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Growing evidence has shown that brain activity at rest slowly wanders through a repertoire of different states, where whole-brain functional connectivity (FC) temporarily settles into distinct FC patterns. Nevertheless, the functional role of resting-state activity remains unclear. Here, we investigate how the switching behavior of resting-state FC relates with cognitive performance in healthy older adults. We analyse resting-state fMRI data from 98 healthy adults previously categorized as being among the best or among the worst performers in a cohort study of >1000 subjects aged 50+ who underwent neuropsychological assessment. We use a novel approach focusing on the dominant FC pattern captured by the leading eigenvector of dynamic FC matrices. Recurrent FC patterns – or states – are detected and characterized in terms of lifetime, probability of occurrence and switching profiles. We find that poorer cognitive performance is associated with weaker FC temporal similarity together with altered switching between FC states. These results provide new evidence linking the switching dynamics of FC during rest with cognitive performance in later life, reinforcing the functional role of resting-state activity for effective cognitive processing.

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Over the last decade, we have observed a revolution in brain structural and functional Connectomics. On one hand, we have an ever-more detailed characterization of the brain's white matter structural connectome. On the other, we have a repertoire of consistent functional networks that form and dissipate over time during rest. Despite the evident spatial similarities between structural and functional connectivity, understanding how different time-evolving functional networks spontaneously emerge from a single structural network requires analyzing the problem from the perspective of complex network dynamics and dynamical system's theory. In that direction, bottom-up computational models are useful tools to test theoretical scenarios and depict the mechanisms at the genesis of resting-state activity. Here, we provide an overview of the different mechanistic scenarios proposed over the last decade via computational models. Importantly, we highlight the need of incorporating additional model constraints considering the properties observed at finer temporal scales with MEG and the dynamical properties of FC in order to refresh the list of candidate scenarios.

Highlights d Causal whole-brain model integrating neurotransmitter data and brain dynamics d This explains the functional effects of serotonin 2A receptor stimulation with LSD d Non-linear effects of specific brainwide distribution of neurotransmitter density d Exciting possibilities for drug discovery and design in neuropsychiatric disorders

A fundamental problem in systems neuroscience is how to force a transition from one brain state to another by external driven stimulation in, for example, wakefulness, sleep, coma, or neuropsychiatric diseases. This requires a quantitative and robust definition of a brain state, which has so far proven elusive. Here, we provide such a definition, which, together with whole-brain modeling, permits the systematic study in silico of how simulated brain stimulation can force transitions between different brain states in humans. Specifically, we use a unique neuroimaging dataset of human sleep to systematically investigate where to stimulate the brain to force an awakening of the human sleeping brain and vice versa. We show where this is possible using a definition of a brain state as an ensemble of “metastable substates,” each with a probabilistic stability and occurrence frequency fitted by a generative whole-brain model, fine-tuned on the basis of the effective connectivity. Given the biophysical limitations of direct electrical stimulation (DES) of microcircuits, this opens exciting possibilities for discovering stimulation targets and selecting connectivity patterns that can ensure propagation of DES-induced neural excitation, potentially making it possible to create awakenings from complex cases of brain injury.

Since the mid 1990s, the intriguing dynamics of the brain at rest has been attracting a growing body of research in neuroscience. Neuroimaging studies have revealed distinct functional networks that slowly activate and deactivate, pointing to the existence of an underlying network dynamics emerging spontaneously during rest, with specific spatial, temporal and spectral characteristics. Several theoretical scenarios have been proposed and tested with the use of large-scale computational models of coupled brain areas. However, a mechanistic explanation that encompasses all the phenomena observed in the brain during rest is still to come. In this review, we provide an overview of the key findings of resting-state activity covering a range of neuroimaging modalities including fMRI, EEG and MEG. We describe how to best define and analyze anatomical and functional brain networks and how unbalancing these networks may lead to problems with mental health. Finally, we review existing large-scale models of resting-state dynamics in health and disease. An important common feature of resting-state models is that the emergence of resting-state functional networks is obtained when the model parameters are such that the system operates at the edge of a bifurcation. At this critical working point, the global network dynamics reveals correlation patterns that are spatially shaped by the underlying anatomical structure, leading to an optimal fit with the empirical BOLD functional connectivity. However, new insights coming from recent studies, including faster oscillatory dynamics and non-stationary functional connectivity, must be taken into account in future models to fully understand the network mechanisms leading to the resting-state activity.

Growing evidence from the dynamical analysis of functional neuroimaging data suggests that brain function can be understood as the exploration of a repertoire of metastable connectivity patterns ('functional brain networks'), which potentially underlie different mental processes.The present study characterizes how the brain's dynamical exploration of resting--state networks is rapidly modulated by intravenous infusion of psilocybin, a tryptamine psychedelic found in "magic mushrooms". We employed a data--driven approach to characterize recurrent functional connectivity patterns by focusing on the leading eigenvector of BOLD phase coherence at single--TR resolution. Recurrent BOLD phase--locking patterns (PL states) were assessed and statistically compared pre--and post--infusion of psilocybin in terms of their probability of occurrence and transition profiles. Results were validated using a placebo session.Recurrent BOLD PL states revealed high spatial overlap with canonical resting--state networks. Notably, a PL state forming a frontoparietal subsystem was strongly destabilized after psilocybin injection, with a concomitant increase in the probability of occurrence of another PL state characterized by global BOLD phase coherence. These findings provide Recently, a number of methodological approaches have been proposed to analyze BOLD connectivity dynamics at high temporal resolution (i.e., single volume / TR), focusing either on BOLD co--activation patterns (