Download High-Density Recording and Topographic Analysis of the Auditory

High-Density Recording and Topographic Analysis of
the Auditory Oddball Event-Related Potential in
Patients with Schizophrenia
Geoffrey F. Potts, Yoshio Hirayasu, Brian F. O’Donnell, Martha E. Shenton, and
Robert W. McCarley
Background: Prior research has shown reductions of the
N1, N2, and P300 auditory event-related potential (ERP)
components in schizophrenic patients. Most studies have
shown a greater P300 reduction in left versus right
temporal leads in schizophrenic patients. These studies
were done with sparse electrode arrays, covering restricted areas of the head, thus providing an incomplete
representation of the topographic field distribution.
Methods: We used a 64-channel montage to acquire
auditory oddball ERPs from 24 schizophrenic patients and
24 controls subjects. The N1, P2, N2, P300, and N2
difference (N2d) amplitudes and latencies were tested for
group and laterality differences. Component topographies
were mapped onto a three-dimensional head model to
display the group differences.
Results: The schizophrenic group showed reduction of the
N1 component, perhaps reflecting reduced arousal or
vigilance, but no N1 topographic difference. An N2d was
not apparent in the schizophrenic patients, perhaps reflecting severe disruption in neural systems of stimulus
categorization. In the patients, the P300 was smaller over
the left temporal lobe sites than the right.
Conclusions: The increased ERP spatial sampling allowed a more complete representation of the dipolar
nature of the P300, which showed field contours consistent
with neural sources in the posterior superior temporal
plane. Biol Psychiatry 1998;44:982–989 © 1998 Society of Biological Psychiatry
Key Words: P300, N1, N2, schizophrenia, event-related
potentials, 64-channel montage
From the Department of Psychiatry, Harvard Medical School, Boston, Massachusetts, and the Veterans Affairs Medical Center, Brockton, Massachusetts.
Address reprint requests to Robert W. McCarley, MD, Brockton VA Medical
Center, Psychiatry 116-A, 940 Belmont Street, Brockton, MA 02401.
Received March 30, 1998; revised June 23, 1998; accepted June 25, 1998.
© 1998 Society of Biological Psychiatry
Introduction
B
etween 300 and 400 msec after the presentation of a
stimulus there is a large deflection in the event-related
potential (ERP), the P300 (Sutton et al 1965). The P300
can be elicited using an auditory oddball paradigm in
which infrequent “oddball” target tones are interspersed
into a stream of frequent “standard” tones, and the subject
is instructed to make some response to, usually to count
silently, the oddball targets. The P300 is sensitive to the
subjective frequency of a stimulus (Ritter et al 1968) and
to its task relevance (Courchesne et al 1975; Donchin
1979). The P300 has been proposed as an index of
multiple cognitive processes, including context updating,
memory consolidation, orienting, processing termination,
and decision making (reviewed in Donchin and Coles
1988; Johnson 1988; Verleger 1988). The P300 is not a
single phenomenon, but is comprised of subcomponents
supported by separate neural substrates (Johnson 1988,
1993; Ruchkin et al 1990). Some of the neural structures
that have been associated with the P300 are the medial
temporal lobe including hippocampus (Neshige and Luders 1992; O’Donnell et al 1993; Tarkka et al 1995), frontal
cortex (Neshige and Luders 1992), the temporal parietal
junction (Knight et al 1989), and auditory cortex in the
superior temporal lobes, including the posterior superior
temporal gyrus (STG; Knight et al 1989; Lovrich et al
1988; Tarkka et al 1995). These P300 neural substrates
have been described using topographic voltage mapping
(Giard et al 1988; Lovrich et al 1988), current density
mapping (Law et al 1993), and dipole modeling
(O’Donnell et al 1993; Tarkka et al 1995), and through
comparison with other methodologies, including magnetoencephalography (Rogers et al 1991; Tarkka et al 1995)
and intracranial recording (Neshige and Luders 1992).
There is a well-established finding of reduced P300
amplitude in schizophrenia (reviewed in Bruder et al 1996;
McCarley et al 1997; Roth et al 1986). Many studies have
found that this P300 amplitude reduction is not uniformly
distributed across the scalp, but that the amplitude reduc0006-3223/98/$19.00
PII S0006-3223(98)00223-6
64-Channel ERP in Schizophrenia
tion is greater at electrodes over the left temporal region
than the right temporal region (e.g., Faux et al 1993;
McCarley et al 1991; Morstyn et al 1983; Salisbury et al
1998; Turetsky et al 1988; but see also Ford et al 1994a;
Pfefferbaum et al 1989; reviews in Bruder et al 1996;
McCarley et al 1997). It has been suggested that differences in task demands may account for some studies not
replicating the P300 lateralization; studies that find lateralization use a silent count task, whereas studies that do
not find lateralization use a motor (key press) response
(Bruder et al 1996). The left lateralized reduction has also
been found in unmedicated schizophrenics (Faux et al
1993) and in first-episode schizophrenics (Salisbury et al
1998), implying that the asymmetry reflects an aspect of
the disease process rather than an effect of medication.
Interestingly, the asymmetry is reversed in left-handed
schizophrenics, i.e., the amplitude reduction is largest over
the right hemisphere for the left-handed patients (Holinger
et al 1992). The electrophysiological asymmetry has been
related to brain structure using magnetic resonance imaging. In a study comparing the volume of temporal lobe
structures with P300 amplitude, McCarley et al (1993)
found that, for schizophrenic subjects, the auditory P300
amplitude reduction over left temporal lobe sites was
correlated to the reduction in volume of the left posterior
STG, one of the probable auditory P300 generators.
Although the P300 has received the most attention, it is
not the only auditory ERP component that is affected by
schizophrenia. Amplitude and latency alterations have also
been reported for the N1 (Ford et al 1994b; Kessler and
Steinberg 1989; O’Donnell et al 1994), the P2 (O’Donnell
et al 1994; Sandman et al 1987), the N2 (Ford et al 1994b;
Javitt et al 1995; O’Donnell et al 1993, 1994; Sandman et
al 1987), and, in the target minus standard difference
wave, the mismatch negativity (Javitt et al 1995) and the
N2 difference (N2d) (O’Donnell et al 1993). These components are thought to arise from a combination of neural
sources in primary and secondary auditory cortical areas in
the superior and lateral temporal lobes, with contributions
from frontal lobe activity (Giard et al 1988, 1994; Hegerl
et al 1994; Pantev et al 1995; Ponton et al 1993; Rogers et
al 1991; Tarkka et al 1995).
The ability to relate scalp-recorded electrical signals to
underlying neural activity depends, in part, on a full and
accurate description of those electrical signals. The actual
linking of scalp recordings to neural generators requires
solving a formal inverse problem; however, this inverse
problem is “ill-posed,” that is, it does not have an unique
solution and small errors in the input data can result in
unconstrained errors in the solution. If an ERP recording
system has only a few electrodes, clustered over a limited
scalp area, then there are large gaps between the electrodes, and some spatial characteristics of the ERP may
BIOL PSYCHIATRY
1998;44:982–989
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not be fully described (Tucker et al 1994; Wikswo et al
1993). If the spatial sampling is sparse, then there can be
spatial aliasing of the signal (Srinivasan et al in press).
Thus if undersampled ERP data were entered into an
inverse formulation, there could be large and unpredictable errors in the resulting solution. It has been demonstrated that nonredundant spatial information can be derived from recording systems with more than 100
electrodes (Gevins et al 1991), and the limit at which
unique information is present at each electrode may be
between 200 and 300 electrodes (Srinivasan et al 1998).
Recently there have been several published studies that
have provided detailed descriptions of the scalp topography of the ERP using dense arrays (64 or more electrodes)
including studies of semantic priming (Curran et al 1993),
working memory (Gevins et al 1996), visual attention
(Potts et al 1996), and auditory attention (Potts et al 1998);
however, to our knowledge, all prior ERP studies in
schizophrenia have been done with low-density recording
arrays (32 or fewer electrodes, sometimes as few as four
midline electrodes), with little or no coverage of inferior
scalp sites, thus the topographic distribution of the scalprecorded electrical field has been incompletely characterized and perhaps distorted.
In this study we examined the field distribution of the
auditory oddball ERP in a group of patients with schizophrenia and group of control subjects, demonstrating the
ability to perform high-density ERP recording in schizophrenic patients. The P300 was analyzed for lateral asymmetry over the temporal scalp leads with the specific
hypothesis of a group by side interaction showing the
temporal region target P300 smaller on the left side than
on the right side in the schizophrenic group, whereas the
control group would not show this asymmetry. Since
abnormalities have been reported in other long-latency
ERP components in schizophrenia, including the N1, P2,
N2, and N2d, these components were subjected to an
exploratory analysis.
Methods and Materials
Subjects
The patient group (n 5 24) was recruited from outpatient
treatment and inpatient wards at the Brockton Veterans Affairs
Medical Center, Brockton, Massachusetts. Diagnoses were made
from the Structured Clinical Interview for DSM-III-R (SCID;
Spitzer et al 1990a). The patient group included 11 of undifferentiated type, 10 paranoid, 1 disorganized, and 1 catatonic
schizophrenic patients; subtype data was unavailable for 1
patient. Subjects were right-handed men between the ages of 26
and 55 years, had no history of electroconvulsive shock treatment
or neurological illness, no alcohol or drug abuse in the last 5
years or lifetime history of drug or alcohol addiction (DSM-III-R
criteria), no alcohol use 24 hours prior to testing, and the ability
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and desire to participate as evidenced by giving informed
consent. Symptom severity was assessed with the Positive and
Negative Syndrome Scale (PANSS; Kay et al 1987; general
mean 5 33.5, SD 5 9.23; positive scale mean 5 17.64, SD 5
5.98; negative scale mean 5 17.86, SD 5 5.34; data missing for
2 subjects). Mean age of disease onset was 21.8 years (SD 5
3.16) and mean duration of illness was 21.5 years (SD 5 6.52).
Twelve subjects were on conventional neuroleptic medications, 5
were on atypical neuroleptics, 1 was on a combination of
conventional and atypical medications (mean chlorpromazine
equivalent 668 mg, SD 5 394), 2 patients were unmedicated at
time of testing, and data were unavailable for 4 subjects. Control
subjects (n 5 24) were recruited by newspaper advertisement.
The same exclusion criteria were applied to the controls as to the
patients with the addition of no lifetime history of mental illness
(SCIO-NP, Spitzer et al 1996). The control group was chosen to
be similar in age (control: mean 5 39 years, SD 5 8.9;
schizophrenic: mean 5 43 years, SD 5 9.7; p 5 .09) and
parental socioeconomic status (SES; control: mean 5 2.7, SD 5
0.98; schizophrenic: mean 5 3.1, SD 5 0.73; p 5 .24) to the
patient group; parental SES data were unavailable for 6 of the
patients.
Stimuli and Tasks
Stimuli were high (1.5 kHz, 97 dB SPL) and low (1.0 kHz, 97 dB
SPL) tones of 40-msec duration (10-msec rise time) presented
pseudorandomly with interstimulus intervals varied between 1.0
and 1.4 sec (1.2-sec mean) through ETYMOTIC insert headphones (Etymotic Research, Elk Grove Village, IL) over a
continuous 70-dB binaural white noise background. The low
tones were designated as Standards and presented on 85% of the
trials; the high tones were designated as Targets and presented on
15% of the trials. There were 600 trials presented in blocks of
100. Subjects were instructed to silently count the number of high
tones presented, resetting their count at the breaks every 100 trials.
Data Collection and Preprocessing
Raw electroencephalographic (EEG) data were collected at 250
samples per second, referenced to the vertex, using two linked
32-channel Neuroscan Synamps (Neuroscan Inc, Herndon, VA)
and a 64-channel Geodesic Sensor Net (Electrical Geodesics
Inc., Eugene, OR). Epochs were 700 msec, in length with a
100-msec prestimulus baseline. The raw EEG data were passed
through a computerized artifact detection algorithm and trials
with out of range data (675 mV) were excluded from further
analysis. The data were digitally low-pass filtered at 30 Hz to
eliminate residual electrical noise. The EEGs were averaged by
stimulus type (Standard, Target) to create the ERP waveforms.
The data were transformed into an average reference representation to attenuate spatial distortions due to choice of reference
sensor (Bertrand et al 1985; Dien 1998; Tucker et al 1994).
Grand average waveforms were created by averaging together
the individual subject averages for each group (Schizophrenic,
Control) and stimulus type. Since some characteristics of the ERP
are only apparent in the target minus standard difference wave, such
a difference waveform was created for each subject group.
Data Analysis
Temporal windows were selected for the N1 (80 –120 msec), P2
(160 –200 msec), N2 220 –260 msec), and P300 (300 – 400 msec
for rising edge amplitude, 300 – 600 msec for peak latency)
components and for the N2d (180 –260 msec) in the difference
wave by visual inspection of the waveforms and the mean
voltage amplitude and peak latency extracted from the windows.
Two different analyses on the mean amplitude (temporal scalp
region and exploratory) and one analysis on the peak latency
(exploratory) were performed on the voltages within each window. To test the a priori hypothesis of left temporal scalp region
P300 reduction in schizophrenia, the P300 amplitude to target
stimuli was measured at the temporal scalp region electrodes
(left/right electrode pairs 15– 47, 16 – 45, 18 – 43, and 23– 42, see
Figure 1). For comparison purposes, the other components were
extracted from the same temporal leads as well. For exploratory
analyses, the amplitude and peak latency of the N1, P2, N2, and
P300 to both standards and targets and the N2d from the target
minus standard difference wave were extracted from a set of
electrodes over the superior scalp where these components had
their peak amplitudes (left/right electrode pairs 6 –56, 3–53,
61– 49, 12– 48, 13– 46, 8 –34, 18 – 43, 19 – 40, 20 –38). Repeatedmeasures analyses of variance (ANOVAs) were performed on
the dependent measures within each window with the within
factors Sensor (the bilateral electrode pairs) and Side (left, right),
and the between factor Group (control, schizophrenic). The
exploratory analyses on the unsubtracted data also had Stimulus
(standard, target) as a factor. All reported probabilities for effects
with more that two degrees of freedom were corrected for
deviations from sphericity with the conservative Geisser–Greenhouse epsilon. Given the large number of tests in the exploratory
analyses (6 components 3 2 measures 5 12 analyses), a p , .01
cutoff value was chosen for reporting the exploratory results.
Topographic maps of the components in the grand average
were created by interpolating between electrodes using the
nearest neighbors algorithm included in the Neuroscan Scan
software package (version 4). A three-dimensional head model
was created by magnetically digitizing an anatomically accurate
plastic head model. The sensor net was placed on the plastic head
and the electrode positions digitized. The topographic maps were
mapped onto the digital head model via the digitized electrode
positions to illustrate the scalp distribution of the electrical fields.
Results
Figure 1 shows the electrode locations in the 64-channel net
with 10/20 system sites included for reference. To show the
analysis windows, a single channel of data (the vertex) is
shown in Figure 2 with the analysis windows delineated.
A Priori Hypothesis Test
For the target P300 in the temporal scalp region leads there
was a Group 3 Side interaction, F(1,46) 5 4.281, p , .05,
showing a left side reduction in the schizophrenic group.
The higher-order interaction with electrode site was not
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Figure 1. Sixty-five-channel electrode locations on a lateral schematic of the head with International 10/20 system sites included for
comparison.
significant. Subsequent t tests comparing the mean amplitude of the four left temporal electrodes to the four right
temporal electrodes in the two groups showed that the left
side was significantly smaller than the right in the patient
group (p , .05), but there was no such difference in the
control group. Figure 3 shows the waveform plots from
electrodes 16 and 45, the electrodes closest to T3 and T4
in the sensor net, showing the left side P300 reduction in
the patient group. The topographic map in Figure 4 shows
the superior posterior positive voltage and anterior inferior
negative dipolar voltage distribution of the P300 and the
left side P300 amplitude reduction in the schizophrenic
group over the left temporal region. There was no
Group 3 Side interaction in the temporal scalp region
leads for the other components.
Exploratory Analyses
In the exploratory analyses, for the N1 there was an effect
for Group, F(1,46) 5 18.068, p , .0001, with the mean
amplitude less negative for the schizophrenic group than
for the controls. There was a main effect for Site, F(8,368)
5 95.037, p , .0001 and Site interacted with Stimulus,
F(8,368) 5 4.932, p , .01.
For the P2 there was a Stimulus by Group interaction,
F(1,46) 5 10.177, p , .01, showing that the P2 was less
positive to the target stimuli in the control group only. There
was also an effect for Site, F(8,368) 5 11.961, p , .0001.
For the N2 there was an effect for Stimulus, F(1,46) 5
19.770, p , .0001, showing more negativity to the target
stimuli. The Stimulus effect interacted with Group,
F(1,46) 5 12.301, p , .001, showing more negativity to
the target stimuli in the control group only. There was an
effect for Site, F(8,368) 5 7.237, p , .01, and the Site
effect interacted with Stimulus, F(8,368) 5 11.670, p ,
.0001, and Side, F(8,46) 5 4.273, p , .001.
For the P300 there was an effect for Group, F(1,46) 5
9.693, p , .01, showing a reduced P300 amplitude in the
schizophrenic group, and there was an effect for Stimulus,
F(1,46) 5 96.778, p , .0001, showing an increased P300
amplitude to the target stimuli. The Group and Stimulus
effects interacted, F(1,46) 5 10.634, p , .005, indicating
that the P300 enhancement to the targets was smaller in
the patient group. There was an effect for Site, F(8,368) 5
28.783, p , .0001, and the Site and Stimulus effects
interacted, F(8,368) 5 3.127, p , .0001.
In the difference wave the N2d was less negative in the
schizophrenic group, F(1,46) 5 15.616, p , .0005. There
was also an effect for Site, F(8,368) 5 8.931, p , .0001.
Figure 5 is the topographic map of the N2d field illustrating the apparent absence of the N2d in the patient group.
In the latency analysis, the N2 and P3 showed a main
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G.F. Potts et al
Figure 3. Target waveforms for the control and schizophrenic
groups at electrodes 16 and 45, the sites closest to T3 and T4 in
the Geodesic Sensor Net, showing the left-side P3 reduction in
the schizophrenic group.
Figure 2. Target and standard waveforms for the control and
schizophrenic groups and the target minus standard waveforms
for both groups from the vertex electrode (65) with the amplitude
analysis windows delineated.
effect for Group, N2: F(1,46) 5 13.397, p , .001; P3:
F(1,46) 5 8.329, p , .01, with later peak latencies in the
schizophrenic group than in the controls (latency adjusting
the N2 and P3 windows did not alter the amplitude effects
except that the N2 Site 3 Side interaction changed from
p , .001 in the original analysis to p , .005 in the latency
adjusted analysis).
Discussion
Like most prior auditory P300 studies in schizophrenia,
these data showed a P300 reduction in the schizophrenic
group. This study also found a specific left temporal scalp
region reduction of the P300 in the schizophrenic group.
The P300 is known to have multiple generators, and one
P300 generator is thought to lie in the posterior STG
(Knight et al 1989; Lovrich et al 1988; Tarkka et al 1995).
A study by McCarley et al (1993) showed correlation
between left temporal P300 amplitude reduction and left
posterior superior temporal gyrus volume reduction in
schizophrenia. The P300 here was reduced in amplitude in
the left temporal leads in the patient group, consistent with
reduction in the amplitude of a temporal lobe P300
generator in the schizophrenic subjects.
The schizophrenic patients in this study also showed an
N1 amplitude reduction, although there was no N1 topographic difference between the groups. The N1 is thought
to be generated in primary and secondary auditory areas in
superior and lateral temporal cortex (Giard et al 1988;
Hegerl et al 1994; Pantev et al 1995; Ponton et al 1993;
Rogers et al 1991; Tarkka et al 1995) with a possible
frontal lobe contribution (Giard et al 1994). The N1 was
not sensitive to task demands here, i.e., it did not vary by
stimulus type. The N1 can be enhanced to relatively
infrequent stimuli in some paradigms, and this enhancement has been attributed to the presence of an underlying
component, the mismatch negativity (MMN), which is
coincident to, but distinct from, the N1 (reviewed in
Näätänen 1990 and 1992). The N1 can also be enhanced
by motivation (Wilkinson and Morlock 1966) and alertness (Fruhstorfer and Bergstrom 1969), both of which may
be reduced in schizophrenic patients. Since the N1 reduction in the schizophrenic group was neither task specific
nor topographically distinct, the reduction could represent
either a general early auditory processing deficit or reduced arousal, vigilance, or motivation in the schizophrenic subjects.
In contrast, the P2 was larger in the schizophrenic group
than in the controls to the target stimuli only, whereas the
N2 was smaller. Actually, the field polarity of both the P2
and the N2 at the superior sites used in the ANOVA was
positive in the average reference, and the voltage was less
positive to the targets in the control group. Thus for both
the P2 and the N2 the voltage was less positive to the
targets for the controls only, suggesting a single effect
spanning both component windows. An inspection of the
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1998;44:982–989
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Figure 4. Target P300 topography from 300 to 400 msec (the
voltage scale has been compressed to better illustrate the topographic distribution). Note the clear dipolar structure of the field
distribution. The schizophrenics show an amplitude reduction,
larger on the left side, and a lack of voltage gradient change near
the left temporal lobe. CT, control; SZ, schizophrenic.
Figure 5. N2d target minus standard difference topography from
180 to 260 msec. The voltage contours are closest together over
frontal areas, consistent with frontal generation. The schizophrenic patients do not appear to show this component. CT,
control; SZ, schizophrenic.
target minus standard difference wave supports this interpretation. For the controls, the vertex difference wave
shows two voltage deflections, a positive deflection coincident with the P300 and an earlier negative deflection
coincident with both the P2 and N2, referred to here as the
N2d after O’Donnell et al (1993). The schizophrenic group
does not show any evidence of an N2d (Figure 4). This is
consistent with O’Donnell et al (1993), who found an N2
reduction in schizophrenia and an even larger reduction of
the difference N2d. The N2 is thought to index stimulus
classification (e.g., target vs. nontarget; Simson et al 1976,
1977a, 1977b), and its reduction or absence in schizophrenia has been interpreted as indicating a disruption of
neural systems of attention (Salisbury et al 1995). Consistent with that interpretation, the N2d here was sensitive to
task demand, occurring only to target stimuli (but only for
the control subjects). The topography of the N2d, as
shown in the three-dimensional maps in Figure 5, shows
an anterior distribution, with negativity over superior
central sites and positivity over inferior frontal sites. The
N2 is generally thought to arise from neural sources in the
superior and medial temporal lobes (Simson et al 1977a,
O’Donnell et al 1993), and N2d reduction in schizophrenia
has been correlated with temporal lobe volume reductions
(O’Donnell et al 1993); however, recent high-density ERP
studies of both the visual and auditory N2d in normal
subjects have suggested that the N2d, like the N1, may
have a distinct frontal contribution (Potts et al 1996;
1998). Some areas of frontal cortex are thought to be
involved with selective attention (Posner and Petersen
1990) and working memory (Goldman-Rakic 1988). Patients with schizophrenia show disruptions of attention
(reviewed by Baff 1993; Nestor and O’Donnell 1998) and
working memory (Goldman-Rakic 1991; Park and Holzman 1992), and frontal lobe dysfunction in schizophrenia
is frequently described in hemodynamic neuroimaging
studies (reviewed by Andreasen et al 1992; Gur and
Pearlson 1993).
Using recent advances in high-density ERP recording
and topographic mapping, this study provided support for
the hypothesis of reduction in strength of a left temporal
lobe P300 generator in schizophrenia. We also found
evidence in the diminished or absent N2d of disruption in
attention networks in schizophrenia. Thus the application
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of technical improvements in ERP acquisition and analysis
to the study of psychopathology has provided a stronger
link between observed scalp electrical field abnormalities,
disturbed cognitive systems, and underlying neural dysfunctions in schizophrenia.
This project was supported by grant MH40799-09 from the National
Institute of Mental Health and by the Veterans Administration through
the Research Center for Basic and Clinical Neuroscience of Schizophrenia (RWM).
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