The Auditory N2 Component in Schizophrenia: Relationship...

26 BIOL PSYCHIATRY 1993;34:26-40

The Auditory N2 Component in Schizophrenia: Relationship to MRI Temporal Lobe Gray Matter and to Other ERP Abnormalities

B.F. O'Donnell, M.E. Shenton, R.W. McCarley, S.F. Faux*, R.S. Smith, D.F. Salisbury, P.G. Nestor, S.D. Pollak, R. Kikinis, and F.A. Jolesz

The N2 component of the auditory event-related potential (ERP) indexes cognitive processes involved in the categorization of deviant stimuli. Although N2 amplitude and latency abnormalities have been reported in schizophrenia, their relationship to MRi structural changes, clinical status, and P3 abnormalities has not been defined. We therefore studied the auditory N2 and P3 components elicited by an oddball paradigm in 15 right.handed male subjects with schizophrenia and 14 control subjects who had quantitative MRi measures of temporal lobe gray-matter structures. To provide a methodological comparison, we measured the auditory N2 from both the target ERP (N2t) and the target-minus-frequent ERP difference (N2d) waveforms. Both N2t and N2d amplitude were bilaterally reduced in schizophrenics, with N2d showing a more pronounced reduction. Within the schizophrenic group, N2 amplitude reduction was associated with reduction in gray-matter volume of the left superior temporal gyrus (STG) and of medial temporal lobe structures bilaterally, and clinically, with greater chronicity. 1:'3 amplitude, in contrast, correlated only with left posterior STG volume, and was more prominently associated with delusions and thought disorder. These findings suggest that the N2 and P3 components, though occurring sequentially in the ERP, tap separable anatomic and behavioral abnormalities in schizophrenia.

Key Words: N2, event-related potentials, scalp topography, magnetic resonance imaging, schizophrenia

From the Department of Psychiatry (BFO, MES, RWM, SFF, RSS, DFS, PG},, SDP). Harvard Medical School. Brockton VA Medical Center, and the De, pmment of Radiology (RK, FAJ), MR! Division, Surgical Planning Labora- tory, Brigham and Women's Hospital, Harvard Medical School,

Correspondence to Dr. Robert W, McCarley, Department of Psychiatry i 16A, 940 Belmont Street, Brockton, MA, 02401, (508) 583 4500 X 367.

Received July 20, 1992; revised April 21, 1993, Portions of this paper were presented at the 1992 Annual Meeting of the American

Psychiatric Association, Washington, D.C. *Currently at the Department of Psychology, Drake University, Des Moines, IA.

Introduction Novel, task-relevant auditory stimuli elicit a negative deflection in the electroencephalogram (EEG) at about 200- 300 msec, the N2 or N200 component, as well as a positive deflection at 300-600 ms, the P3 or P300 component. Although P3 abnormalities are among the most intensively studied physiological disturbances in schizophrenia (Faux et al 1990; McCarley et ai 1991, 1993; Pfefferbaum et al 1984; Roth et a! 1980), the N2 component, in contrast, has received only sporadic investigation in this disorder.

© 1993 Society of Biological Psychiatry 0006-3223/93/$06,00

N2 and MRI in Schizophrenia eIOL PS¥CHtATRY 27 1993;34:26-40

This is in contrast to the N2 in normal subjects, whose cognitive concomitants have been extensively studied, especially by Ritter, Vaughan, and co-workers (Simson et al 1976, 1977; Ritter et al 1979, 1988; Novak et al 1990). They concluded that the N2 component indexes the process of stimulus classification, particularly for discordant or novel stimuli, and that it is topographically and function- ally distinct from the P3 component. The N2 differs from the MMN, a low-amplitude negative component, elicited by low-probability stimuli, in that the N2 (1) occurs only to task-relevant stimuli, whereas the MMN is concep- tualized as an "automatic" mismatch detector; (2) has a longer latency; (3) has a larger amplitude; and (4) shows a different topography. N2 latency increases with increas- ing difficulty of stimulus discriminability and usually coy- aries with reaction time; its amplitude is inversely pro- portional to stimulus probability (Brecher et al 1987; Novak et al 1990; Ritter et al 1979; Sams et al 1985).

There has been no previous investigation of the neural substrates of N2 abnormalities in schizophrenia, although several lines of evidence suggest there are temporal lobe sources of N2 in normal subjects. Simson, Vaughan, and Ritter (1976, 1977) reported that N2 ~p l imde to auditory stimulation was maximum at anterior and central sites, whereas the N2 maximum amplitude to visual stimulation was more lateral and posterior (suggesting a more modality-specific distribution than the P3). On the basis of these topographic differences, the investigators proposed that the auditory N2 component was generated by sources in the supratemporal plane, specifically the posterior superior temporal gyms, whereas the visual N2 component was generated by sources in the prestriate cortex of the occipital lobe. Direct neurophysiological support for supratemporal generation of the auditory N2 component has been reported by Halgren and co-workers (Halgren et al 1992), who found depth-recorded potentials in seizure disorder patients in the region of Heschi's gyrus that were often in the same latency range as the surface-recorded N2 component.

Given the potential use of the N2 as an index of both speed and extent of early processing of novel stimuli, why has it not attained the prominence in schizophrenia studies of the P37 We suggest that this relative neglect is largely due to methodological issues in characterizing the component and the lack of knowledge regarding the clinical and neuropathological significance of N2 abnormalities.

The most important methodological differences between various studies of the N2 in schizophrenia appear to lie in how the component is measured and which sensory modality is used for stimulation. The most recent study, and the one with methodology most similar to the present study, was that of Ogura et al (1991). They studied the auditory N2 component in 54 schizophrenic patients off

medication using a two-tone auditory oddball task. An important methodological feature of this study was the measurement of N2 in two ways: both from the event- related potential (ERP) to target tones (which we will ab- breviate as N2t) and from a difference waveform, generated by subtracting the ERP to frequent tones from the ERP to the rare, target tones (N2d). N2 amplitude, measured from N2d, was reduced in schizophrenic patients, bt~t N2t amplitude was not significantly different. Simi- larly, Roth et al (1980) reported that auditory N2t amplitude was not reduced in schizophrenic patients. This same laboratory (Pfefferbaum et al 1984) found that the amplitude of visual N2d was reduced in schizophrenic patients, although Brecher et al (1987) did not confirm this finding. Taken together, these studies may be interpreted as indicating that the amplitude reduction effect size for N2d is greater than that for N2t, and that the auditory modality shows abnormalities more readily than the visual. As with the P3 ERP component, latency measurements have been variable across studies. Ogura et al (1991) found N2t prolonged in schizophrenic subjects, as did Schreiber et al (1989) in children at risk for schizophrenia, but Roth et al (1980) found no change in schizophrenic subjects.

Thus, a major methodologic issue in studies of the N2 component is whether to use the N2d or the N2t to measure amplitude and latency. In the ERP to target tones, the negative, N2 component deflection overlaps ,,,~,t,. the..., rv~'~°- itive, P2 component deflection. This overlap diminishes the amplitude of both components and may alter latency as well. Because the P2 component is present to both target and nontarget (frequent) tones, one approach to isolating the N2 component for measurement has been to use the N2d, because the subtraction removes the P2 (and also the N 1). This procedure has been routinely used in studies of the N2 in normal subjects (e.g., Novak et ai 1990; Sams et al 1985; Simson et al 1977). The difference ERP is characterized by the absence of the N 1 and P2 components and is also marked by a larger and often earlier N2 component, as well as persistence of the P3 component. In evaluating the difference ERP, the question arose as to whether the N2d could be empirically demonstrated to be a better representation of the component than the N2t. In a methodologically ingenious series of studies, Simson, Vaughan, and Ritter (1976, 1977) examined ERPs elicited by asking subjects to detect tones omitted during the pre- sentation of a regular sequence. Omitted stimuli elicited an N2 and P3 component, because these components are synchronized to cognitive processing, whereas the N 1 and P2 components were absent in the ERP, because these components appear only with external sensory stimulation. The N2 component measured from the target-minus-frequent difference ERP (the N2d) was comparable to the N2 component measured to omitted auditory stimuli in mor-


B.F. O'Donnell et al

phology, amplitude, and topography. In contrast, the average amplitude of the N2 component in the target ERP (N2t) was typically more positive than that elicited by the omitted stimulus. These data suggested that, on empirical as well as theoretical grounds, the difference waveform is the preferred measure, because it is less contaminated by other ERP components than the target waveform. How- ever, because this target-difference waveform comparison has not been routinely used in schizophrenia studies, the present study measures both N2t and i~,:~ a~d compares them.

The second major reason for the relative neglect of the N2 component in schizophrenia is that the N2 abnormalities have not hitherto been anchored to magnetic resonance imaging (MRI) structural changes or related to clinical features of this disorder. Dissociation of N2 and P3 abnormalities in previous studies suggests that these components may be sensitive to different aspects of schizophrenia. The N2 provides a metric for the evaluation of the cognitive processes of stimulus classification and their speed, as well as generation of expectancies. Thus N2 abnormalities in schizophrenics might reflect abnormalities in these cognitive processes and/or disturbance in the neural generators of the component. Because the auditory N2 may have important neural sources in the temporal lobe, a crit- ical question is whether documented abnormalities of temporal lobe structure in schizophrenia might show association with N2 abnormalities. MRI studies have found volume reductions of superior temporal gyrus (Barta et al 1990; Shenton et al 1992) and of medial temporal lobe structures (Barta et al 1990; Bogerts et al 1990; Breier et al 1992; DeLisi et al 1988; De Lisi et al 1991; Jernigan et al 1991; Shenton et al 1992; Suddath et al 1990). Medial temporal lobe abnormalities have been present in both volumetric neuropathological studies (Altschuler et al 1990; Bogerts et al 1985) and in cellular neuropathological studios showing neuronal disarray in hippocampus (Kovelman and Scheibel 1984) (though this was not found by Christinson et al [ 1989] or Bones et al [ 199 I]), cell loss in hippocampus and entorhinal cortex (Arnold et al 1991; Falkai and Bog- errs 1986; Jeste and Lohr 1989), and reduction of pyramidal neuron size in the hippocampus (Bones et al 1991). In an MRI study using the same subjects as evaluated in the present study, schizophrenic subjects had gray-matter volume reductions of the left anterior hippocampus/amygdala complex, left superior temporal gyrus, and the left and right parahippocampal gyrus (Shenton et al 1992). Furthermore, in these subjects, P3 amplitude was correlated with volume reduction of the left posterior superior temporal gyms gray matter, with the largest correlations at electrode sites proximal to the left temporal lobe (McCarley et al 1993).

There were three major aims of the present study evaluating the N2 component in schizophrenia: (1) to compare

the amplitude, latency, and topography of the auditory N2 component between chronic schizophrenic patients and control subjects, using N2 measured both from the target ERPs and from target-minus-frequent subtraction waveforms; (2) to investigate the relationship between amplitude of the N2 component in schizophrenics and the volume abnormalities of specific temporal lobe gray-matter structures measured with high-resolution MRI scans; and (3) to compare and contrast the anatomic and clinical correlates of N2 and P3 abnormalities. In exploratory analyses, the N I and P2 components, elicited by nontarget stimuli in the auditory oddball paradigm, were also evaluated for correlations with MRI structures.

Methods

Subjects Fifteen chronic, right-handed male schizophrenic patients were recruited from the Brockton VA Medical Center. All the subjects were between the ages of 20 and 55 years. All were receiving neuroleptic medication (mean daily dose equivalent to 881 mg of chlorpromazine); 13 were inpa- tients and two were outpatients. DSM-III-R diagnosis was ascertained on the basis of a structured psychiatric inter- view, the Schedule for Affective Disorders and Schizo- phrenia (SADS) (Spitzer and Endicott 1978), and medical chart review. The Schedule for the Assessment of Positive Symptoms (SAPS) (Andreasen 1984) was used to rate positive symptom severity, the Schedule for the Assess- ment of Negative Symptoms (SANS) (Andreasen 1982) was used to rate negative symptoms, and the Thought- Disorder Index (TDI) (Solovay et al 1986) was used to assess severity of formal thought disorder. None of the subjects had a history of electroconvulsive shock treat- ment, history of alcohol or drug abuse (DSM-III-R criteria) within the last 5 years (or any history of addiction), or neurological illness affecting the central nervous system. The average age of onset of schizophrenia was 22.4 __ 3.6 years. The patients had been hospitalized 46% _ 31% of the time after their first episode. Patients had prominent positive symptoms (hallucinations, delusions, or formal thought disorder), with an average SAPS score of 10.1 -4- 3.5 and an average TDI score of 60.4 _ 61.8. Their average SANS score was 9.5 _ 3.6. In the Andreasen topology, 11 of 15 patients were predominantly positive, and four showed a mixed symptom picture.

The control group included 14 participants who were recruited from newspaper advertisements and were matched to the patient sample on the basis of age, sex, and hand- edness. Subjects were excluded if they had alcohol or drug abuse/addiction history, psychiatric or neurological illness, or psychiatric illness in a first-degree relative. All subjc, ct~ :'nc, luded in this study had clinically normal MRI

N2 and MR1 in Schizophrenia BIOL PSYCHIATRY 29 1993;34:26-40

scans. Mean age did not differ between control (37.9 _ 9.1 years) and schizophrenic subjects (37.6 ± 9.2 years). There was no difference (p = 0.41) between the control (10.7 __ 2.5) and schizophrenic (9.9 _+ 2.3) scores on the Information subscale of the Wechsler Adult Intelli- gence Scale-Revised (Wechsler 1981).

ERP Evaluation

RECORDING PROCEDURES. ERPs were recorded using an auditory oddball paradigm. ERPs were elicited by tone pips of 40-msec duration (10-msec rise/fall time) with a 1.2-sec interstimulus interval. Infrequent (p - 0.15) high- pitched tones (1500 Hz, 97 dB sound pressure level) were presented pseudorandomly, interspersed among frequent low-pitched tones (1000 Hz, 97 dB sound pressure level). Tones were presented through Etymotic insert earphones against a background of continuous 70-dB binaural white noise. Subjects were asked to silently count the number of infrequent, high-pitched tones. There was a trend for the counting accuracy of the schizophrenic patients to be worse than that of the control subjects (control accuracy - 0.98 ± 0.04, schizophrenic accuracy - 0.92 ± 0.09, t(27) - 2.01, p - 0.054). While listening to the tones, subjects stared at a central fixation point to reduce eye movements. Subjects received 600 to 1000 tones in this condition. The average number of tones received by control and schizophrenic subjects did not differ (971 _ 107 versus 920 ± 147, t(27) - 1.07, p = 0.30).

ERPs were recorded from 28 tin plate scalp electrodes using an Electro-Cap International electrode cap. Scalp electrode placements included all electrodes in the Inter- national 10-20 System with eight additional interpolated electrodes. Fpl, Fp2, and Cz sites were located manually by International 10-20 measurements, and all other electrodes were positioned by the cap at standard distances. A vertical electro-oculogram (EOG) was recorded using right eye supraorbital and infraorbital electrodes. Hori- zontal EOG was recorded from electrodes at the right and left external canthi. Electrode impedance was maintained at less than 4 k[~. Right and left ear impedance was matched within one kfl. The EEG was filtered using a ban@ass of 0.15-40 Hz, with 36 dB/octave roll-off for low pass and 6 dB/octave for high pass. Single trial epochs were digi- tized and stored on hard disk for later off-line processing. Each ERP consisted of 256 EEG samples over a 700-msec epoch, including a 100-msec prestimulus baseline interval.

DATA PROCESSING. All single-trial epochs were baseline corrected prior to subsequent processing. ERP responses with vertical EOG artifact were corrected through individually computed weighting coefficients at each electrode site using the Semlitsch et al (1986) procedure. After correction for vertical EOG artifact, all epochs with volt-

ages in excess of _ 50 IxV at any site were rejected. Epochs were then sorted into infrequent, target ERP and frequent, nontarget ERP averages.

N2 amplitude and latency was measured from both the target and difference ERPs. Difference ERPs were generated by subtracting frequent from target ERPs. N2 peak latency was measured at the most negative voltage between 180 and 290 msec at the Cz electrode site for both the target (N2t) and difference (N2d) ERPs. After identifying the peak latency at Cz for each subject, the average voltage from 20 msec before the peak to 20 msec after the peak was calculated for all electrode sites in each condition.

Peak P3 latency was measured from the target ERP at the most positive voltage in the 300-450 msec interval at the Cz electrode site. P3 amplitude was measured as the average voltage between 300 and 400 msec from the target ERP, which is the standard method in this laboratory (Faux et al 1990; McCarley et al 1991, 1993). The relationship of P3 amplitude and topography measured along the coronal chain (T3, C3, Cz, C4, and I"4) to temporal region abnormalities has been described in a previous paper (McCarley et al 1993). We here compare the relationship of N2 amplitude to temporal region gray-matter changes and compare the relationship of N2 and P3 abnormalities to both anatomic and clinical disturbances.

The exogenous N 1 and P2 components were also measured for exploratory correlations with MRI regions of interest. Peak N I amplitude and I'2 amplitude were measured at the vertex (Cz) recording of the ERP to frequent stimuli for each subject. N I was measured as the most negative voltage between 90 and 150 msec. P2 was measured as the most positive voltage between 175 and 285 msec. The vertex was chosen for measurement of N 1 and P2 because both components show maximum amplitudes at or near the vertex.

MRI Procedure

IMAGE ACQUISITION. As described in detail elsewhere (Shenton et al 1992), MRIs were obtained from whole brain in the coronal plane using a 1.5-Tesla General Elec- tric SIGNA System. A 3DFT SPGR (spoiled gradient- recalled acquisition in steady state) acquisition was used. Images were obtained with TR - 35 msec, TE = 5 msec, slice thickness - 1.5 ram, one repetition, 45-degree nu- tation angle, 4-cm field of view, matrix - 256 x 256 x 124. This acquisition protocol gives excellent contrast between gray and white matter, with cerebrospinal fluid ap- pearing dark. Although not directly relevant to the present study's comparisons, we note that double-echo spin-echo axial images were used for semiautomated segmentation of whole brain gray, white, and cerebrospinal fluid components, which did not differ in schizophrenics and normal


B.F. O'DonneU et al

subjects (Shenton et al 1991, 1992; Cline et al 1990). After this semiautomated segmentation of gray and white matter, operators manually outlined the gray-matter region of interest (ROI) on each slice between the anterior and posterior landmarks (average intraclass correlation was ri = 0.86). Volumes were then calculated by summing the vox- els across slices. Gray matter ROls within the temporal lobes included the left and right superior temporal gyms, anterior hippocampus-amygdala, hippocampus, and parahippocampus on both sides. Absolute volumes in milli- liters of tissue were used for correlational analyses, because ERP amplitude most likely reflects absolute rather than relative neuronal numbers, t,andmarks for each ROI are described below.

HIPPOCAMPUS-AMYGDALA. This ROI was subdi- vided into anterior and posterior segments. The posterior hippocampus was measured between the mammillary bodies (anterior border) and the last slice containing fibers of the fomix (posterior border) and the splenium of the corpus callosum. Because the gray matter of the anterior hippocampus and the amygdala could not always be distin- guished from each other, a joint ROI containing the amygdala-anterior hippocampus was measured. The most anterior slice of this ROI was defined as the slice showing a white- matter connection (temporal stem) linking the anterior portion of the temporal lobe with the more ventral subcortical portion of the brain. The most posterior slice was that just before the onset of the mammillary bodies.

SUPERIOR TEMPORAL GYRUS GRAY-MATTER. The medial extent of superior temporal gyms (STG) was defined by the limiting fissure of the insula. The anterior and posterior borders of the STG were defined by the extent of the entire amygdalohippocampal complex.

PARAHIPPOCAMPAL GYRUS. Nonsubicular portions of this gyms were defined laterally by the collateral sulcus and a demarcation line drawn across the narrow portion of the gyral isthmus at the deepest portion of the collateral sulcus (the subiculum was included in the hippocampal ROI). The anterior and posterior extent of this structure was defined by the same landmarks as for the anterior and posterior extent of the amygdala-hippocampus.'

Statistical Analysis

All p values reported here are two-tailed. A mixed-model ANOVA was used to compare N2 latency measured at Cz from target and difference ERPs (type of measurement × group). Because the auditory N2 component is typically largest in amplitude at or near central electrode sites, N2 amplitude was analyzed both for a coronal chain (T3, C3,

Cz, C4, and T4) and an anterior-posterior, midline chain of electrodes (Fz, Cz, Pz, and Oz), which intersected at Cz. These two chains would allow detection of lateralized and anterior-posterior differences in N2 component amplitude across electrode sites. Three-way mixed-model analysis of variance (group x type of N2 measurement × electrode site) on amplitude were used to evaluate group

differences in interactions. Post-hoc ANOVAs and t-tests were used to characterize significant interactions.

If a group × electrode site interaction appeared, suggesting a topographic difference between groups, the ANOVA on raw voltages was followed by an ANOVA using normalized voltages. Amplitudes for the eight sites under consideration were scaled by root mean square vector length (McCarthy and Wood 1985). This procedure entails taking the square root of the sum of the squared means of the electrode site values for each group, and dividing the raw voltage values by this scaling factor. This normalization procedure eliminates overall amplitude differences between groups before evaluating topography, i.e., differences in the shape of the amplitude distribution over the scalp (Faux and McCarley 1990; McCarthy and Wood 1985).

Pearson correlation coefficients were used to test for correl~:ions between N2 amplitude and temporal region volumetric measures. Separate correlation coefficients were always computed for each group (control and schizophrenic subjects). In order to reduce the number of statistical tests, three electrode sites were used in the correlational analysis: Cz, T3, and T4. Cz was chosen because the N2 component was largest at Cz in the control group. T3 and T4 were chosen in order to determine if voltages at lateral sites correlated with different anatomic structures than voltage at Cz. The total TDI score was used for correlational analysis after a Iog~o transformation, because the TDI has a log-normal distribution (Shenton et al 1992). Subscores from the SAPS and SANS were used to evaluate correlations between ERP amplitude and symptom severity in schizophrenia.

Correlation coefficients between the N I and P2 components, measured from the ERP to frequent stimuli at Cz, were also calculated within each group for each MRI region.

R e s u l t s

Group Differences ERP MORPHOLOGY AND TOPOGRAPHY. The averaged

ERPs for each group are shown in Figures 1 and 2. Figure 1 shows ERPs from the lateral electrode sites, and Figure 2 shows ERPs from the midline set of electrodes. The frequent ERPs, the target (infrequent) ERPs, and the difference ERPs are shown at each electrode site. N2t refers

N2 and MRI in Schizophrenia BIOL PSYCHIATRY 31 1993;34:26-40

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to N2 measured from the target ERP, and N2d refers to N2 measured from the difference ERP. Figure 3 shows mean voltages of the N2 component for each group for both types of N2 measurement along the coronal and mid line sites.

NI AND P2 COMPONENTS. N I amplitude w a s reduced in schizophrenic patients ( - 2.1 4- 1.3 I~V, mean 4- SD) compared to control subjects ( - 4.4 4- 1.7 ~V, t(27) = -3 .98, p < 0.001), whereas latency did not differ between groups. P2 amplitude was reduced in schizophrenic subjects (3.3 4- 1.8 I~V) compared to control subjects (5.0 _ 3.3 ~V, t(27) --: 2.23, p = 0.04). P2 latency was earlier in schizophrenic patients (204 4. 31 msec) than in control subjects (245 4- 31 msec, t(27) = 3.3, p = 0.002). Although N1 and P2 amplitudes were both

reduced in schizophrenia, neither measure correlated with any of the MRI Rags evaluated in this study.

N2 LATENCY. The ANOVA performed on the two types of N2 latency measurements revealed a group × measurement interaction (F(1,27) = 10.2, p = 0.004). N2t latency was prolonged in the schizophrenic group (265 ± 22 msec) compared to the control group (240 _ 23 msec, t(27) = 2.74, p = 0.01), but there was no difference in N2d latency. N2d latency was 248 ± 27 msec for the schizophrenic group and 250 - 15 msec for the control group (t(27) = 0.17, not significant [N$]).

N2 AMPLITUDE. N2 amplitude was reduced in schizophrenic patients along the coronal (T3 to I"4) electrode sites (F(1,27) = 12.4, p = 0.002). N2d amplitude was larger f more negative) than N2t amplitude (F(1,27) =



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Figure 2. Group average ERPs to frequent and rare target tones at midline anterior to posterior electrode sites. Control group ERPs are drawn with solid lines, and the schizophrenic group ERPs with dotted lines.

52.6, p < 0.001). The difference between schizophrenic and control groups was largest for N2d (F(1,27) - 10.0, p - 0.004 for the group x measurement interaction). There was a main effect for electrode (F(4,108) = 12.2, p < 0.001), indicating larger voltages at the central-frontal, midline electrodes; an electrode x measurement interaction (F = 19.3, p < 0.001); an electrode x group interaction (F(4,108) = 6.6, p < 0.001); and an electrode x group x measurement interaction (F(4,108) = 5.7,

p < 0.001). These electrode interactions were evaluated using within-group ANOVAs for each type of measurement. In the control group, N2t varied among sites, with larger amplitudes at C3, Cz, and C4 than at T3 and T4 (F(4,52) = 8.4, p < 0.001). A similar pattern held for N2d (F(4,52) = 28.8, p < 0.001). For the schizoFhrenic patients, however, this voltage gradient was absent for N2t

(F(4,56) = 0.6, NS), and was only weakly apparent for N2d (F(4,56) = 2.4, p = 0.06).

Schizophrenic patients also showed reduced N2 amplitude along the midline (Fz, Cz, Pz, and Oz) electrode sites (F(I,27) = 8.1, p = 0,008). N2d amplitude was larger than N2t (F(1,27) = 41.8, p < 0.001), and the voltage difference between groups was largest for N2d as well (F(1,27) = 6.9, p = 0.01 for the group x measurement interaction). N2 amplitude was largest at the frontocentral electrode sites (F(3,81) = 6.2, p = 0.001). There was an electrode x group interaction (F(3,81) = 6.2, p = 0.001), an electrode x measurement interaction (F(3,81), p < 0.001), and a group x measurement x electrode interaction (F(3,81) = 3.8, p = 0.01). In control subjects, there was a frontocentral maximum voltage for both N2t (F(3,39) = 5.4, p = 0.003) and N2d (F(3,39)

N2 and MRI in Schizophrenia BIOL PSYCHIATRY 33 1993;34:26-40

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= 16.5, p < 0.001). For the schizophrenic patients, there was no difference amplitude across electrode sites for N2t (F(3,42) = 0.7, NS) or for N2d (F(3,42) = 1.1, NS).

N2 TOPOGRAPHY. The electrode x group interactions in the ANOVAs on raw voltage values suggested that there might be differences in electrical source configuration between groups. In order to distinguish whether these topographic differences could be solely attributed to overall reduction in electrical source strength in the schizophrenics or were due to differences in source configuration as well, amplitudes were scaled by root mean square vector length prior to follow-up ANOVAs. After this scaling procedure, separate ANOVAs were carried out to contrast the groups for each type of N2 measurement. There were no significant electrode x group interactions for either the coronal or midline electrode chains, indicating that the differences between groups could be attributed to variations in the underlying strength of the sources generating the scalp- recorded N2 component.

i)3 TOPOGRAPHY. In this patient sample, the grand average P3 waveform was slightly less at T3 (2. I ± 1.3 pN) than T4 (2.3 ± 1.5 pN), although in this particular patient group, this difference did not reach significance for the entire group (t(14) = - 1.11, p - 0.29). How- ever, further analysis of these schizophrenic individuals (McCarley et al 1993) demonstrated that schizophrenic patients with left posterior ST(] volumes less than any normal subject (n -- 8) had an average T3 amplitude much less than T4, whereas those schizophrenic patients with more normal left posterior STG volumes had symmetric 1"3 and T4 amplitudes.

INDIVIDUAL DISCRIMINATION. Figure 4 presents scat- tergrams of N2t and N2d amplitude values at Cz. The schizophrenic subjects showed low amplitudes with relatively little variation for N2d. The control subjects, in addition to having generally larger amplitude responses, also show greater variability in N2d. Note the lessened separation and greater variability for the N2t measure.

In summary, these results show a global reduction of

=1.

BIOL PSYCHIATRY 1993;34:26-40

B.F. O'Doanell et al

- 2

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-,4

- 6

u N2t

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- 8

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Control Schizophrenic Control Schizophrenic Figure 4. Scattergram showil,g N2d and N2t amplitude at Cz for the control and schizophrenic subjects. Both N2d (t(27) = -3.8, p = 0.001) and N2t (t(27) - --2.6, p = 0.02) differed between groups.

N2 amplitude in schizophrenic subjects compared with controls. However, the reductiou in N2 amplitude was greater when N2 amplitude was measured from the difference (N2d) rather than the target (N2t) ERP, and better schizophrenic-control group separation was also obtained using the N2d. In control subjects, N2 amplitude was largest at frontocentral electrode sites, whereas in schizo- pluenic patients, this gradient was attenuated or absent. These topographic differences between control and schizophrenic subjects could be attributed to overall differences in electrical source strength. In the target ERP, N2 latency was prolonged in schizophrenia, whereas in the difference ERP, N2 latency did not differ between groups.

N2 Amplitude and MR! Gray-Matter RO! Correlations

Table ! shows the correlation between N2 amplitude at T3, Cz, and T4 and volumes of specific gray-matter structures in the temporal lobe in schizophrenic patients. N2d amplitude was correlated with left superior temporal gyrus volume at T3 and T4, and left anterior hippocampus- amygdala volume at T4. Right temporal gray-matter ROI volumes were also correlated with N2d amplitude. N2d

amplitude was correlated with right parahippocampal volume at T3 and Cz, and right hippocampal volume at T3 and Cz. These negative correlations indicate that in schizophrenic patients, smaller gray-matter volume of specific anatomic structures resulted in smaller (less negative) N2 responses.

N2t amplitude was also correlated with the volume of gray-matter structures. N2t amplitude was correlated with left superior temporal gyrus volume at T3, with left parahippocampal volume at Cz, with right parahippocampal volume at Cz, and with right posterior hippocampal volume at Cz.

We had previously found that P3 amplitude at T3 was selectively correlated to the posterior segment of the left ST(], and not the anterior segment. N2 amplitude, however, did not share this specificity. N2d amplitude was correlated with anterior left STG at T3 (r = -0 .56) , as well as the posterior segment at T3 (r = -0 .53) and T4 (r = - 0.54). N2t amplitude was correlated with posterior STG at T3 (r = -0.57).

Among the control subjects, there was only one structural correlation between N2 amplitude and these anatomic structures: N2t amplitude from the target ERP correlated

N 2 a n d M R I i n S c h i z o p h r e n i a BIOL PSYCHIATRY 35 1993;34:26-4o

T a b l e 1. N 2 A m p l i t u d e a n d T e m p o r a l L o b e G r a y - M a t t e r V o l u m e s ' "

N 2 d N2t

M R I R O I T3 C z T4 T3 C z T4

Lef t

Supe r io r t e m p o r a l g y m s - 0 . 65 b - 0 .45 - 0"65b -- 0 -59 ~ -- 0 . 2 9 -- 0 .19

P a r a h i p p o c a m p a l g y m s - 0 . 3 3 - 0 .38 - 0 .38 - 0 . 45 - 0 .51 c - 0 .24

A n t e r i o r h i p p o c a m p u s - - 0 . 4 6 - 0 . 5 0 - 0 .57 c - 0 . 2 6 - 0 . 42 - 0 .20

a m y g d a l a

Pos te r io r h i p p o c a m p u s 0 . 2 3 - 0 . 26 0 .06 - 0 . 15 0 . 0 ! - 0 .07

Right

Supe r io r t e m p o r a l g y m s - 0 . 3 3 - O. 17 - 0 . 34 - 0 . 4 4 - 0. I I 0 .14

P a r a h i p p o c a m p a l g y m s - 0 . 5 6 c - 0 . 59 ~ - 0 .39 - 0 . 45 - 0 . 5 6 ~ - 0 .24

A n t e r i o r h i p p o c a m p u s - O. 28 0.41 0.01 O. 23 0 .43 0 .12

a m y g d a l a

Pos te r io r h i p p o c a m p u s - 0 . 5 2 ¢ - 0 . 5 2 ~ - 0 .33 - 0 . 43 - 0 .6 (F - 0 .47

aN2d was measured from the target-minus-frequent difference waveform. N2t was measured from the ERP to target stimuli, ~p < 0,01. ~p < 0.05,

with right superior temporal gyros volume at T3 (r = 0.67, p < 0.01)and Cz (r - 0.59, p = 0.03).

Comparison of N2 and P3

LATENCIF.& For both groups, N2t latency and N2d latency were earlier than P3 latency (t > 10.0, p < 0.001). Peak latency of P3 in control subjects (367 +_ 29 msec) did not differ from the peak latency in schizophrenic subjects (374 _ 44 msec). Across all subjects, N2t latency correlated with N2d latency, (r(29) = 0.52, p < 0.01). Neither N2 latency measure correlated with P3 latency.

AMPLITUDE. ACroSS all subjects, N2t amplitude was highly correlated with N2d amplitude at Cz(r(29) -- 0.85, p < 0 . 0 0 1 ) . Neither N2 amplitude measure correlated with P3 amplitude.

A N A T O M I C C O R R E L A T I O N S : I N F L U E N C E O N C O M P O -

N E N T TOPOGRAPHY. We have previously noted that the P3 component in schizophrenia correlated only with left superior temporal gyros volume reduction, and that this relationship could be localized to the posterior segment (McCarley et al 1993). N2 correlated with left superior temporal gyros volume but also with medial temporal lobe gray matter structures.

One issue raised by the strong correlation of N2 amplitude with left STG, and of P3 amplitude with left posterior STG, is whether these relationships might also influence topography. This would be especially likely if these regions contributed to the scalp-recorded ERP. In order to test this possibility, maps showing the magnitude of the correlation coefficients at each electrode site between left STG and N2d amplitude~ and between left posterior STG

and P3 amplitude, were generated (Figure 5). These maps indicate that the influence of left STG on N2d amplitude was largest at lateral temporal sites (T3, T5, T4, and T6), whereas the influence of left posterior STG on P3 amplitude was larger on left hemisphere than on right hemisphere sites and was not significant over frontal electrode sites.

ANOVAs were used to test for lateralized effects on component amplitude, using a median split on the MRI volume to group patients and selecting lateral electrode sites that showed significant correlations with the component. A mixed-model ANOVA using the factors group (small or large left STG), laterality (right versus left electrode sites), and electrode position (T3/T4 versus T5#r6) showed an interaction between group and laterality (F(I, 13) - 7.32, p ffi 0.01). This ANOVA indicated that patients with small left STG volumes (

36 BiOL PSYCHIATRY 1993;34:26-40


Correlation of P3 with Left Posterior STG

Correlation of N2 with Left STG

II r < 0.52 B 0.56 0.59 ms

, ' r ' . ' r r r r r

r • 0.62::~::;~. i

Correlation Coefficients

Figure 5. Maps of correlation coefficient magnitudes across 28 electrode sites between N2d and left posterior STG volume, and between P3 and left posterior STG volume, in schizophrenic patients. Coefficient magnitudes greater than 0.51 are significant at p < 0,05.

CLINICAL CORRELATIONS. The correlations between ERP component amplitude and SAPS subscores, SANS subscores, total TDI score, and chronicity were also examined. For SAPS scores, the most robust correlations were between P3 amplitude and the delusion and thought disorder subscores (Table 3). N2t at T3 and N2d at T4 were also correlated with the SAPS thought disorder sub-

score. Log total TDI score significantly correlated with I)3 amplitude at T3 (n = 13, r = - 0 . 5 9 , p = 0.03) but was not significantly correlated with N2d or N2t at T3, T4, or Cz. Increased chronicity (measured as percent time hospitalized since first episode) was associated with reduced N2d amplitude at all three electrode sites ( r > 0.52, p < 0.05), and with reduced P3 amplitude at T3 ( r =

N2 and MRI in Schizophrenia BIOL PSYCHIATRY 3.7 1993;34:26-40

Table 2. N2 and P3 Asymmetries and Left STG Volume in Schizophrenic Patients"

T3 T4

N2d amplitude (t tV) Small left STG (n = 8) 0 .34 4- 1.83 0.18 -- 0 .77

Large left STG (n = 7) - ! .68 - 1.33 - 0 . 4 9 - 1.11

P3 amplitude ( t tV) Small left Posterior ! .64 _ 0 .92 2.19 4- 1.38

STG (n -- 8) Large left posterior 2.61 4- 1.57 2.46 4- 1.73

STG (n = 7)

aSmall left STG volumes were less than 6 nd and large were greater than 6 ml. Small posterior STG volumes were less than 5 ml and large were greater than 5ml.

-0 .57 , p = 0.04) and Cz (r = - 0 . 5 1 , p - 0.05). N2t did not correlate with chronicity. There was only one correlation between an ERP component and a SANS subscore (N2t with asociality, r ffi 0.53, p < 0.04).

Discussion Several major findings emerged from this study. First, auditory N2 amplitude was reduced in chronic, medicated schizophrenic subjects. Second, N2 amplitude was correlated with gray-matter volume reduction in temporal lobe structures. Moreover, N2 and P3 could be dissociated on the basis of their neuroanatomic and clinical correlates. Third, the manner in which N2 was measured had a significant impact on the pattern of results obtained in schizophrenic patients.

N2d, measured from the difference ERP, was more reduced in the schizophrenics than N2t, measured from the target ERP. This pattern of results is similar to that obtained by Ogura et al (1991), who evaluated unmedicated schizophrenic subjects, and found that N2d was re-

Table 3. ERP Correlations With SAPS Subscores

Bizarre Thought

Hallucinations Delusions behavior disorder

N2t T3 0 .46 0.22 0.40 0.68 a

Cz 0 .09 0.05 0.03 0.41

T4 0.53 a - 0 .06 0. ! 9 0 .49

N2d T3 0.01 0.43 0.10 0 .36

Cz - 0. ! 5 0 .32 - 0.06 0 .29

T4 0.31 0 .46 0.21 0 .56 °

P3 T3 - 0 .18 - 0.75 ° - 0.05 - 0.53 a

Cz - 0 . 2 4 - 0 . 5 2 a - 0 . 1 3 - 0 . 5 6 °

T4 - 0 . 1 0 - 0 . 6 7 ° 0.01 - 0 . 4 0

°p < 0.05.

duced in amplitude, whereas N2t was not. Roth et al (1980) measured N2t only and found no reduction in schizophrenic patients. The results of this study also suggest that sample differences in chronicity or severity of temporal lobe abnormality may contribute to differences in N2 amplitude findings between studies.

The topography of the N2 component, using raw voltage measures, was altered in schizophrenia. Whereas control subjects showed a frontocentral maximum voltage, schizophrenic subjects showed a flatter voltage gradient across the scalp. This topographic difference was not significant after normalizing amplitudes within each group. This result indicates that the topographic differences between groups could be accounted for by an overall reduction in the strength of the underlying sources of the scalp N2 component, rather than by alterations in the fundamental configuration of these electrical sources in schizophrenia.

The amplitudes of both N2d and N2t were directly related to volumetric changes of the gray matter of the left superior temporal gyrus arid of bilateral medial temporal lobe structures in schizophrenic patients. These correlations were invariably negative, indicating that as gray- matter volume became less, the N2 component became less negative (smaller). This pattern of correlations suggests that the electrical sources generating the sea|p-recorded N2 component are bilaterally distributed in the temporal lobe. With the exception of the right hippocampus, these structures were significantly reduced in volume in the schizophrenic patients compared to control subjects (Shenton et al 1992). A question raised by these data is whether these correlations between abnormalities of anatomic structures and N2 amplitude are consistent with other data pointing to the loci of N2 generators. Halgren et al (1992) have recently reported depth-recorded ERP activity in the region of Heschl's gyrus concurrent in time with the scalp-recorded N2 component, which is consistent with the correlation between left superior temporal gyrus gray matter volume and N2 amplitude in the present study. The present data, of course, should not be taken to exclude non-temporal lobe sources of N2; we have not evaluated other brain regions.

In terms of the postulated relationship between N2 and task-relevant stimulus discrimination, especially that of discrepant/novel stimuli, the observed N2-neuroanatomic correlations would be reasonable in terms of a model in which hippocampus (and its output zone, the parahippocampal gyms) acts as part of a comparator circuit between input stimuli and stored representations, with auditory association cortex playing a key role for auditory discrimi- nations (Deadwyler et al 1979; Rolls 1990).

A methodological issue addressed in this study is whether the N2 component is better measured from target or dif-

38 BIOL PSYt21tlATRY 1993;34:26-40

B.F. O'Donne!! et al

ference ERPs, a question not previously systematically ~.ddressed in the schizophrenia literature. In normal subjects, however, the literature suggests the N2d is better, because it shows a better match with the N2 component elicited by an omitted stimulus, and the omitted stimulus does not elicit an overlapping P2 component that might otherwise confound N2 measurement (Simson et al 1976, 1977). Consequently, many experimental studies in normal subjects have come to use difference ERPs for N2 measurement (Novak et al 1990; Sams et al 1985).

The N2d has also been used in clinical studies (Brecher et al 1987; Ogura et al 1991; Pfefferbaum et al 1984). Evidence from the present study suggests that although the amplitude and latency of N2d and N2t are highly correlated and both correlate with volume reductions in similar anatomic structures, they cannot be considered quan- titatively equivalent, because (1) N2d amplitude discriminated between schizophrenic and control subjects more robustly, (2) N2d showed more pervasive correlations with MRI structural measures, and (3) N2d was more closely associated with chronicity. N2t, but not N2d, latency was prolonged in the schizophrenic patients.

The present data also suggest that the N2 and P3, though provoked by the same experimental paradigm, can be an- atomically dissociated, N2 amplitude was correlated with both left superior temporal gyrus and medial temporal lobe volume reduction abnormalities, whereas P3 amplitude was uncorrelated with volume reductions in medial temporal lobe structures. In addition, P3 amplitude showed a selective relationship to posterior STG volume, whereas measures of N2 were correlated with both the anterior and posterior STG segments. Although the patients as a group did not show statistically significant N2 or P3 asymmetries° dividing the schizophrenic group on the basis of left STG volume resulted in lateralized asymmetries of the P3 (McCarley et al 1993) and also the N2 component. These findings suggest that differences in the severity of temporal lobe structural abnormalities play a key role in determining whether patients show a left < right P3 asymmetry (Bruder et al 1992; Faux et al 1993; Hollinger et al 1992; Kraft et al 1991; McCarthy et al 1987; Morstyn et al 1983) or a symmetric P3 component (Pfefferbaum et al 1989).

Functional and clinical relationships also suggest the

separability of N2 and P3 components. N2 latency and amplitude were unrelated to P3 latency and amplitude, suggesting that these components represent separate neural processes. Although chronicity affected both N2d and P3 amplitude, P3 amplitude showed a stronger relationship to two positive symptoms, delusions and thought disorder. We have elsewhere presented data indicating that severity of thought disorder shows a selective relationship to left posterior STG volume (Shenton et al 1992). T~ken together, these findings are consistent with our hypothesis that P3 amplitude reduction over the left temporal region, positive symptoms, and left temporal lobe anatomic abnormalities represent a cohesive process in chronic, right- handed male schizophrenic patients (McCarley et al 1991). More generally, these results provide further support for the hypothesis that endogenous auditory ERP abnormalities in schizophrenia may be highly influenced by temporal lobe pathology. Similar results have been obtained from neurologic patient~,, in whom P3 amplitude seems especially affected by strokes to the left Superior temporal gyms (Knight et al 19~;9; Knight 1990), but little affected by loss of anterior medial temporal lobe tissue (Johnson 1988; Stapleton et al 1987).

These results also emphasize the potential power of combining MRI and scalp-recorded ERP studies in the investigation of schizophrenia. ERPs have extremely high temporal resolution, in the millisecond range, literally at the neural speed of thought. Their main limitation has been their relatively poor spatial resolution. We view the use of combined MRI-ERP studies in schizophrenia from two viewpoints: first, it provides a means to correlate functional with structural changes in this disorder. Second, viewed from a broader background, the structural abnormalities of schizophrenia provide examples of "natural experi- ments," akin to, but more subtle than, those of neurologic disorders such as strokes, that enable the linkage of specific ERP abnormalities to particular brain areas.

Supported by NIMH 40,799 (RWM), Department of Veterans Affairs (RWM), The Commonwealth of Massachusetts Research Center (RWM), NIMH Research Scientist Development Award KOI-MH00746.04 (MES), the Scottish Rite Foundation (MES), the Milton Foundation (MES), and the Swiss National Foundation (RK).

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