Cortical Mechanisms of Single-Pulse Transcranial Magnetic Stimulation in Migraine

DOI: https://doi.org/10.1007/s13311-020-00879-6

Abstract-Summary Single-pulse transcranial magnetic stimulation (sTMS) of the occipital cortex is an effective migraine treatment.

Its mechanism of action and cortical effects of sTMS in migraine are yet to be

elucidated.

Pre-treatment with sTMS, however, significantly affected some characteristics of

the cortical spreading depression (CSD) wave, the correlate of migraine aura.

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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.

Extended: Single-pulse transcranial magnetic stimulation (sTMS) has been used

in clinical neurology for decades.

Introduction Recent post-market studies suggested that sTMS may be an effective, well-tolerated treatment option for migraine prevention [485, 486].

How sTMS in migraine interferes with cortical neurons in the visual cortex and

with other neuronal networks has not been clearly defined.

Clinical experience with sTMS-treated migraine patients indicates that these patients do not report the induction of phosphenes while, when the sTMS device is positioned over the motor cortex, it does not elicit any muscle response.

A previous study showed that sTMS blocks mechanical and chemically induced

CSD in animal models of migraine.

The actions of the sTMS parameters used clinically in migraine treatment on

cortical activity have not been previously examined.

We aimed to investigate the cortical effects of sTMS using the actual migraine

treatment configuration.

Methods Baseline recordings of the GCaMP signal were taken from the visual cortex for 5 min before a sTMS pulse (~ 1.1 T) was applied caudal to the cortical window.

Baseline GCaMP signal activity was recorded through the cortical window for

15 min before two 1.1-T sTMS pulses were applied to the visual cortex.

To assess the actions of sTMS on ongoing cortical activity, a stable baseline of spontaneous activity was recorded for at least 20  min from neurons in the visual cortex.

A stable baseline (at least 5 min) of l-glutamate-evoked activity was recorded in the presence of either bicuculline or saclofen and applied randomly, before two sTMS pulses (1.1 T or 0 T) were applied to the visual cortex.

Sixty minutes later, two sTMS pulses (~ 1.1 T) were delivered over the visual cortex and induction of CSD using the same baseline stimulating parameters was attempted every 30 min up to 2 h post-sTMS stimulation.

Results To assess if the sTMS parameters used in the migraine treatment (~ 1.1 T) are actually 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.

To assess the potential actions of sTMS on CSD once initiated following treat- ment with active sTMS stimulation, GCaMP fluorescence was recorded in Snap25-2A-GCaMP6s-D mice.

Only neurons that demonstrated stable spontaneous activity under baseline con-

ditions were selected for treatment with two consecutive sTMS pulses.

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A total of 57 (in 25 animals) and 54 (in 20 animals) cortical neurons responding to l-glutamate microiontophoresis were recorded in the sham-treated (2 T × 0 T) and sTMS-treated (2 T × 1.1 T) groups, respectively.

In the remaining animals at 2 h post-sTMS, parameters for cortical stimulation

were increased until a CSD wave was elicited (median, 2400; IQ, 1400–3200).

Discussion These mechanisms also explain our findings that sTMS increased the threshold of induction of cortical spreading depression (CSD), a well-accepted animal model of migraine aura, given that sTMS had no effect in this model in the presence of GABA antagonists.

The sTMS-induced reduction of spontaneous and glutamatergic cortical activity

found in our study may explain the sTMS actions on blocking CSD [487].

Using a different stimulating paradigm and a larger coil, Murphy et al. [488] sug- gested that sTMS activates inhibitory GABA fibres in the upper cortical layers which, in turn, inhibit the activity of dendritic pyramidal neurons in layer V.  By blocking GABAB receptors, they were able to prevent inhibitory effects of sTMS on the somatosensory cortex.

The results of this study demonstrate the acute cortical inhibitory actions of sTMS with parameters comparable to those that are effective in migraine treatment.

Acknowledgement A machine generated summary based on the work of Lloyd, Joseph O.; Chisholm, Kim I.; Oehle, Beatrice; Jones, Martyn G.; Okine, Bright N.; AL-Kaisy, Adnan; Lambru, Giorgio; McMahon, Stephen B.; Andreou, Anna P. 2020 in Neurotherapeutics.

The role of left prefrontal transcranial magnetic stimulation in episodic migraine prophylaxis