No abstract

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.

Dynamic functional connectivity (dFC) in resting-state fMRI holds promise to deliver candidate biomarkers for clinical applications. However, the reliability and interpretability of dFC metrics remain contested. Despite a myriad of methodologies and resulting measures, few studies have combined metrics derived from different conceptualizations of brain functioning within the same analysis - perhaps missing an opportunity for improved interpretability. Using a complexity-science approach, we assessed the reliability and interrelationships of a battery of phase-based dFC metrics including tools originated from dynamical systems, stochastic processes, and information dynamics approaches. Our analysis revealed novel relationships between these metrics, which allowed us to build a predictive model for integrated information using metrics from dynamical systems and information theory. Furthermore, global metastability - a metric reflecting simultaneous tendencies for coupling and decoupling - was found to be the most representative and stable metric in brain parcellations that included cerebellar regions. Additionally, spatiotemporal patterns of phase-locking were found to change in a slow, non-random, continuous manner over time. Taken together, our findings show that the majority of characteristics of resting-state fMRI dynamics reflect an interrelated dynamical- and informational-complexity profile, which is unique to each acquisition. This finding challenges the interpretation of results from cross-sectional designs for brain neuromarker discovery, suggesting that individual life-trajectories may be more informative than sample means.

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 neuromechanistic biomarker of schizophrenia pathology, including a demonstration of reliability and face validity. Group-level discrimination, individual-level classification, and pathophysiological relevance were assessed using two independent case-control studies of schizophrenia, the Human Connectome Project Early Psychosis (HCPEP) study (controls n=82, non-affective psychosis n=53) and the Cobre study (controls n=71, cases n=59). In this work we introduce a new framework that uses Leading Eigenvector Dynamic Analysis (LEiDA) to capture specific features of dynamic functional connectivity and then implements a novel approach to estimate metastability. We used non-parametric testing to evaluate group-level differences and a naive 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. 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 neuromechanistic biomarker of schizophrenia pathology.

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.