Resilience Beyond Diagnosis: Prospective Neural Correlates of Better-Than-Expected Outcomes in Depression

BackgroundResilience, the ability to adapt positively in the face of adversity, is shaped by the interplay of risk and protective factors. Previous magnetic resonance imaging (MRI) studies on resilience have predominantly focused on single factors, often operationalizing resilience dichotomously as the absence of psychiatric disorders despite adversity. MethodsIn this prospective MRI study, we defined resilience as "better-than-expected" depressive symptom severity (Hamilton Depression Rating Scale) relative to cumulative risk. Using ridge-regularized regression in N=1,804 participants (955 healthy, 849 depressed) from the Marburg-Munster Affective Disorders Cohort Study, we predicted symptom severity and derived residuals as measures of resilience. Residuals were then used to predict gray matter volume (GMV) and cortical thickness at baseline (T1) and two-year follow-up (T2; N=808), using voxel- and surface-based analyses. This approach was complemented by extreme-group comparisons of resilient (better-than-expected outcome) and vulnerable (worse-than-expected outcome) individuals. ResultsCumulative risk explained 51.4% of variance in depressive symptoms at T1 and 44.2% at T2. Residual scores showed moderate stability over time (r=0.31, p<0.001). Region-of-interest and whole-brain analyses revealed no morphometric associations with resilience at T1. In contrast, higher resilience at T1 predicted lower GMV in the left inferior orbitofrontal gyrus (IOFG) and temporal pole at T2 (ROI, pFWE(peak)=0.002, partial r=0.18), with no changes in cortical thickness. ConclusionResilience to cumulative risk, defined as better-than-expected depressive symptom severity, was not associated with immediate brain structural differences. However, prospective analyses revealed smaller GMV in the IOFG and temporal pole over time, potentially reflecting greater neural efficiency or delayed biological costs.