Migraine pathophysiology: anatomy of the trigeminovascular pathway and associated neurological symptoms, CSD, sensitization and modulation of pain

Abstract

Scientific evidence support the notion that migraine pathophysiology involves inherited alteration of brain excitability, intracranial arterial dilatation, recurrent activation and sensitization of the trigeminovascular pathway, and consequential structural and functional changes in genetically susceptible individuals. Evidence of altered brain excitability emerged from clinical and preclinical investigation of sensory auras, ictal and interictal hypersensitivity to visual, auditory and olfactory stimulation, and reduced activation of descending inhibitory pain pathways. Data supporting the activation and sensitization of the trigeminovascular system include the progressive development of cephalic and whole-body cutaneous allodynia during a migraine attack. Also, structural and functional alterations include the presence of subcortical white mater lesions, thickening of cortical areas involved in processing sensory information, and cortical neuroplastic changes induced by cortical spreading depression. Here, we review recent anatomical data on the trigeminovascular pathway and its activation by cortical spreading depression, a novel understanding of the neural substrate of migraine-type photophobia, and modulation of the trigeminovascular pathway by the brainstem, hypothalamus and cortex.

Figure 1

Schematic representation of ascending neuronal pathways of the trigeminovascular system that are involved in the different aspects of migraine.

Figure 2

Electrophysiological recordings showing delayed activation of meningeal nociceptors (top panel) and SpVC trigeminovascular neurons (bottom panel) by cortical spreading depression. (Adapted from Zhang et al., J Neurosci 2010; and Zhang et al., Ann Neurol 2011)

Figure 3

Sensitization of meningeal nociceptors believed to mediate the throbbing nature of migraine pain. Left panel: Schematic representation of peripheral sensitization and periorbital throbbing pain in the human; fMRI evidence showing activation of the trigeminal ganglion during migraine. Right panel: Electrophysiological recording of a neuron in the rat TG showing increased responsiveness to mechanical stimulation of the dura after topical application of inflammatory mediators (IS).

Figure 4

Sensitization of central trigeminovascular neurons in the trigeminal nucleus caudalis believed to mediate cephalic cutaneous allodynia during migraine. Left panel: Schematic representation of central sensitization of SpVC trigeminovascular neurons and cephalic cutaneous allodynia in the human; fMRI evidence showing activation of the spinal trigeminal nucleus during migraine. Right panel: Electrophysiological recording of a neuron in the rat SpVC showing increased responsiveness to innocuous and noxious stimulation of the skin and the corresponding receptive field after induction of central sensitization.

Figure 5

Sensitization of central trigeminovascular neurons in the thalamus believed to mediate the extracephalic (whole-body) cutaneous allodynia during migraine. Left panel: Schematic representation of central sensitization of thalamic trigeminovascular neurons and extracephalic cutaneous allodynia in the human; fMRI evidence showing activation of the thalamus during migraine. Right panel: Electrophysiological recording of a neuron in the rat posterior thalamus showing increased responsiveness to mechanical and thermal stimulation of the skin and the corresponding dural and cutaneous receptive fields after induction of central sensitization by inflammatory mediators (IS) on the dura.

Figure 6

Mechanisms of Photophobia. Top panel: Proposed mechanism for exacerbation of headache by light, hypersensitivity to light in migraine patients and ocular pain induced by light (Adapted from Noseda and Burstein, Curr Opin Neurol 2011). Bottom panel: dura/light-sensitive neurons (red) closely apposed to retinal afferents (green) in the posterior thalamus (Adapted from Noseda et al., Nat Neurosci 2010)

Figure 7

Schematic representation of descending neuronal pathways that modulate trigeminovascular nociceptive transmission in the SpVC.