Mechanisms Underlying Disorders of Consciousness: Bridging Gaps to Move Toward an Integrated Translational Science

Abstract

Aim In order to successfully detect, classify, prognosticate, and develop targeted therapies for patients with disorders of consciousness (DOC), it is crucial to improve our mechanistic understanding of how severe brain injuries result in these disorders. Methods To address this need, the Curing Coma Campaign convened a Mechanisms Sub-Group of the Coma Science Work Group (CSWG), aiming to identify the most pressing knowledge gaps and the most promising approaches to bridge them. Results We identified a key conceptual gap in the need to differentiate the neural mechanisms of consciousness per se, from those underpinning connectedness to the environment and behavioral responsiveness. Further, we characterised three fundamental gaps in DOC research: (1) a lack of mechanistic integration between structural brain damage and abnormal brain function in DOC; (2) a lack of translational bridges between micro- and macro-scale neural phenomena; and (3) an incomplete exploration of possible synergies between data-driven and theory-driven approaches. Conclusion In this white paper, we discuss research priorities that would enable us to begin to close these knowledge gaps. We propose that a fundamental step towards this goal will be to combine translational, multi-scale, and multimodal data, with new biomarkers, theory-driven approaches, and computational models, to produce an integrated account of neural mechanisms in DOC. Importantly, we envision that reciprocal interaction between domains will establish a “virtuous cycle,” leading towards a critical vantage point of integrated knowledge that will enable the advancement of the scientific understanding of DOC and consequently, an improvement of clinical practice.

Network Analysis of Time Series: Novel Approaches to Network Neuroscience

“…Network analysis of time series may prove useful in clinical practice, where considerable focus is on assessing differences between states such as health, anaesthesia (Varley et al, 2020(Varley et al, , 2021b, sleep (Zhu et al, 2014a;Schartner et al, 2017;Chaudhuri et al, 2019), disorders of consciousness (Comolatti et al, 2019;Luppi et al, 2021), or neurobiological illnesses (Subramaniyam and Hyttinen, 2013;Subramaniyam et al, 2015;Ngamga et al, 2016;Gao et al, 2017). More subtle comparisons may also be possible, such as local or global differences between rest and task states (Shine et al, 2018(Shine et al, , 2019a.…”

Coma Science: The Territory and the Map

“…3 Departments of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. 4 Departments of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD,…”

“…CSWG modules were given a set of objectives and a time line, and were instructed to implement a gap analysis approach; in its simplified form, the latter requires the description of a desired state and a current state, and the elaboration of a strategic pathway bridging current to desired. White *Correspondence: rstevens@jhmi.edu 1 Division of Neurosciences Critical Care, Johns Hopkins University School of Medicine, 600 N. Wolfe St, Phipps 455, Baltimore, MD 21287, USA Full list of author information is available at the end of the article papers summarizing the findings of each module appear in this issue of the journal [3][4][5][6].…”

“…The mechanisms module [4] identified key gaps in theoretical and empirical work on mechanisms of consciousness and DOC and proposes a highly integrative analytical approach that considers brain structure and function, is capable of resolving neural phenomena at the microscale and macroscale, and combines data-driven and theory-driven approaches to advance mechanistic knowledge. Luppi et al [4] suggest a testable paradigm in which states of consciousness can be mapped onto a continuum of overlapping dimensions that includes consciousness, environmental connectedness, and responsiveness. They argue that a comprehensive mechanistic account of human brain function is a high-dimensional problem that will require a principled, computational approach to resolve [9].…”

The Curing Coma Campaign and the Future of Coma Research

“…The history of consciousness and theories of how the human brain comes into consciousness have been discussed by scientists, philosophers, and theologians for millennia. [6] During the age of early Greek medicine (and wrestling), compression of the karotides (carotid arteries) was observed to cause karotis (drowsiness). The more severe form of karotis was koma (coma).…”