Neuroimaging of Heterogeneity in Neuropsychiatric Disorders: Toward Disease Progression Modeling

Neuropsychiatric disorders are characterized by substantial biological heterogeneity, with patients sharing the same diagnosis often exhibiting distinct symptom profiles, treatment responses, and longitudinal course of the disease. This heterogeneity limits the clinical utility of traditional symptom-based classifications, currently available biomarkers, and traditional group-level neuroimaging analyses, creating a major challenge for precision medicine. In this review, we provide a conceptual overview of recent paradigms for analyzing disease heterogeneity and integrate them into a coherent, comprehensive conceptual framework for the ultimate goal of disease progression modeling. We identify 3 gradual shifts of research paradigms in neuroimaging-based studies: 1) moving from group-level case-control analyses to normative modeling of individual variability; 2) transitioning from traditional subtype-oriented clustering to continuous dimensional generative modeling; and 3) shifting from disease course analyses to virtual transition modeling according to digital twin brain models. These paradigm shifts are not isolated but can be integrated into a layered and interrelated logical framework, aiming to quantify individual deviations, characterize heterogeneous pathological dimensions, and simulate disease progression trajectories over time. We further discuss how these paradigms can facilitate the development of biologically informed biomarkers, the formulation of personalized treatment plans, and the implementation of trajectory-based intervention measures. Finally, we critically examine the key challenges that must be addressed before clinical translation, including mechanistic interpretability, longitudinal validation, multimodal and multisite data integration, model reproducibility, and prospective cohort validation. Our goal is to promote the development of novel approaches for disease progression modeling, thereby accelerating the translation of experimental research into clinical practice.