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Severe acute brain damage, most often caused by trauma, anoxia or stroke, can result in coma—a transient state characterized by complete absence of wakefulness and of signs of awareness. The recovery of wakefulness without signs of awareness heralds a transition to vegetative state/unresponsive wakefulness syndrome (VS/UWS). Patients in a minimally conscious state (MCS) show reproducible purposeful behaviours but remain unable to communicate. MCS can be divided into MCS+ and MCS depending on the presence or absence of inconsistent language functions. Emergence of MCS (EMCS) is diagnosed when patients regain functional communication. Finally, patients with locked-in syndrome can be misdiagnosed with these disorders of consciousness because of complete paralysis of voluntary muscles, except for eye-coded communication (Gosseries et al., 2014). Prevalence rates of VS/ UWS and MCS are difficult to evaluate because of a lack of systematic surveillance. In the USA, prevalence estimates range from 25 000 to 420 000 for VS/ UWS and from 112 000 to 280 000 for MCS (Hirschberg and Giacino, 2011). In this issue of Brain, Curley and coworkers address the difficult problem of detecting covert awareness in noncommunicative patients with severe brain damage (Curley et al., 2018). The detection of covert awareness in patients with disorders of consciousness after coma has important consequences for diagnosis, prognosis and therapy, including pain management, rehabilitation and end-of-life decisions. However, high rates of misdiagnosis (up to 40%) have repeatedly been reported between VS/ UWS and MCS. At least five repeated behavioural assessments with a validated standardized scale, the Coma Recovery Scale-Revised (CRS-R), are required to make an accurate clinical diagnosis (Wannez et al., 2017). Yet even after exhaustive behavioural assessments are performed, signs of covert awareness can be detected in 20% of patients in a behavioural VS/UWS with functional MRI and EEG command-following paradigms (e.g. Monti et al., 2010; Cruse et al., 2011) or with transcranial magnetic stimulation combined with high-density EEG (TMS-EEG) (Casarotto et al., 2016). These findings have recently led to the definition of a new clinical entity, referred to as MCS*, functional locked-in syndrome or cognitive motor dissociation syndrome (CMD), where patients are behaviourally unresponsive but show evidence of covert awareness with neuroimaging. While the pathophysiology of CMD remains unclear, the majority of patients diagnosed so far had sustained a traumatic brain injury. The recognition of a high prevalence of CMD after severe brain damage creates an urgent need to improve routine diagnosis of covert awareness and to find means to re-establish communication with these behaviourally unresponsive but conscious individuals. Despite constituting a significant advance, functional MRI command-following paradigms are challenging to use in routine clinical practice because of their lack of portability. Curley et al. describe a new approach to detect covert awareness in patients with severe brain damage at the bedside, using repetitive testing with EEG command-following paradigms. The New York team led by Nicholas Schiff used a variety of tasks, aiming to assess within-subject reliability of responses while taking into account between-subject variability in brain physiology after brain damage. They also performed a systematic comparison between EEG, behavioural data and functional MRI command-following paradigms. The new study included 28 patients with severe acquired brain damage and 15 controls. Among these 28 patients, 17 met behavioural criteria for MCS (one of whom also had an assessment while behaviourally in VS/UWS), eight for EMCS (two of whom also had an assessment while behaviourally in MCS) and three for VS/UWS. The authors performed assessments using a 37-electrode EEG system in most subjects (two patients were recorded with 23 and 29 electrodes). Mental imagery tasks consisted of imagining playing tennis, spatial navigation, swimming, and/or finger tapping. Data analysis quantified changes in EEG power during 10–14 s silent periods following task instructions compared to 10–14 s silent periods following instructions to rest. Criteria for a positive response to command required two outcomes: first, results had to show significance in at least one run and a trend towards significance in at least one other run for a difference between task and rest in a given channel for at least two contiguous frequency bins, after a two-group resampling test. Second, results also had to be significant after correction for multiple comparisons across channels using the false discovery rate for a two-group test applied to concatenated data from all runs of a given task. These conservative criteria led to an estimation of false positives of 8% in shuffled data from the ‘tennis’ paradigm. Evidence of EEG command-following was found in 21/28 patients studied (2/3 VS/UWS, 11/17 MCS and all eight EMCS)—and all 15 controls. Evidence of functional MRI response to command was found in 9/23 patients (five EEG command-follower patients could not undergo MRI). This is in contrast with previous studies (Monti et al., 2010; Cruse et al., Scientific Commentaries BRAIN 2018: 141; 1236–1246 | 1239

Functional ‘unlocking’: bedside detection of covert awareness after severe brain damage