The present study used high resolution MRI in conjunction with semi-automated image-processing procedures to measure whole prefrontal cortical gray and prefrontal white matter volume in schizophrenic and control subjects. No significant differences were found between the two groups in either right or left gray matter volume; however, right white matter volume was significantly reduced in the schizophrenic group when compared with control subjects. These results are similar to those of Breier et al. (1992)
, whose methodology has comparable image resolution to that used in the present study. The Breier et al. study also did not find gray matter volume reductions in schizophrenic subjects, but did report white matter volume reduction on both sides of the brain. Buchanan et al. (1993)
also reported white matter abnormalities in schizophrenic subjects.
White matter abnormalities were not found in our previous sample of positive symptom schizophrenic subjects. The different findings are likely to be a result of the different symptom profiles of the previous (positive symptom) and current (negative symptom) groups. In the current study, 11 of the 17 patients had predominately mixed symptoms, four had mainly positive symptoms, and two had mainly negative symptoms. In the previous study, symptom profiles were very different. Eleven of the 14 patients were assessed as having mainly positive symptoms, three patients were characterized as having mixed symptoms, and none of the patients had predominately negative symptoms (Wible et al., 1995
Schizophrenic subjects from our previous and current studies were combined and split into two groups based on SANS total score. This combined analysis showed that the Z
-scores for bilateral white matter volumes were significantly smaller in schizophrenic patients from the higher SANS group (see ). In other words, the higher the SANS score, the smaller the prefrontal white matter volumes. Although much of the methodology stayed constant between the current and previous studies, caution must be taken in interpreting results from combined studies that were performed at different times with differing methodologies. Sanfilipo et al. (2000)
also found an association between white matter volume and negative symptoms in schizophrenic subjects. They reported that the white matter reduction was most severe in the orbitofrontal region. Gur et al. (2000)
reported an association, in women schizophrenic subjects only, between decreased orbital (gray matter) volumes and negative symptoms. In the current sample, we also found a significant correlation between total SANS scores and left frontal gray matter volume in schizophrenic subjects. Together these finding suggest a relationship between prefrontal abnormalities and negative symptoms.
The lack of gray matter or total volume findings is also in agreement with several other studies that have reported no volumetric differences in this area between schizophrenic and control subjects (see ). However, a reduction in white matter volume is likely to signify degeneration or cell death either in the frontal lobe or in regions that project to the frontal lobe. Thus, this finding of white matter reduction is not inconsistent with or contradictory to the reports of gray matter volume reductions that have been reported in several studies (see ). A white matter volume reduction followed by changes in gray matter would suggest different primary pathological loci or processes than would either a finding of only gray matter loss or a finding of both gray and white matter loss combined. These issues need to be resolved in future research.
Temporal lobe pathology has been demonstrated in schizophrenic subjects using both MRI and post-mortem histological studies (for reviews, see Shenton et al., 1997
; Wible et al., 1997
; McCarley et al., 1999
). Correlations were found between volumes of right hippocampal and right prefrontal gray matter volumes in schizophrenic, but not control subjects. These findings are again similar to those of the Breier et al. (1992)
study, which found a significant correlation between the right hippocampal–amygdala complex and right prefrontal white matter in schizophrenic subjects. The previous study from our laboratory found a relationship between anterior portions of the hippocampal–amygdala complex, parahippocampal gyrus, and superior temporal gyrus and prefrontal white and gray volume on the left side in schizophrenic subjects. Again, the differences in correlations may be due to the different symptom profiles of the previous and current patient groups.
The volume correlations found between temporal and prefrontal regions in schizophrenic patients, but not control subjects, may indicate volume reductions in tightly anatomically and functionally linked temporal–prefrontal regions such as hippocampal, superior temporal, cingulate, orbital and inferior frontal regions. A detailed discussion of these ideas and the neuroanatomical relationships can be found in Wible et al. (1997)
As in the previous study, here we hypothesize that a use-dependent and/or developmental pathological process that affects temporal lobe structures may also be affecting prefrontal cortical areas in a parallel manner, resulting in stronger than normal relationships between volumes in these areas (Wible et al., 1997
The lack of detection of gray matter volumetric abnormalities in the current study should be interpreted with caution in light of the sensitivity of MR findings. Abnormalities in cellular orientation, connectivity, receptor distribution and sensitivity, and neurotransmitter distribution, among other factors, are not detectable by MRI and have been previously reported (Benes et al., 1986
). However, a histological study reporting abnormalities in prefrontal areas did not find a significant difference
between schizophrenic and control subjects in the cortical thickness of area 9 of the prefrontal cortex because the differences were not large enough to reach significance (Selemon et al, 1995
The results of this study point to abnormal temporal-prefrontal pathways, a finding for which there is converging evidence from many studies. The findings also suggest that there may be differences in brain pathology or primary brain pathology in accordance with specific schizophrenic symptoms, and that negative symptoms may be associated with prefrontal abnormalities.