Migraine is the most common neurological cause of disability globally (1) with a prevalence of 11.6% worldwide, 13.8% in females, 6.9% in males (2). Migraine features as one of the top 10 causes of disability irrespective of ethnicity, geography, and socioeconomic status (1) affecting work productivity (3) and social functioning (4). The impact on productivity and social functioning is greatest in patients who have been unsuccessful with preventive management (5).
The International Classification of Headache Disorders (ICHD Third Edition) defines chronic migraine as greater or equal to 15 days of headache of which 8 of those days are migraine days (6). Episodic migraine is diagnosed in a patient with migraine who experiences up to 14 headache days a month. Classification criteria for migraine with and without aura are set out in Table 1.
Pain is the symptom that has attracted most attention from patients and physicians over the recent past, although other symptoms have been commented upon for more than a century (7). It is now becoming more widely recognized that other symptoms precede the onset of pain in a migraine attack by up to 72 hours, this is the premonitory phase, and after the resolution of headache pain, this is the postdrome, that can last up to 2 days, can be disabling for patients (8).
This review highlights key points of migraine pathophysiology from the premonitory phase to postdrome with additional focus on how calcitonin gene-related peptide (CGRP) and pituitary adenylate cyclase activating polypeptide (PACAP) are involved. We will only briefly highlight the pathophysiology of aura and photophobia because these topics will be covered in detail in the other reviews in this series (9,10).
THE MIGRAINE CYCLE
Migraine patients often report certain triggers to their migraine attacks, such as bright lights, chocolate, and odors. The more likely situation is that some patients are reporting hypersensitivity toward environmental stimuli as part of the premonitory phase of migraine (11) misidentifying the hypersensitivity or behavior response as a trigger (12,13) and that the patient's experience of premonitory symptoms is predicting a migraine attack (8). The prevalence of premonitory symptoms is likely underreported due to misidentification or inattention to often nonspecific symptoms (14). These symptoms are outlined in Table 2.
Functional imaging studies have demonstrated that activation of the hypothalamus, dorsal pons, midbrain nuclei, periaqueductal gray, and prefrontal, temporal, and occipital cortices (15) are activated in the premonitory phase. Daily functional imaging studies in one migraine patient over 30 days supports the concept of the hypothalamus's pivotal role in the premonitory phase with evidence of increased nociceptive functional connectivity between the hypothalamus and the trigeminal nucleus caudalis (TNC) and the dorsal rostral pons the day before an attack (16) suggesting a change in modulation between these areas. The TNC exhibits a variable cyclical pattern of activation from the preictal to ictal phases of migraine with increased activation of the dorsal pons during an attack (16).
Neuropeptides released from nuclei within the hypothalamus were studied for their role in the premonitory phase. Homeostatic alterations noted in the premonitory phase suggest involvement of the orexin signaling pathway. Orexins A and B are produced in the hypothalamus and are involved in the regulation of sleep wake cycle, regulation of feeding, and autonomic functions (17). Experiments with administration of orexin A or B result in reduction of nociceptive signaling from dural unmyelinated C and Aδ fibers to the trigeminal ganglion (18), supporting their role in migraine. Orexin A promotes feeding through stimulation of neuropeptide Y containing neurons (19). Neuropeptide Y is involved in the sympathetic system. In animal model studies, it has been shown to reduce trigeminal nociceptive activity (20), suggesting a role in modulation of migraine (Figs. 1, 2).
Yawning is a common symptom in the premonitory phase, which is mediated, in part, by dopaminergic pathways (21). Yawning occurs more frequently in migraine patients when exposed to apomorphine, a dopamine receptor agonist (22,23). Dopamine is also shown to modulate the TNC, downregulating nociceptive firing, through projections originating from the A11 nucleus in the hypothalamus (24,25). CGRP is also found in the A11 nucleus and it may have a role in modulation through dopaminergic pathways (24).
Cognitive changes and fatigue may be due to altered brain physiology (14), which has been represented in neurophysiological studies, which include contingent negative variation (26). Contingent negative variation is a slow cortical potential that is related to motivation, attention, and arousal. Studies involving migraine patients have demonstrated inhibited suppression of contingent negative variation with repeated stimuli compared to controls without migraine (27). Contingent negative variation amplitudes are also increased in migraine patients a day before a migraine attack (28) implying neural changes before onset of head pain.
A third of patients who experience migraine also experience aura (29), of which one-third will experience symptoms involving more than one type of phenomenon from separate distinct brain areas (30). Aura can precede, start simultaneously, occur during or, uncommonly, follow head pain (30,31).
The frequency and types of symptoms experienced by migraine patients with aura has recently been described (30). Visual phenomena are most commonly reported followed by sensory, speech disturbances, and lastly motor symptoms (30).
The development of visual aura has been studied and is compared with cortical spreading depression (CSD). CSD is assumed to be the equivalent of aura in humans although CDS in humans during aura is yet to be observed. CSD is a transient EEG depolarization of the cortex followed by a prolonged period of suppressed EEG activity, which self-propagates through the cortex at a rate of 2–6 mm/minutes (32), similar to the rate of visual aura propagation of 3 mm/minutes (33,34). Depolarization results in:
- alteration of intracellular and extracellular electrolytes, resulting in a hyperpolarized state lasting up to 50 seconds (35).
- Release of transmitters including serotonin, glutamate, dopamine, and nitric oxide (35).
- Cortical perfusion changes with an initial wave of hyperemia secondary to vasodilation followed by prolonged oligemia (36). Hypoperfusion during aura has been described with flow studies (37), magnetic resonance imaging (MRI) with blood-oxygen-level-dependant changes (38) and MRI with arterial spin labeling (39). During oligemia, there is impairment of neurovascular responses resulting in mismatch of neuronal activity and blood flow where there is high neuronal activity and reduced cerebral blood flow (36).
There is still debate as to whether CSD can trigger headache. Premonitory symptoms and the biological changes associated with the premonitory phase suggest that aura cannot be the initiating event of migraine and only one-third of patients experience aura. However, one case report has shown spreading hypoperfusion through positron emission tomography (PET) imaging in migraine without aura, suggesting that a CSD event can be phenotypically silent and occurs in migraine without aura (40). CSD also alters signal inputs to the trigeminal cervical complex (TCC). CSD can result in a sustained activation of meningeal nociceptors that input to the TCC (41) through a central mechanism independent of peripheral modifiers (42). Prospective diary data show that headache can occur before or with aura onset and is only consistently related in the same patient in about half of the attacks (30). There is much yet to learn about migraine aura and its relationship with other aspects of the pathophysiology.
Whether head pain starts in the periphery, with activation of dural meningeal afferents, or is central, due to alteration of neural modulation of the TCC, remains a matter of debate.
Stimulation of the dura and intracranial vessel in humans results in head pain (43). Nociceptive transmission from the intracranial vasculature and dura is through unmyelinated C fibers and Aδ fibers from the trigeminal ganglion through predominantly the ophthalmic distribution of the trigeminal nerve (44,45) and upper cervical roots (46,47). The central termination of these fibers, which include the TNC and C1 and C2 spinal nuclei, is collective known as the TCC (47,48). Activation of dural meningeal afferents results in release of neuropeptides including CGRP and PACAP (45,49–51). CGRP and PACAP were shown to modulate the trigeminovascular pathway and dural meningeal nociceptive activity (52–54) and will be discussed later in this review. Activation of the same afferent also activates the superior salivatory nucleus (SSN) and the parasympathetic pathway (55).
The cell bodies of the parasympathetic system originate from the SSN (56). The efferent fibers of the SSN projects parasympathetic projections that synapse at the sphenopalatine ganglion, and then project predominantly through the greater petrosal branch of the facial nerve, to the lacrimal gland, mucous membranes of the nose, and the upper pharynx. Neurons from the TCC project to the SSN forming a reflex connection (57). The SSN provides the parasympathetic component to cranial vasculature where activation results in increased neuronal firing in the TCC (58–60) and increased activity of light-responsive TCC neurons (61).
Stimulation of the SSN also activates the trigeminal autonomic reflex in a retrograde fashion (58,59). Activation of the trigeminal autonomic reflex contributes to cranial autonomic symptoms (58,59). Cranial autonomic symptoms are predominantly mediated by the parasympathetic system (62). Cranial autonomic symptoms in migraine occur in 25%–56% of migraine patients (63–65). They include lacrimation, conjunctival injection, periorbital edema, ptosis, nasal congestion, and rhinorrhoea (63).
The SSN, as well as having connections to the TNC and craniofacial vasculature, also has bidirectional projections to the hypothalamus (56).
Projections from the TCC are also bidirectional (62); the TCC has projections to nuclei in the medulla, pons, and midbrain. These include the rostral ventromedial medulla, nucleus raphe magnus, locus coeruleus, and periaqueductal gray (62). Second-order neurons from the TCC, through the rostral ventromedial medulla, project to the hypothalamus, thalamus, and multiple cortical regions (66,67). Stimulation of the periaqueductal gray and the rostral ventromedial medulla results in inhibition of nociceptive firing from the TCC (68,69).
The somatosensory cortex has an inhibitory effect on nociceptive activity through cortical CSD (70). The hypothalamus projects descending tracts toward the rostral ventromedial medulla, nucleus raphe magnum, locus coeruleus, and periaqueductal gray (71).
The throbbing nature of migraine pain and the exacerbation of pain with physical exertion and Valsalva-like maneuvers are believed to be mediated by peripheral sensitization. Peripheral sensitization occurs with persistent activation of dural first-order trigeminovascular neurons resulting in a reduced threshold to produce a response and a greater response where before sensitization there was minimal or no response (72). Cranial allodynia and extracranial allodynia experienced in migraine is due to persistent activation of TCC second-order neurons and trigeminothalamic third-order neurons to brainstem and diencephalon structures resulting in central sensitization. This is where sensitized second- and third-order neurons have a reduced threshold for activity and a greater magnitude of response resulting in a response to innocuous stimuli (72). Central sensitization is a factor in acute treatment of a migraine attack. Triptans are ineffective in the patient with allodynia if not taken early because central sensitization cannot be blocked by delayed treatment (72).
Sensitivity to light is a troublesome symptom synonymous with migraine and is reported in as high as 80% of patients (73). Photosensitivity can occur as early as the premonitory phase (8,14). The mechanisms of photosensitivity are still being delineated. PET imaging demonstrates activation of the visual cortex during the premonitory phase in patients with light sensitivity (74). Interictally, there is an activation of the visual cortex in migraine patients, when compared to controls in response to light stimulation, suggestive of visual cortex hyperresponsiveness interictally (75).
Three pathways are suggested to be involved in light-attributed nociceptive activity (76). Signaling through retinal photoreceptors increases activity in the TCC when there is increased parasympathetic activity (61). Melanopsin-containing intrinsically photosensitive retinal ganglion cells (ipRGC) are found in the retina and the iris. ipRGC in the eye project to the thalamus, which in turn projects to the somatosensory cortices involved in pain (77). ipGRC likely have a role in light perception but not in image production (76). An animal study, in which the optic nerve was lesioned, found that the trigeminal blink reflex remained increased in the presence of light, compared with absence of light (78). This suggests an alternative pathway by which ipRGC within the iris transmits information in the presence of light, which can activate the trigeminal reflex.
The postdrome has not been well recognized and research into this phase of migraine is still in its infancy (79). This phase of migraine is defined as the period between the resolution of headache and when the patient feels he/she has returned to normal and is debilitating. This period can last for days but for about 50% of patients, it lasts for up to 6 hours after resolution of headache (80) Generally, this phase lasts for less than 1 day (81). The symptoms of the postdrome phase are detailed in Table 3. They are strikingly like the symptoms of the premonitory phase and similar structures are likely involved but current evidence is limited. Migraine patients may present to neuro-ophthalmologists with ongoing photophobia after the headache phase has resolved; it is important to recognize that this is part of the postdromal phase. Pathophysiological analysis of this phase is a subject of current investigation.
Recent interest in migraine is unsurprising with the advent of CGRP pathway monoclonal antibodies, PACAP and PACAP 1 receptor (PAC1) antagonists, as preventive therapies. All CGRP monoclonal antibodies have been effective in preventing episodic and chronic migraine (82–89) with 3 approved for use in migraine prevention in the United States and Europe (90). Development of small-molecule CGRP receptor antagonists, the gepants, stagnated due to liver toxicity (91,92). However, 2 new CGRP antagonists have been developed, without indication of liver toxicity (84,93,94), and new drug applications are pending (90).
Currently, one PACAP antagonist is in preclinical stages of development (95). The results of AMG 301, a PAC1 receptor monoclonal antibody, have recently been presented. Disappointingly, primary and secondary endpoints of mean reduction in migraine days, 50% reduction rate and mean reduction in migraine medication days, were not met (96).
Calcitonin Gene-Related Peptide
CGRP is a 37 amino acid neuropeptide with roles within the cardiovascular, enteric, central, and peripheral nervous systems (97). Four major observations implicate the significant role of CGRP in migraine.
- CGRP is elevated in venous samples of patients in migraine with and without aura (98,99).
- CGRP levels rise during a migraine attack and normalize with sumatriptan administration resulting in resolution of the attack (100).
- CGRP levels in chronic migraine patients remain consistently elevated compared with episodic migraine patients (101).
- CGRP, when infused, can induce migraine in migraine patients with or without aura (102,103).
The α isoform of CGRP is found in the end terminals of C and Aδ fibers of dural meningeal afferent sensory neurons of which cell bodies reside in the trigeminal ganglion (53,103). Infusion of CGRP in healthy volunteers increases blood-oxygen-level-dependent signals on functional MRI studies in the brainstem, whereas a reduced signal was observed in the caudate nucleus, thalamus, and cingulate cortex (52), all involved in TCC modulation.
CGRP has a role in photophobia with evidence of light aversive behavior observed in rodent models that can be induced centrally, by intracerebroventricular injection of CGRP, and peripherally, by intraperitoneal injection of CGRP, and is attenuated by triptans or CGRP receptor antagonists (104–106). CGRP seems to have a role in CSD with evidence of CGRP release during CSD (107), which is attenuated by CGRP antagonists (107,108) Recurrent CSD has been shown to promote CGRP production in multiple brain regions (109).
CGRP is postulated to act in an autocrine manner where a positive feedback loop may be involved in the mechanism of sensitization of afferents of the trigeminal ganglion (110). CGRP is a potent vasodilator where its vasodilatory effect is mediated by nitric oxide (NO)-dependant and NO-independent pathways (111). Vasodilation in migraine is now considered an epiphenomenon (112,113), although NO itself may have a role modulating the ventrolateral medulla, TCC, locus coeruleus, ventrolateral periaqueductal gray, and hypothalamus (114,115). NO has been found to induce CGRP release (116,117), which may contribute to the positive feedback loop.
Pituitary Adenylate Cyclase Activating Polypeptide
PACAP is a potent vasodilating peptide with 2 major isoforms. PACAP-38 is one of the 2 isoforms of PACAP and is the dominant isoform in neuronal tissues (118). The major receptor for PACAP that mediates activation of the TCC experimentally is the PAC1 receptor (119). The following observations have suggested a role for PACAP in migraine:
- Stimulation of the superior sagittal sinus (51) and the trigeminal ganglion induces PACAP release (120), which is ameliorated with sumatriptan (51). Electrical stimulation and nitroglycerin result in elevation of PACAP from the TNC (121). Unlike CGRP, PACAP levels have been found to be lower in migraine patients interictally compared to controls without migraine. However, PACAP levels rise and are found in higher levels in migraine patients compared to controls during a migraine attack (121).
- PACAP infusion can also induce premonitory symptoms (122) and migraine-like attacks in migraine patients (122,123). Careful review of the clinical data suggests some role for vasoactive intestinal peptide receptor activation (124).
- Inhibition of the PAC1 receptor with a monoclonal antibody reduces nociceptive activity from the TCC (125).
The PACAP-38 isoform is made up of 38 amino acids and is found in the trigeminal ganglion, second-order neurons of the TNC, and the dorsal horn (118,124). Preclinical models suggest that PACAP has a role in nociceptive transmission modulating C fiber responses (54). PACAP can stimulate release of CGRP from the TNC, although the mechanism is unclear (126).
The pathophysiology of migraine is complex and is evolving. Current evidence suggests a neurovascular model for the pathophysiology of migraine. Clinical data collected from careful history taking show that migraine attacks start with a premonitory phase that moves into the pain phase before ending in the postdromal phase. Identifying the various symptoms of migraine assists in developing models and developing hypotheses and research protocols both in the preclinical setting and the clinical setting. Extensive research has led to development of new acute and preventive treatments with more avenues being explored. Developing an understanding of migraine not only assists our patients with development of pharmacotherapy but assists us in our history taking, in explaining symptoms, and in explaining the rationale of therapy.
The authors thank Phillip Holland for assistance in the production of the figures herein.
1. GBD 2016 Disease and Injury Incidence and Prevalence Collaborators. Global, regional, and national incidence, prevalence, and years lived with disability for 328 diseases and injuries for 195 countries, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet. 2017;390:1211–1259.
2. Woldeamanuel YW, Cowan RP. Migraine affects 1 in 10 people worldwide featuring recent rise: a systematic review and meta-analysis of community-based studies involving 6 million participants. J Neurol Sci. 2017;372:307–315.
3. Burton WN, Landy SH, Downs KE, Runken MC. The impact of migraine and the effect of migraine treatment on workplace productivity in the United States and suggestions for future research. Mayo Clinic Proc. 2009;84:436–445.
4. Bigal ME, Serrano D, Reed M, Lipton RB. Chronic migraine in the population: burden, diagnosis, and satisfaction with treatment. Neurology. 2008;71:559–566.
5. Martelletti P, Schwedt TJ, Lanteri-Minet M, Quintana R, Carboni V, Diener HC, Ruiz de la Torre E, Craven A, Rasmussen AV, Evans S, Laflamme AK, Fink R, Walsh D, Dumas P, Vo P. 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.
6. Headache Classification Committee of the International headache Society (IHS) the International Classification of headache disorders, 3rd edition. Cephalalgia. 2018;38:1–211.
7. Gowers WR. A Manual of Diseases of the Nervous System. Vol 2, 1st edition. London, United Kingom: J.& A. Churchill, 1886:776–788.
8. Giffin NJ, Ruggiero L, Lipton RB, Silberstein SD, Tvedskov JF, Olesen J, Altman J, Goadsby PJ, Macrae A. Premonitory symptoms in migraine an electronic diary study. Neurology. 2003;60:935–940.
9. Burstein R, Noseda R, Fulton AB. Neurobiology of photophobia. J Neuroophthalmol. 2019;39:94–102.
10. Smith SV. Neuro-ophthalmic symptoms of primary headache disorders: why the patient with headache may present to Neuro-ophthalmology. J Neuroophthalmol. 2019;39:200–207.
11. Schulte LH, Jurgens TP, May A. Photo-, osmo- and phonophobia in the premonitory phase of migraine: mistaking symptoms for triggers?. J Headache Pain. 2015;16:14.
12. Marcus DA, Scharff L, Turk D, Gourley LM. A double-blind provocative study chocolate as a trigger of headache. Cephalalgia. 1997;17:855–862.
13. Hougaard A, Amin FM, Hauge AW, Ashina M, Olesen J. Provocation of migraine with aura using natural trigger factors. Neurology. 2013;80:428–431.
14. Karsan N, Bose P, Goadsby PJ. The migraine premonitory phase. Continuum (Minneapolis, Minn). 2018;24:996–1008.
15. Maniyar FH, Sprenger T, Monteith T, Schankin C, Goadsby PJ. Brain activations in the premonitory phase of nitroglycerin-triggered migraine attacks. Brain. 2014;137:232–241.
16. Schulte LH, May A. The migraine generator revisited: continuous scanning of the migraine cycle over 30 days and three spontaneous attacks. Brain. 2016;139:1987–1993.
17. Holland P, Goadsby PJ. The hypothalamic orexinergic system: pain and primary headaches. Headache. 2007;47:951–962.
18. Bartsch T, Levy MJ, Knight YE, Goadsby PJ. Differential modulation of nociceptive dural input to [hypocretin] orexin A and B receptor activation in the posterior hypothalamic area. Pain. 2004;109:367–378.
19. Yamanaka A, Kunii K, Nambu T, Tsujino N, Sakai A, Matsuzaki I, Miwa Y, Goto K, Sakurai T. Orexin-induced food intake involves neuropeptide Y pathway. Brain Res. 2000;859:404–409.
20. Martins-Oliveira M, Akerman S, Tavares I, Goadsby PJ. Neuropeptide Y inhibits the trigeminovascular pathway through NPY Y1 receptor: implications for migraine. Pain. 2016;157:1666–1673.
21. Argiolas A, Melis MR. The neuropharmacology of yawning. Eur J Pharmacol. 1998;343:1–16.
22. Bene E, Poggioni M, Tommasi F. Video assessment of yawning induced by sublingual apomorphine in migraine. Headache. 1994;34:536–538.
23. Blin O, Azulay JP, Masson G, Aubrespy G, Serratrice G. Apomorphine-induced yawning in migraine patients: enhanced responsiveness. Clin Neuropharmacol. 1991;14:91–95.
24. Charbit AR, Akerman S, Holland PR, Goadsby PJ. Neurons of the dopaminergic/calcitonin gene-related peptide A11 cell group modulate neuronal firing in the trigeminocervical complex: an electrophysiological and immunohistochemical study. J Neurosci. 2009;29:12532–12541.
25. Skagerberg G, Bjorklund A, Lindvall O, Schmidt RH. Origin and termination of the diencephalo-spinal dopamine system in the rat. Brain Res Bull. 1982;9:237–244.
26. Schoenen J. Neurophysiological features of the migrainous brain. Neurol Sci. 2006;27:s77–s81.
27. Kropp P, Gerber WD. Contingent negative variation-findings and perspectives in migraine. Cephalalgia. 1993;13:33–36.
28. Kropp P, Gerber WD. Prediction of migraine attacks using a slow cortical potential, the contingent negative variation. Neurosci Lett. 1998;257:73–76.
29. Rasmussen BK, Olesen J. Migraine with aura and migraine without aura: an epidemiological study. Cephalalgia. 1992;12:221–228; discussion 186.
30. Viana M, Sances G, Linde M, Ghiotto N, Guaschino E, Allena M, Terrazzino S, Nappi G, Goadsby PJ, Tassorelli C. Clinical features of migraine aura: results from a prospective diary-aided study. Cephalalgia. 2017;37:979–989.
31. Russell MB, Olesen J. A nosographic analysis of the migraine aura in a general population. Brain. 1996;119:355–361.
32. Lauritzen M. Pathophysiology of the migraine aura: the spreading depression theory. Brain. 1994;117:199–210.
33. Hansen JM, Baca SM, VanValkenburgh P, Charles A. Distinctive anatomical and physiological features of migraine aura revealed by 18 years of recording. Brain. 2013;136:3589–3595.
34. Lashley KS. Patterns of cerebral integration indicated by the scotomas of migraine. Arch Neurol Psychiatry. 1941;46:331–339.
35. Smith JM, Bradley DP, James MF, Huang CL. Physiological studies of cortical spreading depression. Biol Rev. 2006;81:457–481.
36. Chang JC, Shook LL, Biag J, Nguyen EN, Toga AW, Charles AC, Brennan KC. Biphasic direct current shift, haemoglobin desaturation and neurovascular uncoupling in cortical spreading depression. Brain. 2010;133:996–1012.
37. Olesen J, Friberg L, Olsen TS, Iversen HK, Lassen NA, Andersen AR, Karle A. Timing and topography of cerebral blood flow, aura, and headache during migraine attacks. Ann Neurol. 1990;28:791–798.
38. Hadjikhani N, Sanchez Del Rio M, Wu O, Schwartz D, Bakker D, Fischl B, Kwong KK, Cutrer FM, Rosen BR, Tootell RB, Sorensen AG, Moskowitz MA. Mechanisms of migraine aura revealed by functional MRI in human visual cortex. Proc Natl Acad Sci U S A. 2001;98:4687–4692.
39. Cadiot D, Longuet R, Bruneau B, Treguier C, Carsin-Vu A, Corouge I, Gomes C, Proisy M. Magnetic resonance imaging in children presenting migraine with aura: association of hypoperfusion detected by arterial spin labelling and vasospasm on MR angiography findings. Cephalagia. 2018;38:949–958.
40. Woods RP, Iacoboni M, Mazziotta JC. Bilateral spreading cerebral hypoperfusion during spontaneous migraine headache. N Engl J Med. 1994;331:1689–1692.
41. Zhang X, Levy D, Kainz V, Noseda R, Jakubowski M, Burstein R. Activation of central trigeminovascular neurons by cortical spreading depression. Ann Neurol. 2011;69:855–865.
42. Lambert GA, Truong L, Zagami AS. Effect of cortical spreading depression on basal and evoked traffic in the trigeminovascular sensory system. Cephalalgia. 2011;31:1439–1451.
43. Ray BS, Wolff HG. Experimental studies on headache: pain-sensitive structures of the head and their significance in headache. Arch Surg. 1940;41:813–856.
44. Feindel W, Penfield W, McNaughton F. The tentorial nerves and localization of intracranial pain in man. Neurology. 1960;10:555–563.
45. Penfield W, Mc NF. Dural headache and innervation of the dura mater. Arch Neurol Psychiatry. 1940;44:43–75.
46. Arbab MA, Wiklund L, Svendgaard NA. Origin and distribution of cerebral vascular innervation from superior cervical, trigeminal and spinal ganglia investigated with retrograde and anterograde WGA-HRP tracing in the rat. Neuroscience. 1986;19:695–708.
47. Kaube H, Keay KA, Hoskin KL, Bandler R, Goadsby PJ. Expression of c-Fos-like immunoreactivity in the caudal medulla and upper cervical spinal cord following stimulation of the superior sagittal sinus in the cat. Brain Res. 1993;629:95–102.
48. Goadsby PJ, Hoskin KL. The distribution of trigeminovascular afferents in the nonhuman primate brain macaca nemestrina: a c-fos immunocytochemical study. J Anat. 1997;190:367–375.
49. Goadsby PJ, Edvinsson L, Ekman R. Release of vasoactive peptides in the extracerebral circulation of humans and the cat during activation of the trigeminovascular system. Ann Neurol. 1988;23:193–196.
50. Wolff HG. Headache and Other Head Pain. New York, NY: Oxford University Press, 1948.
51. Zagami AS, Edvinsson L, Goadsby PJ. Pituitary adenylate cyclase activating polypeptide and migraine. Ann Clin Translational Neurol. 2014;1:1036–1040.
52. Asghar MS, Becerra L, Larsson HBW, Borsook D, Ashina M. Calcitonin gene-related peptide modulates heat nociception in the human brain—an fMRI study in healthy volunteers. PLoS One. 2016;11:e0150334.
53. Eftekhari S, Salvatore CA, Calamari A, Kane SA, Tajti J, Edvinsson L. Differential distribution of calcitonin gene-related peptide and its receptor components in the human trigeminal ganglion. Neuroscience. 2010;169:683–696.
54. Zhang YZ, Sjὅlund B, Moller K, Håkanson R, Sundler F. Pituitary adenylate cyclase activating peptide produces a marked and long-lasting depression of a C-fibre-evoked flexion reflex. Neuroscience. 1993;57:733–737.
55. Knight YE, Classey JD, Lasalandra MP, Akerman S, Kowacs F, Hoskin KL, Goadsby PJ. Patterns of fos expression in the rostral medulla and caudal pons evoked by noxious craniovascular stimulation and periaqueductal gray stimulation in the cat. Brain Res. 2005;1045:1–11.
56. Spencer SE, Sawyer WB, Wada H, Platt KB, Loewy AD. CNS projections to the pterygopalatine parasympathetic preganglionic neurons in the rat: a retrograde transneuronal viral cell body labeling study. Brain Res. 1990;534:149–169.
57. May A, Goadsby PJ. The trigeminovascular system in humans: pathophysiologic implications for primary headache syndromes of the neural influences on the cerebral circulation. J Cereb Blood Flow Metab. 1999;19:115–127.
58. Akerman S, Holland PR, Lasalandra MP, Goadsby PJ. Oxygen inhibits neuronal activation in the trigeminocervical complex after stimulation of trigeminal autonomic reflex, but not during direct dural activation of trigeminal afferents. Headache. 2009;49:1131–1143.
59. Akerman S, Holland PR, Summ O, Lasalandra MP, Goadsby PJ. A translational in vivo model of trigeminal autonomic cephalalgias: therapeutic characterization. Brain. 2012;135:3664–3675.
60. Yarnitsky D, Goor-Aryeh I, Bajwa ZH, Ransil BI, Cutrer FM, Sottile A, Burstein R. Possible parasympathetic contributions to peripheral and central sensitization during migraine. Headache. 2003;43:704–714.
61. Okamoto K, Tashiro A, Chang Z, Bereiter DA. Bright light activates a trigeminal nociceptive pathway. Pain. 2010;149:235–242.
62. Akerman S, Holland PR, Goadsby PJ. Diencephalic and brainstem mechanisms in migraine. Nat Rev Neurosci. 2011;12:570–584.
63. Barbanti P, Fabbrini G, Pesare M, Vanacore N, Cerbo R. Unilateral cranial autonomic symptoms in migraine. Cephalagia. 2002;22:256–259.
64. Obermann M, Yoon MS, Dommes P, Kuznetsova J, Maschke M, Weimar C, Limmroth V, Diener HC, Katsarava Z. Prevalence of trigeminal autonomic symptoms in migraine: a population-based study. Cephalagia. 2007;27:504–509.
65. Lai TH, Fuh JL, Wang SJ. Cranial autonomic symptoms in migraine: characteristics and comparison with cluster headache. J Neurol Neurosurg Psychiatry. 2009;80:1116.
66. Noseda R, Jakubowski M, Kainz V, Borsook D, Burstein R. Cortical projections of functionally identified thalamic trigeminovascular neurons: implications for migraine headache and its associated symptoms. J Neurosci. 2011;31:14204–14217.
67. Zagami AS, Lambert GA. Stimulation of cranial vessels excites nociceptive neurones in several thalamic nuclei of the cat. Exp Brain Res. 1990;81:552–566.
68. Knight YE, Goadsby PJ. The periaqueductal grey matter modulates trigeminovascular input: a role in migraine?. Neuroscience. 2001;106:793–800.
69. Edelmayer RM, Vanderah TW, Majuta L, Zhang ET, Fioravanti B, De Felice M, Chichorro JG, Ossipov MH, King T, Lai J, Kori SH, Nelsen AC, Cannon KE, Heinricher MM, Porreca F. Medullary pain facilitating neurons mediate allodynia in headache-related pain. Ann Neurol. 2009;65:184–193.
70. Noseda R, Constandil L, Bourgeais L, Chalus M, Villanueva L. Changes of meningeal excitability mediated by corticotrigeminal networks: a link for the endogenous modulation of migraine pain. J Neurosci. 2010;30:14420–14429.
71. Goadsby PJ, Holland PR, Martins-Oliveira M, Hoffmann J, Schankin C, Akerman S. Pathophysiology of migraine: a disorder of sensory processing. Physiol Rev. 2017;97:553–622.
72. Bernstein C, Burstein R. Sensitization of the trigeminovascular pathway: perspective and implications to migraine pathophysiology. J Clin Neurol. 2012;8:89–99.
73. Choi JY, Oh K, Kim BJ, Chung CS, Koh SB, Park KW. Usefulness of a photophobia questionnaire in patients with migraine. Cephalagia. 2009;29:953–959.
74. Maniyar FH, Sprenger T, Schankin C, Goadsby PJ. Photic hypersensitivity in the premonitory phase of migraine—a positron emission tomography study. Eur J Neurol. 2014;21:1178–1183.
75. Boulloche N, Denuelle M, Payoux P, Fabre N, Trotter Y, Géraud G. Photophobia in migraine: an interictal PET study of cortical hyperexcitability and its modulation by pain. J Neurol Neurosurg Psychiatry. 2010;81:978–984.
76. Wu Y, Hallett M. Photophobia in neurologic disorders. Transl Neurodegener. 2017;6:26.
77. Noseda R, Kainz V, Jakubowski M, Gooley JJ, Saper CB, Digre K, Burstein R. A neural mechanism for exacerbation of headache by light. Nat Neurosci. 2010;13:239–245.
78. Dolgonos S, Ayyala H, Evinger C. Light-induced trigeminal sensitization without central visual pathways: another mechanism for photophobia. Invest Ophthalmol Vis Sci. 2011;52:7852–7858.
79. Bose P, Karsan N, Goadsby PJ. The migraine postdrome. Continuum (Minneapolis, Minn). 2018;24:1023–1031.
80. Giffin NJ, Lipton RB, Silberstein SD, Olesen J, Goadsby PJ. The migraine postdrome: an electronic diary study. Neurology. 2016;87:309–313.
81. Kelman L. The postdrome of the acute migraine attack. Cephalalgia. 2006;26:214–220.
82. Ashina M, Dodick D, Goadsby P, Kudrow D, Reuter U, Tepper S, Cheng S, Leonardi D, Lenz R, Mikol D. Efficacy of erenumab for the treatment of patients with chronic migraine with and without aura (S32.006). Neurology. 2018;90(15 suppl).
83. Detke HC, Goadsby PJ, Wang S, Friedman DI, Selzler KJ, Aurora SK. Galcanezumab in chronic migraine: the randomized, double-blind, placebo-controlled REGAIN study. Neurology. 2018;91:e2211–e2221.
84. Dodick DW, Lipton RB, Ailani J, Lu K, Lakkis H, Finnegan M, Trugman JM, Szegedi A. Ubrogepant for the acute treatment of migraine: efficacy, safety, tolerability, and functional impact outcomes from a single attack phase III study, ACHIEVE I. Headache. 2018;58:1287–1288.
85. Dodick DW, Silberstein SD, Bigal ME, Yeung PP, Goadsby PJ, Blankenbiller T, Grozinski-Wolff M, Yang R, Ma Y, Aycardi E. Effect of fremanezumab compared with placebo for prevention of episodic migraine: a randomized clinical trial. JAMA. 2018;319:1999–2008.
86. Förderreuther S, Zhang Q, Stauffer VL, Aurora SK, Láinez MJA. Preventive effects of galcanezumab in adult patients with episodic or chronic migraine are persistent: data from the phase 3, randomized, double-blind, placebo-controlled EVOLVE-1, EVOLVE-2, and REGAIN studies. J Headache Pain. 2018;19:121.
87. Goadsby PJ, Reuter U, Hallström Y, Broessner G, Bonner JH, Zhang F, Sapra S, Picard H, Mikol DD, Lenz RA. A controlled trial of Erenumab for episodic migraine. N Engl J Med. 2017;377:2123–2132.
88. Lipton RB, Saper J, Ashina M, Biondi D, Bhattacharya S, Hirman J, Schaeffler B, Cady R. A phase 3, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of eptinezumab for the preventive treatment of chronic migraine: results of the PROMISE-2 (prevention of migraine via Intravenous eptinezumab Safety and Efficacy[FIGURE DASH]2) trial. Neurology. 2018;90:e2193–2194.
89. Saper J, Lipton R, Kudrow D, Hirman J, Dodick D, Silberstein S, Chakhave G, Smith J. Primary results of PROMISE-1 (prevention of migraine via intravenous eptinezumab safety and efficacy–1) trial: a phase 3, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of eptinezumab for prevention of frequent episodic migraines (S20.001). Neurology. 2018;90(15 suppl).
90. U.S. Food and Drug Administration. Novel Drug Approvals for 2018, 2018. Available at: https://www.fda.gov/drugs/developmentapprovalprocess/druginnovation/ucm592464.htm
. Accessed February 19, 2019.
91. Ho TW, Connor KM, Zhang Y, Pearlman E, Koppenhaver J, Fan X, Lines C, Edvinsson L, Goadsby PJ, Michelson D. Randomized controlled trial of the CGRP receptor antagonist telcagepant for migraine prevention. Neurology. 2014;83:958–966.
92. Ho TW, Ho AP, Ge Y, Assaid C, Gottwald R, MacGregor EA, Mannix LK, van Oosterhout WP, Koppenhaver J, Lines C, Ferrari MD, Michelson D. Randomized controlled trial of the CGRP receptor antagonist telcagepant for prevention of headache in women with perimenstrual migraine. Cephalagia. 2016;36:148–161.
93. Croop R, Goadsby PJ, Stock DA, Conway CM, Forshaw M, Stock EG, Coric V, Lipton RB. Efficacy, safety, and tolerability of rimegepant orally disintegrating tablet for the acute treatment of migraine: a randomised, phase 3, double-blind, placebo-controlled trial. Lancet. 2019;394:737–745.
94. Lipton RB, Croop R, Stock EG, Stock DA, Morris BA, Frost M, Dubowchik GM, Conway CM, Coric V, Goadsby PJ. Rimegepant, an oral calcitonin gene-related peptide receptor antagonist, for migraine. N Engl J Med. 2019;381:142–149.
95. Moldovan Loomis C, Dutzar B, Ojala EW, Hendrix L, Karasek C, Scalley-Kim M, Mulligan J, Fan P, Billgren J, Rubin V, Boshaw H, Kwon G, Marzolf S, Stewart E, Jurchen D, Pederson SM, Perrino McCulloch L, Baker B, Cady RK, Latham JA, Allison D, Garcia-Martinez LF. Pharmacologic characterization of ALD1910, a potent Humanized monoclonal antibody against the pituitary adenylate cyclase activating peptide. J Pharmacol Exp Ther. 2019;118:253443.
96. Ashina M, Doležil D, Bonner JH, Zhou L, Klatt J, Picard H, Mikol DD. A phase 2a, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of AMG 301 in migraine prevention. J Headache Pain. 2019 In press.
97. Muddhrry PK, Ghatki MA, Spokks RA, Jonhs PM, Pierson AM, Hamid QA, et al. Differential expression of α-CGRP and β-CGRP by primary sensory neurons and enteric autonomic neurons of the rat. Neuroscience. 1988;25:195–205.
98. Goadsby PJ, Edvinsson L, Ekman R. Vasoactive peptide release in the extracerebral circulation of humans during migraine headache. Ann Neurol. 1990;28:183–187.
99. Gallai V, Sarchielli P, Floridi A, Franceschini M, Codini M, Glioti G, Trequattrini A, Palumbo R. Vasoactive peptide levels in the plasma of young migraine patients with and without aura assessed both interictally and ictally. Cephalalgia. 1995;15:384–390.
100. Durham PL, Russo AF. Regulation of calcitonin gene-related peptide secretion by a serotonergic antimigraine drug. J Neurosci. 1999;19:3423–3429.
101. Cernuda-Morollon E, Larrosa D, Ramon C, Vega J, Martinez-Camblor P, Pascual J. Interictal increase of CGRP levels in peripheral blood as a biomarker for chronic migraine. Neurology. 2013;81:1191–1196.
102. Lassen L, Haderslev P, Jacobsen V, Iversen H, Sperling B, Olesen J. CGRP may play a causative role in migraine. Cephalalgia. 2002;22:54–61.
103. Hansen JM, Hauge AW, Olesen J, Ashina M. Calcitonin gene-related peptide triggers migraine-like attacks in patients with migraine with aura. Cephalalgia. 2010;30:1179–1186.
104. Kaiser EA, Kuburas A, Recober A, Russo AF. Modulation of CGRP-induced light aversion in wild-type mice by a 5-HT(1B/D) agonist. J Neurosci. 2012;32:15439–15449.
105. Mason BN, Kaiser EA, Kuburas A, Loomis MCM, Latham JA, Garcia-Martinez LF, Russo AF. Induction of migraine-like photophobic behavior in mice by both peripheral and central CGRP mechanisms. J Neurosci. 2017;37:204–216.
106. Recober A, Kuburas A, Zhang Z, Wemmie JA, Anderson MG, Russo AF. Role of calcitonin gene-related peptide in light-aversive behavior: implications for migraine. The J Neurosci. 2009;29:8798–8804.
107. Tozzi A, de Iure A, Di Filippo M, Costa C, Caproni S, Pisani A, Bonsi P, Picconi B, Cupini LM, Materazzi S, Geppetti P, Sarchielli P, Calabresi P. Critical role of calcitonin gene-related peptide receptors in cortical spreading depression. Proc Natl Acad Sci U S A. 2012;109:18985–18990.
108. Wang M, Jiang L, Wang Y, Bu F. Both anti-CGRP and anti-CALCRL antibodies suppress cortical spreading depression. Cephalalgia. 2017;37(1 suppl):292–293.
109. Wang Y, Tye AE, Zhao J, Ma D, Raddant AC, Bu F, Spector BL, Winslow NK, Wang M, Russo AF. Induction of calcitonin gene-related peptide expression in rats by cortical spreading depression. Cephalalgia. 2016;0:1–9.
110. Close LN, Eftekhari S, Wang M, Charles AC, Russo AF. Cortical spreading depression as a site of origin for migraine: role of CGRP. Cephalalgia. 2018;0:1–7.
111. Hoffmann J, Baca SM, Akerman S. Neurovascular mechanisms of migraine and cluster headache. J Cereb Blood Flow Metab. 2019;39:573–594.
112. Charles A. Vasodilation out of the picture as a cause of migraine headache. Lancet Neurol. 2013;12:419–420.
113. Goadsby PJ. The vascular theory of migraine—a great story wrecked by the facts. Brain. 2009;132:6–7.
114. De R, Koulchitsky SV, Messlinger KB. Nitric oxide synthase inhibition lowers activity of neurons with meningeal input in the rat spinal trigeminal nucleus. Neuroreport. 2003;14:229–232.
115. Tassorelli C, Joseph SA. Systemic nitroglycerin induces Fos immunoreactivity in brainstem and forebrain structures of the rat. Brain Res. 1995;682:167–181.
116. Bellamy J, Bowen EJ, Russo AF, Durham PL. Nitric oxide regulation of calcitonin gene-related peptide gene expression in rat trigeminal ganglia neurons. Eur J Neurosciences. 2006;23:2057–2066.
117. Strecker T, Dux M, Messlinger K. Nitric oxide releases calcitonin-gene-related peptide from rat dura mater encephali promoting increases in meningeal blood flow. J Vasc Res. 2002;39:489–496.
118. Edvinsson L, Tajti J, Szalárdy L, Vécsei L. PACAP and its role in primary headaches. J Headache Pain. 2018;19:21.
119. Akerman S, Goadsby PJ. Neuronal PAC1 receptors mediate delayed activation and sensitization of trigeminocervical neurons: relevance to migraine. Sci Translational Med. 2015;7:308ra157.
120. Tuka B, Helyes Z, Markovics A, Bagoly T, Németh J, Márk L, Brubel R, Reglődi D, Párdutz A, Szolcsányi J, Vécsei L, Tajti J. Peripheral and central alterations of pituitary adenylate cyclase activating polypeptide-like immunoreactivity in the rat in response to activation of the trigeminovascular system. Peptides. 2012;33:307–316.
121. Tuka B, Helyes Z, Markovics A, Bagoly T, Szolcsányi J, Szabó N, Tóth E, Kincses ZT, Vécsei L, Tajti J. Alterations in PACAP-38-like immunoreactivity in the plasma during ictal and interictal periods of migraine patients. Cephalalgia. 2013;33:1085–1095.
122. Guo S, Vollesen ALH, Olesen J, Ashina M. Premonitory and nonheadache symptoms induced by CGRP and PACAP38 in patients with migraine. Pain. 2016;157:2773–2781.
123. Schytz HW, Birk S, Wienecke T, Kruuse C, Olesen J, Ashina M. PACAP38 induces migraine-like attacks in patients with migraine without aura. Brain. 2009;132:16–25.
124. Ashina H, Guo S, Vollesen ALH, Ashina M. PACAP38 in human models of primary headaches. J Headache Pain. 2017;18:110.
125. Hoffmann J, Martins-Oliveira M, Akerman S, Supronsinchai W, Xu C, Goadsby P J. PAC-1 receptor antibody modulates nociceptive trigeminal activity in rat. Cephalagia. 2016;36:141.
126. Jansen-Olesen I, Baun M, Amrutkar DV, Ramachandran R, Christophersen DV, Olesen J. PACAP-38 but not VIP induces release of CGRP from trigeminal nucleus caudalis via a receptor distinct from the PAC1 receptor. Neuropeptides. 2014;48:53–64.
127. Bose P, Goadsby PJ. The migraine postdrome. Curr Opin Neurol. 2016;29:299–301.