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. Author manuscript; available in PMC: 2011 Mar 15.
Published in final edited form as: Biol Psychiatry. 2008 May 9;64(5):385–391. doi: 10.1016/j.biopsych.2008.03.019

Are Auditory-Evoked Frequency and Duration Mismatch Negativity (MMN) Deficits Endophenotypic for Schizophrenia? High-Density Electrical Mapping in Clinically Unaffected First-Degree Relatives, First-Episode and Chronic Schizophrenia

Elena Magno 1,3, Sherlyn Yeap 1,2,3, Jogin H Thakore 1,3, Hugh Garavan 1,2,3, Pierfilippo De Sanctis 1,2, Daniel C Javitt 2,4, John J Foxe 1,2,3,4,#
PMCID: PMC3057136  NIHMSID: NIHMS65996  PMID: 18472090

Abstract

Background

Mismatch negativity (MMN) is a negative-going event-related potential (ERP) component that occurs in response to intermittent changes in constant auditory backgrounds. A consistent finding across a large number of studies has been impaired MMN generation in schizophrenia, which has been interpreted as evidence for fundamental deficits in automatic auditory sensory processing. The aim of this study was to investigate the extent to which dysfunction in MMN generation might represent an endophenotypic marker for schizophrenia.

Methods

We measured MMN to deviants in duration (25 msec, 1000Hz) and deviants in pitch (50 msec, 1200Hz) relative to standard tones (50 msec, 1000Hz) in 45 chronic schizophrenia patients, 25 of their first-degree unaffected biological relatives, 12 first-episode patients, and 27 healthy control subjects.

Results

In line with previous work, MMN amplitudes to duration deviants (but not to pitch deviants) were significantly reduced in patients with chronic schizophrenia compared to control subjects. However, both duration and pitch MMNs were completely unaffected in the first-degree biological relatives and this was also the case for the first-episode patients. Furthermore, length of illness did not predict the extent of MMN deficit.

Conclusions

These findings suggest that the MMN deficit seen in schizophrenia patients is most likely a consequence of the disease and that MMN, at least to basic auditory feature deviants, is at best only weakly endophenotypic for schizophrenia.

INTRODUCTION

Schizophrenia is such a devastating disease in large part because it affects such a widespread realm of brain functions, from higher order cognitive processes such as sustained attention, working memory and executive functions (1–4), to early and late sensory processes in both the visual (5–9) and the auditory domains (10–12). While plenty of effort has been devoted to understanding the prominent cognitive deficits in schizophrenia, increasingly, more studies have revealed how early sensory dysfunction may also be a valuable predictor of the development of the disease. Among the latter, impairments of early auditory processing, such as the reduction of auditory mismatch negativity (MMN) amplitude in patients with schizophrenia, have attracted particular interest in the literature (for a comprehensive review see 13). The MMN is an auditory event-related potential typically elicited by infrequent deviant events presented in a stream of repetitive events, even in the absence of attention (14), and thus it constitutes an excellent and objective measure of the integrity, or breakdown, of auditory sensory networks. It is easy to measure, requiring no explicit task or attention from the subject, and is so robust that it can even be elicited in coma patients (e.g.15).

A central issue in present day research efforts centers on establishing good endophenotypic measures for the development of debilitating mental disorders such as schizophrenia. There is accumulating evidence in the literature that inheritance of some of the genetic liability patterns of schizophrenia is enhanced among unaffected family members of schizophrenia patients, as indicated by mild disruptions of executive functioning, verbal and visual memory, auditory attention and verbal ability, similar to those found in patients (16–19). Side by side with neuropsychological testing and genetic investigations, event-related potentials (ERPs) represent a simple and effective tool for investigating the neurophysiological processes underlying cognitive and sensory dysfunction in schizophrenia. A number of studies of the P50 and P300 potentials have certainly suggested that auditory dysfunction may be endophenotypic for schizophrenia (e.g.20, 21–27). For example, a recent study on electrophysiological measures of auditory processing, as measured in monozygotic twin pairs (20) has shown that impairment in P50 suppression and P300 amplitude and latency are genetically transmitted. Additionally, a recent study on early visual processing has shown impaired P1 generation not only in medicated patients with schizophrenia, but most strikingly in their clinically unaffected first-degree relatives (28). The decreased P1 wave was found in the absence of any age, gender or medication effects, strongly suggesting that it is associated with genetic risk for schizophrenia. The P1 deficit appears to be a very promising candidate as an endophenotypic marker for the disorder, and recent work has begun to uncover specific gene variants responsible for this deficit (29).

It is less clear if the MMN can also be used to identify genetic liability to schizophrenia, since only two relatively small family studies have reported reduced MMN in first-degree relatives of schizophrenic patients (30, 31), while another much larger study found no differences (32). Nonetheless, given the ubiquity of MMN deficit findings in chronic schizophrenia patients, the MMN has been repeatedly predicted to be a useful candidate endophenotype for schizophrenia (20, 33).

The advantage of studying first-degree biological relatives lies in the fact that this population has not developed the disease and yet is more likely to carry the genetic risk for it; and unaffected relatives are not medicated, therefore eliminating the risk of confounding results with the effects of drugs. In the current study, we investigated whether the MMN deficit nearly ubiquitously identified in chronic schizophrenia is also observed in unaffected first-degree biological relatives, in order to evaluate whether this ERP component represents a promising endophenotypic marker for schizophrenia.

A second goal of this study, which involved a large cohort of chronic schizophrenia patients, was to assess the extent to which MMN deficits are linked to the progression of the disease, or whether the deficit is established early in the disease and remains relatively stable thereafter. While recent-onset patients (within 18 months of diagnosis) seem to be predisposed to show an MMN impairment, first-episode schizophrenia patients (within 6 months from first admission) do not appear to show the same deficit (13), suggesting that MMN impairment may occur at a later stage of the disorder. To this end, we also assessed the possible effects of length of illness, and of medication status, on the degree of degeneration of this ERP component.

METHODS AND MATERIALS

Participants

The chronic patient group was comprised of forty-five individuals (14 females; aged 19–63; mean ± SD age = 42.80 ± 12.65 years) with a diagnosis of schizophrenia as defined by DSM-IV criteria (one patient also had concurrent epilepsy). Length of illness, defined as the time since first hospitalization or presentation to the services, ranged from 1 year to 35 years for this group. Eight were inpatients, and 37 were outpatients. All but one of the chronic patients were on antipsychotic medication (23 on atypical, 15 on typical, and 6 on a combination of both) with a mean chlorpromazine equivalent dose of 429.22 mg/day (range 50–1200 mg/day). One chronic patient had ceased taking her medications three months prior to testing and was medication-free at the time of testing. Symptom ratings were analyzed using the Brief Psychiatric Rating Scale or BPRS (34) (mean ± SD score = 37.69 ± 9.98), and the Scale for the Assessment of Negative Symptoms or SANS (35) (mean ± SD score = 37.39 ± 26.37). Twelve additional first-episode patients, unrelated to the chronic patients, also served in this experiment (3 females; aged 17–37 years; mean ± SD age = 24.25 ± 6.17 years). None had any concurrent medical condition. First-episode was defined as those patients within 3 months from first diagnosis (i.e. at time of first hospitalization or presentation to the services). Ten of these first-episode patients were inpatients, and two were outpatients. Only one first-episode patient was medicated at time of testing with 300 mg/day of chlorpromazine; all others were drug-naïve. The first-episode patients mean SANS score was 46.92 ± 11.83, and the mean BPRS score was 38.83 ± 23.66. All patients were free of other medical conditions or substance abuse. Patients were recruited from the St. Vincent’s Hospital Catchment Area in Fairview, Dublin, Ireland.

Twenty-four first-degree biological family members (14 females) were also recruited, according to a criterion of a maximum of three unaffected first-degree relatives for each patient (19 families in total; 5 first-degree relatives from 4 family members were related to first episode patients). These were aged 18–64 (mean ± SD age = 35.7 ± 15 years). The relatives’ group consisted of the parents (7), the siblings (12) or the children (5) of affected individuals meeting DSM-IV criteria for schizophrenia. The control group was comprised of 27 subjects with no family history of psychiatric or neurological disorder (14 female), aged 19–64 (mean ± SD age = 38.0 ± 12.9 years). Relatives and controls were free of any psychiatric illness or symptoms by self-report using criteria from the SCID-NP (36) and all reported no history of alcohol or substance abuse. None was on any psychotropic medication at the time of testing. Healthy control subjects and first-degree relatives received a modest remuneration of € 40 for their time.

Handedness was determined by the Edinburgh Handedness Inventory (37); 6 chronic patients, 2 first-episode patients, 5 relatives and 5 controls were left-handed. All subjects reported no hearing impairment and normal or corrected-to-normal vision. The ethics committee at St. Vincent’s Hospital approved all procedures and all participants signed a written informed consent after the details of the study were fully explained to them and before participating in the study.

Stimuli and task

The task comprised of one experimental block of 30 minutes duration. A rest was given after the first 15 minutes, and additional rests were given if required by the participants. In total, subjects were presented with approximately 3000 auditory stimuli, of which 2400 (80 %) were standard tones of 1000 Hz presented at 50 ms, 300 deviant tones (10 %) of 1000 Hz at 25 ms (dev-dur), and 300 deviant tones (10 %) of 1200 Hz at 50 ms (dev-hz). The stimulus onset asynchrony was 500 ms.

Stimuli were presented binaurally through headphones (Sennheiser-HD600) while participants were asked to ignore the sounds and watched a black and white Charlie Chaplin movie with no sound.

Data acquisition

Continuous EEG was acquired through the ActiveTwo Biosemi™ electrode system from 72 scalp electrodes, digitized at 512 Hz with an open pass-band from DC to 150 Hz. For analysis and display purposes, data were subsequently filtered with a 0-phase-shift 45 Hz low-pass filter (24 dB/octave) after acquisition. No high-pass filter was applied. With the Biosemi system, every electrode or combination of electrodes can be assigned as the “reference”, and this is done purely in software after acquisition. BioSemi replaces the "ground" electrodes used in conventional systems with two separate electrodes: Common Mode Sense (CMS) active electrode and Driven Right Leg (DRL) passive electrode. These 2 electrodes form a feedback loop, which drives the average potential of the subject (the Common Mode voltage) as close as possible to the ADC reference voltage in the AD-box (the ADC reference can be considered as the amplifier "zero"). For a detailed description of the referencing and grounding conventions used by the Biosemi active electrode system, the interested reader is referred to the following website: http://www.biosemi.com/faq/cms&drl.htm. All data were re-referenced to the left mastoid after acquisition, for analysis.

Event Related Potential analysis

Data were analyzed using BESA Version 5.1.6 (Brain Electric Source Analysis) software (www.besa.de). All electrode channels were subjected to an artifact criterion of ±120µV to reject trials with excessive EMG or other artifacts. Blinks and large eye movements were rejected before averaging. Epochs of 200 ms pre-stimulus to 500 ms post-stimulus were analyzed and baseline-corrected relative to the interval -100 to 0 ms. Only the deviants and the standard stimuli that were immediately preceded by standard stimuli were used for averaging. That is, the first standard stimulus following a deviant was excluded from all analyses. The average trial number accepted for the standard, dev-dur and dev-hz respectively was, for the relatives 1526 ± 214, 254 ± 36, 255 ± 32, for the chronic patients was 1507 ± 218, 260 ± 54, 260 ± 60, for the first-episode patients was 1525 ± 373, 252 ± 62, 253 ± 64, and for the control group 1521 ± 204, 252 ± 34, 254 ± 33.

We investigated the possibility of reduction of both MMN types (duration and pitch) in clinically unaffected first-degree biological relatives, as well as the integrity of these components in early stage schizophrenia. MMN was defined as the difference waveform obtained by subtracting the standard tone ERPs from the deviant tone ERPs. For each group and for each MMN type, an average MMN amplitude measure was obtained by averaging individual MMN amplitudes over a set of seven fronto-central electrodes (i.e., AFz, Fz, FCz, F1, FC1, F2 and FC2, see Figure 1). Both duration and pitch MMN amplitudes were maximal in the 140–180 ms interval (Table 1).

Figure 1.

Figure 1

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a) Average amplitudes for the duration and frequency mismatch negativity at seven fronto-central electrode sites. Groups on the x-axis are chronic schizophrenia (Chronic S.) patients, first-episode patients (F-E S.), first-degree healthy biological relatives and healthy control subjects (including a subgroup of 12 age-matched to F-E S.). b) MMN amplitudes at the left (LM) and right (RM) mastoids are plotted illustrating the characteristic polarity inversion of the MMN (i.e. positive values). For illustration purposes, the mastoids data shown were computed from average-referenced data. Amplitudes are in microvolts (µV). Error bars represent standard error of the mean (SEM).

Table 1.

Mean amplitude measures of frequency (MMN-hz) and duration MMN (MMN-dur) in all groups and subgroups using a left mastoid reference. Mean is calculated as the average of 7 fronto-central electrodes. Standard deviations (SD) are in parenthesis. µV is microvolts.

Group MMN-dur (SD) MMN-hz (SD)
Controls (27) −2.74 µV (1.98) −2.22 µV (1.10)
Chronic Patients (45) −1.91 µV (1.35) −1.66 µV (1.61)
First-Degree Relatives (24) −3.33 µV (1.28) −2.81 µV (1.70)
First-Episode Patients (12) −3.21 µV (2.12) −2.80 µV (1.40)
SubGroup MMN-dur (SD) MMN-hz (SD)
Controls (12) −2.71 µV (1.91) −2.33 µV (1.19)
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The mean amplitude measures from the four groups were submitted to a linear mixed model (LMM) with one fixed factor of Group, one random factor of Family Membership (accounting for the fact that some of our sample of first-degree relatives were related with the patients and with each other), and two covariates (age and gender). MMN-dur and MMN-hz mean amplitudes were used as the dependent variable in two separate models.

Age was used as a covariate as it differed across groups: chronic patients were older than relatives [t38 = 7.15, p < .0001] and first-episode patients [t67 = 2.08, p < .05], while first-episode patients were also younger than controls [t37 = 4.51, p < .0001] and than first-degree relatives [t33 = 3.24, p < .005]. As covariance for age could potentially remove the effects of chronicity, a secondary analysis using repeated measures ANOVAs with group as between-subjects factor, gender as covariate, and the duration and frequency MMN mean amplitudes as within-subject factors, was also performed to compare MMN amplitudes across an aged-matched control subgroup and first-episode patients; aged-matched control and chronic patients group; and aged-matched control and relatives group. For the first-episode patients contrast, the control subgroup consisted of 12 controls (6 female) aged 19–31 (mean = 26.3 ± 3.9 years). For relatives and chronic patients the original control group was adequately aged-matched.

For all analyses, uncorrected pairwise comparison tests (least significant difference: LSD) were used for significant group effects. All statistical analyses were reported with a significance level of p < 0.05.

RESULTS

Figure 2 and Figure 3 show a similar MMN pattern across groups for the first few tens of millisecond, with changes across group more prominent after 140 ms for both frequency and duration MMN.

Figure 2.

Figure 2

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Overview of duration MMN waveforms in all four groups. Data shown at seven representative frontal electrode sites were referenced to the LM. Time is in milliseconds (ms). Amplitudes are in microvolts (µV).

Figure 3.

Figure 3

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Overview of frequency MMN waveforms in all four groups. Data shown at seven representative frontal electrode sites were referenced to the LM. Time is in milliseconds (ms). Amplitudes are in microvolts (µV).

The LMM used to compare each mismatch negativity type across the four groups, revealed a significant effect of Group, both for MMN-dur [F3,97 = 4.66, p < .005] and for MMN-hz [F3,91 = 4.01, p < .01]. The effect reflected the reduced amplitude of the MMN-dur in the chronic patients (Figure 2) relative to the control group and the other groups. The MMN-hz was reduced in chronic patients (Figure 3) but only compared to the first-degree relatives and to the first-episode patients, but the random effect of familial membership was also significant (p < .005) for the MMN-hz, suggesting that this component may vary by familiarity association between patients and first-degree relatives.

The subsidiary ANOVAs comparing MMN amplitudes in the first-episode patients and the subgroup of 12 age-matched controls did not show any significant effects, further confirming that MMN was unimpaired in this sample of first-episode patients. The same result was obtained in the contrast between first-degree relatives and controls, although the amplitude of the duration MMN was more pronounced than that of the frequency MMN [F1,48 = 4.75, p < .05]. A group effect was found in the ANOVA used to compare controls and chronic patients, which confirmed that MMN was impaired in the patients [F1,69 = 4.36, p < .05]. As for the previous contrast, MMN-dur was more pronounced than MMN-hz [F1,69 = 5.89, p < .025]. Overall, these pairwise contrasts confirmed that MMN amplitude did not differ across the non-chronic populations (Figure 1).

Finally, within group correlations using amplitudes from MMN-dur and MMN-hz, age, gender, length of illness and medication (the latter for the chronic group alone), only showed significant positive correlations between MMN-hz and MMN-dur (chronics: r = .60; controls: r = .58; relatives: r = .60; p< .01) clearly suggesting that these have a similar pattern. Interestingly, neither age nor length of illness significantly correlated with MMN amplitudes (max r = .20, p = .18), as shown in Figure 4. The dosage of antipsychotic also did not significantly correlate with MMN deficit (max r = .15, p = .33).

Figure 4.

Figure 4

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Scatterplots of duration and frequency mismatch negativity amplitude in relation to length of illness and age for the chronic patients group. Amplitudes are in microvolts (µV).

DISCUSSION

Recent ERP research has focused increasingly on the identification of possible indices of disposition to schizophrenia (16, 18, 28). Among the deficits under the lens, the auditory mismatch negativity (MMN) has generated particularly vigorous research interest given its generally robust impairment in patients with the disease. Here, we investigated the possibility that the widely reported MMN deficit might also be evident in unaffected first-degree biological relatives of patients showing MMN deficits, which would constitute strong evidence that the deficit is genetically linked rather than a function of the disease process itself. Our results, however, are not consonant with this thesis as MMN was wholly unaffected in the present population of first-degree relatives. As such, we must conclude that MMN deficits, at least when evoked by very basic feature deviants (pitch and duration), do not represent an optimal endophenotype for schizophrenia. In support, similar negative results were reported by Bramon and colleagues (32) for duration MMNs in a large sample of first-degree relatives (N=37). On the other hand, two other groups have reported evidence for MMN deficits in first-degree relatives. One study reported significant deficits in the frequency MMN although the number of subjects was relatively small, with just 15 relatives and 16 controls participating, and these subjects were not matched for age (30). It is also worth pointing out that the schizophrenia probands in the Insert Jessen study, of which there were only 11, showed no difference in MMN when compared to the control subjects, raising questions as to how an MMN deficit in relatives could be considered genetically linked when their ill brethren failed to show the deficit. To our knowledge, only one report to date has shown a significantly reduced duration MMN in first-degree relatives (31). In that study, duration MMNs were studied in 17 relatives, compared to 21 controls and 22 chronic patients. MMN amplitudes in the relatives were significantly reduced relative to the control subjects and were not significantly different to those of the patients. In a more recent study by the same group, however, duration MMN was not found to be significantly different between first-degree relatives and controls in a much larger sample (53 relatives versus 44 controls), although the authors do report a trend at an alpha level of 0.085 (38). Taken together, the results from these studies would appear to be largely consistent in showing that the MMN is at best, only very weakly endophenotypic.

Results from first-episode patients are also consistent in pointing to a lack of endophenotypy for the MMN. Both Umbricht (39) and Salisbury (40, 41) have reported normal MMN amplitudes in first-episode patients. Here in our small first-episode sample (N=12), we also find no evidence of a deficit in either the frequency or duration MMN. The consistency of these results across studies must strongly suggest that the duration MMN deficit we did find in the chronic patients is likely tied to the progression of the disease rather than genetic risk factors, as has been previously suggested (39, 40). On the other hand, Javitt (42) found that MMN generation was impoverished in schizophrenia patients within just 1.5 years of their first episode, so the development of the deficit appears to occur relatively rapidly after the first psychotic episode. An obvious question is whether the MMN deficit worsens over time as the illness progresses or if the deficit establishes itself early in the disease and is constant thereafter. Our results are consistent with the latter position, as we found no significant correlation between length of illness and MMN amplitude, suggesting that those who were ill longest were similarly impaired to those who had been ill for a relatively shorter period. As such, the data suggest that the MMN deficit in schizophrenia is largely a consequence of the disease but does not appear to worsen substantially during its progression. Confirmation of this proposition will, however, require a longitudinal study. One such study by Salisbury (41) has suggested that MMN impairment may index progressive volume reductions in Heschl gyrus, as left Heschl's gyrus reduction correlated with MMN reduction in patients in the early years after first hospitalization, despite the fact that their MMN were of normal amplitude at this time. It is worth reiterating that our first-episode patients were all within 3 months of their first admission, although it is quite possible that some may have had a protracted period between the onset of psychosis and their initial hospitalization. Furthermore, dosage of neuroleptic medication in the chronic patient group did not significantly correlate with MMN deficit, consistent with Michie (43), and with the idea that MMN appears insensitive to standard pharmacological treatment in schizophrenia.

The lack of MMN deficits in our present population of first-degree relatives is also noteworthy because using almost exactly the same cohort of relatives, we have previously shown a robust visual P1 deficit (28). This is an important point because of an inherent risk of selection bias in studies of first-degree relatives. That is, it is entirely plausible that it is the healthier members of a given patient’s family that are more likely to remain engaged with the patient over the long term and hence, are more likely to volunteer for disease-related research. Thus, it could be argued that more robust effects might be seen if in an unbiased first-degree group could be sampled. However, the fact that this group has previously shown a strong deficit in their VEP, one that appears to be strongly endophenotypic, argues against a selection bias account here. It is also important to point out that even weakly endophenotypic markers for schizophrenia may still prove very useful as elements of a battery of metrics for risk assessment. That is, compilation of a set of measures, some with high sensitivity but low specificity, others with high specificity but low sensitivity, may prove to be an excellent multivariate strategy for assessing risk, a strategy that has already been applied with some success by Michie, Price and colleagues (38). It was also noted by a reviewer of this paper that the finding of a significant effect of family membership for MMN-hz could well suggest that a deficit in this component may indeed run in schizophrenia families, but that it is manifest in only a subset of these families. If so, this might explain some of the inconsistencies in the literature and may point towards a potential sub-typing strategy.

It is perhaps curious that chronic patients did not show an MMN deficit relative to controls for the pitch deviant, but only for the duration deviant, although their pitch MMN was significantly smaller than that of both of the other groups (relatives and first-episodes). The implication is that duration processing may be significantly more impaired in schizophrenia than pitch processing, a pattern that has also been noted in previous studies (e.g. 42; see 43 for a comprehensive treatment). Michie and colleagues (31) have suggested that the relatively greater deficit for duration MMN may derive from the fact that duration processing involves more complex neural computations than simple pitch processing. If this thesis is accurate, then one fertile area for future investigation will be in the use of so-called Pattern MMN’s (e.g. 44, 45–47). In such studies, MMN can be obtained in healthy controls where to identify what is constant across stimuli requires generation of an abstract rule on a preattentive basis. That is, sounds are pre-attentively grouped and treated as constituting a constancy, not on the basis of their absolute values, but in terms of a constant relationship among the sounds. If the more robust deficit in duration MMN relative to frequency MMN is indeed a function of more complex processing, then measures of MMN to abstract patterns, which would certainly involve far more complex processing, would be much more likely to tax the MMN system. The weak findings regarding endophenotypy for duration MMN might well be amplified using such an approach. Of course, the use of a more complex task to elicit the MMN will also likely invoke different underlying physiological mechanisms to those of the basic MMN, which might in turn be further removed from specific susceptibility genes than a simple pitch or duration MMN.

Conclusions

The present study confirms previous findings in the literature of a deficient duration MMN in patients with chronic schizophrenia. Moreover, the current results offer evidence in support of the notion that MMN alone is not a strong endophenotypic marker for schizophrenia since it is wholly unimpaired in first-degree relatives. Rather, the deficit in this component appears to arise as a consequence of the illness rather than representing a premorbid symptom of it, a contention also supported by the lack of MMN deficits in first-episode patients. The data suggest that visual sensory processing deficits may provide more fertile ground for the development of diagnostic measures than the far more studied auditory system, although efforts to combine multiple endophenotypic markers across sensory modalities may represent the best strategy for future development.

ACKNOWLEDGMENTS

This work was supported in part by grants from the National Institute of Mental Health (MH65350 – JJF). Dr. Magno was supported by a fellowship from the Irish Research Council for the Humanities and Social Sciences (IRCHSS). Dr. Yeap was supported by a fellowship from the Irish Health Research Board (HRB). The authors would like to express their sincere gratitude to the Chief Executive Officer at St. Vincent’s Hospital, Mr. Edward Byrne and to the Director of Nursing, Mrs. Phil Burke, for their ongoing and essential support of the Cognitive Neurophysiology Laboratory.

Footnotes

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FINANCIAL DISCLOSURES

The authors declare that no conflict of interest, financial or otherwise, is related directly or indirectly to the submitted work.

REFERENCES

  • 1.Weinberger DR, Gallhofer B. Cognitive function in schizophrenia. Int Clin Psychopharmacol. 1997;12 Suppl 4:S29–S36. doi: 10.1097/00004850-199709004-00006. [DOI] [PubMed] [Google Scholar]
  • 2.Goldberg TE, Gold JM. In: Bloom FE, Kupfer DJ, editors. New York: Raven Press; 1995. pp. 1245–1257. [Google Scholar]
  • 3.Goldman-Rakic PS. Working memory dysfunction in schizophrenia. J Neuropsychiatry Clin Neurosci. 1994;6:348–357. doi: 10.1176/jnp.6.4.348. [DOI] [PubMed] [Google Scholar]
  • 4.Green MF, Nuechterlein KH, Gaier DJ. Sustained and selective attention in schizophrenia. Prog Exp Pers Psychopathol Res. 1992;15:290–313. [PubMed] [Google Scholar]
  • 5.Foxe JJ, Doniger GM, Javitt DC. Early visual processing deficits in schizophrenia: impaired P1 generation revealed by high-density electrical mapping. Neuroreport. 2001;12:3815–3820. doi: 10.1097/00001756-200112040-00043. [DOI] [PubMed] [Google Scholar]
  • 6.Doniger GM, Foxe JJ, Murray MM, Higgins BA, Javitt DC. Impaired visual object recognition and dorsal/ventral stream interaction in schizophrenia. Arch Gen Psychiatry. 2002;59:1011–1020. doi: 10.1001/archpsyc.59.11.1011. [DOI] [PubMed] [Google Scholar]
  • 7.Foxe JJ, Murray MM, Javitt DC. Filling-in in schizophrenia: a high-density electrical mapping and source-analysis investigation of illusory contour processing. Cereb Cortex. 2005;15:1914–1927. doi: 10.1093/cercor/bhi069. [DOI] [PubMed] [Google Scholar]
  • 8.Schwartz BD, Evans WJ. Neurophysiologic mechanisms of attention deficits in schizophrenia. Neuropsychiatry Neuropsychol Behav Neurol. 1999;12:207–220. [PubMed] [Google Scholar]
  • 9.Butler PD, Schechter I, Zemon V, Schwartz SG, Greenstein VC, Gordon J, et al. Dysfunction of early-stage visual processing in schizophrenia. Am J Psychiatry. 2001;158:1126–1133. doi: 10.1176/appi.ajp.158.7.1126. [DOI] [PubMed] [Google Scholar]
  • 10.Ford JM, White P, Lim KO, Pfefferbaum A. Schizophrenics have fewer and smaller P300s: a single-trial analysis. Biol Psychiatry. 1994;35:96–103. doi: 10.1016/0006-3223(94)91198-3. [DOI] [PubMed] [Google Scholar]
  • 11.Javitt DC, Grochowski S, Shelley AM, Ritter W. Impaired mismatch negativity (MMN) generation in schizophrenia as a function of stimulus deviance, probability, and interstimulus/interdeviant interval. Electroencephalogr Clin Neurophysiol. 1998;108:143–153. doi: 10.1016/s0168-5597(97)00073-7. [DOI] [PubMed] [Google Scholar]
  • 12.Javitt DC, Strous RD, Grochowski S, Ritter W, Cowan N. Impaired precision, but normal retention, of auditory sensory ("echoic") memory information in schizophrenia. J Abnorm Psychol. 1997;106:315–324. doi: 10.1037//0021-843x.106.2.315. [DOI] [PubMed] [Google Scholar]
  • 13.Umbricht D, Krljes S. Mismatch negativity in schizophrenia: a meta-analysis. Schizophr Res. 2005;76:1–23. doi: 10.1016/j.schres.2004.12.002. [DOI] [PubMed] [Google Scholar]
  • 14.Naatanen R, Tervaniemi M, Sussman E, Paavilainen P, Winkler I. "Primitive intelligence" in the auditory cortex. Trends Neurosci. 2001;24:283–288. doi: 10.1016/s0166-2236(00)01790-2. [DOI] [PubMed] [Google Scholar]
  • 15.Fischer C, Luaute J, Nemoz C, Morlet D, Kirkorian G, Mauguiere F. Improved prediction of awakening or nonawakening from severe anoxic coma using tree-based classification analysis. Crit Care Med. 2006;34:1520–1524. doi: 10.1097/01.CCM.0000215823.36344.99. [DOI] [PubMed] [Google Scholar]
  • 16.Appels MC, Sitskoorn MM, Westers P, Lems E, Kahn RS. Cognitive dysfunctions in parents of schizophrenic patients parallel the deficits found in patients. Schizophr Res. 2003;63:285–293. doi: 10.1016/s0920-9964(02)00342-0. [DOI] [PubMed] [Google Scholar]
  • 17.Faraone SV, Seidman LJ, Kremen WS, Toomey R, Pepple JR, Tsuang MT. Neuropsychologic functioning among the nonpsychotic relatives of schizophrenic patients: the effect of genetic loading. Biol Psychiatry. 2000;48:120–126. doi: 10.1016/s0006-3223(99)00263-2. [DOI] [PubMed] [Google Scholar]
  • 18.Snitz BE, Macdonald AW, 3rd, Carter CS. Cognitive deficits in unaffected first-degree relatives of schizophrenia patients: a meta-analytic review of putative endophenotypes. Schizophr Bull. 2006;32:179–194. doi: 10.1093/schbul/sbi048. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19.Tsuang MT, Stone WS, Faraone SV. Towards the prevention of schizophrenia. Biol Psychiatry. 2000;48:349–356. doi: 10.1016/s0006-3223(00)00934-3. [DOI] [PubMed] [Google Scholar]
  • 20.Hall MH, Rijsdijk F, Picchioni M, Schulze K, Ettinger U, Toulopoulou T, et al. Substantial shared genetic influences on schizophrenia and event-related potentials. Am J Psychiatry. 2007;164:804–812. doi: 10.1176/ajp.2007.164.5.804. [DOI] [PubMed] [Google Scholar]
  • 21.Winterer G, Coppola R, Egan MF, Goldberg TE, Weinberger DR. Functional and effective frontotemporal connectivity and genetic risk for schizophrenia. Biol Psychiatry. 2003;54:1181–1192. doi: 10.1016/s0006-3223(03)00532-8. [DOI] [PubMed] [Google Scholar]
  • 22.Winterer G, Egan MF, Raedler T, Sanchez C, Jones DW, Coppola R, et al. P300 and genetic risk for schizophrenia. Arch Gen Psychiatry. 2003;60:1158–1167. doi: 10.1001/archpsyc.60.11.1158. [DOI] [PubMed] [Google Scholar]
  • 23.Myles-Worsley M. P50 sensory gating in multiplex schizophrenia families from a Pacific island isolate. Am J Psychiatry. 2002;159:2007–2012. doi: 10.1176/appi.ajp.159.12.2007. [DOI] [PubMed] [Google Scholar]
  • 24.Myles-Worsley M, Ord L, Blailes F, Ngiralmau H, Freedman R. P50 sensory gating in adolescents from a pacific island isolate with elevated risk for schizophrenia. Biol Psychiatry. 2004;55:663–667. doi: 10.1016/j.biopsych.2003.12.006. [DOI] [PubMed] [Google Scholar]
  • 25.Bramon E, McDonald C, Croft RJ, Landau S, Filbey F, Gruzelier JH, et al. Is the P300 wave an endophenotype for schizophrenia? A meta-analysis and a family study. Neuroimage. 2005;27:960–968. doi: 10.1016/j.neuroimage.2005.05.022. [DOI] [PubMed] [Google Scholar]
  • 26.Cadenhead KS, Light GA, Shafer KM, Braff DL. P50 suppression in individuals at risk for schizophrenia: the convergence of clinical, familial, and vulnerability marker risk assessment. Biol Psychiatry. 2005;57:1504–1509. doi: 10.1016/j.biopsych.2005.03.003. [DOI] [PubMed] [Google Scholar]
  • 27.Clementz BA, Geyer MA, Braff DL. Poor P50 suppression among schizophrenia patients and their first-degree biological relatives. Am J Psychiatry. 1998;155:1691–1694. doi: 10.1176/ajp.155.12.1691. [DOI] [PubMed] [Google Scholar]
  • 28.Yeap S, Kelly SP, Sehatpour P, Magno E, Javitt DC, Garavan H, et al. Are Early Visual Sensory Deficits Endophenotypic for Schizophrenia? High-Density Electrical Mapping in Clinically Unaffected First-Degree Relatives. Arch Gen Psychiatry. 2006;63:1180–1188. doi: 10.1001/archpsyc.63.11.1180. [DOI] [PubMed] [Google Scholar]
  • 29.Donohoe G, Morris DW, De Sanctis P, Magno E, Montesi JL, Garavan H, et al. Early Visual Processing Deficits in Dysbindin-Associated. Biol Psychiatry. doi: 10.1016/j.biopsych.2007.07.022. (in press) [DOI] [PubMed] [Google Scholar]
  • 30.Jessen F, Fries T, Kucharski C, Nishimura T, Hoenig K, Maier W, et al. Amplitude reduction of the mismatch negativity in first-degree relatives of patients with schizophrenia. Neurosci Lett. 2001;309:185–188. doi: 10.1016/s0304-3940(01)02072-9. [DOI] [PubMed] [Google Scholar]
  • 31.Michie PT, Innes-Brown H, Todd J, Jablensky AV. Duration mismatch negativity in biological relatives of patients with schizophrenia spectrum disorders. Biol Psychiatry. 2002;52:749–758. doi: 10.1016/s0006-3223(02)01379-3. [DOI] [PubMed] [Google Scholar]
  • 32.Bramon E, Croft RJ, McDonald C, Virdi GK, Gruzelier JG, Baldeweg T, et al. Mismatch negativity in schizophrenia: a family study. Schizophr Res. 2004;67:1–10. doi: 10.1016/s0920-9964(03)00132-4. [DOI] [PubMed] [Google Scholar]
  • 33.Hall MH, Schulze K, Rijsdijk F, Picchioni M, Ettinger U, Bramon E, et al. Heritability and Reliability of P300, P50 and Duration Mismatch Negativity. Behav Genet. 2006;36:845–857. doi: 10.1007/s10519-006-9091-6. [DOI] [PubMed] [Google Scholar]
  • 34.Overall JE, Gorham DR. The Brief Psychiatric Rating Scale. Psychological Reports. 1962;10:799–812. [Google Scholar]
  • 35.Andreasen NC. The Scale for the Assessment of Negative Symptoms (SANS) Iowa City, IA: The University of Iowa; 1983. [Google Scholar]
  • 36.Spitzer RL, Williams JB, Gibbon M, First MB. The Structured Clinical Interview for DSM-III-R (SCID). I: History, rationale, and description. Arch Gen Psychiatry. 1992;49:624–629. doi: 10.1001/archpsyc.1992.01820080032005. [DOI] [PubMed] [Google Scholar]
  • 37.Oldfield RC. The assessment and analysis of handedness: the Edinburgh inventory. Neuropsychologia. 1971;9:97–113. doi: 10.1016/0028-3932(71)90067-4. [DOI] [PubMed] [Google Scholar]
  • 38.Price GW, Michie PT, Johnston J, Innes-Brown H, Kent A, Clissa P, et al. A multivariate electrophysiological endophenotype, from a unitary cohort, shows greater research utility than any single feature in the Western Australian family study of schizophrenia. Biol Psychiatry. 2006;60:1–10. doi: 10.1016/j.biopsych.2005.09.010. [DOI] [PubMed] [Google Scholar]
  • 39.Umbricht DS, Bates JA, Lieberman JA, Kane JM, Javitt DC. Electrophysiological indices of automatic and controlled auditory information processing in first-episode, recent-onset and chronic schizophrenia. Biol Psychiatry. 2006;59:762–772. doi: 10.1016/j.biopsych.2005.08.030. [DOI] [PubMed] [Google Scholar]
  • 40.Salisbury DF, Shenton ME, Griggs CB, Bonner-Jackson A, McCarley RW. Mismatch negativity in chronic schizophrenia and first-episode schizophrenia. Arch Gen Psychiatry. 2002;59:686–694. doi: 10.1001/archpsyc.59.8.686. [DOI] [PubMed] [Google Scholar]
  • 41.Salisbury DF, Kuroki N, Kasai K, Shenton ME, McCarley RW. Progressive and interrelated functional and structural evidence of post-onset brain reduction in schizophrenia. Arch Gen Psychiatry. 2007;64:521–529. doi: 10.1001/archpsyc.64.5.521. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 42.Javitt DC, Shelley AM, Silipo G, Lieberman JA. Deficits in auditory and visual context-dependent processing in schizophrenia: defining the pattern. Arch Gen Psychiatry. 2000;57:1131–1137. doi: 10.1001/archpsyc.57.12.1131. [DOI] [PubMed] [Google Scholar]
  • 43.Michie PT. What has MMN revealed about the auditory system in schizophrenia? Int J Psychophysiol. 2001;42:177–194. doi: 10.1016/s0167-8760(01)00166-0. [DOI] [PubMed] [Google Scholar]
  • 44.Gaeta H, Friedman D, Ritter W, Hunt G. Age-related changes in neural trace generation of rule-based auditory features. Neurobiol Aging. 2002;23:443–455. doi: 10.1016/s0197-4580(01)00321-9. [DOI] [PubMed] [Google Scholar]
  • 45.Gomes H, Bernstein R, Ritter W, Vaughan HG, Jr., Miller J. Storage of feature conjunctions in transient auditory memory. Psychophysiology. 1997;34:712–716. doi: 10.1111/j.1469-8986.1997.tb02146.x. [DOI] [PubMed] [Google Scholar]
  • 46.Paavilainen P, Jaramillo M, Naatanen R. Binaural information can converge in abstract memory traces. Psychophysiology. 1998;35:483–487. doi: 10.1017/s0048577298970895. [DOI] [PubMed] [Google Scholar]
  • 47.Paavilainen P, Jaramillo M, Naatanen R, Winkler I. Neuronal populations in the human brain extracting invariant relationships from acoustic variance. Neurosci Lett. 1999;265:179–182. doi: 10.1016/s0304-3940(99)00237-2. [DOI] [PubMed] [Google Scholar]

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