Habenula Developmental Trajectories in the ABCD Study

PROJECT SUMMARY/ABSTRACT Converging evidence has linked the habenula (Hb), a small epithalamic structure that inhibits dopaminergic reward signaling, to a wide range of affective, motivational, and motor functions. Abnormalities in Hb circuitry are increasingly implicated in psychiatric and behavioral disorders. In vivo Hb research has proceeded slowly, however, due to technical constraints in magnetic resonance imaging (MRI) that make it difficult to define and characterize this small region. Understanding of the Hb is especially limited in adolescence, a critical period marked by rapid maturation of the reward system and, often, the first emergence of psychiatric disorders. To address these gaps in basic and clinical neuroscience, our proposal leverages the unprecedented scale and quality of high-resolution neuroimaging data available through the Adolescent Brain Cognitive Development (ABCD) study to investigate the development of Hb function in early adolescence and its role in psychiatric illness onset. The proposed research builds on extensive work by our group to develop and refine Hb imaging methodology, including automated segmentation and a region of interest optimization approach that significantly improves Hb fMRI sensitivity, and is supported by substantial data from our laboratory. In independent samples of adult and adolescent healthy controls (HCs), we found a highly consistent pattern of positive Hb intrinsic functional connectivity (iFC) with the dopaminergic ventral tegmental area (VTA), downstream nucleus accumbens (NAc), and cortical salience network (SN), as well as negative Hb iFC throughout the default mode network (DMN). Adults with high vs. low subclinical depression scores exhibited distinct iFC patterns with regions associated with anxiety and depression, including the amygdala and insula. Moreover, adolescents with mood and anxiety disorders had positive Hb iFC with the DMN, and this abnormal Hb-DMN iFC pattern was associated with anxiety severity across both healthy and clinical adolescents, while hyperconnectivity with SN and other expected Hb targets correlated with anhedonia. Building on our compelling findings to date, we propose to study Hb function at Baseline and Year 2 ABCD neuroimaging timepoints in relation to normative (Aim 1) and clinical (Aim 2) developmental trajectories. Subjects will comprise two cohorts of ~3000 adolescents each: clinical subjects, with significant past or current mood and anxiety symptoms, and HCs, with no history of psychiatric diagnoses or clinically significant symptoms. Study procedures will incorporate sophisticated preprocessing and denoising, optimized subject-level Hb definition, neuroanatomically accurate cortical surface mapping, and rigorous non-parametric statistics. Analyses will encompass both resting-state and task fMRI to characterize Hb iFC and activation during specific reward, loss, and inhibitory control processes. We will examine both group differences and associations with psychiatric symptom severity using hypothesis-driven as well as machine learning approaches.