By Dara G. Jamieson, MD
Synopsis: The brain’s ability to modulate pain influences the development and persistence of post-traumatic headache (PTH). Functional magnetic resonance imaging (fMRI) studies in people with PTH show higher pain-induced brain activation in specific regions, such as the postcentral gyrus, superior temporal gyrus, and ventral striatum, as compared to healthy controls. Over 16 weeks of observation, progressive normalization in pain-induced brain activation was seen in the PTH group with headache improvement, with persistently elevated activation in the non-improvement PTH group.
Sources: Ku D, Mao L, Nikolova S, et al. Longitudinal analysis of pain-induced brain activations in post-traumatic headache. Cephalalgia. 2025;45(5):3331024251345160.
Jessen J, Özgül ÖS, Höffken O, et al. Somatosensory dysfunction in patients with posttraumatic headache: A systematic review. Cephalalgia. 2022;42(1):73-81.
Post-traumatic headache (PTH) is a common complication of traumatic brain injury (TBI). It is a secondary headache that develops within seven days after trauma, after regaining consciousness, or after recovering the ability to sense and report pain. If the PTH persists for more than three months, it is referred to as persistent PTH. A PTH can have the clinical features of primary headaches, such as migraine or tension-type headaches. These headaches triggered by trauma may affect the quality of life of people with TBI, including mild TBI. Although central sensitization, impaired pain modulation, neuroinflammation, and trigeminal system activation appear to be involved in the development of PTH, the pathophysiology of PTH is poorly understood, leading to limited treatment options.
Differences in the modulation in pain pathways in the brain influence the development of headaches after TBI and the risk of these headaches becoming chronic. Jessen et al searched the PubMed database for studies examining pain modulation and/or quantitative sensory testing in individuals with PTH after TBI. The authors summarized the knowledge in the medical literature about the sensory function and pain modulatory systems in PTH. Patients with PTH exhibited alterations in sensory processing, including heat hypoalgesia (reduced sensitivity to heat pain) and mechanical hyperalgesia (increased sensitivity to pressure pain) as compared to control groups.
Differences in the sensory profiles depended on the headache phenotype (migraine-like or tension-type-like) and age (young or older) associated with PTH patients. Sensory abnormalities were more prominent in TBI patients with headaches as compared to headache-free TBI patients and healthy controls. Conditioned pain modulation (CPM), which measures the brain’s ability to inhibit pain, was decreased in patients with PTH. A decrease in CPM may predict the development of persistent PTH after mild TBI. Psychological disorders, including depression, anxiety, pain catastrophizing, and post-traumatic stress disorder, are associated with the chronification of headaches after TBI, with a positive correlation between the intensity of the psychological symptoms in individuals with PTH and their headache severity. The pain pathophysiology in PTH includes central sensitization, impaired pain modulation, trigeminal system activation, and neuroinflammation. Damage to pain modulatory systems and cranial sensitization are key contributors to persistent PTH.
Ku et al used functional magnetic resonance imaging (fMRI) scanning with a blood oxygen level-dependent paradigm to investigate pain-induced brain activation in 33 participants with PTH following recent mild TBI and in 33 healthy controls. Thermal heat stimulation from a thermode applied to the left forearm was non-painful or moderately painful as compared to no stimulation. Participants underwent fMRI scanning at baseline, and at four weeks and 16 weeks after the baseline fMRI scan. The participants with PTH kept diaries and were divided into improvement and non-improvement groups based on their headache recovery. Analysis of the fMRI data found that participants with PTH exhibited significantly higher pain-induced brain activation across multiple brain regions as compared to healthy controls. These regions with greater pain activation in the PTH group at baseline included bilateral postcentral gyri, the right superior temporal gyrus, right middle temporal gyrus, left inferior parietal gyrus, right superior parietal gyrus, left ventral striatum, left olfactory cortex, left gyrus rectus, and left middle occipital gyrus.
The group of participants with PTH who showed clinical improvement over time progressed toward normalization of pain-related brain activity. However, the PTH group without improvement in headaches showed sustained hyperactivation in multiple regions, with a significant decreasing trend only in the left ventral striatum, olfactory cortex, and gyrus rectus. The authors stated that their finding “suggests that, while partial recovery of neural function may occur even without symptomatic improvement, complete PTH clinical recovery may require normalization across all the pain-processing regions.” The authors noted the sustained anatomical differences between the PTH improvement and non-improvement groups at 16 weeks in multiple regions, including the right postcentral gyrus, right superior temporal gyrus, right middle temporal gyrus, left postcentral gyrus and left inferior parietal gyrus, and right superior parietal gyrus. The recovery patterns noted on serial fMRI scans were suggested as potential biomarkers indicative of persistent PTH.
Commentary
There are many unanswered clinical questions about PTH. Why are these headaches more likely to occur after mild TBI as compared to more severe trauma? Why are some individuals more likely to develop PTH than others who sustain similar head trauma? What factors inhibit the expected improvement of these acute onset headaches over time since the inciting event? The mechanism of these headaches is largely unknown, other than that they share both clinical and pathophysiological characteristics of primary headaches (such as migraine and tension-type headaches).
As PTH is studied in more detail, both with epidemiological and functional neuroimaging studies, identifying which individuals who sustain head trauma are most likely to experience PTH, and particularly prolonged PTH, should become easier. Prompt recognition of individuals at risk for developing PTH may decrease the length of the disability associated with these headaches. Potential neuroimaging biomarkers may identify those individuals at risk for persistent PTH, leading to the development of targeted interventions and personalized treatment strategies for these individuals who are likely to suffer the most from these debilitating secondary headaches.
Early therapeutic intervention, with the timely and aggressive use of preventive headache medications, modification of lifestyle triggers for headache, and therapy for contributing psychological issues, should be applied to those people with PTH after mild TBI who are recognized to be at risk for developing chronic PTH.
Dara G. Jamieson, MD, is Clinical Associate Professor of Neurology, Weill Cornell Medical College.
The brain’s ability to modulate pain influences the development and persistence of post-traumatic headache (PTH). Functional magnetic resonance imaging (fMRI) studies in people with PTH show higher pain-induced brain activation in specific regions, such as the postcentral gyrus, superior temporal gyrus, and ventral striatum, as compared to healthy controls. Over 16 weeks of observation, progressive normalization in pain-induced brain activation was seen in the PTH group with headache improvement, with persistently elevated activation in the non-improvement PTH group.
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