State-switching and high-order spatiotemporal organization of dynamic functional connectivity are disrupted by Alzheimer's disease.

Spontaneous activity during the resting state, tracked by BOLD fMRI imaging, or shortly rsfMRI, gives rise to brain-wide dynamic patterns of interregional correlations, whose structured flexibility relates to cognitive performance. Here, we analyze resting-state dynamic functional connectivity (dFC) in a cohort of older adults, including amnesic mild cognitive impairment (aMCI, = 34) and Alzheimer's disease (AD, = 13) patients, as well as normal control (NC, = 16) and cognitively "supernormal" controls (SNC, = 10) subjects. Using complementary state-based and state-free approaches, we find that resting-state fluctuations of different functional links are not independent but are constrained by high-order correlations between triplets or quadruplets of functionally connected regions. When contrasting patients with healthy subjects, we find that dFC between cingulate and other limbic regions is increasingly bursty and intermittent when ranking the four groups from SNC to NC, aMCI and AD. Furthermore, regions affected at early stages of AD pathology are less involved in higher order interactions in patient than in control groups, while pairwise interactions are not significantly reduced. Our analyses thus suggest that the spatiotemporal complexity of dFC organization is precociously degraded in AD and provides a richer window into the underlying neurobiology than time-averaged FC connections.