Functional networks reemerge during recovery of consciousness after acute severe traumatic brain injury

Abstract

Integrity of the default mode network (DMN) is believed to be essential for human consciousness. However, the effects of acute severe traumatic brain injury (TBI) on DMN functional connectivity are poorly understood. Furthermore, the temporal dynamics of DMN reemergence during recovery of consciousness have not been studied longitudinally in patients with acute severe TBI. We performed resting-state functional magnetic resonance imaging (rs-fMRI) to measure DMN connectivity in 17 patients admitted to the intensive care unit (ICU) with acute severe TBI and in 16 healthy control subjects. Eight patients returned for follow-up rs-fMRI and behavioral assessment six months post-injury. At each time point, we analyzed DMN connectivity by measuring intra-network correlations (i.e. positive correlations between DMN nodes) and inter-network anticorrelations (i.e. negative correlations between the DMN and other resting-state networks). All patients were comatose upon arrival to the ICU and had a disorder of consciousness (DoC) at the time of acute rs-fMRI (9.2 ± 4.6 days post-injury): 2 coma, 4 unresponsive wakefulness syndrome, 7 minimally conscious state, and 4 post-traumatic confusional state. We found that, while DMN anticorrelations were absent in patients with acute DoC, patients who recovered from coma to a minimally conscious or confusional state while in the ICU showed partially preserved DMN correlations. Patients who remained in coma or unresponsive wakefulness syndrome in the ICU showed no DMN correlations. All eight patients assessed longitudinally recovered beyond the confusional state by 6 months post-injury and showed normal DMN correlations and anticorrelations, indistinguishable from those of healthy subjects. Collectively, these findings suggest that recovery of consciousness after acute severe TBI is associated with partial preservation of DMN correlations in the ICU, followed by long-term normalization of DMN correlations and anticorrelations. Both intra-network DMN correlations and inter-network DMN anticorrelations may be necessary for full recovery of consciousness after acute severe TBI.

Keywords: Coma; Consciousness; Default mode network; Resting-state functional MRI; Traumatic brain injury.

Conflict of interest statement

Conflict of Interest: There is no conflict of interest for any of the authors.

Copyright © 2018 Elsevier Ltd. All rights reserved.

Figures

Fig. 1. Default mode network functional connectivity

Fisher's z-transformed correlation maps of resting-state functional connectivity using four default mode network (DMN) seeds (thresholded height-level P<0.001; cluster-level false discovery rate-corrected P<0.05) in healthy controls, patients who fully recovered consciousness at 6-month follow-up, patients who acutely recovered to MCS/PTCS, and patients with coma or UWS.

Fig. 2. Differences in default mode network functional connectivity between groups

Comparisons of resting-state functional connectivity among groups of interest (thresholded height-level P<0.001; cluster-level false discovery rate-corrected P<0.05). Clockwise from upper left: regions with stronger default mode network (DMN) connectivity in healthy subjects than in patients with acute traumatic disorders of consciousness (DoC); regions with stronger connectivity in patients who fully recovered consciousness at 6 months than in the same patients acutely after TBI; connectivity in healthy subjects compared with patients who fully recovered consciousness by 6-month follow-up; and regions with stronger connectivity in patients with acute MCS/PTCS than in patients with acute coma/UWS. Comparisons used the general linear model with motion as a regressor, accounting for paired measures in the longitudinal comparison of recovered versus acute patients.

Fig. 3. Quantitative connectivity within significant clusters

Mean connectivity z-scores were extracted from the largest clusters generated within each between-group comparison to assess the directionality of observed differences. Compared to healthy subjects, patients demonstrate diminished correlation in DMN nodes (right posterior cingulate cortex [R PCC] shown), as well as pathologic correlation in regions typically anticorrelated with the DMN (left dorsolateral prefrontal cortex [L DLPFC] and left parietal cortex). Unconscious patients have reduced correlation in the right medial prefrontal cortex (R MPFC) and R PCC compared to conscious patients. Among patients followed longitudinally, correlations strengthen in the left PCC (L PCC), and pathological correlations in the L DLPFC appropriately become anticorrelated.

Fig. 4. Global default mode network correlation and anticorrelation

A) Mean global default mode network (DMN) correlation and DMN anticorrelation Fisher's transformed z-scores, by group. Boxes show interquartile range; whiskers extend to minimum and maximum values. Comparisons between coma/UWS, MCS/PTCS, and healthy subjects were conducted with analysis of variance followed by Tukey's test. * = P<0.002; ** = P<0.001. B) Mean global DMN correlation and DMN anticorrelation z-scores in eight patients followed longitudinally. Comparison was conducted with a paired t-test. Open circles represent unconscious patients (coma/UWS), while closed circles represent conscious patients (MCS/PTCS). * = P<0.01.