Postmortem and neuroimaging studies have provided evidence of structural and physiological abnormalities in the brains of patients with schizophrenia. Studies using neuroimaging techniques, studies investigating cognitive impairment, genetic investigations and studies of response to treatment have made advancements in identifying the correlates of the neurobiology and symptoms of schizophrenia.
Neuroimaging has been used to investigate neuroanatomy and neurofunctioning in schizophrenia. Computerized tomography (CT) permitted the first systematic investigations of brain structure in schizophrenia, providing an opportunity to investigate relationships between symptomotology and structure. In this first phase of neuroimaging, investigators attempted to validate the positive and negative subtypes. Enlarged ventricles were associated with more severe negative symptoms as well as more cognitive impairment and greater impairment in premorbid functioning (Johnstone et al. 1976; Weinberger et al. 1980; Andreasen et al. 1982).
Further advancement of technology has provided magnetic resonance imaging (MRI), which allows for high levels of contrast between grey and white matter and cerebrospinal fluid through superior resolution capabilities. Functional neuroimaging allows for the exploration of relationships between symptomatology and dysfunction of specific brain regions. Earlier work used single photon emission computerized tomography (SPECT), while more recent studies utilized positron emission tomography (PET), both of which measure cerebral blood flow. Another method, functional magnetic resonance imaging (fMRI), uses the paramagnetic effects of deoxyhaemoglobin to measure regional blood flow and metabolic activity.
During the second phase of neuroimaging, investigators attempted to identify areas of impaired performance linked with the symptom dimensions in schizophrenia. Liddle et al. examined the three symptom clusters (reality distortion, disorganized symptoms and psychomotor poverty), finding increased cerebral blood flow present in left mesiotemporal structures in patients with hallucinations and delusions as well as increased flow in the right anterior cingulate cortex, left superior temporal gyrus and dorsomedial thalamus. In contrast, a relative decrease in blood flow was observed in the left prefrontal and parietal cortex among patients exhibiting the negative symptom of psychomotor poverty (Friston et al. 1992; Liddle et al. 1992). A number of imaging studies have linked hypofrontality of the frontal lobe with increased negative symptoms in patients with schizophrenia (Volkow et al. 1987; Andreasen et al. 1992, 1994; Wolkin et al. 1992; Schroeder et al. 1995). Other work using PET imaging to assess cerebral blood flow in relation to negative symptom measures was completed by Tamminga et al. (1992), similarly demonstrating decreased cerebral metabolism in frontal and parietal cortex as well as thalamic areas associated with the severity of negative symptoms.
Several studies have indicated that the temporal lobe volume is reduced in people with schizophrenia (Dewan et al. 1983; Cohen et al. 1989; Barta et al. 1997; Buchsbaum et al. 1997).
Others have found reduced activation in the right temporal lobe (Jernigan et al. 1985; Post et al. 1987). Some have suggested that there may be more regionally specific abnormalities in areas such as the superior temporal gyrus or planum temporale which correlate with the presence of hallucinations, positive formal thought disorder or reality distortion (Barta et al. 1990; Shenton et al. 1992; Nelson et al. 1998; Portas et al. 1998).
Imaging technologies continue to reinforce the fact that clearly measurable abnormalities exist in schizophrenia. Imaging research has now shifted from single region models to circuit models. Advances in neuroimaging may help researchers to address the many intriguing questions that remain regarding the abnormalities of these circuits. For example, studies are being carried out to examine whether the differences seen in schizophrenia reflect anatomical or functional circuits misconnected through abnormal brain development, neuronal loss or other regressive changes, an epiphenomenon of treatment, or pathological sequelae of long-term illness. There is a growing consensus from research in first-episode never-medicated patients that fundamental differences exist in brain structure and function that antedate treatment and chronicity effects.
Neuropsychology and cognitive impairment
There have been reports of cognitive impairment in schizophrenia since the illness was first described by Kraepelin (1919) and Bleuler (1911/1950). A remarkably consistent pattern emerges; cognitive impairment is associated with negative (Andreasen & Olsen 1982; Cornblatt et al. 1985; Gaebel et al. 1987; Keilp et al. 1988; Braff 1989; Andreasen et al. 1990; Merriam et al. 1990) and disorganized symptoms (Bilder et al. 1985; Frith et al. 1991), but is not associated with psychotic symptoms (Bilder et al. 1985; Cuesta & Peralta 1995; O’Leary et al. 2000).
Further validating evidence exists. Negative symptoms have been found to be associated with impaired conceptual thinking, object naming and long-term memory (Liddle 1987a,b), a slowing of mental activity (Liddle & Morris 1991) and poor performance on tests of verbal learning and memory, verbal fluency, visual memory and visual - motor sequencing (O’Leary et al. 2000). Disorganized symptoms are associated with poor performance on tests of concentration, immediate recall and list learning (Liddle 1987a,b), an inability to inhibit inappropriate responses (Liddle & Morris 1991), lower verbal IQ and poor concept attainment (O’Leary et al. 2000).