Neuropathology of the Prefrontal Cortex Neuropil in Schizophrenia

Schizophrenia is a brain disease with a multitude of symptoms and deficits in several areas of the brain. While the search for the neuropathological mechanisms of most diseases of the brain remain a forefront in the frontier of brain research, studies in schizophrenia has progressed significantly within the last three decades; however, the central etiological mechanisms of this devastating disease remains a mystery. A new impetus was gained with the landmark study by Johnstone et al., (1976) using computed tomographic (CT) scans, reported dilation of the lateral ventricles in a small group of chronic schizophrenic patients. Following this study, numerous more sophisticated neuroimaging studies using techniques such as magnetic resonance imaging (MRI) and positron emission tomography (PET) scans, consistently showed ventricular enlargement, sulcal widening and cortical atrophy in schizophrenia (Reveley et al., 1982; Andreasen et Al., 1988, 1990, 1994; Lawrie and Abukmeil 1998; Van Horn and McManus 1992). Lateral ventricle studies showed a 20-75% increase in the ventricular to brain ratio (Daniel et al., 1991; Van Horn and McManus 1992) and a median 40% increase in volume using MRI (Lawrie and Abukmeil, 1998). Additionally, some of these volumetric studies also showed an 8% decrease in the overall temporal lobe and 4-12 % decrease in volume of medial temporal structures, such as the hippocampus, parahippocampus and amygdala (Lawrie and Abukmeil 1998). Of significant importance are imaging studies of monozygotic twins discordant for schizophrenia. In all pairs studied the affected twin had the larger ventricles (Reveley et al., 1982; Suddath et al., 1990) and smaller cortical and hippocampal size (Noga et al., 1996). These studies were supported by data from family studies, which showed that the affected relatives had larger ventricles and smaller brain volume (Honer et al., 1994; Sharma et al., 1998; Silverman et al., 1998). Buchanan et al., (1998), in an effort to identify reductions in specific subregions of the frontal lobe, found a 13% decrease in the inferior prefrontal grey matter compared with an average 5% decrease in other frontal regions. MRI studies of subcortical structures showed small decreases in the thalamic volume of schizophrenics (Andreasen et al., 1994; Buchsbaum et al., 1996; Byne et al., 1997, 2001, 2002; Jones 1997, Popken et al., 2000; Young et al., 2000; Brickman et al., 2004). Structural imaging findings and macroscopic changes in the brain provided the impetus for more stereomorphometric and immunocytochemical investigations of the cytoarchitecture of cortical and subcortical structures of post-mortem brains. One particular area of major interest has been the prefrontal cortex (PFC).