Cerebrovascular Reactivity Measures Are Associated With Post-traumatic Headache Severity in Chronic TBI; A Retrospective Analysis.

John Ollinger,Cillian E. Lynch,Kimbra Kenney,L. Christine Turtzo,Ramon Diaz-Arrastia,J. Kent Werner,E. Silverman,Carol Moore,Franck Amyot,Cora Davis

doi:10.3389/fphys.2021.649901

Abstract

ObjectiveTo characterize the relationship between persistent post-traumatic headache (pPTH) and traumatic cerebrovascular injury (TCVI) in chronic traumatic brain injury (TBI). Cerebrovascular reactivity (CVR), a measure of the cerebral microvasculature and endothelial cell function, is altered both in individuals with chronic TBI and migraine headache disorder (Amyot et al., 2017; Lee et al., 2019b). The pathophysiologies of pPTH and migraine are believed to be associated with chronic microvascular dysfunction. We therefore hypothesize that TCVI may contribute to the underlying migraine-like mechanism(s) of pPTH.Materials and Methods22 moderate/severe TBI participants in the chronic stage (>6 months) underwent anatomic and functional magnetic resonance imaging (fMRI) scanning with hypercapnia gas challenge to measure CVR as well as the change in CVR (ΔCVR) after single-dose treatment of a specific phosphodiesterase-5 (PDE-5) inhibitor, sildenafil, which potentiates vasodilation in response to hypercapnia in impaired endothelium, as part of a Phase2a RCT of sildenafil in chronic TBI (NCT01762475). CVR and ΔCVR measures of each participant were compared with the individual’s pPTH severity measured by the headache impact test-6 (HIT-6) survey.ResultsThere was a moderate correlation between HIT-6 and both CVR and ΔCVR scores [Spearman’s correlation = –0.50 (p = 0.018) and = 0.46 (p = 0.03), respectively], indicating that a higher headache burden is associated with decreased endothelial function in our chronic TBI population.ConclusionThere is a correlation between PTH and CVR in chronic moderate-severe TBI. This relationship suggests that chronic TCVI may underlie the pathobiology of pPTH. Further, our results suggest that novel treatment strategies that target endothelial function and vascular health may be beneficial in refractory pPTH.

Highlights

There is a high prevalence of persistent post-traumatic headache, a newly developing or worsening headache disorder following a TBI that persists at least 3 months, among chronic traumatic brain injury (TBI) survivors (Faux and Sheedy, 2008), with 47–95% reporting frequent disabling headaches that are majority migraine-like (Headache Classification Committee of the International Headache Society [IHS], 2013; Defrin, 2014)
Headaches were classified based on a detailed phenotypic questionnaire that incorporates International Classification of Headache Disorders, version 3 (ICHD-3) criteria (Headache Classification Committee of the International Headache Society [IHS], 2018) for the primary headache disorders most commonly reported in post-traumatic headache (PTH)
One healthy control reported a prior history of migraines and one TBI participant reported a prior history of non-migrainous headache disorder

Summary

Introduction

There is a high prevalence of persistent post-traumatic headache (pPTH), a newly developing or worsening headache disorder following a TBI that persists at least 3 months, among chronic traumatic brain injury (TBI) survivors (Faux and Sheedy, 2008), with 47–95% reporting frequent disabling headaches that are majority migraine-like (Headache Classification Committee of the International Headache Society [IHS], 2013; Defrin, 2014). The most common PTH phenotype was migraine headache, but, more importantly, active duty service members with PTH had more phenotypically complex headaches than those with headache disorders that were not associated with TBI (Metti et al, 2020). In this large cohort of active duty service members with and without a history of a recent mTBI, PTH was associated with more features including severity, allodynia, visual/sensory aura, and daily or continuous occurrence compared to headaches presumed unrelated to TBI. While long term PTH outcomes and its impact on military fitness, readiness and retention have not been fully characterized, migraine remains among the most common diagnoses listed in military medical discharges (Accession Medical Standards Analysis and Research Activity, 2019)

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Results

Conclusion