Investigations of mode of action of single pulse Transcranial Magnetic Stimulation (sTMS) in animal models and effectiveness in migraine patients

Student thesis: Doctoral ThesisDoctor of Philosophy


Migraine is the 6th most common cause of disability worldwide with high socio-economic and personal impacts. More than just a headache, it presents with nausea, vomiting, photophobia and phonophobia. Around 30% of patients also experience aura, a transient neurological disturbance, usually preceding the headache phase of the migraine. The underlying physiology of migraine aura is thought to be a spreading wave of cortical spreading depression (CSD).
Neuromodulation techniques have been suggested to hold some promise in the acute and preventive treatment of migraine. One potential neuromodulation treatment is the single-pulse transcranial magnetic stimulation (sTMS). sTMS is a non-invasive neuromodulation treatment, that uses magnetic pulses across the scalp and skull to induce weak electrical currents in the underlying cortical tissue. sTMS has previously been shown to be a successful clinical treatment for patients with migraine with aura, as an acute treatment producing an effective reduction in pain scores for up to 48 hours post-treatment and as a preventative treatment reducing headache days after use for 3 months. Further post-market analysis studies have shown its efficacy in the prevention of migraine. In experimental migraine models, sTMS has also successfully blocked chemical and mechanically induced cortical CSD in vivo, however, the precise mechanism by which sTMS causes this effect remains unclear.
Results from this study illustrate that acute application sTMS modulated activity of the cortex it was directly applied to. sTMS causes inhibition of spontaneous and glutamate induced cortical neuronal activity. sTMS also alters activity of cortical spreading depression, increasing the threshold of activation and altering properties of the wave once initiated. The observations suggest the modulation of excitatory cortical neurons via the recruitment of inhibitory GABAergic systems. sTMS’ effect on glutamate activity and CSD threshold is negated with the use of GABA antagonists. These finding provide a better understanding for how sTMS acts on the cortex to achieve an acute reduction in headache pain. Inhibiting activity within the cortex also has secondary effect on cortically connected brain structures causing reduced activity in the thalamus and hypothalamus. Reducing thalamic activity may disrupt incoming trigeminal spinal signals that drive a migraine attack. These acute effects on the cortex and thalamus accumulate with long term application, with implications for how sTMS is able to act as a preventative treatment. Long term cortical application of sTMS also does not appear to cause sensitisation of the TCC. This would suggest that prolonged use would not develop into a peripheral sensitisation equivalent to medication overuse headache.
In conclusion, this thesis suggests that sTMS can be an effective preventive treatment for a subset of migraine patients. Its mechanisms of action involve acute and long-term interactions with cortical activity, in particular with GABAergic circuits, as well as direct or indirect interactions with subcortical nuclei that are key in migraine pathophysiology.
Date of Award1 Sept 2021
Original languageEnglish
Awarding Institution
  • King's College London
SupervisorAnna Andreou (Supervisor) & Stephen McMahon (Supervisor)

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