The effect of family status and schizotypy on electrophysiologic measures of attention and semantic processing

The Effect of Family Status and Schizotypy on Electrophysiologic Measures of Attention and Semantic Processing Matthew Kimble, Michael Lyons, Brian O’Donnell, Paul Nestor, Margaret Niznikiewicz, and Rosemary Toomey Background: Disturbances in both attention and language are central to the phenomenology of the schizophrenia spectrum disorders. The purpose of this study was to investigate the relative contributions of two factors, family status and schizotypy, on electrophysiologic measures of attention and semantic processing in family members of individuals with schizophrenia. Methods: Fifteen first-degree relatives of individuals with schizophrenia and 15 comparison subject controls participated in diagnostic evaluations, an assessment of schizotypy, and two event-related potential (ERP) paradigms. The first paradigm was an auditory P300 “oddball” task designed to assess attentional functioning. The second was an N400 sentence paradigm particularly sensitive to language processing. Results: Both relatives and individuals higher in schizotypy, but not their respective comparison groups, showed reductions in P300 amplitude. In the N400 paradigm, individuals higher in schizotypy, but not relatives, showed a reduced N400 effect. There were no differences in latency for either group on either component. Conclusions: The results suggest that both family status and schizotypal presentation independently contribute to disturbances in electrophysiologic measures sensitive to attention and language. Whereas higher levels of schizotypy appear to be associated with disturbances in both attention and language processing, family membership appears to place individuals at risk for attentional deficits alone. Biol Psychiatry 2000;47:402– 412 © 2000 Society of Biological Psychiatry Key Words: Schizotypy, ERPs, P300, N400, attention, semantic processing

From the Department of Psychiatry, Boston University School of Medicine (MK), the Department of Psychology, Boston University (ML, RT), the Department of Psychology, University of Massachusetts (PN), and the Department of Psychiatry, Harvard Medical School (MN), Boston, Massachusetts and the Department of Psychology, Indiana University, Bloomington (BO). Address reprint requests to Matthew O. Kimble, Ph.D., Boston VA Medical Center, Psychology 116B-2, 150 South Huntington Avenue, Boston, MA 02130. Received January 6, 1999; revised July 6, 1999; accepted July 12, 1999.

© 2000 Society of Biological Psychiatry

Introduction

I

ndividuals considered at risk for schizophrenia share many clinical and cognitive characteristics with individuals diagnosed with the disorder. Bleuler (1911/1950), for example, recognized the presence of phenotypic similarities between patients with schizophrenia and their close relatives. In later years, ongoing research led Meehl (1962) to suggest the existence of a schizotype, or an individual with a vulnerability for the disorder who also manifests both overt and covert traits within the schizophrenia spectrum. Today, such an individual would be considered “at risk,” indicating that, either because of family status or clinical presentation, the individual is considered to have a greater likelihood for developing a diagnosable schizophrenic disorder. In recent years, there has been substantial research support for the initial clinical impressions of Bleuler and Meehl. Research has demonstrated that phenotypic similarities among schizophrenia spectrum disorders include personality traits (Lenzenweger 1994), disorganized speech patterns (Shenton et al 1989), neurologic soft signs (Erlenmeyer-Kimling et al 1982), neuropsychologic deficits (Kremen et al 1994), and psychophysiologic abnormalities (Matthysse et al 1986). The work with at-risk populations remains active because of the ongoing search for markers of vulnerability in schizophrenia, the advantages of working with subclinical variants of the phenotype, and the relevance such research has on our understanding of the whole range of schizophrenia spectrum disorders, including schizophrenia. Two areas of interest within this larger effort have been the investigation of attention and language dysfunction in the disorders. Individuals with schizophrenia have demonstrated deficits in both attentional capacity and language in neuropsychologic studies (Neuchterlein et al 1994) and in clinical and behavioral measures (Rund and Landro 1990). There is increasing evidence that these abnormalities also exist in individuals considered at risk; however, there has been some debate as to the presence and extent of these disturbances. 0006-3223/00/$20.00 PII S0006-3223(99)00184-5

ERPs and Schizophrenic Risk Factors

The existence of similar attentional and language deficits across the schizophrenia spectrum poses the question of whether these deficits are also associated with similar neurophysiologic abnormalities. Event-related potentials (ERPs) provide a method to test for neurobiologic disturbances associated with attention and language. Two relevant ERP components that have been studied in schizophrenia are the P300 and the N400 components. The P300 is a positive deflection in the electroencephalogram (EEG) that occurs approximately 300 milliseconds after the onset of a stimulus. In normal subjects, P300 amplitude changes as a function of a number of factors, including stimulus intensity, stimulus relevance, emotional valence, and stimulus probability. P300 amplitude is reliably increased to attended, low probability stimuli and, consequently, the P300 is thought to reflect a neurophysiologic index of attentional allocation (Johnson 1986; Wickens et al 1983). Another ERP component, the N400, has been implicated in language processing. The N400 is a negative going ERP component that occurs approximately 400 milliseconds after the onset of a word and changes with the expectancy of that word (Fischler et al 1983). Whereas unexpected words produce large amplitude N400s, expected words produce small or negligible N400s (Kutas and Hillyard 1980). Typically, the N400 is generated in response to sentences in which the final word either makes sense (the congruent condition) or does not make sense (the incongruent condition). In this design, the congruent condition produces small N400s to the expected terminal words, and the incongruent condition results in large N400s to unexpected terminal words. In addition, investigators typically subtract the average from the congruent condition from the average from the incongruent condition to assess the size of the “N400 effect,” a difference waveform that indicates the discrepancy in processing between the two conditions. Numerous studies have reported abnormalities in both P300 and N400 in schizophrenic subjects. Individuals with schizophrenia have been found to have reduced P300s at central and left temporal sites and abnormalities in the N400 at sagittal, midline sites (Grillon et al 1991; McCarley et al 1991; Mitchell et al 1991; Nestor et al 1997; Niznikiewicz et al 1997). The P300 reductions have generally been thought to reflect difficulties in sustained attention and working memory, whereas the N400 abnormalities have been thought to index disturbances in semantic networks. Investigators using ERPs have primarily focused on the P300 ERP. This focus is partly because of the fact that some of the most robust findings in the ERP-schizophrenia literature include P300 amplitude reductions, P300 lateral asymmetries, and P300 latency delays (Faux et al 1988; McCarley et al 1991; Pritchard 1986; Roth and Cannon

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1972). Those studies that have investigated P300 amplitude in individuals considered at risk have produced mixed results. Although some studies have found evidence for P300 amplitude abnormalities in both family members and psychometrically identified subjects (Blackwood et al 1991; Frangou et al 1997; Kidogami et al 1991; Saitoh et al 1984; Schreiber et al 1992), a number of well-designed studies have not found such effects (Friedman et al 1986, 1988; Schreiber et al 1991). A number of reasons is likely for this variability, including differing recruitment strategies (family members vs. psychometrically identified subjects), differing paradigms, and heterogeneity within the schizophrenia spectrum [see Friedman and SquiresWheeler (1994) for a review of this topic]. A few studies have investigated factors that may be related to these equivocal findings. For example, Roxborough et al (1993) found that P300 amplitude reductions were largest in family members that showed frontal and temporal lobe impairment on neuropsychologic tests but were not present in family members who performed well on these tests. Likewise, Josiassen et al (1985) with the use of a somatosensory paradigm reported P300 amplitude differences in undergraduates who scored high on the Chapman physical anhedonia scale but not those who scored high on perceptual aberration (Chapman and Chapman 1980). Trestman et al (1996) reported that schizotypal personality disorder (SPD) subjects had attenuated auditory P300s that were intermediate between control subjects and patients with schizophrenia. Salisbury et al (1996) investigated both central and lateralized effects in clinically identified SPD subjects and found P300 reductions over left temporal sites only and small, nonsignificant reductions over central and parietal sites. These early findings suggest that the variability in the work to date is likely to result from factors that have yet to be clearly identified. The at-risk literature in the N400 is far less developed. This gap in the research is somewhat surprising given substantiated impairments in language categorization and thought disorder in relatives (Johnston and Holzman 1979; Lyons et al 1995; McConaghy 1989; Shenton et al 1989; Voglmaier et al 1994), and the frequency with which N400 abnormalities are found in schizophrenia (Adams et al 1993; Grillon et al 1991; Kimble et al 1993; Koyama et al 1991; Mitchell et al 1991; Niznikiewicz et al 1997). Given the N400’s sensitivity to verbal processing and its usefulness as an electrophysiologic probe, Niznikiewicz et al (1999) undertook a study to investigate the N400 in subjects with SPD. The SPD subjects showed a reduced N400 effect as well as reductions in the N400 to both congruent and incongruent sentences. This study, the only one of its kind to date, established that there are physiologic correlates to language abnormalities in SPD and that

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Table 1. Sample Demographics and Total SIS Score Family Status Relatives

Age Education PSES Total SIS score* Male Right-handed

Schizotypy Comparison

“High”

“Low”

Mean

SD

n

Mean

SD

n

Mean

SD

n

Mean

SD

n

44.1 12.5 3.2 51.3

11.4 2.4 1.1 8.2

15 15 15 15 7 13

43.7 13.7 3.0 54.3

8.1 2.1 1.1 3.4

15 15 15 15 11 15

42.81 12.81 3.2 49.0

11.7 1.7 1.3 6.4

16 16 16 16 9 14

45.1 14.1 3.0 57.1

7.0 1.5 0.9 1.9 9 14

14 14 14 14

Neither relatives nor subjects “high” in schizotypy differed significantly from their respective comparison groups in any of the demographic variables. *Lower SIS scores represent higher endorsement of schizotypal symptoms.

electrophysiologic measures of language processing may be promising in identifying individuals at risk. The at-risk studies in schizophrenia have typically recruited subjects either through family study methodology (i.e., relatives: Friedman et al 1986, 1988; Kidogami et al 1991; Roxborough et al 1993; Saitoh et al 1984; Schreiber et al 1991, 1992, 1998) or clinical methods (i.e., interview, psychometrics: Josiassen et al 1985; Trestman et al 1996). However, few studies have examined the independent contributions and/or additive contributions of both of these risk factors to attentional and language disturbances in schizophrenia spectrum disorders. The current study investigates neurophysiologic indices of attention and language within the same group, looking at the effect of both family status and schizotypy on these measures. The overall design is intended to investigate 1) the presence or absence of electrophysiologic abnormalities of attention in at-risk groups, 2) the presence or absence of electrophysiologic abnormalities in semantic expectancy in at-risk groups, and 3) the relative contribution of family status or schizotypy to such measures. Consistent with previous research, it is our hypothesis that both family status and schizotypy will independently influence P300 and N400 amplitudes in our sample. In addition, we predict that these two factors will interact to produce further effects on the amplitude of both components.

Methods and Materials Fifteen first-degree relatives of individuals with schizophrenia and 15 subjects with no history of mental illness in themselves or their first-degree relatives participated in the study. All subjects were free of psychotropic medications or other medications that might affect an EEG, were native English speakers, attended at least 12 years of school (mean ⫽ 13.1), scored a minimum of 25 on Reading Test of the Wide Range Achievement Test-Revised (Jastak and Wilkonson 1984), and did not have a history of learning disabilities. Exclusion criteria for all subjects included a history of epilepsy or seizures, neurologic or medical disorders

that might compromise neurologic functioning, or a diagnosis of substance abuse or dependence within the past 5 years. First-degree relatives were family members (children or siblings) of veterans who had a psychiatric admission for schizophrenia at a Department of Veterans Affairs Medical Center and had been given a diagnosis of schizophrenia, using the Schedule for Affective Disorders and Schizophrenia-Lifetime Version (Spitzer and Endicott 1978). Relatives were administered the Structured Clinical Interview for DSM-III-R (SCID) (Spitzer et al 1990) and the Scheduled Interview for Schizotypy (Kendler et al 1989). Lifetime diagnoses of the relatives were determined in weekly meetings by two clinical psychologists who were blind to the proband’s diagnosis. A third psychologist’s opinion was sought to resolve disagreements. Comparison subjects were recruited through an employment agency or an advertisement in a local newspaper, asking for healthy volunteers between the ages of 22 and 70. Comparison subjects with an Axis I diagnosis on the SCID or a reported history of mental illness or psychiatric hospitalization in their first-degree relatives were excluded. Groups did not differ statistically on age (range: 28 –70; relative: M ⫽ 44.1, SD ⫽ 11.4; comparison: M ⫽ 43.7, SD ⫽ 8.1), education (range: 9 –16; relative: M ⫽ 12.5, SD ⫽ 2.4; comparison: M ⫽ 13.7, SD ⫽ 2.1), and parental socioeconomic status (Table 1 ). In the control group, 11 participants were male and 4 were female. In the relative group, 7 participants were male and 8 were female. All 15 comparison subjects were right-handed as compared to 13 relatives. All 30 subjects participated in two ERP tasks that occurred during a single session. Written informed consent was obtained after all procedures were explained. The first task was an auditory “oddball” task in which infrequent (p ⫽ .15) target tones (1500 Hz, 97 dB) were presented among frequent (p ⫽ .85) nontarget tones of a lower pitch (1000 Hz, 97 dB). The duration of the tones was 40 milliseconds. The interstimulus interval was 1200 milliseconds. The tones were presented through Etymotic insert earphones (Elk Grove Village, IL) against a background noise of 70 dB binaural white noise. Three blocks of 200 tones were presented, and the subjects were instructed to push a button on a response pad every time they heard the high-pitched tone. The second task was an N400 sentence paradigm in which subjects read sentences on a computer screen and then responded with a button press as to whether the sentence made sense or not.

ERPs and Schizophrenic Risk Factors

The sentences used for stimuli were identical to those used and validated by Niznikiewicz et al (1997). Fifty sentences with semantically congruent final words and 50 sentences with semantically incongruent final words were presented in random order. Congruence was defined by the sentences’ cloze probability. Cloze probability had been previously defined on the basis of undergraduate ratings from 1–10 regarding how sensibly the undergraduates felt the final word completed the sentence. Terminal words considered semantically congruent had a mean cloze probability equal to .75 and were highly constrained by the preceding sentence context. Terminal words considered semantically incongruent had a mean cloze probability equal to .02. All terminal words were of mid to high frequency in the English lexicon (Kucera and Francis 1967). The participant sat 1 m from a computer screen, placed at eye level, on which sentences were presented one word at a time. Individual words had a duration of 300 milliseconds and an interstimulus interval of 800 milliseconds. The final word in each sentence was cued with a period. The sentence was then followed with a row of stars (****). The participants read the sentences silently and were asked to respond as quickly and as accurately as possible after the stars appeared by pushing the “Yes” button on the response pad if the sentence made sense and the “No” button if it did not. “Yes” and “No” button responses were counterbalanced among subjects. Sentences progressed automatically, 2 sec after the appearance of the stars. In both tasks, reaction time and response accuracy were recorded and stored immediately on the stimulus computer. ERPs were recorded from tin plate electrodes using an Electro-cap International electrode cap (Dallas, TX). Three electrodes (Cz, FP1, FP2) were placed using the International 10 –20 convention with all other electrodes positioned by the cap at standard distances and referenced to linked ears. ERPs were recorded at 4 active sites: Fz, Cz, Pz, and Oz. Eye blinks were monitored by use of electrodes placed above and below the right eye. Lateral eye movements were monitored by use of a left and right external canthal montage. Recording did not commence until electrode impedance was below 4 kOhms at all reference and recording sites. During recording, ERPs were transferred directly to a headbox and then a set of Neuroscan (Herndon, TX) amplifiers that filtered the data at a bandpass of DC to 40 Hz (Neuroscan, Inc., EEG amplifiers, 24 dB/octave low pass slope, and 24/dB octave high pass slope). Recording began 100 milliseconds before the onset of the stimulus and continued for 824 milliseconds with a sampling rate of 256 samples/sec. Before analysis and averaging of data, all individual sweeps were baseline corrected, and individual trials with amplitude values greater than ⫾75 were automatically rejected. Eye movement was corrected by use of the regression-based procedure of Semlitsch (Semlitsch et al 1986). Single trials were filtered at 16 Hz. The P300 was measured by use of a peak measure and was specified as the most positive data point between 250 and 550 milliseconds measured from the average, rare waveform. Peak N400 was designated as the most negative point sampled between 300 and 600 milliseconds measured from the average difference waveform. Both peaks were measured relative to a 100 millisecond-prestimulus baseline.

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Evaluation of Schizotypy All 30 subjects participated in a structured personality interview, the Scheduled Interview for Schizotypy (Kendler et al 1989). The interview took approximately 1 hour and was given by trained doctoral students in clinical psychology. All participants were rated by use of Likert scales on 23 personality characteristics. Eighteen of these ratings were based on self-report, and five were based on the interviewer’s observation of personality characteristics. The sample was split on the basis of differences in schizotypal signs and symptoms. This split was done using the factor analysis of the signs and symptoms of schizotypy completed by Kendler et al (1995) in which four factors—negative schizotypy, social dysfunction, avoidant symptoms, and odd speech—were found to best characterize relatives of schizophrenic probands. A total score from all the variables that contributed to the four factors was created, and the total score was split on the median to create two groups: high schizotypy and low schizotypy. The median was chosen as the measure of central tendency given the negative skew present in the interview data. This approach resulted in seven relatives and nine comparison subjects in the high schizotypy group and eight relatives and six comparison subjects in the low schizotypy group. To confirm that both groups demonstrated the predicted abnormality in the P300 and N400, a mixed-model analysis of covariance (ANCOVA) was run with family status (control vs. relative) and schizotypy (low schizotypy vs. high schizotypy) as the between-subjects factors, and condition (P300, frequent vs. rare; N400, congruent vs. incongruent) and electrode (Fz, Cz, Pz, and Oz) as the within-subject factors. Although mean age did not differ between groups, all ANCOVAs used age as a covariate given evidence that the positive slope of P300 latency with time may vary as a function of psychiatric status (O’Donnell et al 1995; Polich 1996). Group effects on P300, N400, and behavioral measures were analyzed separately by use of a 2 ⫻ 2 ⫻ 4 mixed-model ANCOVA with family status (control vs. relative) and schizotypy (low schizotypy vs. high schizotypy) as the between-subject factors and electrode (Fz, Cz, Pz, and Oz) as the within-subject factor.

Results Schizotypy Although relatives reported higher levels of schizotypy on average, the relatives did not significantly differ from comparison subjects on this measure (t ⫽ ⫺1.3, df ⫽ 19, p ⫽ .19). Levene’s test for equality of variance indicated that the relatives were much more variable on this trait (F ⫽ .76, p ⫽ .01) with a number of comparison subjects endorsing no schizotypal symptoms (thus producing a ceiling effect) and three relatives greater than two standard deviations from the sample mean. One relative achieved DSM criteria for SPD. Thus the Scheduled Interview for Schizotypy measure produced negatively skewed data but resulted in more relatives in the low schizotypy group based on the median split (relatives ⫽ 8, comparison ⫽ 6)

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Figure 1. P300 waveforms to rare, target tones at Cz. Relatives are represented by a dashed line, comparison subjects by a solid line.

Figure 2. P300 waveforms to rare, target tones at Cz. High schizotypy subjects are represented by a dashed line, low schizotypy subjects by a solid line.

despite the fact that the relative’s overall average was higher for schizotypal traits (Table 1).

central sites (Fz, Cz, Pz, and Oz) demonstrated a main effect for both schizotypy (F ⫽ 4.65; df ⫽ 1,25; p ⫽ .04; effect size: eta2 ⫽ .16) and family status (F ⫽ 4.07; df ⫽ 1,25; p ⫽ .05; effect size: eta2 ⫽ .14). The family status ⫻ schizotypy interaction was not significant (F ⫽ .17; df ⫽ 1,25; p ⫽ .68; effect size: eta2 ⫽ .01) nor was there any interaction at a particular electrode site (Figures 1 and 2, Table 2).

Accuracy and Reaction Time Groups did not show accuracy and reaction time differences in their button press responses to final words in the N400 task or target tones in the P300 task. The mixedmodel ANCOVA revealed no main or interaction effects for hit rates, false alarms, or reaction time.

GROUP EFFECTS (N4). Analysis of the N400 difference waveform demonstrated a significant “schizotypy” ⫻ “electrode” interaction (F ⫽ 4.18; df ⫽ 1,25; p ⫽ .02; effect size: eta2 ⫽ .35). Post hoc analyses revealed that the effect was significant at the Cz electrode only (F ⫽ 7.87; df ⫽ 1,25; p ⫽ .01; effect size: eta2 ⫽ .24) with N4 amplitudes at Cz significantly smaller for individuals with “high” schizotypy as compared with subjects with “low” schizotypy (Figures 2, 3, and 4, Table 3). There was no main effect for schizotypy (F⫽ 3.95; df ⫽ 1,25; p ⫽ .06; effect size: eta2 ⫽ .14), although subjects high in schizotypy showed a smaller N400 effect across all four electrode sites. The effect of family status on N400 difference waveform amplitude was not significant (F ⫽ 2.80; df ⫽ 1,25; p ⫽ .11; effect size: eta2 ⫽ .10). The overall

P300 and N400 Amplitude CONDITION EFFECT. For the P300 (F ⫽ 12.58; df ⫽ 1,25; p ⫽ .002) and the N400 (F ⫽ 11.35; df ⫽ 1,25; p ⫽ .002), the mixed-model ANCOVA was significant for “condition” with no interactions. The significant condition effect supports the effectiveness of the manipulations with enhanced P300s to rare as compared with frequent tones and larger (more negative) N400s to incongruent as compared with congruent final words. GROUP EFFECTS (P3). Group effects for the P300 and N400 were analyzed by use of the previously outlined three-way ANCOVA. Analysis of the P300 to rare tones at

Table 2. Amplitude of the P300 Component to Rare Tones Amplitude (Microvolts) Family Status Relatives

Schizotypy Comparison

“High”

“Low”

Electrode

Mean

SD

Mean

SD

Mean

SD

Mean

SD

Fz Cz Pz Oz

7.07 9.00 10.31 6.82

4.21 5.57 6.07 5.64

10.89 12.89 13.20 7.79

5.62 6.55 6.04 4.87

7.56 9.49 10.92 6.57

6.60 6.64 6.60 5.77

10.60 12.61 12.69 8.13

3.71 5.64 5.62 4.53

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schizotypy ⫻ family status interaction (F ⫽ 3.22; df ⫽ 1,25; p ⫽ .09; effect size: eta2 ⫽ .11) was also not significant. However, the eta2 ⫽ .11 projects to a power of .41 and further suggests that equal cell sizes of 12 (N ⫽ 48) would generate sufficient power for both a family status ⫻ schizotypy interaction and a main effect for schizotypy. The analysis of the N400 congruent and incongruent waveforms revealed no overall group differences or interactions in N400 amplitude during either condition.

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turbances in semantic processing in individuals high in schizotypy and suggests abnormalities in distinguishing sensible from insensible sentence endings. This finding is consistent with previous work from our lab in which individuals with schizophrenia showed larger N400s to all sentence endings regardless of their congruence (Nestor et al 1997; Niznikiewicz et al 1997). The fact that individuals high in schizotypy were accurate in performing the task and demonstrated a significant N400 effect (even if smaller) suggests that this difference was not because of a general attentional deficit or noncompliance with the task. This study did not find differences in the averages of the congruent and incongruent waveforms. This finding suggests that semantic disturbances in this at-risk sample may be comparatively small and that N400 differences are only evident when assessing the differential processing between congruent and incongruent sentences. However, this overall reduction in the N400 effect in those subjects high in schizotypy may represent the same inability to constrain semantic choices through appropriate use of sentence context that has been hypothesized to exist in schizophrenia (Nestor et al 1997; Niznikiewicz et al 1997). Certainly, the reduced N400 effect suggests a difficulty categorizing language and is consistent with other neuropsychologic and clinical measures that have shown language disturbances in relatives, schizotypes, and schizophrenic persons. Demonstrating that this neurophysiologic abnormality has functional correlates, such as difficulty organizing speech, is in an important next step in defining the nature of language disturbances in the schizophrenia spectrum. Whereas the N400 effect was also smaller in relatives than in comparison subjects, it was not reduced significantly as it was in the high schizotypy group. The fact that the N400 effect was significantly reduced in those subjects high in schizotypy but not relatives has important implications for the utility of the measure as a vulnerability marker for the disorder. In particular, N400 may serve as a marker that is consistent with a schizotypal or schizophrenic clinical presentation but not familial inclusion. Thus, aberrations in semantic processing that are reflected in electrophysiology seem to result more from the mani-

P300 and N400 Latency GROUP EFFECTS. There were no statistically significant main or interaction effects for the P300 or N400 latency at any electrode site for any condition.

Discussion In this study, reductions in the P300 component were associated with both family status and level of schizotypy. This contrasts to reductions in the N400 effect that was affected by the level of schizotypy alone with subjects high as compared with low schizotypy, showing a significantly reduced N400 effect at the Cz electrode. We did not find, however, the predicted interaction effects such that both family status and level of schizotypy interacted to produce the largest differences in P300 and N400 amplitudes. There was no interaction present for the N400 difference waveform amplitude, and, in general, being at risk via either family status or schizotypal presentation was adequate to demonstrate electrophysiologic differences. The fact that there was not an interaction effect suggests that there is little increased risk for electrophysiologic differences associated with inclusion to both groups. The N400 reductions in the difference waveform were present only in subjects high on a measure of schizotypy. To our knowledge, this is only the second study that has investigated and reported N400 differences in a group at risk for schizophrenia and the first to use family members. This finding provides neurophysiologic evidence for disTable 3. Amplitude of the N400 Difference Waveforms

Amplitude (Microvolts) Family Status Relatives

Schizotypy Comparison

“High”

“Low”

Electrode

Mean

SD

Mean

SD

Mean

SD

Mean

SD

Fz Cz Pz Oz

⫺2.87 ⫺3.66 ⫺2.90 ⫺2.24

2.28 3.21 4.21 3.02

⫺4.22 ⫺4.79 ⫺4.85 ⫺3.49

2.42 2.46 3.10 2.89

⫺3.06 ⫺3.18 ⫺2.98 ⫺2.56

2.88 3.40 4.45 3.49

⫺4.10 ⫺5.41 ⫺4.90 ⫺3.21

1.66 1.48 2.58 2.33

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Figure 3. N400 congruent, incongruent, and difference waveforms. Relatives are represented by a dashed line, comparison subjects by a solid line.

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Figure 4. N400 congruent, incongruent, and difference waveforms. High schizotypy subjects are represented by a dashed line, low schizotypy subjects by a solid line.

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festation of the disorder rather than a concurrent psychophysiologic abnormality present in all individuals considered at risk. In contrast, the P300 component continues to show promise as a valuable marker. Not only are P300 reductions present in subjects high in schizotypy, but they were also found in first-degree relatives in this sample. This finding is consistent with other studies that have found reduction in P300 amplitude in individuals at risk (Blackwood et al 1991; Frangou et al 1997; Saitoh et al 1984). This evidence provides further support for efforts to identify the genetic locus for P300 abnormalities, as doing so may distinguish individuals at higher risk for schizophrenia and other psychiatric disturbances from those at lower risk. We did not find any differences in latency for either the P300 or the N400 component. The lack of differences in P300 latency is consistent with other studies that have found no latency differences in high-risk groups (Kidogami et al 1991; Schreiber et al 1992). The fact that we did not find latency differences in the N400 in our at-risk groups when N400 latency delays are one of the more consistent findings in schizophrenia (Bobes et al 1996; Nestor et al 1997; Niznikiewicz et al 1997) suggests that the latency prolongation found in schizophrenic samples may be a specific disease-related pathology that affects stimulus processing speed. It is also possible that our sample size was not adequate to detect differences in this measure. Overall, the results suggest those subjects who were higher as compared with lower on a measure of schizotypy, thus closer to the schizophrenic phenotype, showed a broader range of electrophysiologic abnormalities that included disturbances in measures of both attention and language processing. This finding was present despite the fact that a diagnosis of SPD was not a criterion for inclusion into the high schizotypy group. The high schizotypy group simply represented individuals higher rather than lower on a measure of schizotypy. Given this limitation, the statistically significant findings indicate that electrophysiologic disturbances in attention and language processing may be present even in individuals with higher levels of schizotypal traits that do not necessarily present as a clinical syndrome. In our sample, higher levels of schizotypy were spread evenly among relatives and comparison subjects. Only seven relatives but nine comparison subjects were placed into the high schizotypy group. Whereas mean levels of schizotypy was higher in the relatives, more relatives were placed into the low schizotypy group on the basis of the median split. This pattern of results is due to three relatives who were greater than two standard deviations from the mean on the schizotypy scale, thus affecting the overall

average. Butler et al (1993) have previously demonstrated that comparison subjects for research are often quite high in measures of psychological distress and psychosis proneness. Whereas comparison subjects in this study were excluded on the basis of any Axis I diagnoses, history of mental illness, and history of mental illness in their first-degree relatives, there was obviously no screening for schizotypal personality characteristics, a trait which needed to vary freely among the groups. Subjects in this study, defined as being at risk either through familial membership or levels of schizotypy, did demonstrate a pattern of electrophysiologic disturbances during both linguistic and attention-related tasks similar to those found in schizophrenia. The P300, consistent with past work, appeared sensitive to both family status and schizotypy. The N400 appeared to be a better indicator of the level of schizotypy than it was of risk more broadly defined. This work, in combination with recent investigations of other ERP components such as the P50 (Adler et al 1998; Leonard et al 1996), suggest the continued value of ERPs in identifying cognitive deficits and potential risk markers for schizophrenia. Although the electrophysiologic findings are intriguing, the functional significance of these differences has yet to be resolved. Future studies might improve on the current study by investigating the functional correlates of these electrophysiologic measures through the use of concurrent technologies, including other neuroimaging techniques and neuropsychological assessment.

Research was supported by the Medical Research Service and the Schizophrenia Center of the Department of Veteran Affairs, Brockton; NIMH Pre-doctoral Research Service Award MH-10865 to Dr. Kimble; NIMH grant MH-40779 to Dr. McCarley; and NIMH grant MH-47353 to Dr. Lyons.

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