Brain activation mediates the association between structural abnormality and symptom severity in schizophrenia
Introduction
Schizophrenia is a psychiatric illness characterized by delusions, hallucinations, disordered thought and negative symptoms. Brain morphological and neuroimaging studies have reported subtle and wide-ranging irregularity in schizophrenia, frequently associated with specific symptom profiles. Among the few consistent anatomical findings reported in schizophrenia is abnormality of left posterior superior temporal cortex (Barta et al., 1997, Falkai et al., 1995, Menon et al., 1995, Rossi et al., 1992, Shenton et al., 1992), including the planum temporale (Barta et al., 1997, Falkai et al., 1995, Rossi et al., 1992). The planum temporale is the horizontal aspect of the posterior temporal lobe, it has a leftward asymmetry (Geschwind and Levitsky, 1968), overlapping with Wernicke's area, and is classically associated with language function. The planum temporale largely consists of auditory association cortex; lesion and imaging research indicates involvement in early auditory and phonological processing (Binder et al., 1997, Binder et al., 1996, Caplan et al., 1995, Petersen et al., 1988, Wise et al., 1991). In his review of the structural, functional and clinical literature regarding the planum temporale, Shapleske points out that the planum temporale likely engages in language tasks as a functional unit and is not inherently linguistic (Shapleske et al., 1999).
Reduced gray matter volume in left superior temporal cortex, including planum temporale, is associated with an increased severity of thought disorder in schizophrenia (Menon et al., 1995, Rajarethinam et al., 2000, Rossi et al., 1994, Shenton et al., 1992, Vita et al., 1995). The finding is robust, despite methodological variation in the measurement of cortical abnormality, anatomical definition of brain regions, and assessment of thought disorder. In a recent fMRI study we observed a correlation between left posterior temporal activation during listening to speech and severity of thought disorder in schizophrenic patients (Weinstein et al., 2006). Other investigators have described correlations between activation in temporal cortex and thought disorder during the performance of generative language tasks (Kircher et al., 2001a, Kircher et al., 2001b, Kircher et al., 2002, McGuire et al., 1998).
Although thought disorder has been linked with both temporal lobe function and gray matter volume separately, the possibility that these three variables may be interrelated has not been tested. The planum temporale operates at an earlier linguistic level than that of posterior superior and middle temporal gyri; therefore, the relationship between planum temporale structural abnormality and thought disorder may be arbitrated by the degree of activation in the posterior temporal lobe. Specifically, our hypothesis is that the association between decreased left planum temporale gray matter volume and greater severity of thought disorder is mediated by increased activation in left posterior temporal cortex during receptive language processing.
Mediation implies a very specific type of statistically testable relationship that extends beyond the concept of a partial correlation. True mediation suggests that an intermediate variable functions as a mechanism by which an independent variable exerts its influence on a dependent variable. Although this concept is widely recognized and tested in the social sciences, we are unaware of any investigation to date that has applied the methodology to neuroimaging data. In this study, we used a conventional mediation analysis procedure (Baron and Kenny, 1986) to directly investigate the proposal that temporal lobe functioning is the mechanism by which planum temporale structural abnormality influences severity of formal thought disorder.
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Subjects
Twelve patients with a DSM-IV diagnosis of schizophrenia were recruited from the Schizophrenia Day Program at Vancouver Hospital or through the primary care physician. Subjects were selected according to psychopathology to produce a sample with a range of thought disorder (from none detectable to severe). Diagnosis according to DSM-IV criteria was confirmed by one of the authors (EN). All were right-handed (Annett, 1967) native English speakers with no history of head injury, hearing loss,
Results
TLI scores ranged from 1.50 to 12.75 (M = 5.01, SD = 3.67). SSPI scores ranged from 0 to 19 (M = 9.50, SD = 5.70). A whole-brain regression analysis of the fMRI data, with TLI score entered as a covariate, was conducted to identify regions active during listening to English speech in which BOLD correlated with thought disorder (cluster-level corrected p < 0.05). One cluster of 54 voxels was significant at this criterion, spanning the left middle–posterior superior and middle temporal gyri (maximum at − 48
Discussion
The objective of this study was to investigate whether the association between decreased left planum temporale gray matter volume and severity of thought disorder is mediated by increased activation in left posterior temporal cortex during language processing. Until now, the relationships among these three variables had only been investigated with a pair-wise approach. Brain activation during a simple listening task correlated positively with thought disorder in this sample, and we replicated
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