Machine learning reveals a multimodal, transdiagnostic signature of emotion dysregulation vulnerability across patients, offspring, and controls

Abstract Emotion dysregulation (ED) is a core transdiagnostic feature of several psychiatric disorders, including borderline personality disorder, bipolar disorder, and attention-deficit/hyperactivity disorder. These ED disorders (EDD) exhibit overlapping clinical presentations, shared heritability, and common neurobiological substrates. This study used a transdiagnostic framework to identify early and multimodal markers of vulnerability, particularly in high-risk populations such as the offspring of EDD patients (EDDoff). A total of 237 participants (97 EDD patients, 67 EDDoff, 73 healthy controls) completed a multimodal assessment including clinical evaluations, diffusion and functional MRI, and immune and neurotrophic serum biomarkers. Dimensionality reduction was performed using principal component analysis (PCA), and random forest (RF) models were trained for group classification and symptoms prediction. PCA on the full multimodal dataset yielded eight components, two of which significantly differed between groups, one reflecting high ED and altered hippocampal dynamic functional connectivity (dFC), for which EDDoff showed an intermediate phenotype, and another driven by systemic inflammation, increased in EDD patients only. Modality-specific PCA identified significant inter-modality correlations, including reduced white matter integrity with increasing immune dysregulation, and positive correlations between hippocampal dFC and both ED symptoms and inflammation ( p = < .01 for all correlations). A RF classifier accurately distinguished controls from EDD/EDDoff individuals (85.7% accuracy). Multimodal non-clinical features reliably predicted ED symptoms ( p < .01). This study identifies a specific, clinically relevant, transdiagnostic and multimodal signature of vulnerability to ED, spanning behavioral, neural, and immune systems. This multimodal profile may inform future early intervention strategies targeting at-risk populations, such as EDDoff, to reduce EDD emergence and progression.