| Summary: | Introduction: Post-traumatic headaches (PTH) are common following mild traumatic brain injury (mTBI). There is evidence of altered central pain processing in adult PTH; however, little is known about how children with PTH process pain. The anterior cingulate cortex (ACC) plays a critical role in descending central pain modulation. In this study, we explored whether the functional connectivity (FC) of the ACC is altered in children with PTH. Methods: In this case-control study, we investigated resting-state FC of 5 ACC seeds (caudal, dorsal, rostral, perigenual, and subgenual) in children with PTH ( n = 73) and without PTH ( n = 29) following mTBI, and healthy controls ( n = 27). Post-concussion symptoms were assessed using the Post-Concussion Symptom Inventory and the Child Health Questionnaire. Resting-state functional Magnetic Resonance Imaging (fMRI) data were used to generate maps of ACC FC. Group-level comparisons were performed within a target mask comprised of pain-related regions using FSL Randomise. Results: We found decreased FC between the right perigenual ACC and the left cerebellum, and increased FC between the right subgenual ACC and the left dorsolateral prefrontal cortex in children with PTH compared to healthy controls. The ACC FC in children without PTH following mTBI did not differ from the group with PTH or healthy controls. FC between rostral and perigenual ACC seeds and the cerebellum was increased in children with PTH with pre-injury headaches compared to those with PTH without pre-injury headaches. There was a positive relationship between PTH severity and rostral ACC FC with the bilateral thalamus, right hippocampus and periaqueductal gray. Conclusions: Central pain processing is altered in children with PTH. Pre-existing headaches help to drive this process. Trial registration: The PlayGame Trial was registered in ClinicalTrials.gov database ( ClinicalTrials.gov Identifier: NCT01874847).
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