Assistant Professor of Neuroscience and Neurology, Feil Family Brain and Mind Research Institute and Department
of Neurology, Weill Cornell Medical College; and Visiting Assistant Professor of Clinical Investigation, The Rockefeller University, New York

Dr. Forgacs reports no financial relationships relevant to this field of study.

SYNOPSIS: In a large, prospective, single-center study, more than one in six patients with acute brain injuries may have cognitive-motor dissociation (CMD) (e.g., they harbor capacity to modulate their brain activity in response to motor commands while remaining behaviorally unresponsive at the bedside). Some acute CMD patients were found to have a much higher chance for recovery of neurological functions and for reaching independent levels of activities of daily living by 12 months after brain injury.

SOURCE: Claassen J, Doyle K, Matory A, et al. Detection of brain activation in unresponsive patients with acute brain injury. N Engl J Med 2019;380:2497-2505.

Cognitive-motor dissociation (CMD), the uncoupling of behavioral ability to follow commands from evidence of brain activation in response to motor commands as detected by electroencephalography (EEG) or functional neuroimaging (e.g., “covert” command following), primarily has been described in patients with chronic brain injuries (months to years after a brain injury). In standard clinical practice, bedside responsiveness (e.g., motor activity following the verbal commands “open your eyes,” “squeeze my hand,” or “wiggle your toes”) often is used as a proxy for detection of preserved consciousness. During the early ICU course following severe brain injury, a lack of responsiveness often is considered indicative of the severity of the brain injury (especially if sedative effects are ruled out) and weighed heavily in goals of care decisions (e.g., withdrawal of life-sustaining therapies [WLST]). However, the prevalence of CMD (covert responsiveness) in the setting of acute severe brain injuries as well as the importance of CMD in the prognosis of neurological and functional recovery is unknown.

Claassen et al prospectively assessed all consecutive patients admitted to the neurological ICU of the Columbia University Medical Center in New York. All patients with severe acute brain injuries of any etiology who were diagnosed to be in coma, vegetative state, or minimally conscious state-minus (presence of visual fixation, visual pursuit or localization to pain but no motor response to commands) based on the Coma Recovery Scale – Revised (CRS-R) while undergoing continuous EEG monitoring were considered. Recordings of alternating commands of “keep opening your right (or left) hand” and “stop opening …” were played to patients via headphones multiple times during their admission until they remained clinically unresponsive. Each EEG recording for each patient was trained individually using a machine learning approach (support vector machine) to differentiate between power spectral density across four frequency bands (δ, θ, α, β) during the periods following the alternating commands and used to assess command-related brain activation. Clinical outcomes included recovery of bedside command responsiveness, followed by the time of hospital discharge and a scored structured telephone interview (Glasgow Outcome Scale–Extended [GOS-E]) at 12 months after injury.

A total of 104 patients were enrolled in the study. Sixteen patients (15%) were found to have evidence of brain activation in response to a motor command while remaining unresponsive behaviorally (consistent with CMD) during at least one of their assessments, with a median of four days after ICU admission. Fifty percent of CMD patients (8/16) recovered bedside command by the time of hospital discharge, with a median time of six days following first detection of CMD by EEG, compared to 26% of patients who did not have evidence of CMD. In addition, 44% of CMD patients (7/16) vs. 14% (12/84) of non-CMD patients scored above 4 on the GOS-E scale (indicative of the ability of function independently for at least eight hours daily) at 12 months after the brain injury. Of note, of the six CMD patients who died, four died after a WLST decision and two after progression to brain death, with all six cases following additional systemic and neurological complications after detection of CMD.

COMMENTARY

The results of this paper are alarming and suggest that a significant portion of patients who appear unresponsive at the bedside in the ICU may have measurable levels of preservation of cognitive functions for several days preceding the recovery of bedside responsiveness. Although the extent of this preservation is uncertain and there is no direct evidence based on this study if the detected signals are related to true language comprehension or recognition of the commands, the association between the detection of these signals and the clinical outcome is highly intriguing and warrants further clinical consideration. Patients with evidence of acute CMD likely have greater functional integrity of various brain areas similarly to patients with chronic CMD.

However, given the importance and clinical relevance of this study, some methodological limitations need to be emphasized. Furthermore, independent replication of the results is paramount before this approach can be generalized and considered in clinical practice. For example, the responses even within patients were highly inconsistent (e.g., of the four patients who had more than three assessments, only 1/8, 2/8, 1/5, and 2/5 EEG recording sessions showed positive results [S2 table of paper]). This could be the result of fluctuations in levels of consciousness commonly seen in ICU patients or variation in the level of sedation, but suggests that false-negative results cannot rule out the possibility of some preservation of cognitive functions. Additionally, while the authors, very appropriately, employed false discovery rate (FDR) correction, with the FDR level set at 5%, it is possible that up to five patients (from 104) were categorized falsely as positive for command following. It is important to emphasize that the risk of both false-negative or false-positive findings needs to be interpreted with precise understanding of the methodological details, especially if such considerations are factored into WLST discussions.

Nonetheless, this study represents a critical milestone and will generate several lines of study for patients admitted to ICUs after acute severe brain injuries. Such studies will further refine our understanding of the neural substrates of acute CMD and provide the possibility of early therapeutic interventions. Once these methods are validated and generalized, detection of preserved higher cognitive function as early as possible after acute severe brain injury may aid prognostic decisions that weigh on caregivers and families. Patients identified with such methods should receive continued aggressive care to ensure the best chances for their recovery. Looking forward, the ease of repeated measurements with methods using EEG signals with individualized machine learning approaches may lead to the development of automated or semi-automated methods in the future that could longitudinally trace recovery of cognition independently of recovery of motor functions.