Aberrant brain network connectivity in pre-symptomatic and manifest Huntington's disease: a systematic review

Resting-state functional magnetic resonance imaging (rs-fMRI) has the potential to shed light on the pathophysiological mechanisms of Huntington's disease (HD), paving the way to new therapeutic interventions. A systematic review of the literature was conducted in three online databases according to PRISMA guidelines, using keywords for HD, functional connectivity, and rs-fMRI. We included studies investigating connectivity in pre-symptomatic (pre-HD) and manifest HD gene carriers compared to healthy controls, implementing seed-based connectivity, independent component analysis, regional property and graph analysis approaches. Visual network showed reduced connectivity in manifest HD, while network/areas underpinning motor functions were consistently altered in both manifest HD and pre-HD, showing disease stage-dependent changes. Cognitive networks underlying executive and attentional functions showed divergent anterior-posterior alterations, reflecting possible compensatory mechanisms. The involvement of these networks in pre-HD is still unclear. In conclusion, aberrant connectivity of the sensory-motor network is observed in the early stage of HD while, as pathology spreads, other networks might be affected, such as the visual and executive/attentional networks. Moreover, sensory-motor and executive networks exhibit hyper- and hypo-connectivity patterns following different spatiotemporal trajectories. These findings could help to implement future huntingtin-lowering interventions.