Symptoms of schizophrenia may result from both output (response monitoring) and input (sensory gating) deficits. Response monitoring can be studied using the lateralized readiness potential (LRP) and error related negativity (ERN) components of the scalp-recorded event related potential (ERP). Event-related functional MRI (fMRI) techniques enable activation in specific brain regions to be linked with mental events involved in response processing. We will combine ERP and event-related fMRI techniques to study normal and abnormal response monitoring processes in groups of age and gender matched normal controls and schizophrenic patients. This work is motivated by preliminary data showing that schizophrenics not only have modestly reduced ERNs following errors but also a negative component following correct responses (CRN), along with reduced LRP. Furthermore, many of these patients had reduced activation of the dorsolateral prefrontal cortex (DLPFC), rela5tive to controls, during an event-related fMRI signal detection task. Recent fMRI studies and dipole analyses of ERPs support a role not only for the DLPFC but also for the anterior cingulate cortex (ACC) in processing associated with error monitoring. Other evidence also points to the basal ganglia in the development and execution of action oriented plans. We will use the ERN, CRN and LRP to test a model of response monitoring. FMRI data will be collected in parallel paradigms and be combined with ERP data to assess the spatio-temporal dynamics linking the DLPFC, the ACC and the basal ganglia during both normal and pathological response monitoring. Associations between specific deficits in response monitoring and symptoms of schizophrenia will be assessed. Inputs deficits will be assessed from the modification of startle blink and startle-elicited ERP components by pre-pulses. We will study these phenomena, adding an attention/task condition in order to assess the relationship between gating failures, response monitoring and symptoms of schizophrenia. In summary, we propose to use ERP indicators of response monitoring and sensory gating to illuminate both output and input deficits underlying positive and negative symptoms of schizophrenia. By combining ERP and fMRI methods we will characterize the spatio-tumoral dynamics of the neuroanatomic circuit(s) involved in normal and abnormal response monitoring.
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