Headache and Pain Research

Review Article

Brain Glymphatic and Lymphatic Systems in Migraine: Mechanistic Insights and Neuromodulation Perspectives with an Emphasis on Ultrasound-Based Approaches: Jaeho Kim; Headache Pain Res. 2026;27(1):13-20. Published online February 19, 2026; DOI: https://doi.org/10.62087/hpr.2026.0003; Funded: National Research Foundation of Korea, Ministry of Science and ICT, National Research Council of Science and Technology

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Abstract PDF: Migraine is a prevalent and disabling neurological disorder in which established pathophysiological mechanisms, including trigeminovascular activation and calcitonin gene-related peptide (CGRP) signaling, do not fully account for interindividual susceptibility, chronification, or treatment refractoriness. Advances in neurobiology have drawn attention to brain clearance pathways, specifically the glymphatic system and meningeal lymphatic vessels, as potential modulators of neuroinflammation and cerebrospinal fluid (CSF) dynamics. These systems regulate the exchange and drainage of CSF, interstitial solutes, and immune mediators and are strongly influenced by sleep and state-dependent physiology, both of which are closely linked to migraine pathophysiology. In this narrative review, we describe the anatomical and functional organization of brain lymphatic and glymphatic systems and critically evaluate emerging evidence connecting these pathways to migraine. Indirect human imaging studies and experimental models indicate that alterations in perivascular transport, meningeal lymphatic drainage, sleep disruption, and CGRP-related signaling may converge to modulate brain clearance efficiency in migraine. Although the available evidence remains heterogeneous and largely indirect, these findings offer a coherent framework for integrating clearance-related physiology into existing migraine models. We further discuss neuromodulation as a potential strategy for influencing brain clearance mechanisms. In particular, transcranial low-intensity ultrasound has been shown to enhance CSF movement in vivo, providing direct mechanistic support for clearance modulation. Other neuromodulation modalities may exert indirect effects through autonomic regulation, neural oscillations, or vascular dynamics. While clinical evidence remains preliminary, a clearance-oriented perspective may help guide future biomarker development and translational research in migraine.

Original Articles

Cerebrovascular Hemodynamic Responses to Breath-Holding in Migraine: A Longitudinal Functional Near-Infrared Spectroscopy Study Comparing a Calcitonin Gene-Related Peptide Monoclonal Antibody and Oral Preventive Treatment: Dong A. Yea, Jong Kwan Choi, Yoo Hwan Kim; Headache Pain Res. 2026;27(1):52-63. Published online February 24, 2026; DOI: https://doi.org/10.62087/hpr.2025.0029; Funded: Korean Headache Society

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Abstract PDF Supplementary Material: Purpose: Altered cerebrovascular reactivity has been reported in migraine; however, longitudinal changes during preventive treatment remain unclear. This observational study aimed to describe and compare longitudinal cerebrovascular responses derived from functional near-infrared spectroscopy (fNIRS) during a breath-holding test between patients treated with a calcitonin gene-related peptide (CGRP) monoclonal antibody and those receiving oral preventive medications.
Methods
Twenty-four patients with migraine were enrolled (CGRP group, n=12; oral group, n=12). fNIRS over the prefrontal cortex was performed at baseline and after 3 months during a standardized breath-holding protocol. Oxygenated (HbO), deoxygenated, and total hemoglobin signals were used to derive breath-holding and recovery indices. Clinical outcomes included monthly headache days, acute medication days, disability, mood scales, and Patient Global Impression of Change.
Results
Monthly headache days decreased in both groups (CGRP: Δ=–2.00, p=0.26; oral: Δ=–1.50, p=0.48), with no between- group difference (p=0.85). Acute medication days were significantly reduced only in the CGRP group (Δ=–7.00, p=0.03). Migraine Disability Assessment (MIDAS) scores improved significantly in the CGRP group (Δ=–21.25, p=0.02), with no significant between-group differences. During breath-holding, HbO increased across channels in both groups and was followed by a gradual decline during the recovery phase. Longitudinal analyses demonstrated group-dependent differences in temporal change patterns, with a treatment×time interaction reaching significance at the uncorrected level in a representative channel (Channel 6: F(1,16)=8.448, p=0.010), but not after multiple-comparison correction (p=0.155).
Conclusion
fNIRS with a breath-holding challenge enables longitudinal assessment of cerebrovascular responses during migraine preventive treatment. The observed differences should be interpreted descriptively in terms of temporal change patterns. Larger studies are needed to clarify clinical significance.

Natural Diagnostic Classes of Headache Disorders: Latent Class Analysis of a Population-Based Study: Wonwoo Lee, Seok-Jae Heo, Jungyon Yum, Min Kyung Chu; Headache Pain Res. 2026;27(1):30-42. Published online February 26, 2026; DOI: https://doi.org/10.62087/hpr.2026.0004; Funded: Korean Headache Society

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Abstract PDF Supplementary Material: Purpose: The International Classification of Headache Disorders, 3rd edition (ICHD-3), defines headache diagnoses based on combinations of clinical symptoms. Diagnostic overlap is common, and symptom variability complicates diagnostic classification. We evaluated natural classes of headache disorders using a statistical approach and compared these classes with ICHD-3 diagnostic categories.
Methods
Data from a nationwide, population-based web survey on headache and sleep conducted in South Korea (n=3,030) were analyzed. Participants who reported headache within the past year (n=1,938) were included. Latent class analysis was performed using categorical ICHD-3 diagnostic criteria to identify distinct classes. The characteristics of each class and the distribution of ICHD-3 primary headache diagnoses were examined.
Results
Nine classes were identified, comprising 626, 54, 248, 148, 187, 143, 79, 61, and 392 individuals. Three classes were tension-type headache (TTH)–like: Class 1 was male-dominant mild bilateral TTH, Class 8 represented classic, severe TTH, and Class 9 was mild unilateral TTH. Class 4 showed a typical migraine phenotype and contained most migraine cases. Classes 5 and 6 were dominated by probable migraine (PM) and differed mainly in sensory sensitivity and disability, which were higher in Class 6. Classes 2, 3, and 7 were categorized as “other headache.” Class 2 had the highest prevalence of medication-overuse headache (MOH), whereas Class 3 was characterized by mild headache with nausea. Class 7 showed a mixed-type profile with prominent photophobia. Severity and central sensitization markers were key classifiers.
Conclusion
Latent class analysis identified nine clinically distinct headache classes. PM was clearly distinct from both TTH and migraine. One subtype within the “other headache” class showed the highest MOH burden.

Review Article

Genetic Architecture of Migraine: From Broad Insights to East Asian Perspectives: Joonho Kim, Min Kyung Chu; Headache Pain Res. 2025;26(2):116-129. Published online May 27, 2025; DOI: https://doi.org/10.62087/hpr.2025.0003; Funded: Korea Health Industry Development Institute, Ministry of Health and Welfare, Yonsei University College of Medicine, National Research Foundation of Korea, Ministry of Science and ICT

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1 Citations

Abstract PDF

Migraine is a complex neurological disorder with a strong genetic component, ranging from rare monogenic forms, such as familial hemiplegic migraine (FHM), to common polygenic migraine. FHM is primarily caused by mutations in CACNA1A, ATP1A2, and SCN1A, which affect ion channel function and cortical excitability. Additional genes, including PRRT2, have also been implicated, broadening the genetic landscape of monogenic migraine. Genome-wide association studies (GWAS) have identified multiple susceptibility loci for common migraine, highlighting key pathways related to neuronal excitability and vascular function. These findings have reinforced the neurovascular hypothesis of migraine pathogenesis. GWAS on other headache disorders, such as broadly defined headache or cluster headache, have also revealed both overlapping and distinct genetic risk factors. Genetic studies in East Asians have identified both ancestry-specific risk variants and overlapping loci with European populations, suggesting similarities in biological pathways while also highlighting population-specific differences in migraine susceptibility. Expanding research on the genetics of migraine in East Asian populations is essential for uncovering novel risk factors and improving the generalizability of genetic findings.

Citations

Citations to this article as recorded by

Toward Precision Migraine Care: Genetics, Symptoms, and Big-Data-Driven Approaches
Soo-Jin Cho
Headache and Pain Research.2025; 26(3): 171. CrossRef

Original Article

Validity of Migraine Diagnoses in Korean National Health Insurance Claims Data: Yoonkyung Chang, Soyoun Choi, Byung-Su Kim, Tae-Jin Song; Headache Pain Res. 2025;26(2):154-161. Published online June 19, 2025; DOI: https://doi.org/10.62087/hpr.2025.0004; Funded: Ewha Womans University

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Abstract PDF Supplementary Material

Purpose: Accurate case identification using administrative datasets relies on diagnostic coding, yet these codes’ accuracy for migraine remains uncertain. This study aimed to validate the diagnostic accuracy of International Statistical Classification of Diseases and Related Health Problems 10th Revision (International Classification of Diseases, ICD-10) codes for migraine, migraine without aura (MOA), and migraine with aura (MA) in the Korean National Health Insurance Service database.
Methods
We retrospectively reviewed the electronic medical records of 500 patients (migraine [G43.X], 200; MOA [G43.0], 200; MA [G43.1], 100) from secondary and tertiary hospitals between January 2019 and December 2024. Diagnoses confirmed by headache specialists using the International Classification of Headache Disorders, third edition served as the gold standard. Validation metrics included the positive predictive value (PPV), negative predictive value, sensitivity, specificity, and the kappa statistic. Diagnostic accuracy was assessed based on ICD-10 claim frequency and improved by combining diagnostic codes with prescriptions for migraine medications.
Results
A single ICD-10 claim had a PPV of 74.00%. Accuracy improved significantly with increased claim frequency (≥3 claims: PPV, 81.14%; sensitivity, 98.61%; specificity, 28.26%), particularly when combined with medication prescriptions (≥3 claims with medication: PPV, 94.96%; sensitivity, 91.87%; specificity, 85.37%). MOA (≥3 claims with medication: PPV, 95.20%) and MA (≥3 claims with medication: PPV, 93.65%) showed similar trends. Excellent inter-rater reliability was observed (kappa, 0.806–0.951), with no significant accuracy differences between hospitals.
Conclusion
Employing multiple claims and prescriptions improved the accuracy of migraine diagnoses using ICD-10 codes, supporting the use of this method in epidemiological studies and health policy decisions.

Citations

Citations to this article as recorded by

Toward Precision Migraine Care: Genetics, Symptoms, and Big-Data-Driven Approaches
Soo-Jin Cho
Headache and Pain Research.2025; 26(3): 171. CrossRef

Review Article

Understanding the Connection between the Glymphatic System and Migraine: A Systematic Review: Myoung-Jin Cha, Kyung Wook Kang, Jung-won Shin, Hosung Kim, Jiyoung Kim; Headache Pain Res. 2024;25(2):86-95. Published online July 31, 2024; DOI: https://doi.org/10.62087/hpr.2024.0014; Funded: Pusan National University Hospital

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3 Citations

Abstract PDF

The glymphatic system is a brain-wide perivascular pathway that functions similarly to the lymphatic system in the periphery of the body, playing a crucial role in removing waste from the brain. Although impaired glymphatic function has a well-known relationship with neurodegenerative diseases through abnormal protein accumulation, it is also associated with migraine. While still in its nascent phase, research on the glymphatic system in migraine patients is gradually increasing. This systematic literature review focuses on studies investigating the glymphatic system in migraineurs. Furthermore, it examines the methods used to evaluate the glymphatic system in these studies and their main findings.

Citations

Citations to this article as recorded by

Chronic Migraine Is Associated With Region-Specific High-Grade Enlarged Perivascular Spaces: Retrospective Matched Case-Control Study
Jae Wook Cho, Gha-Hyun Lee, Jiyoung Kim
Journal of Clinical Neurology.2026; 22(1): 113. CrossRef
No Glymphatic Dysfunction in Trigeminal Neuralgia: A Preliminary Study
Barış Genç, Kerim Aslan
Brain and Behavior.2026;[Epub] CrossRef
Diffusion Tensor Imaging-Based Glymphatic Dysfunction Assessments in Migraine Syndromes: Mechanisms and Diagnostic Implications
Emily Lai, Joshua Estin, Jiahao Zhou, Roger Sheffmaker, Manisha Koneru
Biomedicines.2025; 13(12): 2981. CrossRef

Original Articles

Side Shift of Attacks in Cluster Headache: A Prospective Single-center Study: Michelle Sojung Youn, Jun Pyo Kim, Mi Ji Lee; Headache Pain Res. 2024;25(2):96-102. Published online August 28, 2024; DOI: https://doi.org/10.62087/hpr.2024.0013; Funded: Seoul National University, National Research Foundation of Korea, Ministry of Science, ICT and Future Planning, Yuhan company

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1 Citations

Abstract PDF

Purpose: Although strict unilaterality is a characteristic of cluster headache (CH), side shift of attacks has been reported. We aimed to assess the prevalence and patterns of side shifts, as well as their correlations with clinical characteristics and treatment response in CH patients.
Methods
We prospectively recruited and followed up CH patients at a university hospital. Patients with two or more lifetime CH bouts were interviewed about their side shift history using a structured questionnaire. The demographics and disease characteristics were collected at baseline, and the treatment response at 2- to 4-week follow-up examinations was compared between patients with versus without side shifts.
Results
Out of 124 CH patients, 26 (21.0%) experienced side shifts. Sixteen (61.5%) experienced shifts between bouts, 13 (50.0%) within a bout, and four (15.4%) within an attack, with none (0%) reporting bilateral pain during an attack. Among patients who experienced shifts between bouts, six (37.5%) reported a single shift during the entire disease course, while 10 (62.5%) reported multiple shifts between bouts. The demographics, characteristics, and treatment response did not significantly differ according to the history of side shift.
Conclusion
In our study, the prevalence and pattern of side shifts were comparable to the results from earlier studies. The presence of side shifts did not show significant association with a specific clinical profile and their incidence did not impact the treatment response. These findings suggest that side-shifting CH is not a distinct entity or migraine variant, but rather within the spectrum of CH.

Citations

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Pain Lateralization in Cluster Headache and Associated Clinical Factors
Soohyun Cho, Mi Ji Lee, Min Kyung Chu, Jeong Wook Park, Heui-Soo Moon, Pil-Wook Chung, Jong-Hee Sohn, Byung-Su Kim, Daeyoung Kim, Kyungmi Oh, Byung-Kun Kim, Soo-Jin Cho
Journal of Clinical Neurology.2025; 21(3): 220. CrossRef

Associations of Migraine and Tension-type Headache with Glaucoma: Jong-Ho Kim, Young-Suk Kwon, Sang-Hwa Lee, Jong-Hee Sohn; Headache Pain Res. 2024;25(1):54-62. Published online March 29, 2024; DOI: https://doi.org/10.62087/hpr.2024.0002; Funded: Physician scientist training and future medical technology implementation for solving clinical challenges in nervous system

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4 Citations

Abstract PDF

Purpose: It remains unclear whether primary headaches, particularly migraine, are associated with glaucoma. We investigated potential associations between primary headaches, including migraine and tension-type headache (TTH), and primary glaucoma, including open-angle glaucoma (OAG) and closed-angle glaucoma (CAG).
Methods
We used data from the Clinical Data Warehouse collected between 2008 and 2023 to investigate whether migraine and TTH influence the risk of primary glaucoma. We compared the prevalence of primary glaucoma, including OAG, CAG, other glaucoma, and total glaucoma (TG), among patients with migraine, those with TTH, and controls.
Results
This study analyzed 46,904 patients with migraine, 48,116 patients with TTH, and 455,172 controls. Controls were selected based on propensity score matching (PSM). After adjustment for covariates and PSM, the fully adjusted odds ratios (ORs) for patients with migraine were 1.83 for OAG (95% confidence interval [95% CI], 1.33–2.51; p<0.004) and 1.55 for TG (95% CI, 1.26–1.91; p<0.004) compared to controls. Furthermore, in patients with TTH, the ORs for CAG were 2.20 (95% CI, 1.40–3.47; p<0.004) compared to controls. Additionally, patients with migraine had fully adjusted ORs of 1.71 for OAG (95% CI, 1.24–2.36; p<0.004) and 1.41 for TG (95% CI, 1.15–1.73; p<0.004) compared to those with TTH.
Conclusion
Migraine is associated with primary glaucoma, particularly OAG.

Citations

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The association between migraine and glaucoma diseases: A retrospective cohort study
Matan Bar, Ido Peles, Gal Ifergane, Erez Tsumi, Assaf Kratz
Headache: The Journal of Head and Face Pain.2026; 66(1): 144. CrossRef
Exploring Secondary Headaches: Insights from Glaucoma and COVID-19 Infection
Soo-Kyoung Kim
Headache and Pain Research.2025; 26(1): 3. CrossRef
Association between migraine and primary open-angle glaucoma: A two-sample Mendelian randomization study
Dima L Chaar, Aliya Yakubova, Chen Jiang, Thomas J Hoffmann, Alice Pressman, Denis Plotnikov, Hélène Choquet
Cephalalgia Reports.2025;[Epub] CrossRef
Subjective Cognitive Decline Patterns in Patients with Migraine, with or without Depression, versus Non-depressed Older Adults
Sun Hwa Lee, Soo-Jin Cho
Headache and Pain Research.2024; 25(2): 103. CrossRef

Review Articles

COVID-19 Infection-related Headache: A Narrative Review: Yoonkyung Chang, Tae-Jin Song; Headache Pain Res. 2024;25(1):24-33. Published online April 2, 2024; DOI: https://doi.org/10.62087/hpr.2024.0008; Funded: Korea Health Industry Development Institute, Ministry of Health and Welfare

8,910 View
46 Download
5 Citations

Abstract PDF

Severe acute respiratory syndrome coronavirus 2 is the virus responsible for coronavirus disease 2019 (COVID-19), which caused a global pandemic and then became an endemic condition. COVID-19 infection may be associated with clinical manifestations such as respiratory symptoms and systemic diseases, including neurological disorders, notably headaches. Headaches are a common neurological symptom in individuals infected with COVID-19. Furthermore, with the transition to endemicity, COVID-19 infection-related headaches may reportedly persist in the acute phase of COVID-19 infection and in the long term after COVID-19 infection resolves. Persistent headaches after COVID-19 infection can be a significant concern for patients, potentially leading to disability. The present review discusses the clinical characteristics and potential underlying mechanisms of COVID-19 infection-related headaches.

Citations

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Unclosing Clinical Criteria and the Role of Cytokines in the Pathogenesis of Persistent Post-COVID-19 Headaches: A Pilot Case-Control Study from Egypt
Ahmed Abualhasan, Shereen Fathi, Hala Gabr, Abeer Mahmoud, Diana Khedr
Clinical and Translational Neuroscience.2025; 9(1): 5. CrossRef
Exploring Secondary Headaches: Insights from Glaucoma and COVID-19 Infection
Soo-Kyoung Kim
Headache and Pain Research.2025; 26(1): 3. CrossRef
Calcitonin Gene-Related Peptide Monoclonal Antibody Treatment in Nine Cases of Persistent Headache Following COVID-19-Infection
Soyoun Choi, Yooha Hong, Mi-Kyoung Kang, Tae-Jin Song, Soo-Jin Cho
Journal of Korean Medical Science.2025;[Epub] CrossRef
A Prospective Multicenter Study on the Evaluation of Frequency of Idiopathic Intracranial Hypertension in Korea
Byung-Su Kim, Soo-Jin Cho, Kyung-Hee Cho, Seol-Hee Baek, Jong-Hee Sohn, Tae-Jin Song, Wonwoo Lee, Hong-Kyun Park, Soohyun Cho, Junhee Han, Soolienah Rhiu, Myoung-Jin Cha, Mi Ji Lee, Min Kyung Chu
Journal of Korean Medical Science.2025;[Epub] CrossRef
Global, regional, and national burden of headache disorders, 1990–2021, with forecasts to 2050: A Global Burden of Disease study 2021
Tissa Wijeratne, Jiyeon Oh, Soeun Kim, Yesol Yim, Min Seo Kim, Jae Il Shin, Yun-Seo Oh, Raon Jung, Yun Seo Kim, Lee Smith, Hasan Aalruz, Rami Abd-Rabu, Deldar Morad Abdulah, Richard Gyan Aboagye, Meysam Abolmaali, Dariush Abtahi, Ahmed Abualhasan, Rufus A
Cell Reports Medicine.2025; 6(10): 102348. CrossRef

Update on Cluster Headaches: From Genetic to Novel Therapeutic Approaches: Myun Kim, Je Kook Yu, Yoo Hwan Kim; Headache Pain Res. 2024;25(1):42-53. Published online April 22, 2024; DOI: https://doi.org/10.62087/hpr.2024.0009; Funded: Hallym University Medical Center Research Fund

17,595 View
161 Download
10 Citations

Abstract PDF

Cluster headaches affect 0.1% of the population and are four times more common in males than in females. Patients with this condition present with severe unilateral head pain localized in the frontotemporal lobe, accompanied by ipsilateral lacrimation, conjunctival injection, nasal congestion, diaphoresis, miosis, and eyelid edema. Recently, the first genome-wide association study of cluster headaches was conducted with the goal of aggregating data for meta-analyses, identifying genetic risk variants, and gaining biological insights. Although little is known about the pathophysiology of cluster headaches, the trigeminovascular and trigeminal autonomic reflexes and hypothalamic pathways are involved. Among anti-calcitonin gene-related peptide monoclonal antibodies, galcanezumab has been reported to be effective in preventing episodic cluster headaches.

Citations

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Exercise as an abortive treatment for cluster headaches: Insights from a large patient registry
Mi‐Kyoung Kang, Yooha Hong, Soo‐Jin Cho
Annals of Clinical and Translational Neurology.2025; 12(1): 149. CrossRef
Morning Headaches: An In-depth Review of Causes, Associated Disorders, and Management Strategies
Yooha Hong, Mi-Kyoung Kang, Min Seung Kim, Heejung Mo, Rebecca C. Cox, Hee-Jin Im
Headache and Pain Research.2025; 26(1): 66. CrossRef
Does Laterality Matter? Insights Into Unilateral Pain in Cluster Headache
Tae-Jin Song
Journal of Clinical Neurology.2025; 21(3): 157. CrossRef
Pain Lateralization in Cluster Headache and Associated Clinical Factors
Soohyun Cho, Mi Ji Lee, Min Kyung Chu, Jeong Wook Park, Heui-Soo Moon, Pil-Wook Chung, Jong-Hee Sohn, Byung-Su Kim, Daeyoung Kim, Kyungmi Oh, Byung-Kun Kim, Soo-Jin Cho
Journal of Clinical Neurology.2025; 21(3): 220. CrossRef
Subtype shift, relapse rate and risk factors of frequent relapse in cluster headache: A multicenter, prospective, longitudinal observation
Mi Ji Lee, Soo-Kyoung Kim, Min Kyung Chu, Jae Myun Chung, Heui-Soo Moon, Pil-Wook Chung, Jeong Wook Park, Byung-Kun Kim, Kyungmi Oh, Yun-Ju Choi, Jong-Hee Sohn, Byung-Su Kim, Dae Woong Bae, Daeyoung Kim, Tae-Jin Song, Kwang-Yeol Park, Soo-Jin Cho
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Inverse association of obesity with bout periodicity in episodic cluster headache: a multicenter cross-sectional study
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Trigeminal Autonomic Cephalalgias Following Unilateral Dorsolateral Medullary Infarction: A Case Series and Literature Review
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Headache and Pain Research.2025; 26(3): 218. CrossRef
Isolated Dental and Lower-Facial Pain Mimicking Trigeminal Neuropathy: An Indirect Carotid-Cavernous Fistula
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Side Shift of Attacks in Cluster Headache: A Prospective Single-center Study
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Headache and Pain Research.2024; 25(2): 96. CrossRef
Reduction of neck pain severity in patients with medication-overuse headache
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The Journal of Headache and Pain.2024;[Epub] CrossRef

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