• Spatiotemporal patterns of phase-locking tend to be time-invariant. • Global metastability is representative and stable in a cohort of heathy young adults. • dFC characteristics are in general unique to any fMRI acquisition. • Dynamical and informational complexity are interrelated. • Complexity science contributes to a coherent description of brain dynamics.

The disconnection hypothesis of schizophrenia proposes that symptoms of the disorder arise as a result of aberrant functional integration between segregated areas of the brain. The concept of metastability characterizes the coexistence of competing tendencies for functional integration and functional segregation in the brain, and is therefore well suited for the study of schizophrenia. In this study, we investigate metastability as a candidate neuromechanistic biomarker of schizophrenia pathology, including a demonstration of reliability and face validity. Group-level discrimination, individual-level classification, pathophysiological relevance, and explanatory power were assessed using two independent case-control studies of schizophrenia, the Human Connectome Project Early Psychosis (HCPEP) study (controls n = 53, non-affective psychosis n = 82) and the Cobre study (controls n = 71, cases n = 59). In this work we extend Leading Eigenvector Dynamic Analysis (LEiDA) to capture specific features of dynamic functional connectivity and then implement a novel approach to estimate metastability. We used non-parametric testing to evaluate group-level differences and a naïve Bayes classifier to discriminate cases from controls. Our results show that our new approach is capable of discriminating cases from controls with elevated effect sizes relative to published literature, reflected in an up to 76% area under the curve (AUC) in out-of-sample classification analyses. Additionally, our new metric showed explanatory power of between 81–92% for measures of integration and segregation. Furthermore, our analyses demonstrated that patients with early psychosis exhibit intermittent disconnectivity of subcortical regions with frontal cortex and cerebellar regions, introducing new insights about the mechanistic bases of these conditions. Overall, these findings demonstrate reliability and face validity of metastability as a candidate neuromechanistic biomarker of schizophrenia pathology.

Competing and complementary models of resting-state brain dynamics contribute to our phenomenological and mechanistic understanding of whole-brain coordination and communication, and provide potential evidence for differential brain functioning associated with normal and pathological behaviour. These neuroscientific theories stem from the perspectives of physics, engineering, mathematics and psychology and create a complicated landscape of domain-specific terminology and meaning, which, when used outside of that domain, may lead to incorrect assumptions and conclusions within the neuroscience community. Here, we review and clarify the key concepts of connectivity, computation, criticality and coherence—the 4C's—and outline a potential role for metastability as a common denominator across these propositions. We analyse and synthesize whole-brain neuroimaging research, examined through functional magnetic imaging, to demonstrate that complexity science offers a principled and integrated approach to describe, and potentially understand, macroscale spontaneous brain functioning.

Healthy brain functioning depends on balancing stable integration between brain areas for effective coordinated functioning, with bursts of desynchronisation to allow subsystems to reconfigure and express functional specialisation. Metastability, a concept originated in statistical physics and dynamical systems theory, has been proposed as a key signature that characterises this balance. Building on this principle, the neuroscience literature has employed markers of metastability to investigate various aspects of brain function including cognitive performance, healthy ageing, meditation, sleep, responses to pharmacological challenges, and to characterise psychiatric conditions or disorders of consciousness. However, this body of work often uses the notion of metastability heuristically, and sometimes inaccurately, making it hard for the uninitiated to navigate the vast literature, interpret findings, and foster further development of theoretical and experimental methodologies. In this paper we provide a comprehensive review of metastability and its applications in neuroscience, covering its scientific and historical foundations and the practical estimators used to estimate it in empirical data. We also provide a critical analysis of recent theoretical developments, clarifying common misconceptions and paving the road for future developments.

Dynamic Functional Connectivity (dFC) is the study of the dynamic patterns of interaction that characterise brain function. Numerous numerical methods are available to compute and analyse dFC from high-dimensional data. In fMRI, a number of them rely on the computation of the instantaneous Phase Alignment (iPA) matrix (also known as instantaneous Phase Locking). Their limitations are the high computational cost and the concomitant need to introduce approximations with ensuing information loss. Here, we introduce the analytical decomposition of the iPA. This has two advantages. Firstly, we achieve an up to 1000-fold reduction in computing time without information loss. Secondly, we can formally introduce two alternative approaches to the analysis of the resulting time-varying instantaneous connectivity patterns, Discrete and Continuous EiDA (Eigenvector Dynamic Analysis), and a related set of metrics to quantify the total amount of instantaneous connectivity, drawn from dynamical systems and information theory. We applied EiDA to a dataset from 48 rats that underwent functional magnetic resonance imaging (fMRI) at four stages during a longitudinal study of ageing. Using EiDA, we found that the metrics we introduce provided robust markers of ageing with decreases in total connectivity and metastability, and an increase in informational complexity over the life span. This suggests that ageing reduces the available functional repertoire that is postulated to support cognitive functions and overt behaviours, slows down the exploration of this reduced repertoire, and decreases the coherence of its structure. In summary, EiDA is a method to extract lossless connectivity information that requires significantly less computational time, and provides robust and analytically principled metrics for brain dynamics. These metrics are interpretable and promising for studies on neurodevelopmental and neurodegenerative disorders.