Pursuing the Pathophysiology of Schizophrenia

Pursuing the Pathophysiology of Schizophrenia

For decades there existed only indirect techniques to study the living human brain. Now, with the advent of in vivo brain imaging, the structure, chemistry and function of the living hu-man brain in health and disease and in multiple behavioral and pharmacologic states can be directly assessed. With the charac-terization of the human genome, we can begin to link disease characteristics with abnormal regional protein alterations to be-gin to draw together disease characteristics with tissue targets of illness. This will provide critical direct information about brain behavior in schizophrenia to enable productive and integrative data collection.

The observation that persons with schizophrenia perform poorly on tasks that require frontal neocortical function has long suggested that the frontal cortex is involved in the mechanisms of schizophrenia (Bleuler, 1978). Several laboratories have devel-oped this idea further, showing that frontal function is abnormal in schizophrenia (Ingvar and Franzen, 1974; Weinberger et al., 1986), proposing that the disturbed frontal function can influence dopamine dynamics in the striatum (Meyer-Lindenberg et al., 2002), and that symptomatic (Andreasen, 1991), cellular (Lewis, 2000), neuro-chemical (Akbarian et al., 1993), dendritic (Selemon et al., 1995), and expression differences (Middleton et al., 2002) exist in this area in persons with the illness. Other brain regions have also been the focus of considerable productive study in schizophrenia, including the hippocampus (Benes et al., 1991; Gao et al., 2000; Heckers et al., 1998), thalamus (Andreasen et al., 1994; Pakkenberg, 1990), and the cerebellum (Andreasen et al., 1994). Within these brain areas, evi-dence exists for neurochemical abnormalities in dopaminergic trans-mission (Laruelle et al., 1996), in excitatory synaptic function (Gao et al., 2000; Olney and Farber, 1995; Tsai et al., 1995), and in GABA-mediated inhibition (Benes et al., 1996). Multiple formulations of pathophysiology in schizophrenia have been articulated, each based on a body of knowledge and an orientation to the illness.