In vivo biomarkers that can detect long-term neuropathologies from repetitive head impact (RHI) exposure are needed, especially for the neurodegenerative tauopathy chronic traumatic encephalopathy (CTE). Here, we evaluated plasma p -tau217 as a potential biomarker for CTE p -tau pathology, and examined the concordance between plasma p -tau217 and Aβ pathology in an at-risk for CTE sample. The sample included 180 male former football players (120 professional, 60 college), and 56 asymptomatic men without RHI (i.e., controls). Participants completed blood draws, 18F-florbetapir (Aβ+=SUVR≥1.10), and 18F-flortaucipir PET. Traumatic encephalopathy syndrome (TES) diagnoses were made. Single molecule array for plasma p -tau217 (ALZpath) was performed (≥0.6 cutoff used to maximize sensitivity). Nine participants had post-mortem tissue. ANCOVA examined group differences in p -tau217 (football vs controls; TES-CTE no, TES-CTE suggestive, TES-CTE possible/probable). Multivariable regression models tested associations between p -tau217 and florbetapir/flortaucipir PET. Covariates included age, race and APOE e4 . Sample characteristics are in Table 1. p -tau217 concentrations were higher in former football players compared to controls (est. marginal mean difference=-0.217, p  = 0.005). There were no group differences in Aβ-PET SUVR. No differences were found across TES-CTE certainty levels. In football players, higher p -tau217 was associated with higher Aβ-PET SUVR (B=1.380, 95%CI[0.597-2.155], p  = 0.001) but not when Aβ+ ( n  = 17) participants and those with kidney/liver disease ( n  = 5) were excluded. Aβ+ participants had the highest p -tau217 (Figure 1). When compared against Aβ-PET, several false Aβ-positives (high p -tau217, Aβ-) were identified, including one extreme outlier (assay related) and a cluster of Aβ- participants with p -tau217 between 0.60–1.0. There were no associations with flortaucipir SUVR (frontal, mesial temporal, left parietal). Two extreme p -tau217 outliers had autopsy-confirmed CTE stage III (AD-, Table 2). Of the remaining donors, all were AD- and four had CTE (stages II-IV) with ptau217 between 0.125-0.449. Plasma p -tau217 has usefulness in quantifying Aβ pathology but restricted utility for detection of CTE. In this at-risk for CTE sample, p -tau217 and Aβ-PET were associated at the group level. At the individual level, false Aβ-positives (and negatives) existed, including Aβ- participants with high p -tau217. We will explore whether this discrepancy is due to disease or peripheral interference with the N-terminal binding in p -tau assays.

Neurological disorders affect more than 3.4 billion people worldwide and are now the leading cause of disability globally. Despite remarkable advances in neuroscience, substantial inequities remain in access to prevention, diagnosis, treatment, and rehabilitation. World Brain Day 2026 adopts the theme "Brain Health: Access for All", calling for coordinated global action to reduce these disparities. The campaign recognises that equitable access to brain healthcare is essential to achieving healthier individuals, stronger communities, and more resilient health systems. It emphasises prevention across the life course, earlier diagnosis, community-based care, workforce development, and advocacy to improve neurological outcomes worldwide. Built around five core pillars and five strategic priorities, World Brain Day 2026 provides a practical framework for governments, healthcare professionals, researchers, patient organisations, and communities to work together towards equitable access to brain health. The campaign reinforces a simple but urgent message: access delayed is potentially access, and brain health, denied.

OBJECTIVE:Subjective cognitive complaints (SCC) can precede cognitive decline and are associated with demographic, exposure, lifestyle, and psychological factors. Prevalences of SCC and their correlates in individuals with repetitive head impacts (RHI) are poorly understood. This study characterized SCC in former elite American football players by frequency, mood and behavioral correlates, concordance with informant reports, and associations with neuropsychological test performance, cerebrospinal fluid (CSF), and magnetic resonance imaging (MRI) markers of neurodegeneration. METHOD:Former American football players (n = 180) completed measures of global and domain-specific SCC, neuropsychiatric symptom questionnaires, neuropsychological testing, lumbar puncture, and MRI. Elastic net regression evaluated the relative importance of potential SCC correlates. Intraclass correlation coefficients measured concordance between self and informant reports. Multiple linear regressions tested associations between SCC and verbal memory and executive functioning scores. CSF Aβ1-42, p-tau181, t-tau, neurofilament light (NfL), hippocampal volume, and regional cortical thickness were examined for their potential associations with SCC. RESULTS:Rates of SCC ranged from 43 to 77% depending on the domain. Symptoms of depression, impulsivity, and anxiety were strongly associated with SCC. Self- and informant-reported SCC showed moderate inter-rater agreement. Adjusting for age, race, education, APOE ϵ4 carrier status, and depressive symptoms, SCC were associated with lower objective verbal memory and executive functioning performance. SCC were associated with lower parahippocampal cortical thickness but not with hippocampal volume or any of the measured CSF tests. CONCLUSIONS:SCC are strongly associated with neuropsychiatric factors in former American football players. SCC may also be a marker of cognitive decline and neurodegeneration.

Importance:In vivo biomarkers for detecting neuropathologies from repetitive head impacts (RHI), including chronic traumatic encephalopathy (CTE), are needed. Objective:To evaluate the utility of plasma phosphorylated tau 217 (p-tau217), assess its performance as a beta-amyloid (Aβ) biomarker in participants with RHI exposure at risk for CTE, and explore concordance with CTE neuropathology in a postmortem subsample. Design, Setting, and Participants:This longitudinal, multicenter, case-control study used data from the Diagnostics, Imaging, and Genetics Network for the Objective Study and Evaluation of CTE (DIAGNOSE CTE) Research Project, collected from September 2016 to October 2023. Participants were former American football players (case participants) and asymptomatic men unexposed to RHI (control participants). A subsample had available neuropathologic data. Exposures:RHI, traumatic encephalopathy syndrome (TES) diagnoses, and levels of CTE certainty. Main Outcomes and Measures:Plasma p-tau217 (classified as positive [≥0.63 pg/mL], intermediate [0.40-0.62 pg/mL], and negative [<0.40 pg/mL]), Aβ-positron emission tomography (PET; 18F-florbetapir; with Aβ-positive defined as a standardized uptake value ratio [SUVR] ≥1.10), and tau-PET (18F-flortaucipir). TES diagnoses were assigned by multidisciplinary consensus conference. Analyses of postmortem brains controlled for age, race, and APOE ε4 status. Results:Among 231 participants (mean [SD] age, 57.75 [8.25] years), 177 were former football players (117 professional and 60 college) and 54 were unexposed participants. Former football players had higher baseline mean (SD) p-tau217 concentrations than unexposed participants (0.35 [0.26] pg/mL vs 0.27 [0.14] pg/mL; P = .008), although this was driven by a higher proportion of Aβ-PET-positive participants among former players. Plasma p-tau217 increased over time across the sample (B = 0.207 [95% CI, 0.117-0.298]; P < .001), with no significant time × exposure group interactions. Among football players, p-tau217 showed no time × group interactions with TES diagnosis, TES-CTE certainty, or RHI metrics. Higher p-tau217 concentration correlated with higher global Aβ-PET SUVR (B = 0.058 [95% CI, 0.053-3.501; P = .01), with a few discordant cases (5 participants were p-tau217-negative and Aβ-PET-positive; 7 participants were p-tau217-positive and Aβ-PET-negative). P-tau217 had similar areas under the curve for projecting Aβ-PET positivity as cerebrospinal fluid (CSF) p-tau181/Aβ42 and CSF Aβ40/42 measures (p-tau217: AUC, 0.88 [95% CI, 0.80-0.96]; CSF p-tau181/Aβ42: AUC, 0.89 [95% CI, 0.79-1.00]; CSF Aβ40/42: AUC, 0.85 [95% CI, 0.72-0.98]). Among 9 brain donors, 6 had CTE (stages II-IV; none with Alzheimer disease). Seven had negative or intermediate p-tau217, concordant with Aβ-PET. Two p-tau217 outliers with stage III CTE had normal concentrations upon additional testing. Conclusions and Relevance:The findings of this study suggest that plasma p-tau217 concentration is unlikely to be useful for the detection of CTE, but it does show utility for ruling out Aβ pathology in participants at risk for CTE.

Migraine attacks can be provoked in people with underlying primary headache disorders by multiple peripheral mechanisms suggesting the possible convergence of trigeminal nociceptive inputs onto a common, unknown central circuit. As calcitonin gene-related peptide (CGRP) expressing cells in the parabrachial nucleus (PBN) have been implicated in nociplastic pains, we hypothesized that (a) PBN CGRP-expressing neurons and their projections to the central amygdala (CeA) may be an essential central relay of multiple peripheral inputs promoting injury-free migraine headache and (b) this pathway may prioritize threat from activation of cranial afferents over other nociceptive inputs. Periorbital cutaneous allodynia (CA) was determined following supradural application of a cocktail of inflammatory mediators (IM), CGRP or pituitary adenylate cyclase-activating polypeptide (PACAP), or systemic administration of nitroglycerin (NTG) in CalcaCre or wild-type mice. Decreased rearing and photophobia were respectively evaluated as measures of ongoing headache and light-evoked migraine-like pain. Phosphorylation of extracellular signal-regulated kinases (pERK) was evaluated to assess regional neuronal activation. Compared with vehicle, supradural IM increased pERK in the trigeminal nucleus caudalis and PBN, but not in the paraventricular thalamus. Chemogenetic activation (Gq-DREADD) of PBN CGRP neurons elicited CA and photophobia while decreasing rearing. Lesioning of PBN neurons with ibotenic acid suppressed CA produced by supradural IM. Chemogenetic silencing (Gi-DREADD) or expression of tetanus toxin (TeNT) in PBN Calca neurons to prevent neurotransmitter release also inhibited CA elicited by supradural IM, CGRP, PACAP or systemic NTG. CRISPR/Cas9 editing of CeA receptor-associated membrane protein-1 (Ramp1) prevented IM-induced migraine-like symptoms revealing CGRP/CGRP-receptor activation from PBN→CeA projections. In contrast, PBN lesions, chemogenetic manipulation, and TeNT expression in PBN Calca cells and CeA Ramp1 CRISPR/Cas9 editing did not affect acute pain responses induced by hind paw IM injection, intraperitoneal acetic acid, or acute nociceptive behaviors from IM stimulation of the maxillary (V2) and mandibular (V3) branches of the trigeminal nerve. These data reveal a central pathway composed of PBN Calca neurons and CeA CGRP receptor signaling that is both sufficient to elicit migraine-like pain in naive mice and necessary to promote migraine-like pain following activation of the ophthalmic (V1) branch of the trigeminal nerve. Importantly, this pathway is essential for acute pain arising from V1 trigeminal, but dispensable for acute stimuli from other nociceptive afferents. The prioritization of V1 acute nociception suggests evolutionary importance for detecting threats to the head to promote survival through advantageous behaviors such as defensive coping observed in migraine.

BACKGROUND AND OBJECTIVES:The link between repetitive head impact (RHI) exposure, later-life cognitive decline, and neurobehavioral dysregulation (NBD) is not well understood. Recent work has implicated inflammation and limbic dysfunction as relevant RHI correlates. Our goal was to integrate plasma and CSF inflammatory biomarkers, structural brain imaging, and clinical measures in former elite American football players to better understand reasons for RHI-related cognitive and neurobehavioral changes. METHODS:Participants were from the Diagnostics, Imaging, and Genetics Network for the Objective Study and Evaluation of Chronic Traumatic Encephalopathy Research Project, which recruited male former college/professional football players with RHI and asymptomatic unexposed (UE) controls with no history of contact sports, military combat, or traumatic brain injury/concussion. Our study focused on plasma/CSF inflammatory biomarkers (interleukin [IL]-6, tumor necrosis factor [TNF]-α, glial fibrillary acidic protein), limbic white matter (WM) microstructure (diffusion tensor imaging: fractional anisotropy [FA], mean diffusivity [MD]), and clinical measures (memory, executive function, NBD). Hierarchical linear regressions assessed change in variance explained (ΔR2) among inflammation, WM, and clinical outcomes in former football players. Post hoc analyses tested whether associations differed by group (football vs UE; group interactions) or were stronger in football players considered at highest risk of CTE. RESULTS:Our sample included 223 men (n = 170 football players: age 57.2 ± 8.1 years, 33% non-Hispanic/Black; n = 53 UE participants: age 59.4 ± 8.6 years, 34% non-Hispanic/Black). In football players, higher inflammation was associated with lower limbic FA (plasma IL-6: ΔR2 = 0.03 [0.001-0.09], p = 0.03; CSF IL-6: ΔR2 = 0.03 [-0.01 to 0.11], p = 0.03; plasma TNF-α: ΔR2 = 0.05 [0.01-0.11], p = 0.003) and higher limbic MD (CSF IL-6: ΔR2 = 0.06 [0.007-0.15], p = 0.01). Inflammation was more strongly related to limbic WM microstructure in football players than in UE participants. Worse WM microstructure was associated with worse memory in football players (FA: ΔR2 = 0.05 [0.003-0.14], p = 0.007; MD: ΔR2 = 0.07, p = 0.003 [0.008-0.16]). Most of the observed associations were stronger in the CTE probable subgroup. There were no direct associations between plasma or CSF markers of inflammation and cognition. DISCUSSION:In former elite football players, elevated plasma and CSF inflammatory markers were associated with poorer limbic WM microstructure, which in turn related to worse cognition. Given the limbic system's role in cognition and behavior, inflammation may be a modifiable target for RHI-related neurodegeneration. Limitations include the cross-sectional design and limited generalizability to other contact sports, lower levels of play, female athletes, or other RHI sources.

BACKGROUND AND OBJECTIVES:Former American football players exposed to repetitive head impacts (RHI) are at a risk of chronic traumatic encephalopathy (CTE), but chronic pain, polypharmacy, and extensive orthopedic surgeries may also contribute to cognitive and behavioral symptoms. This study evaluated associations between chronic pain, centrally acting medications (CAMs), and orthopedic surgeries with cognitive and behavioral symptoms among former American football players. METHODS:The sample included former professional (PRO) and collegiate (COL) football players and unexposed, asymptomatic men (UE) from DIAGNOSE CTE. Number of CAMs, orthopedic surgeries, and average pain scores were compared between the groups. Among former football players, logistic regression tested associations between CAMs, average pain score, and orthopedic surgeries with diagnoses of cognitive impairment and neurobehavioral dysregulation (NBD) using traumatic encephalopathy syndrome (TES) research criteria. Linear regression tested associations between CAMs, average pain score, and orthopedic surgeries with the Montreal Cognitive Assessment (MoCA) and behavioral and mood symptom scales. Covariates included age, education, race, and total years of football. RESULTS:The study included 236 men (120 PRO, 60 COL, 56 UE). The mean ages were 59.1 (PRO), 53.5 (COL) and 59.6 (UE) years. PRO and COL used more CAMs (mean PRO = 0.76, COL = 1.14, UE = 0.14), had higher average pain scores (PRO = 4.22, COL = 3.21, UE = 1.05), and more orthopedic surgeries than the UE (mean PRO = 2.76, COL = 1.22, UE = 0.34). CAMs and average pain scores were associated with increased odds of consensus diagnosed NBD (CAMs OR = 2.15, 95% CI 1.53 to 3.26; average pain score OR = 1.55, 95% CI 1.32 to 1.85). CAMs and average pain scores were associated with increased measures of impulsivity, depression, anxiety, behavioral regulation, and aggression. CAMs and average pain scores were not associated with consensus diagnosed cognitive impairment, but CAMs were negatively associated with MoCA score (estimate = -0.47, 95% CI -0.81 to -0.13). There was no association between number of orthopedic surgeries and cognition or NBD. DISCUSSION:CAMs and chronic pain are associated with NBD and CAMs are associated with reduced MoCA scores in former American football players.

OBJECTIVE:To assess the role of small-molecule calcitonin gene-related peptide receptor antagonists (gepants) in the acute treatment of migraine, particularly in relation to triptan treatments. BACKGROUND:Triptans have established efficacy and are widely prescribed for the acute treatment of migraine. However, triptans may not be recommended for some individuals due to cardiovascular contraindications and precautions, as well as other comorbidities, and many may discontinue triptans because of inadequate or inconsistent symptom relief or poor tolerability. Several gepants are also indicated for the treatment of migraine (both acute and preventive), and their demonstrated efficacy and safety may address some challenges associated with triptans. METHODS:This narrative review addresses considerations for the acute treatment of migraine through summarizing literature and data from preclinical studies and clinical trials of triptans and gepants. RESULTS:We consider triptans and gepants, where available, first-line treatment options for the acute treatment of migraine. Triptans may be prescribed in the absence of contraindications, significant risk of cardiovascular disease, or risk for or history of medication-overuse headache. In those who have contraindications or precautions for triptans, those who do not have an adequate response to triptans, and those unable to tolerate them, gepants are often an appropriate option. The efficacy and safety of gepants for the acute treatment of migraine has been established through clinical trials and open-label extension studies and based on real-world evidence. Gepants have demonstrated efficacy and tolerability in triptan insufficient responders, perhaps because of their distinct mechanisms of action. Additionally, the safety of gepants, including relative cardiovascular safety, is supported in pivotal controlled trials and open-label extension trials. In experimental settings and through their use as preventive treatment for migraine, gepants appear unlikely to produce medication-overuse headache. In addition, one gepant (ubrogepant) has demonstrated efficacy in preventing headache onset when given during the prodrome, a finding that has not been demonstrated for triptans. A single-arm, open-label study of naratriptan given during the prodrome suggested fewer subsequent headaches, but interpretation is limited because there was no contemporaneous control group. Limited head-to-head clinical trials comparing gepants and triptans have not demonstrated significant differences. Prescribers of both triptans and gepants should be mindful of potential drug-drug interactions. CONCLUSIONS:Key advantages of gepants include their favorable tolerability, efficacy for the acute treatment of both the prodromal/premonitory phase (ubrogepant) and the headache phase of migraine (ubrogepant, rimegepant, zavegepant), lack of cardiovascular contraindications, and lack of association with medication-overuse headache. Disadvantages include limitations due to cost and access and CYP3A4 drug interactions for most gepants. Together, the advantages may help to optimize patient care and lead to better persistence and effectiveness in a real-world setting. Head-to-head studies are needed to clarify the comparative effectiveness of triptans and gepants.

ABSTRACT:Mild traumatic brain injury (mTBI) commonly induces transient acute (APTH) or persistent (PPTH) post-traumatic headache (PTH) that often resembles migraine. As orexin B sensitizes male but not female murine, nonhuman primate, and human dorsal root ganglion neurons and supradural orexin B/orexin receptor 2 (OX2R) signaling elicits migraine-like pain in naïve male, but not female, mice we explored possible sexually dimorphic contributions of orexin B/OX2R to PTH. In mice of both sexes, mTBI-induced transient cephalic allodynia, a surrogate measure of APTH. After APTH resolution, allodynia was reinstated by exposure to normally innocuous stress or by inhalational delivery of a subthreshold concentration of umbellulone, a TRPA1 agonist, suggesting the expression of PPTH. In contrast to these nonselective stimuli, subthreshold supradural orexin B induced PPTH only in male mTBI mice. Intranasal delivery of a CRISPR/Cas9 plasmid to edit trigeminal OX2R expression prevented APTH and development of PPTH selectively in male mTBI mice. Daily oral suvorexant, a dual orexin receptor antagonist (DORA), beginning immediately after mTBI, prevented APTH as well as PPTH. Critically, starting suvorexant treatment after resolution of APTH also prevented stress- or umbellulone-induced PPTH. EEG/EMG-defined sleep architecture or immobility-defined sleep was not disrupted in this mTBI model suggesting that suvorexant benefits are unlikely related to sleep modulation. Our findings reveal a male-specific mechanism of PTH maintained by orexin B/OX2R signaling and suggest that approved DORAs may be beneficial in treating APTH and preventing transition to PPTH in men. Importantly, DORAs may also be effective in men with established PPTH.

INTRODUCTION:Repetitive head impacts (RHI) from contact sports may cause a unique pattern of white matter hyperintensities (WMH) on T2-weighted fluid-attenuated inversion recovery (FLAIR) magnetic resonance imaging (MRI), termed RHI-associated WMH (RHI-WMH). These lesions are punctate, circular, and located at the gray-white matter boundary, an area vulnerable to trauma-related damage. METHODS:We investigated the association of RHI with these lesions in two aging cohorts: (1) former American football players versus asymptomatic unexposed men and (2) individuals with RHI from various contact sports versus non-RHI participants. RHI-WMH were assessed using visual ratings and a novel automated quantification pipeline. RESULTS:Individuals with RHI had greater RHI-WMH by both detection methods in both cohorts. RHI-WMH were associated with plasma neurofilament light and p-tau231, and flortaucipir positron emission tomography (PET) uptake. DISCUSSION:RHI-WMH may represent a new supportive biomarker for the detection of RHI-related neuropathologies later in life.

Chronic traumatic encephalopathy (CTE) is a neurodegenerative tauopathy associated with repetitive head impacts (RHI). Autopsy studies show that RHI influences risk for other later-life neuropathologies, particularly white matter and vascular injury. We have observed a unique pattern of white matter hyperintensities (WMH) on FLAIR MRI in people exposed to RHI (RHI-WMH) characterized by small, discrete lesions near the depths of sulci (Figure 1a). The objective of this study was to characterize this pattern empirically in former American football players and to investigate neuropathology co-localizing with the WMH. The sample included 164 male former football players ( n  = 111 professional, n  = 53 college) and 55 asymptomatic males without RHI from the DIAGNOSE CTE Project (Table 1). Visual ratings of WMH blind to the participant's RHI and clinical status were conducted to count lesions that were a.) within 1.0cm of the gray/white matter boundary, b.) as bright as the cortex, c.) spherical and d.) <1.0cm in size. ANCOVA compared groups on total number of WMH adjusted for age and vascular risk factors. We selected one individual (former professional player) with the typical RHI-WMH pattern and who donated their brain for neuropathological examination. Guided by in vivo MRI, ex vivo MRI was done to locate the WMH near the depths of the sulci in the tissue. Tissue sections were tested for phosphorylated tau immunoreactivity and reactive astrocytes and microglia in areas surrounding the lesion seen on MRI. Number of RHI-WMH was greater in football players compared to controls ( p  = 0.007) (Figure 1b). Number of RHI-WMH was greater in former professional players compared to controls ( p  = 0.001) but not compared to the college players ( p  = 0.983). In the neuropathology case study, we located the punctate RHI-WMH on ex vivo MRI. Immunostaining revealed that the RHI-WMH was adjacent to a sulcus with the pathognomonic CTE p -tau lesion and was characterized by myelin pallor, dense GFAP-positive glial scarring, and increased total and activated microglia (Figure 2). We provide empirical support for exposure to RHI as potentially leading to a unique pattern of WMH. Importantly, histopathological evidence showed that the RHI-WMH co-localized with RHI and CTE-related neuropathologies at the depths of the sulci.

Background Traumatic brain injury (TBI) commonly elicits acute (APTH) and/or persistent (PPTH) post-traumatic headache. Calcitonin gene related peptide (CGRP) has been implicated as a contributor to PTH pathophysiology. We explored the possibility of sexual dimorphism in the effects of CGRP receptor (CGRP-R) blockade in a preclinical model of PTH induced by a mild TBI (mTBI) in male or female mice. Methods Mice were lightly anesthetized and placed on a tissue paper stage prior to receiving a sham procedure or mTBI resulting from a closed-head weight drop injury. Behavioral responses to periorbital and hindpaw tactile (von Frey filaments) or thermal (hot plate) stimuli over the first 14 days post-mTBI were evaluated as measures of APTH. The PPTH phase was studied following the resolution of mTBI-induced APTH at days 14 and 28. PPTH was precipitated by exposure to bright lights (i.e., bright light stress, BLS). Olcegepant was delivered subcutaneously either repeatedly beginning 2 h after mTBI to produce a sustained block of CGRP-R signaling across the APTH phase, or as a single administration on days 14 or 28 post-mTBI to evaluate possible effects during the PPTH phase. Results mTBI, but not sham-procedure, produced periorbital and hindpaw tactile allodynia, as well as thermal hypersensitivity in mice of both sexes. APTH-related hypersensitivity was transient and resolved by day 14 post-injury. No sex differences were observed in the magnitude or duration of APTH-related pain behaviors. Sustained CGRP-R blockade was, however, significantly more effective in female than male mice in inhibiting pain behaviors in the APTH phase and in preventing the emergence of BLS-induced PPTH. CGRP-R blockade following the resolution of mTBI-induced APTH pain behaviors, on either day 14 or 28, minimally altered BLS-induced PPTH in either sex. Conclusions Sustained CGRP-R blockade starting soon after mTBI significantly inhibited APTH and prevented the expression of PPTH with greater analgesic effects in females compared to males. Delayed CGRP-R blockade beginning after resolution of APTH phase was minimally effective in preventing expression of PPTH in either sex. These data are consistent with previous observations that CGRP induces pain behaviors preferentially in females. Early and continuous CGRP blockade following mTBI may represent a viable treatment option for PTH treatment and the prevention of PTH persistence, especially in females.

A growing body of research suggests that impacts to the head, including sub-concussive impacts, carry risks for long-term detrimental effects on cognition and brain health. Despite the potential for negative health consequences associated with sub-concussive impacts, there is currently no reliable and objective method used in clinical practice to assess whether a particular sub-concussive impact affected the brain. In this preliminary study, we developed a machine-learning classifier to detect changes in brain electrophysiological activity following sub-concussive impacts that occur during soccer ball heading. We recorded EEG from soccer players before and after they repeatedly headed a soccer ball, and trained classifiers to distinguish between an individual's EEG patterns before and after these sub-concussive impacts. The classifiers were able to identify post-impact EEG recordings with significantly higher accuracy than would be expected by chance, both 1 h and 24 h after the impacts occurred. After controlling for electrophysiological changes attributed to exercise, changes to brain activity attributable to soccer heading were detectable at 24 h post-heading, but not at 1-h post-heading. The observed time-course of EEG changes mirrors a similar pattern seen in traumatic brain injury, in which an inflammatory cascade is manifest 24 to 48-h post-injury; we suggest that EEG changes following sub-concussive impacts may stem from inflammation or some other physiological process that unfolds on a similar timescale. These results are an important step toward developing an EEG-based tool that can assess whether electrophysiological consequences are present following sub-concussive head impacts.

OBJECTIVE:This study explores and documents the patient experience during the prodrome phase of migraine. BACKGROUND:Migraine attacks can be divided into four stages: the prodrome (or premonitory phase), the aura, the headache phase, and postdrome. Qualitative data on the range of symptoms during the prodrome and their timing relative to headache onset are sparse. Prodromal symptoms may predict the onset of migraine headache pain and provide a clinically useful benchmark for initiation of treatment early in an attack before pain begins. DESIGN/METHODS:Eligible participants with a clinician-confirmed diagnosis of migraine and at least one prodromal symptom were consented, screened, and then participated in 60-min interviews. The interview guide included open-ended questions to elicit spontaneous reports and specific probes about prodromal symptoms based on a clinician-established list. A theory approach was used to analyze the qualitative data collected in interviews to identify key themes and gather insights; data were analyzed using ATLAS.ti. RESULTS:Data collection for this study occurred from March 8, 2022, to May 16, 2022. Twenty interviews were conducted, and analyses demonstrated that concept saturation was achieved. Participants reported 36 unique prodromal symptoms, and each participant experienced a mean of 13 symptoms (standard deviation [SD] = 6.6) and a median of 11 symptoms (interquartile range [IQR] = 7.8-17.0) during the prodrome phase. The most commonly reported prodromal symptoms were nausea (n = 17/20, 85%), fatigue/tiredness (n = 16/20, 80%), sensitivity to light (n = 13/20, 65%), neck pain/stiffness (n = 12/20, 60%), and dizziness/vertigo/light-headedness (n = 10/20, 50%). Of the symptoms reported by at least four participants (n ≥ 4/20, 20%), neck pain/stiffness was rated most bothersome (8.9 out of 10) and sensitivity to light was rated most severe (8.5 out of 10). Almost 40% of all symptoms reported occurred less than 2 h before the start of migraine headache. Of the commonly reported symptoms, nausea (0.8h), sensitivity to light (1.0 h), and dizziness/vertigo/lightheadedness (2.0 h) began closest to headache onset; fatigue/tiredness (4.0 h) and neck pain/stiffness (4.8 h) were the most remote from headache onset. CONCLUSION:This study identified frequently reported prodromal symptoms, with participants commonly reporting that a migraine headache would follow their experience of prodrome within a 1- to 6-h window. Characterizing the prodrome experience may improve measurement strategies for the burden of migraine and create opportunities to treat during the prodromal phase to prevent the onset of moderate or severe headaches.