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Association Between Smaller Left Posterior Superior Temporal Gyrus Volume on Magnetic Resonance Imaging and Smaller Left Temporal P300 Amplitude in First-Episode Schizophrenia
Robert W. McCarley, MD;
Dean F. Salisbury, PhD;
Yoshio Hirayasu, MD, PhD;
Deborah A. Yurgelun-Todd, PhD;
Mauricio Tohen, DrPH;
Carlos Zarate, MD;
Ron Kikinis, MD;
Ferenc A. Jolesz, MD;
Martha E. Shenton, PhD
Arch Gen Psychiatry. 2002;59:321-331.
ABSTRACT
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Background In chronic schizophrenia, the P300 is broadly reduced and shows a localized
left temporal deficit specifically associated with reduced gray matter volume
of the left posterior superior temporal gyrus (STG). In first-episode patients,
a similar left temporal P300 deficit is present in schizophrenia, but not
in affective psychosis. The present study investigated whether the left temporal
P300–left posterior STG volume association is selectively present in
first-episode schizophrenia.
Method P300 was recorded as first-episode subjects with schizophrenia (n =
15) or affective psychosis (n = 18) or control subjects (n = 18) silently
counted infrequent target tones amid standard tones. High-resolution spoiled
gradient-recalled acquisition magnetic resonance images provided quantitative
measures of temporal lobe gray matter regions of interest.
Results Patients with first-episode schizophrenia displayed a reversed P300
temporal area asymmetry (smaller on the left), while magnetic resonance imaging
showed smaller gray matter volumes of left posterior STG relative to control
subjects and patients with affective psychosis (15.4% and 11.0%, respectively),
smaller gray matter volumes of left planum temporale (21.0% relative to both),
and a smaller total Heschl's gyrus volume (14.6% and 21.1%, respectively).
Left posterior STG and the left planum temporale, but not other regions of
interest, were specifically and positively correlated (r>0.5) with left temporal P300 voltage in patients with schizophrenia
but not in patients with affective psychosis or in control subjects.
Conclusion These results suggest that the left temporal P300 abnormality specifically
associated with left posterior STG gray matter volume reduction is present
at the first hospitalization for schizophrenia but is not present at the first
hospitalization for affective psychosis.
INTRODUCTION
THE MOST replicated electrophysiologic abnormality in schizophrenia
is amplitude reduction of the auditory P300.1-3
This event-related potential (ERP) is elicited when subjects detect rare target
tones among differently pitched tones. Abnormalities in P300 may reflect deficits
in cognitive updating, information processing, and selective attention.4-6 The P300 reduction in
schizophrenia cannot be attributed to latency variability on individual trials
or to absence of P300 on a subset of target trials,7-9
and persists even when clinical improvement is observed.8, 10-11
Patients with schizophrenia also show regional P300 amplitude reduction
over the left temporal region.12 The left-lateralized
deficit in schizophrenia appears in patients not taking medication,13 with the use of a nose reference,14
with 64-channel recording,15 and at initial
hospitalization,16 appears in never-medicated
schizotypy,17 and has been independently replicated.2, 18-31
Bruder et al2 noted that most failures to replicate
used a button-press response.8, 32
In addition, difficult tasks, in which the overall amplitude of P300 is reduced,
also diminish the abnormal P300 asymmetry in schizophrenia.9, 30
Patients with chronic or first-episode psychotic affective disorder
show a normal lateral P300 topography, although an overall reduced P300 may
be present.16, 33 Thus, the left
temporal P300 deficit appears especially intriguing because it is specific
to schizophrenia.
P300 has multiple brain generators, including loci in temporal, frontal,
and parietal lobes.34-38
We focus on the putative bilateral posterior temporal lobe generators. With
the use of computed tomography, it was demonstrated that left sylvian fissure
enlargement correlated with left temporal P300 abnormalities in schizophrenia.39 Using quantitative volumetric magnetic resonance
(MR) imaging, we evaluated hippocampus, parahippocampal gyrus, and superior
temporal gyrus (STG) regions of interest (ROI), and found reductions in gray
matter volume on the left on MR images in patients with chronic schizophrenia40 (see reviews41-42).
Only the left posterior STG gray matter volume correlated with the left temporal
P300 amplitude reduction.43
The previous study,43 however, tested
chronically ill patients, did not test an affective psychosis contrast group,
and did not evaluate STG functional substructures of planum temporale and
Heschl's gyrus. The present study addressed these limitations. We tested a
first psychotic episode population largely free of potential chronicity confounds
and a contrast group of patients with first-episode affective psychosis. We
used the same P300 protocol16 and ROI definitions40, 44 as in the previous study,43 but added planum temporale (a major substrate of
language processing,45-46 largely,
but not completely, coextensive with posterior STG) and Heschl's gyrus (primary
auditory cortex).
To be specifically associated with the left temporal P300 deficit, the
ROI's volume should be positively correlated with left temporal P300 amplitude,
but not with P300 from other sites. Any ROI associated with global P300 amplitude
reduction cannot explain a topographically local reduction. Absolute MR imaging
volumes are correlated with P300 amplitude as the absolute volume of neurons,
especially their dendrites, gives rise to the absolute P300 voltages.43 On the basis of previous work from our group,43 we predict a left temporal P300–left posterior
STG/planum association in first-episode schizophrenia.
SUBJECTS AND METHODS
SUBJECTS
Clinical samples included only patients at first hospitalization, and
consisted of 15 patients with schizophrenia (3 female and 12 male; 13 paranoid,
1 disorganized, and 1 undifferentiated) and 18 patients with affective disorder
with psychotic features (3 female and 15 male; 17 with bipolar disorder [all
in manic phase] and 1 with unipolar disorder [whose omission did not affect
the statistical results reported herein]). The date of the first psychiatric
hospitalization defined onset of psychosis, a commonly used definition of
"first episode." We also measured the time of first medication, an objective
estimate of symptom onset (most dates were from hospital records). (The validity
of a retrospective measurement of onset of prodromal symptoms would have been
difficult to verify [see discussions16, 44, 46].)
Nine of the 15 patients with schizophrenia were prescribed either antipsychotic,
antidepressive, or mood-stabilizing medication before admission. For these
9 subjects, the mean duration of preadmission medication was 158.9 days; the
median, 90 days; and the range, 3 to 730 days. Eight of the 18 patients with
affective disorder were prescribed antipsychotic, antidepressive, or mood-stabilizing
medication before this admission. For these 8 subjects, the mean duration
was 217.3 days; the median, 150 days; and the range, 41 to 547 days. Patients
were not necessarily medication compliant (by self-report). Eighteen normal
control subjects (3 female and 15 male) were recruited from the general population
through newspaper advertisements.
Patients' diagnoses were confirmed via the Structured Clinical Interview
for DSM-III-R, Patient Version,47
and control subjects were screened with the Structured Clinical Interview
for DSM-III-R, Non-patient Edition,48
by trained interviewers (D.F.S. and M.E.S.). Inclusion criteria were age between
18 and 55 years, IQ greater than 85, and normal hearing as assessed by audiometry.
Any subject with a documented developmental disorder or learning disability,
neurologic impairment, history of electroconvulsive therapy, seizures, head
injury, or substance dependence within the past 5 years was excluded.
Groups did not differ in age and parental socioeconomic status. Patients
with schizophrenia had significantly lower socioeconomic status than did control
subjects, consistent with their illness. All were right-handed. Samples did
not differ in basic cognitive performance, and patient groups were not different
in medication dosages or clinical severity (Table 1). Consistent with previous studies,13, 16, 44, 46
neither dose nor duration of medication was significantly correlated with
P300 amplitudes or MR imaging volumes after Bonferroni correction in any group.
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Table 1. Subject Demographics*
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All subjects gave written informed consent and were paid for their participation.
All subjects underwent ERP and MR testing. The median interval between ERP
testing and MR imaging was 8 days. Four patients with first-episode schizophrenia,
2 patients with first-episode affective psychosis, and 9 control subjects
were drawn from the previously reported P300 study from our group.16 Fifteen patients with schizophrenia, 14 patients
with affective disorder, and 15 control subjects were also included in a previously
reported MR imaging study by our group of anterior-posterior STG and medial
temporal lobe44 (which included 17 patients
with schizophrenia, 16 patients with affective disorder, and 18 control subjects).
All current subjects were also in our MR imaging study of Heschl's gyrus and
planum temporale46 (which analyzed 20 patients
with schizophrenia, 27 patients with affective disorder, and 22 control subjects).
No subjects were in common with our initial MR imaging and MR imaging–ERP
chronic schizophrenia studies.40, 43
P300 RECORDING
Subjects silently counted infrequent (15%) binaurally presented target
tones (97 dB sound pressure level, 1.5 kHz, 50-millisecond duration, 10-millisecond
rise/fall) among standard tones (97 dB, 1 kHz) against a background of 70-dB
white noise. Electroencephalographic activity was recorded from the scalp
through 28 tin electrodes in preconfigured caps (ElectroCap International,
Eaton, Ohio) with the use of an amplifier-stimulator (Neuroscience, Milpitas,
Calif) and recording software (Neuroscan Labs; Sterling, Va). Electrode sites
included all 10-20 sites excluding T1/2, and including Oz, FTC1/2, TCP1/2,
PO1/2, and CP1/2. Linked earlobes were the reference; the forehead was ground.
Two electrodes located medially to the right eye, one above and one below,
monitored vertical eye movements and blinks. Electrodes placed at the outer
canthi of the eyes monitored horizontal eye movements. All impedances were
below 3 k , and the ears were matched within 1 k. The electroencephalograph
amplifier bandpass was 0.15 (6 dB/octave roll-off) to 40 Hz (36 dB/octave
rolloff). Single trial epochs were digitized at 3.5 milliseconds per sample
over 900 milliseconds, including a 100-millisecond prestimulus baseline. Averaging
and artifact rejection were done offline.
The ERP responses were convolved with a zero phase-shift digital low-pass
filter at 8.5 Hz (24 dB/octave; Neuroscan Labs) to remove ambient electrical
noise, muscle artifact, and alpha contamination. Within each 200-trial block,
epochs from each electrode site were baseline corrected by subtraction of
the average prestimulus voltage and mathematically corrected for eye movement
artifact.53 Subsequently, epochs exceeding
±50 µV at F7, F8, Fp1, or Fp2 were rejected. Averages were computed
for the brain responses to target tones. Peak P300 amplitude, which accounts
for individual variations in P300 latency, and latency were measured as the
most positive point from 250 to 650 milliseconds at each recording site.
MR IMAGING PROCEDURES
The MR images were obtained with a 1.5-T scanner (GE Medical Systems,
Milwaukee, Wis) by means of 2 acquisition protocols.44, 46
A 3-dimensional Fourier transform spoiled gradient-recalled acquisition protocol
produced a coronal series of contiguous images (repetition time, 35 milliseconds;
echo time, 5 milliseconds; 1 repetition; 45° nutation angle; 24-cm field
of view; number of excitations, 1.0; matrix, 256 x 256 [192 phase encoding
steps] x 124). Voxels were 0.9375 x 0.9375 x 1.5 mm. Data
were reformatted in the coronal plane as 124 coronal slices of 1.5-mm thickness
and used for delineating and measuring temporal lobe regions. The second acquisition
resulted in an axial series of contiguous double-echo (proton density and
T2-weighted) images used to assess whole brain volume (repetition time, 3000
milliseconds; echo times, 30 and 80 milliseconds; 24-cm field of view; interleaved
acquisition with 3-mm slice thickness). Voxels were 0.9375 x 0.9375
x 3 mm. A semiautomated segmentation procedure40
was used on the axial double-echo slices to measure total intracranial contents
(ICC), and an anisotropic diffusion filter was used to reduce noise before
processing.54-55
All analyses were performed blinded to subject identity, age, and diagnosis,
and after uniform alignment of images in 3-dimensional space. The ROI included
the gray matter of the STG, amygdala-hippocampal complex, and parahippocampal
gyrus, which were outlined manually on a workstation (Figure 1A). The STG gray matter is lateral, and the amygdala-hippocampal
complex is medial to it, with parahippocampal gyrus most ventral. Gyral boundaries
for STG were made by means of sagittal MR images computed from coronal images.
The ROI began anteriorly at the slice unambiguously depicting the temporal
stem and extended posteriorly to the last slice showing the fornix along the
border of the lateral ventricles. Anterior and posterior portions were divided
at the first slice including the mammillary bodies.40
To separate gray and white matter of STG from the rest of temporal lobe, a
line was drawn in the deepest points of the sulci of the STG (sylvian point
and superior temporal sulcus) for each slice. The internal boundary for STG
was always white matter, and the external boundary, cerebrospinal fluid. Interrater
reliability for these ROI by 3 raters (including Y.H.) for 3 cases were as
follows: STG, r = 0.99 (F2,11 = 6.66);
parahippocampal gyrus, r = 0.99 (F2,11
= 11.3); amygdala-hippocampus, r = 0.95 (F2,11 = 3.71).
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Figure 1. Specific regions of interest examined
in this study. A, Coronal slice (1.5 mm) of the temporal lobe of a normal
comparison subject. The regions of interest illustrated are the gray matter
of the superior temporal gyrus (subject left, red; subject right, green);
more medially, the amygdala-hippocampal complex is shown (left, orange; right,
blue) with the parahippocampal gyrus underneath (left, pink; right, purple).
B, Left lateral view of 3-dimensional reconstructions of the cortical surface
with anterior superior temporal gyrus (light pink) and posterior superior
temporal gyrus (red). C, Coronal slice (1.5 mm) through the temporal lobe
of a normal control subject. The regions of interest here are the gray matter
of Heschl's gyrus (HG) (red on subject left and green on subject right) and
the gray matter of planum temporale (PT) (labeled yellow on subject right
and blue on subject left). D, Three-dimensional reconstruction of HG and PT
superimposed on an axial magnetic resonance slice. Anterior is top; HG is
red on subject left and green on subject right; and PT is blue on subject
left and yellow on subject right.
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The ROI definitions for the planum temporale and Heschl's gyrus volumes
are detailed elsewhere45-46 and
are similar to those of Barta et al.56 Intraclass
correlation coefficients for 10 randomly selected cases evaluated by 3 raters
(including Y.H.) were as follows: r = 0.88 (left
Heschl's gyrus), r = 0.88 (right Heschl's gyrus), r = 0.98 (left planum temporale), and r = 0.95 (right planum temporale).
DATA ANALYSES
Statistics were computed with SPSS software (SPSS Inc, Chicago, Ill).
One-way analysis of variance (ANOVA) with post hoc Tukey honestly significant
difference tests assessed group differences in demographic, clinical, and
basic neuropsychological performance. For ERP measures, a mixed-model repeated-measures
ANOVA was used to test for effects along the sagittal midline and over temporal
lobes, with group (schizophrenia, affective disorder, and control) as the
between-subjects factor and anterior-posterior (AP) site (frontal [Fz], central
[Cz], and parietal [Pz]) or side (left and right midtemporal sites [T3 and
T4] for lateral analyses) as the within-subjects factor. Subsequent mixed-model
repeated-measures ANOVA pairing each group were conducted in the case of significant
group effects or group interactions. For the AP site factor, the Huynh-Feldt 
was used to adjust degrees of freedom for multiple comparisons.
The ICC volume was used to control for differences in head size by computing
relative volume: relative ROI volume = (ROI volume/ICC volume) x 100.
(Testing absolute volumes with ICC as a covariate did not change the results
reported below.) Group differences in ICC were assessed with 1-way ANOVA.
Groups were not significantly different in ICC volume (P>.34; mean ± SD, control, 1541.8 ± 149.2 mL; schizophrenia,
1511.0 ± 105.2 mL; affective psychosis, 1480.4 ± 111.4 mL).
Mixed-model repeated-measures ANOVAs were performed for each ROI, with group
(schizophrenia, affective disorder, and control) as the between-subjects factor
and hemisphere (left and right) as within-subjects factors. Subsequent mixed-model
repeated-measures ANOVA pairing each group were conducted in the case of significant
group effects. In the case of significant group x hemisphere interactions,
1-way ANOVA was performed comparing groups on each side.
Pearson correlations were performed to assess the relationship between
the absolute volume of ROIs and P300 amplitude.43
Conservative 2-tailed probabilities were used. Our prediction, based on previous
work,43 was that reduced left temporal P300
amplitudes would be specifically correlated with posterior STG and planum
temporale volume in patients with schizophrenia, but not in those with affective
disorder or control subjects. Results were considered significant at P<.05.
RESULTS
P300 TOPOGRAPHY
Although the patients showed smaller P300 amplitudes than control subjects
anteriorly along the sagittal midline (Figure
2), there were no significant differences among groups (group: P>.7). All groups showed the expected posteriorly maximum
P300 (AP site: F2,96 = 91.37, P<.001,
= 0.88). Groups did not differ in P300 peak latency along the sagittal midline
(P>.3), and all groups showed the expected increase
in P300 latency posteriorly (AP site: F2,96 = 18.94, P<.001, = 1.0).
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Figure 2. P300 to target tones. A, Event-related
potential waveforms along the sagittal and coronal midlines. Note the relatively
large P300 in all groups at the frontal central and posterior sites. By contrast,
the schizophrenia group shows a reduction at T3, resulting in a significantly
asymmetric P300. B, Topography of P300 across the surface of the scalp. Note
the regionally selective reduction of P300 voltage in patients with schizophrenia
from sites overlying the left temporal lobe.
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Over the midtemporal sites (T3 and T4), the groups showed significantly
different lateral topographies (group x side: F2,48 = 9.46, P<.001). The schizophrenia group was significantly asymmetrical
compared with the affective psychosis group (group x side: F1,31 = 11.0, P = .002) and with the control group
(group x side: F1,31 = 17.01, P<.001).
In contrast, both the affective psychosis group and the control group showed
a significant but different asymmetry from the schizophrenic group, with P300
amplitude larger over the left temporal site than the right (side: F1,34 = 10.93, P = .002). Comparison of groups
at each midtemporal site showed significant group differences at the left
midtemporal site (T3, F2,48 = 3.29, P
= .046), but not at the right midtemporal site (T4). Post hoc analyses of
T3 showed that the patients with schizophrenia displayed smaller amplitudes
than did controls (4.99 vs 6.75 µV, P<.05).
GRAY MATTER VOLUMES
Groups were compared for all ROI, including anterior and posterior subdivisions
(Table 2). Analysis of anterior
STG showed that groups did not differ in volumes, and that the 3 groups showed
an anterior STG larger on the right (hemisphere: F2,48 = 45.98, P<.001). Groups did not differ significantly in posterior
STG volumes (group: F2,48 = 2.97, P =
.06). Groups differed significantly in hemispheric lateralization for posterior
STG volumes (group x hemisphere: F2,48 = 3.67, P = .03). Separate 1-way ANOVA for left and right posterior STG between
the 3 groups showed a significant difference only in left posterior STG volumes
(F2,48 = 6.77, P<.003). Post hoc comparisons
demonstrated a significant left posterior STG volume difference between schizophrenic
patients and control subjects (P<.05; relative
volumes of 0.406% and 0.480%, respectively) and between schizophrenic patients
and patients with affective psychosis (P<.05;
0.406% and 0.456% relative volumes, respectively).
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Table 2. Relative Volumes of Regions of Interest*
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Total (left + right) Heschl's gyrus volume was significantly different
among groups (group: F2,48 = 8.77, P =
.001). The schizophrenia group showed reduced total Heschl's gyrus volumes
compared with the first-episode affective psychosis group (group: F1,31 = 18.35, P<.001) and the control group
(group: F1,31 = 7.00, P = .01). All 3
groups showed greater Heschl's gyrus volume on the left (hemisphere: F2,48 = 10.61, P = .002). Although a separate
1-way ANOVA indicated that left Heschl's volume was selectively reduced in
schizophrenia (Table 2), the group
x side interaction was not significant (P>.4).
Total (left + right) planum temporale volumes were not significantly
different between groups (group: P>.29), but groups
showed significantly different volume asymmetries (group x hemisphere:
F2,48 = 6.93, P = .002). Post hoc tests
showed that the schizophrenia group had a significantly smaller left planum
temporale volume (0.124%) than both the affective psychosis (0.157%) and control
(0.157%) groups.
For the anterior amygdala-hippocampus (predominantly amygdala), there
were no significant relative volume differences between groups (P>.23). Groups showed larger total anterior amygdala-hippocampus relative
volumes on the right (hemisphere: F1,48 = 56.24, P<.001). For posterior amygdala-hippocampus (predominantly hippocampus)
volumes, groups were not significantly different (group: F2,48
= 2.60, P = .085). No hippocampal volume asymmetry
was present in any group.
For the parahippocampal gyrus, data were missing because of technical
problems from 4 patients with affective psychosis and 3 control subjects.
Groups were not significantly different in relative parahippocampal gyrus
volume (P>.22), nor were there any effects of hemisphere
(P>.49) or any interaction between group and hemisphere
(P>.44).
CORRELATION OF P300 AND GRAY MATTER VOLUMES
P300 amplitude was associated with the volume of several ROI (Table 3). The anterior STG, although not
reduced in volume in any of the groups, showed significant correlations with
P300 amplitude in the patient samples, but not in control subjects. These
correlations did not, however, show specificity with left temporal P300 amplitudes.
Instead, anterior STG-P300 correlations were more diffuse and included frontal
and contralateral sites.
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Table 3. Significant Correlations Between MR Imaging ROI and P300 (Pearson r)*
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Left posterior STG volume in the first-episode schizophrenia group was
significantly correlated with P300 amplitude at the midtemporal site, T3 (Figure 3). The maps (Figure 3B) show that the volume of the left posterior STG in the
first-episode schizophrenia group was correlated with P300 across the left
temporal scalp area, precisely the areas where P300 showed regionally specific
reduction in those patients. (This correlation was not driven by those schizophrenic
patients with the smallest volumes. A median split on the schizophrenia group
based on the absolute volume of the STG [6.34 mL] showed no significant differences
in P300 amplitude at temporal sites [P>.44], and
both subsamples were reduced over the left temporal lobe [side: F1,13 = 8.09, P = .01]). The magnitude of the left
posterior STG volume–P300 amplitude correlations progressively diminished
with greater distance away from the left temporal scalp region. In contrast,
there were no significant correlations between left posterior STG volumes
and P300 in the other 2 groups. Right posterior STG volumes showed no correlation
with P300 amplitude anywhere on the scalp for any group.
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Figure 3. Pearson correlation between posterior
superior temporal gyrus (STG) and P300. A, The amplitude of P300 recorded
from the T3 site, overlying the middle of the temporal lobe, is significantly
correlated with the size of the left posterior STG gray matter. B, Topography
of the color-coded magnitude of Pearson correlation coefficients between left
and right posterior STG and P300 across the whole surface of the scalp. Arrow
on color code bar indicates the P<.05 level of
statistical significance. Note that the gray matter volume of the left posterior
STG shows a regionally selective association with P300 amplitude, showing
a strong correlation with P300 recorded over the left temporal lobe, precisely
the area where P300 is abnormally small in schizophrenia. By contrast, the
gray matter volume of the right posterior STG is not significantly correlated
with P300 amplitude anywhere across the surface of the scalp.
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A correlation between left Heschl's gyrus volume in the first-episode
schizophrenia group and P300 amplitude at T3 was present (r = .53, P = .047; Figure 4). However, there was little specificity of the correlations
for the left temporal site, since moderate r values
were present over much of the scalp and there was a significant correlation
at FTC2, a site overlying right frontal and temporal lobes (r = .54, P = .04). As predicted, left Heschl's
gyrus volume did not significantly correlate with P300 amplitude in the other
2 groups.
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Figure 4. Topography of the correlation
between left and right Heschl's gyri and P300. See "Correlation of P300 and
Gray Matter Volumes" subsection of the "Results" section for description.
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Although the left planum temporale volume and left midtemporal P300
association was only marginally significant according to our conservative
2-tailed probability (r = .51, P = .053), the left planum temporale volume showed a regionally specific
association with the P300 deficit in the schizophrenia group (Figure 5). The correlation topography in the schizophrenia group
between P300 amplitude and left planum temporale approximated that of the
left posterior STG (Figure 3), including
a maximum in the left temporal region and a progressively diminishing correlation
pattern at sites progressively more distant from the left temporal maximum.
The degree of the left temporal P300 correlations with the left planum temporale
volume was smaller than with the left posterior STG volume, although not statistically
significantly different. Note further that the right planum (not reduced in
MR imaging volume) did not show significant correlations with P300 amplitude
in first-episode schizophrenia. In the first-episode affective psychosis group,
neither left nor right planum volume was significantly correlated with P300
amplitude. In control subjects, both left and right planum volumes showed
some left and central electrode correlations with P300, but without the degree
of left temporal P300 specificity of correlation in schizophrenia where there
was a pathological reduction of volume.
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Figure 5. Topography of the correlation
between left and right planum temporale and P300. See "Correlation of P300
and Gray Matter Volumes" subsection of the "Results" section for description.
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There were no associations between the volume of medial temporal lobe
structures and P300 amplitude anywhere on the scalp in either first-episode
patient group. In control subjects, there were some significant but isolated
correlations between P300 amplitude at posterior sites and medial temporal
lobe structures.
COMMENT
Patients with first-episode (first-hospitalization) schizophrenia showed
left-lateralized P300 amplitude reduction and left-lateralized reductions
of posterior STG and planum temporale gray matter. In addition, these patients
with first-episode schizophrenia demonstrated a topographically specific association
between the left temporal scalp region P300 voltage reduction and reduced
MR imaging gray matter volume of the posterior portion of the left superior
temporal gyrus and, to a lesser degree, the left planum temporale. In contrast,
neither patients with first-episode affective psychosis nor control subjects
showed the left temporal scalp region P300 amplitude reduction, lateralized
temporal lobe ROI volume reductions, or any regionally specific correlation
between P300 left midtemporal amplitude and any ROI.
These data and previous data from our group43
link functional abnormalities of P300 with anatomic abnormalities in schizophrenia
and highlight the importance of left posterior STG gray matter in the production
of the left temporal P300 deficit in schizophrenia. It is likely that the
left-lateralized reductions in the P300 are due to reductions of gray matter
in the underlying posterior temporal lobe generator. The left-lateralized
P300 amplitude reduction in patients with first-episode schizophrenia replicated
a previous report from our group.16 (The asymmetry
persisted with removal of the 4 common patients with schizophrenia.) Interrelated
regionally restricted P300 voltage abnormality and reduction in left posterior
STG and planum temporale volume appear selective for schizophrenia and present
at first hospitalization, even in the presence of relatively large and normal
midline P300 amplitudes.
Recent reviews41-42,57
showed that 80% of MR imaging studies found left STG volume reduction in schizophrenia,
the highest percentage of any cortical ROI. Left STG gray matter showed even
more specificity, with volume reduction present in 100% of all studies. Since
gray matter is the source of P300, any study not differentiating STG gray
and white matter might not show this STG-P300 correlation.58-59
Ford60 found positive correlations between
central P300 amplitude and overall cortical gray matter volume; the modeling
by Menon et al61 of P300 dipole sources in
healthy subjects as including sources in temporoparietal cortex appears compatible
with our results.
Gray matter volume reductions of posterior STG and planum temporale
lateralized to the left are congruent with previous demonstrations of reversed
planum temporale asymmetry in schizophrenia, particularly as planum temporale
may contain cortical circuits crucial for language comprehension.45-46 Of particular relevance in patients
with schizophrenia was Bruder and colleagues' report62
of the lack of the normal right ear (left hemisphere) dominance for syllable
perception in a dichotic listening task, a finding linked to a reduced N2
and P300 left temporal area amplitude. It is enticing to speculate that the
left planum temporale contains neural circuits fundamental to the thought
disorder of schizophrenia and that the abnormalities observed in both the
MR imaging volume and P300 function may relate to underlying circuit abnormalities
in this cortical substrate of language and auditory processing.
Limitations of the present study include the fact that extratemporal
ROI were not examined. It is possible that other ROI, especially frontal and
parietal, might show correlations with P300. For example, parietal MR imaging
right supramarginal gyrus volumes in patients with chronic schizophrenia63 showed significant positive correlations (r>.51, P .05) with left and right centroparietal
P300 voltages. However, there were no significant correlations with temporal
electrodes, suggesting that this region exerted its main effect centrally
and paracentrally. A further limitation is that the current samples do not
contain enough women to examine sex effects.
In addition, it might be argued that the left temporal P300 and cortical
structural associations reflect only a subset of the associations found in
these data. However, we again emphasize that a crucial factor for interpretation
must be the left temporal P300 regional selectivity of the association, which
was satisfied only by those associations. This study used the classic method
of correlating an anatomic abnormality ("lesion") in a disorder with functional
information, such as that used by Knight et al35
with ERP measures, a host of investigators with neuropsychological data,64-65 and the original analysis of functional
data dating back to Dax (1836; as reported by Kolb and Wishaw66),
Broca,67 and Wernicke68
localizing language and speech functions to the left hemisphere on the basis
of postmortem lesion data. We cannot rule out the possibility that the correlation
might be from some (unknown) third abnormality, although this hypothetical
possibility appears remote on the basis of our knowledge of structural changes
and P300 sources. In summary, the present data suggest that schizophrenia
involves abnormalities in the structure of the left posterior STG and a functional
abnormality, the left temporal P300 scalp deficit, which is itself associated
with the reduced volume of the left posterior STG. Furthermore, these interrelated
structural and functional abnormalities are present at the first hospitalization
in patients with schizophrenia and are specific to schizophrenia rather than
related to psychotic features in general. Future work will include longitudinal
assessments to determine whether pathological changes over time are observed
in structural or functional measures and, if so, how these measures interrelate.
An additional goal will be to relate these brain measures to the clinical
symptoms of these patients with first-episode schizophrenia so as to link
the basic physiologic and anatomic measures to clinical features.
AUTHOR INFORMATION
Submitted for publication November 28, 2000; final revision received
June 13, 2001; accepted June 26, 2001.
This work was supported in part by MERIT and Schizophrenia Center Awards
from the Department of Veterans Affairs Medical Research Service, Washington,
DC; grants 40799 (Dr McCarley), 01110 (Dr Shenton), and 50740 (Dr Shenton)
from the National Institute of Mental Health, Rockville, Md; and the National
Alliance for Research in Schizophrenia and Depression, Great Neck, NY (Dr
Salisbury).
Corresponding author and reprints: Robert W. McCarley, MD or Martha
E. Shenton, PhD, Psychiatry 116, 940 Belmont St, Brockton, MA 02301 (e-mail: robert_mccarley{at}hms.harvard.edu or martha_shenton{at}hms.harvard.edu).
From the Department of Psychiatry, Harvard Medical School, Veterans
Affairs Boston Healthcare System, Brockton, Mass (Drs McCarley, Salisbury,
Hirayasu, and Shenton), Cognitive Neuroscience Laboratory (Drs McCarley, Salisbury,
and Shenton), Brain-Imaging Center (Dr Yurgelun-Todd), and Bipolar and Psychotic
Disorders Program (Drs Tohen and Zarate), McLean Hospital, Belmont, Mass,
and Surgical Planning Laboratory, Division of Magnetic Resonance Imaging,
Department of Radiology, Brigham and Woman's Hospital, Boston, Mass (Drs Hirayasu,
Kikinis, Jolesz, and Shenton).
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