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, N = 34) and Alzheimer's disease (AD, N = 13) patients, as well as normal control (NC, N = 16) and cognitively "supernormal" controls (SNC, N = 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. Brain functions emerge from the coordinated dynamics of many brain regions. Dynamic functional connectivity (dFC) analyses are a key tool to describe such dynamic complexity and have been shown to be good predictors of cognitive performance. This is particularly true in the case of Alzheimer's disease (AD) in which an impoverished dFC could indicate compromised functional reserve due to the detrimental effects of neurodegeneration. Here we observe that in healthy aging, dFC is indeed spatiotemporally organized, as reflected by high-order correlations between multiple regions. However, in people with aMCI or AD, dFC becomes less "entangled," more random-like, and intermittently bursty. We speculate that this degraded spatiotemporal coordination may reflect dysfunctional information processing, thus ultimately leading to worsening of cognitive deficits.