P300 asymmetry in schizophrenia: a meta-analysis
Introduction
Emil Kraepelin described schizophrenia as a syndrome of dementia praecox and suggested that frontal lobe abnormalities would be associated with reasoning, whereas temporal lobe abnormalities would be associated with delusions and hallucinations (McCarley et al., 1993) — symptoms that are now considered as diagnostic criteria for schizophrenia (American Psychiatric Association, 1994). Frontal lobe abnormalities are commonly found in patients with schizophrenia and contribute to deficits in prefrontal control of attention, abstract reasoning, executive function and negative affect symptoms (Weinberger and Berman, 1988, Wolkin et al., 1992, Seidman et al., 1994), although evidence for frontal lobe functional abnormalities by structural MRI investigations is found less consistently than for temporal lobe abnormalities (cf. Hyde and Weinberger, 1990, McCarley et al., 1999). Neuropathological studies in patients with psychosis or schizophrenia suggest that neurodevelopmental abnormalities in the mesial temporal lobe contribute to these disorders (Mendez et al., 1993, Hyde and Weinberger, 1997, Sachdev, 1998), with clinical correlations between epilepsy and schizophrenia also reported (Bruton et al., 1994, Mellers et al., 2000). Thus, prefrontal and temporo–limbic network abnormalities contribute to schizophrenia symptoms and associated information-processing dysfunction (Nuechterlein and Dawson, 1984, Weinberger et al., 1992, Turetsky et al., 1995).
The P300 event-related brain potential (ERP) has been proffered as a putative biological marker of risk for schizophrenia (Friedman and Squires-Wheeler, 1994, Bharath et al., 2000, Blackwood, 2000), because smaller P300 amplitudes are found in patients with schizophrenia compared to controls (Pritchard, 1986, McCarley et al., 1991a, McCarley et al., 1993, Bruder et al., 1999, Ford, 1999). In these studies, the P300 is often elicited with an oddball paradigm, wherein two stimuli are presented in a random series such that one of them occurs relatively infrequently and subjects are instructed to respond to the infrequent target stimulus (Polich, 1998). Although the exact neural loci of normal P300 generation are uncertain (cf. Knight et al., 1989, Polich and Squire, 1993, Halgren et al., 1995a, Halgren et al., 1995b, McCarthy et al., 1997), discriminating the target from a standard stimulus should initiate frontal engagement as a consequence of attentional focus — a major attribute of frontal lobe function (Posner and Petersen, 1990, Knight, 1997). If the neuroelectric events that underlie P300 generation are related to an interaction between frontal lobe and hippocampal/temporal–parietal function (Knight, 1996, Kirino et al., 2000, Demiralp et al., 2001), disease states that affect frontal and temporal/parietal lobe function should also affect P300 measures.
This hypothesis has been supported by findings of smaller P300 amplitudes over left temporal scalp locations relative to the homologous right temporal locations for patients with schizophrenia compared to controls (e.g. Morstyn et al., 1983, McCarley et al., 1993, O'Donnell et al., 1999). Although smaller P300 amplitudes are typically found in patients with schizophrenia over the midline electrodes (e.g. McCarley et al., 1991a, McCarley et al., 1993, Ford, 1999), P300 amplitude lateral asymmetry effects have not been observed so consistently (cf. Pfefferbaum et al., 1989, Ford et al., 1994, Ford et al., 1999a, Ford et al., 1999b, Ford et al., 2000). However, a comprehensive meta-analytsis of P300 schizophrenia studies has found that even though the magnitude of P300 component differences between patients with schizophrenia and control subjects is highly reliable across individual studies (Jeon and Polich, 2001), variation for the group effect size is systematically associated with disease definition, stimulus parameters, task conditions and recording methods (cf. McCarley et al., 1991b, Pfefferbaum et al., 1991, Polich, 1998). The present study employed meta-analytic methods to quantitatively examine P300 amplitude midline electrode and lateral electrode asymmetry effects in studies of schizophrenia and whether such effects are reliable characteristics of this patient group by characterizing its variability across studies (cf. Polich and Herbst, 2000).
Section snippets
Study identification
The studies included in this meta-analysis were identified by computerized searching with MEDLINE for the years between 1966 and 1999, using the key words P300, P3, P3a, P3b, MMN, ERP, schizophrenia, schizophrenics, schizoid and schizotypal and by cross-referencing citations in the obtained reports. This approach identified 291 relevant ERP schizophrenia studies that were then culled using the methods described below, with the results of the general meta-analysis reported elsewhere (Jeon and
Midline topography
Table 1 presents the midline topographic analysis with the individual effect sizes (d) and their 95% CIs for each study and condition. A report listed more than once indicates that the P300 values were obtained from different ERP conditions, with separate listings of each condition from the study presented in the table; if a CI excludes zero, that study demonstrates a significant effect size. Of the 19 auditory oddball P300 schizophrenia studies, 27 conditions contributed midline P300 amplitude
Discussion
The major findings of this meta-analysis were: (1) Pz electrode site showed the strongest effect size for P300 amplitude differences between patients with schizophrenia and controls of midline electrodes, although Cz and Fz also demonstrated reliable albeit weaker effect sizes. (2) P300 amplitude recorded from lateral electrode sites over the temporal/parietal areas evinced larger overall effect sizes from left hemisphere locations, with larger effect size differences obtained for the TCP1
Acknowledgements
This work was supported by a Research Grant from Our Lady of Mercy Hospital, the Catholic University of Korea to (YWJ) and NIDA Grant RO1-DA11737-03 (JP). This paper is NP-13776 from The Scripps Research Institute.
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