TITLE: CAFFEINE AND POSTOPERATIVE NEUROCOGNITIVE RECOVERY PROJECT SUMMARY Delirium is a distressing clinical syndrome characterized by failure of basic cognitive functions that affects approximately 20-50% of older surgical patients. Delirium during surgical recovery is associated with increased mortality, increased healthcare expenditures, and future cognitive and functional decline. Moreover, there is pathophysiologic overlap between delirium and Alzheimer’s Disease-Related Dementias; patients experiencing delirium demonstrate increased risk of future dementia. Unfortunately, the underlying neurobiology of delirium remains incompletely understood, and there are no biologically informed, effective therapies for preventing postoperative delirium and related complications. Our preliminary data suggest that caffeine reduces delirium in the postanesthesia care unit (PACU) after major surgery by shifting cortical dynamics towards neural criticality. Criticality refers to a system state that is poised to dynamically fluctuate to meet demands. For cognition, neural criticality is a potential mechanism by which functionally segregated areas of the brain can be dynamically integrated over space and time to optimize cognition. In our preliminary trial, participants receiving caffeine at the end of surgery demonstrated increased electroencephalographic (EEG) markers of criticality in the PACU concurrent with delirium reduction. Nonetheless, the relationships among caffeine, neural criticality, and postoperative neurocognitive recovery require additional, rigorous testing. Our long-term goal is to improve neurobiological understanding of delirium and related neurocognitive disorders, such that effective therapies can be developed. The objectives of this proposal are to (1) test an intervention for reducing early postoperative delirium while (2) identifying dynamic brain changes that reflect cognitive vulnerability. The central hypothesis is that caffeine will improve postoperative neurocognitive recovery in older adults. We will test this hypothesis via a randomized, placebo-controlled, quadruple-blinded clinical trial. Aim 1 will determine whether caffeine reduces the incidence of early postoperative delirium. Participants (n=250) will be randomized to placebo, low-dose caffeine, or high-dose caffeine in a three-arm parallel design. A sequential randomization design will also be used to test one vs. two days of caffeine therapy. Aim 2 will identify cortical dynamics underlying early postoperative delirium. A wireless, high-density whole-scalp EEG system will enable the analysis of neural criticality and the associations with caffeine and delirium. Lastly, Aim 3 will use the same EEG system to test baseline neural criticality in trial participants meeting criteria for Mild Cognitive Impairment, as deviations from criticality have been reported in patients with this condition as well as Alzheimer’s Disease. Overall, the proposed research is significant becau...