Guidelines of the International Headache Society for controlled trials of pharmacological preventive treatment for persistent post-traumatic headache attributed to mild traumatic brain injury.

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.

Photophobia Contributes to Migraine-Associated Disability and Reduced Work Productivity: Results From the American Registry for Migraine Research (ARMR).

BACKGROUND: Photosensitivity, often called "photophobia" in the migraine literature, is a common and bothersome symptom for most people during their migraine attacks. This study aimed to investigate the association of photophobia severity with work productivity, activity impairment, and migraine-associated disability using data from a large cohort of patients with migraine who were enrolled into the American Registry for Migraine Research (ARMR). METHODS: This study used Photosensitivity Assessment Questionnaire (PAQ) scores to investigate the relationship between photophobia severity with work productivity and activity impairment (using the Work Productivity and Activity Impairment [WPAI] questionnaire) and migraine-related disability (using the Migraine Disability Assessment [MIDAS]) among those with migraine. Summary statistics are presented as means and standard deviations for variables that were normally distributed and as medians and interquartile ranges for variables that were not normally distributed. Multiple linear regression models were developed to measure the relationships between photophobia scores with work productivity and activity impairment and migraine-associated disability, controlling for age, sex, headache frequency, headache intensity, anxiety (using the generalized anxiety disorder [GAD-7]), and depression (using the Patient Health Questionnaire [PHQ-2]). RESULTS: One thousand eighty-four participants were included. Average age was 46.1 (SD 13.8) years, 87.2% (n = 945) were female, average headache frequency during the previous 90 days was 44.3 (SD 29.9), average headache intensity was 5.9 (SD 1.7), median PHQ-2 score was 1 (IQR 0-2), and median GAD-7 was 5 (IQR 2-8). Mean PAQ score was 0.47 (SD 0.32), and median MIDAS score was 38 (IQR 15.0-80.0). Among the 584 employed participants, 47.4% (n = 277) reported missing work in the past week because of migraine, mean overall work impairment was 42.8% (SD 26.7), mean activity impairment was 42.5% (SD 26.2), mean presenteeism score was 38.4% (SD 24.4), and median absenteeism was 0 (IQR 0-14.5). After controlling for age, sex, headache frequency, average headache intensity, PHQ-2 score, and GAD-7 score, there was a statistically significant association between photophobia scores with: a) MIDAS scores (F[7,1028] = 127.42, P < 0.001, R2 = 0.461, n = 1,036); b) overall work impairment (F[7,570] = 29.23, P < 0.001, R2 = 0.255, n = 578); c) activity impairment (F[7,570] = 27.42, P < 0.001, R2 = 0.243, n = 578); d) presenteeism (F[7,570] = 29.17, P < 0.001, R2 = 0.255, n = 578); and e) absenteeism for the zero-inflated (P = 0.003) and negative binomial (P = 0.045) model components (P < 0.001, n = 578). CONCLUSIONS: In those with migraine, severe photophobia is associated with reduced work productivity and higher presenteeism, absenteeism, activity impairment, and migraine-related disability.

Harmonizing Healthy Cohorts to Support Multicenter Studies on Migraine Classification using Brain MRI Data.

Multicenter and multi-scanner imaging studies might be needed to provide sample sizes large enough for developing accurate predictive models. However, multicenter studies, which likely include confounding factors due to subtle differences in research participant characteristics, MRI scanners, and imaging acquisition protocols, might not yield generalizable machine learning models, that is, models developed using one dataset may not be applicable to a different dataset. The generalizability of classification models is key for multi-scanner and multicenter studies, and for providing reproducible results. This study developed a data harmonization strategy to identify healthy controls with similar (homogenous) characteristics from multicenter studies to validate the generalization of machine-learning techniques for classifying individual migraine patients and healthy controls using brain MRI data. The Maximum Mean Discrepancy (MMD) was used to compare the two datasets represented in Geodesic Flow Kernel (GFK) space, capturing the data variabilities for identifying a "healthy core". A set of homogeneous healthy controls can assist in overcoming some of the unwanted heterogeneity and allow for the development of classification models that have high accuracy when applied to new datasets. Extensive experimental results show the utilization of a healthy core. One dataset consists of 120 individuals (66 with migraine and 54 healthy controls) and another dataset consists of 76 (34 with migraine and 42 healthy controls) individuals. A homogeneous dataset derived from a cohort of healthy controls improves the performance of classification models by about 25% accuracy improvements for both episodic and chronic migraineurs.

Prevalence of and Risk Factors for Post-traumatic Headache in Civilian Patients After Mild Traumatic Brain Injury: A TRACK-TBI Study.

OBJECTIVE: To ascertain the prevalence of and risk factors for post-traumatic headache (PTH) attributed to mild traumatic brain injury (mTBI). PATIENTS AND METHODS: A prospective, longitudinal, multicenter cohort study of patients with mTBI and orthopedic trauma controls who were enrolled from February 26, 2014, to August 8, 2018. The baseline assessment was conducted as soon as possible following evaluation at the emergency department. Follow-ups were scheduled at 2 weeks, 3 months, 6 months, and 12 months postinjury. Eligible patients with mTBI included those 18 years of age or older who presented to the emergency department within 24 hours of head injury warranting evaluation by noncontrast head computed tomography scan. Acute PTH was considered present when a patient reported a headache score of greater than or equal to 2 on the Rivermead Post-concussion Questionnaire at 2 weeks postinjury (ie, headache is at least a mild problem compared with pre-injury). Persistent PTH was defined when a patient with acute PTH reported a Rivermead Post-concussion Questionnaire headache score of greater than or equal to 2 at the scheduled follow-up examinations. RESULTS: Acute PTH was reported by 963 (60.4%) of 1594 patients with mTBI at 2 weeks postinjury. Among those with acute PTH, 439 (52.4%) of 837 patients reported persistent PTH at 3 months postinjury. This figure decreased over time and 278 (37.5%) of 742 patients continued to report persistent PTH at 6 months, whereas 187 (28.9%) of 646 patients did so as well at 12 months postinjury. Risk factors for acute PTH included younger age, female sex, fewer years of formal education, computed tomography-positive scans, alteration of consciousness, psychiatric history, and history of migraine. Risk factors for persistent PTH included female sex, fewer years of formal education, and history of migraine. CONCLUSION: Post-traumatic headache is a prevalent sequela of mTBI that persists for at least 12 months in a considerable proportion of affected individuals. The attributable burden necessitates better patient follow-up, disease characterization, improved awareness of PTH in clinical practice, and identification of effective therapies.

Questionnaire and structural imaging data accurately predict headache improvement in patients with acute 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.

Thalamic subfield iron accumulation after acute mild traumatic brain injury as a marker of future post-traumatic headache intensity.

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.

Developing multivariable models for predicting headache improvement in patients with acute post-traumatic headache attributed to mild traumatic brain injury: A preliminary study.

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 R = 0.64 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.

Longitudinal changes in functional connectivity and pain-induced brain activations in patients with migraine: a functional MRI study pre- and post- treatment with Erenumab.

BACKGROUND: Migraine involves central and peripheral nervous system mechanisms. Erenumab, an anti-calcitonin gene-related peptide (CGRP) receptor monoclonal antibody with little central nervous system penetrance, is effective for migraine prevention. The objective of this study was to determine if response to erenumab is associated with alterations in brain functional connectivity and pain-induced brain activations. METHODS: Adults with 6-25 migraine days per month during a 4-week headache diary run-in phase underwent pre-treatment brain functional MRI (fMRI) that included resting-state functional connectivity and BOLD measurements in response to moderately painful heat stimulation to the forearm. This was followed by two treatments with 140 mg erenumab, at baseline and 4 weeks later. Post-treatment fMRI was performed 2 weeks and 8 weeks following the first erenumab treatment. A longitudinal Sandwich estimator analysis was used to identify pre- to post-treatment changes in resting-state functional connectivity and brain activations in response to thermal pain. fMRI findings were compared between erenumab treatment-responders vs. erenumab non-responders. RESULTS: Pre- and post-treatment longitudinal imaging data were available from 32 participants. Average age was 40.3 (+/- 13) years and 29 were female. Pre-treatment average migraine day frequency was 13.8 (+/- 4.7) / 28 days and average headache day frequency was 15.8 (+/- 4.4) / 28 days. Eighteen of 32 (56%) were erenumab responders. Compared to erenumab non-responders, erenumab responders had post-treatment differences in 1) network functional connectivity amongst pain-processing regions, including higher global efficiency, clustering coefficient, node degree, regional efficiency, and modularity, 2) region-to-region functional connectivity between several regions including temporal pole, supramarginal gyrus, and hypothalamus, and 3) pain-induced activations in the middle cingulate, posterior cingulate, and periaqueductal gray matter. CONCLUSIONS: Reductions in migraine day frequency accompanying erenumab treatment are associated with changes in resting state functional connectivity and central processing of extracranial painful stimuli that differ from erenumab non-responders. TRIAL REGISTRATION: clinicaltrials.gov (NCT03773562).

Migraine and Posttraumatic Headache: Similarities and Differences in Brain Network Connectivity.

Posttraumatic 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.

The Characteristics of White Matter Hyperintensities in Patients With Migraine.

Background: The presence of white matter hyperintensities (WMHs) in migraine is well-documented, but the location of WMH in patients with migraine is insufficiently researched. This study assessed WMH in patients with migraine using a modified version of the Scheltens visual rating scale, a semiquantitative scale for categorizing WMH in periventricular, lobar, basal ganglia, and infratentorial regions. Methods: In total, 263 patients with migraine (31 men and232 women) enrolled in the American Registry for Migraine Research (ARMR) from Mayo Clinic Arizona and who had clinical brain magnetic resonance imaging (MRI) were included in this study. Those with imaging evidence for gross anatomical abnormalities other than WMHs were excluded. A board-certified neuroradiologist identified WMHs on axial T2 and fluid-attenuated inversion recovery (FLAIR) sequences. WMHs were characterized via manual inspection and categorized according to the scale's criteria. Results: Results showed that 95 patients (36.1%, mean age: 41.8 years) had no WMHs on axial T2 and FLAIR imaging and 168 patients (63.9%, mean age: 51.4 year) had WMHs. Of those with WMHs, 94.1% (n = 158) had lobar hyperintensities (frontal: 148/158, 93.7%; parietal: 57/158, 36.1%; temporal: 35/158, 22.1%; and occipital: 9/158, 5.7%), 13/168, 7.7% had basal ganglia WMHs, 49/168, 29.1% had periventricular WMHs, and 17/168, 10.1% had infratentorial WMHs. In addition, 101/168 patients (60.1%) had bilateral WMHs and 67/168 (39.9%) had unilateral WMHs (34 right hemisphere/33 left hemisphere). Discussion: Among ARMR participants who were enrolled by Mayo Clinic Arizona and who had clinical brain MRIs, nearly two-thirds had WMHs. The WMHs were the most common in the frontal lobes. Describing the features of WMHs in those with migraine, and comparing them with WMHs attributable to other etiologies, might be useful for developing classifiers that differentiate between migraine-specific WMH and other causes of WMH.

Cutaneous heat and light-induced pain thresholds in post-traumatic headache attributed to mild traumatic brain injury.

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.

Discriminant Subgraph Learning from Functional Brain Sensory Data.

The human brain is a complex system with many functional units interacting with each other. This interacting relationship, known as the functional connectivity network (FCN), is critical for brain functions. To learn the FCN, machine learning algorithms can be built based on brain signals captured by sensing technologies such as EEG and fMRI. In neurological diseases, past research has revealed that the FCN is altered. Also, focusing on a specific disease, some part of the FCN, i.e., a sub-network, can be more susceptible than other parts. However, the current knowledge about disease-specific sub-networks is limited. We propose a novel Discriminant Subgraph Learner (DSL) to identify a functional sub-network that best differentiates patients with a specific disease from healthy controls based on brain sensory data. We develop an integrated optimization framework for DSL to simultaneously learn the FCN of each class and identify the discriminant sub-network. Further, we develop tractable and converging algorithms to solve the optimization. We apply DSL to identify a functional sub-network that best differentiates patients with episodic migraine (EM) from healthy controls based on a fMRI dataset. DSL achieved the best accuracy compared to five state-of-the-art competing algorithms.

T2* reduction in patients with acute post-traumatic headache.

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.

The value of brain MRI functional connectivity data in a machine learning classifier for distinguishing migraine from persistent post-traumatic headache.

Background: Post-traumatic headache (PTH) and migraine often have similar phenotypes. The objective of this exploratory study was to develop classification models to differentiate persistent PTH (PPTH) from migraine using clinical data and magnetic resonance imaging (MRI) measures of brain structure and functional connectivity (fc). Methods: Thirty-four individuals with migraine and 48 individuals with PPTH attributed to mild TBI were included. All individuals completed questionnaires assessing headache characteristics, mood, sensory hypersensitivities, and cognitive function and underwent brain structural and functional imaging during the same study visit. Clinical features, structural and functional resting-state measures were included as potential variables. Classifiers using ridge logistic regression of principal components were fit on the data. Average accuracy was calculated using leave-one-out cross-validation. Models were fit with and without fc data. The importance of specific variables to the classifier were examined. Results: With internal variable selection and principal components creation the average accuracy was 72% with fc data and 63.4% without fc data. This classifier with fc data identified individuals with PPTH and individuals with migraine with equal accuracy. Conclusion: Multivariate models based on clinical characteristics, fc, and brain structural data accurately classify and differentiate PPTH vs. migraine suggesting differences in the neuromechanism and clinical features underlying both headache disorders.

Altered speech patterns in subjects with post-traumatic headache due to mild traumatic brain injury.

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 3 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 yet more precise 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 production may have been more effortful resulting in slower speaking rates and more precise vowel articulation during headache vs. when they were headache-free, suggesting that speech alterations were related to PTH and not solely due to the underlying mTBI.

Distinguishing persistent post-traumatic headache from migraine: Classification based on clinical symptoms and brain structural MRI data.

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.

Impact of abuse on migraine-related sensory hypersensitivity symptoms: Results from the American Registry for Migraine Research.

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.

Headache Characteristics and Psychological Factors Associated with Functional Impairment in Individuals with Persistent Posttraumatic Headache.

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<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<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.