Behavioral flexibility is an important component of human behavior. It allows humans to monitor responses and adjust them to meet the demands of the current situation. Schizophrenia is characterized by responses that are rigid, stereotyped, and perseverative, rather than guided by context. This perseveration may be a consequence of abnormal inhibition in schizophrenia, which has been observed over a wide range of tasks. The objective of this proposal is to use multimodal neuroimaging techniques to identify mechanisms underlying abnormal inhibition and behavioral perserveration in schizophrenia. We will use saccade tasks to examine how the requirement to inhibit a prepotent behavior leads to abnormally strong and persistent effects on the response system in schizophrenia. Related to this goal, we will test hypotheses regarding the source of inhibition during the antisaccade task. Saccade tasks will be used because they have a well defined neural circuitry, and schizophrenia patients show reliable deficits in inhibition during the antisaccade task. Schizophrenia patients and control subjects will perform prosaccade, antisaccade, and NO-GO tasks during both functional magnetic resonance imaging (fMRI) and magnetoencephalography (MEG) sessions. Similar to the antisaccade task, the NO-GO task requires response inhibition;however, it does not require saccade generation. By comparing brain activity during these three conditions, we will determine which component of the antisaccade task leads to perseveration. Combining the spatial precision of event-related fMRI with the high temporal resolution of MEG will allow us to identify the regions involved and the timing of their contribution to normal and abnormal inhibition and perseveration. In addition to the functional neuroimaging data, behavioral measures will be recorded during each session. Multimodal neuroimaging will allow us to precisely delineate the neural bases of intact and compromised cognitive function in schizophrenia. Cognitive deficits in schizophrenia are extremely disabling and relatively resistant to current treatments. Understanding their neural mechanisms will inform the development of treatment for these deficits by providing targets for intervention.
