A concerted effort to tackle the global health problem posed by traumatic brain injury (TBI) is long overdue. TBI is a public health challenge of vast, but insufficiently recognised, proportions. Worldwide, more than 50 million people have a TBI each year, and it is estimated that about half the world's population will have one or more TBIs over their lifetime. TBI is the leading cause of mortality in young adults and a major cause of death and disability across all ages in all countries, with a disproportionate burden of disability and death occurring in low-income and middle-income countries (LMICs). It has been estimated that TBI costs the global economy approximately $US400 billion annually. Deficiencies in prevention, care, and research urgently need to be addressed to reduce the huge burden and societal costs of TBI. This Commission highlights priorities and provides expert recommendations for all stakeholders—policy makers, funders, health-care professionals, researchers, and patient representatives—on clinical and research strategies to reduce this growing public health problem and improve the lives of people with TBI.Additional co-authors: Endre Czeiter, Marek Czosnyka, Ramon Diaz-Arrastia, Jens P Dreier, Ann-Christine Duhaime, Ari Ercole, Thomas A van Essen, Valery L Feigin, Guoyi Gao, Joseph Giacino, Laura E Gonzalez-Lara, Russell L Gruen, Deepak Gupta, Jed A Hartings, Sean Hill, Ji-yao Jiang, Naomi Ketharanathan, Erwin J O Kompanje, Linda Lanyon, Steven Laureys, Fiona Lecky, Harvey Levin, Hester F Lingsma, Marc Maegele, Marek Majdan, Geoffrey Manley, Jill Marsteller, Luciana Mascia, Charles McFadyen, Stefania Mondello, Virginia Newcombe, Aarno Palotie, Paul M Parizel, Wilco Peul, James Piercy, Suzanne Polinder, Louis Puybasset, Todd E Rasmussen, Rolf Rossaint, Peter Smielewski, Jeannette Söderberg, Simon J Stanworth, Murray B Stein, Nicole von Steinbüchel, William Stewart, Ewout W Steyerberg, Nino Stocchetti, Anneliese Synnot, Braden Te Ao, Olli Tenovuo, Alice Theadom, Dick Tibboel, Walter Videtta, Kevin K W Wang, W Huw Williams, Kristine Yaffe for the InTBIR Participants and Investigator

The 'default network' is defined as a set of areas, encompassing posterior-cingulate/precuneus, anterior cingulate/mesiofrontal cortex and temporo-parietal junctions, that show more activity at rest than during attention-demanding tasks. Recent studies have shown that it is possible to reliably identify this network in the absence of any task, by resting state functional magnetic resonance imaging connectivity analyses in healthy volunteers. However, the functional significance of these spontaneous brain activity fluctuations remains unclear. The aim of this study was to test if the integrity of this resting-state connectivity pattern in the default network would differ in different pathological alterations of consciousness. Fourteen non-communicative brain-damaged patients and 14 healthy controls participated in the study. Connectivity was investigated using probabilistic independent component analysis, and an automated template-matching component selection approach. Connectivity in all default network areas was found to be negatively correlated with the degree of clinical consciousness impairment, ranging from healthy controls and locked-in syndrome to minimally conscious, vegetative then coma patients. Furthermore, precuneus connectivity was found to be significantly stronger in minimally conscious patients as compared with unconscious patients. Locked-in syndrome patient's default network connectivity was not significantly different from controls. Our results show that default network connectivity is decreased in severely brain-damaged patients, in proportion to their degree of consciousness impairment. Future prospective studies in a larger patient population are needed in order to evaluate the prognostic value of the presented methodology.

Our results shed light on the functional significance of spontaneous brain activity fluctuations observed in functional magnetic resonance imaging. They suggest that propofol-induced unconsciousness could be linked to a breakdown of cerebral temporal architecture that modifies both within- and between-network connectivity and thus prevents communication between low-level sensory and higher-order frontoparietal cortices, thought to be necessary for perception of external stimuli. They emphasize the importance of thalamocortical connectivity in higher-order cognitive brain networks in the genesis of conscious perception.

Abstract■ Evidence from functional neuroimaging studies on resting state suggests that there are two distinct anticorrelated cortical systems that mediate conscious awareness: an "extrinsic" system that encompasses lateral fronto-parietal areas and has been linked with processes of external input (external awareness), and an "intrinsic" system which encompasses mainly medial brain areas and has been associated with internal processes (internal awareness). The aim of our study was to explore the neural correlates of resting state by providing behavioral and neuroimaging data from healthy volunteers. With no a priori assumptions, we first determined behaviorally the relationship between external and internal awareness in 31 subjects. We found a significant anticorrelation between external and internal awareness with a mean switching frequency of 0.05 Hz (range: 0.01-0.1 Hz). Interestingly, this frequency is similar to BOLD fMRI slow oscillations. We then evaluated 22 healthy volunteers in an fMRI paradigm looking for brain areas where BOLD activity correlated with "internal" and "external" scores. Activation of precuneus/posterior cingulate, anterior cingulate/mesiofrontal cortices, and parahippocampal areas ("intrinsic system") was linearly linked to intensity of internal awareness, whereas activation of lateral fronto-parietal cortices ("extrinsic system") was linearly associated with intensity of external awareness. ■

Emerging neural theories of consciousness suggest a correlation between a specific type of neural dynamical complexity and the level of consciousness: When awake and aware, causal interactions between brain regions are both integrated (all regions are to a certain extent connected) and differentiated (there is inhomogeneity and variety in the interactions). In support of this, recent work by Casali et al (2013) has shown that Lempel-Ziv complexity correlates strongly with conscious level, when computed on the EEG response to transcranial magnetic stimulation. Here we investigated complexity of spontaneous high-density EEG data during propofol-induced general anaesthesia. We consider three distinct measures: (i) Lempel-Ziv complexity, which is derived from how compressible the data are; (ii) amplitude coalition entropy, which measures the variability in the constitution of the set of active channels; and (iii) the novel synchrony coalition entropy (SCE), which measures the variability in the constitution of the set of synchronous channels. After some simulations on Kuramoto oscillator models which demonstrate that these measures capture distinct ‘flavours’ of complexity, we show that there is a robustly measurable decrease in the complexity of spontaneous EEG during general anaesthesia.

Propofol anesthesia is a sleep-like state and slow waves are associated with diminished consciousness even in the presence of high gamma activity.

The mechanisms underlying anesthesia-induced loss of consciousness remain a matter of debate. Recent electrophysiological reports suggest that while initial propofol infusion provokes an increase in fast rhythms (from beta to gamma range), slow activity (from delta to alpha range) rises selectively during loss of consciousness. Dynamic causal modeling was used to investigate the neural mechanisms mediating these changes in spectral power in humans. We analyzed source-reconstructed data from frontal and parietal cortices during normal wakefulness, propofol-induced mild sedation, and loss of consciousness. Bayesian model selection revealed that the best model for explaining spectral changes across the three states involved changes in corticothalamic interactions. Compared with wakefulness, mild sedation was accounted for by an increase in thalamic excitability, which did not further increase during loss of consciousness. In contrast, loss of consciousness per se was accompanied by a decrease in backward corticocortical connectivity from frontal to parietal cortices, while thalamocortical connectivity remained unchanged. These results emphasize the importance of recurrent corticocortical communication in the maintenance of consciousness and suggest a direct effect of propofol on cortical dynamics.

In November 2017, the Lancet Neurology Commission on Traumatic Brain Injury (TBI) highlighted existing deficiencies in epidemiology, patient characterization, identifying best practice, outcome assessment, and evidence generation. The Commission concluded that C needed to address deficiencies in prevention , and made a recommendation for large collaborative studies which could provide the framework for precision medicine and comparative effectiveness research (CER).