Re-awakening the brain: Forcing transitions in disorders of consciousness by external in silico perturbation.

A fundamental challenge in neuroscience is accurately defining brain states and predicting how and where to perturb the brain to force a transition. Here, we investigated resting-state fMRI data of patients suffering from disorders of consciousness (DoC) after coma (minimally conscious and unresponsive wakefulness states) and healthy controls. We applied model-free and model-based approaches to help elucidate the underlying brain mechanisms of patients with DoC. The model-free approach allowed us to characterize brain states in DoC and healthy controls as a probabilistic metastable substate (PMS) space. The PMS of each group was defined by a repertoire of unique patterns (i.e., metastable substates) with different probabilities of occurrence. In the model-based approach, we adjusted the PMS of each DoC group to a causal whole-brain model. This allowed us to explore optimal strategies for promoting transitions by applying off-line in silico probing. Furthermore, this approach enabled us to evaluate the impact of local perturbations in terms of their global effects and sensitivity to stimulation, which is a model-based biomarker providing a deeper understanding of the mechanisms underlying DoC. Our results show that transitions were obtained in a synchronous protocol, in which the somatomotor network, thalamus, precuneus and insula were the most sensitive areas to perturbation. This motivates further work to continue understanding brain function and treatments of disorders of consciousness.

Whole-brain analyses indicate the impairment of posterior integration and thalamo-frontotemporal broadcasting in disorders of consciousness.

The study of the brain's dynamical activity is opening a window to help the clinical assessment of patients with disorders of consciousness. For example, glucose uptake and the dysfunctional spread of naturalistic and synthetic stimuli has proven useful to characterize hampered consciousness. However, understanding of the mechanisms behind loss of consciousness following brain injury is still missing. Here, we study the propagation of endogenous and in-silico exogenous perturbations in patients with disorders of consciousness, based upon directed and causal interactions estimated from resting-state fMRI data, fitted to a linear model of activity propagation. We found that patients with disorders of consciousness suffer decreased capacity for neural propagation and responsiveness to events, and that this can be related to severe reduction of glucose metabolism as measured with [18 F]FDG-PET. In particular, we show that loss of consciousness is related to the malfunctioning of two neural circuits: the posterior cortical regions failing to convey information, in conjunction with reduced broadcasting of information from subcortical, temporal, parietal and frontal regions. These results shed light on the mechanisms behind disorders of consciousness, triangulating network function with basic measures of brain integrity and behavior.

What lies underneath: Precise classification of brain states using time-dependent topological structure of dynamics.

The self-organising global dynamics underlying brain states emerge from complex recursive nonlinear interactions between interconnected brain regions. Until now, most efforts of capturing the causal mechanistic generating principles have supposed underlying stationarity, being unable to describe the non-stationarity of brain dynamics, i.e. time-dependent changes. Here, we present a novel framework able to characterise brain states with high specificity, precisely by modelling the time-dependent dynamics. Through describing a topological structure associated to the brain state at each moment in time (its attractor or 'information structure'), we are able to classify different brain states by using the statistics across time of these structures hitherto hidden in the neuroimaging dynamics. Proving the strong potential of this framework, we were able to classify resting-state BOLD fMRI signals from two classes of post-comatose patients (minimally conscious state and unresponsive wakefulness syndrome) compared with healthy controls with very high precision.

Disruption in structural-functional network repertoire and time-resolved subcortical fronto-temporoparietal connectivity in disorders of consciousness.

Understanding recovery of consciousness and elucidating its underlying mechanism is believed to be crucial in the field of basic neuroscience and medicine. Ideas such as the global neuronal workspace (GNW) and the mesocircuit theory hypothesize that failure of recovery in conscious states coincide with loss of connectivity between subcortical and frontoparietal areas, a loss of the repertoire of functional networks states and metastable brain activation. We adopted a time-resolved functional connectivity framework to explore these ideas and assessed the repertoire of functional network states as a potential marker of consciousness and its potential ability to tell apart patients in the unresponsive wakefulness syndrome (UWS) and minimally conscious state (MCS). In addition, the prediction of these functional network states by underlying hidden spatial patterns in the anatomical network, that is so-called eigenmodes, was supplemented as potential markers. By analysing time-resolved functional connectivity from functional MRI data, we demonstrated a reduction of metastability and functional network repertoire in UWS compared to MCS patients. This was expressed in terms of diminished dwell times and loss of nonstationarity in the default mode network and subcortical fronto-temporoparietal network in UWS compared to MCS patients. We further demonstrated that these findings co-occurred with a loss of dynamic interplay between structural eigenmodes and emerging time-resolved functional connectivity in UWS. These results are, amongst others, in support of the GNW theory and the mesocircuit hypothesis, underpinning the role of time-resolved thalamo-cortical connections and metastability in the recovery of consciousness.

Case Report: Leishmaniasis in a 33-Year-Old Man with Multiple Sclerosis.

Leishmaniasis is a protozoan disease caused by species of genus Leishmania. Immunosuppression increases the risk of severe clinical forms and impairs response to treatment. The expansion of the use of immunomodulatory drugs for different conditions has raised the number of these cases. In this report, we present a case of visceral leishmaniasis in a patient with multiple sclerosis (MS) under fingolimod treatment. He presented with the triad of fever, visceromegaly, and pancytopenia and was diagnosed by the presence of amastigotes in a bone marrow sample. Furthermore, we discuss the previous published cases of MS patients under different immunosuppressant therapies to highlight its risk in endemic areas and suggest a therapeutic approach.

Unifying turbulent dynamics framework distinguishes different brain states.

Significant advances have been made by identifying the levels of synchrony of the underlying dynamics of a given brain state. This research has demonstrated that non-conscious dynamics tend to be more synchronous than in conscious states, which are more asynchronous. Here we go beyond this dichotomy to demonstrate that different brain states are underpinned by dissociable spatiotemporal dynamics. We investigated human neuroimaging data from different brain states (resting state, meditation, deep sleep and disorders of consciousness after coma). The model-free approach was based on Kuramoto's turbulence framework using coupled oscillators. This was extended by a measure of the information cascade across spatial scales. Complementarily, the model-based approach used exhaustive in silico perturbations of whole-brain models fitted to these measures. This allowed studying of the information encoding capabilities in given brain states. Overall, this framework demonstrates that elements from turbulence theory provide excellent tools for describing and differentiating between brain states.

Revealing the Relevant Spatiotemporal Scale Underlying Whole-Brain Dynamics.

The brain rapidly processes and adapts to new information by dynamically transitioning between whole-brain functional networks. In this whole-brain modeling study we investigate the relevance of spatiotemporal scale in whole-brain functional networks. This is achieved through estimating brain parcellations at different spatial scales (100-900 regions) and time series at different temporal scales (from milliseconds to seconds) generated by a whole-brain model fitted to fMRI data. We quantify the richness of the dynamic repertoire at each spatiotemporal scale by computing the entropy of transitions between whole-brain functional networks. The results show that the optimal relevant spatial scale is around 300 regions and a temporal scale of around 150 ms. Overall, this study provides much needed evidence for the relevant spatiotemporal scales and recommendations for analyses of brain dynamics.

Loss of consciousness reduces the stability of brain hubs and the heterogeneity of brain dynamics.

Low-level states of consciousness are characterized by disruptions of brain activity that sustain arousal and awareness. Yet, how structural, dynamical, local and network brain properties interplay in the different levels of consciousness is unknown. Here, we study fMRI brain dynamics from patients that suffered brain injuries leading to a disorder of consciousness and from healthy subjects undergoing propofol-induced sedation. We show that pathological and pharmacological low-level states of consciousness display less recurrent, less connected and more segregated synchronization patterns than conscious state. We use whole-brain models built upon healthy and injured structural connectivity to interpret these dynamical effects. We found that low-level states of consciousness were associated with reduced network interactions, together with more homogeneous and more structurally constrained local dynamics. Notably, these changes lead the structural hub regions to lose their stability during low-level states of consciousness, thus attenuating the differences between hubs and non-hubs brain dynamics.

Characterizing the Dynamical Complexity Underlying Meditation.

Over the past 2,500 years, contemplative traditions have explored the nature of the mind using meditation. More recently, neuroimaging research on meditation has revealed differences in brain function and structure in meditators. Nevertheless, the underlying neural mechanisms are still unclear. In order to understand how meditation shapes global activity through the brain, we investigated the spatiotemporal dynamics across the whole-brain functional network using the Intrinsic Ignition Framework. Recent neuroimaging studies have demonstrated that different states of consciousness differ in their underlying dynamical complexity, i.e., how the broadness of communication is elicited and distributed through the brain over time and space. In this work, controls and experienced meditators were scanned using functional magnetic resonance imaging (fMRI) during resting-state and meditation (focused attention on breathing). Our results evidenced that the dynamical complexity underlying meditation shows less complexity than during resting-state in the meditator group but not in the control group. Furthermore, we report that during resting-state, the brain activity of experienced meditators showed higher metastability (i.e., a wider dynamical regime over time) than the one observed in the control group. Overall, these results indicate that the meditation state operates in a different dynamical regime compared to the resting-state.