Abstract Body

Migraine is a common, complex brain disorder whose pathophysiology is being unravelled by bench to bedside and back iterative advances (1). Migraine consists of overlapping, parallel “phases” that offer insights into brain areas for laboratory exploration.

Pain in migraine involves the activation, or perception of activation, of the pain-producing innervation of intracranial structures, notably the dura mater. The first, ophthalmic division, can be activated by direct stimulation in experimental animals to activate pathways of potential interest. Second order activation occurs in the trigemiinocervical complex that projects, with decussation, in the quintothalamic tract to the neurons of the ventroposteromedial thalamus. Triptans, serotonin 5-HT_1B/1D receptor agonists, gepants, calcitonin gene-related peptide (CGRP) receptor antagonists, and ditans, 5-HT_1F receptor agonists, each reduce nociceptive signalling in this pathway, and are effective in the acute treatment of migraine. Blockade of the pathway with monoclonal antibodies directed at the peptide, or its canonical receptor, are effective in the preventive treatment of migraine. Remarkably, gepants can have both acute attack effects and preventive effects in migraine.

Brain imaging has demonstrated activations in the region of the hypothalamus in migraineurs in the premonitory phase in nitrogylcerin-triggered attacks or in spontaneous attacks. Given premonitory symptoms such as somnolence, yawning, thirst and polyuria, diencephalic structures offer a target for further bench-based studies. Understanding migraine neurobiology has generated new therapies and is likely to continue to do.

References

1. Goadsby PJ, Holland PR, Martins-Oliveira M, Hoffmann J, Schankin C, Akerman S. Pathophysiology of Migraine- A disorder of sensory processing. Physiological Reviews. 2017;97:553-622.

Abstract Body

Although peripheral contributions are present, migraine is primarily a disease of the brain. Numerous migraine symptoms that occur during different phases of the migraine attack localize to the brain. Amongst others, this includes common premonitory symptoms, hypersensitivities to visual and auditory stimuli, extracephalic cutaneous allodynia, and cognitive dysfunction. Aberrant multisensory integration in the brain likely contributes to how exposure to sensory stimuli in one domain can exacerbate symptoms within another, such as exposure to light leading to increased cutaneous sensitivity. Migraine aura is attributed to cortical spreading depolarization, a process that might also activate the trigeminal system and trigger migraine headache.

Imaging studies provide evidence for the brain’s role in migraine, including demonstration of aberrant brain structure and function during and between migraine attacks. Functional imaging studies show cycling activity and connectivity of brain regions as an individual moves through the ictal and interictal phases of migraine. Interictally, the migraine brain demonstrates hyper-excitability of regions that facilitate processing of pain and visual stimuli, reduced activation of pain-inhibiting regions, and aberrant functional connectivity amongst pain-matrix regions and regions within multiple core functional brain networks. Additionally, there is evidence for aberrant regional brain structure, the extent of which often correlates positively with markers of migraine disease burden.

Abstract Body

Since migraine is primarily a disorder of brain function and excitability, functional MRI (fMRI) studies represent a powerful tool to explore central nervous system correlates in migraine. In this frame, fMRI investigations fall into two main categories, specifically the event-related and the resting state ones, exploring respectively the brain activity in response to tasks and the connectivity of specific brain areas or networks at rest. The latter relays on several methodological approaches such as seed-based analysis, independent component analysis (ICA) and graph theory-based analysis. Altogether, resting-state (RS) advanced neuroimaging techniques allow the identification of neuro-anatomical and biologically meaningful spatial brain maps organized in distributed and reproducible functional networks showing spontaneous and simultaneous fluctuations. Nevertheless, in the last decades, a novel RS-fMRI methodological approach emerged to explore the structural neural substrates enabling functional communication within the brain “connectome”. According to the graph theory analysis, the brain network can be investigated as a set of nodes structurally connected by white matter edges. Focusing on event-related fMRI, one of the most widely used methods to study brain activity in migraine patients is to send a controlled painful stimulus to the trigeminal region or to an extra-cephalic region and to analyze the evoked activity of the BOLD signal to the functional MRI. In this scenario, migraine (subtended by a high energy consuming brain) seems to be the evolutionary prices that the human species had to pay to gain a developed and highly connected neocortex and, in turn, a highly performing central nervous system.