Citations

Abstract Objective To investigate the impact of having headaches prior to traumatic brain injury (TBI) on headache features and long‐term patient health outcomes. Background and Methods This was an exploratory analysis of patients with TBI who were enrolled in the American Registry for Migraine Research (ARMR), a multicenter, prospective, longitudinal patient registry composed of patients with International Classification of Headache Disorders, 3rd edition (ICHD‐3)–defined headache diagnoses. The ARMR study enrolled 2,707 patients between February 1, 2016 and May 6, 2020, 565 of whom qualified for this analysis. Those with headaches prior to their TBI were compared to those without headaches prior to their TBI for ICHD‐3 diagnoses, headache frequency and intensity, headache‐related disability (Migraine Disability Assessment score), symptoms of anxiety (General Anxiety Disorder [GAD‐7]), depression (two items from Patient Health Questionnaire‐9), post‐traumatic stress disorder (PTSD), cutaneous allodynia (12‐item Allodynia Symptom Checklist [ASC‐12]), cognitive dysfunction (Migraine Attacks Subjective Cognitive Impairments Scale [Mig‐SCog]), pain interference (Patient‐Reported Outcomes Measurement Information System‐Pain Interference), and work productivity (Work Productivity and Activity Impairment). Results Among 565 participants with TBI, 350 had headaches prior to their TBI. Those with pre‐TBI headaches were less likely to receive a diagnosis of post‐traumatic headache (PTH; 14/350 [4.0%] vs. 21/215 [9.8%], p = 0.006), even though 25.7% reported new or worsening headaches within 7 days of their TBI. Those with pre‐TBI headaches had higher ASC‐12 scores (2.4 ± 3.5 vs. 1.8 ± 3.4, p = 0.030), Mig‐SCog scores (9.3 ± 4.7 vs. 8 ± 4.9, p = 0.004), and GAD‐7 scores (6.9 ± 5.1 vs. 6.2 ± 5.4, p = 0.039), and were more likely to have a migraine diagnosis (335/350 [95.7%] vs. 192/215 [89.3%], p = 0.003). Conclusions Those with headaches prior to TBI are less likely to receive a diagnosis of PTH. They have more severe symptoms of cutaneous allodynia, cognitive impairment, and generalized anxiety. This analysis suggests that pre‐TBI headaches might impact post‐TBI headache diagnoses and associated features.

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 Background/Objective: Changes in speech can be detected objectively before and during migraine attacks. The goal of this study was to interrogate whether speech changes can be detected in subjects with post-traumatic headache (PTH) attributed to mild traumatic brain injury (mTBI) and whether there are within-subject changes in speech during headaches compared to the headache-free state. Methods: Using a series of speech elicitation tasks uploaded via a mobile application, PTH subjects and healthy controls (HC) provided speech samples once every three days, over a period of 12 weeks. The following speech parameters were assessed: vowel space area, vowel articulation precision, consonant articulation precision, average pitch, pitch variance, speaking rate and pause rate. Speech samples of subjects with PTH were compared to HC. To assess speech changes associated with PTH, speech samples of subjects during headache were compared to speech samples when subjects were headache-free. All analyses were conducted using a mixed-effect model design.Results: Longitudinal speech samples were collected from nineteen subjects with PTH (mean age=42.5, SD=13.7) who were an average of 14 days (SD=32.2) from their mTBI at the time of enrollment and thirty-one HC (mean age=38.7, SD=12.5). Regardless of headache presence or absence, PTH subjects had longer pause rates and reductions in vowel and consonant articulation precision relative to HC. On days when speech was collected during a headache, there were longer pause rates, slower sentence speaking rates and less precise consonant articulation compared to the speech production of HC. During headache, PTH subjects had slower speaking rates and altered vowel articulation compared to when they were headache-free. Conclusions: Compared to HC, subjects with acute PTH demonstrate altered speech as measured by objective features of speech production. For individuals with PTH, speech was altered during headache vs. when they were headache-free, suggesting that speech alterations were related to PTH and not solely due to the underlying mTBI.

Abstract Objective To evaluate whether the 15‐day threshold of headache days per month adequately reflects substantial differences in disability across the full spectrum of migraine. Background The monthly frequency of headache days defines migraine subtypes and has crucial implications for epidemiological and clinical research as well as access to care. Methods The patients with migraine ( N = 836) who participated in the American Registry for Migraine Research, which is a multicenter, longitudinal patient registry, between February 2016 and March 2020, were divided into four groups based on monthly headache frequency: Group 1 (0–7 headache days/month, n = 286), Group 2 (8–14 headache days/month, n = 180), Group 3 (15–23 headache days/month, n = 153), Group 4 (≥24 headache days/month, n = 217). Disability (MIDAS), Pain intensity (NRS), Work Productivity and Activity Impairment (WPAI), Pain Interference (PROMIS‐PI), Patient Health Questionnaire‐4 (PHQ‐4), and General Anxiety Disorder‐7 (GAD‐7) scores were compared. Results Mean (standard deviation [SD]) age was 46 (13) years (87.9% [735/836] female). The proportion of patients in each group was as follows: Group 1 (34.2% [286/836]), Group 2 (21.5% [180/836]), Group 3 (18.3% [153/836]), and Group 4 (26.0% [217/836]). There were significant relationships with increasing disability, lost productive time, and pain interference in higher headache frequency categories. There were no significant differences between Group 2 and Group 3 for most measures (NRS, all WPAI scores, PROMIS‐PI, GAD‐7, and PHQ‐4), although MIDAS scores differed (median [interquartile range (IQR)]; 38 [20–58] vs. 55 [30–90], p < 0.001). Patients in Group 1 had significantly lower MIDAS (median [IQR];16 [7–30], p < 0.001), WPAI‐% total active impairment (mean (SD): Group 1 [30.9 (26.8)] vs. Group 2 [39.2 (24.5), p = 0.017], vs. Group 3 [45.9 (24.1), p < 0.001], vs. Group 4 [55.3 (23.0), p < 0.001], and PROMIS‐PI‐T score (Group 1 [60.3 (7.3)] vs. Group 2 [62.6 (6.4), p = 0.008], vs. Group 3 [64.6 (5.6), p < 0.001], vs. Group 4 [66.8 (5.9), p < 0.001]) compared to all other groups. Patients in Group 4 had significantly higher MIDAS (median (IQR): Group 4 [90 (52–138)] vs. Group 1 [16 (7–30), p < 0.001], vs. Group 2 [38 (20–58), p < 0.001], vs. Group 3 [55 (30–90), p < 0.001], WPAI‐%Presenteeism (Group 4 [50.4 (24.4)] vs. Group 1 [28.8 (24.9), p < 0.001], vs. Group 2 [34.9 (22.3), p < 0.001], vs. Group 3 [40.9 (22.3), p = 0.048], WPAI‐% total work productivity impairment (Group 4 [55.9 (26.1)] vs. Group 1 [32.1 (37.6), p < 0.001], vs. Group 2 [38.3 (24.0), p < 0.001], vs. Group 3 [44.6 (24.4), p = 0.019]), and WPAI‐%Total activity impairment (Group 4 [55.3 (23.0)] vs. Group 1 [30.9 (26.8), p < 0.001], vs. Group 2 [39.2 (24.5), p < 0.001], vs. Group 3 [45.9 (24.1), p = 0.025]) scores compared with all other groups. Conclusion Our data suggest that the use of a 15 headache day/month threshold to distinguish episodic and chronic migraine does not capture the burden of illness nor reflect the treatment needs of patients. These results have important implications for future refinements in the classification of migraine.

Background Persistent post-traumatic headache most commonly has symptoms that overlap those of migraine. In some cases, it can be clinically difficult to differentiate persistent post-traumatic headache with a migraine phenotype from migraine. The objective of this study was to develop a classification model based on questionnaire data and structural neuroimaging data that distinguishes individuals with migraine from those with persistent post-traumatic headache. Methods Questionnaires assessing headache characteristics, sensory hypersensitivities, cognitive functioning, and mood, as well as T1-weighted magnetic resonance imaging and diffusion tensor data from 34 patients with migraine and 48 patients with persistent post-traumatic headache attributed to mild traumatic brain injury were included for analysis. The majority of patients with persistent post-traumatic headache had a migraine/probable migraine phenotype (77%). A machine-learning leave-one-out cross-validation algorithm determined the average accuracy for distinguishing individual migraine patients from individual patients with persistent post-traumatic headache. Results Based on questionnaire data alone, the average classification accuracy for determining whether an individual person had migraine or persistent post-traumatic headache was 71.9%. Adding imaging data features to the model improved the classification accuracy to 78%, including an average accuracy of 97.1% for identifying individual migraine patients and an average accuracy of 64.6% for identifying individual patients with persistent post-traumatic headache. The most important clinical features that contributed to the classification accuracy included questions related to anxiety and decision making. Cortical brain features and fibertract data from the following regions or tracts most contributed to the classification accuracy: Bilateral superior temporal, inferior parietal and posterior cingulate; right lateral occipital, uncinate, and superior longitudinal fasciculus. A post-hoc analysis showed that compared to incorrectly classified persistent post-traumatic headache patients, those who were correctly classified as having persistent post-traumatic headache had more severe physical, autonomic, anxiety and depression symptoms, were more likely to have post-traumatic stress disorder, and were more likely to have had mild traumatic brain injury attributed to blasts. Discussion A classification model that included a combination of questionnaire data and structural imaging parameters classified individual patients as having migraine versus persistent post-traumatic headache with good accuracy. The most important clinical measures that contributed to the classification accuracy included questions on mood. Regional brain structures and fibertracts that play roles in pain processing and pain integration were important brain features that contributed to the classification accuracy. The lower classification accuracy for patients with persistent post-traumatic headache compared to migraine may be related to greater heterogeneity of patients in the persistent post-traumatic headache cohort regarding their traumatic brain injury mechanisms, and physical, emotional, and cognitive symptoms.

Abstract Background and Objectives Prior studies have established an association between a history of abuse and the development of migraine. This cross‐sectional observational study explored the relationship between self‐reported abuse history with migraine‐related sensory hypersensitivity symptoms. Methods In total, 588 adult patients with migraine from the American Registry for Migraine Research completed questionnaires: Generalized Anxiety Disorder‐7, Patient Health Questionnaire‐2 for depression, Photosensitivity Assessment Questionnaire, Hyperacusis Questionnaire, and Allodynia Symptom Checklist. Using four binary screening questions, patients were asked to self‐report if they believed they had suffered emotional, physical, or sexual abuse in their lifetime. Differences in questionnaire scores between groups with and without a history of abuse were determined. Regression models adjusted for age, sex, and basic headache features analyzed the relationship between abuse history and sensory hypersensitivity symptoms. Moderation analysis explored the role of headache frequency in this relationship. Mediation analysis assessed the indirect (Mediated) effect (IE) of abuse on sensory hypersensitivity through depression or anxiety. Additional models analyzed relationships between sensory hypersensitivity symptoms and abuse subtypes or the number of abuse subtypes. Results Of 588 participants, 222 (38%) reported a history of abuse. Patients with a history of abuse reported statistically significantly greater average headache frequency (7.6 vs. 4.7 days, p = 0.030). Patients with a history of abuse also reported higher average or median questionnaire scores: anxiety (7.6 vs. 4.7, p < 0.001, d = 0.56), depression (1.7 vs. 1.3, p = 0.009, d = 0.24), photophobia (0.54 vs. 0.44, p < 0.001, d = 0.32), hyperacusis (19.6 vs. 14.9, p < 0.001, d = 0.49), ictal allodynia (6.0 vs. 3.0, p < 0.001, d = 0.46), and interictal allodynia (1.0 vs. 0.0, p < 0.001, d = 0.30). After controlling for patient age, sex and years lived with headache, abuse maintained a significant association with every sensory hypersensitivity measure. Headache frequency significantly moderated the relationship between a history of abuse with increased ictal allodynia ( p = 0.036). Anxiety significantly mediated the relationships between abuse with photophobia (IE = 0.03, 95% CI = 0.01–0.04), hyperacusis (IE = 1.51, 95% CI = 0.91–2.24), ictal allodynia (IE = 0.02, 95% CI = 0.01–0.04), and interictal allodynia (IE = 0.02, 95% CI = 0.01–0.06). Depression significantly mediated the relationship between abuse with photophobia (IE = 0.02, 95% CI = 0.01–0.03) and with hyperacusis (IE = 0.45, 95% CI = 0.11–0.88). The association between the individual subtypes of abuse and the number of subtypes of abuse with sensory hypersensitivity symptoms varied. Conclusion A history of abuse is associated with greater migraine‐related sensory hypersensitivity symptoms. To reduce the impact of abuse on migraine symptoms, future studies should explore mechanistic connections between abuse and migraine‐associated symptoms.

Abstract Objective Persistent posttraumatic headache (PPTH), one of the most common symptoms following mild traumatic brain injury, is often associated with substantial functional disability. The objective of this study was to assess the contribution of demographics, headache characteristics, and psychological symptoms to disability associated with PPTH. Methods Participants completed the State-Trait Anxiety Inventory (STAI), the Beck Depression Inventory (BDI), the Pain Catastrophizing Scale (PCS), and the Migraine Disability Assessment (MIDAS) questionnaire. Two linear regression models were formulated to interrogate the relationships between 1) demographics and headache characteristics with the MIDAS questionnaire and 2) demographics, headache characteristics, and psychological symptoms with the MIDAS questionnaire. A two-way stepwise regression using the Akaike information criterion was performed to find a parsimonious model describing the relationships between demographics, headache characteristics, and psychological measures with the MIDAS questionnaire. Results Participants included 58 patients with PPTH and 39 healthy controls (HCs). The median MIDAS score among those with PPTH was 48.0 (first quartile [1Q] = 20.0, third quartile [3Q] = 92.0), indicative of severe disability. Compared with the HCs, those with PPTH had higher scores on the BDI, STAI, and PCS. Older age predicted lower MIDAS scores (age: B=–0.11, P&lt;0.01), whereas higher headache frequency, greater headache intensity, and higher trait anxiety scores predicted higher MIDAS scores in individuals with PPTH (headache frequency: B=0.07, P&lt;0.001; headache intensity: B=0.51, P=0.04; trait anxiety score: B=1.11, P=0.01). Conclusions Individuals with PPTH had substantial psychological symptoms and headache-related disability. Disability was partially explained by age, headache frequency and intensity, and trait anxiety. Holistic management of patients with PPTH to address headaches and psychological symptoms might reduce headache-associated disability.

Background and Objective: Symptoms of persistent post-traumatic headache (PPTH) most often resemble those of migraine, including the presence of photo-, phono-, and cutaneous hypersensitivities. The severity of these hypersensitivity symptoms in those with PPTH compared to those with migraine has yet to be fully elucidated. The objective of this study was to compare symptoms of sensory hypersensitivities between PPTH, migraine, and healthy controls (HCs). Further defining characteristics of PPTH and its similarities to migraine might assist with developing future diagnostic criteria for PPTH and provide insights into PPTH mechanisms. Methods: This analysis included 56 individuals with PPTH attributed to mild traumatic brain injury, 30 with migraine, and 36 HCs. To assess sensory hypersensitivities, all subjects completed the Allodynia Symptom Checklist-12, the Photosensitivity Assessment Questionnaire, and the Hyperacusis Questionnaire. Differences among groups were assessed using Fisher’s exact test, Kruskal–Wallis, or Mann–Whitney U test. Results: PPTH and migraine groups had greater severity of cutaneous, photo-, and phono-hypersensitivity symptoms compared to HCs. There were no statistically significant differences between the PPTH and migraine groups for cutaneous allodynia (median [first quartile, third quartile]; PPTH: 4.0 [2.0, 7.0]; migraine: 5.0 [3.0, 8.0]; p = 0.54) or photosensitivity severity (PPTH: 5.0 [2.0, 7.0]; migraine: 5.0 [2.0, 6.0]; p = 0.53). Those with PPTH had higher hyperacusis scores compared to those with migraine (PPTH: 23.0 [17.0, 31.0]; migraine: 13.5 [9.0, 24.0]; p = 0.001). Conclusion: Sensory hypersensitivity symptoms among individuals with PPTH are at least as severe as those experienced by people with migraine. Results further confirm symptom similarities between PPTH and migraine and could suggest that PPTH and migraine have a partially shared underlying pathophysiology.

Background and Objectives The association between migraine, depression, and anxiety has been established, but the impact of these psychiatric comorbidities on functional impairment in people with migraine has been under‐investigated. The purpose of this cross‐sectional observational study was to investigate the relationship between anxiety and depression symptoms on migraine‐related disability, pain interference, work interference, and career success in a cohort of patients with migraine. Methods This analysis included 567 migraine patients who had been enrolled into the American Registry for Migraine Research (ARMR) between February 2016 and June 2019. Patients completed the Generalized Anxiety Disorder‐7 (GAD‐7) and Patient Health Questionnaire‐2 (PHQ‐2) to measure symptoms of anxiety and depression, respectively. Patients completed the Migraine Disability Assessment Scale (MIDAS), Pain Interference (PROMIS pain short) questionnaire, and Work Productivity and Activity Interference (WPAI) questionnaire to measure levels of functional impairment at work and in daily activities. In addition, patients answered questions designed for ARMR regarding education and career interference. Models were created to describe the relationship between severity of psychiatric symptoms (anxiety and depression), and each outcome of interest (WPAI, MIDAS, pain interference, reporting that migraine had interfered with career success). Each model was controlled for age, sex, headache frequency, years with migraine, and average headache intensity. Results Among the 567 patients with migraine, mean (SD) age was 47.1 (13.7), 87.3% were female, and average headache frequency was 19.1 (9.3) days/month. PHQ‐2 scores were positively associated with scores on MIDAS ( b = 0.06, SE = 0.01, P ≤ .001), pain interference ( b = 1.4, SE = 0.2, P < .001), and WPAI including absenteeism ( b = 0.16, SE = 0.04, P = .007), presenteeism ( b = 2.7, SE = 1.1, P = .012), overall work productivity impairment ( b = 3.7, SE = 1.2, P = .001), and activity impairment ( b = 3.0, SE = 1.2, P = .009). PHQ‐2 scores were also associated with reporting that migraine interfered with career success ( b = 0.34, SE = 0.08, P ≤ .001). GAD‐7 scores were not associated with MIDAS, pain interference, WPAI, or reduced career success. Conclusions Severity of depression symptoms in patients with migraine is associated with migraine‐related disability, work interference, pain interference, and reduced career success. Patients with more severe symptoms of depression are more likely to have greater functional impairment. A management approach that addresses depression in those with migraine may lead to improvements in patient functioning.

Abstract Background Close associations between insomnia with other clinical factors have been identified in migraine, but there have been few studies investigating associations between insomnia and clinical factors in patients with persistent post-traumatic headache (PPTH). The study objective was to contrast the severity of insomnia symptoms in PPTH, migraine, and healthy controls, and to identify factors associated with insomnia in patients with PPTH vs. migraine. Methods In this cross-sectional cohort study, 57 individuals with PPTH attributed to mild traumatic brain injury, 39 with migraine, and 39 healthy controls were included. Participants completed a detailed headache characteristics questionnaire, the Migraine Disability Assessment Scale (MIDAS), Insomnia Severity Index (ISI), Hyperacusis Questionnaire (HQ), Allodynia Symptom Checklist, Photosensitivity Assessment Questionnaire, Beck Depression Inventory (BDI), State-Trait Anxiety Inventory, Post-Traumatic Stress Disorder (PTSD) checklist, Ray Auditory Verbal Learning Test, and the Trail Making Test A and B to assess headache characteristics, disability, insomnia symptoms, sensory hypersensitivities, and neuropsychological factors. Fisher’s test and one-way ANOVA or Tukey’s Honest Significant Difference were used to assess group differences of categorical and continuous data. Stepwise linear regression analyses were conducted to identify clinical variables associated with insomnia symptoms. Results Those with PPTH had significantly higher ISI scores (16.7 ± 6.6) compared to migraine patients (11.3 ± 6.4) and healthy controls (4.1 ± 4.8) ( p < 0.001). For those with PPTH, insomnia severity was most strongly correlated with the BDI (Spearman's rho ( Common.EditSubmissionSteps.Transform.EquationText ) = 0.634, p < 0.01), followed by Trait Anxiety ( Common.EditSubmissionSteps.Transform.EquationText = 0.522, p < 0.01), PTSD ( Common.EditSubmissionSteps.Transform.EquationText = 0.505, p < 0.01), HQ ( Common.EditSubmissionSteps.Transform.EquationText = 0.469, p < 0.01), State Anxiety ( Common.EditSubmissionSteps.Transform.EquationText = 0.437, p < 0.01), and MIDAS scores ( Common.EditSubmissionSteps.Transform.EquationText = 0.364, p < 0.01). According to linear regression models, BDI, headache intensity, and hyperacusis scores were significantly positively associated with insomnia severity in those with PPTH, while only delayed memory recall was negatively associated with insomnia severity in those with migraine. Conclusions Insomnia symptoms were more severe in those with PPTH compared to migraine and healthy control cohorts. Depression, headache intensity, and hyperacusis were associated with insomnia in individuals with PPTH. Future studies should determine the bidirectional impact of treating insomnia and its associated symptoms.