Brain Structural and Functional Abnormalities Associated with Acute Post-Traumatic Headache: Iron Deposition and Functional Connectivity

Background The purpose of this study was to interrogate brain iron accumulation in participants with acute post-traumatic headache (PTH) due to mild traumatic brain injury (mTBI), and to determine if functional connectivity is affected in areas with iron accumulation. We aimed to examine the correlations between iron accumulation and headache frequency, post-concussion symptom severity, number of mTBIs and time since most recent TBI. Methods Sixty participants with acute PTH and 60 age-matched healthy controls (HC) underwent 3T magnetic resonance imaging including quantitative T ₂ ^* maps and resting-state functional connectivity imaging. Between group T ₂ ^* differences were determined using T-tests (p < 0.005, cluster size threshold of 10 voxels). For regions with T ₂ ^* differences, two analyses were conducted. First, the correlations with clinical variables including headache frequency, number of lifetime mTBIs, time since most recent mTBI, and Sport Concussion Assessment Tool (SCAT) symptom severity scale scores were investigated using linear regression. Second, the functional connectivity of these regions with the rest of the brain was examined (significance of p < 0.05 with family wise error correction for multiple comparisons). Results The acute PTH group consisted of 60 participants (22 male, 38 female) with average age of 42 ± 14 years. The HC group consisted of 60 age-matched controls (17 male, 43 female, average age of 42 ± 13). PTH participants had lower T ₂ ^* values compared to HC in the left posterior cingulate and the bilateral cuneus. Stronger functional connectivity was observed between bilateral cuneus and right cerebellar areas in PTH compared to HC. Within the PTH group, linear regression showed negative associations of T ₂ ^* and SCAT symptom severity score in the left posterior cingulate (p = 0.05) and with headache frequency in the left cuneus (p = 0.04). Conclusions Iron accumulation in posterior cingulate and cuneus was observed in those with acute PTH relative to HC; stronger functional connectivity was detected between the bilateral cuneus and the right cerebellum. The correlations of decreased T ₂ ^* (suggesting higher iron content) with headache frequency and post mTBI symptom severity suggest that the iron accumulation that results from mTBI might reflect the severity of underlying mTBI pathophysiology and associate with post-mTBI symptom severity including PTH.