It's now clear that a migraine attack is not simply headache, but includes multiple phases, including the prodrome phase, in some patients the aura phase, then the headache phase, and then the postdrome phase, which follows headache during a migraine attack.¹ And, between attacks, we call that the interictal period, where there's no particular migraine attack symptoms, but there may still be underlying pathophysiology.^2-5 Recent studies suggest that there are several different anatomical regions and different molecular pathways that are involved in the evolution of a migraine attack through its different phases and involved in the diverse symptoms that are associated with these phases.^6-9

It's now quite clear that the hypothalamus is playing a significant role in a migraine attack.¹ And, this makes sense, because the hypothalamus is involved in maintaining homeostasis, and its activation has been implicated in a number of prodromal symptoms that may be involved in homeostasis, including such symptoms as appetite change and fatigue.^1,10 Imaging studies consistently indicate that the hypothalamus is activated in the earliest phases of the migraine attack, before pain begins.^11,12 So, this sort of hypothalamic role may, again, be something that is part of the early phases in the prodrome that are leading up to the pain phase of a migraine attack.¹

It's also clear that multiple other neuropeptides are involved in homeostatic functions, and it's possible that these other peptides could also be involved in some of the early phases or the prodromal symptoms that are observed during a migraine attack.¹ So, for example, leptin is a hormone that is produced in the gut and in fat cells that is clearly involved in appetite, but may also be involved in sleep function as well.^13,14 Neuropeptide Y, a peptide that's present diffusely in the peripheral and central nervous system, is involved in both regulation of appetite and also involved in sleep as well.^15,16 And, orexin-A and -B are peptides that are produced primarily in the hypothalamus that clearly have a role in sleep and may also have a role in appetite.^17,18 So, these changes in homeostatic function during prodromal phase may involve a variety of different peptides, including these three, as well as others.¹

Cortical spreading depression is a slowly propagated wave of depolarization or excitation of brain activity followed by a depression of brain activity, and it has for some time been assumed that this spreading wave of activity is associated with the migraine aura.^1,19 So, the spreading changes in visual function that are associated with the visual aura are believed to be due to this phenomenon that is propagating slowly across the occipital cortex.²⁰ It's been hypothesized that cortical spreading depression may lead to the activation and sensitization of the trigeminal vascular system, and functional imaging studies have demonstrated hyperexcitability and increased functional connectivity in the cortex and cerebellum in patients with migraine with aura.^21-25 And, it's possible that these changes are related to this phenomenon of cortical spreading depression.²³

There are a number of new findings on the underlying pathophysiology of migraine.^1,20 The headache phase of migraine is associated with a distinct pathophysiology that may involve sensitization of the peripheral and central nervous system.^8,26 There's activation of nociceptors in the trigeminal system that are relayed through the trigeminal ganglion that signal from the periphery to the central nervous system, generating a sensation of pain.^8,27 The upper cervical nerve roots may also be involved in transmitting pain during the headache phase.²⁰ It's believed that repeated activation of the trigeminovascular system may then result in a state of hypersensitivity, which may potentiate pain signals and could contribute to common migraine nonpain symptoms as well.^8,26 For example, primary nociceptors and central trigeminovascular neurons may respond to innocuous stimulation of the skin, as if it were noxious, and this is what we call allodynia or cutaneous allodynia, where normal touch is perceived as uncomfortable or painful.^28-30

There are several neuropeptides implicated in head pain and peripheral and central sensitization of the trigeminovascular system and other systems during the headache phase.¹ For example, calcitonin gene-related peptide and pituitary adenylate-cyclase-activating polypeptide, CGRP and PACAP, and their receptors are expressed in the trigeminovascular system and in the cranial and parasympathetic systems.^6,31 And, clinical evidence suggests that they play a significant role in migraine.^32,33 Preclinical studies with PACAP and CGRP suggest that both neuropeptides may also play a role in photophobia or light sensitivity that may occur during the headache phase of a migraine attack.¹

There are a number of new findings, again, related to the phases of the migraine attack and how these progress.^6-9 One of the important points to make is that while we distinguish the prodrome and the headache phase and the postdrome, there may be substantial overlap between these different phases of a migraine attack.^1,34 There are a number of similarities, particularly between the prodrome and the postdrome, in terms of the symptoms that are present during these different phases.^1,34 So, although, again, we divide them into these fairly discrete phases, the point is that there may be a continuum and a continuous evolution of neurochemical and anatomical events that progress throughout a migraine attack.^1,34 The exact neurological events that underlie these different symptoms remain uncertain.^1,34

There's been a continued evolution in our understanding of migraine pathophysiology, and, although our understanding remains limited, it's now clear that there are anatomical structures and neuropeptides that are involved in the different phases of the migraine attack.^1,20

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