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

Abstract

Objective: To 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 methods: 22 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.

Results: There 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.

Conclusion: There 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.

Keywords: cerebrovascular reactivity; chronic; migraine; post-traumatic headache; traumatic brain injury.

FIGURE 1

Structural imaging, CVR and ΔCVR maps for representative participants. Brain images of one healthy control (Female, 49 yo) and three TBI acquired with FLAIR (first row) and fMRI BOLD during hypercapnia challenge (2nd and 3rd row). The second row displays CVR maps at baseline and the third row the difference between two hypercapnia challenges due to oral ingestion of 50 mg sildenafil (ΔCVR). The control subject displayed high CVR values in gray matter and low CVR values in white matter, with a mean CVR value of 0.227%BOLD/mmHg in the whole brain. For the control, sildenafil didn’t potentiate CVR (ΔCVR image) with ΔCVR = –0.005%BOLD/mmHg. However, TBI subjects (with or without FLAIR hyperintensity) exhibited focal CVR deficits which are generally potentiated by 50mg sildenafil. Each subject was characterized by their HIT-6 score (36 for TBI#1, 56 for TBI#2 and 59 for TBI#3); CVR value (0.190, 0.183, and 0.152%BOLD/mmHg) and ΔCVR values (0.010, 0.183, and 0.023%BOLD/mmHg).

FIGURE 2

Correlations between HIT-6, CVR, and ΔCVR in chronic TBI. (A) Linear correlation between post-traumatic headache (HIT-6 score) and cerebrovascular reactivity in 22 symptomatic TBI patients in chronic stage. Spearman r = −0.50 (p = 0.018). (B) Linear correlation between delta CVR (potentiation of CVR after 50 mg of sildenafil) and HIT-6 score in our group of 22 moderate/severe TBI. The Spearman’s r = 0.46 (p = 0.03).