. Profile analyses of data in both comparisons (normal controls versus schizophren- ics (300-400 msec) and normal controls versus schizophrenics (353-453 msec)) are statistically signifi- cant, but these analyses must be confirmed by normal- ized amplitude data, as is done in section iii below, before statistically rigorous conclusions can be made.
(ii) Group amplitude differences at each scalp elec- trode site ("protected"t contrasts). Protected t con- trasts comparing individual scalp regions under both time windows of analysis were maximal at Tcpl (t values are listed in the caption of Fig. 2), a finding consistent with the t-SPM topography. As indicated in Fig. 2, protected t tests were large and statistically significant for left temporal electrode sites (T3 and Tcpl). As might be expected, t contrasts were uni- formly reduced when latency adjusted values, rather than standard values (300-400 msec), were used in the analysis of the schizophrenic group. Latency adjust- ment, relative to the standard time window, appeared to capture more of the P300 component in schizo- phrenics, thus increasing overall amplitude values. However, the topographic pattern of normal vs. schizophrenic group difference, as measured by pro- tected t values, remained the same for both time windows, with left-sided electrodes producing the largest statistical discrimination between groups (see Fig. 2).
(iii) Test of topographic interaction using normaliza- tion. Fig. 3 illustrates normalized group values. It can be seen that, for the schizophrenic group, the distribu- tion of normalized amplitudes were very similar for both time windows, 300-400 msec and 353-453 msec (latency-adjusted). However, both time windows showed that the schizophrenic group had a L < R topography that contrasted with the L > R topography of the normal control group. These schizophrenic vs. normal control group differences in normalized topo- graphic distribution were tested by profile analysis of parallelism and found to be statistically significant for both the latency-adjusted (F(4, 23)= 3.63, P < 0.05) and latency non-adjusted time windows (F(4, 23)= 6.56, P <0.05) for the schizophrenic group. The strength of these tests of interaction, as measured by Mahalanobis D2, were both over 2.0; values over 1 are considered large effects (see Discussion in J. Stevens, 1986, p. 140). These findings indicated the presence of
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Normal Controls o - 300-400 m s e c
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Fig. 3. Normalized P300 mean integrated amplitudes compared by groups, scalp region, and time window of integration. It can be seen that, for the schizophrenic group, both time windows (300-400 msec and 353-453 msec) showed a L < R topography that contrasted with the L > R topography of the normal control group. These schizophrenic vs. normal control group differences in normalized topographic distribution were tested by profile analysis of parallelism and found to be statistically significant. These results provide statisti- cal confirmation of group topographic differences in P300 amplitude. Data were normalized according to the following formula: Nij k = (Vii k - M I N ) / ( M A X - M I N ) , where N equals a normalized voltage for the kth person, the jth electrode and the ith group; V equals the raw integrated voltages for each level of i, j, and k; MIN equals the smallest mean voltage for each i and j: MAX equals the largest mean voltage for each i and j. To allow clear visualization of normalized means, S.E.M. bars are not displayed, but are as follows for T3, Tcpl , Cz, Tcp2, and T4 sites, respectively: normal controls (300-400 msec) - 0.21, 0.32, 0.47, 0.25, 0.22; schizophrenics (3(/0-400 msec) - 0.30, 0.53, 0.94, 0.43, 0.30; schizophrenics (adjusted latency) - 0.51,
0.84, 1.15, 0.63, 0.48.
a strong group-by-electrode site interaction. These re- sults provide statistical confirmation of the topographic differences between schizophrenics and normal con- trois that are visually apparent in grand-averaged wave
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Fig. 4. Mean integrated P300 amplitude (300-400 msec) of individual members of the schizophrenic and normal control group at the T3 electrode site. The criterion level value of 2 k~V (horizontal line) was the same as used in previous studies, e.g., Faux et al. (1988, 1990); it correctly classified 13/14 normal controls and 11/14 schizophrenics
forms (Fig. 1) and in the non-normalized mean ampli- tude data in Fig. 2.
(4) P300 separation of individuals in the schizophrenic and control groups
Fig. 4 shows that the 2 /zV criterion level at T3 (300-400 msec), established in previous studies, cor- rectly categorized 13/14 normal control individuals and 11/14 schizophrenics. Comparison of schizophren- ics latency adjusted values with normal control values (300-400 msec) showed only slightly less group discrim- ination, separating 10/14 schizophrenics. For compar- ative purposes we examined separation at other elec- trode sites, using post hoc criterion values since, unlike the T3 site, there were no a priori criteria established. The degree of separation produced at each electrode site was evaluated by using the midpoint between group means. Under the assumption of normality, homogene- ity of variance, and equal "prior" probabilities, the midpoint criterion will tend to produce the fewest total misclassifications without bias toward either group (Stevens 1986). For 300-400 msec this yielded 3 mis- classifications at T3 and Tcpl; there were 9 misclassifi- cations at Cz and 4 at Pz, the most frequently used scalp midline electrode sites. Tcp2 and T4 sites pro- duced 4 and 5 misclassifications, respectively. The re- maining scalp electrode sites also showed more mis- classifications than T3 and Tcpl.
Discussion
These results confirm previous findings of P300 asymmetry in schizophrenia (Morstyn et al. 1983; Faux et al. 1988, 1990) and suggest that neuroleptic medica- tion does not greatly influence the detection and mea- surement of P300 topographic alterations in schizo- phrenics relative to normal controls.
These results add to the evidence in the literature for variability of findings of P300 latency delays in schizophrenics compared to normals in that latency delays found in the present data were not statistically apparent at the group level in 4 previous P300 studies from our laboratory. Such differences in our findings could be due either to state-dependent factors associ- ated with medication withdrawal and/or subject pool differences (Bronx VA vs: Brockton VA and the Mass. Mental Health Center pools). While the present study was not specifically designed to assess either of these potential factors, it is notable that both the medication- naive subject and the subject off medication for the longest time period (71 months) had latency delays greater than the schizophrenic group mean, suggesting medication withdrawal may not be a critical factor. Nonetheless, a systematic study of patients on and off medication is needed; use of first episode patients would be helpful in ruling out withdrawal from chronic
medication as a factor in latency changes. However, it must be emphasized that, whatever the source of the latency delay, the present data suggest that latency alterations in unmedicated schizophrenics do not dra- matically change the statistical landscape of topo- graphic alterations as they have been described in medicated schizophrenics.
Comparisons between the off-medication schizo- phrenic and normal control groups confirmed our pre- vious findings of differences between medicated schizophrenic and normal controls in that: (1) t statis- tic mapping showed that left temporal scalp regions maximized the statistical separation between groups, (2) MANOVA profile analysis of P300 "normalized" topography validated the presence of a group-by-scalp region interaction, (3) at the T3 scalp electrode, statis- tical discrimination of schizophrenics and normal con- trois was more than 85% accurate using the 2 p.V criterion established in previous studies of medicated schizophrenics. These results also extend the generaliz- ability of our previous studies as they were acquired using a different subject pool. Overall, these data strengthen the argument that P300 asymmetries in schizophrenia are robust to neuroleptic medication ef- fects. As a statistical and methodological point, the heterogeneity of variance at different electrode sites (Fig. 2) should be emphasized as necessitating a MANOVA analysis and rendering an ANOVA analysis inappropriate (Faux and McCarley 1990); the hetero- geneity of variance confirms previous work in medi- cated patients (Faux et al. 1990).
The P300 left temporal feature may be related to left-lateralized temporal lobe abnormalities in schizo- phrenia. We found a high correlation of P300 left temporal scalp region amplitude with left sylvian fis- sure enlargement on CT scans (McCarley et al. 1989), a presumptive indicator of left-lateralized temporal lobe tissue loss. In MRI studies, left-lateralized temporal lobe tissue loss has been demonstrated both in neocor- tical superior temporal gyrus (and associated with audi- tory hallucinations; see Barta et al. 1990) and also in medial limbic structures (Bogerts et al. 1985; Brown et al. 1986; Barta et al. 1990). Knight et al. (1989) found, in stroke patients, that superior temporal gyrus was essential for P300 production. Evidence reviewed else- where (McCarthy et al. 1987; Smith et al. 1990) points to P300 generators in medial temporal lobe and there are preliminary indications of the importance of lateral electrodes for registering this activity. Recent data from combined MRI-EP studies in our laboratory indi- cate that the P300 left temporal amplitude reduction can be associated with volume reduction in the left superior temporal gyrus (McCarley et al. 1992). Con- vergifig lines of evidence suggesting left-lateralized ab- normalities in schizophrenia have come from measures as diverse as cerebral blood flow (Gut et al. 1985, 1989)
40
and reaction time to a visual-spatial task (Posner et al. 1988).
Despite the statistical strength of the P300 findings, several cautions must be emphasized regarding their clinical and electrophysiological interpretation. We have not yet compared data in the same patients on and off medication, nor have we tested a significant number of patients without previous exposure to neu- roleptics. However, these findings are clearly consistent with studies which have tested patients not only in larger numbers but with greater days off medication (see Blackwood et al. 1987; Brecher et al. 1987 for midline electrode data). This study is distinct, however, in being the first to measure topographic asymmetries in an unmedicated population.
We are currently comparing the P300 topography of schizophrenics with other psychopathological popula- tions. However, the specificity of our P300 findings remains a question until these studies are complete and until other populations have been studied, such as patients with schizophreniform and depressive psy- choses. Our findings should not be taken to suggest that we are proposing P300 as a clinical diagnostic measure. Also, we urge caution in extrapolating from scalp recordings to localization of brain sources, since ERP scalp distributions cannot unambiguously localize underlying source generators. Nevertheless, the pres- ence of an asymmetric P300 scalp distribution is consis- tent with the notion that a pathological process has modified, perhaps primarily on the left, the character- istics of source generators in schizophrenia. Recent work by Scherg and Von Cramon (1986) may assist in developing models of evoked potential sources that can be tested with MR1 techniques capable of detecting structural abnormalities in putative source loci.
In sum, the present data suggest that: (1) neurolep- tic medication does not influence the measurement of P300 topographic asymmetries in schizophrenia; and (2) P300 topographic asymmetries in schizophrenia are a robust finding, now having been seen in 4 different studies.
We gratefully acknowledge the technical and editorial advice of Dr. Brian O'Donuell and Mr, Scott Smith; and the administrative assistance of Carla Kohberger.
Supported by the Department of Veterans Affairs Medical Re- search Service (RWM), NIMH 40,799 (RWM), The Commonwealth of Massachusetts Research Center (RWM), NIMH Research Train- ing Grant T32MHI6259 (PGN), NIMH Research Scientist Develop- ment Award MHK-K01-MH00746-02 (MES), the National Alliance for Research on Schizophrenia and Depression (NARSAD, SFF) and a Schizophrenia Biological Research Center award (No. 4125- 020, General Medical Research Division of the Dept. of Veterans Affairs, KLD). A preliminary version of these data has been pre- sented and an abstract published (Faux et al., P300 asymmetries in unmedicated schizophrenics. In: C.H.M. Brunia, A.W.K. Gaillard
S.F. FAUX ET AL.
and A. Kok (Eds.), Psychophysiological Brain Research (Proc. EPIC 1X Congress), Vol. II. Tilburg Univ. Press, Tilburg, 1990: 209-212).
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