Cortical and Striatal Functional Connectivity in Juvenile-Onset Huntington's Disease

Huntington's disease (HD) is a neurodegenerative disorder caused by a CAG repeat expansion in the HTT gene, with a rare juvenile-onset form (JoHD) marked by early, rigid motor symptoms. This study examined cortical and subcortical resting-state connectivity in JoHD, hypothesizing preserved cortical networks but altered striatal connectivity, in line with early subcortical atrophy despite relatively spared cortical volume.

Participants included children and young adults with clinician-confirmed Juvenile-Onset Huntington's Disease (JoHD; n = 19) and gene-non-expanded (GNE) controls (n = 64), both drawn from longitudinal studies at the University of Iowa. Resting-state functional MRI scans were analyzed to assess canonical cortical network and striatal connectivity, and linear mixed-effects models tested group differences and associations with motor, cognitive, and clinical outcomes.

JoHD participants showed reduced connectivity within the left somatomotor network and striatal circuits, despite largely typical cortical network connectivity. Striatal connectivity was associated with disease burden and cognitive ability, while left somatomotor connectivity was unrelated to clinical outcomes.

These findings support the hypothesis of antagonistic pleiotropy in JoHD, where early neural advantages-such as relatively preserved or possibly enhanced cortical function-may contribute to later striatal vulnerability and degeneration. The observed left-lateralized somatomotor hypoconnectivity aligns with prior volumetric and gene expression research, highlighting the role of excitotoxic glutamatergic input and the selective vulnerability of high-functioning circuits in disease progression.