Disruption of posteromedial large-scale neural communication predicts recovery from coma

Abstract

Objective: We hypothesize that the major consciousness deficit observed in coma is due to the breakdown of long-range neuronal communication supported by precuneus and posterior cingulate cortex (PCC), and that prognosis depends on a specific connectivity pattern in these networks.

Methods: We compared 27 prospectively recruited comatose patients who had severe brain injury (Glasgow Coma Scale score <8; 14 traumatic and 13 anoxic cases) with 14 age-matched healthy participants. Standardized clinical assessment and fMRI were performed on average 4 ± 2 days after withdrawal of sedation. Analysis of resting-state fMRI connectivity involved a hypothesis-driven, region of interest-based strategy. We assessed patient outcome after 3 months using the Coma Recovery Scale-Revised (CRS-R).

Results: Patients who were comatose showed a significant disruption of functional connectivity of brain areas spontaneously synchronized with PCC, globally notwithstanding etiology. The functional connectivity strength between PCC and medial prefrontal cortex (mPFC) was significantly different between comatose patients who went on to recover and those who eventually scored an unfavorable outcome 3 months after brain injury (Kruskal-Wallis test, p < 0.001; linear regression between CRS-R and PCC-mPFC activity coupling at rest, Spearman ρ = 0.93, p < 0.003).

Conclusion: In both etiology groups (traumatic and anoxic), changes in the connectivity of PCC-centered, spontaneously synchronized, large-scale networks account for the loss of external and internal self-centered awareness observed during coma. Sparing of functional connectivity between PCC and mPFC may predict patient outcome, and further studies are needed to substantiate this potential prognosis biomarker.

Figure 1. Large-scale spontaneously synchronized networks

Whole-brain functional connectivity maps of covariance were computed in both groups (i.e., comatose patients and controls) following a hypothesis-driven approach. Two seed-based structures were analyzed: posterior cingulate cortex (PCC) and precuneus (PreCu). Color intensity depicts level of synchronicity (red and blue for positive and negative temporal signals correlations, respectively). All p values are corrected for false discovery rate at the whole brain level (p value <0.0001, corrected for false discovery rate).

Figure 2. Comparison between intrinsic PCC synchronized networks identified in patients who were comatose and controls

(A) Color intensity depicts differences of synchronicity between both groups (purple and green for positive and negative differences, respectively). (B) Spatial distribution of differences of temporal synchronicity values between patients and controls. All p values are corrected for false discovery rate at the whole brain level (p value <0.0001, corrected for false discovery rate). IFC = inferior frontal cortex; mPFC = mesial prefrontal cortex (BA9); PCC = posterior cingulate cortex; SMG = supramarginal gyrus (BA40).

Figure 3. Intrinsic PCC synchronized networks identified in comatose patients with anoxic and traumatic injury compared with controls

One seed-based structure was analyzed (PCC) (p value <0.0001, corrected for false discovery rate). Both etiologic subgroups are represented (i.e., traumatic and anoxic mechanism, upper and middle panel, respectively). In addition, overlapping resting-state networks, in which activity is spontaneously synchronized with PCC in both traumatic and anoxic comatose patients compared with controls, are depicted in the lower panel. PCC = posterior cingulate cortex.

Figure 4. Predictive role of PCC-mPFC coupling measured during coma state and neurologic outcome

The linear regression between patient outcome CRS-R and early-recorded PCC-mPFC coupling at rest (A) suggested a significant link between PCC-mPFC functional connectivity and patient neurologic recovery (Spearman ρ = 0.93, p < 0.003). Functional connectivity strength between PCC-mPFC assessed at scan time (B) was significantly different between comatose patients who recovered consciousness (REC) and those who evolved toward a minimally conscious state (MCS) or a vegetative state (VS) 3 months after the brain injury (Kruskal-Wallis test, p < 0.001). PCC-mPFC synchronicity at rest was not different between REC and controls. mPFC = medial prefrontal cortex; NS = not significant; PCC = posterior cingulate cortex.