Delirium is a sudden state of confusion that is associated with increased morbidity and mortality, impaired long- term cognition and loss of independence. Although there are substantial costs ? financial, societal and individual ? delirium is unfortunately bereft of therapies, largely due to the limited understanding of its pathogenesis. The long-term goal of the proposed research program is to develop preventative and therapeutic approaches to delirium. In this application, I seek to identify the neural correlates of delirium, and subsequent cognitive decline as the first step in a translational research program to address this therapeutic void. The strategy is based on the Cognitive Disintegration model: we hypothesize that delirium results from an acute breakdown in neural network connectivity. In essence, delirium results when ?information integration? falls below a critical threshold in vulnerable networks. We use network connectivity as a surrogate of the capacity to integrate information. We will test the hypothesis that impaired preoperative cingulate functional connectivity is associated with increased risk of postoperative delirium following adjustment for confounding variables. This will inform patient risk stratification and the development of preclinical models of delirium. An important observation that motivates this approach is the finding that cognition is not globally impaired in delirium; rather, specific cognitive functions, such as attention and executive function, are particularly affected. Furthermore, while the electroencephalogram (EEG) hallmark of delirium is increased slow wave activity, the patients are not asleep. We reconcile this difference by hypothesizing that there is ?local? slow wave activity in delirium. If proven, this would provide a mechanism for the breakdown in network connectivity in delirium and provide rationale for the study of the vulnerability of specific brain regions in both future clinical and translational studies. In experimental extensions, we plan to study the change in connectivity of different brain regions associated with delirium through source reconstruction of the EEG. Finally we will address the role of pre-delirium connectivity in the associations between delirium and long-term cognitive decline, hypothesizing that preoperative connectivity modulates the impact of delirium on long-term cognition. This will provide greater insight into the long-term impact of delirium. The funding will be used to conduct a perioperative cohort study, collecting clinical, cognitive, imaging and EEG data. This application will provide comprehensive insights into the neural network changes predisposing to, and associated with, postoperative delirium and its long-term cognitive sequelae. While postoperative delirium is a major public health issue warranting significant scientific focus and investment, we also expect our findings to have wider ramifications for the neuroscience of sleep and other disorders of consciousness.
The proposed research has direct public health implications given the major impact of delirium on the health trajectory, up to and including increased mortality, and the lack of therapeutic options for the condition. This present application is also immediately relevant to the NIH's mission of fostering innovative research strategies for improving health through identification of the causes, preventive approaches, and management of delirium. This application will result in novel insights into the pathogenesis of delirium, redefine patient risk stratification, support therapeutic development, and identify the mediators of the long-term cognitive effects associated with a delirium episode. Our long-term aims are to define the clinical neural correlates of delirium and explore the underlying mechanisms in translational studies focused on developing novel therapeutics, before embarking on randomized controlled trials with the goal of improving patient outcomes.