Identification of common genetic and molecular signatures in migraine and comorbid conditions.

The strong bidirectional associations and shared mechanistic pathways between migraine and its comorbidities support a shift from a purely headache-centered approach toward an integrated, comorbidity-informed management framework. Such an approach is grounded in the convergent pathophysiological mechanisms (Table  1 ) and multifactorial risk architecture (summarized in Fig.  3 ) and has important implications for routine clinical practice. Table 1 List of the main comorbidities of migraine and their proposed pathophysiological mechanisms Comorbidity Genetic CSD Neurotransmitter and Neuropeptide Dysregulation Immune-Inflammatory Metabolic disturbance Autonomic Dysfunction and Central Sensitization Structural and Functional Brain Alterations Epilepsy √ √ Psychiatric disorders √ √ √ √ √ Sleep disorders √ √ √ √ √ Cardio-cerebrovascular diseases √ √ √ √ Multiple sclerosis √ √ √ √ Asthma √ Other pain disorders √ √ √ √ Gastrointestinal diseases √ √ √ Metabolic-endocrine diseases √ √ √ √ List of the main comorbidities of migraine and their proposed pathophysiological mechanisms Fig. 3 Schematic representation of the common risk factors for migraine and its comorbidities. These risk factors can be categorized into four categories: intrinsic factors (e.g., genetics, sex), psychological factors (e.g., stress, anger), physiological factors (e.g., obesity, hypertension), and behavioral factors (e.g., physical inactivity, smoking, alcohol consumption). The comorbidities associated with the corresponding types of risk factors are also listed separately. Created with BioRender.com Schematic representation of the common risk factors for migraine and its comorbidities. These risk factors can be categorized into four categories: intrinsic factors (e.g., genetics, sex), psychological factors (e.g., stress, anger), physiological factors (e.g., obesity, hypertension), and behavioral factors (e.g., physical inactivity, smoking, alcohol consumption). The comorbidities associated with the corresponding types of risk factors are also listed separately. Created with BioRender.com First, systematic screening for common comorbidities should be performed in all migraine patients, especially those with high-frequency episodic migraine (HFEM), chronic migraine, or MA. Assessment should include validated tools for depression/anxiety, sleep quality, cardiovascular risk factors (e.g., smoking, blood pressure, lipid profile), allergic history, gastrointestinal symptoms, and—in women—endocrine and gynecological conditions such as endometriosis. For specific comorbidities, additional evaluations are warranted: in migraine‑epilepsy comorbidity, detailed history should clarify whether headache is pre‑ictal, ictal, post‑ictal, or inter‑ictal, and electroencephalogram (EEG) monitoring may be needed to capture events; in patients with prominent sleep complaints, polysomnography can identify OSA or RLS; and in those with suspected MS or cardio‑cerebrovascular disease, neuroimaging is crucial for differential diagnosis and risk stratification. Early identification of comorbidities not only clarifies the clinical picture but also informs therapeutic choices and predicts long-term outcomes. Second, pharmacologic strategy should be tailored to the predominant comorbidity profile, prioritizing agents with evidence for dual efficacy. As summarized in Table  2 , several drug classes exhibit pleiotropic actions across migraine and specific comorbidities: Table 2 Recommended clinical drugs used to treat migraine and comorbidities, along with their mechanism and side effects Comorbidity Recommended Mechanism Side effect Reference Epilepsy Valproate, Topiramate, Verapamil, Flunarizine Valproate: its mechanisms include blocking-sustained repetitive firing mediated by sodium channels, enhancing GABA levels, inhibiting glutamate action at the NMDA receptor, and modulating serotonergic as well as dopaminergic transmission; Topiramate: it blocks voltage-gated sodium Channels and enhances the action of GABA on chloride channels, and reduces the opening of L-type calcium channels; Verapamil: it is a selective calcium antagonist, and reduces the opening of L-type calcium channels, and Inhibits P-glycoprotein; Flunarizine: a selective calcium antagonist. Valproate: weight gain, hair loss, polycystic ovarian syndrome, and birth defects and learning disabilities in children born to mothers taking it; Topiramate: paresthesias, dysphasia, weight loss, and sedation; Verapamil: hypotension and constipation; Flunarizine: tiredness, weight gain, gastrointestinal problems depression, hyperkinesia, tremor and parkinsonism [ 206 , 210 ] Psychiatric disease 1. MDD: Amitriptyline 2. Anxiety: Amitriptyline 3. BD: Lamotrigine, Topiramate Amitriptyline: TCAs, it inhibits serotonin and norepinephrine reuptake; Lamotrigine: it blocks rapid neuronal firing mediated by voltage-gated sodium channels. It also interacts with N and P/Q-type voltage-gated calcium channels. Amitriptyline: dry mouth, slight dizziness, constipation, tachycardia, confusion Lamotrigine: dizziness, nausea, drowsiness [ 48 , 49 , 63 ] Sleep disorders 1. RLS: Pramipexole 2. Insomnia: Suvorexant Pramipexole: a dopamine receptor agonists; Suvorexant: a dual orexin receptor antagonis. Pramipexole: nausea, drowsiness, yawning, hypotension Suvorexant: somnolence, headache, fall, dry mouth [ 68 , 82 , 211 ] Cardio-Cerebrovascular disease 1. Arterial hypertension: β-blocker; Candesartan, Lisinopril 2. Stroke: Aspirin β-blocker: it binds to β-adrenergic receptors, and prevents the agonistic effects of neurotransmitters and catecholamines on the β receptors; Candesartan, Lisinopril: it is a angiotensin II receptor blockers; Aspirin: it inhibits the synthesis of prostaglandins, bradykinin, histamine β-blocker: dizziness, hypotension Candesartan, Lisinopril: respiratory infection, cough, dizziness, weak, and headache; Aspirin: gastrointestinal irritation, allergy [ 100 , 109 ] Multiple sclerosis Acute treatment: NSAIDs; Prophylactic treatment: β-blocker NSAIDs: it inhibits the synthesis of prostaglandins, bradykinin, histamine; β-blocker: it binds to β-adrenergic receptors, and prevents the agonistic effects of neurotransmitters and catecholamines on the β receptors; NSAIDs: gastrointestinal irritation, allergy β-blocker: dizziness, hypotension [ 145 , 154 ] Asthma 1. Montelukast 2. N-α-methylhistamine Montelukast: it is a leukotriene antagonists which blocking leukotriene-induced bronchial and intracranial vascular inflammation; N-α-methylhistamine: it is a H3/H4 receptors modulators Montelukast: nervous system side effects, gastrointestinal side effects N-α-methylhistamine: weight gain, drowsiness, dizziness, mild reversible depression, dyspepsia and palpitation [ 155 , 212 ] Other pain disorders 1. FM: Amitriptyline 2. TMD: Propranolol Amitriptyline: a TCA which inhibits serotonin and norepinephrine reuptake; Propranolol: a β-blocker which binds to β-adrenergic receptors, and prevents the agonistic effects of neurotransmitters and catecholamines on the β receptors Amitriptyline: dry mouth, slight dizziness, constipation, tachycardia, and confusion Propranolol: dizziness, hypotension [ 213 , 214 ] Digestive system disease 1. Gastroparesis: Metoclopramide; triptans; 2. IBS: Amitriptyline Metoclopramide: a dopamine receptor antagonists and 5-HT 4 agonist; triptans: a selective 5-HT 1B/1D receptor agonist which inhibits the excitation of the trigeminal nucleus; Amitriptyline: a TCAs which inhibits serotonin and norepinephrine reuptake r Metoclopramide: Restlessness, drowsiness, fatigue, and lassitude; Triptans: nausea, lassitude, dizziness Amitriptyline: dry mouth, slight dizziness, constipation, tachycardia, and confusion [ 131 , 215 ] Metabolic-endocrine disease 1. DM: Topiramate 2. Endometriosis: Danazol Topiramate: an AEDs which inhibits the opening and activation of sodium ion channels Danazol: it is a gonadotropin-suppressant that acts on the estrogen receptor and inhibits the efficacy of estrogen Topiramate: dizziness, confusion of consciousness Danazol: liver dysfunction, endocrine and metabolic disorders [ 198 , 216 ] Recommended clinical drugs used to treat migraine and comorbidities, along with their mechanism and side effects Valproate: its mechanisms include blocking-sustained repetitive firing mediated by sodium channels, enhancing GABA levels, inhibiting glutamate action at the NMDA receptor, and modulating serotonergic as well as dopaminergic transmission; Topiramate: it blocks voltage-gated sodium Channels and enhances the action of GABA on chloride channels, and reduces the opening of L-type calcium channels; Verapamil: it is a selective calcium antagonist, and reduces the opening of L-type calcium channels, and Inhibits P-glycoprotein; Flunarizine: a selective calcium antagonist. Valproate: weight gain, hair loss, polycystic ovarian syndrome, and birth defects and learning disabilities in children born to mothers taking it; Topiramate: paresthesias, dysphasia, weight loss, and sedation; Verapamil: hypotension and constipation; Flunarizine: tiredness, weight gain, gastrointestinal problems depression, hyperkinesia, tremor and parkinsonism 1. MDD: Amitriptyline 2. Anxiety: Amitriptyline 3. BD: Lamotrigine, Topiramate Amitriptyline: TCAs, it inhibits serotonin and norepinephrine reuptake; Lamotrigine: it blocks rapid neuronal firing mediated by voltage-gated sodium channels. It also interacts with N and P/Q-type voltage-gated calcium channels. Amitriptyline: dry mouth, slight dizziness, constipation, tachycardia, confusion Lamotrigine: dizziness, nausea, drowsiness 1. RLS: Pramipexole 2. Insomnia: Suvorexant Pramipexole: a dopamine receptor agonists; Suvorexant: a dual orexin receptor antagonis. Pramipexole: nausea, drowsiness, yawning, hypotension Suvorexant: somnolence, headache, fall, dry mouth 1. Arterial hypertension: β-blocker; Candesartan, Lisinopril 2. Stroke: Aspirin β-blocker: it binds to β-adrenergic receptors, and prevents the agonistic effects of neurotransmitters and catecholamines on the β receptors; Candesartan, Lisinopril: it is a angiotensin II receptor blockers; Aspirin: it inhibits the synthesis of prostaglandins, bradykinin, histamine β-blocker: dizziness, hypotension Candesartan, Lisinopril: respiratory infection, cough, dizziness, weak, and headache; Aspirin: gastrointestinal irritation, allergy Acute treatment: NSAIDs; Prophylactic treatment: β-blocker NSAIDs: it inhibits the synthesis of prostaglandins, bradykinin, histamine; β-blocker: it binds to β-adrenergic receptors, and prevents the agonistic effects of neurotransmitters and catecholamines on the β receptors; NSAIDs: gastrointestinal irritation, allergy β-blocker: dizziness, hypotension 1. Montelukast 2. N-α-methylhistamine Montelukast: it is a leukotriene antagonists which blocking leukotriene-induced bronchial and intracranial vascular inflammation; N-α-methylhistamine: it is a H3/H4 receptors modulators Montelukast: nervous system side effects, gastrointestinal side effects N-α-methylhistamine: weight gain, drowsiness, dizziness, mild reversible depression, dyspepsia and palpitation 1. FM: Amitriptyline 2. TMD: Propranolol Amitriptyline: a TCA which inhibits serotonin and norepinephrine reuptake; Propranolol: a β-blocker which binds to β-adrenergic receptors, and prevents the agonistic effects of neurotransmitters and catecholamines on the β receptors Amitriptyline: dry mouth, slight dizziness, constipation, tachycardia, and confusion Propranolol: dizziness, hypotension 1. Gastroparesis: Metoclopramide; triptans; 2. IBS: Amitriptyline Metoclopramide: a dopamine receptor antagonists and 5-HT 4 agonist; triptans: a selective 5-HT 1B/1D receptor agonist which inhibits the excitation of the trigeminal nucleus; Amitriptyline: a TCAs which inhibits serotonin and norepinephrine reuptake r Metoclopramide: Restlessness, drowsiness, fatigue, and lassitude; Triptans: nausea, lassitude, dizziness Amitriptyline: dry mouth, slight dizziness, constipation, tachycardia, and confusion 1. DM: Topiramate 2. Endometriosis: Danazol Topiramate: an AEDs which inhibits the opening and activation of sodium ion channels Danazol: it is a gonadotropin-suppressant that acts on the estrogen receptor and inhibits the efficacy of estrogen Topiramate: dizziness, confusion of consciousness Danazol: liver dysfunction, endocrine and metabolic disorders Antiepileptics (e.g., valproate, topiramate) are first-line for migraine with comorbid epilepsy and are also effective in BD and obesity-related migraine. However, attention must be given to teratogenic risks (valproate) and cognitive side effects (topiramate) [ 206 ]. Certain antidepressants (e.g., amitriptyline, venlafaxine) benefit migraine patients with MDD, anxiety, FM, or IBS. Note that the efficacy and side effects of serotonergic drugs may exhibit sex differences, with greater sensitivity often seen in females [ 40 ]. CGRP-targeted monoclonal antibodies prevent migraine and may independently improve comorbid MDD, FM, and RLS, offering a novel mechanism-based option for overlapping conditions. Their efficacy and safety in patients with active cardiovascular disease or stroke history require individualized assessment [ 207 ]. Novel biologic agents, such as monoclonal antibodies targeting PACAP and its receptors, have shown preliminary efficacy in migraine prevention and may concurrently modulate stress-related and affective symptoms [ 64 ]. Orexin receptor antagonists, originally developed for insomnia, are being investigated for their potential to address both migraine and sleep disturbances through dual mechanism of action. Antihypertensives (e.g., β-blockers, candesartan) are preferred when migraine coexists with hypertension or prior stroke, whereas triptans should be avoided in patients with established cardiovascular disease. Histamine-receptor modulators (e.g., N-α-methylhistamine) and leukotriene antagonists (e.g., montelukast) represent emerging strategies for migraine with asthma or atopic diathesis [ 155 ]. Nucleic acid-based therapies represent a promising frontier. Given the central role of CGRP and TRP channels in migraine pathophysiology, these targets may be amenable to nucleic acid-based modulation in the future, offering the potential for sustained therapeutic effects with reduced dosing frequency. However, significant translational hurdles remain, and such approaches are currently speculative. Antiepileptics (e.g., valproate, topiramate) are first-line for migraine with comorbid epilepsy and are also effective in BD and obesity-related migraine. However, attention must be given to teratogenic risks (valproate) and cognitive side effects (topiramate) [ 206 ]. Certain antidepressants (e.g., amitriptyline, venlafaxine) benefit migraine patients with MDD, anxiety, FM, or IBS. Note that the efficacy and side effects of serotonergic drugs may exhibit sex differences, with greater sensitivity often seen in females [ 40 ]. CGRP-targeted monoclonal antibodies prevent migraine and may independently improve comorbid MDD, FM, and RLS, offering a novel mechanism-based option for overlapping conditions. Their efficacy and safety in patients with active cardiovascular disease or stroke history require individualized assessment [ 207 ]. Novel biologic agents, such as monoclonal antibodies targeting PACAP and its receptors, have shown preliminary efficacy in migraine prevention and may concurrently modulate stress-related and affective symptoms [ 64 ]. Orexin receptor antagonists, originally developed for insomnia, are being investigated for their potential to address both migraine and sleep disturbances through dual mechanism of action. Antihypertensives (e.g., β-blockers, candesartan) are preferred when migraine coexists with hypertension or prior stroke, whereas triptans should be avoided in patients with established cardiovascular disease. Histamine-receptor modulators (e.g., N-α-methylhistamine) and leukotriene antagonists (e.g., montelukast) represent emerging strategies for migraine with asthma or atopic diathesis [ 155 ]. Nucleic acid-based therapies represent a promising frontier. Given the central role of CGRP and TRP channels in migraine pathophysiology, these targets may be amenable to nucleic acid-based modulation in the future, offering the potential for sustained therapeutic effects with reduced dosing frequency. However, significant translational hurdles remain, and such approaches are currently speculative. Third, it is crucial to carefully consider the drug-disease interactions and safety profiles in comorbid populations. For example, certain antidepressants may worsen symptoms of RLS, while dopamine agonists used for RLS can trigger MA [ 68 ]. Disease-modifying therapies for MS (e.g., interferon-β) have also been reported to exacerbate headache in certain individuals [ 154 ]. Clinicians should remain alert to potential mood‑switching (e.g., induction of mania) when using antidepressants in patients with BD [ 41 ]. Additionally, the risk of drug interactions should be considered when combining migraine preventives with therapies for other conditions, such as MS. The side-effect profiles outlined in Table  2 —such as weight gain with valproate, sedation with pramipexole, or gastrointestinal irritation with NSAIDs—should be weighed against individual patient characteristics, including age, sex, metabolic status, cardiovascular risk, and concomitant medications. Fourth, non-pharmacological intervention measures should be regarded as an important part of comprehensive management. Many of the modifiable risk factors depicted in Fig.  3 —such as stress, poor sleep, physical inactivity, and dietary habits—can all be addressed through structured lifestyle and behavioral interventions. For example, cognitive-behavioral therapy for insomnia or anxiety, continuous positive airway pressure (CPAP) for OSA [ 68 ], regular aerobic exercise, dietary modifications (e.g., gluten-free diet in CD and IgG-based elimination diets in IBS or FD [ 126 ]), probiotic supplementation, and stress-reduction techniques can ameliorate both migraine and comorbid conditions while enhancing the efficacy of pharmacologic therapies. In addition to lifestyle and behavioral modifications, device-based neuromodulation therapies have emerged as valuable non-pharmacological options. nVNS has demonstrated efficacy in both acute and preventive treatment of migraine and may simultaneously improve symptoms of gastroparesis and migraine-associated sleep disturbance by modulating autonomic and affective circuits [ 131 , 208 ]. Transcranial magnetic stimulation (TMS), particularly single-pulse TMS, has been approved for the treatment of refractory migraine and shows promise in comorbid depression [ 40 ]. Remote electrical neuromodulation (REN) and external trigeminal nerve stimulation (eTNS) offer additional device-based alternatives with favorable safety profiles, making them suitable for patients who are intolerant to pharmacotherapy or have contraindications to specific drug classes [ 209 ]. Finally, the effective management of complex comorbid presentations often requires multidisciplinary collaboration. Comprehensive treatment involving neurologists, psychiatrists, cardiologists, pulmonologists, gastroenterologists, and pain specialists can facilitate the development of coherent, individualized regimens that address the full spectrum of symptoms while minimizing therapeutic conflicts. However, the implementation of these management strategies in real-world clinical practice faces numerous challenges. First, the symptomatic overlap between migraine and comorbid conditions—such as fatigue, sleep disturbances, and mood changes—often leads to underdiagnosis or misdiagnosis, delaying appropriate intervention. Second, treatment decisions are frequently complicated by potential drug–drug interactions, contraindications, and the lack of high-quality evidence from clinical trials that include patients with multiple comorbidities. Third, patient heterogeneity in terms of genetic background, lifestyle factors, and disease trajectories makes it difficult to apply standardized treatment guidelines to individual cases. Fourth, access to multidisciplinary care and advanced therapies—such as anti-CGRP monoclonal antibodies or neuromodulation devices—remains limited in many regions due to cost, reimbursement policies, or lack of specialized expertise. Finally, adherence to long-term preventive regimens is often poor in comorbid populations, where polypharmacy and side effect burden can be substantial. These real-world limitations underscore the urgent need for a more integrated, patient-centered approach that moves beyond the traditional headache-centric model. In summary, a comorbidity-aware management paradigm—integrating systematic screening, mechanism-based pharmacotherapy (see Table  2 for drug specifics), vigilant risk monitoring, and multimodal non-drug strategies—offers a rational approach to improving headache control, reducing the burden of coexisting diseases, and enhancing overall quality of life in patients with migraine. Looking forward, the future of migraine pharmacotherapy lies in expanding beyond single-target, symptom-focused agents toward multi-mechanism drugs that simultaneously address shared pathophysiological pathways across comorbid conditions. This will increasingly involve combination strategies that leverage synergistic effects while minimizing dose-related adverse events. Such a paradigm shift—from a one-size-fits-all approach to mechanism-based, comorbidity-informed treatment selection—holds the potential to significantly improve outcomes for patients with migraine and its associated disorders.

This review has outlined the strong, frequently bidirectional links between migraine and various conditions affecting the nervous, cardio-cerebrovascular, immune, endocrine, and gastrointestinal systems. These evidences indicate that the pathological physiological process involves multiple factors interacting and interrelating with each other rather than having a single unified mechanism. Several key overlapping pathways play major roles here. For instance, migraines share a common genetic structure with most comorbidities (Fig.  4 ); CSD serves as an electrophysiological hub linking MA, epilepsy, and stroke vulnerability; dysregulation of neurotransmitter and neuropeptide systems (e.g., 5-HT, dopamine, CGRP, and PACAP) simultaneously modulate both pain and affective states; neuroimmune activation and systemic inflammation serve as a common basis for migraine, autoimmune diseases, asthma, and metabolic comorbidity; central sensitization acts as a core mechanism underlying the overlap with other chronic pain conditions such as FM and TMD; dysfunction of the hypothalamus–brainstem axis and the autonomic nervous system contribute to comorbidity with sleep and gastrointestinal disorders; and cerebral metabolic imbalance links migraine with insulin resistance and energy dysregulation. Fig. 4 Schematic diagram showing the susceptibility genes and related loci associated with migraine and its comorbidities, including epilepsy, depression, anxiety, bipolar disorders, restless legs syndrome, stroke, obesity, and diabetes mellitus. Created with BioRender.com Schematic diagram showing the susceptibility genes and related loci associated with migraine and its comorbidities, including epilepsy, depression, anxiety, bipolar disorders, restless legs syndrome, stroke, obesity, and diabetes mellitus. Created with BioRender.com Future research should prioritize the identification of reliable biomarkers—such as circulating neuropeptides, genetic risk scores, or neuroimaging signatures—that can facilitate early diagnosis and stratification of patients with specific comorbidity profiles. In-depth mechanistic studies at the molecular and circuit levels are urgently needed to dissect causal relationships and identify novel therapeutic targets. Moreover, platform clinical trials designed to evaluate mechanism-based therapies in well-defined comorbid populations will be essential to move beyond symptom-oriented management toward precision medicine. A deeper understanding of the pathophysiological mechanism linking migraine to its comorbidities will not only advance migraine therapeutics but also promote the formation of a more comprehensive treatment model, ultimately improving outcomes and quality of life for affected individuals.

Migraine is a common chronic neurological disorder characterized by recurrent, moderate-to-severe, pulsating headaches. According to the International Classification of Headache Disorders, 3rd edition (ICHD-3), migraine attacks usually present as unilateral headache last 4–72 h and are often accompanied by nausea, vomiting, photophobia, and autonomic dysfunction. Based on the presence or absence of aura symptoms, migraine can be classified into migraine with aura (MA) and migraine without aura [ 1 , 2 ]. The condition is usually female-predominant and affects approximately 15% of the global population. Epidemiological data show significant geographical variation in migraine prevalence: the highest rates are found in Europe and Southeast Asia (25%-35%), whereas China has a relatively lower prevalence of about 9% [ 3 ]. The high prevalence and disability associated with migraine impose a substantial burden on patients’ quality of life and contributes significantly to familial and societal costs [ 4 ]. The pathophysiology of migraine is complex and remains incompletely understood. Accumulating evidence suggests that migraine is a disorder of brain network excitability involving abnormal sensory processing, dysfunctional pain modulation, and altered neurovascular interactions. Several pathophysiological theories have been proposed, including the vascular hypothesis, neurogenic inflammation theory, genetic susceptibility, and cortical spreading depression (CSD) [ 5 ]. Among them, CSD—a slowly propagating wave of neuronal and glial depolarization—is widely recognized as a key mechanism underlying migraine aura, while activation of the trigeminovascular system and the release of vasoactive neuropeptides, particularly calcitonin gene-related peptide (CGRP), are considered central to the generation of migraine [ 6 ] (Fig.  1 ). Importantly, these mechanisms are not confined to the central nervous system (CNS) but involve systemic inflammatory, autonomic, endocrine, and metabolic pathways, suggesting that migraine may represent a multisystem disorder rather than a purely episodic headache condition. Fig. 1 Schematic illustration of important neuronal structures and connections in the trigeminovascular afferent pathways involved in migraine headache. The nociceptive pathway begins with the activation of first-order neurons in the trigeminal ganglion (TG), which innervate meningeal vessels. These neurons project centrally to second-order neurons in the brainstem trigeminocervical complex (TCC), which comprises the trigeminal nucleus caudal (TNC) and the C1–C2 dorsal horns of the cervical spinal cord. The TCC, in turn, sends ascending projections to third-order neurons in specific thalamic nuclei (e.g., the VPM, Po). Finally, these thalamic neurons relay the signal to a diffuse cortical network, including the somatosensory and associative cortices, culminating in the perception of headache and associated sensory disturbances. M1/M2, primary/secondary motor cortices; S1/S2, primary/secondary somatosensory cortices; V1/V2, primary/secondary visual cortices; Ins, insula; PtA, parietal association; RS, retrosplenial; Au, auditory; Ect, ectorhinal; VPM, Po, ventroposteromedial and posterior nuclei of the thalamus; PAG, periaqueductal gray; NCF, nucleus cuneiformis; SSN, superior salivatory nucleus; RVM, rostral ventromedial medulla. Created with BioRender.com Schematic illustration of important neuronal structures and connections in the trigeminovascular afferent pathways involved in migraine headache. The nociceptive pathway begins with the activation of first-order neurons in the trigeminal ganglion (TG), which innervate meningeal vessels. These neurons project centrally to second-order neurons in the brainstem trigeminocervical complex (TCC), which comprises the trigeminal nucleus caudal (TNC) and the C1–C2 dorsal horns of the cervical spinal cord. The TCC, in turn, sends ascending projections to third-order neurons in specific thalamic nuclei (e.g., the VPM, Po). Finally, these thalamic neurons relay the signal to a diffuse cortical network, including the somatosensory and associative cortices, culminating in the perception of headache and associated sensory disturbances. M1/M2, primary/secondary motor cortices; S1/S2, primary/secondary somatosensory cortices; V1/V2, primary/secondary visual cortices; Ins, insula; PtA, parietal association; RS, retrosplenial; Au, auditory; Ect, ectorhinal; VPM, Po, ventroposteromedial and posterior nuclei of the thalamus; PAG, periaqueductal gray; NCF, nucleus cuneiformis; SSN, superior salivatory nucleus; RVM, rostral ventromedial medulla. Created with BioRender.com Consistent with this systemic perspective, migraine often coexists with a range of comorbid conditions. Epidemiological studies have demonstrated strong associations between migraine and cardio-cerebrovascular diseases (e.g., stroke), immune diseases (e.g., asthma), respiratory diseases (e.g., obstructive sleep apnea, OSA), digestive diseases (e.g., irritable bowel syndrome, IBS), endocrine diseases (e.g., endometriosis), other chronic pain conditions (e.g., fibromyalgia), psychiatric disorders (e.g., depression), as well as epilepsy [ 7 ] (Fig.  2 ). The presence of these comorbidities tends to complicate the clinical presentation and worsen the prognosis, thereby increasing the overall disease burden. Current migraine management relies largely on pharmacological interventions aimed at acute symptom relief or attack prevention, including nonsteroidal anti-inflammatory drugs (NSAIDs), triptans, CGRP-targeting agents, and onabotulinum toxin A for chronic migraine [ 8 , 9 ]. While these therapies have improved migraine care, they are primarily symptom-oriented and do not adequately address the shared pathophysiological mechanisms underlying migraine and its comorbidities. Moreover, comorbid conditions may influence drug efficacy, tolerability, and safety, further complicating clinical decision-making. Therefore, a deeper understanding of the common biological pathways linking migraine with its comorbidities is essential for optimizing integrated and personalized treatment strategies. Fig. 2 Schematic illustrating migraine and its common comorbidities. Migraine can be comorbid with a variety of diseases, including neurological, psychiatric, cardiovascular-cerebrovascular, gastrointestinal, metabolic-endocrine, pain and immune disorders. Created with BioRender.com Schematic illustrating migraine and its common comorbidities. Migraine can be comorbid with a variety of diseases, including neurological, psychiatric, cardiovascular-cerebrovascular, gastrointestinal, metabolic-endocrine, pain and immune disorders. Created with BioRender.com In this review, we summarize current evidence on the pathophysiological mechanisms shared between migraine and its major comorbidities and discuss the clinical implications of these interactions, with particular emphasis on comorbidity-oriented therapeutic approaches. Elucidating these links may not only advance our understanding of migraine pathogenesis but also contribute to the development of more comprehensive and effective management strategies.

Migraine and epilepsy are both common chronic, paroxysmal neurological disorders. They share several clinical features, such as episodic attacks, possible aura phenomena, and generally normal interictal periods. Strong epidemiological evidence supports a bidirectional relationship between them. A large meta-analysis revealed a 52% higher prevalence of migraine in people with epilepsy than in those without epilepsy, whereas the prevalence of epilepsy is 79% greater in people with migraine than in non-migraine patients [ 10 ]. Specifically, the median prevalence of epilepsy in migraine patients is 5.9% (range: 1%-17%), which was significantly higher than that in the general population (0.5%-1%). On the other hand, the prevalence of migraine in people with epilepsy ranges from 8.4% to 20% [ 11 ]. A retrospective study from Iceland further indicated that children with epilepsy under 16 years of age had an almost fourfold increased risk of MA compared with healthy controls [ 12 ]. This bidirectional comorbidity relationship provides evidence for shared pathophysiological mechanisms. Both migraine and epilepsy involve abnormal neuronal excitability: migraine is associated with cerebral hyperresponsiveness following cephalic stimuli, whereas epilepsy results from paroxysmal, synchronous neuronal discharges [ 13 ]. According to a study, CSD is a transient depolarization wave of neuronal and glial cells that spreads slowly across the cerebral cortex and is accompanied by the suppression of electrical activity [ 14 ]. This process involves massive ionic shifts, including a marked increase in extracellular potassium and decreases in sodium and calcium, and triggers the release of excitatory neurotransmitters such as glutamate. By activating N-methyl-D-aspartic acid receptor (NMDA) receptors, glutamate further enhances potassium efflux and glutamate release, forming a positive feedback loop that sustains and propagates CSD [ 15 ]. CSD is widely regarded as the mechanism underlying migraine aura, and it also appears to activate the trigeminovascular system to initiate headache. Studies have confirmed that CSD can occur before or during epileptic seizures [ 16 , 17 ]. Thus, epilepsy-related spreading depolarizations may help explain the higher risk of MA in patients with epilepsy. However, the role of CSD in generalized seizures remains unclear, suggesting that other mechanisms may be involved. Genetic susceptibility constitutes another key factor underlying migraine-epilepsy comorbidity. Specific genetic mutations can cause both disorders, most notably in hemiplegic migraine (HM), a rare subtype of MA. HM can be categorized into sporadic (SHM) and familial (FHM) forms and further subdivided into three main subtypes (HM1-3) based on the causative gene [ 18 ]. Importantly, the distinct functional consequences of these mutations—whether gain-of-function (GOF) or loss-of-function (LOF)—dictate the resulting cellular hyperexcitability and differential clinical phenotypes. FHM1 ( CACNA1A gene): This gene encodes the α1 subunit of the neuronal voltage-gated P/Q-type calcium channel (Ca v 2.1), which is crucial for presynaptic glutamate release. FHM1-associated mutations (e.g., R192Q and S218L) typically result in a gain-of-function (GOF). This GOF leads to enhanced calcium influx at lower voltages and increased spontaneous and evoked release of excitatory neurotransmitters, particularly glutamate. The resulting glutamatergic hyperactivity lowers the threshold for CSD, driving the migraine phenotype. Conversely, severe GOF mutations like S218L cause excessive cortical hyperexcitability that extends beyond CSD generation to trigger synchronous epileptiform discharges, explaining the severe FHM1 phenotype accompanied by fatal seizures and coma [ 19 , 20 ]. Clinical cases have also linked other mutations (e.g., W1684R, V1696F, and I1709T [ 21 ]) to FHM1-epilepsy comorbidity. FHM2 ( ATP1A2 gene): This gene encodes the α2 subunit of the Na + /K + ATPase pump. FHM2 mutations are generally characterized by a loss-of-function (LOF), which impairs astrocytic clearance of extracellular potassium and glutamate, leading to increased neuronal network excitability. Numerous ATP1A2 mutation sites (e.g., G301R, R348P, and R689Q [ 21 ]) have been identified in patients with comorbid FHM2 and epilepsy. Transgenic models carrying the G301R mutation exhibit increased susceptibility to both CSD and epileptiform activity [ 22 ]. FHM3 ( SCN1A gene): This gene encodes the α1 subunit of the voltage-gated sodium channel Na v 1.1. FHM3 mutations generally cause a GOF, which can accelerate recovery from fast inactivation, increase neuronal excitability, promote CSD propagation and lead to FHM3 and epilepsy (including focal and generalized seizures). Missense mutations such as L263V, T1174S, and Q1489K [ 21 ] have been reported in such cases. Other Genes: The PRRT2 gene encodes a presynaptic transmembrane protein involved in calcium-dependent neurotransmitter release and negatively regulates voltage-gated sodium channels. PRRT2 mutations, particularly frameshift mutations, typically result in a LOF due to haploinsufficiency. This LOF removes the negative regulation on SNARE-mediated vesicular fusion and sodium channels, leading to neuronal hyperexcitability. This shared mechanism of synaptic dysregulation links PRRT2 to epilepsy and migraine [ 23 ], suggesting that it is a potential fourth FHM gene. Furthermore, genome-wide linkage analyses of large families have identified novel shared susceptibility loci, including 9q21-q22 [ 24 ], 12q24.2-q24.3, and 14q12-q23 [ 25 ], suggesting that the existence of yet-to-be-identified susceptibility genes contributes to the comorbidity of common forms of migraine and epilepsy. FHM1 ( CACNA1A gene): This gene encodes the α1 subunit of the neuronal voltage-gated P/Q-type calcium channel (Ca v 2.1), which is crucial for presynaptic glutamate release. FHM1-associated mutations (e.g., R192Q and S218L) typically result in a gain-of-function (GOF). This GOF leads to enhanced calcium influx at lower voltages and increased spontaneous and evoked release of excitatory neurotransmitters, particularly glutamate. The resulting glutamatergic hyperactivity lowers the threshold for CSD, driving the migraine phenotype. Conversely, severe GOF mutations like S218L cause excessive cortical hyperexcitability that extends beyond CSD generation to trigger synchronous epileptiform discharges, explaining the severe FHM1 phenotype accompanied by fatal seizures and coma [ 19 , 20 ]. Clinical cases have also linked other mutations (e.g., W1684R, V1696F, and I1709T [ 21 ]) to FHM1-epilepsy comorbidity. FHM2 ( ATP1A2 gene): This gene encodes the α2 subunit of the Na + /K + ATPase pump. FHM2 mutations are generally characterized by a loss-of-function (LOF), which impairs astrocytic clearance of extracellular potassium and glutamate, leading to increased neuronal network excitability. Numerous ATP1A2 mutation sites (e.g., G301R, R348P, and R689Q [ 21 ]) have been identified in patients with comorbid FHM2 and epilepsy. Transgenic models carrying the G301R mutation exhibit increased susceptibility to both CSD and epileptiform activity [ 22 ]. FHM3 ( SCN1A gene): This gene encodes the α1 subunit of the voltage-gated sodium channel Na v 1.1. FHM3 mutations generally cause a GOF, which can accelerate recovery from fast inactivation, increase neuronal excitability, promote CSD propagation and lead to FHM3 and epilepsy (including focal and generalized seizures). Missense mutations such as L263V, T1174S, and Q1489K [ 21 ] have been reported in such cases. Other Genes: The PRRT2 gene encodes a presynaptic transmembrane protein involved in calcium-dependent neurotransmitter release and negatively regulates voltage-gated sodium channels. PRRT2 mutations, particularly frameshift mutations, typically result in a LOF due to haploinsufficiency. This LOF removes the negative regulation on SNARE-mediated vesicular fusion and sodium channels, leading to neuronal hyperexcitability. This shared mechanism of synaptic dysregulation links PRRT2 to epilepsy and migraine [ 23 ], suggesting that it is a potential fourth FHM gene. Furthermore, genome-wide linkage analyses of large families have identified novel shared susceptibility loci, including 9q21-q22 [ 24 ], 12q24.2-q24.3, and 14q12-q23 [ 25 ], suggesting that the existence of yet-to-be-identified susceptibility genes contributes to the comorbidity of common forms of migraine and epilepsy. Migraine is closely comorbid with several psychiatric disorders, particularly major depressive disorder (MDD), anxiety disorders, and bipolar disorder (BD). Extensive epidemiological studies have established that these associations are characterized by bidirectionality and a dose‒response relationship. The comorbidity with MDD is particularly prominent. The risk of MDD is 2–4 times greater in individuals with migraine than in the general population [ 26 , 27 ], and this relationship is bidirectional, with each disorder increasing the risk for new onset [ 28 , 29 ]. Crucially, a dose‒response relationship exists, whereby a higher frequency of migraine attacks is associated with a significantly greater risk of comorbid MDD [ 30 , 31 ]. The link with anxiety disorders is robust, with some studies indicating an association strength that exceeds that of MDD [ 27 ]. Anxiety is not only independently associated with an increased risk of migraine [ 32 ], but its severity is also correlated with migraine frequency and serves as a significant predictor for the transition from episodic to chronic migraine [ 31 ]. The comorbidity with BD is also well established. The prevalence of migraine is significantly greater in patients with BD, especially those with BD type II, and among females than in the general population [ 33 , 34 ]. Serotonergic system Serotonergic system Current research posits that low serotonin (5-hydroxytryptamine, 5-HT) levels constitute a key neurobiological basis of depression. Similarly, plasma 5-HT levels are reduced during the interictal phase of migraine, and low 5-HT may increase migraine risk [ 35 ]. Depletion of tryptophan, a precursor of 5-HT, exacerbates symptoms of both depression and migraine [ 36 ]. Preclinical evidence further supports its central role: CNR1 (encoding cannabinoid receptor 1) knockout mice exhibit depression-like behaviors following stress [ 37 ], and this gene is also associated with migraine risk [ 38 ], suggesting that modulation of 5-HT and other neurotransmitters by the endocannabinoid system may be a critical link in comorbidity. Notably, while tricyclic antidepressants (TCAs) and psilocybin (a 5-HT 2A receptor agonist) are effective for both conditions, selective serotonin reuptake inhibitors (SSRIs) are ineffective for migraine prophylaxis, whereas triptans (5-HT 1B/1D agonists) are specific acute migraine treatments [ 39 , 40 ]. These findings collectively suggest that the neurotransmitter abnormalities underlying comorbidities are not merely related to absolute 5-HT levels but also involve functional differences in specific receptor subtypes and neural circuits. Moreover, central serotonergic activity is reduced during both the depressive and euthymic phases of BD [ 41 ]. 2. Dopaminergic system Dopaminergic system Hypofunction of the dopaminergic system is linked to a lack of motivation and attentional deficits in depression and is also implicated in prodromal migraine symptoms (e.g., yawning, somnolence) [ 42 ]. Genetic studies suggest that polymorphisms in the DRD2 gene are associated with a comorbid risk for migraine MA, MDD, and anxiety disorders [ 43 ]. Functionally, DRD2 primarily acts as a presynaptic autoreceptor regulating neurotransmitter release. During migraine attacks, decreased endogenous dopamine release in the striatum of patients may be related to pain and sensory hypersensitivity [ 44 ]. Preclinical studies have shown that DRD2 antagonists can reverse migraine-related allodynia, elevated CGRP levels, and brainstem c-fos activation, whereas DRD2 agonists exert antimigraine effects by modulating AMPA receptor trafficking via the PI3K/SFK pathway [ 40 ]. 3. Glutamatergic/GABAergic systems Glutamatergic/GABAergic systems An imbalance between excitation and inhibition is a shared mechanism in migraine and psychiatric disorders. Clinical studies have shown elevated glutamate levels in the cerebrospinal fluid of migraine patients, whereas in BD patients, glutamate is upregulated in the anterior cingulate cortex and downregulated in the hippocampus [ 41 ]. Therapeutically, lamotrigine (which inhibits glutamate release) is effective for both MA and the depressive phase of BD [ 45 , 46 ]. GABAergic drugs such as topiramate are used for migraine prophylaxis and are also effective for the manic phase of BD [ 47 , 48 ]. Ketamine, an NMDA receptor antagonist, has rapid efficacy for both treatment-resistant migraine and MDD [ 40 ]. Migraine and psychiatric disorders share a significant genetic foundation. Twin studies estimate the heritability of both migraine and MDD to be approximately 40–50%, with approximately 20% of the variance attributable to shared genetic factors [ 42 , 49 ]. Genetic risk score analyses confirmed a significant genetic correlation between them (rG = 0.32) [ 50 ]. Parental migraine has also been identified as a risk factor for BD in offspring, even in the absence of parental BD [ 51 ]. Genetic studies have revealed numerous risk genes associated with migraine-MDD comorbidity, including MTHFR , ANKDD1B , KCNK5 , TPH2 , DBR2 , GABRA3 , and BDNF [ 42 , 52 ]. The 5-HTTLPR polymorphism of the serotonin transporter gene SLC6A4 is linked to increased risk for anxiety disorders, MDD, and migraine [ 42 , 48 ]. A recent genome-wide association study (GWAS) revealed 14 loci shared between migraine and MDD and 36 loci shared between migraine and schizophrenia [ 53 ]. Another study reported that TRPV1 (rs222741) and TRPM8 (rs7577262) may be associated with migraine comorbid with anxiety risk, whereas TRPV1 (rs222741), TRPV4 (rs3742037), TRPM8 (rs17862920), and SLC17A8 (rs11110359) may be linked to migraine comorbid with depression risk [ 54 ]. Furthermore, specific genes have been implicated in the comorbidity of migraine and BD. Multiple GWASs have identified genetic variants in KIAA0564 , LMX1A , NRG1 , SLC24A3 , and NEBA that may be associated with this comorbidity [ 41 , 55 ]. Studies indicate that patients with comorbid migraine and MDD exhibit more pronounced reductions in total brain, gray matter, and white matter volumes than those with either condition alone [ 56 ]. Lirng et al. reported elevated myo-inositol to creatine ratios in the left and right dorsolateral prefrontal cortex of comorbid patients, suggesting glial dysfunction [ 57 ]. Functional imaging reveals abnormalities in the function and connectivity of affective-motivational brain regions—including the anterior cingulate cortex, anterior insula, prefrontal cortex, amygdala, and hippocampus—in both migraine and various psychiatric disorders, constituting a shared substrate for emotion‒pain integration [ 39 , 48 ]. Neuroimaging and circuit research further elucidates key shared abnormalities in specific brain regions and pathways. For example, transcranial sonography has demonstrated that reduced echogenicity of the dorsal raphe nucleus is associated with MDD and, in migraine patients, correlates with depressive symptoms and attack frequency [ 46 , 58 ]. Dysfunction of the locus coeruleus‒norepinephrine (LC‒NE) system, which affects cognitive‒emotional regulation in MDD and mediates trigeminal sensitization in migraine patients, may be a core mechanism underlying the shared thalamic‒prefrontal connectivity abnormalities in both disorders [ 59 , 60 ]. Concurrently, increased functional connectivity between the thalamus and regions such as the somatosensory cortex and insula is observed in both migraine and MDD patients, which may be the neural basis for their shared sensory hypersensitivity [ 61 , 62 ]. Neuropeptides play dual roles in pain and mood regulation. CGRP is a key mediator in migraine. Clinically, anti-CGRP monoclonal antibodies (mAbs) not only prevent migraine but also may independently improve comorbid depressive symptoms, indicating that CGRP is directly involved in mood regulation [ 63 ]. Animal studies have shown that in migraine models, the inhibition of orexin receptor 1 (OX1R) in the hypothalamus increases anxiety-like behaviors and spontaneous migraine-like headache behaviors, whereas in depression models, the activation of this pathway reverses depression-like behaviors, suggesting that the orexin system modulates both the sensory and affective dimensions of pain [ 46 ]. Pituitary adenylate cyclase-activating polypeptide (PACAP) is another key shared mediator expressed in CNS neural circuits related to pain, stress, and depression. PACAP can induce migraine-like symptoms and activate the hypothalamic‒pituitary‒adrenal (HPA) axis and limbic brain regions involved in stress and depression [ 46 ]. Injection of PACAP can trigger migraine attacks in migraine patients, and monoclonal antibodies targeting PACAP have preliminarily shown efficacy in reducing migraine days in early trials [ 64 ], warranting further clinical investigation. PACAP levels are elevated in several brain regions of MDD patients. Preclinical evidence indicates that PACAP can rapidly reverse stress-induced depression-like behaviors and is necessary for the therapeutic effects of drugs such as paroxetine and ketamine. However, it also promotes depression-like behaviors in specific brain regions (e.g., the PVN and CeA), indicating a complex role [ 40 ]. Fluctuations in estrogen, through modulation of the 5-HT, dopaminergic, and GABAergic systems as well as CGRP and BDNF, are key factors in the increased comorbidity risk of migraine and MDD in women [ 65 ]. Animal experiments have confirmed that estrogen enhances, while testosterone reduces, susceptibility to CSD [ 35 ]. Chronic and acute stress are common triggers and exacerbating factors for both migraine and various psychiatric disorders [ 39 ]. Early life adversity significantly increases the risk of developing migraine and MDD in adolescence and adulthood and is associated with abnormal development and connectivity in multiple brain regions [ 40 ]. Preclinical studies have confirmed that maternal separation stress can induce migraine-like phenotypes (e.g., photic and tactile hypersensitivity) and depression-/anxiety-like behaviors in adulthood [ 66 , 67 ], with a more pronounced effect in females. Simultaneously, dysregulation of the HPA axis and subsequent neuroinflammation represent a common pathway linking stress, MDD, anxiety, and migraine [ 48 ]. Moreover, PACAP interacts with glucocorticoids, coregulating stress responses and influencing mood and migraine susceptibility [ 40 ]. Elevated levels of proinflammatory cytokines (e.g., IL-1β, IL-6, and TNF-α) have been observed during migraine attacks, as well as in patients with MDD and BD [ 46 ]. Studies have shown that neuroinflammation mediated by microglial activation is a crucial mechanism through which stress contributes to the comorbidity of migraine and psychiatric disorders. In addition, preclinical and animal studies support the role of inflammation in inducing pain sensitization and depression-like behaviors [ 46 ]. Consequently, targeting inflammatory pathways may offer novel therapeutic strategies for comorbid conditions. In summary, shared mechanisms such as CSD, genetic susceptibility, and monoaminergic dysfunction underscore the neurobiological overlap between migraine and both epilepsy and psychiatric disorders. These convergent pathways not only explain their bidirectional comorbidity but also provide a foundation for understanding how similar mechanisms—particularly those involving autonomic and metabolic dysregulation—may underlie the comorbidities discussed in the following sections.

Migraine and sleep disorders exhibit a close bidirectional co-morbidity relationship, often exacerbating each other and forming a vicious cycle. Epidemiological studies have confirmed that the prevalence of various sleep problems is significantly greater in migraine patients than in the general population and that self-reported poor sleep quality is associated with more frequent headache attacks and an increased risk of chronic illness [ 68 ]. Conversely, sleep disturbances are common triggers and perpetuating factors for migraine [ 69 ]. This widespread co-occurrence suggests shared underlying neuroanatomical structures and neurochemical mechanisms. Insomnia is the most common comorbid sleep disorder. Large-scale prospective studies indicate that insomnia increases the risk of new-onset migraine 11 years later by 40% (RR = 1.4) [ 70 ]. Conversely, migraine patients have a doubled risk (OR = 1.7–2.1) of developing insomnia after 11 years, with the risk increasing with increasing headache frequency [ 71 ]. This bidirectional association is independent of anxiety and depression [ 68 ]. However, it may not be specific to migraine, as some studies have shown no significant difference in insomnia prevalence across headache subtypes [ 68 ]. Patients with OSA frequently experience awakening headaches (29%) and tension-type headaches (15%), but the proportion of those with typical migraine is relatively low (8%) [ 72 ]. Although large-scale polysomnography-based epidemiological studies have not reported a significantly greater prevalence of OSA in migraine patients [ 73 ], clinical observations suggest that OSA may trigger migraine in susceptible individuals and promote its chronicity. Obesity is a significant shared risk factor for both OSA and migraine (particularly chronic migraine) [ 68 ]. The prevalence of restless leg syndrome (RLS) in migraine patients (8.7%–39.0%) is significantly greater than that in the general population (5%–10%) [ 69 ]. A meta-analysis reported a pooled prevalence of RLS of 17.0% in migraine patients versus 7.0% in controls [ 74 ]. The prevalence of migraine is markedly greater in subjects with RLS than in those without RLS, and migraine severity is greater in patients with comorbid RLS [ 75 ], indicating a significant correlation. The comorbidity between migraine and narcolepsy remains controversial. Some studies reported a migraine incidence as high as 23.5%–37% in narcolepsy patients, significantly exceeding that reported in healthy controls (4.9%) [ 76 ], whereas other controlled studies reported no significant associations [ 77 ]. The hypothalamus and brainstem are core regions that regulate sleep‒wake cycles, pain, and circadian rhythms, and their dysfunction may explain the observed bidirectional relationship between migraine and sleep disorders [ 69 ]. Clinical data indicate abnormalities in the microstructure of rapid eye movement (REM) sleep (e.g., reduced cyclic alternating pattern) in migraine patients [ 78 ]. Concurrently, hypothalamic activity is altered up to 24 h before a migraine attack, with associated changes in functional connectivity to brainstem pain modulatory areas (e.g., periaqueductal gray, PAG) [ 79 ]; patients with narcolepsy (especially type 1 with cataplexy) exhibit significant loss of hypothalamic orexin neurons [ 80 ]. Furthermore, alterations in gray matter volume have been observed in the cerebellum, lingual gyrus, precentral gyrus, and postcentral gyrus in patients with migraine and insomnia [ 81 ]. Both migraine and RLS may involve iron dyshomeostasis, with increased iron deposition in deep brain nuclei linked to migraine attacks and brain iron deficiency playing crucial roles in RLS pathogenesis [ 82 ]. Melatonin, which targets hypothalamic circadian rhythms, has shown preventive effects against migraine in some clinical trials [ 83 ]. Dopaminergic system Dopaminergic system Dysfunction of the hypothalamic A11 dopaminergic nucleus is a core mechanism in RLS, with its descending projections inhibiting spinal sympathetic outflow and nociceptive transmission [ 68 ]. Additionally, symptoms during the migraine prodrome and headache phases (yawning, drowsiness, mood changes, and irritability) and the hypersensitivity of migraineurs to dopaminergic agonists suggest a role for dopamine in migraine pathophysiology. This may be because A11 nucleus dysfunction facilitates neuronal firing in the trigeminocervical complex and increases spinal sympathetic activity, thereby causing or exacerbating both migraine and RLS [ 68 ]. Indeed, one study revealed that the dopamine receptor agonist pramipexole not only alleviated RLS symptoms but also reduced migraine frequency in patients with both conditions [ 84 ]. However, other evidence indicates that dopamine agonists that are effective for treating RLS can trigger aura symptoms in migraine patients; conversely, dopamine antagonists can treat acute migraine but may induce RLS-like symptoms [ 85 ]. These findings suggest that the comorbid pathophysiology is more complex than a simple monoaminergic imbalance. 2. Serotonergic (5-HT) system Serotonergic (5-HT) system 5-HT is involved in wakefulness maintenance and pain modulation. Plasma 5-HT levels are low in individuals with migraine and increase during an attack. Animal models have shown that a high-serotonin state increases susceptibility to CSD [ 86 ]. Clinically, the association between migraine and somnambulism (a parasomnia) may be related to 5-HT metabolic abnormalities [ 87 ]. 3. Orexinergic system Orexinergic system Hypothalamic orexin neurons modulate trigeminovascular tone, participate in pain transmission and modulation, and coordinate with brainstem nuclei (locus coeruleus, dorsal raphe) to regulate sleep‒wake transitions [ 68 ], serving as a key link between narcolepsy and migraine. Orexin A exerts antinociceptive effects, whereas orexin B may be pronociceptive, which is mediated through different receptors (OX1R/OX2R) [ 88 ]. Clinically, the dual orexin receptor antagonist suvorexant is used for insomnia and has shown potential therapeutic promise for migraine in preclinical models, but a clinical trial of another dual orexin receptor antagonist, filorexant, did not show significant efficacy for migraine prevention [ 89 ]. 4. Neuropeptide systems Neuropeptide systems The relationship between CGRP and sleep disorders is not fully understood. There are reports of RLS symptoms emerging in two migraine patients following anti-CGRP mAb treatment [ 90 ]; conversely, another report noted improvement in both migraine and RLS symptoms in one patient with comorbid conditions after anti-CGRP mAb therapy [ 91 ]. A recent retrospective study revealed that anti-CGRP mAb treatment significantly improved RLS symptoms [ 92 ], central sensitization, and headache-related disability in patients with comorbid migraine and RLS [ 93 ]. Migraine and RLS share a significant common genetic basis. Multiple GWAS have revealed that genetic variants (e.g., in MEIS1 , LGR6 , VSTM2L , and CCDC141 ) are associated with an increased risk of RLS in migraine patients [ 94 – 96 ]. Furthermore, a GWAS in a Han Chinese population identified several loci (e.g., HDAC9 rs1178326) significantly associated with the comorbidity of insomnia and migraine [ 97 ]. Migraine attacks exhibit a circadian pattern with peaks in the morning or nighttime [ 68 ], and patients with chronic migraine may experience a phase delay in melatonin secretion [ 83 ]. The glymphatic system, which is primarily active during sleep, clears interstitial waste [ 83 ], which may explain why sleep often alleviates migraine attacks. Schain et al. reported that CSD in mice led to closure of the perivascular space and transient impairment of glymphatic flow [ 98 ]. These findings suggest that sleep deprivation or poor sleep quality may contribute to migraine onset and chronification by impairing glymphatic clearance and the accumulation of neurotoxic substances. Migraine, particularly MA, is widely recognized as a significant independent risk marker for cardio-cerebrovascular diseases. Substantial epidemiological evidence indicates a clear and complex association between the two. Strong evidence has demonstrated that migraine patients, especially those with MA, have a significantly increased risk of ischemic stroke (risk ratio ~ 2.0), with the risk being particularly pronounced among young women, smokers, and users of oral contraceptives [ 99 , 100 ]. Furthermore, patients with active migraine (i.e., experiencing attacks within the past 12 months) and those with higher attack frequencies are at increased risk of stroke [ 101 ]. Notably, this association is not confined to stroke alone. MA is also linked to an increased risk of a broader range of cardiovascular events, including myocardial infarction (MI), angina, and cardiovascular mortality [ 100 , 102 ]. Large cohort studies have further identified that migraine is associated with increased risks of atrial fibrillation/flutter and venous thromboembolism [ 100 , 103 ]. Moreover, recent meta-analyses have confirmed an elevated risk of MI and cardiovascular death in migraine (especially MA) patients [ 104 ]. Neuroimaging studies have revealed a relatively high prevalence of asymptomatic brain infarcts and white matter lesions among MA patients, with these abnormalities being particularly common in the posterior circulation territory [ 105 , 106 ]. However, some studies suggest that among women with established stroke, comorbid migraine does not increase the overall burden of white matter lesions [ 107 ]. These findings help examine the complex relationship between the two conditions. Subclinical markers of vascular pathology, such as retinal microvascular abnormalities, are also more common in migraine patients [ 108 ]. Notably, among women who have experienced a stroke, those with comorbid migraine are more often classified as “cryptogenic”, suggesting a pathogenesis potentially distinct from traditional types [ 107 ]. CSD serves as the physiological substrate of migraine aura and acts as a central link connecting MA and stroke. Neuroimaging evidence indicates that CSD can induce a sustained reduction in cerebral blood volume, which in turn leads to a 20–30% decrease in cerebral blood flow lasting for several hours. In extreme cases, this hemodynamic change may trigger ischemic infarction [ 99 , 109 ]. Recent research has further elucidated the microvascular mechanism underlying this hypoperfusion. During CSD, pericytes surrounding first-order cortical capillaries exhibit sustained calcium elevation and strong vasoconstriction, potentially driving the clinically observed “cortical hypoperfusion” phenomenon [ 110 ]. Recurrent CSD may also contribute to cerebral ischemic pathology by inducing neuroinflammation and activating matrix metalloproteinases, thereby disrupting the blood‒brain barrier [ 99 ]. Importantly, CSD is not exclusive to migraine. Surrounding an acute brain infarct, spontaneous “periinfarct depolarizations” occur in the ischemic penumbra. This depolarization is phenomenologically identical to CSD, further exacerbates metabolic supply‒demand mismatches and promotes infarct expansion [ 111 ]. This ischemia-induced CSD can also activate the trigeminovascular system. This explains why “onset headache” occurs in up to 27% of patients with acute ischemic stroke, some of whom have migraine-like features [ 111 ]. Overall, CSD represents a pathophysiological continuum. Its outcome—ranging from benign reversibility in migraine aura to destructive or even fatal consequences in cerebral ischemia—fundamentally depends on the local tissue energy state at the time of occurrence. This explains the divergent manifestations of the same electrophysiological phenomenon in the two conditions [ 112 ]. Thus, CSD constitutes a key electrophysiological bridge underlying the bidirectional association between migraine and stroke. However, CSD alone cannot readily explain extracerebral (e.g., cardiac) vascular events. Genetic syndromes characterized by the co-occurrence of migraine and stroke suggest a genetic link [ 101 ]. Malik et al. reported a shared genetic susceptibility, identifying common variants at different loci that may influence the risk of both migraine and ischemic stroke [ 113 ]. However, the more substantial genetic overlap observed in the MO subgroup suggests that shared genetic traits may not fully explain the stronger population-based association found between MA and stroke. A GWAS confirmed that migraine and cardiovascular diseases share genetic risk loci beyond chance expectations, highlighting PHACTR1 as a common risk locus for various vascular phenotypes, including migraine, coronary artery disease, and cervical artery dissection [ 114 ]. Another GWAS revealed extensive genes shared between migraine and cardiovascular disease [ 115 ]. Furthermore, a polymorphism near the FGF23 gene is associated with both migraine and, in men, white matter lesions and subclinical brain infarcts [ 111 ]. Hautakangas et al., in a large-sample GWAS, demonstrated that migraine susceptibility loci are enriched in genes encoding vascular and neural tissues [ 116 ]. A recent Mendelian randomization (MR) study confirmed a genetic causal association between migraine and stroke, identifying potential drug target genes such as KCNK5 , PLXNB1 , and MDK associated with both risks [ 117 ]. Meanwhile, monogenic syndromes characterized by migraine and stroke provide direct evidence for shared vascular and metabolic mechanisms [ 118 ]. Endothelial dysfunction constitutes a core link between migraine and vascular disease. It involves impaired vascular reactivity along with a proinflammatory and prothrombotic endothelial phenotype. A variety of evidence supporting this systemic disturbance in migraine patients. At the level of repair capacity, migraine patients exhibit reduced numbers and impaired function of circulating endothelial progenitor cells (EPCs), indicating compromised intrinsic vascular repair mechanisms [ 119 ]. In terms of endothelial activation and injury, studies have revealed that women with MA have significantly elevated levels of endothelial microparticles, which is a known marker of endothelial dysfunction [ 120 ]. With respect to hypercoagulability, research suggests that abnormal coagulation and enhanced platelet activation in migraine patients (especially MA patients) potentially promote thrombosis [ 100 ]. A case‒control study confirmed a significant synergistic effect between elevated coagulation protein levels and a history of migraine in increasing ischemic stroke risk [ 121 ]. Additionally, a considerable proportion of migraine patients (particularly women) exhibit coronary vasomotor dysfunction (e.g., vasospastic or microvascular angina), which may represent an important shared clinical phenotype between migraine and nonobstructive coronary artery disease [ 100 ]. Migraine patients often carry a greater burden of traditional cardiovascular risk factors, such as obesity, smoking, dyslipidemia, hypertension, and metabolic syndrome. These factors may be more prominent in MA patients and synergistically increase cardio-cerebrovascular risk with migraine [ 122 ]. Female-specific cardiovascular risk factors (gestational hypertension and preeclampsia) are also more common in women with migraine [ 123 ]. Critically, however, many studies have shown that the association between MA and ischemic stroke remains significant even in populations with low Framingham risk scores and that carotid atherosclerosis may be less severe in migraine patients. This finding suggests that nonatherosclerotic mechanisms likely play a more central role [ 101 ]. Meta-analyses indicate that migraine (especially migraine without aura) is an independent risk factor for cervical artery dissection and its resulting ischemic stroke [ 111 ]. GWAS analyses also confirmed a genetic correlation between cervical artery dissection and migraine, particularly migraine without aura [ 111 ]. Dissection may trigger secondary migraine attacks through mechanisms such as hypoperfusion or the release of substances from the injured endothelium [ 101 ]. Patent foramen ovale (PFO) is a key anatomical factor linking migraine (especially MA), cryptogenic stroke, and paradoxical embolism. The prevalence of PFO is significantly greater in the MA population than in the general population [ 118 ]. Microemboli (e.g., air, cholesterol) from the venous system shunt right-to-left through a PFO can potentially trigger cerebral ischemia or directly induce CSD [ 109 , 111 ]. Clinical studies have also revealed that air microemboli during transcranial Doppler ultrasound can provoke aura in MA patients [ 118 ]. Furthermore, PFO closure has been shown to effectively reduce migraine attack frequency or headache days, significantly improving symptoms, especially in MA [ 124 ]. Therefore, PFO likely contributes to a continuous clinical spectrum—from aura to silent lesions and overt infarction—by providing a source of microemboli that trigger CSD in migraine-prone brains with cortical hyperexcitability. Multiple large cohort studies have shown that MA is associated with an increased risk of atrial fibrillation (AF), and this association may partially mediate the elevated risk of cardioembolic stroke in MA patients [ 101 , 118 ]. The mechanism may involve autonomic dysfunction-induced arrhythmia or AF-related microembolism triggering CSD [ 118 ]. Cases of new-onset MA following catheter ablation, along with observations of improved migraine symptoms postablation in some patients, further support the potential role of microembolism in triggering MA [ 118 ]. The complex interaction between the CNS and the gastrointestinal (GI) tract, termed the “gut-brain axis,” involves the transmission of neuroendocrine, immune, and metabolic information. Clinically, patients with migraine often present with GI symptoms such as nausea, vomiting, and altered bowel habits (leading to constipation or diarrhea). Furthermore, migraine commonly cooccurs with various GI disorders, including IBS, gastroesophageal reflux disease (GERD), Helicobacter pylori infection (HPI), gastroparesis, and functional dyspepsia (FD), suggesting a potential link between these two disorders. A large number of epidemiological studies have confirmed this association [ 125 ]. For instance, cohort studies have shown that the OR for migraine in IBS patients is 40%-80% higher than that in non-IBS individuals, and the cumulative incidence of IBS among migraine patients is more than twice that of the general population [ 126 , 127 ]. A retrospective study also indicated a higher prevalence of various GI disorders in migraine patients, with the strongest correlations observed for GERD and IBS [ 128 ]. Despite the differences in results, a meta-analysis containing five studies revealed that the prevalence of HPIs among migraine patients was approximately 45%, which was significantly higher than the 33% reported in healthy controls. And for MA patients, the correlation of HPI caused by CagA-positive strains may be stronger [ 129 ]. Another meta-analysis reported an overall OR of 2.8 for the association between HPIs and migraine and highlighted the potential benefit of HPI eradication for some migraine patients [ 130 ]. Delayed gastric emptying is a common physiological marker of gastroparesis and FD. Research has confirmed that the gastric emptying time is significantly prolonged both during and between acute migraine attacks, which can impact the absorption of oral medications [ 131 ]. Among patients with gastroparesis, the comorbidity rate of migraine can reach 36.6%; similarly, approximately 68% of FD patients experience comorbid migraine. Other GI disorders, such as celiac disease (CD), inflammatory bowel disease (IBD), and cyclical vomiting syndrome (CVS), may also be associated with migraine [ 127 , 132 ]. The enteric nervous system (ENS) connects to the CNS via parasympathetic and sympathetic fibers. Nausea and vomiting commonly accompanying migraine attacks are associated with vagus nerve dysfunction and sympathetic/parasympathetic tone imbalance. The TNC in the brainstem receives sensory input from the face, scalp, and meninges, whereas the adjacent nucleus tractus solitarius (NTS) is the main center receiving visceral sensory afferents from the GI tract. Under pathological conditions, repetitive noxious stimuli from the GI tract activate the NTS, which may subsequently stimulate the TNC via NTS-TNC connections, leading to central sensitization and triggering the trigeminal vascular system, resulting in neurogenic inflammation and migraine [ 133 ]. From a therapeutic perspective, the efficacy of noninvasive vagus nerve stimulation (nVNS) in simultaneously improving both migraine and gastroparesis symptoms emphasizes the importance of this pathway [ 131 ]. The activation of intestinal immunity and systemic inflammation serves as a crucial bridge in this comorbidity. Proinflammatory cytokines such as TNF-α, IL-1β, and IL-6 increase during migraine attacks and can influence nociceptive processing within the trigeminal pathway [ 132 ]. Importantly, the brain and gut share a network of communicating immune cells, forming the cellular foundation for comorbidity. Systemic low-grade inflammation or specific immune signals arising from intestinal disturbances (e.g., dysbiosis, infection) may influence the activity of central immune cells via circulation or neural pathways (e.g., the vagus nerve). For example, the activation of dural mast cells and microglia in the TNC is a recognized component of neurogenic inflammation and central sensitization in migraine [ 134 ]. GI disease states may act as amplifiers within the gut‒brain axis by remotely modulating the activity of these cells through the release of inflammatory mediators. Specific GI conditions reinforce this link: HPIs can induce a chronic immune‒inflammatory response, releasing cytokines such as IL-10 and potentially exacerbating inflammatory states during migraine attacks [ 132 ]. In CD, elevated levels of IFN-γ and TNF-α may participate in migraine pathogenesis by modulating neuropeptides such as CGRP [ 135 ]. Abnormalities in multiple neurotransmitter and neuropeptide systems form a shared molecular basis for the comorbidity of migraine and GI disorders. As a core mediator in migraine, CGRP is also widely distributed within the enteric nervous system. In addition to its role in causing cerebral vasodilation and neurogenic inflammation during migraine attacks, CGRP is involved in regulating GI motility, secretion, and local immunity, acting as a key signaling molecule in bidirectional gut–brain communication [ 134 ]. Animal studies suggest that CGRP may be involved in afferent sensitization and visceral hypersensitivity associated with IBS [ 136 ]. Clinical data indicate that CGRP may be linked to HPI, CD, and hepatobiliary diseases [ 129 ] and that CGRP infusion can induce significant GI symptoms [ 127 ]. The gut produces approximately 95% of the body’s 5-HT, which precisely modulates GI motility, secretion, and sensation through various receptor subtypes. Studies utilizing serotonergic drugs suggest that 5-HT plays a role in regulating gastric emptying and symptoms related to GI dysfunction [ 137 ], while changes in 5-HT 1B/1D receptor function are closely related to trigeminovascular system activation in migraine. Furthermore, TCAs are used for migraine prevention and for the treatment of GI disorders such as FD and IBS [ 137 ]. In addition to playing an important role in the pathophysiology of migraine, abnormalities in the glutamate pathways are also implicated in the pathogenesis of various GI disorders, such as IBD, IBS, and GERD [ 138 ]. Clinically, the dopamine receptor antagonist metoclopramide is primarily used to treat gastroparesis and nausea and is also effective for acute migraine treatment [ 137 ]. Additionally, cholecystokinin (CCK)—an important brain-gut peptide that inhibits gastric emptying—plays a significant role in the digestive system. Like CGRP, CCK is present in the PAG and TG and may be involved in endogenous pain signaling systems, and animal experiments have shown that its levels are elevated in the PAG of migraine rats [ 132 , 139 ]. The gut microbiota is a core participant in the gut-brain axis, and its dysregulation is an important link between the two pathological states [ 129 ]. Studies have shown that migraine patients have altered gut microbiota composition, such as decreased beneficial bacteria and enhanced microbial metabolic pathways related to tryptophan degradation and glutamate metabolism [ 140 ]. Gut microbiota dysbiosis may contribute to both migraine susceptibility and GI symptoms through multiple pathways, including affecting immune homeostasis, regulating the availability of neurotransmitter precursors, impairing intestinal barrier function, and modifying systemic inflammation levels. Animal experiments have confirmed that antibiotic-induced microbiota dysbiosis contributes to chronic migraine-like pain by increasing TNF-α levels, which can be reversed by microbiota restoration [ 141 ]. Preliminary clinical trials have shown that probiotic and synbiotic interventions are able to reduce migraine attack frequency and analgesic use [ 125 , 142 ], providing a basis for treatment targeting the microbiota. In summary, migraine shares with cardio-cerebrovascular, sleep, and gastrointestinal disorders a complex interplay of CSD-induced hemodynamic changes, autonomic nervous system imbalance, and gut–brain axis dysfunction. These mechanisms underscore the systemic nature of migraine and pave the way for exploring how immune-inflammatory pathways further extend the comorbidity network to include autoimmune and chronic pain conditions, as detailed in Sect.  3.

A growing body of research suggests a close link between migraine and immune system disorders. Multiple sclerosis (MS) is an autoimmune disease characterized primarily by inflammatory demyelination of the CNS white matter and represents a leading cause of nontraumatic disability in young adults. A significant and bidirectional clinical comorbidity exists between migraine and MS. Epidemiological studies confirm that the prevalence of migraine among MS patients is approximately 2–3 times higher than that in the general population (OR = 1.96–2.60) [ 143 , 144 ], whereas the risk of developing new-onset MS is increased by approximately 39% in individuals with migraine [ 144 ]. Neuroimaging reveals that both conditions are prone to white matter lesions, albeit with differing characteristics, forming a basis for both differentiation and association [ 144 , 145 ]. A large-scale prospective cohort study indicated that the risk of developing migraine (but not other headache types) significantly increased several years before the onset of typical MS symptoms [ 146 ]. Clinical observations indicate that migraine attacks often precede the clinical diagnosis of MS by several years, and headache can be an early symptom of MS [ 144 ]. Neuroimmune inflammation is a core mechanism linking migraine and MS. Both conditions result in a proinflammatory state: migraine patients present a reduced number of regulatory T cells in peripheral blood [ 147 ], whereas the levels of proinflammatory cytokines (such as IL-1β and TNF-α) are increased [ 148 ]. Animal experiments further demonstrated that in migraine models, the proinflammatory cytokine IL-17 A can more readily cross the blood‒brain barrier (BBB) and activate the trigeminal nucleus caudalis (TNC) via microglia-mediated neuroinflammation [ 149 ]. In addition, CGRP, which plays a key role in the pathophysiology of migraine, can interact with receptors on glial cells within the trigeminal system to enhance proinflammatory signaling. CGRP-mediated neuroglial interactions suggest a possible immunomodulatory link in the inflammatory environment of MS [ 148 ]. Neuroimmune mechanisms also play crucial roles in MS pathogenesis. For example, the levels of IL-10 and TNF-α tend to be elevated during both migraine attacks and MS relapses [ 143 ]. CSD can activate matrix metalloproteinases, disrupt BBB integrity and allow peripheral immune cells to enter the CNS and encounter myelin antigens [ 144 ], potentially initiating or exacerbating an autoimmune response against the CNS, thus providing a condition for the development of MS. Furthermore, high levels of T helper cells and their related cytokines and chemokines have been found in the CNS lesions and cerebrospinal fluid of MS patients, leading to BBB disruption and the activation of resident astrocytes and microglia, ultimately resulting in neuroinflammation [ 150 ]. Clinical studies have also revealed that high-sensitivity C-reactive protein levels are greater in MS patients with comorbid migraine, suggesting that systemic inflammation may be more pronounced in comorbid patients [ 143 ]. Although MR studies have not confirmed a causal effect of migraine on MS, they have identified several loci within the major histocompatibility complex region (e.g., HCG20 , HLA-B ) that concurrently increase the risk for both migraine and MS [ 151 ], indicating a potential shared immunologically relevant genetic background. Structural lesions in specific brain regions and reorganization of functional networks form the neuroanatomical basis of this comorbidity. Studies have shown that MS patients with PAG lesions have a fourfold increased risk of migraine-like headaches [ 152 ]. The PAG is a key descending pain modulatory center, and its damage can directly lead to a failure of pain inhibition. Functional MRI studies further revealed that reorganization of connectivity between the PAG and networks such as the default mode and sensorimotor networks is correlated with the frequency and severity of migraine attacks in comorbid patients [ 153 ]. Additionally, MS-related cortical demyelination may lead to abnormally increased cortical excitability, thereby increasing susceptibility to CSD. This could be one of the mechanisms underlying migraine (particularly MA) in some MS patients [ 154 ]. Asthma is an atopic disease with polygenic inheritance, and environmental factors also play an important role in its pathogenesis. Numerous epidemiological studies have confirmed a significant and bidirectional comorbid relationship between migraine and asthma, which is more pronounced in females than in males [ 155 ]. Studies have showed that asthma is also known to be a risk factor for new-onset migraine [ 156 ]. A meta-analysis involving over one million individuals demonstrated a mutual increase in the probability and risk of developing migraine and asthma [ 157 ], suggesting shared pathophysiological underpinnings. Notably, previous use of antiasthma or antiallergic medications has been associated with a reduced risk of migraine [ 158 ], indicating that such drugs may have a potential prophylactic role in patients with both conditions. In addition, the prevalence of allergic conditions such as allergic rhinitis and atopic dermatitis is also significantly greater in migraine patients than in healthy controls [ 7 ]. Asthma is characterized by chronic airway inflammation and hyperreactivity. The association between migraine and bronchial hyperreactivity suggests that systemic inflammation may be a key mechanism linking the two conditions [ 155 ]. Transient receptor potential vanilloid subfamily member 1 (TRPV1) is expressed on sensory afferent fibers and trigeminal nociceptors. Studies have shown that TRPV1 can be activated by heat, acids, and various inflammatory mediators, leading to the release of neuropeptides (e.g., CGRP), which trigger the neurogenic inflammation and vasodilation and are involved in migraine genesis [ 159 ]. Similarly, in patients with asthma, TRPV1 expressed on airway C fibers can be activated by endogenous or exogenous stimuli, thereby exacerbating airway inflammation and hyperreactivity [ 160 ]. Histamine is a key mediator linking allergic reactions and migraine. In asthma, allergens cross-link with IgE on the surface of mast cells, triggering the release of histamine and other mediators, leading to bronchoconstriction and inflammation. In migraine, activation of the trigeminal nerve leads to the release of CGRP, which promotes the degranulation of meningeal mast cells and the release of active substances such as histamine, thereby aggravating neurogenic inflammation and vascular reactions [ 155 ]. Studies have shown that serum IgE and histamine levels are significantly higher in migraine patients than in controls, with histamine levels being significantly greater during headache attacks than during interictal periods [ 161 ]. A meta-analysis also confirmed elevated IgE levels in patients with atopic migraine, suggesting an overactive immune system in the comorbid mechanism [ 162 ]. Although histamine cannot directly cross the BBB, it acts primarily through its receptors. For example, activation of histamine 1 receptor (H 1 R) induces nitric oxide (NO) synthesis, increases vascular permeability, and participates in triggering migraine [ 155 ]. Histamine 3 receptor (H 3 R) may modulate vascular permeability and pain transmission by inhibiting the neurogenic edema response [ 155 ]. Mast cells are located around the trigeminal nerve endings and meningeal vessels and are the main source of histamine. Their activation is an important link connecting peripheral immune responses and central pain pathways [ 155 ]. Both migraine and asthma exhibit a strong genetic predisposition. Family studies have revealed that migraine patients have a significantly increased risk of developing allergic diseases (OR = 1.83)[ 163 ], whereas a history of allergy, migraine, and parental asthma are independent risk factors for comorbid migraine in asthma patients. Furthermore, both disorders share common environmental triggers, such as weather changes, seasonal variations, emotional stress, and sleep disturbances. These factors can induce or exacerbate both conditions by activating both the neuroendocrine and immune systems [ 155 ]. Patients with migraine often experience pain in other parts of the body and present significant comorbidities with other chronic pain syndromes, including fibromyalgia (FM), low back pain, and temporomandibular disorders (TMDs) [ 7 ]. Epidemiological studies have confirmed a strong correlation between migraine and FM: the prevalence of headache in FM patients is high (35–88%), with migraine being the most common type (45–80%). Conversely, approximately one-third of patients with primary headache have comorbid FM [ 164 ]. Cohort studies have revealed a bidirectional association with the risk of developing each condition [ 165 ], and the frequency of migraine attacks shows an independent dose‒response relationship with the risk of comorbid FM [ 166 ]. Additionally, botulinum toxin A is an effective treatment for patients with chronic migraine comorbid with FM [ 167 ]. Similarly, substantial evidence confirms that TMD and primary headaches (especially migraine and tension-type headache) are highly comorbid. In specialist clinic studies, the prevalence of TMD among female patients with migraine and chronic migraine (86.8% and 91.3%, respectively) was significantly greater than that in headache-free controls (33.3%) [ 168 ]. Conversely, among TMD clinic patients, migraine is also the most common type of primary headache (prevalence up to 55.3%) [ 169 ]. Population-based studies further indicate that TMD symptoms are more common in all headache types, with the strongest association observed for migraine [ 170 ]. The coexistence of these conditions synergistically increases the disease burden, leading to increased pain intensity, increased attack frequency, greater disability, and facilitation of the transition to chronic pain [ 171 ]. Pain in TMD is primarily mediated by the masticatory muscles and temporomandibular joint, which are innervated by the mandibular division (V3) of the trigeminal nerve, whereas migraine pain often occurs in regions innervated by the ophthalmic division (V1). Nociceptive information from both converges in the TNC in the brainstem and continues into the cervical spinal dorsal horn (collectively known as the trigeminocervical complex), where it shares ascending central pain pathways with the thalamus and cortex. Preclinical studies have confirmed that TMD-like pain evoked from masticatory muscles (e.g., masseter muscles) can activate and sensitize trigeminal neurons, which also receive nociceptive input from the intracranial dura mater (V1 territory) [ 171 ]. This provides a mechanistic explanation for how TMD may trigger headache-like responses, or vice versa. Central sensitization is a core convergent point linking the chronification of pain in migraine, FM, and TMD. It refers to the hyperexcitability of neurons and neural circuits within nociceptive pathways and is characterized by increased neuronal excitability, enhanced synaptic efficacy, and reduced inhibition. Chronic orofacial pain stimuli (from TMD), migraine attacks, or persistent nociceptive input from deep tissues such as muscles and joints can induce and maintain the sensitization of nociceptive neurons in the TNC or spinal dorsal horn and higher central centers, leading to hyperalgesia and allodynia [ 172 ]. Studies have shown that comorbid TMD and migraine patients have a higher incidence of allodynia, a hallmark of central sensitization [ 171 ]. Neuroimaging studies have confirmed hyperactivation in brain regions responsible for pain processing (e.g., anterior cingulate cortex, insula) in both FM and migraine patients [ 164 ]. CGRP plays a central role in migraine pathogenesis. Emerging evidence indicates that CGRP is also involved in the pathological process of TMD [ 171 ]. Preclinical studies have shown that CGRP infusion exacerbates the sensitization of trigeminovascular neurons induced by masticatory muscle pain [ 173 ]. These findings suggest that CGRP may be a key molecular link between TMD and migraine. Recent retrospective clinical studies further confirmed that CGRP mAbs are not only effective in treating headache in migraine patients comorbid with FM but also significantly reduce FM-related somatic pain and global disability, with the improvement in FM correlating significantly with a reduction in migraine-related disability [ 174 ]. Dysfunction of the hypothalamus‒brainstem axis and abnormalities in the levels of various neurotransmitters/neuromodulators are common features shared by migraine and FM. Cerebrospinal fluid from FM patients shows decreased levels of serotonin and norepinephrine metabolites, elevated substance P, and altered endocannabinoid levels [ 175 ]. FM is associated with a state of low-grade inflammation. When FM is comorbid with conditions featuring more pronounced inflammation, such as migraine or osteoarthritis, NSAIDs may alleviate pain more effectively by suppressing these stronger inflammatory processes, thereby indirectly improving overall FM symptoms [ 176 ]. Similar dysregulation of monoaminergic systems and neuropeptides is involved in migraine. This explains why drugs that act on these pathways (e.g., TCAs and SNRIs) have therapeutic effects on both disorders [ 164 , 175 ]. Both FM and migraine show familial aggregation and are associated with polymorphisms in genes related to the serotonergic, dopaminergic, and catecholaminergic systems [ 164 ]. Preliminary research suggests that the association between TMD pain and migraine (particularly in women) may be partly attributable to shared genetic risk factors, such as the estrogen receptor alpha gene (ESR1) [ 170 , 177 ]. Female sex, estrogen fluctuations, psychosocial stress, anxiety, depression, and sleep disturbances are common risk factors or comorbidities for FM, TMD, and migraine, potentially confounding or mediating their relationships [ 171 , 175 ]. Collectively, the evidence presented in this section reveals that neuroimmune activation, systemic low-grade inflammation, and central sensitization serve as common threads linking migraine with multiple sclerosis, asthma, and other chronic pain disorders. These shared inflammatory and pain-amplifying mechanisms not only exacerbate disease burden but also set the stage for understanding the metabolic and endocrine disturbances that further modulate migraine susceptibility, as discussed in the final section.

A complex and at times paradoxical association exists between metabolic-endocrine disorders and migraine. Diabetes mellitus (DM), obesity, and endometriosis are among the most intensively studied comorbidities. The relationship between DM and migraine is “paradoxical”. Substantial epidemiological evidence indicates that a diagnosis of either T1DM or T2DM is associated with a reduced risk of migraine onset, suggesting a possible protective effect [ 178 ]. Concurrently, women with active migraine have a lower risk of developing T2DM [ 179 ]. Conversely, some studies indicate that patients with chronic migraine have an increased risk of insulin resistance and metabolic syndrome, and the severity of migraine attacks is greater in those with insulin resistance [ 180 ]. A large meta-analysis synthesizing this bidirectionality revealed that DM (especially T1DM) is negatively correlated with the occurrence of migraine, whereas migraine (especially migraine without aura) is positively correlated with the incidence of DM [ 181 ]. Obesity is a well-established risk factor and promoter of chronic migraine. Epidemiological studies have shown that the risk of migraine is increased in obese individuals, exhibiting a dose‒response relationship: higher body mass index (BMI) is correlated with increased headache attack frequency, severity, and disability [ 182 ]. Furthermore, central obesity (increased visceral fat) is associated with more severe cutaneous allodynia and migraine-related disability [ 183 ]. Endometriosis, which involves aberrant secretion and metabolism of estrogen, is widely reported to be comorbid with migraine. Case‒control and cohort studies have demonstrated that the risk of migraine is significantly greater in patients with endometriosis, and vice versa [ 184 , 185 ]. This association is particularly pronounced in adolescents (OR = 4.7), and a linear relationship exists between migraine severity and the probability of having endometriosis [ 186 ]. Several systematic meta-analyses also confirmed that patients with endometriosis have a greater risk of migraine (especially MA) [ 187 , 188 ]. GWAS analyses revealed a significant positive genetic correlation between migraine and T2DM (rG ≈ 0.06–0.07), indicating a shared genetic predisposition and identifying dozens of SNP loci and associated genes [ 189 ]. MR analysis based on single-cell data revealed AP4E1 and HSD17B12 as key genes in migraine-T2DM comorbidity [ 190 ]. Obesity itself has a polygenic basis involving numerous nervous system-related genes, and its comorbidity with migraine may partly stem from an additive genetic load [ 191 ]. Multiple genetic studies have consistently confirmed a significant genetic basis for the comorbidity between migraine and endometriosis. Large-scale GWAS and twin studies have revealed a significant positive genetic correlation between the two (rG ≈ 0.27–0.38), and this comorbidity primarily originates from shared genetic susceptibility rather than a direct causal relationship [ 192 ]. Multiple trait genetic analyses have identified several shared risk gene loci (e.g., NGF and FSHB ) [ 193 ]. These shared loci suggest that biological processes such as sex hormone signaling, inflammatory responses, and cell adhesion play key roles in the pathogenesis of both disorders [ 194 , 195 ]. Candidate gene studies provide more fine-grained evidence; for example, specific single nucleotide polymorphisms in the estrogen receptor genes ESR1 and ESR2 have been found to be associated with both disorders, reinforcing the notion that sex hormone-related pathways are a core component of the shared genetic basis [ 196 ]. Current research strongly supports cerebral energy metabolic imbalance as a central pathway linking migraine and metabolic disorders. Hypoglycemia is a well-recognized trigger of migraine, as it directly results in a lack of energy supply to neurons in the brain. Fasting or insulin-induced hypoglycemia can significantly prolong the duration of CSD, thereby triggering or exacerbating migraine attacks. In contrast, a hyperglycemic state can resist the initiation of CSD and accelerate its recovery [ 197 ]. Concurrently, inherent brain energy metabolism abnormalities exist in migraine patients. Magnetic resonance spectroscopy (MRS) studies have revealed reduced ATP levels and mitochondrial phosphorylation potential in the brains of migraineurs during the interictal period [ 198 ]. Neuroimaging studies also revealed a metabolic imbalance in the visual cortex of interictal migraine patients, characterized by increased neuronal activation relative to relatively insufficient resting glucose uptake [ 199 ]. This imbalance forms the pathophysiological cornerstone of migraine attacks. Chronic insulin resistance may lead to mitochondrial dysfunction and neuroinflammation and promote migraine chronification [ 200 ]. This finding provides a possible explanation for the paradoxical observation that migraine risk first increases but then decreases from the “preinsulin resistance state” to “confirmed diabetes.” Indeed, Gary et al. reported that CGRP can modulate insulin secretion and may reduce the risk of developing T2DM [ 201 ], whereas Rosta et al. reported that insulin can induce CGRP release by activating TRPV1 receptors on trigeminal afferents, thereby sensitizing meningeal nociceptors and increasing headache susceptibility [ 202 ]. Furthermore, in addition to regulating blood glucose and body weight, preclinical studies have shown that glucagon-like peptide-1 (GLP-1) and its receptor agonists can inhibit neuroinflammation and modulate CGRP release via central receptors, thereby attenuating migraine-like behaviors [ 203 ]. Estrogen-dependent chronic inflammation is the pathological basis of endometriosis. Studies indicate that estrogen fluctuations can influence the course of migraine and are involved in modulating CSD susceptibility and the serotonergic system [ 198 ]. Additionally, estrogen can induce hyperinsulinemia and hypoglycemia, further exacerbating migraine in patients [ 192 ]. Thus, their comorbidity may stem from a shared sensitivity to estrogen signaling pathways. Animal experiments have demonstrated that mice with endometriosis exhibit elevated serum prolactin levels, which can sensitize trigeminal afferent fibers and increase susceptibility to migraine attacks. Inhibiting pituitary prolactin secretion with the dopamine receptor agonist cabergoline reversed this neuronal sensitization and headache susceptibility, suggesting the potential role of the prolactin signaling pathway in migraine prevention [ 204 ]. As a key neuropeptide in migraine attack, research has revealed that CGRP dysregulation manifests at multiple levels in comorbid states: plasma CGRP levels are elevated in obese individuals [ 182 ]; abnormal fluctuation patterns of CGRP across the menstrual cycle are observed in migraine patients with comorbid endometriosis [ 205 ]. Furthermore, amylin, which is structurally similar to CGRP, is elevated in obesity and diabetes, and its analogs can induce migraine [ 182 ], indicating the extensive role of this peptide family in the crosstalk between metabolism and pain. Both obesity and endometriosis are accompanied by a state of chronic low-grade inflammation. Proinflammatory cytokines (e.g., IL-1β and TNF-α) released from adipose tissue or ectopic endometrial lesions can permeate areas outside the blood‒brain barrier or circulate to affect the trigeminovascular system, lowering its activation threshold and leading to peripheral and central sensitization [ 182 , 192 ]. Proinflammatory adipokines (e.g., adiponectin, leptin, resistin) released from adipose tissue are significantly elevated in the plasma of patients with both episodic and chronic migraine, constituting the inflammatory basis for obesity-migraine comorbidity [ 7 ]. Moreover, the frequent co-occurrence of migraine, chronic pelvic pain (e.g., in endometriosis), and fibromyalgia further supports central sensitization as a shared pathophysiological foundation [ 192 ]. In conclusion, migraine and metabolic-endocrine disorders such as diabetes, obesity, and endometriosis are interconnected through cerebral energy imbalance, hormonal fluctuations, and shared genetic susceptibility involving sex hormone and inflammatory pathways. These findings reinforce the concept of migraine as a multisystem disorder and highlight the need for integrated therapeutic strategies that address both neurological and systemic metabolic targets.