CLINICAL HANDBOOK OF SCHIZOPHRENIA

4. Brain Imaging 39with neuroleptic agents (more abnormality among treated patient groups). A few researchershave suggested that the modest and sometimes contradictory nature of thesefindings also may be related to the unstructured nature of the behavioral state of patientsat “rest.” Thus, more recent studies have used cognitive challenge tasks to standardizecognitive activities during scanning and to stimulate particular brain systems that are hypothesizedto be impaired. Many of the tasks have targeted cognitive challenge of thefrontal cortex, and results from PET and SPECT studies again have been mixed but demonstratea small overall hypofrontality effect.Although there has been a focus on frontal lobe function, other regions haveemerged as sites of functional abnormality based on PET studies of metabolism andblood flow. For example, lower metabolism among patients with schizophrenia has beenshown for both the basal ganglia and temporal lobes. The function of the hippocampushas been of particular interest given the known structural abnormalities in this region andthe putative role of the medial temporal lobe in memory deficits found in schizophrenia.Studies of patients at rest have been mixed, with metabolic studies often finding reducedvalues among patients, and blood flow studies finding hyperactivity. The PET literatureon the response of the hippocampus to learning and retrieval challenge tasks is small, butagain there are findings of both under- and overactivation of the region. The role of thelevel of performance deficits as a possible moderator of these effects deserves furtherstudy. PET studies have also been used to examine brain functioning related to hallucinations,either by comparing hallucinators to nonhallucinators or by examining blood flowor metabolism during self-reported hallucinations. Findings have been inconsistent, butthere is some suggestion that hallucinations may be related to abnormalities of the functionof speech perception areas in the superior temporal gyrus.PET and SPECT studies using receptor ligands have examined in vivo evidence forthe involvement of several neurotransmitter systems in the pathogenesis of schizophrenia.In general, these studies have confirmed the theory of hyperstimulation of dopamine D 2receptors in the striatum among patients. The few studies that have tested directly for theexistence of postulated deficits in D 1 receptor-modulated dopamine activity in theprefrontal cortex have had mixed results, however. PET receptor studies have also beenused to examine mechanisms of treatment response. These investigations have confirmedthat treatment with antipsychotic medications results in D 2 receptor blockade, and havefound that although clinical response is optimal between 50 and 80% occupancy, there isno observable correlation between D 2 occupancy and response within that window. Imagingstudies have also investigated the mechanism of action of second-generationantipsychotics, which seem to have slightly greater efficacy than first-generation agentsand are preferred due to better side effect profiles. Many of these agents share a high ratioof serotonin 5-HT 2A receptor affinity to D 2 receptor affinity, but this does not appear tobe directly related to their efficacy, since imaging studies have failed to find response atdoses that led to maximal 5-HT 2A occupancy but suboptimal D 2 occupancy. Rather, imagingevidence suggests that incidental 5-HT 1A agonism from the combined antagonismof 5-HT 2A and D 2 receptors, by increasing prefrontal dopamine function, may lead toclinical efficacy. The role of glutamate also is of particular interest in schizophrenia, andnew radiotracers are being developed to examine this neurotransmitter system in vivo.Functional Magnetic Resonance ImagingAlthough PET and SPECT imaging have contributed greatly to our knowledge aboutmetabolic, cerebrovascular, and neuropharmacological abnormalities in schizophrenia,the advent of fMRI in the early 1990s was heralded as a welcome addition to the arsenalof functional imaging research techniques. fMRI takes advantage of naturally occurring