Temporal Dynamics of Depression in Premanifest Huntington's Disease: A Network Dysconnection Approach

Depression emerges years before motor signs in Huntington's disease gene expansion carriers (HDGECs), yet the neural mechanisms underlying this temporal relationship remain unclear. A growing body of evidence links depression in HDGECs to striatal and default mode network (DMN) regions, however, the longitudinal evolution of network dysfunction and its relationship to depressive symptoms has not been characterized. The study included 105 HDGECs (53 Females, Mage = 43, Mean CAG repeat length = 43) from the largest longitudinal study of premanifest HD, TrackOn-HD. Here, we applied spectral dynamic causal modelling to examine effective connectivity changes over 24 months, alongside voxel-based morphometry of grey matter atrophy and linear mixed models of depressive symptoms, including volumetry. We show that depression-related network dysconnection operates independently of regional grey matter atrophy, with HDGECs exhibiting widespread striatal volume loss but no differential atrophy patterns between depression groups. Critically, we demonstrate that larger posterior cingulate cortex volumes predicted increased depression severity specifically in HDGECs with depression history, across both Beck Depression Inventory-II (p = .041) and Hospital Anxiety and Depression Scale-Depression Subscale (p = .002). Spectral dynamic causal models explained 88.6% of variance in depression groups and 90.4% in non-depression groups, demonstrating robust model performance. Longitudinal effective connectivity analyses revealed distinct dysconnection profiles: HDGECs with depression history showed widespread interhemispheric alterations including progressive inhibitory changes of striatal-DMN circuits and aberrant hippocampal regulatory control, while those without depression exhibited more focal dysconnection. These patterns occurred despite no group differences in grey matter atrophy trajectories across striatal or cortical regions over the 24-month period. Furthermore, we identify that clinically elevated depressive symptoms associate with differential connectivity patterns of the PCC and hippocampus depending on depression history, suggesting pathological mechanisms become progressively maladaptive. Our findings challenge that structural preservation confers functional resilience in neurodegeneration, instead suggesting pathological mechanisms and revealing that functional network reorganization in relatively preserved regions drives depression vulnerability in premanifest HD.