Depression reduces structurally informed network flexibility in premanifest Huntington's disease

Objective : The extent to which structural connectivity constrains effective connectivity in both depression and neurodegenerative contexts remains poorly understood. In particular, the relationship between structural connectivity aberrations and effective dysconnectivity associated with depression in Huntingtons disease remains uncharacterized. Here, we applied a novel procedure that implements structural connectivity-informed spectral dynamic causal modelling to examine how structural connectivity shapes directed inter-regional influences in premanifest Huntingtons disease gene expansion carriers (HDGECs) with and without depression history. Method : Using spectral dynamic causal modeling embedded in a hierarchical empirical Bayes framework, we analyzed fMRI data from 98 premanifest HDGECs across default mode network and striatum (caudate and putamen). HDGECs were split into two groups based on either having a history of depression or not, and depression severity on both the Beck Depression Inventory, 2nd Edition (BDI-II) and Hospital Anxiety and Depression Scale, Depression Subscale (HADS-D) was used to measure clinically elevated depression symptoms. Leave-one-out cross-validation was implemented to test predictive validity. Results : Model evidence substantially favored structurally informed over uninformed approaches across all participants. For HDGECs, having a history of depression was associated with reduced baseline variability in effective connectivity (decreased α parameter), with particularly tight regularization of near-zero-valued structural connections toward zero effective connectivity values while leaving strongly connected pathways relatively unaffected. Effects converged on striatal self-connectivity and hippocampal-striatal pathways, with distinct patterns emerging between depression history groups. Notably, clinically elevated depression revealed differential connectivity signatures, with right caudate self-connectivity showing positive correlations with clinical cut-offs for HDGECs with and without depression history. In leave-one-out cross-validation, specific connections including DMN-to-striatum (BDI: r = -0.31, p = .002; HADS-D: r = -0.33, p = .001), right hippocampus-to-left caudate (BDI: r = -0.46, p < .001; HADS-D: r = -0.30, p = .002), and left caudate-to-left putamen (BDI: r = -0.48, p < .001; HADS-D: r = -0.30, p = .003) significantly predicted individual differences in depression severity scores. Conclusion : Together, these findings link reduced network flexibility to depression vulnerability in premanifest neurodegeneration, providing a mechanistic bridge between anatomical constraints, effective connectivity alterations, and clinical depression phenotypes.