Schizophrenia patients frequently describe disturbances suggestive of an impaired ability to gate irrelevant stimuli and focus on the relevant stimuli. The prepulse inhibition (PPI) paradigm is a unique psychophysiological tool for studying the initial processing of sensory stimuli by examining the inhibition of the amplitude of the startle eyeblink reflex. Several studies have shown that schizophrenia patients have a dramatic deficit in PPI that occurs when the startle-eliciting stimulus is preceded by a weak stimulus. This finding has been interpreted as a deficit in automatic attentional processing. The applicants have shown that schizophrenia patients exhibit deficits in the attentional modulation of PPI, suggesting an additional controlled processing deficit. In the same study, healthy individuals with greater PPI during an attended prepulse showed greater relative glucose metabolic rates (rGMR) in prefrontal cortex as measured by FDG-PET. Patients showed this relationship only for Brodmann area 10 and had low rGMR in prefrontal cortex. The applicants findings support animal models of deficient sensorimotor gating in schizophrenia. The present pilot study will extend this line of research by further integrating clinical neuroimaging, cognitive, and psychophysiological approaches to understanding attentional abnormalities in schizophrenia. FDG-PET scans will be used to rigorously examine cortical-striatal-thalamic circuitry activation in 12 medicated schizophrenia patients and 12 age-and-sex matched healthy controls. PET scans will be obtained on two separate days one week apart. A standard PPI paradigm including simultaneous psychophysiological measurement of PPI will be employed on both scan days; on one scan day, however, subjects will passively attend to prepulse stimuli and, on the other day, subjects will be instructed to actively attend to particular prepulse stimuli. In addition, structural and event-related functional MRI (fMRl) will be obtained in these same individuals. The fMRI session will involve an attention-to-prepulse task which is similar to that employed in the PET component. This project uses complementary PET and fMRI technology. FDG-PET subtraction will allow an examination of activation in key cortical-striatal-thalamic PPI circuitry based on individually coregistered anatomical MRI region of interest tracings with absolute glucose quantification for specific identification of regional change and 20-slice coverage of whole brain without susceptibility artifacts. fMRl, with intrinsically higher temporal resolution, will allow a parceled examination of brain activation following attended and ignored PPI stimuli separately. Based on animal models, the applicants will test the hypothesis that deficits in automatic and controlled modulation of PPI observed in schizophrenia are associated with specific functional abnormalities in cortical-striatal-thalamic circuitry thought to modulate PPI.
| Hazlett, Erin A; Buchsbaum, Monte S; Zhang, Jing et al. (2008) Frontal-striatal-thalamic mediodorsal nucleus dysfunction in schizophrenia-spectrum patients during sensorimotor gating. Neuroimage 42:1164-77 |
