Cortical mechanisms in migraine

Abstract

Migraine is the second most prevalent disorder in the world; yet, its underlying mechanisms are still poorly understood. Cumulative studies have revealed pivotal roles of cerebral cortex in the initiation, propagation, and termination of migraine attacks as well as the interictal phase. Investigation of basic mechanisms of the cortex in migraine not only brings insight into the underlying pathophysiology but also provides the basis for designing novel treatments. We aim to summarize the current research literatures and give a brief overview of the cortex and its role in migraine, including the basic structure and function; structural, functional, and biochemical neuroimaging; migraine-related genes; and theories related to cortex in migraine pathophysiology. We propose that long-term plasticity of synaptic transmission in the cortex encodes migraine.

Keywords: cerebral cortex; cortical spreading depression; long-term potentiation; migraine; pathophysiology.

Figure 1.

Pain pathways of migraine in the brain. Peripheral sensory information is first collected by the trigeminal nerve to the trigeminal ganglia (first order neurons in the trigeminal system). Then the trigeminocervical complex, including the trigeminal subnucleus caudalis (TNC) and dorsal horn of the first cervical segments, are the second order central nervous system relay in the trigeminal system, receive input from trigeminal ganglia. Thalamus (Thal.), as the third-order relay in the trigeminal system, receives direct projection from TNC (blue arrows) and modulate the activity of pain-related cortex, such as anterior cingulate cortex (ACC), insula cortex (IC), and primary/secondary somatosensory cortex (S1/S2). Moreover, sensory inputs from periphery are relayed by TNC neurons and further projected to affective/motivational circuits through parabrachial nucleus (PBN, red arrows) and cerebellar cortex (green arrows). A1, primary auditory cortex; Amyg, amygdala; PFC, prefrontal cortex; V1, primary visual cortex.

Figure 2.

Synaptic model for long-term potentiation (LTP) in cortex. The hyperexcitability of presynaptic neurons leads to increased release of glutamate, which combines with postsynaptic NMDA receptors (NMDARs), and causes increased postsynaptic Ca²⁺ in dendritic cells. Ca²⁺ serves as an important intracellular signal for triggering a series of biochemical events that contribute to the expression of AMPA receptors (AMPAR) and LTP. Under migraine conditions, calcitonin gene-related peptide (CGRP) might serve as another important signaling molecule for activating adenylyl cyclase 1 (AC1) and contributing to the expression of LTP. Furthermore, interneurons can inhibit or disinhibit the activity of postsynaptic neurons by releasing γ-aminobutyric acid (GABA). GABA_AR, γ-aminobutyric acid type A receptor; cAMP, cyclic AMP; CaM, calmodulin; PKA, protein kinase A; MAPK, mitogen-activated protein kinase; CaMKIV, Ca²⁺-calmodulin-dependent protein kinase IV; CREB, cAMP response element-binding protein; CRE, cAMP response element.