In an attempt to organize the imaging findings, Murray and coworkers raised the possibility that there are 2 types of this disease: one with ventricular enlargement and a negative family history and the other with normal ventricles and a positive family history. In the first group of sporadic, “acquired” schizophrenia, environmental factors, such as birth injury, and EEG abnormalities (see in the following text) were considered to be more frequent. In summarizing the many cerebral changes observed in schizophrenic patients, Harrison concluded that several are quite consistent. These include mild enlargement of the lateral and third ventricles; decreased cortical volume, perhaps disproportionate in the temporal lobe; microscopically, diminution in size of cortical and hippocampal neurons; a diminished number of neurons in the dorsal thalamus; and a notable absence of gliosis.
EEG data, for the most part not useful, were alluded to earlier. Detailed neuropsychologic testing has disclosed deficits in attention and abnormalities of the P300 waves (cortical “event-related” potentials). These deficits correlate with reduced cognitive activation activity in functional MRI. It is unclear, however, if these changes represent primary defects or are secondary to an inherent lack of motivation.
Attention has also been drawn to the regional alterations of cerebral blood flow in chronic stable schizophrenic patients, as revealed by positron emission tomography (PET) and functional MRI. Weinberger and colleagues (1986) and Liddle and Barnes have reported a decrease in blood flow in the prefrontal areas during cognitive tasks. Friston and associates found consistent abnormalities in the left parahippocampal region in all forms of chronic schizophrenia. Studies of regional glucose metabolism and postmortem norepinephrine measurements have yielded equivocal data, although most patients show a reduction in glucose metabolism in the thalamus and frontal cortex. Several lines of investigation point to the medial part of the left temporal lobe and related limbic and frontal systems as being the focus of a developmental abnormality (see Tsuang et al and Friston et al for pertinent references). According to Sabri and colleagues, the inconsistent findings on functional imaging may be accounted for by correlations between certain blood flow patterns and specific symptoms. For example, the formal thought disorder corresponded to increased flow in the frontal and temporal regions, whereas delusions and hallucinations were associated with reduced flow in the cingulate, left frontal, and temporal areas. Our colleague Silbersweig and his coworkers have performed PET studies in schizophrenic patients while they were experiencing auditory hallucinations and found increased blood flow mainly in both thalami, left hippocampus, and right striatum, but also in the parahippocampal, orbitofrontal, and cingulate areas. One of their drug-naive patients with visual and auditory hallucinations showed activation in these regions.
When certain hallucinogens, such as mescaline and lysergic acid diethylamide (LSD), were first observed to induce hallucinations and abnormalities of thinking, it was hoped that they might provide experimental models of schizophrenia. This hope was never realized but there are instances, difficult to interpret, in which these drugs have induced a prolonged relapse in a schizophrenic patient. The psychosis caused by these drugs implicates serotonin (5-HT2A) systems, an idea now resurrected as noted below. Similarly, when methionine, a potent source of methyl groups, was observed to exacerbate the symptoms of some schizophrenic patients, it was thought that a primary metabolic fault had been discovered.