Arguments against the role of cortical spreading depression in migraine

Abstract

Cortical spreading depression (CSD) is a wave of increased electrocortical activity and vasodilation, followed by sustained decreased activity and prolonged vasoconstriction. Although the discovery of CSD has been ascribed to Leão, rather than vasoconstriction, he only observed a depression of neural activity combined with vasodilation, with much weaker stimulation than used by his followers. There is a longstanding belief that CSD underlies migraine aura, with its positive symptoms such as mosaic patterns and its negative symptoms such as scotoma, and a similar propagation speed and vasoreaction pattern. However, there are many arguments against this theory. CSD is difficult to evoke in man, and electroencephalography (EEG) readings are not flattened during migraine (as opposed to EEG during CSD). Moreover, in contrast to CSD, migraine can occur bilaterally, and is not accompanied by a disrupted blood-brain barrier, increased cerebral metabolism, or cerebral cell swelling. Calcitonin gene-related peptide, which is thought to be characteristic of migraine pain, is increased in the blood from the external jugular vein during migraine in humans, but not during CSD in cats or rats. Moreover, CSD does not explain the appearance of premonitory symptoms or allodynia, long before the actual onset of aura. In addition, there is a variation in the pain mechanisms of migraine and CSD, and in their reaction to transcranial magnetic stimulation and several pharmacologic interventions. Finally, the origin of putative CSD in migraine is currently unknown.

Effect of Non-invasive Vagus Nerve Stimulation on Resting-State Electroencephalography and Laser-Evoked Potentials in Migraine Patients: Mechanistic Insights

“…The potential contribution of basal EEG modulation to improve or resolve a single migraine attack is a matter of debate. A possible interference with the CSD phenomena seems quite speculative because the occurrence of CSD in migraine attacks without aura is debatable ( Ayata, 2010 ; Borgdorff, 2018 ). Alternatively, the possible acute modulation of EEG rhythms may be a sign of the central action of nVNS on a large range of associative cortical areas involved in attentional behavior and descending pain control.…”

“…The possible effect on CSD is difficult to be demonstrated. The scalp EEG showed CSD in patients with aneurismal subarachnoid hemorrhage and hemispheric stroke, as well as in patients suffering from brain trauma, while during migraine aura the critical EEG signal is not flattened ( Drenckhahn et al, 2012 ; Borgdorff, 2018 ). In any case, we included the analysis of nVNS effects on resting state EEG, in the hypothesis that a clear action on the brain rhythms could in some way interfere with the evolution of CSD.…”

“…Based on these animal models and human fMRI evidence, three mechanisms of action may be implicated for the effect of nVNS in treating migraine attacks: a central modulation of the cortical and subcortical sites involved in descending pain modulation, a direct modulation of nociceptive afferents to the trigeminal spinal nucleus, or an inhibiting effect on the bioelectrical activity and possibly on CSD phenomena that lead to trigemino-vascular system activation. This latter hypothesis seems less compelling in the case of migraine attacks without aura, where the existence of the CSD phenomenon is unclear and the resolution of CSD not clinically detectable ( Ayata, 2010 ; Borgdorff, 2018 ).…”

Mitochondrial Migraine: Disentangling the angiopathy paradigm in m.3243A>G patients

“…This is comparable to glutamate induced gap-junctional slow calcium waves in astrocyte syncytium, hypothesized to be responsible for the slowly preceding aura signs. 9…”

“…11 The serotonin release may cause pain and dilatation of the extracerebral arteries (migraine without aura) and in higher concentrations may provoke vasoconstriction and thus being responsible for the slowly preceding aura signs. 9 Distal of the increased endothelial cell volume a decreased shear stress is expected which might lead to decreased mitochondrial homeostasis and induces inflammation (Figure 3). F I G U R E 3 Proposed sequence of the mitochondrial disease migraine cascade.…”