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.

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.

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.

Altered Hypothalamic Region Covariance in Migraine and Cluster Headache: A Structural MRI Study.

OBJECTIVES: The hypothalamus plays a key role in both migraine and cluster headache (CH). As brain region-to-region structural correlations are believed to reflect structural and functional brain connectivity patterns, we assessed the structural covariance patterns between the volume of the hypothalamic region and vertex-by-vertex measurements of cortical thickness in patients with migraine and in those with CH relative to healthy controls (HC). METHODS: T1-weighted images were acquired on a 3T MRI scanner for a total of 59 subjects including 18 patients with CH (age: mean = 43.8, SD = 12.4), 19 with migraine (age: mean = 40.1, SD = 12.2), and 22 HCs (age: mean = 39.1, SD = 8.2). Imaging was collected between attacks (migraineurs) and during out-of-bout phases (CH). Data were post-processed using FreeSurfer version 6.0 and within-group correlations between hypothalamic region volume with cortical thickness were explored using a whole-brain vertex-wise linear model approach. Between-group differences in correlation slopes between hypothalamic region volume and vertex-by-vertex measurements of cortical thickness were interrogated using post-hoc comparisons. RESULTS: There were no significant between-group differences (migraine vs CH; migraine vs HC; or CH vs HC) for age, sex, total brain volume or volume of the left or right hypothalamic region. For each group, there were significant positive correlations (P < .01) between right and left hypothalamic region volumes with cortical thickness measurements. HC had significant positive correlations between hypothalamic region volume and cortical thickness over large portions of the superior and rostral medial frontal, orbitofrontal cortex and rostral anterior cingulate, and smaller clusters in the superior and middle temporal, posterior cingulate, fusiform, and precentral cortex. Post-hoc analysis showed significant differences in covariance patterns in those with migraine and CH relative to HC, with both migraine patients and CH having weaker structural covariance of hypothalamic region volume with frontal and temporal cortical thickness. CONCLUSION: Recent evidence suggests hypothalamic region connectivity to frontal and temporal areas to be relevant for regulating pain perception. Thus, the diminished structural covariance in migraineurs and CH might suggest abnormal functioning of the pain control circuitry and contribute to mechanisms underlying central sensitization and chronification of pain.

The American Registry for Migraine Research: Research Methods and Baseline Data for an Initial Patient Cohort.

BACKGROUND: The American Registry for Migraine Research (ARMR) is a multicenter, prospective, longitudinal patient registry, biorepository, and neuroimaging repository that collects clinical data, electronic health record (EHR) data, blood samples, and brain imaging data from individuals with migraine or other headache types. In this manuscript, we outline ARMR research methods and report baseline data describing an initial cohort of ARMR participants. METHODS: Adults with any International Classification of Headache Disorders (ICHD) diagnosis were prospectively enrolled from one of the 8 participating headache specialty centers. At baseline, ARMR participants complete web-based questionnaires, clinicians enter the participant's ICHD diagnoses, an optional blood specimen is collected, and neuroimaging data are uploaded to the ARMR neuroimaging repository. Participants maintain the ARMR daily headache diary longitudinally and follow-up questionnaires are completed by participants every 3 months. EHR data are integrated into the ARMR database from a subset of ARMR sites. Herein, we describe the ARMR methodology and report the summary data from ARMR participants who had, from February 2016 to May 2019, completed at least 1 baseline questionnaire from which data are reported in this manuscript. Descriptive statistics are used to provide an overview of patient's sociodemographics, headache diagnoses, headache characteristics, most bothersome symptoms other than headache, headache-related disability, comorbidities, and treatments. RESULTS: Data were available from 996 ARMR participants, enrolled from Mayo Clinic Arizona, Dartmouth-Hitchcock Medical Center, University of Utah, University of Colorado, Thomas Jefferson University, University of Texas Health Science Center at Houston, Georgetown University Medical Center, and DENT Neurological Institute. Among ARMR participants, 86.7% (n = 864) were female and the mean age at the time of enrollment was 48.6 years (±13.9; range 18-84). The most common provider-reported diagnosis was chronic migraine (n = 622), followed by migraine without aura (n = 327), migraine with aura (n = 196), and medication overuse headache (n = 65). Average headache frequency was 19.1 ± 9.2 days per month (n = 751), with 68% reporting at least 15 headache days per month. Sensitivity to light was the most frequent (n = 222) most bothersome symptom overall, other than headache, but when present, cognitive dysfunction was most frequently (n = 157) the most bothersome symptom other than headache. Average migraine disability assessment (MIDAS) score was 52 ± 49 (n = 760), (very severe headache-related disability); however, 17% of the ARMR population had MIDAS scores suggesting "no" or "mild" disability. The most common non-headache health issues were allergies (n = 364), back pain (n = 296), neck pain (n = 296), depression (n = 292), and anxiety (n = 278). Nearly 85% (n = 695) of patients were using preventive medications and 24.7% were using non-medication preventive therapy (eg, vitamins and neuromodulation). The most common preventive medication classes were neurotoxins, anticonvulsants, antidepressants, vitamins/supplements, and anticalcitonin gene-related peptide ligand or receptor-targeted monoclonal antibodies. Nearly 90% (n = 734) of ARMR participants was taking medications to treat migraine attacks, with the most common classes being triptans, non-steroidal anti-inflammatory drugs, antiemetics, acetaminophen, and combination analgesics. CONCLUSIONS: ARMR is a source of real-world patient data, biospecimens, and brain neuroimaging data that provides comprehensive insight into patients with migraine and other headache types being seen in headache specialty clinics in the United States. ARMR data will allow for longitudinal and advanced analytics that are expected to lead to a better characterization of patient heterogeneity, healthcare resource utilization, identification of endophenotypes, factors that predict treatment outcomes and clinical course, and ultimately advance the field toward precision headache medicine.