Cortical Mechanisms of Single-Pulse Transcranial Magnetic Stimulation in Migraine

Joseph O Lloyd,Adnan Al-Kaisy,Martyn G Jones,Anna P Andreou,Stephen B Mcmahon,Beatrice Oehle,Giorgio Lambru,Kim I Chisholm,Bright N Okine

doi:10.1007/s13311-020-00879-6

Abstract

Single-pulse transcranial magnetic stimulation (sTMS) of the occipital cortex is an effective migraine treatment. However, its mechanism of action and cortical effects of sTMS in migraine are yet to be elucidated. Using calcium imaging and GCaMP-expressing mice, sTMS did not depolarise neurons and had no effect on vascular tone. Pre-treatment with sTMS, however, significantly affected some characteristics of the cortical spreading depression (CSD) wave, the correlate of migraine aura. sTMS inhibited spontaneous neuronal firing in the visual cortex in a dose-dependent manner and attenuated l-glutamate-evoked firing, but not in the presence of GABAA/B antagonists. In the CSD model, sTMS increased the CSD electrical threshold, but not in the presence of GABAA/B antagonists. We first report here that sTMS at intensities similar to those used in the treatment of migraine, unlike traditional sTMS applied in other neurological fields, does not excite cortical neurons but it reduces spontaneous cortical neuronal activity and suppresses the migraine aura biological substrate, potentially by interacting with GABAergic circuits.

Highlights

Migraine is a common [1], highly disabling [2], primary headache condition, characterised by debilitating, long-lasting headaches, associated with sensory symptoms [3]
To assess if the Single-pulse transcranial magnetic stimulation (sTMS) parameters used in the migraine treatment (~ 1.1 T) are exciting cortical neurons acutely, sTMS at 1.1 T (600 V) was applied over the visual cortex of Snap25-2A-GCaMP6s-D mice while GCaMP fluorescence was recorded. sTMS had no effect on GCaMP fluorescence (p = 0.134; Fig. 1C–E)
To assess the potential actions of sTMS on superficial blood vessels, the fluorescent dye dextran was injected in C57BL/6 mice. sTMS at 1.1 T was applied over the visual cortex of mice while dextran fluorescence was recorded

Summary

Introduction

Migraine is a common [1], highly disabling [2], primary headache condition, characterised by debilitating, long-lasting headaches, associated with sensory symptoms [3]. The hypothalamus is suggested to play a crucial role in attack initiation, the cortex has been highlighted in a recent fMRI study as an area. Thomas’s NHS Foundation Trust, King’s Health Partners, London, UK 5 Headache Centre, Guy’s and St Thomas’s NHS Foundation Trust, King’s Health Partners, London, UK with an important role in migraine initiation [5]. Electrophysiological studies have shown altered cortical activity in the ictal and pre-ictal phases, within the occipital cortex [6, 7]. Migraine aura is generally considered to be due to a wave of cortical spreading depression (CSD), emanating from the occipital visual cortex [8]. Work in animal models of migraine suggests that CSD may give rise to migraine headache through peripheral or central mechanisms, or both [9,10,11]

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