Multimodal Biomarkers of Consciousness in Acute Severe Traumatic Brain Injury

Abstract

Predicting outcome for patients with acute severe traumatic brain injury (TBI) is imprecise, relying on neurological examination, structural neuroimaging, and resting-state electroencephalography (EEG) to serve as proxies for brain function. We implemented a multimodal assessment protocol to determine whether detection of consciousness using advanced tools, including standardized behavioral evaluation, advanced EEG, and functional magnetic resonance imaging (fMRI), is associated with functional outcome in patients with acute severe TBI admitted to the intensive care unit (ICU). We tested the association between 6-month Disability Rating Scale (DRS) scores and acute level of consciousness on the Coma Recovery Scale-Revised (CRS-R); responses to active-motor-imagery and passive-language EEG and fMRI; and resting-state fMRI default mode network (DMN) connectivity. We consecutively enrolled 55 patients with acute severe TBI. Six-month outcome was available in 45 (45.2 ± 20.7 years old, 70% male), of whom 10 died, all due to withdrawal of life-sustaining treatment (WLST). All deaths occurred in participants who were not behaviorally following commands. Lower (i.e., better) 6-month DRS scores were observed in participants who were younger (ρ = 0.401; 95% confidence interval [CI: 0.078, 0.649]; p = 0.006]) and who were conscious (median DRS score difference [95% CI]: −11 [−20, −2]; p = 0.003) or following commands (−9 [−20, −1]; p = 0.011) on CRS-R assessment in the ICU. Evidence of command-following on EEG or fMRI did not strengthen this relationship. In participants without command-following on the CRS-R, we detected responses to active-motor-imagery (i.e., cognitive motor dissociation [CMD]) in 6/34 (18%) of participants on EEG and 8/24 (33%) participants on fMRI. We detected responses to passive-language stimuli (i.e., covert cortical processing [CCP]) in 30/33 (91%) of participants on EEG and 18/24 (75%) on fMRI. However, neither CMD nor CCP was associated with outcome on the DRS or several secondary outcome measures (e.g., dichotomous DRS, Glasgow Outcome Scale-Extended), an unexpected result that may reflect the modest sample size and high rate of WLST. In exploratory analyses, an intact DMN and the magnitude of DMN connectivity were associated with 6-month outcome on secondary outcome measures. Collectively, our results suggest that the level of consciousness in the ICU, assessed with a standardized behavioral measure, may predict recovery from severe TBI. Further research, conducted at multiple sites and with larger samples, is required to determine whether integrating behavioral, EEG, and fMRI biomarkers of consciousness is more predictive than behavioral assessment alone.