Open research questions in Migraine and Headache Studies

What the literature leaves open

• Background Previous studies have revealed that migraine patients have unique alterations in their electroencephalography (EEG) microstates; however, no studies have explored the neural responses of migraine patients to therapeutic treatment through EEG microstate analysis.

  EEG microstate responses of migraine patients to transcutaneous electrical nerve stimulation · 2026 · DOI

• In a placebo-controlled trial, fremanezumab reduced monthly migraine days and depressive symptom scores in participants with a DSM-5-defined history of major depressive disorder and active symptoms; whether mood improvement was independent of reduced migraine burden remains uncertain.

  EXPLORING THE POTENTIAL BIDIRECTIONAL RELATIONSHIP BETWEEN MIGRAINE AND DEPRESSION: A NARRATIVE REVIEW · 2026 · DOI

• 8 Future research should explore the causal pathways linking migraine, pain, and healthcare expenditures using longitudinal data. Bedsides, a key limitation is that the MEPS variable used does not distinguish migraine-specific pain from pain due to other conditions.

  The economic burden of pain in migraine: a national study of U.S. healthcare expenditures · 2026 · DOI

• Future research should explore functional and metabolic alterations in subcortical structures to better understand the neurobiologic under- pinnings of migraine. While the glymphatic system plays a role in various neuro- logical diseases, its involvement in migraine remains unclear. The pathophysiology remains unclear but is likely related to altered neuronal signaling. van den Berg1 1Leiden University Medical Center, Leiden, Netherlands The Journal of Headache and Pain 2026, 27(S1):P133 Objective Menstrual migraine (MM) is linked to hormonal fluctuations, but the precise role of sex hormones remains unclear. However, the influence of hormonal events on the clinical course of migraine after menopause remains unclear. The underlying pathophysiological mechanism remains unclear, but proposed explanations include microembolic events, the release of bubbles from the catheter, or the action of local inflammatory media- tors or vasoactive substances. Conclusion Cortical changes in migraine patients align with the FCD criteria, but further research is needed to establish or exclude a causal relationship between them. However, pain lateralization in primary stabbing headache (PSH) has not been systematically investigated. However, the cognitive profile associated with cervicogenic headache (CGH) remains poorly understood. Persistent pain beyond vascular healing remains poorly understood.

  Abstracts from the 19th European Headache Congress (EHC) · 2026 · DOI

• The use of mitochondrial cofactors such as riboflavin, coenzyme Q10, and L‐arginine as adjuncts to standard preventive strategies has been supported by only limited evidence.

  Headache in mitochondrial diseases: From migraine to stroke‐like episodes · 2026 · DOI

• ackground: Migraine is a major cause of disability globally, yet its epidemiological impact on postmenopausal women (aged ≥55 years) is not well understood.

  Global, regional, and national burden of migraine in postmenopausal women: a 32-year analysis from the global burden of disease study 1990–2021 · 2026 · DOI

• Abnormal activation in regions such as the cuneus, precuneus, and superior occipital gyrus may serve as preliminary indicators that warrant further investigation into visual aura mechanisms, while changes in the middle cingulate gyrus and angular gyrus may be associated with cognitive-emotional aspects of migraine, although this remains exploratory.

  A preliminary study on brain functional magnetic resonance imaging in migraine patients with visual aura using visual stimulation · 2026 · DOI

• Several limitations of this study must be acknowledged. Finally, the timing of CVR altera- tions could not be determined from a single scan; a study design in which fMRI is completed daily across a series of attacks, as has been done previously [41], could help clarify this point.

  Cerebrovascular reactivity in migraine: a breath-hold BOLD fMRI study · 2026 · DOI

• Conclusions: Phasic EDA may warrant further investigation as a potential physiological indicator related to nociplastic pain mechanisms and next-day headache.

  Wearable Nocturnal Autonomic and Sleep Biomarkers for Predicting Next-Day Headache and Identifying Nociplastic Pain in Patients with Migraine · 2026 · DOI

• Despite the promising evidence, several limitations must be acknowledged. The overall certainty of evidence in many meta-analyses remains low, and heterogeneity in study design, intervention protocols, and outcome measures complicates direct comparisons. Additionally, while exercise is generally beneficial, it may also act as a trigger in some individuals, as 16 suggested by epidemiological data identifying physical exertion among common migraine triggers (Aderinto et al., 2024). Future research should focus on high-quality randomized controlled trials with standardized protocols, as well as investigations into personalized exercise prescriptions based on phenotype, chronotype, and comorbidities. Table 3.

  Exercise as Medicine in Migraine: Clinical Outcomes, Mechanisms, and Long-Term Therapeutic Potential · 2026 · DOI

• The present study outcomes indicate that realworld prescription of lasmiditan largely aligns with the dosage recommendations outlined in the product label. The study’s new-user design and broad enrollment, spanning approximately 400 patients across 53 medical sites nationwide, enhance the generalizability of its findings to Japan’s diverse migraine population, even during the early phase of lasmiditan’s market adoption. However, important limitations inherent to post-marketing observational studies should be considered while interpreting the results. First, as a single-arm, non-randomized study, the results are primarily descriptive and cannot be used to draw causal conclusions regarding treatment effects. As a result of the descriptive nature of this study and the relatively small sample sizes within many subgroups, comparative interpretations were approached cautiously.

  Real-World Safety and Effectiveness of Lasmiditan in Patients with Migraine: A Post-Marketing Observational Study in Japan · 2026 · DOI

• Some limitations should be acknowledged. The restricted group of experts participating in the voting and the imbal- ance in the panel composition, characterized by a lower representation of GPs compared with specialists, repre- sent the main limitation of this Delphi. The higher rep- resentation of specialists within the panelists reflects the selection of participants with documented expertise in 1 3Neurological Sciences (2026) 47:500 500 Page 10 of 13 migraine management. While specialists’ input is essen- tial for defining evidence-based clinical pathways, this imbalance may have influenced the consensus, particu- larly regarding diagnostic approaches and therapeutic management in primary care. Moreover, the limited par- ticipation of GPs may have reduced the extent to which the consensus reflects real-world workload constraints and decision-making processes in general practice. Nev- ertheless, the inclusion of GPs, albeit limited, allowed the incorporation of primary care perspectives in migraine management, a field in which GP involvement in research remains limited, and should therefore also be considered as a distinct contribution of this work. The lack of general neurologists among the panelists also represents a relevant limitation of this work. Their input could provide additional insights into the feasibility, organization, and practical implementation of optimal care strategies in routine clinical settings. Future initiatives should involve a greater representation of GPs, as well as general neurologists and other HCPs, to broaden perspectives and refine care path- ways for migraine management across different levels of care. In addition, the Delphi involved only Italian experts and panelists, limiting the generalizability of the results. The absence of representation from all Italian regions may have influenced the findings, considering the regional variability in healthcare regulations. The coordinated involvement of GPs, general neurolo- gists, and headache specialists is necessary to optimize the migraine subject journey, relieve pressure on headache centers, and enable the provision of adequate care. Future projects are needed to ensure greater participation from GPs, to provide a clearer representation of their standpoint, strengthen their collaboration with specialists, and enhance the continuity of migraine care. Acknowledgements Paolo Mariani provided methodological organi- zation on the project on behalf of Health Publishing & Services Srl. Enzo Troncone provided assistance with the manage- ment of Butterfly Decisions AI-Assisted Decision-Making software platform. Authors’ contribution PB, CT, FV, MDT, IR: conceptualization of the study, statement design, data analysis, writing, and editing the manu- script. FDC, RDI, CDL, CF, LG, SG, EM, TM, RM, RO, RR, DT: writing and editing the manuscript. All authors read and approved the final version of the manuscript. Funding Medical writing was provided by Alessandra Rossi, PhD, and Barbara Bartolini, PhD, at HPS – Health Publishing & Services Srl and was funded by Pfizer, Italy. All authors were paid contractors to Pfizer in connection with the de- velopment and revision of this manuscript. Piero Barbanti, Cristina Tassorelli, Fabrizio Vernieri, Marina De Tommaso, and Innocenzo Rainero were members of the steering committee responsible for de- veloping the 36 statements of the Delphi project. All other authors par- ticipated as members of the voting panel.

  Building bridges in migraine management: consensus pathways on best practices across primary and specialist care in Italy · 2026 · DOI

• These findings suggest that public health and clinical interven- tions focusing on improving sleep hygiene and reducing leisure-time SB could be promising avenues for migraine prevention in adults, whereas the role of promoting phys- ical activity alone appears more complex and warrants further investigation.

  Associations of sleep, sedentary behavior, and physical activity with incident migraine: a prospective cohort study · 2026 · DOI

• The main strength of our research lies in its large-scale, prospective cohort design, which, coupled with ISM, allowed for a comprehensive examine the associations between sleep, PA, SB and migraine risk in a general adult population. Several limitations should be considered. First, as an observational study, it precludes causal inference. In particular, the associations observed do not establish directionality, and reverse causation, whereby migraine itself may influence sleep patterns and sedentary behav- ior, remains a plausible alternative explanation. Second, reliance on self-reported data for behaviors introduces the potential for recall bias and misclassification. Taking sleep as an example, polysomnography (PSG) remains the only objective method for assessing sleep disorders [48], while the results we obtained were based on the questionnaire, which might lead to potential inaccuracy. Furthermore, the equal weighting of sleep score may not reflect their true relative contributions to migraine risk, and snoring is an imperfect surrogate for sleep apnea and may introduce misclassification. Third, our measure of SB did not capture occupational or transport-related sitting, thus representing only leisure-time sedentary exposure. Fourth, the exclusion of participants with miss- ing PA data (~ 20%) could have introduced selection bias, although sensitivity analyses using multiple impu- tation yielded consistent results. Fifth, the diagnosis of migraine based on ICD-10 codes and self-report, rather than ICHD-3. This likely resulted in substantial under- ascertainment, particularly of milder or undiagnosed cases. As our research data indicated, the prevalence of migraine in the baseline population was only around lower than that 3.1% (15,664/502370), significantly observed in the general population (approximately 12%). Consequently, our findings primarily pertain to clinically recognized, healthcare-seeking migraine, which would likely bias our effect estimates toward the null, meaning the true associations in the general population may be stronger than those we observed. Sixth, the ISM is sub- ject to inherent assumptions, which may not fully reflect real-world behavioral dynamics. Our estimates thus represent hypothetical substitution effects rather than observed behavioral modifications. Finally, although we adjusted for numerous covariates, residual confounding from unmeasured factors (e.g., detailed work patterns, specific medications, or psychiatric comorbidities) remains possible.

  Associations of sleep, sedentary behavior, and physical activity with incident migraine: a prospective cohort study · 2026 · DOI

• A key strength of the present study is its complementary cohort design: the Chinese clinical cohort identified the association between RAR and ICHD-3-diagnosed migraine in patients presenting with headache, while the NHANES cohort provided complementary epidemiological evidence regarding self-reported severe headache or migraine in the general population. In addition, we performed EPV and VIF assessments to support model stability and used RCS analysis to explore potential nonlinearity. We also collected detailed clinical features of migraine patients in the Chinese cohort, which adds clinical context to the findings. Nonetheless, several critical limitations of this study must be addressed. First, the Chinese clinical cohort was recruited from a single structural heart disease center, which may introduce selection bias and limit the generalizability of our findings to broader migraine populations. In addition, this cohort was retrospective and analyzed using a complete-case approach, so exclusion of patients with missing RAR components or covariate data may also have introduced selection bias. Second, the NHANES outcome was defined by a single self-reported question of “severe headache or migraine in the past three months.” For conservative interpretation, this endpoint should be regarded as self-reported severe headache or migraine rather than clinically confirmed migraine. Outcome misclassification is possible, and we cannot rule out the inclusion of other severe primary headache disorders. Third, the retrospective observational design of the Chinese cohort and the cross-sectional design of the NHANES cohort preclude causal inference and may have led to underreporting of photophobia, phonophobia, and nausea in routine documentation. Moreover, the exploratory analysis involving BMI cannot establish mediation or mechanism because temporal ordering is unavailable. Finally, the relatively limited sample size and substantial baseline imbalances in the Chinese cohort may have contributed to imprecision at the extreme end of the RAR distribution. Although multivariable regression was used to adjust for measured covariates, residual confounding cannot be fully excluded. Accordingly, future investigations should adopt well-defined, large-scale, multicenter, prospective study designs to confirm the observed associations and to improve understanding of the biological processes that may underlie them. Additionally, studies using propensity score matching (PSM) or inverse probability weighting (IPW) to reduce baseline imbalances, and Mendelian randomization to explore potential causal relationships are warranted.

  The association between red blood cell distribution width to albumin ratio and migraine: evidence from clinical and population-based cohorts · 2026 · DOI

• Using a DAG, we demonstrated that sex and gender are two distinct, but interrelated concepts that may have dif- ferent effects on health, depending on their definitions. Our approach allows modeling the complexity of social reality, where biological and social aspects of sex and gender can be theoretically conceptualized together in a DAG and modeled within the same model using SEM. This approach is useful to help understand the mecha- nisms that may contribute to sex differences in health outcomes. To the best of our knowledge, this study is the first to conceptualize and measure gender as a latent vari- able in an SEM, which is a flexible and versatile technique that can be adapted to different socio-cultural contexts and different gender definitions or available variables. Another clear advantage of SEM over gender scores, which are based on logistic regression, is the possibility to include a non-dichotomous exogenous sex variable. However, our results should be interpreted with cau- tion. The SEM is based on key assumptions such as nor- mality of the noise terms, no multicollinearity, and linear relationships between the variables [46]. Some of these assumptions could not be verified or are not met in our model, including the normal distribution of the latent gender variable. The effect of sex in our example cannot be interpreted as merely biological. We do not have any information about which sex-related aspects drive the effect – e.g., hormonal or genetic factors, having only data on sex assigned at birth. Part of the sex differences could still be explained by socio-behavioral mechanisms [21] not included in the model. Our study was limited by the availability, completeness, and type of variables in the SOEP panel. Sex assigned at birth was assessed as dichotomous, not taking inter- sex variations and recent official categories in Germany (diverse and no entry) into account. Self-identification of gender identity was not included in the dataset. All health conditions were assessed as self-reported diagno- ses, possibly introducing bias by not accounting for dif- ferences in access or utilization of healthcare services. Several variables were not available or were not included that would have been relevant for our research question, such as hormone levels, use of oral contraceptive pills, medication, alcohol consumption, dyslipidemia, obesity, physical activity, and stress. Due to the scope of our paper, we were unable to take socialization differences regarding immigration history or early-life social class into account in a more nuanced analysis. Intersectional analyses should be further explored, including a variety of diversity categories that may shape gendered socialization processes. With sex and gender as exposures, we aimed to mea- sure the causal effect of non-intervenable variables, con- tributing to a discussion that has been ongoing [69, 70]. Future perspectives could focus on mediation analyses within SEM models using a causal framework which may open up possibilities for intervenable pathways [71, 72]. Including mediation analyses to the SEM latent gender Kern et al. Biology of Sex Differences (2026) 17:73 model would furthermore allow for more nuanced analy- ses of additional relevant behavioral factors as well as for estimating the total effect of gender on health outcomes.

  Sex and gender effects on incidence of migraine and stroke: a longitudinal observational study based on the german socio-economic panel · 2026 · DOI

• This study has several limitations. The GBD utilizes a wide range of data sources, includ- ing those from the World Health Organization, disease registries, and surveys, and employs rigorous data validation and cross-validation techniques to address discrepancies. Neverthe- less, despite its comprehensive nature, GBD data may still introduce bias, particularly in low SDI regions where healthcare infrastructure is limited, which may result in under-reporting. For migraines, although the GBD integrates data from 506 sources, in regions with limited direct data availability, it relies on statistical modeling approaches, such as DisMod MR 2.1 and spatiotemporal Gaussian process regression (ST-GPR), and applies 95% uncertainty intervals (UI) to quantify uncertainty in the estimates [19]. While these models help address data gaps, estimates from these regions may still encounter challenges related to accuracy. Furthermore, cul- tural differences in the perception and reporting of pain could introduce additional biases in the data. Future research should focus on improving data collection methods, particularly in under- represented regions. CONCLUSIONS From 1990 to 2021, the global burden of migraine increased significantly. Although the overall burden of women will be higher, the prevalence and incidence rate of men increased 312 Pain Ther (2025) 14:297–315 faster—possibly driven by lifestyle changes or improved diagnosis. Historically, these male trends have been overlooked. The growing bur- den among male individuals requires prioritized intervention strategies, including early diagnosis and targeted health education. In addition, the significant increase in the prevalence of adoles- cents (< 20 years) also deserves our attention.

  The Global Burden of Migraine: A 30-Year Trend Review and Future Projections by Age, Sex, Country, and Region · 2024 · DOI

• The slightly lower percentage of migraine in the Bulgarian sample (10.1%) compared to global data could be due to both population-genetic causes and differences in age range surveyed, but these factors were not definitively separated.

  CHARACTERIZATION OF HYPERTENSION AND MIGRAINE IN RELATION TO SEX, AGE AND AB0 BLOOD GROUP AFFILIATION · 2022 · DOI

• BACKGROUND AND PURPOSE: Behavioral medicine interventions that directly reduce arousal and negative emotions, such as relaxation training (RT), are conceptually different from interventions that temporarily increase negative emotions, such as written emotional disclosure (WED), but no studies have directly compared their efficacy.

  Relaxation Training and Written Emotional Disclosure for Tension or Migraine Headaches: A Randomized, Controlled Trial · 2008 · DOI

• Background/Objectives: There is limited evidence supporting the use of lomerizine, a calcium channel blocker approved for migraine prophylaxis in Japan, in children.

  Lomerizine Prophylaxis for Pediatric Migraine: Efficacy and Predictors of Treatment Response—A Retrospective Cohort Study · 2026 · DOI

• However, limited evidence in Japan exists on the association of age, sex, employment, income, and family caregiving with patient-reported outcomes (PROs) and migraine treatment patterns.

  Characteristics and Treatment Patterns in People with Burden of Migraine: A Subgroup Analysis of the OVERCOME Japan 2nd Study · 2026 · DOI

• Moreover, the role of the dominant venous sinus drainage pattern in CM remains to be elucidated.

  Association of transverse sinus stenosis and dominant venous sinus drainage pattern with chronic migraine: A matched case-control study · 2026 · DOI

• However, the clinical significance of this imaging finding in CM remains unclear.

  Association of transverse sinus stenosis and dominant venous sinus drainage pattern with chronic migraine: A matched case-control study · 2026 · DOI

• Abstract Peripheral nerve decompression for focal migraine trigger sites has shown promising results internationally but has not been described previously as a clinical series from India.

  Migraine Surgery in India: Early Experience and Outcomes from a Pioneering Surgical Series · 2026 · DOI

• Further research on the effect of newer MHT formulations on postmenopausal headache is warranted.

  Menopausal hormone therapy, migraine history, and headache severity: Results from the Women's Health Initiative Hormone Therapy clinical trials · 2026 · DOI

Most-cited papers in Migraine and Headache Studies

• Burden of Migraine in the United States · Archives of Internal Medicine · 1999 · 725 citations
• Quality of Life in Childhood Migraines: Clinical Impact and Comparison to Other Chronic Illnesses · PEDIATRICS · 2003 · 321 citations
• Global, regional, and national burden and trends of migraine among women of childbearing age from 1990 to 2021: insights from the Global Burden of Disease Study 2021 · The Journal of Headache and Pain · 2024 · 173 citations
• The Global Burden of Migraine: A 30-Year Trend Review and Future Projections by Age, Sex, Country, and Region · Pain and Therapy · 2024 · 113 citations
• International Headache Society global practice recommendations for the acute pharmacological treatment of migraine · Cephalalgia · 2024 · 102 citations
• International Headache Society Global Practice Recommendations for Preventive Pharmacological Treatment of Migraine · Cephalalgia · 2024 · 99 citations
• Ophthalmoplegic “Migraine” or Recurrent Ophthalmoplegic Cranial Neuropathy · Journal of Child Neurology · 2012 · 94 citations
• Indoleamine Hallucinogens in Cluster Headache: Results of the Clusterbusters Medication Use Survey · Journal of Psychoactive Drugs · 2015 · 93 citations
• A Monoclonal Antibody to PACAP for Migraine Prevention · New England Journal of Medicine · 2024 · 87 citations
• Ubrogepant: First Approval · Drugs · 2020 · 87 citations

Most recent work

• Efficacy of ophthalmic tetracaine for acute migraine relief: A randomized, placebo-controlled trial in the emergency department · Clinical Neurology and Neurosurgery · 2026
• Pharmacological mechanisms underlying neurovascular alterations related to resistant and refractory migraine: CGRP pathways and beyond · The Journal of Headache and Pain · 2026
• Migraine and Stroke Risk in Postmenopausal Women in the Women's Health Initiative · Neurology · 2026
• A conceptual framework to assess health-related quality of life and treatment effectiveness in headache disorders from the patient perspective · Journal of Plastic, Reconstructive & Aesthetic Surgery · 2026
• Exercise as Medicine in Migraine: Clinical Outcomes, Mechanisms, and Long-Term Therapeutic Potential · Journal of Education Health and Sport · 2026
• Machine Diagnostics and Machine Phenotyping of Migraine · Neurology · 2026
• Sex and gender effects on incidence of migraine and stroke: a longitudinal observational study based on the german socio-economic panel · Biology of Sex Differences · 2026
• Associations of sleep, sedentary behavior, and physical activity with incident migraine: a prospective cohort study · BMC Public Health · 2026
• Association of GABRA1 Polymorphisms with Migraine with Aura: A Preliminary Case–Control Study in a Turkish Cohort · Journal of Contemporary Medicine · 2026
• A GABAergic neural circuit from the suprachiasmatic nucleus to DG drives cognitive impairment in migraine mice · The Journal of Headache and Pain · 2026

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