Cephalalgia[JOURNAL]
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200 papers
Greater occipital nerve injection with methylprednisolone as transitional therapy in episodic cluster headache: Results from an RCT.
Brandt RB, Mulleners WM, Couturier E … +7 more , Carpay JA, Gerlach OHH, Niesters M, Haan J, van Zwet EW, Ferrari MD, Fronczek R
Cephalalgia · 2025 Sep · PMID 40990636 · Publisher ↗
ObjectiveWe investigated whether greater occipital nerve injection (GON injection) with 80 mg of methylprednisolone at the onset of a cluster headache episode would reduce attack frequency faster than standard therapy wi...
ObjectiveWe investigated whether greater occipital nerve injection (GON injection) with 80 mg of methylprednisolone at the onset of a cluster headache episode would reduce attack frequency faster than standard therapy with verapamil alone, and reduce the need for verapamil and the risk of adverse events (AEs).MethodsThis was an investigator-initiated, randomised, double-blind, 12-week clinical trial. Participants received GON injection with 80 mg of methylprednisolone (n = 36) or placebo (n = 34) within two weeks (median) after the onset of a cluster episode, followed by standard verapamil therapy and e-diary monitoring. The primary endpoint was the mean daily dose of verapamil over the entire 12-week study period. Key secondary endpoints were reduction in the mean daily dose of verapamil over the first four weeks and attack frequency reduction in the first week.ResultsIn the verum vs. placebo group, the mean daily dose of verapamil during the total 12-week study period did not differ (232 ± 188 mg vs. 244 ± 143 mg; Δ = 12 mg, 95% confidence interval (CI) = -68 to 92; = 0.230). However, exploratory analysis of the secondary endpoints showed a lower verapamil dose in the first four weeks in the methylprednisolone group compared to placebo (227 ± 126 mg vs. 287 ± 107 mg; mean Δ 60 mg; 95% CI = -4 to -116), as was the median number of attacks at week 1 (7 (interquartile range = 2-11.75) vs. 10 (interquartile range = 6-17.5); 95% CI = -1.0 to -8.0), the mean attack intensity at week 1 (5.7 ± 1.9 vs. 6.6 ± 1.8; 95% CI = 0.0-1.8) and throughout the 12-week study period (5.0 ± 1.8 vs. 5.9 ± 1.9; 95% CI = 0.01-1.8), and the number of days with adverse events (455/2520 (18%) vs. 605/2850 (21%); p < 0.01). There were no serious AEs.ComclusionsThis study failed to establish its primary endpoint. However, exploratory analysis of the secondary endpoints revealed that GON injection with 80 mg of methylprednisolone at the beginning of a cluster headache episode followed by standard therapy verapamil is a safe transitional treatment that provides faster reduction in attack frequency and intensity than verapamil alone, decreases the mean verapamil dose over the first four weeks with consequently fewer adverse events in the first four weeks after the injection.Trial RegistrationThis study is registered on Clinicaltrials.gov with registration number NCT04014634 at 08-07-2019. First inclusion was on 30-07-2019.
Overlap between perceived triggers, premonitory symptoms and symptom persistence across migraine phases: A REFORM study.
Thuraiaiyah J, Christensen RH, Al-Khazali HM … +3 more , Wiggers A, Ashina M, Ashina H
Cephalalgia · 2025 Aug · PMID 40980937 · Publisher ↗
AimTo evaluate the overlap between commonly reported trigger factors and corresponding premonitory symptoms in individuals with migraine.MethodsThis cross-sectional study analyzed data based on participant recall obtaine...
AimTo evaluate the overlap between commonly reported trigger factors and corresponding premonitory symptoms in individuals with migraine.MethodsThis cross-sectional study analyzed data based on participant recall obtained through semi-structured interviews. Individuals diagnosed with migraine were enrolled from September 2020 to June 2022. Participants underwent semi-structured interviews to record their usual trigger factors, premonitory symptoms, non-headache symptoms during the headache and postdromal symptoms. The primary outcome was to assess whether reporting specific trigger factors increased the likelihood of experiencing corresponding premonitory symptoms. Furthermore, the presence of non-headache symptoms across migraine phases was examined.ResultsAmong the 632 participants (mean age 44.6 ± 12.0 years; 89% female), the most frequent triggers were sleep disturbances (70.1%), stress (67.7%) and alcohol consumption (59.0%). Common premonitory symptoms included tiredness (39.9%), concentration difficulties (35.0%) and neck pain (33.2%). Significant associations were found between specific triggers and premonitory symptoms: bright light with premonitory photophobia (odd ratio (OR) = 2.79; 95% confidence interval (CI) = 1.90-4.12; < 0.001), loud noise with premonitory phonophobia (OR = 4.26; 95% CI = 2.77-6.59; < 0.001) and sleep disturbances with premonitory tiredness (OR = 1.74; 95% CI = 1.15-2.64; = 0.009).ConclusionsOur results reveal a notable overlap between specific migraine triggers and corresponding premonitory symptoms, implicating that some perceived triggers could be early signs of an impending attack. Moreover, the continuation of most premonitory symptoms into the postdromal phase suggest that migraine-related symptoms extend across a broader temporal continuum than previously recognized.Trial RegistrationNCT04603976.
Microglial TRPV2-mediated neuroinflammation promotes central sensitization through microglial polarization in a vestibular migraine mouse model.
Zhai Q, Li H, Chen Q … +3 more , Zhang N, Huang Y, Pan Y
Cephalalgia · 2025 Aug · PMID 40980934 · Publisher ↗
BackgroundNeuroinflammation, which is mediated by microglial activation, contributes to central sensitization, a key mechanism in vestibular migraine (VM). Transient receptor potential vanilloid 2 (TRPV2)-mediated calciu...
BackgroundNeuroinflammation, which is mediated by microglial activation, contributes to central sensitization, a key mechanism in vestibular migraine (VM). Transient receptor potential vanilloid 2 (TRPV2)-mediated calcium influx enhances nucleotide-binding oligomerization domain; leucine-rich repeat, and pyrin domain-containing protein 3 (NLRP3) inflammasome assembly, potentially driving inflammation. This study investigated the role of TRPV2 in VM pathogenesis.MethodsA VM model was established via repeated intraperitoneal injections of nitroglycerin and kainic acid-induced vestibular nerve terminal impairment. Periorbital thresholds and vestibular scores were measured to assess allodynia and vestibular dysfunction. Western blotting and immunofluorescence were used to evaluate TRPV2, ionized calcium-binding adapter molecule 1 (IBA1), interleukin-1β and NLRP3 expression in the spinal trigeminal nucleus caudalis (Sp5c) region. , BV2 cells treated with lipopolysaccharide and interferon-γ were transfected with TRPV2 small interfering RNA. TRPV2 activity was analyzed via patch-clamp electrophysiology. Microglial polarization and morphology were examined via flow cytometry and immunofluorescence, with a focus on CD16, CD63, CD206 and CD163 markers. NLRP3 inflammasome activation was assessed through western blotting and immunofluorescence.ResultsVM-related behaviors, including allodynia and dizziness, were successfully reproduced. Central sensitization in the Sp5c was marked by increased TRPV2 expression in microglia, as demonstrated by co-localization with the microglial marker IBA1. , TRPV2 inhibition in BV2 cells shifted microglial polarization from the pro-inflammatory M1 state to the anti-inflammatory M2 state. Additionally, TRPV2 blockade significantly reduced NLRP3 inflammasome activation and the levels of proinflammatory cytokines.ConclusionsTRPV2 regulates microglial activation and NLRP3 inflammasome activity via polarization mechanisms, contributing to central sensitization in VM. These findings highlight the critical role of TRPV2 in VM pathogenesis and its potential as a therapeutic target.
Impact and care gaps of headache disorders in active-duty military personnel: A cross-sectional study from a European armed forces population.
Göbel CH, Müller U, Witte H … +4 more , Heinze-Kuhn K, Heinze A, Cirkel A, Göbel H
Cephalalgia · 2025 Sep · PMID 40965955 · Publisher ↗
AimPrimary headache disorders such as migraine and tension-type headache are highly prevalent in military populations and may severely impact operational performance and readiness. Despite this, data from many European a...
AimPrimary headache disorders such as migraine and tension-type headache are highly prevalent in military populations and may severely impact operational performance and readiness. Despite this, data from many European armed forces are lacking. This study investigates headache phenotypes, diagnosis, treatment and functional impairment in active-duty personnel of a major European military organization.MethodsThis cross-sectional cohort study utilized an anonymous 33-item online questionnaire distributed across military medical centers in Germany between May and July 2023. The survey assessed demographics, headache types according to the International Classification of Headache Disorders, 3rd edition (ICHD-3), diagnostic awareness, treatment history and headache-related disability using the Migraine Disability Assessment Score (MIDAS).ResultsOf the 1189 participants, 914 (77%) completed the survey. Among them, 839 (94.9%) reported experiencing headaches in the past 12 months. Based on ICHD-3 criteria, 227 individuals (27.1%) met the complete set of criteria for migraine, while 246 (29.2%) were classified as probable migraine. Tension-type headache was reported by 222 respondents (26.5%), and cluster headache was resported by 34 (4.1%). Notably, 61.4% of participants had never received a formal diagnosis and only 38.6% had ever sought medical care for their headaches. Functional impairment was substantial: 63.8% reported losing at least one workday in the past three months due to headache. Among those with migraine, an average of 3.9 workdays per month were lost. Despite this burden, only 27.3% of individuals with migraine had ever used preventive medication.ConclusionsPrimary headache disorders are common, underdiagnosed and inadequately treated in this military population, leading to significant functional and operational impairment. Our findings underscore the urgent need for improved screening, diagnosis and evidence-based treatment strategies in uniformed health systems. The results may inform similar efforts in other military and high-demand occupational settings.
Dorso lateral prefrontal cortex stimulation with TMS in chronic migraine individuals refractory to anti-CGRP monoclonal antibodies: Clinical, neuropsychological and neurophysiological effects.
Clemente L, Paparella G, Scannicchio S … +7 more , Abbatantuono C, Tancredi G, Ladisa E, Delussi MD, Ammendola E, Prudenzano AMP, de Tommaso M
Cephalalgia · 2025 Sep · PMID 40961282 · Publisher ↗
BackgroundPeople with high-frequency episodic migraine or chronic migraine may have resistant or refractory forms. The lack of efficacy of pharmacologic therapies is a major clinical challenge that requires alternative s...
BackgroundPeople with high-frequency episodic migraine or chronic migraine may have resistant or refractory forms. The lack of efficacy of pharmacologic therapies is a major clinical challenge that requires alternative strategies, including neuromodulation and exploration of new targets to improve disease management. The present study aimed to test the effectiveness of an accelerated protocol of theta burst stimulation (iTBS) via the dorso lateral prefrontal cortex (DLPFC) in a group of chronic migraine individuals who did not respond to monoclonal antibodies against calcitonin gene-related peptide (CGRP). The co-primary outcomes were the reduction in monthly headache frequency, use of symptomatic medication and perceived pain intensity. In parallel we wanted to understand the possible role of the prefrontal cortex in the emotional and cognitive functions likely responsible for treatment failure and to offer a possible non-pharmacologic option to individuals with difficult-to-treat migraine. To this end, we measured clinical outcomes along with an electroencephalogram (EEG) and behavioral responses to cognitive and emotional tests related to prefrontal functions.MethodsThis study was conducted in a controlled, single-blind design in 12 people with chronic refractory migraine. An accelerated protocol of iTBS on DLPFC was preceded by a sham session and followed by a two-month follow-up. Clinical data were collected and a neuropsychological assessment including anxiety, depression and cognitive profile was performed. Cognitive and emotional Stroop testing was performed at baseline, after sham and real stimulation, and at follow-up during high-density EEG recording to obtain event-related potentials (N2, N400 and late sustained potential (LP)). Stroop data from an age- and sex-matched control group were compared with those of migraine individuals.ResultsMonthly headache days, monthly medication days and headache intensity improved after real stimulation. A similar trend emerged for anxiety, depression, and cognitive performance. The Stroop test was impaired in the baseline, as evidenced by an increase in reaction time and a decrease in N2 and LP in the cognitive task, which returned to normal after real iTBS and at follow-up.ConclusionsThe results support the efficacy of iTBS as a non-invasive neuromodulation approach for the treatment of chronic, refractory migraine. They tentatively point to the role of cognitive fog and psychopathological symptoms in refractoriness to anti-CGRP drugs, which should be confirmed in larger multicenter studies, and suggest this non-pharmacological approach as another promising therapeutic option for people with difficult-to-treat migraine.
Reaching international consensus on the definition of refractory migraine using the Delphi method.
Robblee J, Khan FA, Marmura MJ … +18 more , O'Brien HL, Robbins LD, Samaha MK, Levin M, Sacco S, Ornello R, Nahas SJ, Hesse H, Ehrlich A, Sprouse-Blum AS, Sun-Edelstein C, Jenkins B, Seng EK, Joshi S, Barad MJ, Lee MJ, Aurora SK, Prieto Peres MF
Cephalalgia · 2025 Sep · PMID 40953156 · Publisher ↗
AimDespite its frequency in tertiary headache centers, the International Classification of Headache Disorders, 3rd edition (ICHD-3) does not include refractory migraine. Multiple definitions have been proposed with a rec...
AimDespite its frequency in tertiary headache centers, the International Classification of Headache Disorders, 3rd edition (ICHD-3) does not include refractory migraine. Multiple definitions have been proposed with a recent 2020 proposal for both refractory migraine and resistant migraine by the European Headache Federation (EHF). The aim is to reach an international consensus on the definition of refractory migraine.MethodsThis study is a Delphi consensus carried out by a group of international experts in headache medicine. Following a focus group, a panel of 20 experts and one facilitator reviewed the EHF proposed criteria to build upon their definitions. The Delphi consensus was conducted across five rounds. Questions with >70% consensus were deemed to have strong agreement, 60-70% consensus was deemed minor agreement, and <60% deemed no agreement. A final meeting was held to discuss any concerns and specific wording.ResultsThe Delphi consensus led to the development of four key categories: refractory migraine, probable refractory migraine, resistant migraine, and treatment-responsive migraine. Similar to the EHF 2020 definitions, refractory migraine requires treatment failure of all evidence-based classes, and resistant migraine requires failure of at least three classes. Probable refractory migraine criteria were designed to account for situations where treatment access barriers may prevent trials of certain medication classes (e.g. pediatrics, low to middle-income countries, lack of insurance coverage). Finally, treatment-responsive migraine criteria were developed to allow for standardization in research studies comparing refractory or resistant migraine to migraine that is treatment-responsive.ConclusionsThese four categories may aid in enrollment for studies on pathophysiology, biomarkers, and new treatment targets. Clinically, the criteria for refractory and resistant migraine will help with clinical decision-making by reinforcing the need to try evidence-based treatments and by providing guidance regarding when to try more aggressive treatment approaches. These criteria may also increase attention to this population's disease burden to help advocate for them as a specific migraine subgroup. Field testing in diverse clinical settings will be needed, but it is recommended that ICHD-3 considers inclusion of these four categories in their appendix.
Subtype shift, relapse rate and risk factors of frequent relapse in cluster headache: A multicenter, prospective, longitudinal observation.
Lee MJ, Kim SK, Chu MK … +14 more , Chung JM, Moon HS, Chung PW, Park JW, Kim BK, Oh K, Choi YJ, Sohn JH, Kim BS, Bae DW, Kim D, Song TJ, Park KY, Cho SJ
Cephalalgia · 2025 Sep · PMID 40944404 · Publisher ↗
AimTo prospectively determine subtype shift, relapse rate and risk factors of frequent relapse in cluster headache (CH).MethodsThis multicenter cohort study recruited patients with CH at baseline visits between September...
AimTo prospectively determine subtype shift, relapse rate and risk factors of frequent relapse in cluster headache (CH).MethodsThis multicenter cohort study recruited patients with CH at baseline visits between September 2016 and January 2019 and planned to prospectively follow them up for up to five years. The subtype (episodic vs. chronic) was reassessed at baseline visit 2 (2-4 weeks) and serial follow-up visits if unremitted. We assessed the subtype shift of the index bout (i.e. the bout at the baseline visit) in all patients and relapse rates in those with episodic CH who were in an active bout at the time of recruitment. Relapse (i.e. bout recurrence) was prospectively collected via clinic visit or telephone interview at 3 ± 1 months, 1, 2, 3, 4 and 5 years (each ±6 months) after the baseline visit. Risk factors of frequent relapse were analyzed by comparing the incidence rate ratio (IRR) of relapse using Poisson regression analysis (model 1, static variables in all patients; model 2, time-related variables in patients with two or more lifetime bouts) accounted for different follow-up periods using an offset term.ResultsIn 295 patients (58 with first-ever bouts) enrolled, CH subtypes were episodic, chronic and unclassified in 252, 11 and 32 at baseline. At baseline V2, CH subtype was re-determined to be chronic in seven (12.1%) of 58 patients with first-onset CH ("primary chronic CH") and nine (3.8%) of 237 with a history of episodic CH ("secondary chronic CH"). When excluding known chronic CHs at baseline, the incidence of chronic CH newly found during a prospective observation was 3.8% in patients with first-onset CH and 1.4% in those with a history of episodic CH. In 244 patients with episodic CH in an active bout at the time of recruitment, the relapse rate was 0.29 (95% confidence interval (CI) = 0.27-0.32; < 0.001) per person-year after 5.9 ± 1.37 follow-up visits over a mean duration of 4.2 ± 1.32 years. Models 1 and 2 indicated that age (adjusted IRR = 0.97; 95% CI = 0.95-0.98), longer disease duration (adjusted IRR = 0.97; 95% CI = 0.95-1.00), first-ever bout (adjusted IRR = 0.35; 95% CI = 0.20-0.57), regular (one or more per week) alcohol consumption (adjusted IRR = 0.60; 95% CI = 0.45-0.81), and longer between-bout interval of previous bouts (adjusted IRR = 0.72; 95% CI = 0.60-0.87) were associated with less relapse. Seasonal rhythmicity (adjusted IRR = 1.66; 95% CI = 1.20-2.33) and increasing attack intensity across bouts (adjusted IRR = 1.66; 95% CI = 1.06-2.59) were associated with frequent relapse.ConclusionsThe present study provides data on the subtype shift and relapse rate of CH based on the prospective observation. Although our observation is only limited to a five-year time frame, our findings may suggest that disease activity increases after onset and then regress with age and time, and that seasonal rhythmicity and increasing attack intensity across bouts indicate higher propensity to relapse.
Through the eyes of Janus: Remission and disease activity in cluster headache.
Naber WC, Fronczek R
Cephalalgia · 2025 Sep · PMID 40944403 · Publisher ↗
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Visual snow vs. migraine aura: Debate summary and novel insights into the syndrome.
Braca S, Santoro V, Sebastianelli G … +3 more , Schankin CJ, Goadsby PJ, Puledda F
Cephalalgia · 2025 Sep · PMID 40944402 · Publisher ↗
Visual snow syndrome (VSS) manifests as continuous, fine-grained visual static that is often accompanied by other visual symptoms. Its frequent association with migraine, particularly migraine with aura (MwA), has prompt...
Visual snow syndrome (VSS) manifests as continuous, fine-grained visual static that is often accompanied by other visual symptoms. Its frequent association with migraine, particularly migraine with aura (MwA), has prompted debate regarding a shared pathogenic substrate. To interrogate this relationship, we performed a narrative review of clinical, neuroimaging and electrophysiological studies on VSS and MwA. The clinical picture of VSS is a persistent phenomenon that does not fluctuate with the migraine cycle and shows no response to therapeutics established to be useful in migraine. Moreover, structural and functional neuroimaging in VSS consistently demonstrates selective abnormalities within primary visual, salience and attentional networks, paralleled by distinctive evidence of glutamatergic dysregulation and impaired top-down suppression in electrophysiological recordings. Collectively, the available evidence supports VSS as a discrete disorder marked by aberrant salience assignment and impaired sensory gating, with clinical features and pathophysiology that are separate from those of MwA. While features such as shared serotonergic dysregulation, involvement of comparable cortical territories and high comorbidity suggest overlap between MwA and VSS, these similarities are likely better attributed to a shared predisposition for increased cortical excitability than to a single nosological entity. Future research aiming to characterize further network abnormalities in VSS will be pivotal for guiding the development of targeted therapies.
Brain imaging in migraine with and without aura: Similarities and differences.
Casillo F, Sebastianelli G, Abagnale C … +4 more , Di Renzo A, Ziccardi L, Parisi V, Coppola G
Cephalalgia · 2025 Sep · PMID 40936449 · Publisher ↗
BackgroundWhether migraine with aura (MA) is a biologically independent entity from migraine without aura (MO) is still debated. Similarities and differences between MO and MA have been extensively investigated in recent...
BackgroundWhether migraine with aura (MA) is a biologically independent entity from migraine without aura (MO) is still debated. Similarities and differences between MO and MA have been extensively investigated in recent years through several neuroimaging studies, providing valuable insights into their underlying pathophysiology. To provide a better understanding of functional and structural differences between MO and MA, we conducted a narrative review of neuroimaging studies in these two conditions.MethodsA comprehensive PubMed search for neuroimaging studies in MO and MA was conducted in May 2025. We included studies that directly compared the two conditions using diffusion tensor imaging, voxel-based morphometry, surface-based morphometry, functional MRI and arterial spin labeling studies. No publication date restrictions were applied.ResultsOverall, patients with MA exhibited heightened engagement of the visual regions, cerebellum and thalamus. However, both MO and MA shared common activation of parts of the salience network and involvement of similar visual areas, including the striate and extrastriate cortices. However, contrasting results and several inconsistencies emerged from the analysis of different imaging studies. These included the lack of specification regarding the phase of the migraine cycle during which the scans were conducted, the inclusion of patients under migraine prevention, small sample sizes, and different approaches to data and statistical analysis (including a more liberal approach to interpreting results).ConclusionsAlthough several biases influence the reliability of most findings, patients with MA exhibited higher involvement of visual processing regions, decreased cerebellar antinociceptive activity and impaired thalamic information filtering. Whether this pattern represents the consequence of the recurrence of cortical spreading depression or a primary predisposition to it remains to be determined. Future studies with a rigorous and standardized approach are needed to understand the differences between MO and MA.
Optimising combined treatment for migraine and temporomandibular disorders (TMDs).
Romero-Reyes M, Akerman S, Rapoport AM
Cephalalgia · 2025 Sep · PMID 40936448 · Publisher ↗
Temporomandibular disorders (TMDs) and migraine are highly prevalent, overlapping pain conditions that cause considerable burden in the population. These two disorders are of different etiology and pathophysiology, but b...
Temporomandibular disorders (TMDs) and migraine are highly prevalent, overlapping pain conditions that cause considerable burden in the population. These two disorders are of different etiology and pathophysiology, but both are mediated by the trigeminal system. Due to the interrelated anatomy and physiology of the craniofacial and cervical structures, shared molecular links and mutual feedback, there is an inherent potential for exacerbation of symptomatology, perpetuation and progression; however, on a positive note, there is good potential for developing integrated, mutually beneficial management protocols when migraine and TMDs are comorbid. Currently, there are no established protocols of management, and the literature is limited in studies exploring dual therapeutic protocols. So, the question is, how can management be optimized with the evidence available? We should start by recognizing the need for multidisciplinary management to improve patient outcomes and we must highlight the importance of the dialogue between headache medicine and dentistry. The meeting point is where the dental discipline and the specialty of orofacial pain reside. The underlying pathophysiology of this comorbidity points to the need to decrease mutual exacerbation inputs. Therefore, it is fundamental to identify contributing factors of potential sensitization, such as the presence of parafunctional behaviors, cervical spine contributors, the presence of other comorbidities and headache hygiene. Current evidence supports management recommendations that should be developed by a multidisciplinary team as an integrated plan with combination therapy including both pharmacological and non-pharmacological approaches to optimize management. This multidisciplinary team should include the medical provider (neurologist/headache medicine expertise), the dentist specialized in orofacial pain, the physical therapist and the behavioral medicine specialist. Research is needed to support evidence-based integrated protocols for the management of comorbid migraine and TMDs. Evidence has shown that calcitonin gene-related peptide (CGRP) is also involved in TMDs. CGRP-targeting therapies may hold future opportunities for pharmacological monotherapy addressing this comorbidity.
Impact of psychiatric comorbidity, resilience and executive function on childhood and adolescent headaches: A narrative review.
Arruda MA, Arruda R, da Silva JA
Cephalalgia · 2025 Sep · PMID 40936447 · Publisher ↗
BackgroundThe impact of psychiatric comorbidities in children and adolescents with headache disorders can be more comprehensively understood through a biopsychosocial perspective, which examines the dynamic interplay of...
BackgroundThe impact of psychiatric comorbidities in children and adolescents with headache disorders can be more comprehensively understood through a biopsychosocial perspective, which examines the dynamic interplay of factors beyond headache attacks. Resilience and executive function emerge within this framework, playing a central role in development psychopathology and other critical domains.MethodsThis narrative review aimed to examine the impact of psychiatric comorbidity on migraine and/or high-frequency headaches (HFH) in children and adolescents through a biopsychosocial perspective centered on the role of resilience and executive function (EF), exploring their potential clinical implications. PubMed was searched for English language articles of human participants, from birth to 18 years, published up to 10 April 2025.ResultsClinical and population-based studies suggest that children and adolescents with migraine and/or HFH are at an increased risk of low resilience and EF impairments. Preliminary interaction and multivariate analyses suggest that high vulnerability (the counterpart to resilience) exerts a moderating role in the psychiatric comorbidity of migraine, as well as a mediating effect in the association of HFH with psychiatric symptoms and disorders. Candidate predictors of psychiatric comorbidity in youths with migraine and/or HFH include EF impairment, high vulnerability, female sex, low socioeconomic status, prenatal exposure to tobacco, poor academic performance and headache attacks accompanied by nausea and vomiting.ConclusionsThe multidimensional impact of psychiatric comorbidities on children and adolescents with headache disorders is clearly demonstrated by consistent evidence of their adverse effects on headache severity and chronification, as well as negative outcomes in quality of life, cognitive performance, academic achievement and overall patient well-being, leading to long-term continuity across childhood, adolescence and adulthood. Most of this impact is probably due to the interactions between reduced resilience, increased vulnerability and EF impairment. This narrative review underscore the relevance of routinely assessing psychiatric symptoms, resilience, executive function skills and school functioning in children and adolescents with headache disorders. Future studies should examine whether early interventions focused on resilience, vulnerability and EF can prevent psychiatric comorbidities and improve headache outcomes in children and adolescents with migraine and/or HFH.
Deciphering the mechanisms: Pathophysiology of migraine-related cognitive dysfunction.
Fernandes C, Gil-Gouveia R
Cephalalgia · 2025 Sep · PMID 40936446 · Publisher ↗
Migraine is increasingly understood as a disorder of brain network dysfunction, where attack-related cognitive symptoms (attention deficits, slowed processing speed and executive dysfunction) can be as disabling as pain...
Migraine is increasingly understood as a disorder of brain network dysfunction, where attack-related cognitive symptoms (attention deficits, slowed processing speed and executive dysfunction) can be as disabling as pain and may persist into the interictal period. Such symptoms are associated with functional and structural changes across the migraine cycle, involving the prefrontal cortex, thalamus, hypothalamus, hippocampus and cerebellum. Interictal deficits in working memory, visuospatial processing, verbal fluency and executive function are also documented. Rodent models show impairments in learning and memory, while humans studies suggest that cortical hyperresponsiveness and deficient sensory habituation contribute to altered attentional processing, reflecting thalamocortical dysfunction and abnormal synaptic plasticity as underlying mechanisms. Cognitive performance is modulated by disease severity, chronification, hormonal fluctuations, psychiatric comorbidities, sleep disturbances and medication use. Anxiety, depression and sleep disorders negatively affect working memory, executive function and attention, while medication overuse further impairs visuospatial skills and orientation. Dementia risk appears heightened in migraine patients with frequent and severe attacks, as clinic-based studies consistently report cognitive deficits in this cohorts, unlike population-based studies. While longitudinal cohorts find no increased dementia risk, meta-analyses suggest a modest risk elevation. Differences are likely due to methodological differences in cognitive testing and diagnostic approaches. Cognitive dysfunction in migraine is multidimensional, involving intrinsic neuronal mechanism and external modulators, supporting the need for rational management strategies and treatment interventions.
Generative chatbots in headache education and research: A narrative review.
Romozzi M, García-Azorín D, Rubio-Beltran E … +1 more , Labastida-Ramírez A
Cephalalgia · 2025 Sep · PMID 40934090 · Publisher ↗
Generative artificial intelligence (AI) chatbots, powered by large language models, are emerging as transformative tools with diverse applications in healthcare. This narrative review aims to explore their unique potenti...
Generative artificial intelligence (AI) chatbots, powered by large language models, are emerging as transformative tools with diverse applications in healthcare. This narrative review aims to explore their unique potential for addressing significant gaps in headache education and research, with a main focus on primary headache disorders, a substantial global health burden. In headache education, chatbots can provide tailored, individual information to patients. This improved accessibility could increase the adherence to treatment, reducing the risk of chronification, resulting in a better quality of life. Similarly, clinicians, particularly non-headache specialists, can access a wealth of up-to-date information on headache disorders, including clinical training simulations, which would facilitate reaching a correct diagnosis and optimize treatment. In headache research, generative chatbots can assist by streamlining data collection and analysis, aiding complex experimental setups, and supporting clinical trials, thus accelerating the discovery pipeline. While generative chatbots have demonstrated significant promise for revolutionizing the headache field, challenges persist, with the most important being ensuring data accuracy and privacy. Future developments should focus on pre-training with headache-specific curated databases, multimodal integration, and establishing robust regulatory and ethical frameworks among users (patients, researchers, clinicians), and AI developers to address its limitations. With responsible development, generative chatbots hold the potential to bridge current gaps in headache education and meaningfully advance medical research from bench to bedside, and beyond.
PACAP versus CGRP in migraine: From mouse models to clinical translation.
Pietra AD, Kuburas A, Russo AF
Cephalalgia · 2025 Sep · PMID 40931761 · Full text
Migraine is a complex neurological disorder involving multiple neuropeptides that modulate nociceptive and sensory pathways. The most studied peptide is calcitonin gene-related peptide (CGRP), which is a well-established...
Migraine is a complex neurological disorder involving multiple neuropeptides that modulate nociceptive and sensory pathways. The most studied peptide is calcitonin gene-related peptide (CGRP), which is a well-established migraine trigger and therapeutic target. Recently, another peptide, pituitary adenylate cyclase-activating polypeptide (PACAP), has emerged as an alternative target for migraine therapeutics. This review compares the roles of PACAP and CGRP in preclinical mouse models of migraine. PACAP shares similarities with CGRP, and both are expressed in peripheral and central migraine-relevant regions. However, CGRP is more abundant in the trigeminal pain system, whereas PACAP is more prominent in parasympathetic ganglia that may contribute to autonomic aspects of migraine. PACAP and CGRP act on receptors that can activate overlapping but distinct intracellular signaling pathways. While both peptides elevate cAMP levels to activate protein kinase A, PACAP is more effective than CGRP at engaging an alternative cAMP pathway involving small G proteins, as well as Gq-mediated calcium pathways. Moreover, PACAP and CGRP induce similar migraine-like behaviors in mice, including cephalic and plantar mechanical allodynia, photophobia and non-evoked pain, but they do so by largely independent pathways. Notably, PACAP-mediated photophobia and mechanical allodynia symptoms are not blocked by CGRP-targeted therapies in mice. Finally, we discuss how preclinical PACAP and CGRP studies have translated to the clinic, with the exception of a PACAP type I receptor monoclonal antibody. Overall, CGRP and PACAP are likely to act by parallel and non-redundant roles in migraine pathophysiology, which suggests that a combined targeting of CGRP and PACAP may offer a more effective strategy for treating migraine.
Transition of headache care from childhood to adulthood: Focusing needs, barriers, and models of care. A position paper of the IHS Child and Adolescent Committee.
Özge A, Valeriani M, Guidetti V … +12 more , Sakai F, Uludüz D, Topaloğlu P, Abu-Arafeh I, Gelfand AA, Grazzi L, Wang SJ, Mack KJ, Hikita T, Bruijn J, Orr SL, Hershey AD
Cephalalgia · 2025 Sep · PMID 40905708 · Publisher ↗
Headache disorders are among the most common neurological conditions in children and adolescents, often continuing into adulthood and causing substantial personal and societal burdens. Yet, the transition from childhood...
Headache disorders are among the most common neurological conditions in children and adolescents, often continuing into adulthood and causing substantial personal and societal burdens. Yet, the transition from childhood to adult headache care remains under-addressed, with critical clinical practice, policy, and research gaps. This narrative review synthesizes existing evidence and expert perspectives to highlight the urgent need for structured, developmentally appropriate transition models in headache care. It explores the evolving clinical features of headache in adolescence, increased vulnerability to different comorbidities, and changing health system expectations. We present a needs assessment reflecting the educational, emotional, and practical demands of patients and families. We identify provider- and system-level barriers, such as insufficient training, limited structured protocols, and inequitable access to specialized care, as significant obstacles to effective continuity. Drawing from established transition of care frameworks in other neurological conditions (e.g., epilepsy), we propose a dual-pathway model for headache care. We suggest key recommendations for clinicians and policymakers to promote anticipatory, patient-centered, and equitable developmental care strategies. International collaboration is essential to establish standardized guidelines and research priorities supporting optimal long-term outcomes and sustained quality of life for young people with headache disorders.
Migraine stigma and general knowledge of migraine: A cross-sectional European survey.
Goadsby PJ, Ruiz de la Torre E, Maassen van den Brink A … +7 more , Irimia P, Mitsikostas DD, Ashina M, Terwindt GM, Hurtado D, Lampl C, Pozo-Rosich P
Cephalalgia · 2025 Sep · PMID 40891742 · Publisher ↗
BackgroundThe stigma associated with migraine impacts patients' quality of life, mental health and their willingness to seek treatment. The present study aimed to gain insights into the stigma from the patient's perspect...
BackgroundThe stigma associated with migraine impacts patients' quality of life, mental health and their willingness to seek treatment. The present study aimed to gain insights into the stigma from the patient's perspective and to assess migraine knowledge among people without the condition.MethodsThis cross-sectional descriptive, quantitative study used two surveys (survey 1, open April 2023 to July 2023; survey 2, September 2023 to November 2023). The surveys were distributed to local patient organisations across 26 European countries and nine countries in South and North America, Asia and Oceania.ResultsSurvey 1 received 3712 answers. Most respondents were women (3444; 92.8%), 45-54 years (1090; 29.4%) and experienced severe migraine (2047; 55.1%). Most participants viewed their migraine as disabling (2655; 71.5%) and felt that medical professionals only partially understood (2135; 57.5%). Survey 2 gathered 774 responses, with most of the participants being partners (202; 26.1%), friends (196; 25.3%) or other relatives (110; 14.2%) of individuals with migraine. The significant majority of respondents demonstrated a high understanding of migraine (573; 74.0%) and predominantly recognised migraine as disabling and impacting personal and professional life. Responders felt a high degree of stigma, more from work colleagues and medical professionals than from their social network.ConclusionsThe disabling nature of migraine, combined with the associated stigma, aggravates the challenges faced by patients. There is an urgent need for improved medical education, public awareness campaigns and possible revisions in medical terminology to better support people with migraine and mitigate the stigma they encounter. Importantly, medical professionals need to re-double efforts to check their behaviour to avoid adding to the burden of our patients.
Nerve matters: Longitudinal microstructural change in the trigeminal nerve is associated with durable pain relief after surgery for trigeminal neuralgia.
Danyluk HJ, Dhillon A, Ayri A … +2 more , Beaulieu C, Sankar T
Cephalalgia · 2025 Sep · PMID 40891642 · Publisher ↗
BackgroundMany patients with medically-refractory trigeminal neuralgia (TN) fail to achieve lasting pain relief following surgery targeting the trigeminal nerve (cranial nerve five; CNV). While some studies using MRI dif...
BackgroundMany patients with medically-refractory trigeminal neuralgia (TN) fail to achieve lasting pain relief following surgery targeting the trigeminal nerve (cranial nerve five; CNV). While some studies using MRI diffusion tensor imaging (DTI) suggest that preoperative CNV microstructure may predict surgical response, the findings remain inconsistent. Furthermore, the relationship between post-surgical CNV microstructural changes and long-term pain relief is not well understood. Using a novel CNV-nerve specific DTI protocol, the present study aimed to determine whether: (1) preoperative CNV microstructure differentiates surgical responders from non-responders and (2) sustained pain relief after surgery is associated with distinct postoperative microstructural changes in CNV.MethodsWe conducted a single-centre, prospective, longitudinal study in TN patients undergoing microvascular decompression (MVD) or percutaneous rhizotomy by balloon compression (BC). Patients underwent preoperative and postoperative (one week, one month, six months and one year) high-resolution DTI scanning of CNV using a novel fluid-attenuated inversion recovery DTI protocol. Healthy controls (HC) were scanned at a single timepoint using the same protocol. CNV microstructure was inferred primarily from fractional anisotropy (FA), supplemented with other diffusion metrics. Responders were defined as patients with immediate and complete pain relief (Barrow Neurological Institute facial pain scale I or IIIa) sustained for at least two years.ResultsThirty-five TN patients (22 MVD and 13 BC) and 19 HC were studied. There was no difference in FA between HC CNV and affected ipsilateral or unaffected contralateral CNV in TN patients. However, CNV ipsilateral to the painful side of the face showed microstructural alteration in the form of reduced FA compared to the contralateral, unaffected CNV (0.45 vs. 0.49, = 0.0017). This was largely driven by eventual surgical responders (n = 18, FA ipsilateral 0.45 vs. contralateral 0.49, = 0.049), whereas non-responders (n = 17) showed no such difference ( = 0.15). Following surgery, responders showed early reduction in ipsilateral CNV FA by one month (0.45 vs. 0.38, = 0.013), sustained at six months (0.38, = 0.021) and one year (0.37, = 0.006). The same pattern was observed for MVD and BC responders. Conversely, non-responders exhibited no significant postoperative CNV FA change. Postoperative pain-free timepoints were associated with significantly lower ipsilateral CNV FA compared to painful states or HC on average (0.39 vs. 0.45 or 0.47, < 0.0001) and in individual patients experiencing multiple pain recurrences after repeat operations.ConclusionsLong-term pain relief after TN surgery requires the induction of specific and sustained microstructural changes in the treated CNV, irrespective of surgical modality.
Reinterpreting migraine in a societal evolutionary context.
Ifergane G
Cephalalgia · 2025 Sep · PMID 40891641 · Publisher ↗
Abstract loading — click title to view on PubMed.
Rethinking migraine with aura: Why cortical spreading depolarization (depression), not aura, causes headaches.
Moskowitz MA
Cephalalgia · 2025 Sep · PMID 40891631 · Publisher ↗
Cortical spreading depolarization (depression) underlies migrainous aura and is posited to cause its headache. At times, aura may start before headache, auras may start at the same time as, or shortly after headache onse...
Cortical spreading depolarization (depression) underlies migrainous aura and is posited to cause its headache. At times, aura may start before headache, auras may start at the same time as, or shortly after headache onset, or sometimes without any headache at all. We suggest that the extent of spread and not the spread limited to eloquent cortex, is the key variable in the genesis of headache. Consistent with this notion, a first human case studied electrophysiologically showed that cortical spreading depolarization spreads extensively and silentlyWe propose a Buildup Hypothesis to explain headache generation in migraine with aura. Buildup occurs because cortical spreading depression releases noxious chemicals from cortical cells that accumulate in tissues and cerebrospinal fluid to reach levels sufficient to trigger pial afferents and cause pain. The extent of silent (or relatively silent) spread determines significant buildup. This Buildup Hypothesis helps to explain (1) typical and shorter latencies between end of aura and headache onset (approximately 0-20 minutes) and (2) why headache may not develop after aura (insufficient buildup), and also addresses temporal discrepancies such as headaches starting before an aura (i.e. subclinical spread with buildup in advance of aura). Hence, aura and headache are distinct consequences of cortical spreading depolarization.
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