Traumatic brain injury (TBI) is a leading cause of disability worldwide. Yet, our understanding of the mechanisms of this condition is limited, especially in the acute setting. Here, we investigated the relationship between functional connectivity and common clinical assessments, like the Glasgow Coma Scale (GCS) at admission and modified Rankin scale at 3-months (mRS) to determine if functional connectivity can provide a broader representation of the brain’s networks than these standard tests.

We performed a retrospective analysis of resting state functional MRI and clinical data in 58 patients (41.28 ± 18.63) scanned acutely/subacutely (≤ 31 days). Then, for a secondary analysis, we included 50 more patients who presented after either a first or a repeat incident and were scanned either acutely/subacutely or chronically (<2 yrs) (all together 108 patients, 46.4 ± 20.1yrs). Using a 268-node functional atlas, we derived 35,778 unique edges, based on which we calculated the mean functional connectivity of 10 resting state networks and used those to establish a link to TBI severity and functional outcome.

Our analysis showed that when dividing sub/acute patients (n=58) based on GCS severity, only the Subcortical network showed a significant discrimination between mild and moderate-severe GCS at admission (P<0.001), with hyperconnectivity noted in mild patients, and hypoconnectivity – in moderate-severe GCS patients. This difference appeared to be mainly driven by the thalami (Right, P=0.002; Left P<0.001). Similar results were observed when investigating GCS subscores at admission (Eyes, Motor, Verbal, all P<0.001). Further, when evaluating mRS outcomes at 3-months against functional connectivity, differences were noted within the Motor, Cerebellum and Medial-Frontal networks, though none survived multiple comparisons. Importantly, we found the DMN and mRS to be correlated but with a limited relationship (r2= 0.18). Lastly, we performed a post-hoc analysis (n=108) to investigate if the hyperconnectivity in the Subcortical network of sub/acute mild GCS patients remained irrespective of acuity of scanning (i.e. acute/ chronic) or frequency of TBI (i.e. first/ repeat). Our analysis showed that GCS severity appeared to be the main driver of functional connectivity within the Subcortical network, whereas acuity of scanning, alongside GCS severity contributed to the results of chronically scanned patients.

While GCS and 3-month mRS scores offer some meaningful insights, their limited capture of the neural representation underscores the need to investigate whether other early clinical assessments correlate more robustly with early resting state networks or whether such networks themselves could predict future outcomes.

The authors have declared no competing interest.

This study was funded by NINDS K23NS112596-01A1 and Yale School of Medicine.

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The Institutional Review Board of Yale University School of Medicine gave ethical approval for this work.

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes