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Mismatch Negativity in Chronic Schizophrenia and First-Episode Schizophrenia
Dean F. Salisbury, PhD;
Martha E. Shenton, PhD;
Carlye B. Griggs, BA;
Aaron Bonner-Jackson;
Robert W. McCarley, MD
Arch Gen Psychiatry. 2002;59:686-694.
ABSTRACT
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Background Mismatch negativity (MMN) is an event-related brain potential that is
sensitive to stimulus deviation from a repetitive pattern. The MMN is thought
primarily to reflect the activity of sensory memory, with, at most, moderate
influences of higher-level cognitive processes, such as attention. The MMN
is reported to be reduced in patients with chronic schizophrenia. However,
it is unknown whether MMN is reduced in patients with first-episode schizophrenia
(at first hospitalization).
Methods Subject groups comprised patients with chronic schizophrenia (n = 16)
and older control subjects (n = 13), and patients with first-episode schizophrenia
(n = 21) and younger control subjects (n = 27). The MMN was visualized by
subtracting the averaged event-related brain potential to standard tones (1
kHz [95% of all tones]) from the event-related brain potential to pitch-deviant
tones (1.2 kHz [5% of all tones]). The MMN voltage was the mean voltage from
100 to 200 milliseconds.
Results Pitch-deviant MMN was reduced by approximately 47% in patients with
chronic illness along the sagittal midline relative to controls. The MMN was
not reduced in patients with first-episode schizophrenia. All 4 groups showed
approximately 64% larger MMN to pitch-deviant tones over the right hemisphere
compared with the left hemisphere.
Conclusions The pitch-deviant MMN reductions present in patients with chronic schizophrenia
are not present at first hospitalization. The sensory, echoic memory functions
indexed by MMN seem unaffected early in the schizophrenia disease process.
Reductions in MMN amplitude may develop over time and index the progression
of the disorder, although that can only be definitively determined by longitudinal
assessments.
INTRODUCTION
MISMATCH NEGATIVITY (MMN) is a brainwave to stimuli deviating from preceding
repetitive stimuli, thought to reflect the operations of echoic memory, generally
uninfluenced by cognitive operations.1-2
(However, some studies3-4 report
small attention effects.) Mismatch negativity has been elicited by changes
in pitch,5 intensity,6
location,7 and tone sequences.8
The MMN is reliable9 across sessions.
Mismatch negativity is generated in the primary auditory cortex,10-17
but the secondary auditory cortex may be activated as the stimulus deviance
increases.13, 15, 18
A frontal lobe component may be activated, and is thought to reflect the passive
drawing of attention.2, 18-19
The MMN likely reflects N-methyl-D-aspartate channel
current influx in cortical layers II and III, based on extracellular recordings
in the monkey cortex.20 In humans, Oranje et
al21 did not detect reduced MMN following ketamine
hydrochloride (an N-methyl-D-aspartate antagonist)
administration, but Umbricht et al22 did; the
latter finding is consistent with N-methyl-D-aspartate/glutamate
involvement in MMN generation.
The MMN is intriguing given the interest in gating abnormalities and N-methyl-D-aspartate involvement in patients with schizophrenia.
Using pitch deviants, Javitt et al23-27
showed reduced MMN in patients with schizophrenia, a finding replicated by
several others28-32
and also observed for MMN measured using magnetoencephalography.33
Several studies27-28 report correlations
between negative symptoms and MMN amplitude. The MMN reduction is apparently
not ameliorated by either typical (haloperidol [Haldol]) or atypical (clozapine)
medication.31
The MMN to duration deviants is consistently reduced in patients with
schizophrenia.28, 34-37
However, some studies37-40
of pitch deviants failed to detect reductions. Several possibilities exist
for these failures, including different interstimulus intervals and deviant
probabilities, and peak vs interval amplitude measurement.25, 32, 37
Another confound is the control of attention. Attention-related potentials
(eg, Nd and N2b) might overlap MMN if tones are attended.41
Two studies30, 33 reported
that MMN was more reduced over the left hemisphere in patients with schizophrenia,
and Javitt et al24 reported a trend-level reduction
on the left side. One abstract42 reported that
MMN amplitude in patients with schizophrenia correlated with the volume of
primary auditory cortex (Heschl gyrus), but not with the remainder of the
posterior superior temporal gyrus. Using functional magnetic resonance imaging,
Wible et al43 showed bilateral reduction of
Heschl gyrus MMN activation in patients with schizophrenia.
To our knowledge, MMN has never been reported in patients with first-episode
schizophrenia. Javitt et al26 reported marginal
(P = .06) reductions in outpatients within 3 years
of their first episode. Salisbury et al44 and
Umbricht et al45 published abstracts suggesting
that MMN is not reduced at the first episode. Measurement in patients with
first-episode schizophrenia of variables that are pathological in those with
chronic schizophrenia avoids confounds related to chronicity. For example,
subjects with first-episode schizophrenia show the same left hemisphere deficit
in P346 as patients with chronic schizophrenia47-48 and the same left posterior superior
temporal gyrus49 and planum temporale50 reductions as patients with chronic schizophrenia,51-52 with these functional and structural
abnormalities correlated.53-54
Their presence in patients with first-episode schizophrenia indicates pathological
features not related to chronicity and of central importance to the disease.
Their absence in patients with first-episode schizophrenia suggests a process
secondary to either an ongoing degenerative process or chronicity effects.
This work was undertaken to determine whether MMN was reduced in patients
with chronic schizophrenia and patients with first-episode schizophrenia when
attention was maintained on a visual task.
PATIENTS AND METHODS
SUBJECTS
Sixteen male inpatients with chronic schizophrenia from McLean Hospital
were compared with 13 male control subjects without any history of psychiatric
disorder. Chronic illness was defined as 3 or more hospitalizations (mean
± [SD] duration of illness, 14.3 ± [8.5] years). Also, 21 patients
who were first hospitalized for schizophrenia (including 3 women) were compared
with 27 control subjects without any history of psychiatric disorder (including
7 women). Controls were recruited from the general population through newspaper
advertisement. Patients' diagnoses were confirmed via the
Structured Clinical Interview for DSM-III-RPatient Edition (SCID-P),55 and controls
were screened using the Structured Clinical Interview for DSM-III-RNon-Patient Edition (SCID-NP),56 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 a learning disability, a neurological impairment, or a history
of electroconvulsive therapy, seizures, head injury, or substance dependence
within the past 5 years was excluded. Each patient group did not differ from
its respective control group in age or parental socioeconomic status. Subject
demographic characteristics and basic cognitive functioning, and clinical
scales and medication values for the patients are presented in Table 1. All subjects gave written informed consent and were paid
to participate.
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Table 1. Demographic, Neuropsychological, and Clinical Data*
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PROCEDURES
Subjects were presented with 1600 binaural tone pips (3 per second).
Standard tones were 1 kHz, 75 dB, 100 milliseconds in duration, with 10-millisecond
rise/fall times (1520 trials). Deviant tones were 1.2 kHz, 75 dB, 100 milliseconds
in duration, with 10-millisecond rise/fall times (80 trials). During tone
presentation, subjects sat 1 m from a cathode-ray tube on which was displayed
a checkerboard with green and red squares. Subjects were instructed to ignore
the tones and to make a right thumb response on a keypad each time the checkerboard
squares reversed colors asynchronously, with a range of 430 to 1500 milliseconds.
Tracking performance was monitored, and subjects were admonished to maintain
the task.
Electroencephalographic activity was recorded from the scalp through
28 tin electrodes in preconfigured caps (ElectroCap International, Eaton,
Ohio). Electrode sites included all International 10-20 System sites, excluding
T1 and T2 and including Oz, FTC1, FTC2, TCP1, TCP2, PO1, PO2, CP1, and CP2.
Linked earlobes were used as the reference, and the forehead was used as ground.
Electrodes located medially to the right eye, one above and one below, were
used to monitor vertical eye movements. Electrodes placed at the outer canthi
of the eyes were used to monitor horizontal eye movements. Electrode impedances
were below 3 k , and the ears were matched within 1 k . The electroencephalograph
amplifier bandpass was 0.15 Hz (6 dB per octave roll-off) to 40 Hz (36 dB
per octave roll-off). Electroencephalographic activity and stimulus markers
were recorded continuously, digitized at 1.96 milliseconds per sample. Averaging
and artifact rejection were performed off-line. Continuous data were epoched
about the stimulus onset. Each epoch was of 350-millisecond duration, including
a 50-millisecond prestimulus baseline. Within each 1600-trial block, epochs
from each electrode site were baseline corrected by subtraction of the average
prestimulus voltage, and mathematically corrected for eye movement artifact.57 Subsequently, epochs exceeding ±50 µV
at F7, F8, Fp1, or Fp2 were rejected. Averages were computed for the brain
responses to standard and deviant tones. Event-related brain potentials to
standard tones were subtracted from event-related brain potentials to deviant
tones. The resulting MMN subtraction waveform was digitally low-pass filtered
at 20 Hz to remove any high-frequency artifact. The MMN amplitude was measured
as the mean voltage from 100 to 200 milliseconds.30
DATA ANALYSIS
Analyses used mixed-model repeated-measures analysis of variance. Two
main analyses of MMN amplitude were performed. Midline analyses had one within-subjects
factor of electrode site (Fz, Cz, and Pz). Group was the between-subjects
factor. Regional analyses had 2 within-subjects factors, region (frontal:
F3, F4, FTC1, FTC2, C3, and C4; temporal: T3, T4, T5, T6, TCP1, and TCP2;
and parieto-occipital: P3, P4, PO1, PO2, O1, and O2) and hemisphere (left
and right). Group was the only between-subjects factor. Degrees of freedom
were adjusted with the Huynh-Feldt for factors with more than 2 levels.
For correlations with clinical variables, the Pearson product moment correlation
was used. All tests used 2-tailed probabilities. Results were considered significant
at P .05.
RESULTS
The patients with chronic schizophrenia showed a reduced MMN relative
to their controls over the entire surface of the scalp, yet both groups showed
larger MMN to tonedeviants over the right compared with the left temporal
sites (Figure 1). Analysis along
the sagittal midline (Fz, Cz, and Pz) revealed that the MMN was smaller in
the patients with schizophrenia by approximately 43% (F1,27 = 7.96, P = .009) (Table 2).
Both groups showed more negative MMN frontally (F2,54 = 21.88, P<.001, = 0.69). The MMN amplitudes over each
hemisphere from the frontal, temporal, and parieto-occipital regions were
compared between groups (Figure 1).
Patients with chronic schizophrenia had smaller lateral MMN amplitudes than
their controls (F1,27 = 7.61, P = .01).
The MMN amplitude was greatest over the frontal sites and reduced more posteriorly
(F2,54 = 36.85, P<.001, = 0.73).
This topography did not differ between groups (P>.21).
The MMN displayed a hemispheric asymmetry that was different for the 3 regions
(region x hemisphere: F2,54 = 6.65, P
= .003, = 1.0). An analysis of hemisphere effects in each region revealed
that MMN amplitude was larger over the right hemisphere for the temporal sites
(F1,27 = 4.30, P = .048), but not for
the parieto-occipital (P = .09) or the frontal (P>.48) sites.
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Figure 1. Mismatch negativity difference
waveforms across the surface of the head in patients with chronic schizophrenia
and in a comparison group without any history of psychiatric disorder. The
3 shaded areas from the anterior to the posterior represent the left hemisphere
frontal, temporal, and parieto-occipital regions, respectively (homologous
for the right hemisphere).
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Table 2. Mismatch Negativity Amplitudes
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In light of previous reports24, 30, 33
of left-greater-than-right reductions of MMN in patients with schizophrenia,
each lateral site over temporal and parietal lobes was compared between the
patients with chronic schizophrenia and their controls. There was no support
for a differential hemispheric reduction: the MMN seemed to be equally reduced
in patients for each hemisphere.
There were no significant associations in the patients with chronic
schizophrenia between MMN amplitude at Fz and total Brief Psychiatric Rating
Scale (BPRS) scores or any factor of the BPRS (thinking disturbance, hostile-suspiciousness,
withdrawal-retardation, and anxious depression). Exploratory analyses between
clinical measures and MMN across the scalp revealed several significant associations.
The MMN at the right frontal site (F4) was associated with the withdrawal-retardation
factor (r = 0.49, P = .05);
the greater the negative symptoms, the smaller the MMN. The MMN amplitude
at the left midtemporal site (T3) was associated with the total BPRS score
and the thinking disturbance factor. The greater the total BPRS score, the
smaller the MMN at T3 (r = 0.52, P = .04), and the greater the thinking disturbance factor, the smaller
the MMN at T3 (r = 0.55, P
= .03). The MMN from the site at the junction of the left temporal and parietal
lobes (TCP1) was also associated with the thinking disturbance factor. The
greater the thinking disturbance, the more abnormal the MMN (r = 0.54, P = .03). By contrast, MMN amplitudes
from over the right temporal lobe were associated with the hostile-suspiciousness
scale. The greater the hostile-suspiciousness factor of the subject, the larger
that subject's MMN at T4 (r = -0.49, P = .05), T6 (r = -0.52, P = .04), and TCP2 (r = -0.52, P = .04).
In contrast to the patients with chronic schizophrenia, the patients
with first-episode schizophrenia showed an MMN similar in amplitude to their
controls (Figure 2). Patients with
first-episode schizophrenia and their controls showed larger MMN to tonedeviants
over the right hemisphere. The patients with first-episode schizophrenia were
not significantly different from their controls along the sagittal midline
(P>.44). Both groups showed the largest MMN amplitude
frontally, with a decreasing gradient posteriorly (F2,92 = 40.90, P<.001, = 0.66). The midline distribution did
not differ between groups (P>.34). To exclude a failure
to detect group differences between the controls and the subjects with first-episode
schizophrenia because of the larger site factor, each site was separately
compared. No midline site was significantly different between subjects with
first-episode schizophrenia and controls. The maximum effect size was at Pz
(d = 0.32), and would need approximately 175 subjects
per group to attain significance, assuming a power of 0.8. The patients with
first-episode schizophrenia were not significantly different from the controls
in overall MMN amplitude at lateral sites (P>.32).
The MMN amplitude was greatest over the frontal sites and reduced more posteriorly
(F2,92 = 73.67, P<.001, = 0.72).
This regional effect did not differ between groups (P>.52).
The MMN was significantly greater over the right hemisphere (F1,46
= 6.18, P = .02). Again, to exclude a failure to
detect group differences between the controls and patients with first-episode
schizophrenia because of the larger regional or site factors, each site was
separately compared between these 2 groups. No lateral site was significantly
different between patients with first-episode schizophrenia and their controls.
The maximal effect size was at T6 (d = 0.4), and
would need approximately 99 subjects per group to attain significance, assuming
a power of 0.8.
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Figure 2. Mismatch negativity difference
waveforms across the surface of the head in patients with first-episode schizophrenia
and in a comparison group without any history of psychiatric disorder.
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There was no significant association in first-episode schizophrenia
between MMN amplitude at Fz and total BPRS scores, the thinking disturbance
factor, the hostile-suspiciousness factor, or the withdrawal-retardation factor
(r = -0.003, P = .99).
However, there were several associations between these clinical scales and
MMN amplitude at other sites. All of the significant correlations were negative,
which, because MMN is a negative potential, suggest that greater scores on
these measures of psychopathological features were related to larger MMN amplitudes.
There were widespread associations between the anxious depression factor and
MMN amplitude, including Fz (r = -0.51, P = .02). This factor correlated with nearly all sites,
except for the inferior temporal sites (r range, -0.44
to -0.68). Greater BPRS total scores were generally associated with
larger MMN amplitudes for all but the frontal sites (r
range, -0.44 to -0.55). Thinking disturbance and hostile-suspiciousness
scores tended to be associated with MMN from parietal and occipital sites
(r range, -0.44 to -0.58).
Finally, sex seemed to have no effect. Restricting analyses to men only
did not change the significant effects reported.
COMMENT
Patients with chronic schizophrenia showed widespread MMN reductions
to pitch deviants with attention focused on the visual modality. Patients
with chronic schizophrenia and their controls showed larger MMN amplitudes
over the right hemisphere compared with the left, consistent with the expected
lateral distribution of MMN to tone pips.58-59
(The MMN elicited by vowel deviants shows a left-sided augmentation.60-61) The MMN topography did not differ
between patients with chronic schizophrenia and their controls, suggesting
a similar constellation of active sources.44, 62
Left-sided abnormalities of MMN were not observed in the patients with chronic
schizophrenia, in contrast to a previous report.30
This difference may reflect the control of attention in this study or that
the previous study30 tested patients with negative
symptoms who were refractory to treatment in contrast with the current patients
with positive symptoms. The correlations with clinical variables were in accord
with the literature,27-28 showing
smaller frontal MMN with greater negative symptoms. The smaller left temporal
MMN associated with greater thinking disturbance was similar to the previous
finding of an association between greater hallucinatory behavior and smaller
left-sided inferior frontal MMN.30
Patients with first-episode schizophrenia did not differ from their
controls in MMN amplitude. It remains unclear whether the apparent differences
between groups at the posterior sites reflect a spurious signal-to-noise effect
or a small but nonsignificant reduction in the patients, perhaps reflecting
the beginning of an aberrant reduction. Patients with first-episode schizophrenia
and their controls showed larger MMN amplitude over the right hemisphere,
consistent with the expected lateral distribution of MMN to tone pips. We
saw no evidence for different MMN topographies in the patients vs the controls.
The correlation between MMN amplitudes and clinical scales in the patients
with first-episode schizophrenia is paradoxical because more pathological
symptoms were associated with larger MMN activity, unlike the inverse association
in the patients with chronic schizophrenia. We suggest that the pattern of
symptoms at first hospitalization is volatile and statelike rather than stable
and traitlike. The difficulty in finding clear-cut understandable correlations
between clinical symptoms and structural magnetic resonance imaging findings
at the first episode has been noted.51 Longitudinal
testing of these patients will help clarify this issue.
The first-episode sample might contain a subset of subjects with reduced
MMN who will develop a chronic illness, masked by a larger subset of patients
with normal MMN who will not be hospitalized later. An inspection of the distributions
revealed no bimodal distribution (Kolmogorov-Smirnov tests failed to detect
a nonnormal distribution). It remains a tantalizing possibility that MMN reductions
may develop over time from schizophrenia onset and present an objective physiological
index of progressive cortical deterioration. Our planned longitudinal testing
of these patients with first-episode schizophrenia will help test this hypothesis.
The MMN reduction in the patients with chronic schizophrenia is consistent
with decreased preattentive processing in these patients. It remains unclear
whether these findings are related to some disease process or to secondary
effects, like long-term neuroleptic treatment. Catts et al28
reported that the MMN was reduced in unmedicated patients (including 4 of
11 drug-naive patients), suggesting that medication may not play a role, although
a role cannot be excluded because most patients were exposed to neuroleptic
agents. The normal pitch-deviant MMN in patients with first-episode schizophrenia
suggests little involvement of the MMN cortical generators in pathological
processes early in the disease process. Given the robust decrement of MMN
in patients with chronic schizophrenia, the normal MMN in patients with first-episode
schizophrenia, and the presence of left-localized abnormalities of P300 in
patients with first-episode schizophrenia46
that correlate with reduced left posterior superior temporal gyrus gray matter
volume,54 we hypothesize that MMN may be an
index of progressive neuropathological features in patients with schizophrenia.
We speculate that the normal MMN at first hospitalization decreases over time
in patients with schizophrenia, reflecting some ongoing neurochemical event
such as glutamate-mediated excitotoxic reduction of dendritic fields.63 The abnormal P300 at first episode may reflect more
severe pathological features of the tertiary cortex in the posterior superior
temporal gyrus gray matter, with the later MMN reduction reflecting the progressive
involvement of the primary auditory cortex. The data of Javitt et al26 bear on this possibility: within 3 years of their
first episode of schizophrenia, patients showed marginally reduced MMN (P = .06) to pitch deviants, but not as reduced as that
of the sample with chronic schizophrenia. (Their duration-deviant MMN was
quite reduced, but analysis of tone duration may necessitate more complex
processing and likely activates a right posterior MMN generator.64)
In a psychophysical study of auditory just-noticeable differences, Rabinowicz
et al65 showed that patients with first-episode
schizophrenia did not differ from controls, whereas long-term inpatients did.
These data suggest some role of disease duration on simple auditory processing
in patients with schizophrenia. Alternately, the MMN reduction observed in
patients with chronic schizophrenia may be secondary to long-term neuroleptic
medication effects. A longitudinal examination of this cohort, with subjects
taking either typical or atypical neuroleptic agents, will help address this
possibility.
Several caveats about the present study should be noted. Because duration
deviants were not presented, it remains unknown whether the MMN elicited by
this type of deviant would reveal an abnormality in these patients with first-episode
schizophrenia. Stimuli with a short interstimulus interval and a low deviant
probability were presented; these maximally elicit MMN. It is not known whether
MMN abnormalities might be evident with different stimulation parameters.
Although removal of the female patients did not alter the effects in the first-episode
sample, the relatively smaller sample of women with first-episode schizophrenia
and the lack of any women with chronic schizophrenia make any inferences about
sex most difficult.
In summary, MMN reduction to pitch deviants is present in patients with
chronic schizophrenia but absent in patients with first-episode schizophrenia.
Mismatch negativity may reflect an objective psychophysiological index of
progressive pathophysiological features during the early course of the disease.
It remains to be determined whether MMN amplitude decrements can be ascribed
to a primary disease process or to some secondary process, and whether MMN
amplitude correlates with the gray matter volume of the Heschl gyrus, the
putative source of pitch-deviant MMN.
AUTHOR INFORMATION
Submitted for publication February 13, 2001; final revision received
September 7, 2001; accepted October 1, 2001.
This study was supported in part by the Merit Review Award Program (Drs
McCarley and Shenton) and Schizophrenia Center Awards (Dr McCarley) from the
Department of Veterans Affairs, Washington, DC; grants MH 40977 (Dr McCarley),
MH 01110 (Dr Shenton), and MH 50747 (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).
We thank Daniel Umbricht, MD, for suggesting acceptable filtering settings;
and Iris Fischer, Paola Mazzoni, and Deirdre Farrell for their technical assistance.
Corresponding author and reprints: Robert W. McCarley, MD, Psychiatry
116A, Boston Veterans Affairs Healthcare System, 940 Belmont St, Brockton,
MA 02301 (e-mail: robert_mccarley{at}hms.harvard.edu).
From Harvard Medical School, Department of Psychiatry, McLean Hospital,
Belmont, Mass, and the Boston Veterans Affairs Healthcare System, Brockton,
Mass.
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