Warning: mkdir(): Permission denied in /home/virtual/lib/view_data.php on line 81 Warning: fopen(/home/virtual/pfmjournal/journal/upload/ip_log/ip_log_2022-05.txt): failed to open stream: No such file or directory in /home/virtual/lib/view_data.php on line 83 Warning: fwrite() expects parameter 1 to be resource, boolean given in /home/virtual/lib/view_data.php on line 84 The under-recognized but essential role of the limbic system in the migraine brain: a narrative review

The under-recognized but essential role of the limbic system in the migraine brain: a narrative review

Article information

Precis Future Med. 2022;6(1):2-8
Publication date (electronic) : 2022 February 24
doi : https://doi.org/10.23838/pfm.2020.00142
1Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
2Department of Neurology, Mayo Clinic, Phoenix, AZ, USA
Corresponding author: Chin-Sang Chung Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul 06351, Korea Tel: +82-2-3410-3596 E-mail: cspaul@naver.com
Received 2020 October 5; Revised 2022 February 23; Accepted 2022 February 23.


Migraine is a very common brain disorder that causes throbbing headaches of moderate-to-severe intensity that are associated with a variety of symptoms like nausea, vomiting, multisensory hypersensitivity, dizziness, fatigue, cognitive dysfunction, and sleep problems, among others. The diverse symptomatology of migraine hints at the complexity of the disease and implies the involvement of multiple nervous system components, including the somatosensory, executive, autonomic, endocrine, and arousal networks. The major pathophysiologic mechanisms responsible for migraine attacks have been identified over the past several decades, and the elucidation of these mechanisms has brought about remarkable advances in therapeutic strategies, including the creation of anti-calcitonin gene-related peptide therapeutics—the newest addition to the list of anti-migraine therapies. However, current knowledge on the pathophysiologic mechanisms of migraine remains incomplete and treatments are only partially effective, with the involvement of the limbic system being less often recognized and symptoms related to the limbic system being undertreated. This article reviews recent advances in understanding the pathophysiologic roles of the limbic system in migraine and how the limbic system contributes to clinical features observed in migraine.


Data from the 2016 Global Burden of Disease study show that migraine affects approximately 1.04 billion people worldwide, causes greater disability than any other headache disorder, and ranks second among the most disabling neurologic disorders after stroke [1]. Recurrent, painful headaches are the most agonizing and burdensome problem in individuals suffering from migraine. However, migraine is also associated with a variety of non-headache symptoms such as dyspepsia, photophobia, phonophobia, cognitive complaints, and increased pain perception during and between migraine attacks [2]. The constellation of symptoms associated with migraine suggests that it is mediated not only by neural networks responsible for pain, but also by pathways involved in visual, auditory, autonomic, endocrine, psychological, behavioral, cognitive, and arousal functions [3]. From this perspective, migraine can be regarded as a multifaceted disorder involving numerous brain networks [4]. Furthermore, it is essential to recognize, understand and manage these non-headache symptoms that might modify the long-term clinical course of migraine and further reduce the quality of life (QoL) for patients with migraine. In this review article, the authors aimed to provide update on recent advances regarding the pathophysiologic roles of the limbic system in migraine and the contribution of the limbic system with regards to clinical features observed in migraine.


The complex neurobiological mechanisms that underlie the development of headaches in the migraineur’s brain and the responsible neural pathways are relatively well defined [5]. The trigeminal neurovascular system is a key component of the migraine headache, consisting of sensory afferents that innervate the meninges and intracranial vasculature, the three branches of the trigeminal nerve that innervate the face and anterior head, the trigeminal ganglion, and the trigeminal nucleus caudalis of the brainstem. Ascending projections from the trigeminal nucleus caudalis project to the thalamus and then to multiple regions of the cerebral cortex and cerebellum that participate in sensory discriminative, affective, cognitive, and integrative aspects of the pain experience. The peripheral and central components of this system can become sensitized during and perhaps even between migraine attacks, lowering the threshold for activation and resulting in cranial and extracranial allodynia [3,5].

Activation of the trigeminovascular system is associated with the release of vasoactive neuropeptides such as calcitonin gene-related peptide (CGRP), a potent vasodilator that plays a major role in the generation and facilitation of pain and pain-related symptoms in migraine. Along with release of CGRP there is release of other vasoactive neuropeptides, dilatation of the meningeal vessels, extravasation of plasma proteins, and degranulation of mast cells. Numerous proinflammatory mediators are then released, promoting neurogenic inflammation and stimulation of meningeal nociceptors. Eventually, the pain circuits of migraine are perpetuated [6,7].

Anti-CGRP monoclonal antibodies that block either the CGRP receptor or ligand were approved by regulatory agencies and were launched in the USA and Europe in 2018 and in Korea in late 2019 for migraine prevention. Small molecule CGRP antagonists were approved for the symptomatic therapy of migraine attacks in the USA in late 2019 and early 2020. A large body of pre-clinical and translational research and the efficacy of these CGRP-blocking therapies in clinical trials confirm the role of CGRP in migraine [3,8-12].

Despite successes in the development of novel migraine-specific agents, there is still need for even more effective migraine therapies [13]. In general, about 50% of patients will respond to any one migraine preventive medication, and the response is almost always less than complete, meaning that there continue to be recurrent migraine attacks albeit with a lower frequency. This suggests that the mechanisms underlying migraine are multifactorial within and between patients. Inadequate preventive and symptomatic therapy results in greater migraine-related burden and a higher risk for developing chronic migraine and an associated condition called “medication overuse headache (MOH).” Given the current state of migraine therapeutics, a more holistic approach to treatment is required, with therapies that target the pain pathways and other mechanisms that lead to the non-pain symptoms and comorbidities of migraine.


Migraine headaches are often accompanied by a variety of non-pain symptoms such as photophobia, phonophobia, gastrointestinal dysfunction, cognitive complaints, and increased pain perception that increase the burden of the disease, decrease the QoL, and worsen the long-term clinical course for many people with migraine. Many of these non-pain symptoms seem to originate from dysfunction of the limbic system and its associated neurolimbic networks [14].

A dysfunctional limbic system presents with aforementioned non-pain symptoms at every phase of a migraine attack, including the prodromal, ictal, and postdromal (or hangover) phases, as well as during the interictal period [2]. The limbic system is strongly associated with the catastrophizing and migraine chronification that often leads to MOH [15].

Two recent studies (migraine in America symptoms and treatment [MAST] [16] and Chronic Migraine Epidemiology and Outcomes [CaMEO] [17]) have shown that patients with migraine reported a significantly higher prevalence of comorbid conditions such as insomnia, depression, anxiety, gastric ulcers/gastrointestinal bleeding, angina, and epilepsy. The presence of more comorbidities was associated with increasing headache intensity and frequency. In clinical practice, it is often observed that certain prophylactic agents that act on the limbic system are quite effective in patients who present with neurolimbic comorbid symptoms (authors’ experience). Table 1 lists the major neurolimbic comorbidities of migraine [16-47].

The neurolimbic comorbidities of migraine


The limbic system consists of several regions including cingulate cortex, parahippocampal gyrus, hippocampal formation, amygdala, septal area, and hypothalamus. This system relays and integrates multiple inputs from both the body and the environment and filters or modulates the generation of emotional, homeostatic, and cognitive responses. The limbic system is composed of structures that are involved in specific functions such as the regulation of hunger and thirst; sexual satisfaction; and responses to pain, pleasure, and sensory information, particularly from the olfactory system. This system is also responsible for controlling aggressive or violent behavior, emotions such as anger and fear, and the functions of the autonomic nervous system, which include the regulation of pulse rate, blood pressure, breathing, and arousal. Because the limbic system functions as an “alarm system” of the brain, it may also be the first group of neural networks that recognize the start of migraine-related brain activities [14,48].

The somatosensory neural networks responsible for generating pain during migraine attacks pass mainly through the posterior part of the brain, including the trigeminocervical complex in the brainstem, thalamus, somatosensory cortex, and other cortical and cerebellar regions [5]. On the other hand, the networks responsible for neurolimbic features, particularly those that are emotional or psychiatric in nature, are located in the middle (hypothalamus and anterior cingulate cortex), medial temporal (amygdala and hippocampus), and anterior (prefrontal cortex) parts of the brain [14]. In these regions, serotonin plays a key role in the neurobiological mechanisms behind the emotional or psychiatric comorbidities observed in patients with migraine; however, the exact role of serotonergic mechanisms in the brain in this context remains a matter of controversy [49].

It is possible that the limbic system might contribute to the development of higher frequency migraine (e.g., chronic migraine), medication overuse, and to MOH; however, despite its possible contributions to the clinical features of migraine, there have been few studies, both in scientific research and in clinical practice, on the limbic system in this context.

From a therapeutic viewpoint, it should be noted that bidirectional connections exist between the pain-modulating circuits of the brainstem and the limbic system, including the prefrontal cortex; these connections mutually influence the expression of migraine. Thus, any imbalance in this bidirectional neurolimbic system, as in a migraine brain, can modify the neurolimbic environment and affect the patient’s mood, emotions, stress, personality, or coping styles, thus enhancing their vulnerability to migraine disease and migraine attacks [14]. The interplay between the neurolimbic system with the somatosensory system and the extent of dysfunction of these systems likely impact the presentation of migraine.

In this respect, the authors propose that neurolimbic symptoms should be assessed and considered when diagnosing and managing patients with migraine. Doing so allows for a more holistic approach to the patient with migraine and can lead to optimization of patient outcomes. Therapeutic strategies, either pharmacologic or non-pharmacologic, that target somatosensory and neurolimbic factors must be designed and tested through clinical trials to create more effective abortive and prophylactic treatments for migraine. Thus, it is strongly advised to screen for comorbid factors in all patients with migraine, particularly in refractory cases, and to consider these factors in the diagnostic and therapeutic planning [14,50]. Identifying the individual pathophysiologic mechanisms that underlie comorbid symptoms or conditions will allow for the management of patients to be individualized and adjusted accordingly. Such approaches would be valuable in improving the treatment of migraine and its related problems.


Chronic migraine has a worldwide prevalence of 1% to 2% [51,52]. Several factors increase the risk of transforming from episodic migraine to chronic migraine, which is defined as 15 or more headache days per month including at least 8 days with migraine attacks per month; these include the overuse of acute pain/migraine medications, caffeine consumption, poor sleep hygiene as may be indicated by snoring, obesity, inadequate treatment of acute migraine attacks, lack of physical exercise, female sex, allodynia, head injuries, low socioeconomic status, depression, anxiety, stressful life events, post-traumatic stress, and comorbid pain disorders. Many of these factors have psychological components and might be associated with limbic system dysfunction [53,54].

Overuse of acute medications used to treat migraine attacks (triptans and ergots) or other pain conditions (opioids, non-steroidal anti-inflammatory agents, and combination analgesics) can increase the risk of someone with episodic migraine transforming to chronic migraine. Patients can find themselves in a vicious cycle that starts with headaches leading to increasing acute medication intake which then causes even more frequent headaches and greater medication use. Recent imaging studies have shown that overuse of acute migraine medications or psychotropic agents is associated with functional and anatomic changes in the limbic system [55].

In patients with MOH, resting state functional connectivity is decreased between the precuneus and the regions of the default mode network (DMN) (the frontal and parietal cortices) while it is increased between the precuneus and hippocampal/temporal areas. Functional connectivity between precuneus and frontal regions are negatively correlated with migraine duration and positively correlated with self-evaluation of medication dependence. Grey matter volumes (GMVs) of the precuneus, hippocampus, and frontal regions are also negatively correlated to migraine duration. Functional connectivity within the DMN is correlated with the anxiety scores of patients with MOH, while GMV in this network are associated with depression scores [55,56].

In another study on MOH patients, it was found that the volumes of the superior temporal, fusiform, and occipital middle gyrus of the left hemisphere were decreased while the volume of the left inferior temporal/lateral ventricle and middle frontal sulcus were increased. The left temporal superior gyrus volume was negatively correlated with depression scores, number of medications taken per month, and medication dependence scores [57].

Magnetic resonance imaging studies revealed that, in patients with MOH, the fiber tracts passing through the left hippocampus and the volume of anxiety-related hippocampal subfields were decreased. Changes in the grey matter of the brain were also observed in patients with MOH who also have psychiatric comorbidities like anxiety and depression. Furthermore, the volume of the periaqueductal grey matter of the midbrain was also significantly increased in these patients, which was positively correlated with more migraine-related disability and higher levels of anxiety. An increase in GMV was also found bilaterally in the thalamus and ventral striatum, while a significant decrease was detected in the frontal regions including the orbitofrontal cortex, anterior cingulate cortex, left and right insula, and precuneus [57-59]. The changes of structure and function in pain processing regions might be reversible and normalized following discontinuation of the overused medication and proper treatment of MOH [60].


The limbic system of patients with migraine appears to be perpetually involved during the course of the disease, even when the classical trigeminal neurovascular system is at rest [61]. The limbic system is responsible for non-headache symptoms and comorbidities of migraine that are commonly present and contribute to long-term patient outcomes. Neurolimbic symptoms and comorbidities remain poorly assessed and underemphasized in migraine, and therapeutic strategies for these symptoms also remain underdeveloped and underutilized.

Neurolimbic system-mediated symptoms and comorbidities contribute to the chronification of migraine and impact the patient’s QoL and treatment satisfaction. Therefore, therapeutic strategies that stabilize or balance the neurolimbic system are required; these include psychological supportive care (mindfulness training), lifestyle modifications, and more aggressive pharmacologic and non-pharmacologic therapies such as cognitive behavioral therapy, acceptance-commitment therapy, and narrative medicine. Finally, neurolimbic symptoms and comorbidities must be recognized when diagnosing migraine and the impact of migraine therapies on these symptoms and comorbidities must be closely monitored.


No potential conflict of interest relevant to this article was reported.


Conception or design: CSC, TJS.

Acquisition, analysis, or interpretation of data: CSC, TJS.

Drafting the work or revising: CSC, TJS.

Final approval of the manuscript: CSC, TJS.


1. GBD 2016 Headache Collaborators. Global, regional, and national burden of migraine and tension-type headache, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol 2018;17:954–76.
2. Martelletti P, Schwedt TJ, Lanteri-Minet M, Quintana R, Carboni V, Diener HC, et al. My migraine voice survey: a global study of disease burden among individuals with migraine for whom preventive treatments have failed. J Headache Pain 2018;19:115.
3. Dodick DW. Migraine. Lancet 2018;391:1315–30.
4. Chong CD, Schwedt TJ, Hougaard A. Brain functional connectivity in headache disorders: a narrative review of MRI investigations. J Cereb Blood Flow Metab 2019;39:650–69.
5. Goadsby PJ, Holland PR. An update: pathophysiology of migraine. Neurol Clin 2019;37:651–71.
6. Russo AF. CGRP as a neuropeptide in migraine: lessons from mice. Br J Clin Pharmacol 2015;80:403–14.
7. Deen M, Correnti E, Kamm K, Kelderman T, Papetti L, Rubio-Beltran E, et al. Blocking CGRP in migraine patients: a review of pros and cons. J Headache Pain 2017;18:96.
8. Schwedt TJ. New and emerging treatments for the acute and preventive therapy of migraine and other headaches. Headache 2019;59 Suppl 2:1–2.
9. Silberstein SD, Dodick DW, Bigal ME, Yeung PP, Goadsby PJ, Blankenbiller T, et al. Fremanezumab for the preventive treatment of chronic migraine. N Engl J Med 2017;377:2113–22.
10. Schwedt T, Reuter U, Tepper S, Ashina M, Kudrow D, Broessner G, et al. Early onset of efficacy with erenumab in patients with episodic and chronic migraine. J Headache Pain 2018;19:92.
11. Stauffer VL, Dodick DW, Zhang Q, Carter JN, Ailani J, Conley RR. Evaluation of galcanezumab for the prevention of episodic migraine: the EVOLVE-1 randomized clinical trial. JAMA Neurol 2018;75:1080–8.
12. de Vries T, Villalon CM, MaassenVanDenBrink A. Pharmacological treatment of migraine: CGRP and 5-HT beyond the triptans. Pharmacol Ther 2020;211:107528.
13. Lipton RB, Munjal S, Buse DC, Alam A, Fanning KM, Reed ML, et al. Unmet acute treatment needs from the 2017 migraine in America symptoms and treatment study. Headache 2019;59:1310–23.
14. Maizels M, Aurora S, Heinricher M. Beyond neurovascular: migraine as a dysfunctional neurolimbic pain network. Headache 2012;52:1553–65.
15. Schwedt TJ, Alam A, Reed ML, Fanning KM, Munjal S, Buse DC, et al. Factors associated with acute medication overuse in people with migraine: results from the 2017 migraine in America symptoms and treatment (MAST) study. J Headache Pain 2018;19:38.
16. Buse DC, Reed ML, Fanning KM, Bostic R, Dodick DW, Schwedt TJ, et al. Comorbid and co-occurring conditions in migraine and associated risk of increasing headache pain intensity and headache frequency: results of the migraine in America symptoms and treatment (MAST) study. J Headache Pain 2020;21:23.
17. Lipton RB, Seng EK, Chu MK, Reed ML, Fanning KM, Adams AM, et al. The effect of psychiatric comorbidities on headache-related disability in migraine: results from the Chronic Migraine Epidemiology and Outcomes (CaMEO) study. Headache 2020;60:1683–96.
18. Song TJ, Cho SJ, Kim WJ, Yang KI, Yun CH, Chu MK. Anxiety and depression in probable migraine: a population-based study. Cephalalgia 2017;37:845–54.
19. Lampl C, Thomas H, Tassorelli C, Katsarava Z, Lainez JM, Lanteri-Minet M, et al. Headache, depression and anxiety: associations in the Eurolight project. J Headache Pain 2016;17:59.
20. Muneer A, Farooq A, Farooq JH, Qurashi MS, Kiani IA, Farooq JS. Frequency of primary headache syndromes in patients with a major depressive disorder. Cureus 2018;10e2747.
21. Chu HT, Liang CS, Lee JT, Yeh TC, Lee MS, Sung YF, et al. Associations between depression/anxiety and headache frequency in migraineurs: a cross-sectional study. Headache 2018;58:407–15.
22. Smitherman TA, Kolivas ED, Bailey JR. Panic disorder and migraine: comorbidity, mechanisms, and clinical implications. Headache 2013;53:23–45.
23. Minen MT, Begasse De Dhaem O, Kroon Van Diest A, Powers S, Schwedt TJ, Lipton R, et al. Migraine and its psychiatric comorbidities. J Neurol Neurosurg Psychiatry 2016;87:741–9.
24. Jette N, Patten S, Williams J, Becker W, Wiebe S. Comorbidity of migraine and psychiatric disorders: a national population-based study. Headache 2008;48:501–16.
25. Breslau N, Lipton RB, Stewart WF, Schultz LR, Welch KM. Comorbidity of migraine and depression: investigating potential etiology and prognosis. Neurology 2003;60:1308–12.
26. Lipton RB, Hamelsky SW, Kolodner KB, Steiner TJ, Stewart WF. Migraine, quality of life, and depression: a population-based case-control study. Neurology 2000;55:629–35.
27. Breslau N, Davis GC, Schultz LR, Peterson EL. Joint 1994 Wolff Award Presentation. Migraine and major depression: a longitudinal study. Headache 1994;34:387–93.
28. Dresler T, Caratozzolo S, Guldolf K, Huhn JI, Loiacono C, Niiberg-Pikksoot T, et al. Understanding the nature of psychiatric comorbidity in migraine: a systematic review focused on interactions and treatment implications. J Headache Pain 2019;20:51.
29. Serafini G, Pompili M, Innamorati M, Gentile G, Borro M, Lamis DA, et al. Gene variants with suicidal risk in a sample of subjects with chronic migraine and affective temperamental dysregulation. Eur Rev Med Pharmacol Sci 2012;16:1389–98.
30. Cho S, Lee MJ, Park HR, Kim S, Joo EY, Chung CS. Effect of sleep quality on headache-related impact in primary headache disorders. J Clin Neurol 2020;16:237–44.
31. Walters AB, Hamer JD, Smitherman TA. Sleep disturbance and affective comorbidity among episodic migraineurs. Headache 2014;54:116–24.
32. Kim J, Cho SJ, Kim WJ, Yang KI, Yun CH, Chu MK. Insufficient sleep is prevalent among migraineurs: a population-based study. J Headache Pain 2017;18:50.
33. Song TJ, Cho SJ, Kim WJ, Yang KI, Yun CH, Chu MK. Poor sleep quality in migraine and probable migraine: a population study. J Headache Pain 2018;19:58.
34. Vgontzas A, Pavlovic JM. Sleep disorders and migraine: review of literature and potential pathophysiology mechanisms. Headache 2018;58:1030–9.
35. Buse DC, Rains JC, Pavlovic JM, Fanning KM, Reed ML, Manack Adams A, et al. Sleep disorders among people with migraine: results from the Chronic Migraine Epidemiology and Outcomes (CaMEO) study. Headache 2019;59:32–45.
36. Wang KA, Wang JC, Lin CL, Tseng CH. Association between fibromyalgia syndrome and peptic ulcer disease development. PLoS One 2017;12e0175370.
37. Penn IW, Chuang E, Chuang TY, Lin CL, Kao CH. Bidirectional association between migraine and fibromyalgia: retrospective cohort analyses of two populations. BMJ Open 2019;9e026581.
38. Evans RW, de Tommaso M. Migraine and fibromyalgia. Headache 2011;51:295–9.
39. Kurth T, Scher AI. Suicide risk is elevated in migraineurs who have comorbid fibromyalgia. Neurology 2015;85:1012–3.
40. Liu HY, Fuh JL, Lin YY, Chen WT, Wang SJ. Suicide risk in patients with migraine and comorbid fibromyalgia. Neurology 2015;85:1017–23.
41. Ottman R, Lipton RB. Comorbidity of migraine and epilepsy. Neurology 1994;44:2105–10.
42. Mutlu A. Association between epilepsy and headache. Neurol Sci 2018;39:2129–34.
43. Liao J, Tian X, Wang H, Xiao Z. Epilepsy and migraine: are they comorbidity? Genes Dis 2018;5:112–8.
44. Bagheri MH, Jalli R, Hoseyni Moghadam A. New MRI finding in migraineurs: mesial temporal sclerosis. J Biomed Phys Eng 2020;10:459–66.
45. David M, Santos B, Barros W, Silva T, Franco C, Matos R. Neuroimaging investigation of memory changes in migraine: a systematic review. Arq Neuropsiquiatr 2020;78:370–9.
46. Newman-Norlund RD, Rorden C, Maleki N, Patel M, Cheng B, Androulakis XM. Cortical and subcortical changes following sphenopalatine ganglion blocks in chronic migraine with medication overuse headache: a preliminary longitudinal study. Womens Midlife Health 2020;6:7.
47. Nahman-Averbuch H, Schneider VJ 2nd, Chamberlin LA, Kroon Van Diest AM, Peugh JL, Lee GR, et al. Identification of neural and psychophysical predictors of headache reduction after cognitive behavioral therapy in adolescents with migraine. Pain 2021;162:372–81.
48. O’Carroll CP. Migraine and the limbic system: closing the circle. Psychopharmacol Bull 2007;40:12–23.
49. Deen M, Christensen CE, Hougaard A, Hansen HD, Knudsen GM, Ashina M. Serotonergic mechanisms in the migraine brain: a systematic review. Cephalalgia 2017;37:251–64.
50. Schulman EA, Lake AE 3rd, Goadsby PJ, Peterlin BL, Siegel SE, Markley HG, et al. Defining refractory migraine and refractory chronic migraine: proposed criteria from the Refractory Headache Special Interest Section of the American Headache Society. Headache 2008;48:778–82.
51. Munksgaard SB, Madsen SK, Wienecke T. Treatment of medication overuse headache: a review. Acta Neurol Scand 2019;139:405–14.
52. Natoli JL, Manack A, Dean B, Butler Q, Turkel CC, Stovner L, et al. Global prevalence of chronic migraine: a systematic review. Cephalalgia 2010;30:599–609.
53. Lipton RB. Tracing transformation: chronic migraine classification, progression, and epidemiology. Neurology 2009;72(5 Suppl):S3–7.
54. Lipton RB, Fanning KM, Serrano D, Reed ML, Cady R, Buse DC. Ineffective acute treatment of episodic migraine is associated with new-onset chronic migraine. Neurology 2015;84:688–95.
55. Chanraud S, Di Scala G, Dilharreguy B, Schoenen J, Allard M, Radat F. Brain functional connectivity and morphology changes in medication-overuse headache: clue for dependence-related processes? Cephalalgia 2014;34:605–15.
56. Chong CD, Dumkrieger GM, Schwedt TJ. Structural covariance patterns in migraine: a cross-sectional study exploring the role of the hippocampus. Headache 2017;57:1522–31.
57. Meyer M, Di Scala G, Edde M, Dilharreguy B, Radat F, Allard M, et al. Brain structural investigation and hippocampal tractography in medication overuse headache: a native space analysis. Behav Brain Funct 2017;13:6.
58. Chen Z, Chen X, Liu M, Ma L, Yu S. Lower hippocampal subfields volume in relation to anxiety in medication-overuse headache. Mol Pain 2018;14:1744806918761257.
59. Riederer F, Marti M, Luechinger R, Lanzenberger R, von Meyenburg J, Gantenbein AR, et al. Grey matter changes associated with medication-overuse headache: correlations with disease related disability and anxiety. World J Biol Psychiatry 2012;13:517–25.
60. Schwedt TJ, Chong CD. Medication overuse headache: pathophysiological insights from structural and functional brain MRI research. Headache 2017;57:1173–8.
61. Lee MJ, Park BY, Cho S, Park H, Kim ST, Chung CS. Dynamic functional connectivity of the migraine brain: a resting-state functional magnetic resonance imaging study. Pain 2019;160:2776–86.

Article information Continued

Table 1.

The neurolimbic comorbidities of migraine

System Specific conditions References
Psychiatric disorders Depression, anxiety, panic disorder, bipolar disorder, personality disorders, stress, suicide attempts [16-29]
Sleep disorders Insomnia, parasomnias, restless leg syndrome, sleep apnea, poor sleep quality and duration [30-35]
Chronic pain Fibromyalgia [36-40]
Epilepsy Seizures, independent of type [41-44]
Cognitive dysfunction Memory changes [45-47]