Inflammation in Migraine and Autonomic Cephalalgias: Mechanisms, Myths, and Meaning

Headache disorders, particularly migraine and autonomic cephalalgias, have long stood at the crossroads of vascular, neural, and immune theories. Since the mid-20th century, the notion of inflammation as a key driver of headache pathophysiology has shaped both clinical classification and therapeutic strategies. Initially labeled “vascular headaches,” these conditions were presumed to arise from meningeal and trigeminovascular inflammation. However, recent advances in neuroscience and immunology have reshaped this narrative, revealing that inflammation may not act as a uniform or singular cause but rather as a dynamic contributor within a broader neurovascular-immune network. Imaging, biomarker, and histological studies have demonstrated activation of glial cells, cytokine release, and neurogenic inflammation in migraine and cluster headache models, while immunomodulatory treatments have yielded mixed results. Despite considerable progress, uncertainty persists regarding whether inflammatory processes are initiating events, secondary reactions, or merely epiphenomena of pain generation. The ongoing debate underscores the need for integrative, evidence-based approaches that can distinguish causality from correlation in the inflammatory hypotheses of headache.

This Research Topic aims to critically examine inflammation’s role in the pathogenesis, maintenance, and treatment of migraine and autonomic cephalalgias. It seeks to clarify the molecular and cellular interactions underpinning neuroimmune signaling and to evaluate the robustness of mechanistic claims that have guided decades of research. Contributors are encouraged to dissect the strength and limitations of prevailing hypotheses, identify methodological gaps, and explore innovative diagnostic and therapeutic paradigms targeting inflammatory pathways. The ultimate goal is to establish a balanced perspective on the biological relevance of immune activation in primary headache disorders, fostering translational insights that inform prevention, diagnosis, and personalized management strategies.

To gather further insights into the complex interplay between inflammation and primary headache disorders, we welcome multidisciplinary contributions spanning preclinical, clinical, and translational research. The scope of this Research Topic encompasses mechanistic elucidation, methodological advances, and therapeutic explorations. We invite Original Research, Review articles, Opinion and Perspective pieces, and Case Studies addressing, but not limited to, the following themes:
- Immune cell and cytokine involvement in migraine and cluster headache.
- Neuroinflammation and neuron–glia–immune system interactions.
- Novel methodologies or biomarkers for investigating inflammation in headaches.
- Debates surrounding the “vascular” versus “inflammatory” headache hypotheses.
- Translational work on pharmacological and non-pharmacological anti-inflammatory interventions.
- Genetic, epigenetic, and environmental modulators of inflammatory activity in headache disorders.

Article types and fees

This Research Topic accepts the following article types, unless otherwise specified in the Research Topic description:

• Brief Research Report
• Case Report
• Clinical Trial
• Data Report
• Editorial
• FAIR² Data
• General Commentary
• Hypothesis and Theory
• Methods
• ... View all formats

Articles that are accepted for publication by our external editors following rigorous peer review incur a publishing fee charged to Authors, institutions, or funders.

Article types

This Research Topic accepts the following article types, unless otherwise specified in the Research Topic description:

• Brief Research Report
• Case Report
• Clinical Trial
• Data Report
• Editorial
• FAIR² Data
• General Commentary
• Hypothesis and Theory
• Methods
• Mini Review
• Opinion
• Original Research
• Perspective
• Policy and Practice Reviews
• Policy Brief
• Review
• Systematic Review

Keywords: migraine, cluster headache, neuroinflammation, trigeminovascular system, neuroimmune signaling, glial cell activation, cytokine release, inflammatory biomarkers, immunomodulatory therapy, autonomic cephalalgias

Important note: All contributions to this Research Topic must be within the scope of the section and journal to which they are submitted, as defined in their mission statements. Frontiers reserves the right to guide an out-of-scope manuscript to a more suitable section or journal at any stage of peer review.