The Journal of Headache and Pain

Migraine is a prevalent and disabling brain disorder characterized by recurrent headache attacks alternating with pain-free periods. Patients with migraine exhibit altered brain activation in response to experimental nociceptive stimuli compared to healthy controls, suggesting impaired pain inhibition mechanisms. However, the relevance of these alterations to the underlying pathophysiology of migraine attacks remains unclear. To explore this relationship, we propose a novel pain imagery paradigm aimed to induce brain activation patterns associated with migraine attacks specifically during pain-free. The task required patients to alternate between imagining a severe migraine attack and being headache free, while healthy controls imagined severe physical head pain (e.g., toothache) and pain relief. We collected fMRI data from 14 episodic migraine without aura patients in the interictal phase and 15 healthy controls performing this task. Both patients and controls activated pain-related brain areas during imagery of pain relative to pain relief. Moreover, controls also activated the medial pain system associated with pain inhibition and attentional modulation of pain via top-down pathways. In contrast, patients significantly deactivated these areas, namely the anterior cingulate cortex and dorsolateral prefrontal cortex. Collectively, our findings indicate altered functioning of pain networks in migraine patients, suggesting a disease-related dysregulation of pain inhibition. Eventually, the proposed attack imagery paradigm may provide a promising alternative to studies of pain mechanisms in migraine research.

IntroductionEpisodic migraine is reflected by cyclic changes in behaviour and cortical processing. We aimed to identify how Functional connectivities change over the entire migraine cycle. MethodsBy using longitudinal neuroimaging and a whole-brain connectivity analysis approach, we tested 12 episodic migraine patients across 82 FMRI recordings during spontaneous headache attacks with Follow-up measurements over the pain-free interval without any external stimulation. ResultsWe Found that Functional connectivities linearly increased over the interictal interval. In the prodromal phase, we observed the strongest connections between the anterior agranular insula and the posterior orbitofrontal cortex with sensory, motor, and cingulate areas. The strengths of the connections dropped during the headache. Peak connectivity during the prodromal phase and its collapse during the headache can be regarded as a mechanism of normalising cortical processing. ConclusionsThe strongest connections during the ictal phase of the migraine cycle may contribute to the variety of symptoms of migraine attacks including headache, sensory hypersensitivity, and autonomous symptoms. We speculate about a malfunction at the molecular level in agranular frontal and insular regions, which needs to be addressed in subsequent studies. Article highlightsO_LIWe investigated functional connectivities over an entire migraine cycle. C_LIO_LIWe found cycle-related connectivity changes for two proximate agranular regions. C_LIO_LIThe prodromal increase and the collapse of connectivity during the headache may reflect normalising cortical processing. C_LI

Abstract Background/HypothesisMonoclonal antibodies targeting calcitonin gene-related peptide (CGRP mAbs) are effective drugs for migraine prevention. Worsening of symptoms following their discontinuation challenges their consideration as disease-modifying migraine drugs (DMMD). This study investigates whether changes in sensory processing and cortical network efficiency under CGRP mAb treatment. Methods22 patients suffering episodic migraine (21 female, 46.2{+/-}13.8 years) and 22 age-/gender-matched controls received visual and somatosensory evoked potentials (VEPs, SSEPs) assessments, and quantitative electroencephalography (qEEG). Patients were investigated before (V0),after three months (V3), and headache characteristics additionally followed-up at 6 and 12 months, of treatment with CGRP mAbs. Controls were assessed only once. ResultsFacilitation of VEP at V0 in patients shifted to habituation at V3 following treatment with CGRP mAbs ({Delta}slope: -0.37{+/-}0.83, p=0.03). VEP habituation at V3 did not differ from controls. SSEPs were equally attenuated in patients and controls throughout the study. QEEG parameters in patients indicated impaired network efficiency at V0 that normalized at V3, and were unlike evoked potential studies correlated with six and twelve month outcomes. Conclusion/ InterpretationImproved cortical network efficiency and sensory processing suggests disease-modifying effects of CGRP mAbs with delayed clinical effects on headache. Relapse after withdrawal may reflect insufficient central adaptation in some patients.

Opioids are regularly prescribed for migraine and can result in medication overuse headache and dependence. We recently showed that pituitary adenylate cyclase activating polypeptide (PACAP) is upregulated following opioid administration or in a model of chronic migraine. The goal of this study was to determine if PACAP was a link between opioid use and headache chronification. We tested the effect of PACAP-PAC1 receptor inhibition in novel models of opioid-exacerbated migraine pain and aura; and examined the co-expression between mu opioid receptor (MOR), PAC1, and PACAP in headache-associated brain and peripheral regions. To model opioid exacerbated migraine pain, mice were injected daily with morphine (10 mg/kg) or vehicle for 11 days. On days 3,5,7,9, and 11 they also received the known human migraine trigger nitroglycerin (0.1 mg/kg) or vehicle. To model opioid exacerbated aura, mice were treated with vehicle or morphine twice daily for 4 days (20 mg/kg on days 1-3, 40 mg/kg on day 4), a well-established paradigm for causing opioid-induced hyperalgesia. On day 5 they underwent cortical spreading depression, a physiological correlate of migraine aura. The effect of the PAC1 inhibitor, M65 (0.1 mg/kg), was tested in these models. Fluorescent in situ hybridization was used to investigate the expression of MOR, PAC1, and PACAP. Only mice treated with combined morphine and nitroglycerin developed chronic cephalic allodynia (n=18/group). M65 reversed this hypersensitivity (n=9/group). Morphine significantly increased the number of CSD events (n=8-9/group); and M65 decreased this exacerbation by morphine (n=8-12/group). PAC1 and/or PACAP were highly co-expressed with MOR, and varied by region (n=6/group). MOR and PACAP were co-expressed in the trigeminal ganglia, while MOR and PAC1 receptor showed near complete overlap in the trigeminal nucleus caudalis and periaqueductal gray. The cortex showed similar cellular co-expression between MOR-PACAP and MOR-PAC1. These results show that opioids facilitate the transition to chronic headache through induction of PACAPergic mechanisms. Antibodies or pharmacological agents targeting PACAP or PAC1 receptor may be particularly beneficial for the treatment of opioid-induced medication overuse headache.

BackgroundMigraine is typically precipitated by unaccustomed changes in ones internal state and/or external environment. Migraine symptoms largely involve increased, noxious, awareness of bodily changes and external stimuli. Links have been proposed between migraine and interoception (sensing and interpreting internal states), but direct evidence is limited. MethodsUnmedicated, otherwise healthy, age-matched female participants were grouped by migraine tendency: control (no unprovoked headaches, n=19); low-frequency (<=3 migraines/month, n=20); high-frequency (>=4 migraines/month, n=19). Interoception was assessed, interictally, with standardised questionnaires such as MAIA-2 and a widely used heartbeat counting task. ResultsThe notable significant questionnaire-based difference was in the noticing, not distracting domain of the MAIA-2; controls were least likely to continue activities despite experiencing physical discomfort, and high-frequency migraineurs most likely. Follow-up questioning clarified that this behaviour related predominantly to migraine-related symptoms. The heartbeat task found no differences in accuracy, but lower confidence in the low-frequency migraine group than the control and high-frequency groups. ConclusionsWe suggest that low interoceptive confidence is a risk factor for migraine, whilst amplification of interoceptive signals caused by migraine restores this confidence, but at the price of migraines disabling symptoms. Self-reported tendency to deliberately ignore physical discomfort, including that caused by migraine, may result in more migraine attacks.

BackgroundBeneficial effects of dopamine agonist treatment on migraine have been reported but remain to be properly tested. Aimto examine the effect of cabergoline as preventive treatment for migraine. Primary endpointChange in monthly migraine days (MMD). MethodsIn a randomized, double-blind, placebo-controlled pilot study, 36 adults with episodic and chronic migraine were enrolled. Following a 28-days baseline period, participants received cabergoline 0.5 mg or placebo once weekly for 12 weeks as add-on treatment. An electronic headache diary was completed by the participant, and pertinent headache questionnaires and blood tests were collected at baseline and following the treatment period. The trial was registered with ClinicalTrials.gov (NCT05525611). FindingsMean (SD) baseline MMD was 13.6 (4.1) in the cabergoline group and 14.0 (5.3) in the placebo group. In participants with episodic migraine (n= 20), the change in mean MMD (SE) from baseline to the last 28 days of the treatment period was -5.4 (1.3) (cabergoline) as compared to -1.8 (0.9) (placebo) [odds ratio: 0.79 (95% CI 0.65 - 0.95), p=0.014]. In participants with chronic migraine (n=13), the reduction in MMD with cabergoline was not significant (p=0.6). Patients global impression of change significantly improved after cabergoline as compared to placebo in the entire group of participants (p=0.006). The number of participants with episodic migraine achieving [&ge;] 50% reduction in MMD tended to increase after cabergoline (p=0.07). Seven participants receiving cabergoline and 4 participants receiving placebo experienced adverse effects, none of which were serious. InterpretationsPreventive cabergoline treatment exhibited clinically meaningful improvement in episodic migraine without serious adverse effects. This provides proof-of-concept to justify a sufficiently powered phase 2 trial with different cabergoline dosing regimens as preventive treatment of episodic migraine. FundingThis study has received no external funding.

Despite migraine being one of the top five most prevalent childhood diseases, a lack of knowledge about pediatric migraine limits effective treatment strategies; standard adult pharmaceutical therapies are less effective in children and can carry undesirable side-effects. Non-pharmacological therapies have shown some success in adults; however, to appropriately apply these in children we need to understand pediatric migraines underlying biology. One theory is that migraine results from an imbalance in cortical excitability. Magnetic resonance spectroscopy (MRS) studies show changes in GABA and glutamate levels (the primary inhibitory and excitatory neurotransmitters in the brain, respectively) in multiple brain regions. Although there is indirect evidence of abnormal excitability in pediatric migraine, GABA and glutamate levels have yet to be assessed. The purpose of this study was to measure levels of GABA and glutamate in the thalamus, sensorimotor cortex and visual cortex of children with migraine using MRS. We found that children with migraine and aura had significantly lower glutamate levels in the visual cortex as compared to control children, opposite to results seen in adults. Additionally, we found significant correlations between metabolite levels and migraine characteristics; higher GABA levels were associated with a higher migraine burden. We also found that higher glutamate in the thalamus and higher GABA/Glx ratios in the sensorimotor cortex were associated with duration since diagnosis, i.e., having migraines longer. Lower GABA levels in the sensorimotor cortex were associated with being closer to their next migraine attack. Together this indicates that GABA and glutamate disturbances occur early in migraine pathophysiology and emphasizes that evidence from adults with migraine cannot be immediately translated to paediatric sufferers. This highlights the need for further mechanistic studies of migraine in children, to aid in the development of more effective treatments.

IntroductionMedical students are vulnerable group to migraine, one of the most common type of headache worldwide. The aim of the present study was to determine the prevalence of migraine and related disability among medical students of Bangladesh. MethodsThis cross-sectional study was conducted among 1327 students from six medical colleges Bangladesh during March 2021 through a self-administered online survey. ID Migraine scale and MIDAS scale were used to screen migraine and migraine related disability respectively. Frequency distribution, and Chi-square test, t-test along with multiple logistic regressions model were used to determine the prevalence and associated factors of migraine respectively. ResultsThe overall prevalence of migraine among the participants was 19%. The prevalence was higher among females (27%) than males (8%). Female sex (aOR 4.11, 95% CI 2.79-6.03) and poor sleep quality (aOR 2.07, 95% CI 1.48-2.91) were identified as independent risk factors of migraine. More than 90% migrainures reported to suffer from moderate to severe headache. Nausea was most commonly reported associated symptom (83.5%) followed by photophobia (72%) and vomiting (53%). Self-reported mental stress (55%), irregular sleep (49%), noise (30.5%), and usage of electronic device (30.5%) were most commonly reported triggering factor of migraine attack. More than half of the sufferers reported severe migraine related disability (MIDAS score [&ge;] 21). ConclusionsThe prevalence of migraine among medical students of Bangladesh is alarmingly high. Frequent migraine attacks and severe intensity of headache cause a substantial level of disability among the sufferers. Cautious avoidance of the triggering factors through appropriate interventions and prophylactic medication can mitigate the negative impact of migraine as well as improve the quality of life.

ObjectiveTo characterize the role of the amygdala in episodic (EM) and chronic (CM) migraine, we evaluated amygdala volumes, functional connectivity (FC), and associations with clinical and affective measures. MethodsEighty-eight patients (44 with EM and 44 age- and sex-matched patients with CM) completed anatomical and resting-state functional MRI scans. Amygdala volumes and resting-state FC to three core large-scale cognitive control networks (default mode (DMN), salience (SN), central executive (CEN)) were compared between groups. Associations between amygdala volume and FC, measures of headache severity (frequency and intensity), and cognitive-affective measures (depression, anxiety, pain catastrophizing) were evaluated. ResultsCompared to EM, patients with CM had larger amygdala volume bilaterally. Headache frequency and intensity were associated with increased left and right amygdala volume, and depression was associated with increased right amygdala volume. Patients with CM also demonstrated increased left amygdala FC with the DMN, which across patients was related to headache frequency. Left amygdala FC to the SN was correlated with headache intensity while right amygdala FC to the CEN was correlated with pain catastrophizing. ConclusionOur findings reveal increased amygdala volume and FC with large-scale neurocognitive networks in patients with CM compared to EM. Aberrant amygdala volume and FC measures were associated with increased migraine severity, depression, and pain catastrophizing, pointing to a link between emotion and pain in migraine. Our findings provide novel insights into amygdala involvement in chronic migraine and may inform future interventions aimed at preventing the progression of both headache and its negative cognitive-affective symptoms.

IntroductionHeadaches significantly impair quality of life, and primary headaches are among the most common neurological complaints. Stimulating carotid baroreceptors via carotid sinus massage (CSM) combined with modified Trendelenburg positioning may modulate autonomic activity and alleviate acute headache symptoms. Thus, this study evaluated the effectiveness and safety of this combined approach (CSM+T). MethodsSeventeen patients (14 females; ages 16-64) with tension-type headaches (6), chronic migraines (10), or mixed-headaches (1) and various comorbidities received up to three 15-second CSM+T applications at one-minute intervals. Pain was assessed using a 10-point visual analog scale (VAS), while heart rate (HR), blood pressure (BP), and oxygen saturation (SpO2) were recorded before and after the intervention. A 24-hour follow-up evaluated headache recurrence and adverse effects. ResultsSixteen patients experienced significant pain reduction (median decrease: 9 VAS points; p < 0.0001) without complications. Pain relief persisted 24 hours without the need for additional medication or adverse effects. HR, BP, and SpO2 decreased following CSM+T. A negative correlation was observed between HR reduction and pain relief. Among responders, migraine patients had a smaller mean HR decrease than tension-type headache patients, yet both groups achieved similar median pain relief. These results suggest that a more pronounced cardiovagal response does not necessarily confer greater analgesia, implying additional central or multifactorial mechanisms. ConclusionCSM+T appears to be a safe and effective non-pharmacological intervention for rapid headache relief in a heterogeneous patient population. Larger, controlled trials are warranted to confirm these findings and refine clinical protocols.

AO_SCPLOWBSTRACTC_SCPLOWThere is growing evidence that migraine is associated with attentional abnormalities, both during and outside migraine attacks, which would impact the cognitive processing of sensory stimulation. However, these attention alterations are poorly characterized and their neurophysiological basis is still unclear. Nineteen migraineurs without aura and nineteen healthy participants were recruited to perform a task which used visually-cued auditory targets and distracting sounds to evaluate conjointly top-down and bottom-up attention mechanisms. Magnetoencephalography (MEG) signals were recorded. We investigated anticipatory alpha activity (power increase and decrease) and distractor-induced gamma activity as markers for top-down (inhibition and facilitation) and bottom-up attention, respectively. Compared to healthy participants, migraineurs presented a significantly less prominent alpha power increase in visual areas in anticipation of the auditory target, indexing a reduced inhibition of task-irrelevant visual areas. However, there was no significant group difference regarding the alpha power decrease in the relevant auditory cortices in anticipation of the target, nor regarding the distractor-induced gamma power increase in the ventral attention network. These results in the alpha band suggest that top-down inhibitory processes in the visual cortices are deficient in migraine but there is no clear evidence supporting a disruption of top-down facilitatory attentional processes. This relative inability to suppress irrelevant sensory information may be underlying the self-reported increased distractibility and contribute to sensory disturbances in migraine.

Migraine is a prevalent and disabling neurological disorder, characterized by difficulties in regulating headache activity, sensory processing, and cognitive-emotional states. Brain entropy quantifies the complexity of neural dynamics, where reduced entropy may reflect diminished neural adaptability, but its assessment with fMRI in migraine remains limited. Here, we examined alterations in brain entropy and their associations with clinical burden, attack timing, and symptomatology. Resting-state fMRI data were acquired from adults with episodic migraine, chronic migraine, and healthy controls. Following standard preprocessing, voxel-wise sample entropy was computed, and group differences were assessed using ANCOVA with age and sex as covariates. Associations with clinical burden and symptom measures were examined within affected regions. In chronic migraine, attack timing-related changes in entropy were further explored, and the largest Lyapunov exponent (LLE) was estimated to characterize chaotic dynamics underlying attack-related complexity changes. Migraine patients showed reduced entropy in sensory, attentional, and default mode regions compared to controls, most pronounced in chronic migraine. Lower entropy correlated with greater headache frequency and longer illness duration. In chronic migraine, entropy relatively increased during attacks in multisensory integration regions and was associated with positive and elevated LLEs, indicating partially restored complexity with weakly chaotic dynamics. Patients experiencing phonophobia and nausea also exhibited increased entropy in multisensory and default mode regions. Our findings demonstrate widespread reductions in brain entropy in migraine, reflecting impaired neural adaptability, whereas attacks may transiently restore complexity partially through chaotic dynamics. These results advance understanding of migraine pathophysiology and highlight potential targets for therapeutic intervention. Highlights- Migraine is marked by reduced brain entropy across sensory, attentional and default mode regions, which correlates with disease burden. - Reduced entropy reflects constrained neural adaptability within affected regions. - Migraine attacks transiently restore entropy, suggesting partial recovery of neural adaptability. - Positive and elevated Lyapunov exponents indicate a shift toward weakly chaotic dynamics during attacks. - Symptoms such as phonophobia and nausea are linked to increased entropy in multisensory integration and default mode regions.

ObjectivesTo summarize the baseline methods for the Headache Assessment Via Digital Platform in United States (Head-US) study and report accuracy of self- reported diagnosis of migraine on the platform, and patterns of acute and preventive treatment use among participants with migraine. BackgroundThe HeAD-US is a new, ongoing cohort study of patients with migraine in the US, centered around comprehensive data collection via the Migraine Buddy platform, a smartphone app. Data from such platforms can be used to provide real-world insights, capturing patients voices directly. MethodsParticipants from the Migraine Buddy app completed baseline surveys assessing demographics, headache characteristics, and treatment use. Migraine diagnosis was determined using the AMS/AMPP diagnostic module, and treatment effectiveness was evaluated using the migraine Treatment Optimization Questionnaire (mTOQ-6, defined as scores [&ge;] 6 indicating moderate-to-maximum efficacy). ResultsOf 6810 participants who completed the baseline questionnaire, 6267 (92.0%) met migraine criteria and were included in the rest of the study. Participants had an average age of 41.5 years (SD=13.1, range 18-88), 5692 (90.8%) were female, 3924 (62.6%) met criteria for episodic migraine and 2343 (37.4%) met criteria for chronic migraine. Of the participants, 52.6% were using acute over-the-counter (OTC) medications, 73.2% were using acute prescription medications, 2.4% were using medical devices, and 60.1% were on preventive treatments. There was no significant difference in treatment effectiveness between participants on polytherapy (37.6%) and those on monotherapy (39.5%, p = 0.168). Among the 2621 patients on monotherapy with acute medications, the most common categories were triptans (39.0%), OTCs (28.2%), and gepants (20.8%). For patients on prescription monotherapy, individuals using gepants reported the highest rate of effective treatment (53.3%) in head-to-head comparison with triptans (47.28%, p=0.036), and opioid/barbiturates (27.1%, p<0.001). ConclusionsHeAD-US participants have higher rates of chronic migraine and headache-related disability in comparison with large-scale epidemiologic studies. The HeAD-US study offers a valuable opportunity to leverage real-world data for understanding migraine patients, their treatment patterns, and outcomes.

BackgroundNew Daily Persistent Headache (NDPH) is an enigmatic syndrome characterized by a distinct onset headache that becomes continuous and unremitting within 24 hours and persists for at least 3 months without underlying structural cause. Patients may experience years or decades of pain with negative impacts on functionality and quality of life. Although characteristically treatment resistant, case reports of response to pharmacologic therapies exist, though with great heterogeneity and without generalizability. Given NDPH is incompletely characterized and displays phenotypic variability, it is possible that better sub-population identification might yield more targeted therapeutic directions. MethodsWe conducted a retrospective chart review of adult patients seen within the University of Pittsburgh Medical Center System who received an NDPH International Classification of Diseases 9 or 10 code between 2011-2019. 5,926 patient charts were reviewed and only those who satisfied International Classification of Headache Disorders, 3rd edition criterion were further analyzed. Two independent data collectors reviewed each chart. Results466 individuals satisfied NDPH diagnostic criteria. Median age at first consultation was 37.1 years, with 66.7% of the population identifying as female. Length of NDPH duration at the last consultation was 1.75 years. Headache onset exhibited no obvious seasonality. Headaches were unilateral in 12.5% of cases and severe pain was reported in 79.1% of cases with documented pain severity. Thunderclap onset was observed in 5.8% of cases. Further categorization into migraine (MP) and tension (TP) phenotypes found approximately even distribution, 207 and 214 respectively. Both MP and TP exhibited demographics, precipitating factors, and prognostic types reflective of the general population. In comparison to TP, MP patients described increased prevalence of severe pain (48.3% vs 14.0%), nausea (68.6% vs 33.6%), vomiting (25.1% vs 7.0%), light-sensitivity (85% vs 27.1%), noise-sensitivity (80.7% vs 24.8%), and osmophobia (19.3% vs 3.7%). Comparison of MP and TP exacerbating factors found increased reporting of physical activity (23.7% vs 10.3%). Chronicity of MP and TP found similar breakdowns with 26.1% vs 23.4% reporting 5+ years of headache. ConclusionsNDPH is a refractory, severe pain headache disorder that exhibits no seasonality for onset, with equal breakdown of MP and TP subtypes.

Precision medicine has emerged as a powerful approach to improve treatment outcomes for many medical conditions by consideration of the genetic characteristics of the patient. Migraine is likely to be the worlds most common neurological disorder affecting over 1 billion people, approximately 700 million of whom are women. Yet, patient sex, the most basic genetic difference, is rarely considered in selection of therapies for people with migraine. Preclinical studies reveal that calcitonin gene-related peptide (CGRP), a neurotransmitter thought to be causal in promoting migraine in many patients, elicits female selective pain and headache-like responses. Consistent with this, we report a subgroup analysis of publicly available clinical data evaluating small molecule CGRP receptor antagonists for the acute migraine revealing preferential efficacy in women. Analyses of human post-mortem sensory neurons from male and female donors reveal sexual dimorphism at transcript, protein and functional levels. These findings raise the possibility that regardless of common diagnosis and phenotype, mechanisms promoting migraine pain may differ between sexes. Such qualitative sex differences suggest that clinical trials should include sex-specific analyses, that sex stratified treatment guidelines may improve treatment outcomes in migraine and that the uniform therapeutic approach to pain-related disorders in men and women requires reassessment.

BackgroundThe Delta-opioid receptor (DOR) has gained attention as a promising target for the treatment of migraine and headache disorders. This is largely attributed to its unique pharmacological profile, which suggests that DOR-targeting treatment offers effective therapeutic benefit with a lower risk of medication overuse headache (MOH), reduced abuse liability, and minimal potential for physical dependence. These advantages have driven the development of a novel DOR agonist PN6047 (3-[[4-(dimethylcarbamoyl) phenyl]-[1-(thiazol-5-ylmethyl)-4-piperidylidene] methyl]benzamide), which has completed Phase I clinical trial and showed a favorable safety and tolerability profile. Although PN6047 has shown promising effects in neuropathic pain models, its efficacy in preclinical models of headache-associated pain remains to be evaluated. Here, we investigated the effects of PN6047 in models of migraine-associated pain and aura as well as post-traumatic headache (PTH) and MOH. MethodsC57BL6/J mice were used to examine the effects of PN6047 in the following migraine models: chronic intermittent nitroglycerin (NTG)-induced migraine-associated pain, PTH, KCl-induced cortical spreading depression (CSD), and optogenetic evoked CSD in a freely behaving transgenic mice expressing ChR2-eYFP. In addition, we tested whether chronic PN6047 induced MOH and whether it could prevent the development of MOH induced by sumatriptan. ResultsA single injection of PN6047 blocked chronic cephalic allodynia established by chronic intermittent NTG and PTH. Moreover, chronic PN6047 treatment prevented the development of MOH induced by sumatriptan, without causing MOH itself. In addition, PN6047 significantly reduced the number of CSD events in the KCl-induced CSD model, and delayed CSD onset triggered in freely behaving mice along with subsequent CSD-evoked allodynia. ConclusionPN6047, a novel DOR agonist, strikingly blocks headache-associated mechanism and symptoms in preclinical models of chronic migraine, migraine aura, PTH, and MOH. Importantly, prolonged PN6047 treatment did not induce MOH or analgesic tolerance. Together, these data demonstrate that despite the distinct mechanisms underlying migraine and headache disorder, PN6047 exhibits robust efficacy without inducing MOH, and displays a favorable safety and tolerability profile.

Mild traumatic brain injury (mTBI) often leads to migraine-like post-traumatic headache (PTH), yet effective treatments are limited. Clinical and preclinical studies have shown that mTBI disrupts glymphatic transport of cerebrospinal fluid in the brain. We hypothesized that altered glymphatic transport might underlie facial allodynia commonly associated with migraine and PTH. A closed-head impact model was used to induce mTBI in mice. Facial allodynia, a symptom of PTH and migraine, was evaluated using periorbital von Frey testing. Glymphatic influx was assessed using slice-based imaging of a fluorescent tracer injected into the cisterna magna. Here we show that prazosin (PZN), an 1-noradrenergic receptor antagonist, restores glymphatic function and treats facial allodynia induced by calcitonin gene-related peptide (CGRP) and a nitric oxide donor in mice. In contrast, propranolol, a {beta}-noradrenergic receptor antagonist, was ineffective. Even in the absence of mTBI, CGRP reduced glymphatic function and PZN was able to restore glymphatic function in the dorsal cortex. Importantly, the role of glymphatic function was confirmed by the lack of PZN efficacy in aquaporin-4 knockout mice. These findings indicate that targeting 1-noradrenergic receptors to enhance glymphatic transport may offer a therapeutic strategy for treating migraine and PTH.

Background and ObjectivesThe complexity of neural circuits and the heterogeneity of brain networks are barriers for further improving the efficacy of DBS. This study aimed to establish a clinical paradigm to personalize the design of DBS in patients with refractory headache, which would constitute a milestone in this field. MethodsWe implanted 14 stereoelectroencephalography electrodes in a patient with refractory migraine for clinical monitoring and electrophysiological recording. During monitoring, we collected the VAS score in 5-min increments, and recorded electrophysiological data in real-time. Data were classified into two types of symptoms (high and low symptoms) for determining the spectral power features of specific brain regions reflecting pain fluctuations, which we called Biomarker, using statistical analyses and cross-validated machine-learning models. During stimulation, we tested the clinical effect through a systematic bipolar stimulation survey and blinded sham-controlled stimulation studies, and collected real-time electrophysiological data. Based on the identification of brain areas with clinical improvement, the optimal target for stimulate was determined by validating the clinical response against the biomarker, and phase-amplitude coupling finally. ResultsFor biomarker, RNAc-HFO was the most considerably correlated with VAS score (rho = 0.5292, p < 0.0001), and differed significantly between mild and severe pain levels (p = 0.0003), also with the greatest weighting in the characteristic ranking. The machine-learning model showed an accuracy and AUC remaining at 75.51% and 0.77, respectively, for RAC-HFO. For target, LdACC was identified as the most effective stimulation target, based on the VAS score reported over the stimulation period. VAS score (p = 0.006), RNAc-HFO (p = 0.0029) were significantly improved after stimulation compared to pre-stimulation in LdACC. The significant modulatory effect of RNAc-HFO by the low-frequency phase of LdACC also confirmed the modulatory effect of LdACC and RNAc during headache fluctuation. DiscussionAs a pilot study for exploring precise and personalized DBS in refractory migraine, we identified the biomarker and optimal target via the integration of clinical and electrophysiological data. The concept of the proposed data-driven approach to optimizing personalized treatment strategies for DBS may create a new frontier in the field of refractory headache and pain.

Background: Growing evidence implicates the hypothalamus as a key structure in migraine pathophysiology; however, our understanding of its precise role and of the specific nuclei involved remains limited. We combined MRI data from our laboratory with publicly available MRI datasets from OpenNeuro to examine hypothalamic subunit volumes in episodic migraine and assess the specificity of these alterations relative to chronic pain conditions. Methods: Structural MRI combined with an automated atlas-based segmentation algorithm and a discovery-replication design was employed to investigate cross-sectional volumetric differences across 5 bilateral hypothalamic subunits in two independent migraine cohorts: DS1-MIG (DS1-MIG-base, n = 111 patients, n = 35 controls) and DS2-MIG (n = 27 patients, n = 31 controls). The adjusted volumes were compared between groups using MANOVA as an omnibus test, followed by Welch t-tests to test univariate follow-up. Longitudinal volumetric changes were additionally assessed in DS1-MIG participants with available follow-up scans using linear mixed models. To assess the specificity of findings to migraine, the same pipeline was applied to two chronic pain datasets, one including patients with fibromyalgia (DS-FM, n = 33 patients, n = 33 controls) and the other including patients with trigeminal neuralgia (n = 119 patients, n = 55 controls). Results: MANOVA revealed significant multivariate group differences in the discovery and replication migraine cohorts (DS1-MIG-base: = .006; DS2-MIG: = .008). Follow-up univariate analyses identified a consistent enlargement of the left anterior-superior subunit across both cohorts (FDR = .023 in DS1-MIG-base and FDR = .046 in DS2-MIG), representing the only cross-cohort replication finding. Beyond this shared signature, DS2-MIG exhibited additional significant enlargements of the right anterior-inferior and right tubular-inferior subunits. Longitudinal analyses in DS1-MIG showed that hypothalamic subunit volumes remained broadly stable over time within both migraine patients and control participants. No significant volumetric alterations were detected in the fibromyalgia or trigeminal neuralgia cohorts, either in multivariate or univariate analyses, underscoring migraine-specific findings. Conclusions: These findings provide evidence for subunit-specific hypothalamic structural alterations in migraine localized in the left anterior hypothalamic subunit. The stability of these differences over time and their absence in other chronic pain conditions suggest a migraine-specific structural organisation of hypothalamic circuitry.

Backgroundthe Alice in Wonderland syndrome (AIWS) is a transient neurological disturbance characterized by visual and somatosensory misperceptions most frequently associated with migraine. The heterogeneity of the etiologies and techniques applied to investigate the reported cases have so far prevented to draw strong conclusions about the origin of AIWS symptoms. Some lines of evidence suggest that AIWS and migraine might share common pathophysiological mechanisms, therefore we set out to investigate the common and distinct neurophysiological alterations associated with these conditions in a population of migraineurs. Methodswe acquired resting-state fMRI data from 12 migraine patients with AIWS, 12 patients with migraine with typical aura (MA) and 24 age-matched healthy controls (HC). We then compared the interictal thalamic seed-to-voxel and ROI-to-ROI cortico-cortical resting-state functional connectivity between the 3 groups. Resultswe found a common pattern of altered thalamic connectivity in MA and AIWS, compared to HC, with more profound and diffuse alterations observed in AIWS. The ROI-to-ROI functional connectivity analysis highlighted an increased connectivity between a lateral occipital region corresponding to area V3 and the posterior part of the superior temporal sulcus (STS) in AIWS, compared to both MA and HC. The posterior STS is a multisensory integration area, while area V3 is considered the starting point of the cortical spreading depression (CSD), the neural correlate of migraine aura. This interictal hyperconnectivity might increase the probability of the CSD to directly diffuse to the posterior STS or trigger a diaschisis phenomenon causing the AIWS symptoms during the ictal phase. Conclusionstaken together, these results suggest that AIWS in migraineurs might be a form of complex migraine aura, characterized by the involvement of associative and multisensory integration areas. The altered connectivity between early visual and multisensory associative areas provides a model for the pathophysiology of AIWS associated with other transient neurological conditions or with a structural etiology.