Cortical spreading depression and headache—a closed gap?

Spreading depression (SD), or spreading depolarization, is a slowly propagating, near-complete depolarization wave of neurons and glial cells spreading across the cortex.¹ This phenomenon is also known as cortical spreading depression (CSD). Other than potentially contributing to the underlying pathophysiology of migraine aura, SD is thought to be an intrinsic brain activity causing headache.¹ At the recent 14^th Congress of the European Headache Federation (EHF) held virtually on 29 June – 2 July 2020, Professor Rami Burstein (Harvard University, Boston, USA) provided an overview of the sequence of events occurring between the onset of aura and the activation of nociceptors in his presentation “Bridging the gap between cortical spreading depression and headache.”

From CSD onset to dural macrophage activation

Migraine with aura is thought to be initiated in CSD and can be followed by headache 20–40 minutes later.² However, Prof. Burstein remarked that the headache can, in some cases, follow immediately after the occurrence of CSD. He proceeded to detail the sequence of events leading to headache, starting from the onset of aura in the cortex—within the blood–brain barrier (BBB)—to the activation of nociceptors in the meninges outside of the BBB.

Prof. Burstein then explained that CSD leads to the rapid dilatation and prolonged constriction of pial arteries. This is followed by the complete closure of the paravascular space and the instantaneous activation of pial macrophages after CSD.^3,4 He continued by describing the sequence, stating that dural artery dilatation happens four minutes after CSD, and the plasma protein extravasation co-occurs with dural artery dilatation. Pial, subarachnoid and dural dendritic cell activation occurs 6–12 minutes post-CSD, and dural macrophages are then activated 20 minutes after the CSD.⁴ Furthermore, the close proximity of dural macrophages and dendritic cells to transient receptor potential cation channel subfamily V member 1 (TRPV1)-positive axons supports the role of these immune cells in modulating head pain.⁴

Prof. Burstein finished his detailed explanation by stating that the C‑fiber and wide-dynamic range neuron activation happens 30–45 minutes after CSD occurrence and Aδ-meningeal nociceptor activation, followed by high-threshold trigeminovascular neuron activation, which occurs 30–40 minutes post-CSD. This pathway ultimately leads to what Prof. Burstein described as the delayed release of calcitonin gene‑related peptide (CGRP). In this commonly-observed scenario, headache onset is delayed with respect to the occurrence of aura or CSD.

An alternative scenario

In addition to this sequence, an alternative scenario is also possible, Prof. Burstein noted, one where CSD and the dilatation and constriction of pial arteries can induce immediate C-fiber activation and early CGRP release. In this alternative scenario, headache occurs immediately after or at the same time, as CSD and does not require the aforementioned steps, including dural macrophage activation. Activation of pial macrophages may therefore be more relevant to cases with co-occurring aura and migraine, while dural macrophage activation is more relevant to cases where headache begins 20–30 minutes after aura.⁴ In Prof. Burstein’s opinion, pial artery dilatation and constriction should be enough for the immediate activation of C-fibers in this speculative scenario. However, further investigation on CSD leading to headache is needed.