Biochemical Modulation and Pathophysiology of Migraine

Background: Migraine is a common disabling neurological disorder where attacks have been recognized to consist of more than headache. The premonitory, headache, and postdromal phases are the various phases of the migraine cycle, where aura can occur before, during, or after the onset of pain. Migraine is also associated with photosensitivity and cranial autonomic symptoms, which includes lacrimation, conjunctival injection, periorbital edema, ptosis, nasal congestion, and rhinorrhoea. This review will present the current understanding of migraine pathophysiology and the relationship to the observed symptoms. Evidence acquisition: The literature was reviewed with specific focus on clinical, neurophysiological, functional imaging, and preclinical studies in migraine including the studies on the role of calcitonin gene-related peptide (CGRP) and pituitary adenylate cyclase activating polypeptide (PACAP). Results: The phases of the migraine cycle have been delineated by several studies. The observations of clinical symptoms help develop hypotheses of the key structures involved and the biochemical and neuronal pathways through which the effects are mediated. Preclinical studies and functional imaging studies have provided evidence for the role of multiple cortical areas, the diencephalon, especially the hypothalamus, and certain brainstem nuclei in the modulation of nociceptive processing, symptoms of the premonitory phase, aura, and photophobia. CGRP and PACAP have been found to be involved in nociceptive modulation and through exploration of CGRP mechanisms, new successful treatments have been developed. Conclusions: Migraine is a complex neural disorder and is important to understand when seeing patients who present to neuro-ophthalmology, especially with the successful translation from preclinical and clinical research leading to successful advances in migraine management.

Disease of the Year: Migraine Section Editors: Kathleen B. Digre, MD Deborah I. Friedman, MD, MPH Biochemical Modulation and Pathophysiology of Migraine Calvin Chan, BBMedSc, MBChB, Diana Y. Wei, BSc, MBBS, Peter J. Goadsby, MD, PhD Background: Migraine is a common disabling neurological disorder where attacks have been recognized to consist of more than headache. The premonitory, headache, and postdromal phases are the various phases of the migraine cycle, where aura can occur before, during, or after the onset of pain. Migraine is also associated with photosensitivity and cranial autonomic symptoms, which includes lacrimation, conjunctival injection, periorbital edema, ptosis, nasal congestion, and rhinorrhoea. This review will present the current understanding of migraine pathophysiology and the relationship to the observed symptoms. Evidence Acquisition: The literature was reviewed with specific focus on clinical, neurophysiological, functional imaging, and preclinical studies in migraine including the studies on the role of calcitonin gene-related peptide (CGRP) and pituitary adenylate cyclase activating polypeptide (PACAP). Results: The phases of the migraine cycle have been delineated by several studies. The observations of clinical symptoms help develop hypotheses of the key structures involved and the biochemical and neuronal pathways through which the effects are mediated. Preclinical studies and functional imaging studies have provided evidence for the role of multiple cortical areas, the diencephalon, especially the hypothalamus, and Headache Group, Department of Basic and Clinical Neuroscience (CC, DYW, PJG), Institute of Psychology, Psychiatry and Neuroscience, King’s College London, London, United Kingdom; and NIHRWellcome Trust King’s Clinical Research Facility (CC, DYW, PJG), SLaM Biomedical Research Centre, King’s College Hospital, London, United Kingdom. P. J. Goadsby reports grants and personal fees from Amgen and EliLilly and Company, and personal fees from Alder Biopharmaceuticals, Allergan, Autonomic Technologies Inc, Biohaven Pharmaceuticals Inc, Dr Reddy’s Laboratories, Electrocore LLC, eNeura, Impel Neuropharma, MundiPharma, Novartis, Teva Pharmaceuticals, Trigemina Inc, and WL Gore, and personal fees from MedicoLegal work, Massachusetts Medical Society, Up-to-Date, Oxford University Press, and Wolters Kluwer, and a patent magnetic stimulation for headache assigned to eNeura without fee. This paper represents independent research funded by the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health and Social Care. Address correspondence to Peter J. Goadsby, MD, PhD, Wellcome Foundation Building, King’s College Hospital, London SE5 9PJ, United Kingdom; E-mail: [e-mail] 470 certain brainstem nuclei in the modulation of nociceptive processing, symptoms of the premonitory phase, aura, and photophobia. CGRP and PACAP have been found to be involved in nociceptive modulation and through exploration of CGRP mechanisms, new successful treatments have been developed. Conclusions: Migraine is a complex neural disorder and is important to understand when seeing patients who present to neuro-ophthalmology, especially with the successful translation from preclinical and clinical research leading to successful advances in migraine management. Journal of Neuro-Ophthalmology 2019;39:470–479 doi: 10.1097/WNO.0000000000000875 © 2019 by North American Neuro-Ophthalmology Society M igraine 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). Chan et al: J Neuro-Ophthalmol 2019; 39: 470-479 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Disease of the Year: Migraine TABLE 1. ICHD3 diagnostic criteria for migraine with and without aura (6) Migraine Without Aura A. At least 5 attacks fulfilling criteria B–D B. Headache attacks lasting for 4–72 hr* C. Headache has at least 2 of the following 4 characteristics: 1. unilateral location 2. pulsating quality 3. moderate or severe pain intensity 4. aggravation by or causing avoidance of routine physical activity D. During headache at least one of the following: 1. nausea and/or vomiting 2. photophobia and phonophobia Migraine With Aura A. At least 2 attacks fulfilling criteria B and C B. One or more of the following fully reversible aura symptoms: 1. visual 2. sensory 3. speech and/or language 4. motor 5. brainstem 6. retinal C. At least 3 of the following 6 characteristics: 1. at least one aura symptom spreads gradually over $5 min 2. two or more aura symptoms occur in succession 3. each individual aura symptom lasts for 5–60 min 4. at least one aura symptom is unilateral 5. at least one aura symptom is positive 6. the aura is accompanied, or followed within 60 min, by headache *2–72 hours in children and adolescents ,18. ICHD3, International Classification of Headache Disorders, Third Edition. 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 Premonitory Phase 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 Chan et al: J Neuro-Ophthalmol 2019; 39: 470-479 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 Ad fibers to the trigeminal ganglion (18), supporting their role in TABLE 2. Premonitory symptoms Symptom Group Neurocognitive Homeostatic alterations Sensory hypersensitivity Symptoms Concentration difficulty, fatigue, memory impairment, depression, elation, and irritability Food cravings, thirst, urinary frequency, constipation, yawning, and sleep disturbance Neck stiffness, photophobia, phonophobia, osmophobia, and nausea Adapted from Karsan et al (14) and Giffin et al (8). 471 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Disease of the Year: Migraine 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 neu- rophysiological 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. Aura 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). FIG. 1. Ascending pathways and key structures in migraine pathophysiology. Sensory afferents from the branches of the trigeminal nerve (V1, V2, V3) project through the trigeminal ganglion (TG) and synapse at the trigeminal cervical complex (TCC), which consists of the trigeminal nucleus caudalis (TNC) and the C1 and C2 contributions of the upper spinal dorsal horn. Afferents from the intracranial vessel travel predominantly through the V1 and the C1 and C2, where C1 and C2 contributions travel through the dorsal root ganglion (DRG). Second-order neurons from the TCC project to the locus coeruleus (LC), the rostral ventromedial medulla (RVM) which in turn project to the periaqueductal gray (PAG) and higher diencephalon structures which in turn project to various cortical regions. A reflex connection exists between the TCC and the superior salivary nucleus (SuS) where parasympathetic outflow travels through the sphenopalatine ganglion. 472 Chan et al: J Neuro-Ophthalmol 2019; 39: 470-479 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Disease of the Year: Migraine FIG. 2. Key structures and descending pathways in the modulation of the trigeminal cervical complex (TCC). Modulation of the TCC also involves dopaminergic pathways through the A11 nucleus in the hypothalamus and is mediated by the locus coeruleus (LC), periaqueductal gray (PAG), through the rostral ventromedial medulla resulting in an inhibition of TCC neuronal firing. The superior salivary nucleus (SuS) has bidirectional connections with the hypothalamus where stimulation of the TCC by the SuS increases neuronal firing within the TCC. Cortical spreading depression can also increase TCC neuronal activity directly and indirectly. 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 selfpropagates 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: 1. alteration of intracellular and extracellular electrolytes, resulting in a hyperpolarized state lasting up to 50 seconds (35). 2. Release of transmitters including serotonin, glutamate, dopamine, and nitric oxide (35). 3. Cortical perfusion changes with an initial wave of hyperemia secondary to vasodilation followed by prolonged oligemia (36). Hypoperfusion during aura has been Chan et al: J Neuro-Ophthalmol 2019; 39: 470-479 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 473 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Disease of the Year: Migraine 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. Headache Phase 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 Ad 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 474 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). Photophobia 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 lightattributed nociceptive activity (76). Signaling through retinal photoreceptors increases activity in the TCC when there is increased parasympathetic activity (61). Melanopsincontaining 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 Chan et al: J Neuro-Ophthalmol 2019; 39: 470-479 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Disease of the Year: Migraine ipRGC within the iris transmits information in the presence of light, which can activate the trigeminal reflex. Postdrome 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. IMPORTANT NEUROPEPTIDES 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. 1. CGRP is elevated in venous samples of patients in migraine with and without aura (98,99). 2. CGRP levels rise during a migraine attack and normalize with sumatriptan administration resulting in resolution of the attack (100). 3. CGRP levels in chronic migraine patients remain consistently elevated compared with episodic migraine patients (101). Chan et al: J Neuro-Ophthalmol 2019; 39: 470-479 TABLE 3. Postdromal symptoms Symptom Group Symptoms Neurocognitive Lethargy, mood changes, difficulty concentrating, and sleep disturbances Nausea, vomiting, flatulence, constipation, diarrhea, abdominal pain, food craving, anorexia, urination, and fluid retention Head soreness, photophobia, phonophobia, and speech disturbance Homeostatic alterations Sensory hypersensitivity Adapted from Bose et al (127). 4. CGRP, when infused, can induce migraine in migraine patients with or without aura (102,103). The a isoform of CGRP is found in the end terminals of C and Ad 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 NOindependent 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 475 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Disease of the Year: Migraine 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: 1. 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). 2. 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). 3. 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). CONCLUSIONS 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. 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