Longitudinal task-negative network analyses in preclinical Huntington's disease

Functional neuroimaging studies have reported task-related brain activation changes in preclinical individuals carrying the Huntington's disease (HD) gene mutation (preHD). Little is known about "task-negative" activity, i.e., patterns of task-related deactivation in preHD, and about the stability of any deactivation changes over the course of the disease. Here, we explored task-related deactivation and functional connectivity of "task-negative" networks (TNNs) in preHD followed over a time period of 2 years. Thirteen far-from-onset preHD (mean time to estimated motor onset = 19.5 years) and thirteen healthy controls were investigated. We used functional magnetic resonance imaging (fMRI), a verbal working memory task, and uni- and multivariate analysis techniques for fMRI data. Behavior was similar in preHD and controls at baseline and did not change 2 years later. At both time points, deactivation was similar in preHD and controls. Within two spatio-temporally distinct TNNs, preHD had lower functional connectivity in the posterior cingulate cortex and higher functional connectivity in the left anterior prefrontal cortex compared to controls (p < 0.05, cluster-corrected). These findings remained stable at follow-up. Anterior prefrontal connectivity correlated with disease burden scores both at baseline and at follow-up. Over time, preHD exhibited higher connectivity in a dorsal cingulate region. Functional connectivity differences within this region were inversely associated with changes of motor function. These data provide first evidence for TNN connectivity changes in preHD followed over a period of 2 years. The relationship between dorsal cingulate connectivity and motor function suggests that "task-negative" activity may capture time-sensitive neural and functional processes in preHD