The neuropathology of schizophrenia. A focus on the subcortex

Investigations into the neuropathology of schizophrenia have increasingly altered the perception of the illness. Early studies focused on finding consistent and discrete areas of cortical pathology in the brain material of schizophrenic patients. After nearly a half century of study, little evidence emerged from a great body of data suggesting any consistent, discrete neuropathologic finding associated with this illness. This lack of evidence led to obvious frustration on the part of researchers and movement within the psychiatric community towards significantly less brain-based theories of the genesis of schizophrenia. With the advent of new technologies such as enhanced structural imaging (CT, MRI), functional imaging (PET, SPECT), and better neuropathologic methods, the focus of schizophrenia research has again turned towards the brain. Ultimately, hypotheses regarding the cause of schizophrenia will be proved or disproved on neuropathologic evidence. Few, if any, modern schizophrenia researchers would make the argument that there is a single, consistent neuropathologic lesion that is responsible for the entire illness of schizophrenia. Current theories tend to interpret the wide variety of neuropathologic changes in this illness as evidence of disturbed nervous system maturation--either acquired or inherent--or perhaps as a response to damage with aberrant neuronal regeneration. Evidence for a neurodegenerative disorder has not proved to be compelling. Furthermore, these theories emphasize dysfunction of elements of distributed neuronal systems, including subcortical systems, not discrete "lesions." The danger with the theoretic approach of distributed systems is, as Steriade and McCarley noted so well, that the flexibility of this idea can "mean a retreat into vagueness so that hypotheses concerning the role of multiple interrelated structures in the genesis of a given behavioral state cannot be proved wrong." (p 23). Despite the risks, this approach to investigation promises to offer more than just information pertinent to schizophrenia research; it offers insights into the mechanisms of behavior as a product of integrated brain function.