CLINICAL HANDBOOK OF SCHIZOPHRENIA

4. Brain Imaging 41events. However, there is a trade-off in terms of spatial resolution and limits to the regionsthat can be sensitively measured, because measurements must be recorded at thescalp, with localization inferred statistically. MEG is quite sensitive to current flows orientedtangentially to the scalp and is less affected by the conductance of the brain, skull,and scalp than EEG, but it cannot detect radially oriented electrical current.Most EEG and MEG studies of schizophrenia have examined the electrical potentialsor magnetic fields that are evoked in response to a transient cognitive activity, referred toas event-related potentials (ERPs) or event-related fields (ERFs). The greatest body of evidenceconcerns a positive-going wave that is observed 300 ms after presentation of anovel stimulus, the P300, which may arise from several sources, including prefrontal, parietaland temporal cortex locations. Reduced P300 amplitudes consistently have beenfound among patients with schizophrenia, with some evidence for greater left-sided abnormalities.Although P300 abnormalities are also found in other psychiatric populations,the laterality effects may be more specific to schizophrenia. Another focus ofschizophrenia ERP research has been on early, automatic responses, such as the P50 andmismatch negativity. Among healthy individuals, the P50 response, which may be generatedin the auditory cortex, is suppressed to the second of two rapidly presented auditorystimuli. Patients with schizophrenia show less suppression, interpreted as a failure of sensorygating. In addition, the normal negative-going response to deviant stimuli, termedmismatch negativity and thought to be generated in prefrontal and superior temporal cortex,is diminished in amplitude among schizophrenia patients. The N400 response to semanticincongruity also has been shown to be longer in latency among patients. Tantalizingresults from a handful of recent studies have linked electrophysiological deficitssuch as reduced P300 and mismatch negativity amplitudes to psychosocial outcome, butmore work is needed to determine the specificity of these findings to schizophrenia.Interpretative Challenges Common to FunctionalImaging TechniquesIn addition to the pitfalls inherent to particular functional imaging methods, there arealso general challenges that must be considered in interpreting the results of functionalimaging studies. First, there is the issue of generalizability. Because of the expense of datacollection and analysis, functional imaging studies often employ small sample sizes. Althoughefforts are made to select a sample from the population in an unbiased manner,lack of representativeness is bound to occur, because of both the small samples and thedemands of neuroimaging that may exclude some patients (e.g., the need to lie still, risksof claustrophobia, or fears about radiation). This makes it difficult to generalize from theconclusions in any single study and also confounds efforts to combine results across studies.Second, attempts to measure brain function are complicated by limitations in ourknowledge of how mental activity influences neurophysiology. For example, the basicquestion of whether good task performance is related to more or less regional blood flowand oxygenation has not been thoroughly answered, although it likely depends on manyfactors. Studies of the “resting state,” which attempt to circumvent this problem, arelikely instead to reflect a complicated mix of mental activities with variable underlyingpatterns of brain activity. Requiring participants to engage in a particular cognitive challengetask may reduce the variability in brain response somewhat, but there are still individualdifferences in motivation, attention, strategy, performance, and response to failureor success. Many of these factors may differ systematically between patients and controls,and the neuroimaging investigator must decide which element(s) should be matched betweengroups. Once this is determined, there is the further challenge of figuring out howto control for group differences. For example, whereas some investigators have argued