Original articleDuration mismatch negativity in biological relatives of patients with schizophrenia spectrum disorders
Introduction
Evidence that individuals with schizophrenia have a deficit in early auditory processing first emerged from an electrophysiologic measure, mismatch negativity (Shelley et al 1991). Mismatch negativity (MMN) is an auditory event-related potential (ERP) generated whenever the auditory system detects a deviant sound relative to a background of repetitive auditory stimulation (Winkler et al 1996). It is typically recorded from sequences of auditory stimuli in which low-probability deviant sounds are interspersed among frequent standard sounds while the subject’s attention is directed elsewhere by requiring them to read a book (as in Sams et al 1985), carry out a visual task (as in Alho 1992), or watch a video of choice (as in Kraus et al 1996). There have been reports of MMN for deviants on a variety of auditory dimensions: frequency (Sams et al 1985), intensity (Näätänen et al 1978), duration (Näätänen et al 1989), and spatial location (Paavilainen et al 1989), as well as for more complex stimulus features such as temporal information (Tervaniemi et al 1994), phonemes (Aaltonen et al 1987), and spectrotemporal patterns (Schröger et al 1992).
Mismatch negativity is obtained by subtracting the ERP to the frequent standard sounds from the ERP to the deviant sounds. The resultant subtraction waveform typically reveals a negativity that is maximal at frontocentral sites and peaks between 150 and 250 msec after the onset of the deviant sound (Näätänen 1990). Source analysis studies indicate that a major contribution to MMN originates in the left and right auditory cortices located on the supratemporal plane (Alho 1995). The orientation and location of supratemporal generators is such that the negativity observed is maximal at frontocentral sites and reverses polarity at sites located below the supratemporal plane (e.g., electrodes placed over the mastoid bone; Scherg et al 1989). In addition to supratemporal generators, a number of studies have also observed an additional dipole located in frontal regions of the brain Giard et al 1990, Rinne et al 2000. The relationship between the supratemporal and proposed frontal MMN generators remains somewhat unclear. One hypothesis is that the generation of a MMN to a detected irregularity in the environment might be the initial stage in alerting the organism to a novel stimulus (Näätänen 1992). If the supratemporal MMN surpasses some threshold amplitude, then the frontal generator may be activated and trigger a passive switch in attention (Schröger 1997), resulting in a subsequent positivity, P3a (Escera et al 2000). Support for this hypothesis was provided by Rinne et al (2000), who demonstrated later activation of the frontal relative to supratemporal MMN generator.
In the first published report of MMN in schizophrenia (Shelley et al 1991), MMN to tone pips that were deviant in duration relative to the background of standards was recorded in a small sample of medicated patients and compared with age- and gender-matched control subjects. The MMN amplitude in response to duration increments (deviants 100 msec vs. standards 50 msec) was found to be significantly reduced in patients. Although a similar pattern was evident for duration decrements, the group difference failed to reach statistical significance.
This original observation of MMN reduction in schizophrenia was subsequently replicated for both duration Catts et al 1995, Javitt et al 2000, Kasai et al 1999, Lembreghts and Timsit-Berthier 1993, Michie et al 2000a, Todd et al 2000, Todd 2001 and frequency Alain et al 1998, Hirayasu et al 1998, Javitt et al 1993, Javitt et al 1995, Javitt et al 1998, Javitt et al 2000, Kreitschmann-Andermahr et al 1999, Oades et al 1996, Oades et al 1997, Shelley et al 1999, Umbricht et al 1998. Yet although there have been a small number of reports that frequency MMN is not reduced in patients Kathmann et al 1995, Michie et al 2000a, O’Donnell et al 1994, a reduced duration MMN has been observed even in patients who produce substantial frequency MMNs (Michie et al 2000a). Furthermore, there is some preliminary evidence that duration MMN is reduced even in patients with a recent onset of their illness, defined as within 3 years of first presentation, whereas frequency MMN is preserved (Javitt et al 2000; Javitt, personal communication). Both duration and frequency MMN, however, are reduced in patients with a duration of illness exceeding 10 years (see figure 1 and table in Javitt et al 2000). In addition, the reduction in duration MMN occurs in unmedicated patients and hence cannot be attributed to the effects of current neuroleptic medications (Catts et al 1995), although an effect of prior medication cannot be eliminated because there have been no published reports of MMN in never-medicated patients.
The available evidence from studies of patients with psychiatric disorders suggests that MMN reduction, particularly to duration deviants, appears to be specific to a diagnosis of schizophrenia or schizoaffective disorder Catts et al 1995, Umbricht et al 2001. Importantly, duration MMN is significantly smaller in patients with a schizophrenia or schizoaffective disorder compared with patients with either a bipolar disorder or major depression (Umbricht et al 2001), neither of whom can be distinguished from control subjects. Frequency MMN, on the other hand, did not discriminate between schizophrenia spectrum patients and patients with a major affective disorder (Umbricht et al 2001). Mismatch negativity is reduced in other clinical conditions, such as in children with learning problems (Kraus et al 1996) and adults with dyslexia Baldweg et al 1999, Kujala et al 2000, children with cleft palates (Cheour et al 1998), and patients with Alzheimer’s disease (Pekkonen et al 1994). There is preliminary evidence that adult dyslexics show a different pattern from schizophrenia patients in that duration MMN is unaffected but frequency MMN is reduced (Baldweg et al 1999). In Alzheimer’s disease, the normal age-related decay in frequency MMN as a function of increasing interstimulus interval (ISI) (Pekkonen et al 1993) is exacerbated (Pekkonen et al 1994). In contrast, schizophrenia patients are no more affected by increasing ISI than are control subjects (Shelley et al 1999). Although much more research is needed to determine the nature of the variables and experimental parameters that produce MMN changes in clinical conditions and psychiatric disorders, there are already some promising data that the changes associated with a diagnosis in the schizophrenia spectrum range can be distinguished from those seen in other conditions.
The issue addressed in the research reported in this article is whether first-degree biological relatives of patients with schizophrenia spectrum disorders also show reduced duration MMN. Such an observation in healthy, unaffected relatives would suggest that early auditory processing deficits are an endophenotype marker of the vulnerability or predisposition to the disorder (Michie et al 2000b). An additional benefit from such an observation is that the reduction in MMN cannot be attributed to the effects of prior medication or other illness related factors.
Section snippets
Participants
Participants were recruited as part of a large family study of schizophrenia in which assessments of cognitive functioning (attention, memory, verbal fluency, behavioral inhibition and processing speed) were obtained together with electrophysiologic measures (MMN amplitude, P50 test-conditioning ratios, and P300 amplitude and latency) from patients with schizophrenia, first-degree unaffected relatives of patients, and healthy control volunteers. Preliminary MMN data are reported from 22
Results
The MMN waveforms at Fz, Cz, and Pz for the three groups are shown in Figure 1. An analysis of variance (ANOVA) of MMN amplitude with group (patients, relatives, control subjects) and repeated measures factors of laterality (left, right, midline) and anterior–posterior location (frontal, central, parietal) gave rise to a significant effect of group [F(2,57) = 4.639, p = .014] and a significant anterior–posterior gradient [F(2,114) = 67.746, p = .001]. There were no significant interactions.
Discussion
Our study provides the first evidence that duration MMN is reduced in first-degree biological relatives of patients with schizophrenia spectrum disorders. A recent study of first-degree relatives (Jessen et al 2001) found similar results for frequency MMN, although the same study failed to find a difference between patients and control subjects whereas our study shows a similar decrease in duration MMN amplitude in both patients and relatives. It must be acknowledged, however, that our study
Acknowledgements
This study was supported by National Health and Medical Research Grant Nos. 960579 and 990701, grants from the University of Western Australia Faculty of Medicine and Dentistry Small Bequest Research Fund in the area of Biological Research into Mental Diseases, and research infrastructure support from the Center for Clinical Research in Neuropsychiatry. The authors thank B. Burg, A. Kent, J. Johnston, R. Frima, K. Dedman, D. Rock, H. Wichmann, and J. Box for assistance with patient recruitment,
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