Special Contribution

Yonago Acta medica 2007;50:23–32

Mismatch Negativity as a Psychophysiological Index of
Cognitive Function in Schizophrenia
Kazuyuki Nakagome, Satoru Ikezawa, Sheng Hong Pu
Division of Neuropsychiatry, Department of Multidisciplinary Internal Medicine, School of
Medicine, Tottori University Faculty of Medicine, Yonago 683-8504 Japan

It is now widely accepted that cognitive deﬁcits, beyond other psychiatric symptoms (e.g.,delusion, hallucination, emotional ﬂattening, social withdrawal and apathy), is far most
relevant to social functional outcome in schizophrenia. Accordingly, the treatment target has been shifted to the area, developing new drugs that facilitate cognitive function
and building up new psychosocial rehabilitation programs that directly approach thecognitive deﬁcits. Despite the desirability to target these deﬁcits, no standard neuropsychological test batteries exist for assessing the level of cognitive function. Mismatch
negativity (MMN), an auditory event-related potential component, is a measure of preattentive information processing and its amplitude has repeatedly been demonstrated tobe reduced in schizophrenia. MMN deﬁcits are a robust feature in chronic schizophrenia and indicate abnormalities in automatic context-dependent auditory information
processing and auditory sensory memory in schizophrenia. Moreover, the deﬁcits havebeen related to poor social functioning level and social skills acquisition, hypofunction of
NMDA system, and illness duration, which indicate the validity of accepting MMN as abiomarker of the disease. In this article, we present a summary of the discussions about
the plausibility of MMN to be used as a neurobiological index for assessing the cognitive
function and also its predictability of social functional outcome in schizophrenia.
Key words: cognitive function; functional outcome; mismatch negativity; N-methyl-d-aspartate; schizophrenia

noticed as the core feature of schizophrenia since
Bleuler described “schizophrenias” almost one
hundred years ago. Attention has been increasingly focused on cognition since Green (1996)
clearly demonstrated that the cognitive impairment was the strongest factor that should affectthe social and functional outcome. Green (1996)
divided the functional outcome into three sections
according to type of outcome measure. The ﬁrst
section represents community (social and occupational) functioning and the second, assessment ofsocial problem solving and the third, ability to ac-

Cognitive impairment
as a core feature of schizophrenia
Schizophrenia is a major mental disorder, which
is clinically diagnosed based on a set of characterized “positive” (e.g., hallucinations, delusions
and psychomotor excitement), “negative” (e.g.,
emotional ﬂattening, social withdrawal and apathy) and “cognitive” (disturbances in memory, attention and problem solving) symptoms. Amongthese symptoms, cognitive impairment has been

Abbreviations: CPT, continuous performance test; ERP, event-related potential; MATRICS, Measurement and Treatment Research to Improve Cognition in Schizophrenia; MMN, mismatch negativity; NMDA, N-methyl-d-aspartate;
PCP, phencyclidine; SCD, scalp current density analysis

23

K. Nakagome et al.

Table 1. Major features of cognitive impairment of schizophreniaa) All domains of cognition, including attention, executive function, secondary (storage) memory, working memory,and semantic memory, may be affected.
b) The pattern of deﬁcits may vary widely among individuals with schizophrenia.
c) The mean deﬁcit in these domains may be 1–3 standard deviations below normal, although about 15% of patientswith schizophrenia test within the normal range in all domains.
d) For most patients, impairment is only slowly progressive after the ﬁrst episode of psychosis.
e) Some components of the deﬁcit are present during childhood and early adolescence but usually in mild form.
f) Deﬁcits in speciﬁc types of cognition are of key importance for work and social function in schizophrenia, more
so even than positive or negative symptoms.
Reprinted from Cognition, schizophrenia, and the atypical antipsyochotic drugs, by Meltzer et al., Proceedings of the National Academyof Sciences of the United States of America, 1999, volume 96, pages 13591–13593. Copyright© 1993–2005 by The National Academy of
Sciences of the United States of America, all rights reserved.

drugs for the treatment of cognitive impairments
in schizophrenia. Also, in the ﬁeld of psychosocial treatment, “cognitive remediation therapy”,
which refers to the procedures used to directly
improve cognitive function, has attracted growinginterest of individuals engaged in psychiatric services.

quire psychosocial skills from their psychosocial
rehabilitation programs. Among various cognitive domains, verbal memory was associated withall types of functional outcome, vigilance wasrelated to social problem solving and executivefunctioning was related to community functioning. The major features of the cognitive impairment of schizophrenia are summarized in Table 1(Meltzer et al., 1999).
The conventional antipsychotic drugs suchas chlorpromazine and haloperidol, referred toas dopamine antagonists, were certainly effective against “positive” symptoms but generally
ineffective against “negative” and “cognitive”
symptoms. Meanwhile, many researchers demonstrated that the new drugs, referred to as serotonin
dopamine antagonist and multi-acting receptortargeted antipsychotics, or atypical antipsychotic
drugs, showed a favorable effect on cognition
using neuropsychological test batteries, however,whether the new drugs could affect the social
functional outcome was not at all clear. One of
the reasons for the negative results could be thatthe effect size of the drugs (0.5–1.5 SD) on cognitive function was not ample enough to reach thenormal level (the difference between patients withschizophrenia and normal controls being 1.0–3.0SD) and thus, was unable to affect the social functional outcome. There has been a national projectsponsored by National Institute of Mental Healthnamed MATRICS (Measurement and Treatment
Research to Improve Cognition in Schizophrenia)
in the United States, which aims to develop novel

The assessment ofcognitive impairment in schizophrenia
The assessment of cognitive impairment inschizophrenia has owed much to neuropsychological test batteries. As noted above, the ﬁndings
are in agreement in that the new drugs are effective on cognitive function in general, however, thespeciﬁcity of the effect of each drug has not beenclariﬁed. Although the pharmacological proﬁlesof these drugs were clearly different between eachother, the cognitive proﬁles that were affected bythese drugs were not as clearly distinct as expected.
The inconsistent and nonspecific findings
are, at least in part, caused by the relatively weakvalidity of neuropsychological tests. First, as
prompt response is required in many tests, theperformance level is affected not only by thestimulus processing speed but also by the motor
speed, which makes the interpretation of the results difﬁcult. Moreover, as the assessment using
neuropsychological tests depend solely on behavioral indices, they are subject to motivational
24

MMN index cognitive function in schizophrenia

allow the splitting of the overlapped components
arising from the cortex that show distinct sink/
source patterns. Formally, it is based on simplifications of Poisson’s equation relating the fieldpotential at any point in the conductive medium
to their underlying current generators, so that a
local generator of an extracellular negativity (current sink) corresponds to local neuronal depolarization, while a local generator of a positivity(current source) corresponds to hyperpolarization. Although the anatomical and physiologicalorganization of putative generator regions must be
carefully evaluated before attributing physiological correlates to SCD components, it can be reasonably assumed that SCD is useful in elucidating
the cortical activities associated with the component speciﬁed.
Concerning the advantage of electrophysiological methods such as event-related potentials(ERP) in temporal resolution, they allow the earlystages of sensory and perceptual information processing, as well as later cognitive and premotor
processes to be distinguished precisely in time.
Moreover, overall processing speed can be assessed without contamination by motor dysfunction. Disadvantages include the fact that ERP
components have not been identified across thefull array of candidate cognitive domains underconsideration and are relatively limited in measuring sustained processing.
Up to date candidate components for the assessment of cognitive impairment in schizophrenia may come from sensory and early cognitive
processing. For instance, mismatch negativity(MMN, see Fig. 1), an early auditory ERP elicited by deviant stimuli even though the subjects
ignored the series of stimuli, has some attractive
features such as good test-retest reliability (Kathmann et al., 1999; Kujala et al., 2001) and has
been shown to correlate with functional outcome(Light and Braff, 2005). MMN is an ERP component that is generated when a stimulus violates
the invariance or regularity of the previous seriesof standard stimuli. MMN has been considered
to be independent of subjects’ attention, however,some studies have reported that under exceptional

inﬂuences, which should also be contaminated in
the assessment of cognitive function. Finally, theconstruct validity of neuropsychological tests has
not been well established. For instance, “continuous performance test (CPT)” is usually intended
to measure vigilance as well as sustained attention over time (Cornblatt et al., 1989). During thetask, subjects are presented with single letters or
numbers in a short duration that appear at a rapid
ﬁxed rate. The subjects are required to respondwith a button press each time a predesigned target
stimulus appears. It can be assumed that otherpsychometric properties such as automatic stimulus perceptual capacity, independent from either
vigilance or attention, may contribute to the CPT
performance. Also, in our previous study, we investigated the relationship between the scores in
Tower of Hanoi test and Wisconsin Card Sorting
Test, which are both well known as measures ofexecutive functioning, however, we found no relationship between them in schizophrenia patients(Katoh et al., 2003).
In the MATRICS project, researchers are
now focusing on several neuroimaging and electrophysiology biomarkers to gain reliable andsensitive indices associated with the brain activity
underlying more speciﬁc cognitive domains. As
is well known, electrophysiological methods aresuperior in terms of time sensitivity but limited inspatial resolution as compared with neuroimaging
methods. Magnetoencephalogram measurements
hold high quality of spatial information as wellas time sensitivity, whereas they still have limitation in that they can only detect the current in thetangential direction to the scalp. Scalp current
density analysis (SCD) is another method used for
improving spatial resolution, which was calculated by taking the Laplacian of the scalp potential
surface generated by spherical spline interpolation (Nunez, 1981; Perrin et al., 1989). As SCD
computation is equivalent to applying a high-passspatial filter to the potential fields, the maxima
and minima of their distribution are clearer thanthose of the potential ﬁelds. Moreover, since thesensitivity of the SCD mappings decreases withthe depth of the generator in the brain, they may
25

K. Nakagome et al.

A

B�������
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C������

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��������

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Fig. 1. MMN waveform (A) and amplitude/SCD topographies(B, C).
A: The upper figure represents ERP waveforms elicited bydeviant (bold line) and standard (dashed line) stimuli. The
lower ﬁgure shows difference waveforms subtracting ERPs
to standard stimuli from those to deviant stimuli.
B: The upper ﬁgure represents the MMN peak amplitude (144ms) topography projecting the 3-D locations onto the 2-D
plane. The lower ﬁgures represent the amplitude topography projected on the reconstructed 3-D brain image.
C: The same ﬁgures as (B) using SCD instead of amplitude
data.

sensory memory. This early component has thepossible advantage of being relatively automaticand less prone to “noise” from top-down cognitiveinﬂuences or practice effects, thereby potentiallybeing more direct probes of the functional integrity of underlying neural structures. MMN canbe contrasted with later components such as theP300, the error-related negativity, or slow waves
such as the contingent negative variation, which
are thought to reﬂect some of the critical cognitive disturbances in schizophrenia but are subject
to top-down inﬂuences such as task instructions
or strategy differences. Furthermore, numerous studies have identified the neural substrates
generating MMN in primary and secondary auditory cortices (Hari et al., 1984; Scherg et al., 1989;
Javitt et al., 1994; Alho, 1995; Levänen et al., 1996;
Celsis et al., 1999; Opitz et al., 1999, 2002; Downar
et al., 2001; Jemel et al., 2002; Müller et al., 2002;
Liebenthal et al., 2003; Sabri et al., 2004) and in
frontal cortex (Giard et al., 1990; Levänen et al.,
1996; Rinne et al., 2000; Yago et al., 2001; Downar
et al., 2001, 2002; Jemel et al., 2002; Müller et al.,
2002; Opitz et al., 2002; Liebenthal et al., 2003;
Sabri et al., 2004); however, those generating latercircumstances attention can indirectly modulate
MMN (Trejo et al., 1995; Sussman et al., 1998).
MMN is best observed in the difference waveform subtracting the ERP responses to standard
stimuli from those to deviant stimuli and usually
peaks within 100 and 240 ms after the deviant
stimulus is presented. It’s maximum negativity
is seen over fronto-central region and it reverses
its polarity near the mastoid in a nose-referenced
montage. Larger differences between the standards and deviants and lower probability of thedeviants are associated with larger MMN amplitude. In the most simple paradigm an infrequent
stimulus that differs in any physical characteristic
such as frequency, duration, intensity or location
is presented among repeatedly presented standard
stimuli, however, violations of more abstract regularities not directly related to physical characteristics of the stimuli (e.g., repetition of a tone inseries of alternating tones) also generate MMN.
Thus, MMN generation depends on the context
in which a speciﬁc stimulus is presented. MMN
is therefore considered an index of preattentive
auditory processing, reﬂecting automatic contextdependent information processing and auditory
26

MMN index cognitive function in schizophrenia

cy MMN deﬁcits associated with illness durationand thus, may index ongoing neuropathologicalchanges in the auditory cortex in schizophrenia.
In line with the view, Yamasue et al. (2004) demonstrated that the magnetic global ﬁeld power ofmismatch response to change in phonemes in theleft hemisphere was signiﬁcantly correlated withleft planum temporale gray matter volume in patients with schizophrenia. The finding suggeststhat structural abnormalities of the planum temporale may underlie the abnormalities of MMN
generation in schizophrenia.

components have not been so clearly identiﬁed.
Näätänen and Michie (1979) suggested afunctional dissociation between the two generators, with the temporal generator associated withestablishment of memory traces and comparison
with incoming stimulus attributes and the frontal
generator related to involuntary triggering of attention invoked by the detected change. Althougha few studies have provided some support for thisview (Müller et al., 2002; Sabri et al., 2004, 2006;
Shalgi et al., 2007), direct evidence for the suggested division of function between the superior
temporal and frontal cortices is still lacking.

MMN in schizophrenia

MMN deﬁcits associated with
suppressed NMDA action in schizophrenia

MMN deﬁcits, mostly amplitude reduction, are arobust feature in chronic schizophrenia and indicate abnormality in preattentive context-dependent auditory information processing and sensory
memory in these patients. Overall, the mean effect size on MMN amplitude reduction was 0.99
(95% confidence intervals: 0.79–1.2) (Umbricht
and Krljes, 2005).
Since the ﬁrst report of abnormal MMN inschizophrenia by Shelley et al. (1991), there havebeen numerous studies on MMN in schizophrenia
using various stimulus conditions (e.g., type of
deviants, probability/degree of deviants) and subjects’ populations (e.g., sex, age, duration of illness). Generally, in terms of the probability anddegree of deviant stimulus, the lower the probability and the stronger the deviance, the larger theamplitude of MMN becomes. Most frequently
used types of deviance were those differing intone frequency and tone duration. MMN elicited by the deviant stimuli differing in duration
appeared more impaired in schizophrenia thanthose differing in tone frequency (Michie et al.,
2000; Javitt et al., 2000b; Umbricht et al., 2003),
however, the meta-analysis reported by Umbricht
and Krljes (2005) demonstrated that the difference between types failed to reach significancelevel. Moreover, they suggested that the frequen-

The evidence from genetic, brain imaging, clinicaland pharmacologic studies suggests that schizophrenia is a heterogeneous group of disorders(Kirkpatrick et al., 2001; Harrison and Weinberger,
2004). All current antipsychotics exert their effects primarily by blocking the D2 dopamine receptors. However, with the exception of clozapine
in a subgroup of patients, the conventional andeven new drugs leave most patients substantiallydisabled due to negative symptoms and cognitive impairments. There is now strong reason tosuspect abnormalities in N-methyl-d-aspartate(NMDA) receptor function may contribute tothese symptoms that are resistant to antipsychotic
medications.
Since their introduction nearly 50 years ago,the dissociative anaesthetics such as ketamine andphencyclidine (PCP) were known to cause a psychotic syndrome that was difﬁcult to distinguishfrom schizophrenia (Itil et al., 1967). Based uponemerging pharmacology of the NMDA receptors,
Javitt and Zukin (1991) proposed that the psychomimetic effects of PCP were due to blockadeof the NMDA receptors. Since then, numerous
studies demonstrated that negative and cognitive
symptoms as well as neurophysiological signs ofschizophrenia were sensitive to the psychomimetic effects of ketamine even in low dose level27

K. Nakagome et al.

2
1

in which subjects were required to press a button
whenever the letter “A” was followed by the letter “X” while all other sequences were to be ignored) characterized by speciﬁc increases of BX
errors (erroneous response to “X” not precededby “A”), reﬂecting a failure to form and use transient memory traces of task relevant information.
Thus, NMDA receptor dysfunction was thought
to underly deficits in transient memory at bothautomatic and controlled levels of information
processing in schizophrenia.

A

0
–1
–2
–3

Peak Amplitude, µV–4Preinfusion Baseline
Ketamine Infusion

–5
–6

–100
2
1

0

100

200

300

B

0
–1
–2
–3
–4

MMN deﬁcits andcognitive impairments in schizophrenia

–5
–6

–100

0

100

200

300

Latency, ms

It cannot be emphasized too strongly that themain goal of psychiatric treatment is not only torelieve the symptom levels or even improve cognitive impairments per se, but also to ameliorate
the patients’ sufferings presumably by reinforcing
their social skills and facilitating their levels of
QOL. Therefore, whether MMN represents thedomain of cognitive function closely related to social functional outcome is obviously an essential
point from clinical point of view.
MMN deﬁcits in schizophrenia do not seemto be related consistently to symptom domains, although a few studies found signiﬁcant correlations
with negative symptom levels (Catts et al., 1995;
Hirayasu et al., 1998; Javitt et al., 2000a; Kasai etal., 2002). Given the strong evidence from studies by Näätänen and their colleagues (Näätänen
et al., 1992) that MMN indexes auditory sensory
memory and automatic context-dependent information processing, it is surprising that not muchattention has been given to possible relationshipsof deﬁcits in MMN to deﬁcits in higher cognitive
functions. There are only few studies reporting
such relationships, suggesting that MMN deﬁcits
are particularly pronounced in patients with memory impairment (Baldeweg et al., 2004; Umbricht
et al., 2004; Kawakubo et al., 2006). Baldeweg
et al. (2004) used a new stimulation protocol
with continuously changing (“roving”) standard
stimuli in order to measure the effect of standard

Fig. 2. Effects of ketamine administration on MMN in
the pitch (A) and duration (B) deviance condition (n =20).
The gray lines represent the MMN wave during thebaseline recording before ketamine administration; theblack line, during infusion of ketamine; and the dark area,
the difference between the two curves (i.e., the reductionof MMN during ketamine administration) (Reprinted withpermission from Ketamine-induced deﬁcits in auditory and visualcontext-dependent processing in healthy volunerrs: Implicatioans for models of cognitive deﬁcits in schizophrenia, by Umbricht
et al., Archives of General Psychiatry, volume 57, pages 1139–
1147. Copyright© 2000 by the American Medical Association.
All rights reserved).

(Krystal et al., 1994; Radant et al., 1998; Adler etal., 1999; Newcomer et al., 1999; Umbricht et al.,
2000; Lahti et al., 2001).
Javitt et al. (1996) used a combination of
intracortical recording and pharmacological micromanipulations in monkeys and demonstrated
that both competitive and noncompetitive NMDA
antagonists blocked the generation of MMN.
These ﬁndings suggest that, on a neurophysiological level, MMN represents selective current ﬂow
through open, unblocked NMDA channels. Alsoin humans, Umbricht et al. (2000) reported 27%
and 21% reduction of MMN amplitude causedby ketamine administration in pitch and duration
deviance conditions, respectively (Fig. 2). Moreover, the authors demonstrated that ketamine induced performace deﬁcits in the AX-CPT (CPT28

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Fig. 3. MMN is signiﬁcantly associated with clinician-rated global assessments of functioning in schizophrenia patients at frontocentral electrodes ( = 0.01). The different shades represent the degree of association between GAF Scalescores and MMN across individual electrode site using Spearman nonparametric rank correlations. Signiﬁcant associations were present at the following electrodes: F3, F4, F7, F8, FC1, FC2, FC5, FC6, Fz, C3, C4, CP1, CP2, and Cz. The
panel on the right shows the position of electrode F3 and the correlation of MMN to GAF Scale score (r = –0.65, P < 0.001)(Reprinted with permission from Mismatch negativity deﬁcits are associated with poor functioning in schizophrenia patients, by Light
and Braff, Archives of General Psychiatry, volume 62, pages 127–136. Copyright© 2005 by the American Medical Association. All
rights reserved).

in response to speech sound may be of greater importance than MMN in response to simple tones.

repetitions on MMN (memory trace effect), which
was robustly correlated with the degree of neuropsychological memory impairment in generalrather than static measures of ERP magnitude.
Kawakubo et al. (2006) measured MMN elicitedby change in tone duration and phoneme durationin 23 schizophrenia patients in addition to evaluation for auditory verbal memory and executivefunction. They found that MMN under the phoneme duration condition was signiﬁcantly associated with scores for verbal memory but not withexecutive function whereas tone duration MMN
was not correlated with indices of either verbal
memory or executive function. Considering thatverbal memory is thought to be one of the main
targets in treatment, due to the large effect size of
it’s impairment in schizophrenia patients as compared with the performance in healthy individuals
and also it’s strong relationship with various types
of functional outcome (Green et al., 1996), theﬁndings suggest that further assessment of MMN

MMN deﬁcits
related to functional outcome?
Let us now focus on our main concern, that is,
the relationship between MMN deﬁcits and social
functional outcome. Can measurement of MMN
be of use in assessing the community functioning
level and/or ability of social problem solving and/or ability to acquire psychosocial skills from their
psychosocial rehabilitation programs? Do MMN
deficits predict poor social functional outcome
longitudinally? Not enough answers have beenobtained yet.
Light and Braff (2005) first reported that
MMN deficits were associated with poor social
functional status. In their study greater MMN
deficits were associated with lower Global As29

K. Nakagome et al.

in genes coding for the various subunits of the
NMDA receptor in a subgroup of patients deﬁned
by MMN deﬁcits. Moreover, as a preattentional
cognitive index, MMN may accurately characterize the integrity of sensory network dysfunction
free of attentional or motivational artifacts, which
is an additional advantage of this component to be
used as a biomarker.
It remains controversial, however, in termsof which domain of higher cognitive functions
MMN deficits are associated with. Moreover,
we have only limited information about the relationship between MMN and social functional
outcome in schizophrenia. Taking into consideration the MMN in response to speech sound was
associated with verbal memory and also with social skills acquisition, further studies using moresophisticated paradigms, such as those assessing
language functions might be promising.

sessment of Functioning (GAF) Scale ratings andalso with lower level of independence in community living situation (Fig. 3). Kawakubo et al. (inpress) investigated the relationship between MMN
and the degree of social skills acquisition following 3 months training in schizophrenia patients tosee whether MMN can predict social skills acquisition longitudinally. They found that larger SCD
values for right frontal/temporal MMN elicitedby across phoneme change (deviant stimulus; /o/,standard stimulus; /a/) at baseline were significantly associated with the degree of improvement
in total social skills scores assessed by a structured role play test. It should be noted that SCD
computation improves spatial resolution level and
Giard et al. (1990) successfully differentiated thecurrent activities arising from the temporal generator and those from the frontal generator involving mainly the right hemisphere by using SCD.
The ﬁndings that the social skills acquisition was
associated with the right frontal/temporal SCD
component but not with the bilateral temporal
SCD components may indicate that the social
skills acquisition was more strongly related to
involuntary triggering process of attention rather
than auditory sensory memory function. Moreover, tone duration MMN along with phoneme
duration MMN showed no relationship with social skills acquisition. As in the study mentioned
above done by the same research group, the impairment in early automatic processing of speechsound may be relevant to schizophrenia patients’social functional outcome.

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MMN index cognitive function in schizophrenia

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Received June 15, 2007; accepted July 23, 2007
Corresponding author: Kazuyuki Nakagome, MD

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