I aim to identify a data-driven taxonomy of depression and anxiety from multiple neurobiological measures of brain function, physiology and behavior that is not constrained by existing diagnostic boundaries. Anxiety Disorders and Major Depressive Disorder are highly prevalent and together cost over $100 billion per year in care and lost productivity. While the symptoms used in the diagnosis of these disorders convey useful information and reflect real phenomenology, the way in which symptoms are grouped makes for fuzzy diagnostic boundaries, with substantial symptom overlap across disorders, yet vast symptom heterogeneity within. Moreover, experiments aiming to identify the neural contribution to dysfunction have been intrinsically tied to these traditional diagnostic categories As a consequence, we do not have a clear understanding of how the neural circuitry underlying depression and anxiety relates to the expressed symptoms at the level of physiology and behavior, independent from these traditional diagnoses. These blurry diagnostic lines hamper our progress toward understanding the mechanisms of dysfunction and developing novel, targeted therapeutics. Therefore, it would be beneficial to establish a complementary characterization of anxiety and depression that reflects cohesive clusters of distinct neural causes. Addressing these issues I propose to use a data driven approach to develop an alternate classification for depression and anxiety.
Under Aim 1 I will use computational methods on a rich existing dataset of over 600 participants, to derive dimensional constructs of emotion processing from neuroimaging probes of emotion reactivity and regulation and determine how these constructs are associated with other levels of function spanning behavior, physiology and self-report.
Under Aim 2 I will use sparse clustering algorithms to classify individual subjects according to the neuroimaging constructs and then determine how each classification is expressed across behavioral, physiological and self-report symptom measures, independent of traditional diagnosis. To address Aim 3 I will use experimental stress probes to parse state versus trait-like components of the relationships between neuroimaging and each other unit of measurement. The outcome will be a novel classification that will advance our progress toward both understanding the mechanisms of neural dysfunction in depression and anxiety as well as developing novel therapeutics for targeting such dysfunction. Critically, the proposed multi-modal approach utilizes unsupervised machine learning algorithms to identify the underlying patterns within this complex system in a manner that is free from the assumptions of the current diagnostic paradigms. The resulting characterization from this approach will provide a dimensional space to understand the natural variation in neural circuit function and how this variation relates to each person's functional phenotype. Such a characterization will be a significant step forward in transforming the way that depression and anxiety are understood, removing stigma, and allowing novel treatments to be developed from mechanistic models that can be more effectively translated to the clinic.
Anxiety Disorders and Major Depressive Disorder, which are among the most frequently occurring psychiatric conditions and are associated with serious personal and societal cost, are still defined by a set of descriptive symptoms that are ignorant to the underlying neurobiology. This proposal uses advanced computational methods to identify an alternative, yet complementary, model of depression and anxiety directly linked to brain function, physiology and behavior. The resulting characterization would provide a novel, biologically based dimensional space to understand an individual's symptom profile, transform the way the way that depression and anxiety are understood and allow novel treatments to be developed from mechanistic models that can be more effectively translated to the clinic.
