Background: There is growing support for the use of resting state functional connectivity (rsFC) as a tool to monitor impairment and recovery of brain function after traumatic brain injury (TBI; Hayes et al., 2016). Altered connectivity has been shown in key functional networks, such as the default mode network (DMN), in the acute (Iraji et al., 2015) and chronic phase after injury (Mayer et al., 2011; Rigon et al., 2016). However, few studies have assessed long-term recovery of brain function using rsFC following TBI (Venkatesan et al., 2015). Thus the time frame of functional brain recovery is unknown. To better understand recovery of brain function after TBI, we examined changes in whole-brain functional connectivity from anterior and posterior seeds in the DMN in the sub-acute and long-term phases post-TBI. We also examined the effect of age of injury on rsFC long-term recovery patterns.

Method: Resting-state functional magnetic resonance imaging scans (fMRI) were obtained from the controlled access datasets distributed from the DOD- and NIH-supported Federal Interagency Traumatic Brain Injury Research (FITBIR) Informatics Systems [DOI: 10.23718/FITBIR/1503293]. Thirty-nine patients (25.6% female, age mean=42.30) completed two resting-state fMRI scans after sustaining a mild to severe TBI at approximately 10 days (sub-acute; Glasgow Outcome Scale Extended [GOS-E]=6.03 , SD=1.77) and 18 months (long-term; GOS-E=6.87, SD=1.56) post-injury. Seed-to-voxel analyses assessed rsFC from anterior medial prefrontal cortex (aMPFC) and posterior cingulate cortex (PCC) seeds in the DMN. Effect of age on functional recovery was compared between younger (age 18-45; n=20; GOS-E=6.69, SD=1.70) and older (age 46+; n=19; GOS-E=5.53, SD=1.70) patients.

Results: Differences in DMN rsFC were found between the sub-acute and long-term phases. Eighteen months post-injury, increased rsFC from the aMPFC seed to cortical and subcortical regions, as well as increased rsFC from the PCC seed to frontal and temporal regions was shown. In addition, different patterns of rsFC were shown dependent on age at 18 months post-injury. Specifically, younger patients showed widespread increases in rsFC from the aMPFC and increased rsFC from the PCC to frontal regions. However, older patients demonstrated limited recovery of rsFC at 18-months post-injury. Importantly, no age differences in GOS-E were noted at 10 days and 18-months post-injury suggesting that age differences in rsFC were not due to injury severity.
Conclusion: Our results demonstrate that age at time of injury significantly impacts long-term recovery of brain function following TBI. Furthermore, our results suggest that rsFC is a sensitive tool that can be used to monitor recovery of brain function; however, factors such as age of injury must be considered. Future studies should also examine the association between rsFC with cognitive and behavioral symptoms.

Age differences in long-term recovery of brain function after traumatic brain injury