Migraine: multiple processes, complex pathophysiology

Abstract

Migraine is a common, multifactorial, disabling, recurrent, hereditary neurovascular headache disorder. It usually strikes sufferers a few times per year in childhood and then progresses to a few times per week in adulthood, particularly in females. Attacks often begin with warning signs (prodromes) and aura (transient focal neurological symptoms) whose origin is thought to involve the hypothalamus, brainstem, and cortex. Once the headache develops, it typically throbs, intensifies with an increase in intracranial pressure, and presents itself in association with nausea, vomiting, and abnormal sensitivity to light, noise, and smell. It can also be accompanied by abnormal skin sensitivity (allodynia) and muscle tenderness. Collectively, the symptoms that accompany migraine from the prodromal stage through the headache phase suggest that multiple neuronal systems function abnormally. As a consequence of the disease itself or its genetic underpinnings, the migraine brain is altered structurally and functionally. These molecular, anatomical, and functional abnormalities provide a neuronal substrate for an extreme sensitivity to fluctuations in homeostasis, a decreased ability to adapt, and the recurrence of headache. Advances in understanding the genetic predisposition to migraine, and the discovery of multiple susceptible gene variants (many of which encode proteins that participate in the regulation of glutamate neurotransmission and proper formation of synaptic plasticity) define the most compelling hypothesis for the generalized neuronal hyperexcitability and the anatomical alterations seen in the migraine brain. Regarding the headache pain itself, attempts to understand its unique qualities point to activation of the trigeminovascular pathway as a prerequisite for explaining why the pain is restricted to the head, often affecting the periorbital area and the eye, and intensifies when intracranial pressure increases.

Figure 1.

From prodromes to headache: proposed hypothesis for the initiation of headache by the hypothalamus and brainstem. A, Hypothalamic–parasympathetic pathway for the activation of meningeal nociceptors by neurons that regulate homeostasis, circadian rhythms, and autonomic functions (adapted from Burstein and Jakubowski, 2005). Hypothalamically mediated activation of preganglionic parasympathetic neurons in the SSN can trigger the release of acetylcholine, vasoactive intestinal peptide, and nitric oxide from meningeal terminals of postganglionic parasympathetic neurons in the SPG. B, C, Neurochemical pathways capable of modulating the excitability of relay thalamocortical neurons in response to deviation from physiological (food intake, sleep) and emotional (stress, anxiety) homeostasis. The illustration (top right) shows the hypothalamic and brainstem origin of each of the pathways found to converge on thalamic trigeminovascular neurons (adapted from Kagan et al., 2013; Noseda et al., 2014). The photomicrographs show the extent of innervation by vesicular glutamate transporter, vesicular GABA transporter, serotonin transporter, dopamine beta hydroxylase, tyrosine hydroxylase, histamine, melanin-concentrating hormone, and orexin A. D, Conceptual illustration of how brainstem tone (allostatic load) may allow the headache to develop incosistently in response to identical changes in external and internal conditions. Brainstem “state of tone” can limit afferent nociceptive drive in migraine-susceptible individuals (adapted from Borsook and Burstein, 2012). Fluctuation of activity in brainstem neurons is thought to drive adaptive behavior. In the context of migraine, this can apply to the modulation of nociceptive signals from the meninges. The gating of these signals depends on the threshold of the neural networks that modify these afferent signals. Thus, the robustness of the “gate” that allows nociceptive signals to drive central trigeminovascular neurons (and thus headache) is dictated by brainstem tone. When the brainstem tone is high [red dot below line of migraine threshold (MT)], nociceptive signals are inhibited; and when the brainstem tone is low (red dot above MT), afferent signals are not effectively blocked. The model illustrates the following three functional brainstem states: (1) normal state, when cyclical brainstem activity is high, the potency of pain facilitation (enhanced synaptic strength in the dorsal horn) is too high to allow nociceptive signals from the periphery to drive the central neurons into the active state (left); (2) threshold state, at threshold, the system has reached a primed state that could tip into a functional state that would allow nociceptive drive from the dura to activate the central trigeminovascular neurons (middle); and (3) migraine state, when cyclical brainstem activity is low (more sensitive to stimuli), nociceptive signals from the periphery can drive the central neurons into the active state (right). A11, Hypothalamic dopaminergic nucleus; C1/C2, cervical spinal cord segments; DR, dorsal raphe nucleus; DTM, dorsal tuberomammary hypothalamic nucleus; LC, locus ceruleus; LH, lateral hypothalamus, PeF, perifornical area; RMg, nucleus raphe magnus; TG, trigeminal ganglion.

Figure 2.

Activation and sensitization of the trigeminovascular pathway provide anatomical and physiological substrates for migraine headache and its associated symptoms. A, Intricate anatomy of the trigeminovascular pathway. B–D, Single-unit recording showing delayed (B, C) and immediate (D) activation of a meningeal nociceptor (B) and two SpV neurons (C, D) following the induction of CSD in the visual cortex of the rat. E, Activation and sensitization of a meningeal nociceptor. Baseline responses to mechanical stimulation of the dura (blue) increase (red) after exposure to inflammatory soup (IS). F, Activation and sensitization of a trigeminovascular neuron in the SpV. Baseline responses to mechanical stimulation of the periorbital skin (blue) increased (red) after a brief exposure of the dura to IS. G, Activation and sensitization of thalamic trigeminovascular neurons. Baseline responses to mechanical stimulation of the lower limb (blue) increased in magnitude and duration (red) following brief application of IS to the dura. H, Contrast analysis of BOLD signals registered in fMRI scans of the human trigeminal ganglion during migraine attacks. I, Contrast analysis of BOLD signals registered in fMRI scans of the human SpV following innocuous mechanical stimulation of the periorbital skin during migraine. J, Contrast analysis of BOLD signals registered in fMRI scans of the human thalamus following innocuous mechanical stimulation of the skin on the dorsum of the hand during migraine. Red/yellow area depicts the periorbital area of referred pain. Purple/yellow areas depict region of cephalic and extracephalic allodynia. Au, Auditory cortex; C6–C7, sixth and seventh spinal cord segments; DRG, dorsal root ganglion; Ins, insular cortex; Ect, ectorhinal cortex; LP, lateral posterior thalamic nucleus; M1/M2, primary and secondary motor cortices; PAG, periaqueductal gray; PB, parabrachial nucleus; PtA, parietal association cortex; Pul, pulvinar; RS, retrosplenial cortex; S1/S2, primary and secondary somatosensory cortices; TG, trigeminal ganglion; V1/V2, primary and secondary visual cortex. Parts of this figure were adapted from Strassman et al., 1996; Burstein et al., 1998, ; and Zhang et al., 2010 and .

Figure 3.

Functional (MRI_Funct) and morphometric (MRI_Morph) changes in the migraine brain. The examples illustrate changes in functional and morphological measures in cortical (somatosensory) and subcortical (basal ganglia) areas, as well as sex differences in male and female migraineurs. Bottom left conceptualizes dendritic tree density (blue = volume loss; red = volume gain). Somatosensory cortex: increased somatosensory activation to a noxious stimulus (pain threshold +1C) applied to the face (forehead) and increased cortical thickness in episodic migraineur. MRI_Funct shows bilateral activation in the primary somatosensory cortex (top; yellow-orange). MRI_Morph shows significant changes in cortical volume (green) in high vs low episodic migraineurs vs healthy control subjects. Basal ganglia: decreased activation (top) in the caudate (MRI_Funct) in high-frequency vs low-frequency episodic migraineurs in response to a noxious heat stimulus (pain threshold +1C) is associated with increased volume (MRI_Morph) in the structure (bottom). Sex differences: overlap of disease-related and sex-related functional differences (MRI_Funct) in men vs women (top; orange-red) showing decreased activation in episodic migraineurs to a noxious stimulus (pain threshold +1C) applied to the face (forehead). Also shown are decreased activations in female episodic migraineurs (F_M) vs healthy control subjects (C). Bottom shows increased cortical thickness in female migraineurs (F_M) vs male migraineurs (M_M) in the insula. Other areas showing a similar sex difference included the precuneus. The issue of sex-related changes in the migraine brain have been reviewed previously (Borsook et al., 2014). Parts of this figure are adapted from Maleki et al., 2011b, ,; and Borsook et al., 2013.