Migraine Pathophysiology and Treatment Strategies

Migraine is a common neurovascular disorder characterised by recurrent, unilateral headaches often accompanied by sensory disturbances. Its pathophysiology centres on aberrant activation of the trigeminovascular system, cortical spreading depression and altered excitability of central pain pathways. Release of vasoactive neuropeptides, notably calcitonin gene-related peptide (CGRP), induces vasodilatation and neurogenic inflammation, perpetuating nociceptive signalling. Genetic studies have revealed rare variants in ion-channel and synaptic genes that modulate susceptibility to migraine with and without aura, highlighting the importance of neuronal excitability and vascular regulation. Treatment strategies encompass acute therapies to abort attacks, such as triptans and novel small-molecule antagonists of CGRP receptors, and preventive approaches to reduce attack frequency and severity. Preventive options range from oral agents (beta-blockers, anticonvulsants and antidepressants) to on-demand neuromodulation and biologics targeting the CGRP pathway. Tailoring treatment to individual clinical profiles and comorbidities, with patient education and regular follow-up, is essential to improve outcomes and quality of life.

Research from Nature Portfolio

Recent genomic analyses have uncovered rare high-impact variants in migraine subtypes, revealing novel therapeutic targets. A comprehensive study of European cohorts distinguished between migraine with aura and without aura, identifying loss-of-function mutations in genes encoding synaptic proteins and ion channels. One rare frameshift variant in PRRT2 markedly increases risk of migraine with aura and epilepsy, while protective variants in SCN11A and regulatory variants affecting KCNK5 suggest avenues for pain modulation. These findings provide molecular insights into subtype-specific mechanisms and support the development of targeted therapies. In parallel, expert consensus has refined diagnostic and management pathways through a structured ten-step approach. This framework emphasises precise phenotyping, differentiation from secondary causes, shared decision-making and patient education. It integrates best practices for acute and preventive therapies across populations—including children, pregnant individuals and older adults—and outlines strategies for evaluating treatment response, managing comorbidities and planning long-term follow-up. Together, these studies bridge basic science and clinical care, advancing personalised migraine management.

Migraine Pathophysiology and Treatment Strategies publication trend

The graph below shows the total number of articles in migraine pathophysiology and treatment strategies across all publications each year (not limited to Nature Index journals).

Technical terms

Cortical spreading depression: a propagating wave of neuronal and glial depolarisation linked to migraine aura.

Trigeminovascular system: the network of trigeminal nerve fibres and intracranial blood vessels involved in migraine pain transmission.

Calcitonin gene-related peptide (CGRP): a neuropeptide that mediates vasodilatation and neurogenic inflammation in migraine.

Aura: transient neurological symptoms, such as visual disturbances, that precede or accompany a migraine attack.

Monoclonal antibody: a laboratory-engineered immunoglobulin designed to bind specific targets, such as CGRP or its receptor, to prevent migraine.

References

1. Global, regional, and national burden of disorders affecting the nervous system, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021. The Lancet Neurology (2024).
2. Rare variants with large effects provide functional insights into the pathology of migraine subtypes, with and without aura. Nature Genetics (2023).
3. The global prevalence of headache: an update, with analysis of the influences of methodological factors on prevalence estimates. The Journal of Headache and Pain (2022).
4. Diagnosis and management of migraine in ten steps. Nature Reviews Neurology (2021).
5. European Headache Federation guideline on the use of monoclonal antibodies targeting the calcitonin gene related peptide pathway for migraine prevention – 2022 update. The Journal of Headache and Pain (2022).