Updated review on the link between cortical spreading depression and headache disorders

ABSTRACT

Introduction: Experimental animal studies have revealed mechanisms that link cortical spreading depression (CSD) to the trigeminal activation mediating lateralized headache. However, conventional CSD as seen in lissencephalic brain is insufficient to explain some clinical features of aura and migraine headache.

Areas covered: The importance of CSD in headache development including dysfunction of the thalamocortical network, neuroinflammation, calcitonin gene-related peptide, transgenic models, and the role of CSD in migraine triggers, treatment options, neuromodulation, and future directions are reviewed.

Expert opinion: The conventional understanding of CSD marching across the hemisphere is invalid in gyrencephalic brains. Thalamocortical dysfunction and interruption of functional cortical network systems by CSD may provide alternative explanations for clinical manifestations of migraine phases including aura. Not all drugs showing CSD blocking properties in lissencephalic brains have efficacy in migraine headache and monoclonal antibodies against CGRP ligand/receptors which are effective in migraine treatment, have no impact on aura in humans or CSD properties in rodents. Functional networks and molecular mechanisms mediating and amplifying the effects of limited CSD in migraine brain remain to be investigated to define new targets.

KEYWORDS:

• Cortical spreading depression
• migraine
• aura
• headache
• thalamocortical dysfunction
• brain networks
• treatment targets
• calcitonin gene-related peptide
• transcranial magnetic stimulation
• vagal nerve stimulation

Article highlights

• Canonical cortical spreading depression (CSD) as seen in lissencephalic brain is inadequate to explain some of the clinical features of aura and migraine.

• Alternative views of considering CSD as a tool that interfere with thalamocortical circuit, cortical hubs and large-scale functional brain networks, may help us gain a better insight into aura and migraine pathophysiology.

• New targets in migraine therapy may include stimulation techniques to reset altered local circuits and large-scale brain networks, cholinergic modulation and treatments targeting glio-vascular dysfunction including insufficient energy metabolism and inflammation.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.