The Neural Mechanisms of Sleep and Migraine

Student thesis: Doctoral ThesisDoctor of Philosophy

Abstract

Whilst a bidirectional relationship between sleep and migraine has long been postulated, this remains mainly speculative, and the underlying neural mechanisms remain to be determined. In this thesis we sought to explore this with clinical and preclinical methodologies. It was hypothesised that disrupted sleep-wake and nociception-regulating neural networks including key brainstem and diencephalic structures alter the thresholds for attack initiation and increase migraine susceptibility.

Firstly, we used a meta-analytic approach to determine whether migraine patients have altered sleep, identifying that they have poorer subjective sleep quality and altered sleep physiology including reduced rapid-eye-movement sleep, compared to healthy controls. By collating data from users of the Migraine Buddy application (Healint Ltd.) and conducting Bayesian regression models we explored whether changes in sleep were predictors of an attack and conversely whether experiencing an attack would predict changes in subsequent sleep. We determined that interrupted sleep and deviations from typical sleep were potential predictors of a next day migraine attack but having an attack did not predict sleep duration.

Secondly, we utilised mouse models of sleep deprivation and demonstrated that this led to orofacial mechanical allodynia - a commonly reported migraine phenotype indicative of sensitisation of the trigeminovascular system. Mechanistic insight was provided in that orexin-A, a hypothalamic arousal-promoting peptide which stabilises sleep-wake transitions reversed this phenotype.

Finally, we explored whether familial natural short sleepers (FNSS) which are reported to have increased orexin expression, are less susceptible to migraine-related phenotypes using a transgenic mouse line harbouring the P384R mutation in the hDEC2 gene. We observed no significant differences in migraine-related phenotypes at baseline, however, when exposed to a clinical migraine trigger (nitroglycerin) FNSS mice demonstrated reduced orofacial hypersensitivity and photophobia, indicative of decreased migraine susceptibility. FNSS also displayed alterations in metabolites underlying energy metabolism and oxidative stress, suggesting a potential link between metabolism and headache pathophysiology.

Taken together, the data in this thesis has shed light on the relationship between sleep and migraine, highlighting alterations in sleep as a potential precipitant of migraine attacks, and identifying genetic mechanisms underlying sleep regulation which may curtail migraine development, as well as possible therapeutic targets based on the orexinergic system. Although further work is needed to fully understand this neural basis, this has promising clinical implications and has furthered our understanding of migraine pathophysiology.
Date of Award1 Dec 2023
Original languageEnglish
Awarding Institution
  • King's College London
SupervisorPhilip Holland (Supervisor) & Jan Hoffmann (Supervisor)

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