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Original Article |

Mismatch Negativity in Chronic Schizophrenia and First-Episode Schizophrenia FREE

Dean F. Salisbury, PhD; Martha E. Shenton, PhD; Carlye B. Griggs, BA; Aaron Bonner-Jackson; Robert W. McCarley, MD
[+] Author Affiliations

From Harvard Medical School, Department of Psychiatry, McLean Hospital, Belmont, Mass, and the Boston Veterans Affairs Healthcare System, Brockton, Mass.


Arch Gen Psychiatry. 2002;59(8):686-694. doi:10.1001/archpsyc.59.8.686.
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Published online

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 from100 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.

Figures in this Article

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,1017 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 al2327 showed reduced MMN in patients with schizophrenia, a finding replicated by several others2832 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.28,3437 However, some studies3740 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.

SUBJECTS

Sixteen male in patients 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 (including7 women). Controls were recruited from the general population through newspaper advertisement. Patients' diagnoses were confirmed via the Structured Clinical Interview for DSM-III-R–Patient Edition (SCID-P),55 and controls were screened using the Structured Clinical Interview for DSM-III-R–Non-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.

Table Graphic Jump LocationTable 1. Demographic, Neuropsychological, and Clinical Data*
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 through28 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 kΩ, and the ears were matched within 1 kΩ. 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 ϵ 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.

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 tone–deviants 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, ϵ = 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, ϵ = 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 × hemisphere: F2,54 = 6.65, P= .003, ϵ = 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.

Place holder to copy figure label and caption
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. The3 shaded areas from the anterior to the posterior represent the left hemisphere frontal, temporal, and parieto-occipital regions, respectively (homologous for the right hemisphere).

Graphic Jump Location
Table Graphic Jump LocationTable 2. Mismatch Negativity Amplitudes

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 tone–deviants 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, ϵ = 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, ϵ = 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.

Place holder to copy figure label and caption
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.

Graphic Jump Location

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.

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 of11 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 in patients 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.

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, Psychiatry116A, Boston Veterans Affairs Healthcare System, 940 Belmont St, Brockton, MA 02301 (e-mail: robert_mccarley@hms.harvard.edu).

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Shelley  AMWard  PBCatts  SVMichie  PTAndrews  AMcConaghy  N Mismatch negativity: an index of preattentive processing deficit in schizophrenia. Biol Psychiatry. 1991;301059- 1062
Link to Article
Kasai  KOkazawa  KNakagome  KHiramatsu  KHata  AFukuda  MHonda  MMiyauchi  MMatsuchita  M Mismatch negativity and N2b attenuation as an indicator for dysfunction of the preattentive and controlled processing for deviance detection in schizophrenia: a topographic event-related potential study. Schizophr Res. 1999;35141- 156
Link to Article
Todd  JMichie  PTBudd  TWRock  DJablensky  AV Auditory sensory memory in schizophrenia: inadequate trace information? Psychiatry Res. 2000;9699- 115
Link to Article
Michie  PTBudd  TWTodd  JRock  DWichmann  HBox  JJablensky  AV Duration and frequency mismatch negativity in schizophrenia. Clin Neurophysiol. 2000;1111054- 1065
Link to Article
O'Donnell  BFHokama  HMcCarley  RWSmith  RSSalisbury  DFMondrow  ENestor  PGShenton  ME Auditory ERPs to non-target stimuli in schizophrenia: relationships to probability, task-demands, and target ERPs. Psychophysiology. 1994;17219- 231
Link to Article
Kathmann  NWagner  MRendtorff  NEngel  RR Delayed peak latency of the mismatch negativity in schizophrenics and alcoholics. Biol Psychiatry. 1995;37754- 757
Link to Article
Kirino  EInoue  R The relationship of mismatch negativity to quantitative EEG and morphological findings in schizophrenia. J Psychiatr Res. 1999;33445- 456
Link to Article
Alho  KWoods  DLAlgazi  A Processing of auditory stimuli during auditory and visual attention as revealed by event-related potentials. Psychophysiology. 1994;31469- 479
Link to Article
Ward  PBLoneragan  CLiebert  BCatts  SVChaturvedi  SPearson  MGanser  ELRedenbach  JMichie  PTAndrews  SMcConaghy  N MRI measures of auditory cortex area correlate with an ERP index of auditory sensory memory in schizophrenia [abstract]. Schizophr Res. 1995;15102
Link to Article
Wible  CGKubicki  MYoo  SSKacher  DFSalisbury  DFAnderson  MCShenton  MEHirayasu  YKikinis  RJolesz  FAMcCarley  RW A functional magnetic resonance imaging study of auditory mismatch in schizophrenia. Am J Psychiatry. 2001;158938- 943
Link to Article
Salisbury  DFFarrell  DCShenton  MEFischer  IAZarate  CMcCarley  RW Mismatch negativity is reduced in chronic but not first episode schizophrenia[abstract]. Biol Psychiatry. 1999;45suppl25S
Link to Article
Umbricht  DJavitt  DBates  JPollack  SLieberman  JKane  J Auditory event-related potentials (ERP) in first episode and chronic schizophrenia [abstract]. Biol Psychiatry. 1997;41suppl46S
Salisbury  DFShenton  MESherwood  ARFischer  IAYurgelun-Todd  DATohen  MMcCarley  RW First-episode schizophrenic psychosis differs from first-episode affective psychosis and controls in P300 amplitude over left temporal lobe. Arch Gen Psychiatry. 1998;55173- 180
Link to Article
Morstyn  RDuffy  FHMcCarley  RW Altered P300 topography in schizophrenia. Arch Gen Psychiatry. 1983;40729- 734
Link to Article
Salisbury  GFShenton  MEMcCarley  RW P300 topography differs in schizophrenia and manic psychosis. Biol Psychiatry. 1999;4598- 106
Link to Article
Hirayasu  YShenton  MESalisbury  DFDickey  CCFischer  IAMazzoni  PKisler  TArakaki  HKwon  JSAnderson  JEYurgelun-Todd  DTohen  MMcCarley  RW Lower left temporal lobe MRI volumes in patients with first-episode schizophrenia compared with psychotic patients with first-episode affective disorder and normal subjects. Am J Psychiatry. 1998;1551384- 1391
Shenton  MEKikinis  RJolesz  FAPollak  SDLeMay  MWible  CGHokama  HMartin  JMetcalf  DColeman  MMcCarley  RW Abnormalities of the left temporal lobe and thought disorder in schizophrenia: a quantitative magnetic resonance imaging study. N Engl J Med. 1992;327604- 612
Link to Article
Kwon  JSMcCarley  RWHirayasu  YAnderson  JEFischer  IAKikinis  RJolesz  FAShenton  ME Left planum temporale volume reduction in schizophrenia. Arch Gen Psychiatry. 1999;56142- 148
Link to Article
Hirayasu  YMcCarley  RWSalisbury  DFTanaka  SKwon  JSFrumin  MSnyderman  DYurgelun-Todd  DKikinis  RJolesz  FAShenton  ME Planum temporale and Heschl gyrus volume reduction in schizophrenia. Arch Gen Psychiatry. 2000;57692- 699
Link to Article
McCarley  RWShenton  MEO'Donnell  BFFaux  SFKikinis  RNestor  PGJolesz  FA Auditory P300 abnormalities and left posterior superior temporal gyrus volume reduction in schizophrenia. Arch Gen Psychiatry. 1993;50190- 197
Link to Article
McCarley  RWSalisbury  DFHirayasu  YYurgelun-Todd  DATohen  MZarate  CKikinis  RJolesz  FAShenton  ME Association between smaller left posterior superior temporal gyrus volume on magnetic resonance imaging and smaller left temporal P300 amplitude in first-episode schizophrenia. Arch Gen Psychiatry. 2002;59321- 331
Link to Article
Spitzer  RLWilliams  JBWGibbon  MFirst  MB Structured Clinical Interview for DSM-III-R–Patient Edition (SCID-P, Version 2.0).  Washington, DC American Psychiatric Press1990;
Spitzer  RLWilliams  JBWGibbon  MFirst  MB Structured Clinical Interview for DSM-III-R–Non-Patient Edition (SCID-NP, Version 1.0).  Washington, DC American Psychiatric Press1990;
Semlitsch  HVAnderer  PSchuster  PPresslich  O A solution for reliable and valid reduction of ocular artifacts applied to the P300 ERP. Psychophysiology. 1986;23695- 703
Link to Article
Nordby  HHammerborg  DRoth  WTHugdahl  K ERPs for infrequent omissions and inclusions of stimulus elements. Psychophysiology. 1994;31544- 552
Link to Article
Alain  CWoods  DLOgawa  KH Brain indices of automatic pattern processing. Neuroreport. 1994;6140- 144
Link to Article
Alho  KConnolly  JFCheour  MLehtokoski  AHuotilainen  MVirtanen  JAulanko  RIlmoniemi  RJ Hemispheric lateralization in preattentive processing of speech sounds. Neurosci Lett. 1998;2589- 12
Link to Article
Näätänen  RAlho  K Mismatch negativity: the measure for central sound representation accuracy. Audiol Neurootol. 1997;2341- 353
Link to Article
Johnson  R On the neural generators of the P300 component of the event-related potential. Psychophysiology. 1993;3090- 97
Link to Article
Olney  JWFarvar  NB Glutamate receptor dysfunction and schizophrenia. Arch Gen Psychiatry. 1995;52998- 1007
Link to Article
Kasai  KNakagome  KItoh  IKoshida  IHata  AIwanami  AFukuda  MHiramatsu  K-IKato  N Multiple generators in the auditory automatic discrimination process in humans. Neuroreport. 1999;102267- 2271
Link to Article
Rabinowicz  EFSilipo  GGoldman  RJavitt  DC Auditory sensory dysfunction in schizophrenia. Arch Gen Psychiatry. 2000;571149- 1155
Link to Article

Figures

Place holder to copy figure label and caption
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. The3 shaded areas from the anterior to the posterior represent the left hemisphere frontal, temporal, and parieto-occipital regions, respectively (homologous for the right hemisphere).

Graphic Jump Location
Place holder to copy figure label and caption
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.

Graphic Jump Location

Tables

Table Graphic Jump LocationTable 1. Demographic, Neuropsychological, and Clinical Data*
Table Graphic Jump LocationTable 2. Mismatch Negativity Amplitudes

References

Näätänen  RGaillard  AWK The orienting reflex and the N2 deflection of the event-related potential(ERP). Gaillard  AWKRitter  WedsTutorials in Event-Related Potentials Research: Endogenous Components. North Holland–Amsterdam, the Netherlands North Holland Publishing Co1983;119- 141
Näätänen  R The role of attention in auditory information processing as revealed by event-related potentials and other measures of cognitive function. Behav Brain Sci. 1990;13201- 288
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Gomes  HMolholm  SRitter  WKurtzburg  DCowan  NVaughan  HG  Jr Mismatch negativity in children and adults, and effects of an attended task. Psychophysiology. 2000;37807- 816
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Oades  RDDittman-Balcar  AZerbin  DGrzella  I Impaired attention-dependent augmentation of MMN in nonparanoid vs paranoid schizophrenic patients: a comparison with obsessive-compulsive disorder and healthy subjects. Biol Psychiatry. 1997;411196- 1210
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Paavilainen  PKarlsson  MLReinikainen  KNäätänen  R Mismatch negativity to change in spatial location of an auditory stimulus. Electroencephalogr Clin Neurophysiol. 1989;73129- 141
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Schroger  EPaavilainen  PNäätänen  R Mismatch negativity to changes in a continuous tone with regularly varying frequencies. Electroencephalogr Clin Neurophysiol. 1994;92140- 147
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Scherg  MVajsar  JPicton  T A source analysis of the human auditory evoked potentials. J Cogn Neurosci. 1989;1336- 355
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Javitt  DCSteinschneider  MSchroeder  CEVaughan  HG  JrArezzo  JC Detection of stimulus deviance within primate primary auditory cortex: intracortical mechanisms of mismatch negativity (MMN) generation. Brain Res. 1994;667192- 200
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Kropotov  JDNäätänen  RSevostianov  AVAlho  KReinikainen  KKropotova  OV Mismatch negativity to auditory stimulus change recorded directly from the human temporal cortex. Psychophysiology. 1995;32418- 422
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Tiitinen  HSinkkonen  JReinikainen  KAlho  KLavikainen  JNäätänen  R Selective attention enhances the auditory 40-Hz transient response in humans. Nature. 1993;36459- 60
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Näätänen  RAlho  K Generators of electrical and magnetic mismatch response in humans. Brain Topogr. 1995;7315- 320
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Näätänen  R The mismatch negativity: a powerful tool for cognitive neuroscience. Ear Hear. 1995;166- 18
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Javitt  DCSteinschneider  MSchroeder  CEArezzo  JC Role of cortical N-methyl D-aspartate receptors in auditory sensory memory and mismatch negativity generation: implications for schizophrenia. Proc Natl Acad Sci U S A. 1996;9311962- 11967
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Oranje  Bvan Berckel  BNMKemner  Cvan Ree  JMKahn  RSVerbaten  MN The effects of a sub-anaesthetic dose of ketamine on human selective attention. Neuropsychopharmacology. 2000;22293- 302
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Umbricht  DSchmid  LKoller  RVollenweider  FXHell  DJavitt  D Ketamine-induced deficits in auditory and visual context–dependent processing in healthy volunteers. Arch Gen Psychiatry. 2000;571139- 1147
Link to Article
Javitt  DCDoneshka  PZylberman  IRitter  WVaughan  HG  Jr Impairment of early cortical processing in schizophrenia: an event-related potential confirmation study. Biol Psychiatry. 1993;33513- 519
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Javitt  DCDoneshka  PGrochowski  SRitter  W Impaired mismatch negativity generation reflects widespread dysfunction of working memory in schizophrenia. Arch Gen Psychiatry. 1995;52550- 558
Link to Article
Javitt  DCGrochowski  SShelley  AMRitter  W Impaired mismatch negativity (MMN) generation in schizophrenia as a function of stimulus deviance, probability, and interstimulus/interdeviant interval. Electroencephalogr Clin Neurophysiol. 1998;108143- 153
Link to Article
Javitt  DCShelley  AMSilipo  GLieberman  JA Deficits in auditory and visual context–dependent processing in schizophrenia: defining the pattern. Arch Gen Psychiatry. 2000;571131- 1137
Link to Article
Javitt  DCShelley  AMRitter  W Associated deficits in mismatch negativity generation and tone matching in schizophrenia. Clin Neurophysiol. 2000;1111733- 1737
Link to Article
Catts  SVShelley  AMWard  PBLiebert  BMcConaghy  NAndrews  SMichie  PT Brain potential evidence for an auditory sensory memory deficit in schizophrenia. Am J Psychiatry. 1995;152213- 219
Alain  CHargrave  RWoods  DL Processing of auditory stimuli during visual attention in patients with schizophrenia. Biol Psychiatry. 1998;441151- 1159
Link to Article
Hirayasu  YPotts  GFO'Donnell  BFKwon  JSArakaki  HAkdag  JSLevitt  JJShenton  MEMcCarley  RW Auditory mismatch negativity in schizophrenia: topographic evaluation with a high-density recording montage. Am J Psychiatry. 1998;1551281- 1284
Umbricht  DJavitt  DNovak  GPollack  SLiberman  JKane  J Effects of clozapine on auditory event-related potentials in schizophrenia. Biol Psychiatry. 1998;44716- 725
Link to Article
Shelley  AMSilipo  GJavitt  D Diminished responsiveness of ERPs in schizophrenic subjects to changes in auditory stimulation parameters: implications for theories of cortical dysfunction. Schizophr Res. 1999;3765- 79
Link to Article
Kreitschmann-Andermahr  TRosburg  TMeier  TVolz  H-PNowak  HSauer  H Impaired sensory processing in male patients with schizophrenia: a magnetoencephalographic study of auditory mismatch detection. Schizophr Res. 1999;35121- 129
Link to Article
Shelley  AMWard  PBCatts  SVMichie  PTAndrews  AMcConaghy  N Mismatch negativity: an index of preattentive processing deficit in schizophrenia. Biol Psychiatry. 1991;301059- 1062
Link to Article
Kasai  KOkazawa  KNakagome  KHiramatsu  KHata  AFukuda  MHonda  MMiyauchi  MMatsuchita  M Mismatch negativity and N2b attenuation as an indicator for dysfunction of the preattentive and controlled processing for deviance detection in schizophrenia: a topographic event-related potential study. Schizophr Res. 1999;35141- 156
Link to Article
Todd  JMichie  PTBudd  TWRock  DJablensky  AV Auditory sensory memory in schizophrenia: inadequate trace information? Psychiatry Res. 2000;9699- 115
Link to Article
Michie  PTBudd  TWTodd  JRock  DWichmann  HBox  JJablensky  AV Duration and frequency mismatch negativity in schizophrenia. Clin Neurophysiol. 2000;1111054- 1065
Link to Article
O'Donnell  BFHokama  HMcCarley  RWSmith  RSSalisbury  DFMondrow  ENestor  PGShenton  ME Auditory ERPs to non-target stimuli in schizophrenia: relationships to probability, task-demands, and target ERPs. Psychophysiology. 1994;17219- 231
Link to Article
Kathmann  NWagner  MRendtorff  NEngel  RR Delayed peak latency of the mismatch negativity in schizophrenics and alcoholics. Biol Psychiatry. 1995;37754- 757
Link to Article
Kirino  EInoue  R The relationship of mismatch negativity to quantitative EEG and morphological findings in schizophrenia. J Psychiatr Res. 1999;33445- 456
Link to Article
Alho  KWoods  DLAlgazi  A Processing of auditory stimuli during auditory and visual attention as revealed by event-related potentials. Psychophysiology. 1994;31469- 479
Link to Article
Ward  PBLoneragan  CLiebert  BCatts  SVChaturvedi  SPearson  MGanser  ELRedenbach  JMichie  PTAndrews  SMcConaghy  N MRI measures of auditory cortex area correlate with an ERP index of auditory sensory memory in schizophrenia [abstract]. Schizophr Res. 1995;15102
Link to Article
Wible  CGKubicki  MYoo  SSKacher  DFSalisbury  DFAnderson  MCShenton  MEHirayasu  YKikinis  RJolesz  FAMcCarley  RW A functional magnetic resonance imaging study of auditory mismatch in schizophrenia. Am J Psychiatry. 2001;158938- 943
Link to Article
Salisbury  DFFarrell  DCShenton  MEFischer  IAZarate  CMcCarley  RW Mismatch negativity is reduced in chronic but not first episode schizophrenia[abstract]. Biol Psychiatry. 1999;45suppl25S
Link to Article
Umbricht  DJavitt  DBates  JPollack  SLieberman  JKane  J Auditory event-related potentials (ERP) in first episode and chronic schizophrenia [abstract]. Biol Psychiatry. 1997;41suppl46S
Salisbury  DFShenton  MESherwood  ARFischer  IAYurgelun-Todd  DATohen  MMcCarley  RW First-episode schizophrenic psychosis differs from first-episode affective psychosis and controls in P300 amplitude over left temporal lobe. Arch Gen Psychiatry. 1998;55173- 180
Link to Article
Morstyn  RDuffy  FHMcCarley  RW Altered P300 topography in schizophrenia. Arch Gen Psychiatry. 1983;40729- 734
Link to Article
Salisbury  GFShenton  MEMcCarley  RW P300 topography differs in schizophrenia and manic psychosis. Biol Psychiatry. 1999;4598- 106
Link to Article
Hirayasu  YShenton  MESalisbury  DFDickey  CCFischer  IAMazzoni  PKisler  TArakaki  HKwon  JSAnderson  JEYurgelun-Todd  DTohen  MMcCarley  RW Lower left temporal lobe MRI volumes in patients with first-episode schizophrenia compared with psychotic patients with first-episode affective disorder and normal subjects. Am J Psychiatry. 1998;1551384- 1391
Shenton  MEKikinis  RJolesz  FAPollak  SDLeMay  MWible  CGHokama  HMartin  JMetcalf  DColeman  MMcCarley  RW Abnormalities of the left temporal lobe and thought disorder in schizophrenia: a quantitative magnetic resonance imaging study. N Engl J Med. 1992;327604- 612
Link to Article
Kwon  JSMcCarley  RWHirayasu  YAnderson  JEFischer  IAKikinis  RJolesz  FAShenton  ME Left planum temporale volume reduction in schizophrenia. Arch Gen Psychiatry. 1999;56142- 148
Link to Article
Hirayasu  YMcCarley  RWSalisbury  DFTanaka  SKwon  JSFrumin  MSnyderman  DYurgelun-Todd  DKikinis  RJolesz  FAShenton  ME Planum temporale and Heschl gyrus volume reduction in schizophrenia. Arch Gen Psychiatry. 2000;57692- 699
Link to Article
McCarley  RWShenton  MEO'Donnell  BFFaux  SFKikinis  RNestor  PGJolesz  FA Auditory P300 abnormalities and left posterior superior temporal gyrus volume reduction in schizophrenia. Arch Gen Psychiatry. 1993;50190- 197
Link to Article
McCarley  RWSalisbury  DFHirayasu  YYurgelun-Todd  DATohen  MZarate  CKikinis  RJolesz  FAShenton  ME Association between smaller left posterior superior temporal gyrus volume on magnetic resonance imaging and smaller left temporal P300 amplitude in first-episode schizophrenia. Arch Gen Psychiatry. 2002;59321- 331
Link to Article
Spitzer  RLWilliams  JBWGibbon  MFirst  MB Structured Clinical Interview for DSM-III-R–Patient Edition (SCID-P, Version 2.0).  Washington, DC American Psychiatric Press1990;
Spitzer  RLWilliams  JBWGibbon  MFirst  MB Structured Clinical Interview for DSM-III-R–Non-Patient Edition (SCID-NP, Version 1.0).  Washington, DC American Psychiatric Press1990;
Semlitsch  HVAnderer  PSchuster  PPresslich  O A solution for reliable and valid reduction of ocular artifacts applied to the P300 ERP. Psychophysiology. 1986;23695- 703
Link to Article
Nordby  HHammerborg  DRoth  WTHugdahl  K ERPs for infrequent omissions and inclusions of stimulus elements. Psychophysiology. 1994;31544- 552
Link to Article
Alain  CWoods  DLOgawa  KH Brain indices of automatic pattern processing. Neuroreport. 1994;6140- 144
Link to Article
Alho  KConnolly  JFCheour  MLehtokoski  AHuotilainen  MVirtanen  JAulanko  RIlmoniemi  RJ Hemispheric lateralization in preattentive processing of speech sounds. Neurosci Lett. 1998;2589- 12
Link to Article
Näätänen  RAlho  K Mismatch negativity: the measure for central sound representation accuracy. Audiol Neurootol. 1997;2341- 353
Link to Article
Johnson  R On the neural generators of the P300 component of the event-related potential. Psychophysiology. 1993;3090- 97
Link to Article
Olney  JWFarvar  NB Glutamate receptor dysfunction and schizophrenia. Arch Gen Psychiatry. 1995;52998- 1007
Link to Article
Kasai  KNakagome  KItoh  IKoshida  IHata  AIwanami  AFukuda  MHiramatsu  K-IKato  N Multiple generators in the auditory automatic discrimination process in humans. Neuroreport. 1999;102267- 2271
Link to Article
Rabinowicz  EFSilipo  GGoldman  RJavitt  DC Auditory sensory dysfunction in schizophrenia. Arch Gen Psychiatry. 2000;571149- 1155
Link to Article

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