Schwedt, Todd J.

Background Post-traumatic headache is very common after a mild traumatic brain injury. Post-traumatic headache may persist for months to years after an injury in a substantial proportion of people. The pathophysiology underlying post-traumatic headache remains unknown but is likely distinct from other headache disorders. Identification of brain areas activated in acute and persistent phases of post-traumatic headache can provide insights into the underlying circuits mediating headache pain. We used an animal model of mild traumatic brain injury-induced post-traumatic headache and c-fos immunohistochemistry to identify brain regions with peak activity levels across the acute and persistent phases of post-traumatic headache. Methods Male and female C57BL/6 J mice were briefly anesthetized and subjected to a sham procedure or a weight drop closed-head mild traumatic brain injury . Cutaneous allodynia was assessed in the periorbital and hindpaw regions using von Frey filaments. Immunohistochemical c-fos based neural activity mapping was then performed on sections from whole brain across the development of post-traumatic headache (i.e. peak of the acute phase at 2 days post- mild traumatic brain injury), start of the persistent phase (i.e. >14 days post-mild traumatic brain injury) or after provocation with stress (bright light). Brain areas with consistent and peak levels of c-fos expression across mild traumatic brain injury induced post-traumatic headache were identified and included for further analysis. Results Following mild traumatic brain injury, periorbital and hindpaw allodynia was observed in both male and female mice. This allodynia was transient and subsided within the first 14 days post-mild traumatic brain injury and is representative of acute post-traumatic headache. After this acute post-traumatic headache phase, exposure of mild traumatic brain injury mice to a bright light stress reinstated periorbital and hindpaw allodynia for several hours – indicative of the development of persistent post-traumatic headache. Acute post-traumatic headache was coincident with an increase in neuronal c-fos labeling in the spinal nucleus of the trigeminal caudalis, primary somatosensory cortex, and the nucleus accumbens. Neuronal activation returned to baseline levels by the persistent post-traumatic headache phase in the spinal nucleus of the trigeminal caudalis and primary somatosensory cortex but remained elevated in the nucleus accumbens. In the persistent post-traumatic headache phase, coincident with allodynia observed following bright light stress, we observed bright light stress-induced c-fos neural activation in the spinal nucleus of the trigeminal caudalis, primary somatosensory cortex, and nucleus accumbens. Conclusion Examination of mild traumatic brain injury-induced changes in peak c-fos expression revealed brain regions with significantly increased neural activity across the acute and persistent phases of post-traumatic headache. Our findings suggest mild traumatic brain injury-induced post-traumatic headache produces neural activation along pain relevant pathways at time-points matching post-traumatic headache-like pain behaviors. These observations suggest that the spinal nucleus of the trigeminal caudalis, primary somatosensory cortex, and nucleus accumbens may contribute to both the induction and maintenance of post-traumatic headache.

Abstract Objective To assess healthcare costs and healthcare resource utilization (HCRU) among adult patients who newly initiated erenumab in the United States. Methods This retrospective, non‐interventional analysis included adult patients (aged ≥18 years) newly initiating erenumab and who had three consecutive monthly claims for erenumab (11/1/2017–9/1/2019) from the Komodo Health database. Outcomes included migraine‐related and all‐cause costs, use of other preventive/acute migraine medications, and HCRU. All outcomes were compared during the 180‐day pre‐ versus the 180‐day post‐index periods. Cost outcomes were also assessed for longer periods including post‐index Days 91–270 and monthly mean post‐index costs for the longest time of continuous insurance enrollment. Results Overall, 1839 patients with migraine were included for analysis. Compared to the 180‐day pre‐index period, an increase in total migraine‐related costs (+$2639; p < 0.0001), migraine‐related prescription costs (+$3435, p < 0.0001), all‐cause total costs (+$2977; p < 0.001), and all‐cause prescription costs (+$4102; p < 0.0001) were observed during the 180‐day post‐index period after adjusting for covariates. Conversely, reduction in migraine‐related medical costs (−$896; p < 0.0001), and significantly lower odds of migraine‐related emergency room visits (odds ratio [OR] 0.60, 95% confidence interval [CI] 0.44–0.82; p = 0.001), migraine‐related office visits (OR 0.58, 95% CI 0.53–0.64; p < 0.0001), and migraine‐related neurologist visits (OR 0.69, 95% CI 0.63–0.75; p < 0.0001) were observed during the 180‐days post‐index period. There were significant decreases in the odds of having overall preventive migraine medications (OR 0.81, 95% CI 0.75–0.87; p < 0.0001), acute‐migraine medications (OR 0.92, 95% CI 0.85–1.00; p = 0.038), and triptan (OR 0.79, 95% CI 0.73–0.85; p < 0.0001) during the 180‐day post‐index period. Sensitivity analyses on cost outcomes found no statistically significant differences in pre‐index migraine‐related costs compared to post‐index migraine‐related costs when assessing longer post‐index follow‐up periods. Conclusion Initiation of therapy with a novel treatment is often associated with an increase in overall healthcare costs due to the entrance costs associated with novel therapy. For a chronic condition such as migraine, cost versus health benefits should be evaluated over a long period (e.g., ≥2 years) to better understand the true benefits of therapy. Data from this study suggest that the entrance cost for erenumab, the primary driver of the high post‐index prescription costs gets mitigated by reduced medical costs over long‐term follow‐up. The results indicate better disease management in adult patients with migraine, which should be an important consideration for both patients and payors, as these findings have shown an offset between migraine‐related prescription and medical costs.

Abstract Objective To examine whether sensory hypersensitivity contributes to headache‐related disability in a secondary analysis of patients with post‐traumatic headache. Background Up to one‐third of individuals with traumatic brain injuries report persistent headache 3 months post‐injury. High rates of allodynia and photophobia have been observed in clinical studies and animal models of post‐traumatic headache, but we do not fully understand how sensory amplifications impact post‐traumatic headache‐related disability. Methods We identified a cross‐sectional sample of patients from the American Registry for Migraine Research database with new or worsening headaches post‐head injury from 2016 to 2020 and performed a secondary analysis of those data. We modeled the relationship between sensory sensitivity and Migraine Disability Assessment scores using questionnaires. Candidate variables included data collection features (study site and year), headache‐related and general clinical features (headache frequency, migraine diagnosis, abuse history, sex, age, cognitive and affective symptom scores), and sensory symptoms (related to light, sound, and touch sensitivity). Results The final sample included 193 patients (median age 46, IQR 22; 161/193, 83.4% female). Migraine Disability Assessment scores ranged from 0 to 260 (median 47, IQR 87). The final model included allodynia, hyperacusis, photosensitivity, headache days per month, abuse history, anxiety and depression, cognitive dysfunction, and age ( R 2 = 0.43). An increase of one point in allodynia score corresponded to a 3% increase in headache disability (95% CI: 0%–7%; p = 0.027), an increase of one‐tenth of a point in the photosensitivity score corresponded to a 12% increase (95% CI: 3%–25%; p = 0.002), and an increase of one point in the hyperacusis score corresponded to a 2% increase (95% CI: 0%–4%; p = 0.016). Conclusions Increased photosensitivity, allodynia, and hyperacusis were associated with increased headache‐related disability in this sample of patients with post‐traumatic headache. Symptoms of sensory amplification likely contribute to post‐traumatic headache‐related disability and merit an ongoing investigation into their potential as disease markers and treatment targets.

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.