Task-Based fMRI Reveals a Diagnosis-Dependent Amygdala Lateralization in Major Depressive Disorder, Borderline Personality Disorder, and Comorbidities.

This study examined whether major depressive disorder (MDD) and borderline personality disorder (BPD) comorbidity (MDD-BPD) represents an additive pathophysiology or a distinct neurobiological entity using amygdala-focused neuroimaging. Participants (n = 217) underwent fMRI during an emotional face-matching task. An independent clinical sample (n = 1,032) was applied to identify comorbidity bridging factors. Mediation analysis examined whether each comorbidity factor independently mediated the association between amygdala functional lateralization and comorbid diagnostic status. BPD-only patients showed right-lateralized amygdala hyperreactivity, which was absent in the MDD-only group, and the MDD-BPD group exhibited bilateral amygdala activation. The combined BPD group (BPD-only and MDD-BPD) showed bilateral amygdala hyperreactivity versus controls, whereas combined MDD groups (MDD-only and MDD-BPD) exhibited left-lateralized hyperreactivity. Two comorbidity bridging factors (emotional instability and negative self-concept) were identified, and each independently mediated the relationship between amygdala lateralization and comorbidity. Cumulatively, MDD-BPD comorbidity represents a neurobiologically distinct diagnosis-dependent syndrome characterized by disorder-specific amygdala activation patterns and transdiagnostic psychological vulnerability.