Andrea Wijtenburg
$797,157
SERENA S SPUDICH
Yale University
Connecticut
National Institute of Mental Health (NIMH)
Individuals with neuropsychiatric manifestations of post-acute sequelae of SARS-CoV-2 infection (neuro-PASC) report cognitive impairment, new or worsening anxiety and/or depression, altered sleep, autonomic dysfunction, headache, dizziness, post-exertional malaise, and/or neuropathy, among other symptoms. Currently, an estimated 10% of individuals who contract SARS-CoV-2 go onto develop PASC, which represents an enormous disability as well as clinical, social, and economic burden worldwide. Yet, there is a large gap in our understanding of how neuro-PASC alters the function of the brain leading to persistent symptoms and deficits. In response to RFA-NS-23-021, this proposal is aimed at merging two powerful lines of investigation here at Yale to provide a biological basis for the clinical symptoms observed. The first strength is the NeuroCOVID Clinic at Yale, which has seen over 600 patients with neuro-PASC. We then created The COVID Mind Study at Yale under the leadership of Dr. Spudich and have enrolled over 90 participants with neuro-PASC and 60 controls with no PASC. The clinic and study will serve as key sources of subject recruitment. The second strength is the robust and innovative neuroscience and neuroimaging group at Yale under the leadership of Dr. Constable. His group has leveraged the NIH interest in the human connectome and developed methods that link circuit-level (dys)function in the brain to cognitive profiles measured through standardized testing and clinical symptoms. This framework uses a powerful predictive modeling approach and machine learning strategies to localize circuit (dys)function and quantify the contributions of different networks to clinical symptoms and behavior. With both of these strengths, we are ideally positioned to investigate this critical public health issue. Our preliminary data from The COVID Mind Study demonstrates significant cognitive deficits in individuals with neuro-PASC, particularly in language, working memory, declarative memory, non-dominant motor function, and perception compared to COVID negative controls. They also demonstrate greater negative valence issues, including depression, rumination, apathy, anxiety, and perceived stress. We also demonstrated the neuro-PASC group had significantly lower cerebral blood flow in the left superior parietal lobule compared to PASC negative controls using MRI perfusion imaging. To date, there have been no comprehensive assessments of the impact of neuro-PASC on brain function. Using novel methodology developed for this project centered on predictive models for generating reliable associations, we will identify the circuit level brain changes, potential compensatory mechanisms in each cognitive domain, and understand the distinct role of mood alterations in neuro-PASC. We will generate targets for the development of future treatment strategies in neuro-PASC. Our overarching hypothesis is that there are distinct changes in the brain-behavior circuits in individuals with neuro- PASC that will provide key insight into the pathophysiology of this disorder and guide future treatments. The outcome of these studies will have a major impact in how such patients are perceived and managed.