Structural, Functional, and Neurobehavioral Consequences of Adolescent COVID-19

Project Summary In the USA, SARS-CoV-2 has infected more than 16 million children and adolescents, who are undergoing critical periods of brain development when higher cognitive abilities are acquired, and mental illnesses typically emerge. Autopsy, blood, and CSF studies during acute COVID-19 reported neuroinflammation, which can alter cerebral white and gray matter morphometry, microstructure, and brain function. These brain alterations are associated with elevated risks for cognitive deficits and mental illness. A major gap in our current knowledge exists in understanding how SARS-CoV-2 infection during adolescence may impact brain structure and function and consequently, cognition and mental health. To address this gap, we will utilize pre-/post-pandemic neuroimaging, cognitive, and psychiatric symptom data from the Adolescent Brain Cognitive Development (ABCD) Study®. We will test the overall hypothesis that neuroinflammation during acute SARS-CoV-2 infection leads to brain changes that are detectable on MRI, including lasting alterations in macro and microstructural and functional abnormalities, which in turn mediate poorer cognitive performance and mental health. In Aim 1, we will identify morphometric (on structural MRI) and microstructural (on diffusion tensor imaging) abnormalities associated with SARS-CoV-2 infection by comparing longitudinal MRI data between those with (COVID+) and without a prior documented COVID-19 history (COVID-) to evaluate group differences on cortical thickness, cortical surface areas, subcortical volumes, and microstructural measures across baseline, year 2 and year 4 follow-up visits. Aim 2 will determine whether SARS-CoV-2 infection alters brain function using the Emotional N-Back task. We will longitudinally compare brain activation patterns and performance scores between the COVID+ and COVID- groups. Aim 3 will evaluate whether SARS-CoV-2 infection is associated with increased risks for neurobehavioral abnormalities. We will use data from the NIH Toolbox® Cognitive Battery and Kiddie Schedule for Affective Disorders and Schizophrenia 5 to longitudinally compare cognitive performance and anxiety/depression prevalence between the two groups. Lastly, mediation analyses will be performed to assess the direct and indirect impact of changes in brain structure and function on cognition and mental health. For all Aims, sex differences and sex-specific effects will be evaluated. Throughout this 3-year project, I will be supported by my sponsor, Dr. Linda Chang, and my co-sponsors, Drs. Amal Isaiah, Gloria Reeves, and Thomas Ernst, who will provide interdisciplinary expertise and training to me in the areas of COVID- 19, neuroimaging, neurodevelopment, cognitive assessments, clinical research, MRI data processing and analyses, data mining, and adolescent psychiatry. Furthermore, my training will be sufficiently supplemented with coursework, seminars, career workshops, conferences, and mentorship opportunities to allow me to fully develop into a well-rounded, independent investigator in clinical neuroimaging research.