Connectome-based growth models reveal individual heterogeneity and neurophysiological subtypes of subthreshold depression

Motivation: Subthreshold depression (StD) poses a high risk for major depressive disorder and exhibits substantial clinical heterogeneity. However, the neurobiological substrates underlying this heterogeneity remain largely unknown. Goal(s): Quantitatively assess the heterogeneity in individual functional connectome abnormalities in StD, and based on this, identify distinct neurophysiological subtypes. Approach: We constructed normative models of the functional connectome to identify individual deviations and determine subtypes in StD. Results: StD participants showed remarkable heterogeneity in individual deviations, leading to the identification of two subtypes. These subtypes exhibit differences in brain deviation patterns, depressive symptoms, gene expression profiles, and treatment responses. Impact: The findings provide valuable insights into the understanding of heterogeneous clinical forms of StD and offer promising implications for future precise diagnosis and treatment of this condition.