Chong, Catherine D

Background Persistent headache attributed to traumatic injury to the head is divided into two subtypes, one attributed to moderate or severe traumatic injury and another attributed to mild traumatic injury (i.e., concussion). The latter is much more prevalent, in part because more than 90% of cases with traumatic brain injury are classified as mild. The pathophysiology of persistent post-traumatic headache is poorly understood and the underlying mechanisms are likely multifactorial. There is currently no approved treatment specifically for persistent post-traumatic headache, and management strategies rely on medications used for migraine or tension-type headache. Therefore, high-quality trials are urgently needed to support clinical decision-making and optimize management strategies. International guidelines can facilitate appropriate trial design and ensure the acquisition of high-quality data evaluating the efficacy, tolerability, and safety of available and novel pharmacological therapies for the preventive treatment of persistent post-traumatic headache. Methods The development of this guideline was based on a literature review of available studies in MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials, along with a review of previously published guidelines for controlled trials of preventive treatment for episodic and chronic migraine. The identified literature was critically appraised, and due to the scarcity of scientific evidence, recommendations were primarily based on the consensus of experts in the field. Objective To provide guidelines for designing state-of-the-art controlled clinical trials aimed at evaluating the effectiveness of preventive treatments for persistent post-traumatic headache attributed to mild traumatic brain injury.

Background Our prior work demonstrated that questionnaires assessing psychosocial symptoms have utility for predicting improvement in patients with acute post-traumatic headache following mild traumatic brain injury. In this cohort study, we aimed to determine whether prediction accuracy can be refined by adding structural magnetic resonance imaging (MRI) brain measures to the model. Methods Adults with acute post-traumatic headache (enrolled 0–59 days post-mild traumatic brain injury) underwent T1-weighted brain MRI and completed three questionnaires (Sports Concussion Assessment Tool, Pain Catastrophizing Scale, and the Trait Anxiety Inventory Scale). Individuals with post-traumatic headache completed an electronic headache diary allowing for determination of headache improvement at three- and at six-month follow-up. Questionnaire and MRI measures were used to train prediction models of headache improvement and headache trajectory. Results Forty-three patients with post-traumatic headache (mean age = 43.0, SD = 12.4; 27 females/16 males) and 61 healthy controls were enrolled (mean age = 39.1, SD = 12.8; 39 females/22 males). The best model achieved cross-validation Area Under the Curve of 0.801 and 0.805 for predicting headache improvement at three and at six months. The top contributing MRI features for the prediction included curvature and thickness of superior, middle, and inferior temporal, fusiform, inferior parietal, and lateral occipital regions. Patients with post-traumatic headache who did not improve by three months had less thickness and higher curvature measures and notably greater baseline differences in brain structure vs. healthy controls (thickness: p < 0.001, curvature: p = 0.012) than those who had headache improvement. Conclusions A model including clinical questionnaire data and measures of brain structure accurately predicted headache improvement in patients with post-traumatic headache and achieved improvement compared to a model developed using questionnaire data alone.

Objectives The objective of this longitudinal study was to determine whether brain iron accumulation, measured using magnetic resonance imaging magnetic transverse relaxation rates (T2*), is associated with response to erenumab for the treatment of migraine. Methods Participants (n = 28) with migraine, diagnosed using international classification of headache disorders 3rd edition criteria, were eligible if they had six to 25 migraine days during a four-week headache diary run-in phase. Participants received two treatments with 140 mg erenumab, one immediately following the pre-treatment run-in phase and a second treatment four weeks later. T2* data were collected immediately following the pre-treatment phase, and at two weeks and eight weeks following the first erenumab treatment. Patients were classified as erenumab responders if their migraine-day frequency at five-to-eight weeks post-initial treatment was reduced by at least 50% compared to the pre-treatment run-in phase. A longitudinal Sandwich estimator approach was used to compare longitudinal group differences (responders vs non-responders) in T2* values, associated with iron accumulation. Group visit effects were calculated with a significance threshold of p = 0.005 and cluster forming threshold of 250 voxels. T2* values of 19 healthy controls were used for a reference. The average of each significant region was compared between groups and visits with Bonferroni corrections for multiple comparisons with significance defined as p < 0.05. Results Pre- and post-treatment longitudinal imaging data were available from 28 participants with migraine for a total of 79 quantitative T2* images. Average subject age was 42 ± 13 years (25 female, three male). Of the 28 subjects studied, 53.6% were erenumab responders. Comparing longitudinal T2* between erenumab responders vs non-responders yielded two comparisons which survived the significance threshold of p < 0.05 after correction for multiple comparisons: the difference at eight weeks between the erenumab-responders and non-responders in the periaqueductal gray (mean ± standard error; responders 43 ± 1 ms vs non-responders 32.5 ± 1 ms, p = 0.002) and the anterior cingulate cortex (mean ± standard error; responders 50 ± 1 ms vs non-responders 40 ± 1 ms, p = 0.01). Conclusions Erenumab response is associated with higher T2* in the periaqueductal gray and anterior cingulate cortex, regions that participate in pain processing and modulation. T2* differences between erenumab responders vs non-responders, a measure of brain iron accumulation, are seen at eight weeks post-treatment. Less iron accumulation in the periaqueductal gray and anterior cingulate cortex might play a role in the therapeutic mechanisms of migraine reduction associated with erenumab.

Abstract Objectives/Background Post‐traumatic headache (PTH) is a common symptom after mild traumatic brain injury (mTBI). Although there have been several studies that have used clinical features of PTH to attempt to predict headache recovery, currently no accurate methods exist for predicting individuals’ improvement from acute PTH. This study investigated the utility of clinical questionnaires for predicting (i) headache improvement at 3 and 6 months, and (ii) headache trajectories over the first 3 months. Methods We conducted a clinic‐based observational longitudinal study of patients with acute PTH who completed a battery of clinical questionnaires within 0–59 days post‐mTBI. The battery included headache history, symptom evaluation, cognitive tests, psychological tests, and scales assessing photosensitivity, hyperacusis, insomnia, cutaneous allodynia, and substance use. Each participant completed a web‐based headache diary, which was used to determine headache improvement. Results Thirty‐seven participants with acute PTH (mean age = 42.7, standard deviation [SD] = 12.0; 25 females/12 males) completed questionnaires at an average of 21.7 (SD = 13.1) days post‐mTBI. The classification of headache improvement or non‐improvement at 3 and 6 months achieved cross‐validation area under the curve (AUC) of 0.72 (95% confidence interval [CI] 0.55 to 0.89) and 0.84 (95% CI 0.66 to 1.00). Sub‐models trained using only the top five features still achieved 0.72 (95% CI 0.55 to 0.90) and 0.77 (95% CI 0.52 to 1.00) AUC. The top five contributing features were from three questionnaires: Pain Catastrophizing Scale total score and helplessness sub‐domain score; Sports Concussion Assessment Tool Symptom Evaluation total score and number of symptoms; and the State‐Trait Anxiety Inventory score. The functional regression model achieved for modeling headache trajectory over the first 3 months. Conclusion Questionnaires completed following mTBI have good utility for predicting headache improvement at 3 and 6 months in the future as well as the evolving headache trajectory. Reducing the battery to only three questionnaires, which assess post‐concussive symptom load and biopsychosocialecologic factors, was helpful to determine a reasonable prediction accuracy for headache improvement.

Abstract Objective To explore alterations in thalamic subfield volume and iron accumulation in individuals with post‐traumatic headache (PTH) relative to healthy controls. Background The thalamus plays a pivotal role in the pathomechanism of pain and headache, yet the role of the thalamus in PTH attributed to mild traumatic brain injury (mTBI) remains unclear. Methods A total of 107 participants underwent multimodal T1‐weighted and T2* brain magnetic resonance imaging. Using a clinic‐based observational study, thalamic subfield volume and thalamic iron accumulation were explored in 52 individuals with acute PTH (mean age = 41.3; standard deviation [SD] = 13.5), imaged on average 24 days post mTBI, and compared to 55 healthy controls (mean age = 38.3; SD = 11.7) without history of mTBI or migraine. Symptoms of mTBI and headache characteristics were assessed at baseline (0–59 days post mTBI) ( n = 52) and 3 months later ( n = 46) using the Symptom Evaluation of the Sports Concussion Assessment Tool (SCAT‐5) and a detailed headache history questionnaire. Results Relative to controls, individuals with acute PTH had significantly less volume in the lateral geniculate nucleus (LGN) (mean volume: PTH = 254.1, SD = 43.4 vs. controls = 278.2, SD = 39.8; p = 0.003) as well as more iron deposition in the left LGN (PTH: T2* signal = 38.6, SD = 6.5 vs. controls: T2* signal = 45.3, SD = 2.3; p = 0.048). Correlations in individuals with PTH revealed a positive relationship between left LGN T2* iron deposition and SCAT‐5 symptom severity score at baseline ( r = −0.29, p = 0.019) and maximum headache intensity at the 3‐month follow‐up ( r = −0.47, p = 0.002). Conclusion Relative to healthy controls, individuals with acute PTH had less volume and higher iron deposition in the left LGN. Higher iron deposition in the left LGN might reflect mTBI severity and poor headache recovery.

AbstractPosttraumatic headache (PTH) is the most common symptom following mild traumatic brain injury (mTBI) (also known as concussion). Migraine and PTH have similar phenotypes, and a migraine-like phenotype is common in PTH. The similarities between both headache types are intriguing and challenge a better understanding of the pathophysiological commonalities involved in migraine and PTH due to mTBI. Here, we review the PTH resting-state functional connectivity literature and compare it to migraine to assess overlap and differences in brain network function between both headache types. Migraine and PTH due to mTBI have overlapping and disease-specific widespread alterations of static and dynamic functional networks involved in pain processing as well as dysfunctional network connections between frontal regions and areas of pain modulation and pain inhibition. Although the PTH functional network literature is still limited, there is some evidence that dysregulation of the top-down pain control system underlies both migraine and PTH. However, disease-specific differences in the functional circuitry are observed as well, which may reflect unique differences in brain architecture and pathophysiology underlying both headache disorders.

Abstract Objective The purpose of this study was to characterize cutaneous heat and light‐induced pain thresholds in people with post‐traumatic headache (PTH) compared with healthy controls (HCs). Background Photophobia and allodynia are common in PTH, and there is emerging evidence to support multimodal sensory dysfunction. Methods In this age‐ and sex‐matched cohort study, individuals with PTH ( n = 20) and HCs ( n = 20), aged 18–65 years, were recruited from an institutional database of research volunteers, from the concussion clinic, and via the use of approved flyers posted on the Mayo Clinic Campus in Scottsdale, Arizona. Participants were assessed using the Allodynia Symptom Checklist (ASC‐12), Photosensitivity Assessment Questionnaire (PAQ), State Trait Anxiety Inventory (STAI), and Beck Depression Inventory (BDI). Quantitative sensory testing quantified heat pain thresholds. A light stimulation device quantified light‐induced pain thresholds. Subsequently, heat pain thresholds were obtained immediately, 10, and 40 min after a bright light stressor. Results The mean photophobia symptom severity score, based on the PAQ, was higher in participants with PTH compared with HCs, mean 0.62 (SD = 0.25) versus mean 0.24 (SD = 0.24), p < 0.001. Light‐induced pain thresholds were lower in participants with PTH (median = 90.5 lux and quartiles = 17.8 to 378.5) compared with HCs (median = 863.5 lux and quartiles = 519.9 to 4906.5) and were independent from BDI and STAI ( p < 0.001). Allodynia scores did not differ between participants with PTH and HCs after adjusting for BDI and STAI scores. Baseline forehead heat pain thresholds were not different, participants with PTH mean 41.9°C (SD = 0.89) versus HCs mean 44.3°C (SD = 0.89), p = 0.061; however, forearm heat pain thresholds were lower in participants with PTH compared with HCs, mean 40.8°C (SD = 0.80) versus mean 44.4°C (SD = 0.80), p = 0.002. The forehead heat pain threshold change from baseline post bright light stressor in participants with PTH versus HCs was different immediately (mean −1.2 (SD = 0.53), p = 0.025), 10 min (mean −1.8 (SD = 0.74), p = 0.015), and 40 min (mean −1.8 (SD = 0.88), p = 0.047). The forearm heat pain threshold change immediately post bright light stressor in participants with PTH versus HCs was different, mean −1.9°C (SD = 0.58), p = 0.001, however, not different at 10 and 40 min. Conclusions Photophobia is higher and light‐induced pain thresholds are lower in participants with PTH. Exposure to a light stressor reduced heat pain thresholds in participants with PTH immediately post bright light stressor, but not in HCs. This study provides evidence for multimodal sensory dysfunction in people with PTH.

Objectives Although iron accumulation in pain-processing brain regions has been associated with repeated migraine attacks, brain structural changes associated with post-traumatic headache have yet to be elucidated. To determine whether iron accumulation is associated with acute post-traumatic headache, magnetic resonance transverse relaxation rates (T2*) associated with iron accumulation were investigated between individuals with acute post-traumatic headache attributed to mild traumatic brain injury and healthy controls. Methods Twenty individuals with acute post-traumatic headache and 20 age-matched healthy controls underwent 3T brain magnetic resonance imaging including quantitative T2* maps. T2* differences between individuals with post-traumatic headache versus healthy controls were compared using age-matched paired t-tests. Associations of T2* values with headache frequency and number of mild traumatic brain injuries were investigated using multiple linear regression in individuals with post-traumatic headache. Significance was determined using uncorrected p-value and cluster size threshold. Results Individuals with post-traumatic headache had lower T2* values compared to healthy controls in cortical (bilateral frontal, bilateral anterior and posterior cingulate, right postcentral, bilateral temporal, right supramarginal, right rolandic, left insula, left occipital, right parahippocampal), subcortical (left putamen, bilateral hippocampal) and brainstem regions (pons). Within post-traumatic headache subjects, multiple linear regression showed a negative association between T2* in the right inferior parietal/supramarginal regions and number of mild traumatic brain injuries and a negative association between T2* in bilateral cingulate, bilateral precuneus, bilateral supplementary motor areas, bilateral insula, right middle temporal and right lingual areas and headache frequency. Conclusions Acute post-traumatic headache is associated with iron accumulation in multiple brain regions. Correlations with headache frequency and number of lifetime mild traumatic brain injuries suggest that iron accumulation is part of the pathophysiology or a marker of mild traumatic brain injury and post-traumatic headache.

Abstract BackgroundThe presence of white matter hyperintensities (WMH) in migraine is well-documented, but the location of brain WMH in patients with migraine are insufficiently researched. Although recent semi-automatic software packages have been developed for calculating WMH, visual inspection remains the gold standard for measuring WMH. The goal of this study was to assess WMH in patients with migraine using a modified version of the Scheltens visual rating scale, a semiquantitative scale for categorizing WMH in the following brain regions: periventricular, lobar (frontal, temporal, parietal, occipital), basal ganglia, and infratentorial regions.Methods263 patients with migraine (31 male/232 female; mean age: 48.0) who were enrolled in the American Registry for Migraine Research from Mayo Clinic with a diagnosis of episodic (n = 46; 17.5%) or chronic migraine (n = 217; 82.5%) and who had brain magnetic resonance imaging were included in this study. Those with imaging evidence for gross anatomical abnormalities other than WMH were excluded. WMH were identified on axial T2 and FLAIR sequences by a board certified neuroradiologist. WMH were characterized via manual inspection and categorized according to the scale’s criteria.Results95 patients (36.1 %: mean age: 41.8) had no WMH on axial T2 and FLAIR imaging and 168 patients (63.9%, mean age: 51.4) had WMH. Of those with WMH, 94.1% (n = 158) had lobar hyperintensities (frontal: 148/158, 93.7%; parietal: 57/158, 36.1%; temporal: 35/158, 22.1%; occipital: 9/158, 5.7%), 13/168, 7.7% had basal ganglia WMH, 49/168, 29.1% had periventricular WMH, and 17/168, 10.1% had infratentorial WMH. 101/168 patients (60.1%) had bilateral WMH and 67/168 (39.9%) had unilateral WMH (34 right hemisphere /33 left hemisphere). 30.0% of patients with WMH did not have WMH reported in their clinical radiology reports.DiscussionNearly 2/3 of patients with migraine had WMH. They were most common in the lobar regions, specifically in the frontal lobe. The categorization of WMH in migraine using the modified Scheltens visual rating scale could help in future studies to clarify the relationship between WMH and headache features and might be a useful method for developing classifiers that differentiate between migraine-specific WMH and other causes of WMH.