REVIEWS Recovery from disorders of consciousness: mechanisms, prognosis and emerging therapies Brian L. Edlow 1,2, Jan Claassen3, Nicholas D. Schiff4 and David M. Greer 5 ✉ 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 electro- physiological therapies that are creating new opportunities to improve the lives of patients with DoC. Disorders of consciousness (DoC) are characterized In this Review, we discuss mechanisms of recovery by alterations in arousal and/or awareness, and com- from DoC and prognostication of outcome, as well as 1Center for Neurotechnology mon causes of DoC include cardiac arrest, traumatic emerging treatments for patients along the entire tempo- and Neurorecovery, brain injury (TBI), intracerebral haemorrhage and ral continuum of DoC. We consider these advances within Department of Neurology, Massachusetts General ischaemic stroke. The past several decades have wit- the context of a clinical framework for classifying the Hospital, Boston, MA, USA. nessed major advances in our understanding of DoC, behavioural features of DoC that has evolved over 2Athinoula A. Martinos Center giving new hope for meaningful recovery in some the past 50 years. In this framework, coma is defined 3 for Biomedical Imaging, patients. This new understanding has come via eluci- as the complete absence of arousal and awareness , the Massachusetts General dation of the mechanisms underlying these disorders, vegetative state (later renamed ‘unresponsive wake- Hospital, Charlestown, increased accuracy of prognostication and the use of fulness syndrome’ (VS/UWS))4 is defined as arousal MA, USA. new therapeutic approaches. DoC exist on a tempo- without awareness5,6 and the minimally conscious state 3 Department of Neurology, ral continuum1, and the principles and confounders (MCS) is defined as minimal, reproducible but incon- Columbia University Medical 7 Center, New York of evaluation, prognostication and treatment change sistent awareness . Recently, MCS was sub-stratified Presbyterian Hospital, over time. The acute stage of DoC encompasses the into MCS without language (MCS–) and MCS with New York, NY, USA. time spent at the place where the injury occurred, in language (MCS+)8, a behavioural distinction that might 4Feil Family Brain Mind the emergency department and in the intensive care have prognostic relevance9,10. The behavioural features Research Institute, Weill unit (ICU), whereas the subacute and chronic stages of language expression and comprehension that distin- Cornell Medical College, New York, NY, USA. extend to time spent in inpatient rehabilitation hospi- guish MCS+ from MCS– include command-following, tals, chronic nursing facilities and, for some patients, intelligible verbalization and intentional communica- 5Department of Neurology, Boston University School of the home. The boundaries that delineate each stage of tion, the presence of any one of which is sufficient to 9 Medicine, Boston, MA, USA. recovery are inherently arbitrary. Recent guidelines indicate MCS+ . The ‘upper bound’ of DoC continues ✉e-mail: [email protected] operationally define the acute period of DoC as the to be debated, but in this Review we consider patients 2 https://doi.org/10.1038/ first 28 days after injury , with the subacute-to-chronic who have emerged from MCS into a confusional state as s41582-020-00428-x period following thereafter. still experiencing a disorder of consciousness, because a NATURE REVIEWS | NEUROLOGY VOLUME 17 | MARCH 2021 | 135 REVIEWS Key points opportunities, as we are increasingly able to detect con- sciousness, monitor its progress, identify its neuronal • A common pathophysiological mechanism underlying disorders of consciousness substrate and develop therapies to improve recovery. (DoC) is the withdrawal of excitatory synaptic activity across the cerebrum produced Hence, we focus on diagnostic tools that identify patients by deafferentation or disfacilitation of neocortical, thalamic and striatal neurons. with a potential for recovery and personalized therapies • Recovery from coma involves various mechanisms, culminating in the restoration of that could promote this recovery. Finally, we highlight excitatory neurotransmission across long-range corticocortical, thalamocortical and gaps in knowledge in the field of DoC and consider how thalamostriatal connections. rapid advances in diagnostic, prognostic and therapeutic • The re-emergence of consciousness is associated with a shift in patterns of neuronal modalities could fill these gaps to, ultimately, improve activity across the corticothalamic system that can be measured with EEG, PET or resting-state functional MRI. the lives of patients with DoC. • Task-based functional MRI and EEG can reveal cognitive motor dissociation in up Pathogenesis of DoC to 15–20% of patients who seem unresponsive on behavioural examination, and emerging evidence suggests that early detection of cognitive motor dissociation in Cellular and circuit-based mechanisms. Coma is the intensive care unit predicts 1-year functional outcomes. caused by several kinds of brain injury that can occur • Amantadine is the only therapy that has been associated with the acceleration of either alone or in combination. These insults are dif- 15 recovery of consciousness in a randomized controlled trial of patients with subacute fuse bihemispheric lesions , bilateral lesions within the traumatic DoC, but multiple pharmacological and neuromodulatory therapies are rostral paramedian brainstem16,17, bilateral diencepha- now being tested. lon lesions with unilateral brainstem involvement18, or • Emerging advances in diagnostic and prognostic techniques provide new opportunities metabolic or toxic encephalopathies that produce wide- to detect consciousness, monitor its recovery, elucidate its neuronal substrate and spread dysfunction of the corticothalamic system and its identify the therapeutic potential of promoting re-emergence of consciousness connections with the basal ganglia and limbic system15. in a subset of patients with DoC. Regardless of aetiology, the common pathophysiologi- cal mechanism underlying coma is broad withdrawal of excitatory synaptic activity across the cerebral cortex19,20. confusional state is characterized by persistent dysfunc- This downregulation of neuronal firing rates is produced tion across multiple cognitive domains, behavioural by either direct structural loss of inputs or reduced input dysregulation, symptom fluctuation, disorientation and, to neocortical and thalamic neurons, resulting in a pro- hence, altered consciousness. cess known as ‘disfacilitation’19,21–23. Disfacilitation occurs A recent addition to the diagnostic classification as excitatory neurotransmission is withdrawn and the scheme of patients with DoC is the concept of cogni- neuronal membrane potential passively hyperpolarizes tive motor dissociation (CMD)11, also known as cov- owing to a dominance of potassium leakage currents. ert consciousness. CMD is characterized by volitional Under broad disfacilitation, as might occur in coma brain activity detected by task-based functional MRI caused by diffuse injury or in the healthy brain under (fMRI) or EEG in a patient whose bedside behavioural general anaesthesia, a very slow rhythm (<1 Hz) can diagnosis suggests coma, VS/UWS or MCS–. Although arise across the corticothalamic system19,24. many questions remain about the incidence, clinical characteristics, prognostic expectations and therapeu- Restoration of cerebral network activity. Both cellular tic responsiveness of patients with CMD, emerging evi- and circuit mechanisms underlie recovery from coma, dence indicates that these patients represent a distinct as excitatory neurotransmission is restored across subgroup of patients with DoC, whose brain networks corticocortical, thalamocortical and thalamostriatal and clinical features might fundamentally differ from connections24–26. Thus, reversible coma can be the result those of other subgroups (Fig. 1). Therefore, we devote of multiple mechanisms that globally alter neuronal substantial space in this Review to the discussion of function or disable specific circuits15. For structural patients who are diagnosed with CMD in the acute and brain injuries, one proposed mechanism of recovery — subacute-to-chronic stages of recovery.