Depression in Premanifest Huntington's Disease: Aberrant Effective Connectivity of Striatum and Default Mode Network

Depression frequently precedes motor symptoms in Huntington's disease gene expansion carriers (HDGECs), yet the neural mechanisms remain poorly characterized.

We investigated effective connectivity between the default mode network (DMN) and striatal regions in HDGECs.

We analyzed 3-T resting-state functional magnetic resonance imaging data from 98 HDGECs (48.98% females; mean age, 42.82 years). Spectral dynamic causal modeling estimated subject-level connectivity, whereas parametric empirical Bayes determined group-level effective connectivity differences between participants with a diagnosed depression history and those without, across current, remitted, and never-depressed states. Brain-behavior associations with clinical depression measures were examined.

Model estimation was excellent (89.82% variance-explained). HDGECs with depression history showed decreased inhibitory posterior cingulate cortex-to-hippocampal connectivity, increased hippocampus-to-posterior cingulate cortex inhibition, and increased inhibitory influence of striatum on DMN. HDGECs with a depression history showed increased inhibitory striatal influence on DMN, including left putamen, a propensity for right hippocampal involvement, and disinhibitory posterior cingulate-hippocampal connectivity. Current versus never-depressed comparisons showed more pronounced dysconnectivity, with stronger striatum-to-network connections. Current versus remitted depression exhibited distinct patterns with increased medial prefrontal cortex-to-posterior cingulate cortex connectivity, increased medial prefrontal cortex self-connectivity, and decreased posterior cingulate cortex-to-medial prefrontal cortex connectivity.

These findings establish distinct striatal-network interaction patterns in depression for HDGECs that differ from non-neurological depression. Our findings suggested the posterior DMN-posterior cingulate and hippocampus-as drivers of depression for HDGECs and potential involvement of right DMN in keeping with compensatory patterns broadly in HD. These connectivity patterns could serve as functional biomarkers for depression in HDGECs. © 2025 International Parkinson and Movement Disorder Society.