CLINICAL HANDBOOK OF SCHIZOPHRENIA

42 I. CORE SCIENCE AND BACKGROUND INFORMATIONfor statistical covariation of the effect of task performance, others have advocated for apriori matching of samples or testing both patients and controls at multiple levels of difficulty.A third interpretive challenge for functional neuroimaging is the possible confoundingeffect of antipsychotic medication. Although structural imaging studies share thischallenge to some degree, the confound may be greater for functional imaging, becausemedications may affect both neural activity and hemodynamic factors measured as aproxy for neural activity. If functional neuroimaging is used to draw conclusions aboutthe nature of underlying brain pathology in schizophrenia by comparing patients andhealthy controls, the fact that most samples of patients include many people takingantipsychotic medications must be considered. Longitudinal treatment studies haveshown that antipsychotic agents can increase cortical and subcortical blood flow amongpatients, so a finding of normal or increased activity compared to controls might bepartly accounted for by medication effects. On the other hand, antipsychotic medicationsmay also increase resting perfusion, which can decrease the amount of change in brain responsedue to challenge that can be observed with hemodynamic methods, thus biasingtoward findings of less apparent neural activity. Because researchers are beginning to addressall of these challenges, the quality of functional neuroimaging studies should improvein the future.FUTURE DIRECTIONSIn addition to improvements in methods, several new directions of neuroimaging researchhold great promise for leading to a better understanding of schizophrenia and its treatment.The first direction is toward greater integration between imaging modalities. Littleis currently known, for instance, about how structural and neurochemical abnormalitiesrelate to known deficits in functional brain response. Does a single process lead to bothvolume loss and poor brain response in the temporal cortex, or are there separate causes?Studies that combine careful structural measurements with spectroscopy and functionalimaging could address this issue. Similarly, investigators are starting to combine fMRIand EEG in an effort to take advantage of fMRI’s high spatial resolution and EEG’s hightemporal resolution. This should help to pinpoint the location and timing of functionalabnormalities within the same study. The second future direction in functional imaging isa greater emphasis on techniques and analytical methods that examine the interaction betweenbrain regions. Hypothesized abnormalities of structural and functional connectivityamong patients with schizophrenia based on interpretations of previous findings haveonly recently been examined directly. As mentioned earlier, DTI can be used to measurethe integrity of white matter tracts. In addition, multivariate statistical methods can beused to examine how brain areas vary together in both size and function. Since it is likelythat the complex behavioral patterns in schizophrenia are generated by the interaction ofmultiple areas, measures of abnormal connectivity may be much better predictors of clinicaland cognitive symptoms and functional outcome than size or response of single regions.A third future direction is the growing use of functional imaging measures in treatmentstudies. Functional brain response appears to be a fairly sensitive index of changewith pharmacological treatment and can therefore shed light on the mechanism of improvement,as well as correlates of treatment response. Finally, an exciting new researcharea involves the combination of functional neuroimaging and measurement of geneticpolymorphisms and gene products. These studies offer the promise of a better understandingof how genes influence brain function among patients with schizophrenia and may elucidatethe pathway between liability for the disorder and its phenotypic expression.