Pathophysiology of Migraine: A Disorder of Sensory Processing

Abstract

Plaguing humans for more than two millennia, manifest on every continent studied, and with more than one billion patients having an attack in any year, migraine stands as the sixth most common cause of disability on the planet. The pathophysiology of migraine has emerged from a historical consideration of the "humors" through mid-20th century distraction of the now defunct Vascular Theory to a clear place as a neurological disorder. It could be said there are three questions: why, how, and when? Why: migraine is largely accepted to be an inherited tendency for the brain to lose control of its inputs. How: the now classical trigeminal durovascular afferent pathway has been explored in laboratory and clinic; interrogated with immunohistochemistry to functional brain imaging to offer a roadmap of the attack. When: migraine attacks emerge due to a disorder of brain sensory processing that itself likely cycles, influenced by genetics and the environment. In the first, premonitory, phase that precedes headache, brain stem and diencephalic systems modulating afferent signals, light-photophobia or sound-phonophobia, begin to dysfunction and eventually to evolve to the pain phase and with time the resolution or postdromal phase. Understanding the biology of migraine through careful bench-based research has led to major classes of therapeutics being identified: triptans, serotonin 5-HT_1B/1D receptor agonists; gepants, calcitonin gene-related peptide (CGRP) receptor antagonists; ditans, 5-HT_1F receptor agonists, CGRP mechanisms monoclonal antibodies; and glurants, mGlu₅ modulators; with the promise of more to come. Investment in understanding migraine has been very successful and leaves us at a new dawn, able to transform its impact on a global scale, as well as understand fundamental aspects of human biology.

FIGURE 1.

The migrainous brain interictally. Imaging studies in the migraineurs' brain interictally demonstrate there is reduced activation of the spinal trigeminal nuclei in response to trigeminal nociceptive stimulation, which normalizes prior to the next migraine attack. This change might reflect an increased susceptibility of the brain to generate the subsequent attack in the sense of a defective top-down modulation of trigeminal input. [From Stankewitz et al. (749).]

FIGURE 2.

The migrainous migraine during the premonitory phase. In nitroglycerin-induced migraine attacks, H₂¹⁵O-PET demonstrated increased rCBF in the posterior hypothalamic region (A and B), the periaqueductal grey region (C and D), and dorsal pons (E and F), which are highlighted by circles. The color bar indicates the color coding of the Z scores (559). From a clinical perspective, the hypothalamus might be involved in the premonitory symptoms prior to the experience of head pain. Such symptoms involve tiredness, concentration problems, yawning, appetite alterations, and frequent urination. Activation in the midbrain and PAG likely reflects a mechanism through which nociceptive head pain symptoms may be generated. [From Maniyar et al. (559), by permission of Oxford University Press.]

FIGURE 3.

The migrainous brain during migraine head pain. Many studies have demonstrated that migraine attacks are associated with an increase of rCBF in mesencephalon and pons, which cannot be found in experimental head pain, indicating specificity for migraine attacks (842). After termination of the migraine attack with sumatriptan, these changes persisted, suggesting involvement in migraine generation or sustentation, rather than specifically trigeminally mediated pain. [From Weiller et al. (842). Reprinted by permission from Macmillan Publishers Ltd.]

FIGURE 4.

Anatomy of the trigeminovascular system–ascending projections. The trigeminal ganglion (TG) gives rise to pseudo-unipolar trigeminal primary afferents which synapse on intra- and extracranial structures (blood vessels) as well as the spinal cord trigeminocervical complex (TCC). Second-order neurons from the TCC ascend in the quintothalamic (trigeminothalamic) tract synapsing on third-order thalamocortical neurons. Direct and indirect ascending projections also exist to the locus coeruleus (LC), periaqueductal grey (PAG), and hypothalamus. The third-order thalamocortical neurons in turn synapse on a diffuse network of cortical regions including the primary and secondary motor (M1/M2), somatosensory (S1/S2), and visual (V1/V2) cortices. A reflex connection from the TCC to the superior salivatory nucleus (SuS) exists, which projects via the sphenopalantine ganglion (SPG) providing parasympathetic innervation to the extra- and intracranial structures. Ins, insula; PtA, parietal association; RS, retrosplenial; Au, auditory; Ect, ectorhinal; RVM, rostral ventromedial medulla.

FIGURE 5.

Modulation of trigeminovascular nociceptive transmission–descending projections. The trigeminocervical complex (TCC) is subject to direct and indirect descending pain modulatory pathways arising in the cortex. Direct projections exist from primary somatosensory (S1) and insular (Ins) cortices while indirect projections arising in S1 that project via the hypothalamus. A local corticothalamic circuit also exists which can modulate trigeminothalamic processing. Hypothalamic projections again form direct TCC modulatory projections as well as indirect projections via the locus coeruleus (LC) and periaqueductal gray (PAG) which can further pass via the rostral ventromedial medulla (RVM). This complex network of direct and indirect pathways provides potent anti- and pro-nociceptive modulation of incoming trigeminal nociceptive signaling, the dysfunction of which is thought to contribute to triggering migraine attacks. SPG, sphenopalantine ganglion; SuS, superior salivatory nucleus; TG, trigeminal ganglion.

FIGURE 6.

Anatomy of the trigemino-autonomic pathway believed to contribute to head pain and cranial autonomic symptoms in migraine. A: schematic representation of trigemino-autonomic pathway includes the peripheral and central projections of the trigeminovascular system (black neurons). There is also a trigemino-autonomic reflex connection from the trigeminocervical complex (TCC; grey neuron), to the superior salivatory nucleus (green cell; SuS) and its parasympathetic projection to the cranial vasculature, predominantly via the greater petrosal nerve (green projection) and its synapse with the pterygopalatine (also known as sphenopalatine) ganglion (PG), as well as via the facial (VIIth cranial) nerve (purple neuron). B: electrophysiological recording of neurons in the rat TCC is activated by SuS stimulation. First there is a shorter latency response (C) believed to be activated by antidromic activation of the trigemino-autonomic reflex, and a longer latency response (C and D) caused by activation of the parasympathetic outflow to the cranial vasculature; there is a signal which traverses the nociceptive meninges, which subsequently causes activation of the central trigeminovascular projection to the TCC. E: lacrimal gland/duct (yellow cell in B) blood flow also increases concurrent with SuS stimulation, as a result of the parasympathetic projection to the lacrimal gland. TG, trigeminal ganglion. [C–E modified from Akerman and co-workers (25, 26).]

FIGURE 7.

Proposed mechanism of descending modulation of trigeminovascular nociceptive transmission through brain stem nuclei, mediated by 5-HT and endocannabinoids. A: the spontaneous firing of neurons in the TCC is modulated by microinjection of CB₁-mediated endocannabinoids (ACPA) in the ventrolateral periaqueductal grey (vlPAG), with transient inhibition of firing. B: ACPA microinjection in the vlPAG also inhibits dural-evoked nociceptive firing in the TCC, an effect that is replicated by naratriptan microinjection. We propose that the mechanism of action of this inhibitory effect is by modulating descending GABAergic projections (C and D). At the level of the vlPAG GABAergic projection (blue), neurons synapse with glutamatergic projections (purple) to “OFF” and “ON” cells in the rostral ventromedial medulla (RVM). Tonic release of GABA (blue circles) controls the level of descending inhibition to the TCC, via “OFF” and “ON” cell activity in the RVM. Cannabinoid (CB₁, green) and triptan (5-HT_1B/1D, orange) receptors are located presynaptically on these GABAergic projections. Orexin 1 (Ox1, red) receptors are also located postsynaptically on the glutamatergic projections. Endogenous release or exogenous administration of ECs (green circles) and 5-HT agonists (yellow circles) activate presynaptic receptors inhibiting the release of GABA, increasing the likelihood of activation of the descending glutamatergic projections to “OFF” cells in the rostral ventromedial medulla (RVM). Activation of postsynaptic Ox1 receptors are also thought to stimulate the production and release of ECs from the postsynaptic cell, activating presynaptic CB₁ receptors and inhibiting GABA release, disinhibiting, and thus activating glutamatergic projections to “OFF” cells in the RVM. This implies that orexin peptides may also be involved in this mechanism of descending control. C: at the same time a hypothesized projection (dashed lines) from the descending glutamatergic projection also synapses with an inhibitory interneuron (light blue neuron-dashed lines) in RVM, which inhibits activity of “ON” cells. Activation of RVM “OFF” cells and inhibition of “ON” cell results in switching off activity at the level of the trigeminocervical complex (TCC) second-order neuron. D: additionally at the level of the RVM, CB₁ receptors situated presynaptically on GABAergic projections to “OFF” cells, when activated by endogenous or exogenous ECs, inhibit the release of GABA, increasing “OFF” cell activity by disinhibition. Likewise, we propose that presynaptic CB₁ receptors on glutamatergic projections to “ON” cells inhibit the release of glutamate blocking “ON” cell activation, and thus reducing activity at the level of the TCC. “ON” cell activity may also be inhibited by CB₁ receptor-mediated inhibition of presynaptic release of GABA from neurons that synapse on inhibitory interneurons (light blue neuron-dashed lines). There is also thought to be a state-dependent and bidirectional control of pain modulation through serotonergic projections from the RVM to the TCC that is distinct to “ON” and “OFF” cell modulation. [Data in A and B adapted from Akerman et al. (24).]

FIGURE 8.

Proposed mechanisms for the neural basis of photophobia in migraine. A: it is proposed that there is convergence of photic signals from the retina, via an intact optic nerve, onto posterior thalamic neurons that also receive nociceptive inputs from the dura mater, via the trigeminothalamic tract. These inputs subsequently project to nociceptive areas of the cortex (S1 and S2) resulting in the exacerbation of migraine headache by light, and areas of the visual cortex that cause hypersensitivity to light itself. B: PET imaging during the interictal phase of migraine demonstrates that 600-1,800 Cd/m² light causes activation in the visual cortex in migraineurs, whereas in controls there is no activation (bottom panel). During pain in the trigeminal distribution, light does cause activation in the visual cortex of control subjects, and a hypersensitive response in the visual cortex of migraineurs. C: during migraine, low-intensity light (240 Cd/m²) also causes activation in the visual cortex which is significantly greater compared with that after headache relief with sumatriptan and headache-free interval. Also, activation of the visual cortex to the low level light after headache relief is still greater than that during headache-free interval. These data indicate that further physiological mechanisms may contribute to the hypersensitivity to light as it appears to be not dependent on a trigeminovascular nociceptive input. [B and C adapted from Boulloche et al. (116) and Denuelle et al. (208), with permission from BMJ Publishing Group, Ltd.]

FIGURE 9.

Anatomy and pharmacology of the hypothalamic nuclei and brain stem nuclei involved in energy homeostasis and pain modulation in the context of migraine. Projections to and from specific nuclei within the hypothalamus are involved in the complex neural circuitry of energy homeostasis, including the arcuate (ARC), paraventricular (PVN), ventromedial (VMH), dorsomedial (DMH), and lateral (LH) hypothalamic neurons. In the ARC, energy homeostasis is controlled by orexigenic neuropeptides [stimulating (+) food intake and decrease energy expenditure] neuropeptide Y (NPY) and agouti-related peptide (AgRP) and anorexigenic peptides [inhibit (−) food intake and increase energy expenditure] proopiomelanocortin (POMC) and cocaine and amphetamine-regulated transcript (CART). Peripheral circulating hormones insulin and leptin inhibit NPY/AgRP and stimulate POMC/CART neurons. Communication among these neural circuits is further controlled by the release of orexin A and B, corticotropin-releasing factor (CRF), melanin-concentrating hormone (MCH), γ-aminobutyric acid (GABA), glutamate (GLU), and brain-derived neurotrophic factor (BDNF), among others. The role these nuclei have in potentially triggering migraine, as a consequence of altered feeding and changes in energy homeostasis, is through their descending projections to brain stem nuclei known to be involved in the modulation of pain processing related to headache. These include direct PVN projections to the trigeminocervical complex (TCC), VMH projections to the periaqueductal grey (PAG) and the locus coeruleus (LC), and indirect communication through the ventral tegmental area (VTA) and nucleus tractus solitarius (NTS). Hypothetically altered feeding will affect neuronal processing in the ARC, and subsequently in other hypothalamic nuclei through its connections to them, including the PVN, VMH, and LH. Their control of transmission of nociceptive inputs to the trigeminovascular system may be altered, which ultimately produces the perception of noxious input from the craniofacial region and activation of trigeminovascular system, with a specific injury or insult. NPY1R and NPY5R, NPY receptors; OX1R and OX2R, orexin receptors; ObRb, long “signaling” isoform of the leptin receptor; INSR, insulin receptor; 3V, 3rd ventricle.