R.C. Shondel1, E.R. Becker1, G.C. Wetmore1, A.D. Price1, R.M. Schuster1, L.G. England1, M.D. Goodman1 1University Of Cincinnati, Cincinnati, OH, USA
Introduction: Traumatic brain injury (TBI) remains prevalent among trauma patients with associated short- and long-term morbidity and mortality. Current TBI treatment is as heterogenous as the outcomes but can involve downregulation of the sympathetic nervous system through beta blockade, and recently the converse, upregulation of the parasympathetic nervous system, has been considered. The aim of this study was to determine if upregulation of the parasympathetic nervous system through vagus nerve stimulation (VNS) could mitigate the systemic response to TBI.
Methods: A weight drop TBI model was utilized followed by VNS for 10 minutes at 5mAmps, 1.00ms, and 2Hz. Mice were randomized to either TBI or no TBI. For serum TBI biomarker analysis, intervention occurred 2 hours post-TBI and cohorts (n=5) included sham operation, left vagotomy, right vagotomy, open left VNS, and open right VNS. Serum was then collected at either 6 hours or 24 hours post-TBI and was analyzed for biomarkers of TBI severity including glial fibrillary acidic protein (GFAP) and ubiquitin carboxyl-terminal hydrolase L1 (UCHL1). For serum inflammatory marker analysis and rotational thromboelastometry (ROTEM), bilateral VNS occurred either at 1-hour post-TBI (n=12) or 1, 4, and 24 hours (n=11) post-TBI with whole blood collection immediately following intervention. Viscoelastic coagulation testing included non-activated (NATEM), extrinsic (EXTEM) and fibrinogen (FIBTEM) thromboelastometry.
Results: Serum GFAP was increased at 6 hours post-TBI in the TBI group compared to the no TBI group (p<0.05). This GFAP elevation persisted at 24 hours in TBI with left VNS (982±799 pg/mL, p=0.039) and TBI with left vagotomy (463±166 pg/mL, p=0.002) compared to the no TBI group (288±387 pg/mL) (Figure). Additionally, within no TBI cohorts, right VNS had significantly lower GFAP levels compared to right vagotomy (14±11 vs. 118±29 pg/mL, p=0.004). By comparison, UCHL1 was unchanged by TBI at 6- and 24-hour timepoints. Significant findings for 1-hour serum inflammatory markers between VNS and TBI control included an increase in IL-2 (1.8±1.1 vs. 1.1±0.4 pg/ml, p<0.05) and an increase in MCP-1 (233.8±191.7 vs. 96.3±30.4 pg/ml, p=0.03). No significant findings were noted in 24-hour serum inflammatory markers or any of the coagulation analyses.
Conclusion: Following TBI, GFAP levels remained elevated at 24 hours with both VNS and vagotomy. Outside the context of TBI, VNS decreased GFAP levels relative to vagotomy. Although typically considered as a marker of worsening brain injury, GFAP has numerous roles related to astrocytes including astrogliosis and ultimately neurogenesis. Furthermore, inflammatory markers were found to be acutely elevated at 1-hour post VNS but returned to baseline with repeat VNS at 24 hours. Taken together, persistently elevated GFAP and acutely elevated inflammatory markers may not be a sign of worsening TBI, but could be an early sign of healing by astrocytosis induced by VNS.