Dynamic Functional Network Biomarkers of Emotion Regulation Flexibility in Internalizing Disorders

About This Grant

Project Summary/Abstract. Close to 20% of Americans suffer from internalizing disorders like depression, anxiety, and posttraumatic stress in their lifetime (National Center for Health Statistics, 2023). These conditions disproportionally affect young adults, and prevalence rates have risen 30% in the past five years (Santomauro et al., 2021). Moreover, there is considerable comorbidity across internalizing disorders and heterogeneity within disorders (Price et al., 2019; Spinhoven et al., 2014), highlighting the need to identify transdiagnostic biomarkers for effective screening and treatment. Deficits in emotion regulation (ER) is a hallmark risk factor for internalizing disorders (Aldao et al., 2010, 2016). Specifically, low flexibility in ER strategy use – the inability to use a large and varied repertoire of strategies flexibility according to contextual demands – has been linked to internalizing disorders transdiagnostically (Wen et al., 2021, 2024, 2025). However, the neurobiological mechanisms by which flexibility in ER influences internalizing disorders remain largely unclear. Elucidating such mechanisms is a critical step to advancing effective, targeted clinical interventions. In this K99/R00, three aims are proposed to examine the mechanism of ER flexibility in internalizing disorder etiology. In the K99 phase, a large-scale longitudinal dataset (PI: Craske) containing resting state fMRI data and self-reported ER from young adults with varying levels of internalizing disorder severity will be analyzed. Dynamic co-activation pattern analysis will be used to identify functional brain network dynamics (e.g., transitions between the salience, default mode, and central executive networks), and examine associations with ER flexibility as assessed by an innovative, validated index of ER flexibility developed by the Candidate (Wen et al., 2021, 2024; Aim 1). These functional brain network dynamics will then be evaluated in relation to broad symptom dimensions underlying internalizing disorders transdiagnostically (Aim 2). In the R00 phase, new data will be collected for individuals with clinical levels of internalizing symptom severity. Variables include internalizing symptoms, ER flexibility, functional network dynamics, stress, and cognitive control that is theorized to underlie ER (LeMoult & Gotlib, 2019). Path analyses will be conducted to compare two models with hypothesized neurobiological pathways by which ER flexibility influences broad internalizing symptom dimensions (Aim 3). This proposed K99 training will be conducted with Dr. Michelle Craske (primary mentor) and Dr. Lucina Uddin (co-mentor) at UCLA, with guidance from an advisory committee of experts in neuroimaging and psychopathology research. This environment will help the Candidate achieve the career development goal of acquiring of new skillsets in functional neuroimaging and knowledge in functional brain dynamics. The proposed training will provide the Candidate with intellectual and technical training needed to launch an independent research program at a top academic institution studying the neurobiological mechanisms by which emotional processes influence the etiology for internalizing disorders broadly.