This revised application requests continuing support to evaluate characteristics of information processing deficits in schizophrenia. Central to this research is the dissociation of processing effort from informational utilization. We suggest that most schizophrenia patients are actively expending effort to attend to information, while cognitive deficits reflect disturbances in analysis, integration, and manipulation of information. We propose to assess changes in pupil diameter because the pupillary system is exquisitely sensitive to differential activation on the basis of processing effort and informational complexity. A key objective is to evaluate differential sympathetic and parasympathetic innervation of the pupil to quantify the extent of cognitive deficits, while providing evidence for intact effortful processing in the same schizophrenia patients. Psychophysiological assessment will be carried out as patients perform tasks varying in attentional and processing demands. In the current application, special emphasis has been placed on paradigms associated with the concept of working memory, which has strongly impacted current views of processing deficits in schizophrenia. A psychiatric control group of depressed individuals also will be studied. To delineate the pathways that contribute to the changes in the pupillary control system, two non-invasive methodologies are employed. 1) The contribution of the parasympathetic pathway will be enhanced through modulation of illumination. 2) In schizophrenia patients and healthy control subjects, the final sympathetic and parasympathetic pathways will be isolated at separate experimental sessions by temporary pharmacological blockade of the complementary neuromusculature junction of the pupil. Direct evaluation of the relationship of pupillary changes and activation of brain regions will be accomplished by a study of concurrent pupillary and neuroimaging data in schizophrenia patients and healthy controls. Elucidating the neurophysiological systems that are affected in patients provides a rationale for exploring etiological factors and treatment strategies. Differentiation of processing capacity from general mental effort, in particular, allows a clear examination of the types of cognitive deficits in schizophrenia. Findings will further pinpoint functional systems to be examined using current and future imaging technologies.
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