Regular articleSustained attention impairment correlates to gray matter decreases in first episode neuroleptic-naive schizophrenic patients
Introduction
Schizophrenia is a disabling mental disorder characterized by a multiplicity of signs and symptoms. Patients have a mixture of cognitive and emotional disturbances in a variety of functional systems such as perception, language, inferential thinking, and emotional expression and experience Nieuwenstein et al 2001, Nuechterlein et al 1997. Attentional impairment is the most usual cognitive dysfunction in schizophrenia (Cornblatt and Kelip, 1994). The Continuous Performance Test (CPT) is an attentional task on which schizophrenics’ scores have been consistently low Cornblatt and Malhotra 2001, Cornblatt et al 1998; Franke et al 1994, Katz et al 1996, Laurent et al 1999, Liu et al 2000. A typical CPT requires attention to a continuous stream of data demonstrated by response to specific target stimuli. The identical pairs version of the CPT (CPT-IP) is a more complicated variation in which subjects identify the repetition of any item in a sequence (Cornblatt et al., 1989). In schizophrenia research, there is some evidence that attentional deficits in sustained attention, measured by CPT-IP, have a high genetic component Chen et al 1998, Cornblatt and Malhotra 2001, Egan et al 2000, are developmentally stable (Cornblatt and Malhotra, 2001), and do not improve with antipsychotic treatment (Liu et al., 2000). Performance deficits on the CPT-IP have been reported in chronic schizophrenic patients Cornblatt et al 1989, Cornblatt et al 1997, Laurent et al 2000, but also in adolescents and adult patients in the earliest stages of illness Cornblatt et al 1997, Cornblatt et al 1998, in nonpsychotic relatives of patients Franke et al 1994, Laurent et al 1999, Laurent et al 2000, and in the at-risk offspring of schizophrenic parents (Mirsky, 1995). In addition, impairment on the CPT-IP seems to be specific to schizophrenia when compared to depression and to adolescents at risk for affective disorders Cornblatt et al 1989, Cornblatt et al 1999.
PET studies have shown that performing an adapted version of CPT increased the cerebral blood flow in the frontal lobes in normal subjects but not in schizophrenics Buchsbaum et al 1992, Schroeder et al 1994. These results support the hypothesis of a frontal component for the attentional dysfunction in schizophrenia. However, in a PET study, Katz et al. (1996), proposed a dysfunctional thalamocortical circuitry to explain the CPT impairment. In their fMRI-CPT studies, Volz et al. (1999) found that schizophrenics exhibited a decreased activation in the rigth mesial prefrontal cortex, the rigth cingulate, and the left thalamus compared to controls; Barch et al. (2001) showed a dysfunction in the dorsolateral prefrontal cortex among medication-naive first-episode patients with schizophrenia
The main MRI structural findings in schizophrenia include ventricular enlargement, medial temporal lobe involvement (amygdala, hippocampus, and parahippocampal gyrus), superior temporal gyrus involvement, parietal lobe involvement (particularly the inferior parietal lobule and its subdivision into angular and supramarginal gyrus), and subcortical brain region involvement, including the cerebellum, basal ganglia, corpus callosum, thalamus, and cavum septi pellucidum (for a review, see Shenton et al., 2001).
Most imaging studies have focused on specific brain regions and have been inspired by current hypotheses. In addition, they have used manual delineation of cerebral regions of interest, which inevitably reduces reproducibility due to differences in human expertise and intraobserver variations. In contrast, voxel-based morphometry (VBM) allows whole brain analysis Paillère-Martinot et al 2001, Wilke et al 2001, Wright et al 1999. It applies statistical models to test for significant differences between groups on a voxel-by-voxel basis throughout the whole brain. So one of its major advantages is the fact that data processing is almost completely user-independent, and inter- and intraobserver variations are avoided (Ashburner and Friston, 2000). VBM was originally devised to detect cortical thinning in a way that could not be confounded by volume changes; it does so by removing positional and volume differences through spatial normalization. VBM has become an established instrument in morphometry (Ashburner and Friston, 2001), and is the most appropriate tool for detecting differences in gray matter density of structures that are part of neuronal networks. In schizophrenia VBM has generally been used to investigate structural abnormalities Hulshoff Pol et al 2001, Paillère-Martinot et al 2001, Wright et al 1999, Wilke et al 2001, but has also been used to relate morphometry to the clinical status of patients. Wilke et al. (2001) investigated the interrelation of disease severity with brain morphology. Paillère-Martinot et al. (2001) also studied the relationship between clinical symptoms and anatomical abnormalities. To our knowledge, no previous studies have analyzed the possible structural correlates of a well-known cognitive impairment (such as the CPT-IP performance) in schizophrenia.
This study identifies the cerebral regions related to attentional dysfunction in schizophrenia. We hypothesized that structures in the frontoparietal circuitry such as the thalamus, cingulate gyrus, angular and supramarginal gyrus, and their connections could be involved in the impaired performance of the CPT-IP test.
Section snippets
Subjects
Thirteen male first-episode patients with a DSM-IV-diagnosis of schizophrenia (all paranoid subtype) were included in this study (mean age = 23.76 years; SD = 5.65 years). Patients were recruited from the Psychiatry Service of the Hospital Clinic of Barcelona. All were neuroleptic naive at the time of exploration. Consensus diagnoses were established by both a junior (IB) and a senior (MB) psychiatrist after independent assessments. The assessments were performed at study entry and 1 year later
CPT-IP results
The performance parameters of controls and schizophrenic patients are given in Table 2. The schizophrenic patients showed significantly more commission and omission errors than controls, and a significant impairment in the d’ score.
VBM: GM studies
Local GM concentration was decreased in patients in several clusters (see Table 3 and Fig. 1) comprising the anterior cingulate gyrus (BA 32), the inferior left frontal gyrus, and right claustrum. Subcortically, differences were found in the left pulvinar and
Discussion
In our VBM study, we found a significant decrease in gray matter density in several brain regions that have previously been reported to be impaired in schizophrenia. The decrease in the inferior left frontal gyrus, the left hippocampus, and parahippocampi gyrus in patients agrees with the results reported by Hulshoff Pol et al 2001, Paillère-Martinot et al 2001 and Wilke et al. (2001) in their VBM studies. Ananth et al. (2002) in their Optimized VBM study, reported gray matter differences in
Acknowledgements
This study was supported by a grant (2001 SGR 00139) from the Generalitat de Catalunya. Pilar Salgado-Pineda was supported by a grant from the University of Barcelona.
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