Early detection of consciousness in patients with acute severe traumatic brain injury

Abstract

See Schiff (doi:10.1093/awx209) for a scientific commentary on this article. Patients with acute severe traumatic brain injury may recover consciousness before self-expression. Without behavioural evidence of consciousness at the bedside, clinicians may render an inaccurate prognosis, increasing the likelihood of withholding life-sustaining therapies or denying rehabilitative services. Task-based functional magnetic resonance imaging and electroencephalography techniques have revealed covert consciousness in the chronic setting, but these techniques have not been tested in the intensive care unit. We prospectively enrolled 16 patients admitted to the intensive care unit for acute severe traumatic brain injury to test two hypotheses: (i) in patients who lack behavioural evidence of language expression and comprehension, functional magnetic resonance imaging and electroencephalography detect command-following during a motor imagery task (i.e. cognitive motor dissociation) and association cortex responses during language and music stimuli (i.e. higher-order cortex motor dissociation); and (ii) early responses to these paradigms are associated with better 6-month outcomes on the Glasgow Outcome Scale-Extended. Patients underwent functional magnetic resonance imaging on post-injury Day 9.2 ± 5.0 and electroencephalography on Day 9.8 ± 4.6. At the time of imaging, behavioural evaluation with the Coma Recovery Scale-Revised indicated coma (n = 2), vegetative state (n = 3), minimally conscious state without language (n = 3), minimally conscious state with language (n = 4) or post-traumatic confusional state (n = 4). Cognitive motor dissociation was identified in four patients, including three whose behavioural diagnosis suggested a vegetative state. Higher-order cortex motor dissociation was identified in two additional patients. Complete absence of responses to language, music and motor imagery was only observed in coma patients. In patients with behavioural evidence of language function, responses to language and music were more frequently observed than responses to motor imagery (62.5-80% versus 33.3-42.9%). Similarly, in 16 matched healthy subjects, responses to language and music were more frequently observed than responses to motor imagery (87.5-100% versus 68.8-75.0%). Except for one patient who died in the intensive care unit, all patients with cognitive motor dissociation and higher-order cortex motor dissociation recovered beyond a confusional state by 6 months. However, 6-month outcomes were not associated with early functional magnetic resonance imaging and electroencephalography responses for the entire cohort. These observations suggest that functional magnetic resonance imaging and electroencephalography can detect command-following and higher-order cortical function in patients with acute severe traumatic brain injury. Early detection of covert consciousness and cortical responses in the intensive care unit could alter time-sensitive decisions about withholding life-sustaining therapies.

Keywords: EEG; consciousness; functional MRI; intensive care unit; traumatic brain injury.

© The Author (2017). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Figures

Figure 1

Regions of interest for functional MRI analysis. (A) Anterior view of the supplementary motor area (SMA) and premotor cortex (PMC) region of interest (blue) used to assess motor imagery fMRI responses, as well as the Heschl’s gyrus (HG, yellow) and superior temporal gyrus (STG, red) regions of interest used to assess language and music functional MRI responses. All regions of interest are rendered in MNI152 space and superimposed upon a coronal image at the level of the mid-thalamus and an axial image at the level of the STG. (B) Sagittal (left), coronal (middle), and axial (right) images of the supplementary motor areas/premotor cortices, Heschl’s gyrus, and superior temporal gyrus regions of interest.

Figure 2

Schematic of the three dimensions of detecting consciousness. Patients were assessed for motor function and overt cognitive function via bedside behavioural evaluation with the CRS-R and CAP. Covert cognition that evades detection by behavioural evaluation was assessed with functional MRI (fMRI) and EEG. Levels of consciousness indicated by overt cognition are defined as coma, vegetative state (VS), minimally conscious state without language function (MCS−), minimally conscious state with language function (MCS+), post-traumatic confusional state (PTCS), complete locked-in syndrome (CLIS), locked-in syndrome with preservation of minimal motor function (LIS), and full recovery. Cognitive motor dissociation (CMD) is defined by functional MRI or EEG responses demonstrating command-following on an active motor imagery task despite absence of behavioural evidence of language function. Higher-order cortex motor dissociation (HMD) is defined as functional MRI and EEG responses within association cortex (e.g. Wernicke’s area) during passive language or music stimuli despite absence of behavioural evidence of language. Using the behavioural diagnosis as the reference standard, patients without behavioural evidence of language (coma, vegetative state, and MCS−) are classified as true negatives (TN) if there are no functional MRI or EEG responses. Patients with behavioural evidence of language [MCS+, PTCS, CLIS (with assistive communication devices), LIS, and full recovery] are classified as false negatives (FN) if there are no functional MRI or EEG responses, and true positives (TP) if there are functional MRI and EEG responses.

Figure 3

Stimulus-based functional MRI responses and EEG topographic plots. Functional MRI (fMRI) and EEG results are shown for the language, music and motor imagery paradigms for representative subjects: a healthy subject (C2), a patient with behavioural and functional MRI/EEG evidence of language function (Patient P9), a patient with no behavioural evidence of language but functional MRI evidence of command-following (CMD; Patient P6), a patient with no behavioural evidence of language but functional MRI/EEG evidence of cortical activation to passive stimuli (HMD; Patient P2), and a patient without behavioural or functional MRI/EEG evidence of language (Patient P3). Functional MRI data are shown as Z-statistic images to demonstrate stimulus-specific responses. Z-statistic images are thresholded at cluster-corrected Z scores of 3.1 (inset colour bar) and superimposed on T1-weighted axial images. All EEG data are shown as topographic plots illustrating the averaged weights attributed to each electrode by the classifier, based on their ability to differentiate between the two conditions for each paradigm (e.g. language versus rest). Red colours show coefficient values > 0. Blue colours show values < 0 (inset colour bar). The larger the absolute value of a feature weight (either positive or negative), the more important it was for discriminating between stimulus and rest conditions. Functional MRI data are in radiological convention; EEG data are in anatomical convention.

Figure 4

EEG classifier results in HMD. For a patient who met the prespecified criteria for HMD (P2), we show spectral power changes during the language paradigm for the eight electrodes with the largest weights (i.e. the electrodes that best discriminated between language and rest; see inset colour bar). A decrement in delta power was observed at each electrode [units = 10log(µV2/Hz)], with a more pronounced change in the left hemisphere in the temporal region known to be involved in language processing (electrode T3). For electrode F7, the decrement in delta power was 11.7 microvolts. d = delta; t = theta; a = alpha; b = beta. The overall P-value in this analysis was P = 0.01.

Figure 5

Functional MRI evidence of command-following in CMD. Functional MRI data are shown as Z-statistic images to demonstrate stimulus-specific responses in a patient whose behavioural evaluation suggested a vegetative state (Patient P14). Z-statistic images are thresholded at cluster-corrected Z scores of 3.1 (inset colour bar) and superimposed on T1-weighted axial images. There is functional MRI evidence of command-following on the motor imagery task (arrow), indicating CMD. In the bottom panel, a 3D rendering of the functional MRI response to the motor imagery task is shown (arrow). This response is located within the prespecified supplementary motor area/premotor cortex region of interest. Specifically, the response is located within the premotor cortex (PMC) in close neuroanatomic proximity to a right frontal contusion. The images in the top row are shown in radiological convention. Notably, despite functional MRI activation within the superior temporal gyrus during the language stimulus (top left), the patient was classified as having an absent response to language because of the absence of a response within Heschl’s gyrus. Ins = insula; LV = lateral ventricle.

Figure 6

Percentage of functional MRI and EEG responders in patients and healthy subjects. Results for patients without behavioural evidence of language function (Language−; i.e. CRS-R/CAP-based behavioural diagnosis indicates coma, vegetative state, or MCS−) are represented as red bars. Results for patients with behavioural evidence of language function (Language+; i.e. CRS-R/CAP-based behavioural diagnosis indicates MCS+ or post-traumatic confusional state) are represented as blue bars. Results for healthy subjects (Control) are represented as purple bars.