An event-related functional magnetic resonance imaging study of an auditory oddball task in schizophrenia

Abstract

Schizophrenia is a diffuse brain disease that affects many facets of cognitive function. One of the most replicated findings in the neurobiology of schizophrenia is that the event-related potentials to auditory oddball stimuli are abnormal, effects believed to be related to abnormalities in attentional and memory processes. Although event-related potentials provide excellent resolution regarding the time course of information processing, such studies are poor at characterizing the spatial location of these abnormalities. To address this issue, we used event-related functional magnetic resonance imaging techniques to elucidate the neural areas underlying target detection in schizophrenia. Consistent with recent event-related functional magnetic resonance imaging results, target processing by control participants was associated with bilateral activation in the anterior superior temporal gyri, inferior and superior parietal lobules, and activation in anterior and posterior cingulate, thalamus, and right lateral frontal cortex. For the schizophrenic patients, selective deficits were observed in both the extent and strength of activation associated with target processing in the right lateral frontal cortex, thalamus, bilateral anterior superior temporal gyrus, anterior and posterior cingulate, and right inferior and superior parietal lobules. These findings are consistent with the evidence for abnormal processing of oddball stimuli suggested by event-related potential studies in schizophrenic patients, but provide much more detailed evidence regarding the anatomical sites implicated. These data are consistent with the hypothesis that schizophrenia is characterized by a widespread pathological process affecting many cerebral areas, including association cortex and thalamus.

Introduction

Schizophrenia is one of the most enigmatic and complex disorders of the central nervous system. Its complexity is reflected in its diverse and heterogeneous clinical presentation, including symptoms of impairment in nearly all domains of mental function. Abnormalities in sensory processing, attention, and memory stand out against a background of diffuse impairment.

Event-related potentials (ERPs) have been used successfully for over two decades to demonstrate various abnormalities of sensory and cognitive processes in patients with schizophrenia. One of the most replicated neurobiological findings in schizophrenia are abnormalities in the P3 ERP to low-probability auditory target stimuli (Blackwood et al., 1991, Ebmeier et al., 1990, Faux et al., 1993, Ford et al., 1994a, McCarley et al., 1993, O'Donnell et al., 1995a, Salisbury et al., 1998, Strik et al., 1993). The P3 is a large positive component of the ERP peaking about 250–500 ms following the onset of task-relevant, low-probability stimuli (Donchin and Coles, 1988). The P3 is most commonly elicited using an ‘oddball’ paradigm. In this paradigm, a participant is required to respond to (or count) infrequent target stimuli randomly interspersed among frequent non-target stimuli. The P3 is believed to be a manifestation of processes related to attention, decision-making, and memory or contextual updating (Alexander et al., 1996, Donchin, 1981, Donchin and Coles, 1988, Johnson, 1988, Johnson, 1993).

P3 amplitude abnormalities to auditory stimuli have been found in first-episode psychotic patients (Salisbury et al., 1998), chronic medicated schizophrenic patients (Ebmeier et al., 1990, Faux et al., 1988, Ford et al., 1994a, McCarley et al., 1993, Pritchard, 1986), and schizophrenic patients withdrawn from medication (Faux et al., 1993, Ford et al., 1994b), and after clinical improvement (Eikmeier et al., 1992, Ford et al., 1994b, Rao et al., 1995). There are also some topographical abnormalities in the P3 response in schizophrenia, namely that the P3 amplitude reduction appears to be greater over left than right temporal lobe sites (Faux et al., 1988, Faux et al., 1990, Faux et al., 1993, Glabus et al., 1994, Heidrich and Strik, 1997, McCarley et al., 1993, O'Donnell et al., 1995b, Salisbury et al., 1998). McCarley et al. (1991) interpreted this asymmetry as evidence supporting the hypothesis that the left temporal lobe plays an important role in the pathogenesis of schizophrenia, especially in the generation of positive symptoms (McCarley et al., 1991).

Interestingly, McCarley and colleagues have shown that this P3 asymmetry is present in first-episode psychotic schizophrenic patients (Salisbury et al., 1998). Furthermore, they did not find this effect in a group of first-episode affective disorder patients. These findings suggest that the topography of the P3 might be useful in making a differential diagnosis of schizophrenia or affective disorder. Thus, ERP data on the P3 response to task-relevant auditory target stimuli have provided an improved understanding of schizophrenia that is potentially of great clinical relevance. However, the ERP methodology is limited in a number of respects, most notably in that the neural sources generating the scalp fields are difficult to localize.

Using positron emission tomography (PET) and single photon emission computed tomography (SPECT) to measure regional blood flow during oddball tasks, researchers have shown that the bilateral lateral frontal cortex, anterior cingulate, and posterior occipital/temporal/parietal junction are involved in oddball processing (Ebmeier et al., 1995, Shajahan et al., 1997a). Furthermore, SPECT studies have demonstrated that there is reduced frontal activation in schizophrenia during oddball tasks (Shajahan et al., 1997a). Blackwood et al. (1994) observed that the latency of the P3 correlated with resting regional blood flow in the cingulate, left fronto/temporal regions and left parietal regions However, event-related studies are impractical with PET and SPECT, and therefore, the hemodynamic response associated with individual events (e.g. target stimuli) cannot be selectively resolved. Thus, these studies do not demonstrate unambiguously that the observed effects are selective to target processing. Moreover, the exact relevance of these latter data to P3 abnormalities in schizophrenia remains unclear.

Other methods have been used to localize the neural sources involved in target processing during oddball tasks. These methods include topographical and ERP source localization techniques (Potts et al., 1998), depth electrode recordings (Baudena et al., 1995, Halgren, 1980, Halgren et al., 1995a, Halgren et al., 1995b, Halgren et al., 1998), and studies of patients with focal brain lesions (Knight, 1984, Knight et al., 1989, Paller et al., 1992, Yamaguchi and Knight, 1995). These studies have implicated areas within the frontal, temporal, and parietal lobes as being involved in oddball processing.

Recent developments in functional magnetic resonance (fMRI) imaging have shown that it is possible to measure the hemodynamic response for distinct events. Event-related fMRI (erfMRI), as it has been coined, has opened new avenues of research for hemodynamic imaging (Josephs et al., 1997, Rosen et al., 1998). Several groups of investigators have performed erfMRI studies of cerebral activity associated with processing low-probability stimuli. McCarthy et al. (1997) found that low-probability visual stimuli elicited activation in the middle frontal gyrus, inferior parietal lobe and posterior cingulate. Menon et al. (1997) found that target stimuli in the auditory modality generated activity in the inferior parietal lobe, thalamus and anterior cingulate (see also Opitz et al., 1999). Using an MR pulse sequence that allowed imaging of the entire brain, we found that low-probability task-relevant target visual (Kiehl et al., 2000a) and auditory (Kiehl et al., in press) stimuli elicit activation in bilateral anterior superior temporal gyri, thalamus, inferior and superior parietal lobules, anterior and posterior cingulate and lateral frontal cortex. These same cerebral sites are active whether participants are responding manually or silently counting the visual (Kiehl and Liddle, 1999c) or auditory target stimuli (Kiehl and Liddle, 1999b). We have shown recently that these sites are activated when participants respond to target stimuli with either their right or left hand (Kiehl and Liddle, 1999a). We have also demonstrated that neural activity in these sites is reproducible after 6 weeks in a test–retest study in healthy participants (Kiehl and Liddle, 1999h).

Polich and colleagues have shown that the P3 has a similar morphology and topography during three-tone auditory oddball tasks, two-tone auditory oddball tasks, and infrequent single-tone auditory target detection tasks (Katayama and Polich, 1996, Polich and Margala, 1997). Similarly, we have demonstrated that target processing during each of these paradigms activates the bilateral anterior superior temporal gyri, thalamus, inferior and superior parietal lobules, anterior and posterior cingulate and right lateral frontal cortex (Kiehl and Liddle, 1999d, Kiehl and Liddle, 1999f). Thus, the observation that the same cerebral sites are activated during paradigms used to elicit a P3 suggests that these sites are involved in the generation of the P3 response to target stimuli. We note that in the former studies, it was not possible to determine precisely whether the observed hemodynamics reflect generators specific to the P3 and/or to other electrical components such as the N1, a negative potential observed approximately 100 ms after low-probability task relevant target stimuli. To address this issue, we recently performed a ‘gap’ detection study in which participants were asked to detect a missing stimulus in a stream of auditory stimuli. ERP studies have shown that detecting the missing stimulus elicits a strong P3 response with little or no early N1 component (Friedman, 1984, Sutton et al., 1967). Consistent with our previous research, gap detection was associated with activation in the bilateral anterior superior temporal gyri, thalamus, inferior and superior parietal lobules, anterior and posterior cingulate and right lateral frontal cortex, providing strong evidence that these neural areas are related to the scalp recorded P3 response (Kiehl and Liddle, 1999g).

The purpose of the present study was to elucidate the cerebral sites activated during auditory target detection in schizophrenic patients and control participants. We employed an identical experimental methodology as in our previous studies of auditory oddball target detection (Kiehl and Liddle, 1999a, Kiehl and Liddle, 1999b, Kiehl and Liddle, 1999d, Kiehl and Liddle, 1999e, Kiehl and Liddle, 1999f, Kiehl and Liddle, 1999g, Kiehl and Liddle, 1999h, Kiehl et al., in press). We hypothesized that we would replicate in this new sample of healthy participants the same pattern of activation for target stimuli as we have observed in previous studies. Based on the extensive literature demonstrating P3 amplitude abnormalities in schizophrenia, we predicted that there would be underactivity at some or all of the multiple sites implicated in oddball detection in healthy subjects.