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      Recovery from disorders of consciousness: mechanisms, prognosis and emerging therapies

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          Abstract

          Substantial progress has been made over the past two decades in detecting, predicting and promoting recovery of consciousness in patients with disorders of consciousness (DoC) caused by severe brain injuries. Advanced neuroimaging and electrophysiological techniques have revealed new insights into the biological mechanisms underlying recovery of consciousness and have enabled the identification of preserved brain networks in patients who seem unresponsive, thus raising hope for more accurate diagnosis and prognosis. Emerging evidence suggests that covert consciousness, or cognitive motor dissociation (CMD), is present in up to 15–20% of patients with DoC and that detection of CMD in the intensive care unit can predict functional recovery at 1 year post injury. Although fundamental questions remain about which patients with DoC have the potential for recovery, novel pharmacological and electrophysiological therapies have shown the potential to reactivate injured neural networks and promote re-emergence of consciousness. In this Review, we focus on mechanisms of recovery from DoC in the acute and subacute-to-chronic stages, and we discuss recent progress in detecting and predicting recovery of consciousness. We also describe the developments in pharmacological and electrophysiological therapies that are creating new opportunities to improve the lives of patients with DoC.

          Abstract

          In this Review, the authors discuss recent progress in the detection and prediction of recovery of consciousness in patients with disorders of consciousness caused by severe brain injuries. They describe the ongoing development of pharmacological and electrophysiological therapies designed to enhance recovery.

          Key points

          • A common pathophysiological mechanism underlying disorders of consciousness (DoC) is the withdrawal of excitatory synaptic activity across the cerebrum produced by deafferentation or disfacilitation of neocortical, thalamic and striatal neurons.

          • Recovery from coma involves various mechanisms, culminating in the restoration of excitatory neurotransmission across long-range corticocortical, thalamocortical and thalamostriatal connections.

          • The re-emergence of consciousness is associated with a shift in patterns of neuronal activity across the corticothalamic system that can be measured with EEG, PET or resting-state functional MRI.

          • Task-based functional MRI and EEG can reveal cognitive motor dissociation in up to 15–20% of patients who seem unresponsive on behavioural examination, and emerging evidence suggests that early detection of cognitive motor dissociation in the intensive care unit predicts 1-year functional outcomes.

          • Amantadine is the only therapy that has been associated with the acceleration of recovery of consciousness in a randomized controlled trial of patients with subacute traumatic DoC, but multiple pharmacological and neuromodulatory therapies are now being tested.

          • Emerging advances in diagnostic and prognostic techniques provide new opportunities to detect consciousness, monitor its recovery, elucidate its neuronal substrate and identify the therapeutic potential of promoting re-emergence of consciousness in a subset of patients with DoC.

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          Most cited references300

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          Dissociable intrinsic connectivity networks for salience processing and executive control.

          Variations in neural circuitry, inherited or acquired, may underlie important individual differences in thought, feeling, and action patterns. Here, we used task-free connectivity analyses to isolate and characterize two distinct networks typically coactivated during functional MRI tasks. We identified a "salience network," anchored by dorsal anterior cingulate (dACC) and orbital frontoinsular cortices with robust connectivity to subcortical and limbic structures, and an "executive-control network" that links dorsolateral frontal and parietal neocortices. These intrinsic connectivity networks showed dissociable correlations with functions measured outside the scanner. Prescan anxiety ratings correlated with intrinsic functional connectivity of the dACC node of the salience network, but with no region in the executive-control network, whereas executive task performance correlated with lateral parietal nodes of the executive-control network, but with no region in the salience network. Our findings suggest that task-free analysis of intrinsic connectivity networks may help elucidate the neural architectures that support fundamental aspects of human behavior.
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            The human brain is intrinsically organized into dynamic, anticorrelated functional networks.

            During performance of attention-demanding cognitive tasks, certain regions of the brain routinely increase activity, whereas others routinely decrease activity. In this study, we investigate the extent to which this task-related dichotomy is represented intrinsically in the resting human brain through examination of spontaneous fluctuations in the functional MRI blood oxygen level-dependent signal. We identify two diametrically opposed, widely distributed brain networks on the basis of both spontaneous correlations within each network and anticorrelations between networks. One network consists of regions routinely exhibiting task-related activations and the other of regions routinely exhibiting task-related deactivations. This intrinsic organization, featuring the presence of anticorrelated networks in the absence of overt task performance, provides a critical context in which to understand brain function. We suggest that both task-driven neuronal responses and behavior are reflections of this dynamic, ongoing, functional organization of the brain.
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              Spontaneous fluctuations in brain activity observed with functional magnetic resonance imaging.

              The majority of functional neuroscience studies have focused on the brain's response to a task or stimulus. However, the brain is very active even in the absence of explicit input or output. In this Article we review recent studies examining spontaneous fluctuations in the blood oxygen level dependent (BOLD) signal of functional magnetic resonance imaging as a potentially important and revealing manifestation of spontaneous neuronal activity. Although several challenges remain, these studies have provided insight into the intrinsic functional architecture of the brain, variability in behaviour and potential physiological correlates of neurological and psychiatric disease.
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                Author and article information

                Contributors
                dgreer@bu.edu
                Journal
                Nat Rev Neurol
                Nat Rev Neurol
                Nature Reviews. Neurology
                Nature Publishing Group UK (London )
                1759-4758
                1759-4766
                14 December 2020
                : 1-22
                Affiliations
                [1 ]GRID grid.32224.35, ISNI 0000 0004 0386 9924, Center for Neurotechnology and Neurorecovery, Department of Neurology, , Massachusetts General Hospital, ; Boston, MA USA
                [2 ]GRID grid.32224.35, ISNI 0000 0004 0386 9924, Athinoula A. Martinos Center for Biomedical Imaging, , Massachusetts General Hospital, ; Charlestown, MA USA
                [3 ]Department of Neurology, Columbia University Medical Center, New York Presbyterian Hospital, New York, NY USA
                [4 ]GRID grid.5386.8, ISNI 000000041936877X, Feil Family Brain Mind Research Institute, Weill Cornell Medical College, ; New York, NY USA
                [5 ]GRID grid.189504.1, ISNI 0000 0004 1936 7558, Department of Neurology, , Boston University School of Medicine, ; Boston, MA USA
                Author information
                http://orcid.org/0000-0001-7235-8456
                http://orcid.org/0000-0002-2026-8333
                Article
                428
                10.1038/s41582-020-00428-x
                7734616
                33318675
                7787b03d-f71d-4395-b599-d439bc170a80
                © Springer Nature Limited 2020

                This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.

                History
                : 23 October 2020
                Categories
                Review Article

                disorders of consciousness,brain injuries
                disorders of consciousness, brain injuries

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