Translational approaches to study neural networks in migraine and sleep

Sleep and migraine share a common pathophysiological substrate (Holland et al. 2014), that remains to be fully characterised.
We recently demonstrated that migraineurs have poorer sleep quality and altered sleep architecture (Stanyer et al. 2021), in
agreement with a proposed impact of sleep disruption in migraine attack onset (Kelman. 2007). Historically, the brainstem
serotonergic and hypothalamic orexinergic systems are both involved in the regulation of sleep/wake cycles, and they have been
similarly implicated in disorders of arousal, so called NREM parasomnias and migraine (Holland et al. 2006).

NREM parasomnias are undesirable physical or behavioural phenomena that occur during entry into sleep, within sleep, or during
partial arousals from sleep (American Academy of Sleep Medicine, 2005) and include confusional arousals, sleepwalking
(somnambulism), and sleep terrors. They are collectively termed "disorders of arousal" (Broughton, 1968) because of the
autonomic and motor arousal that propels the patient towards partial wakefulness. Most episodes arise from sudden but
incomplete arousal from slow-wave sleep (Jacobson et al., 1965; Kavey et al., 1990; Espa et al., 2000). Episodes are generally
characterized by misperception and relative unresponsiveness to external stimuli, mental confusion and disordered
interoception, automatic behaviours, and variable retrograde amnesia.

Interestingly, both migraine and parasomnias have been linked with diverse psychiatric conditions (Messina et al. 2018), all of
which have been linked to dysregulation of interoceptive monitoring by the brain. Modern correlative studies have further
suggested links between cardiac and respiratory changes and affect regulation, including correlations between cardiac
interoception with anxiety and functional alterations in the insular cortex, with central roles in the processing of physiological
signals and the regulation of emotions. Importantly, the insular cortex has been similarly shown as one of the main subcortical
hubs in migraine (Borsook et al. 2019) and parasomnias (Flamand et al. 2018).

Currently, little is known about macroscopic and microscopic sleep structure in both migraine and parasomnias, and their
relationship with the serotonergic and orexinergic systems, hubs of activity such as the insular cortex, and the emergence of other
comorbid psychiatric and cognitive symptoms.

Using clinically-translational EEG and potentially subsequent imaging, this project will characterise brain-activity during
sleep/wake in preclinical animals. We will then explore alterations in validated preclinical models of migraine and transgenic mice
harbouring human mutations that alter sleep physiology. Exploring a set of hypothesised mechanisms that may lead to increased
migraine susceptibility and disorders or arousal (Phase-1). The findings will contribute towards further modelling of the
pathological neural-circuitry, using precise targeting of brain regions and cellular subpopulations by chemo- and/or opto-genetics
that can be interrogated using invasive (e.g. miniscope/electrophysiology) and non-invasive (e.g. fMRI) approaches, as
appropriate (Phase-2).

The final, clinical phase (Phase-3), will build on this, whilst focusing on sleep disturbance/parasomnias, as an overlooked
prodromal symptom of migraine, which may provide an exciting opportunity for therapeutic intervention. With a particular focus
on the insular cortex as a shared neural hub using neurostimulation/high-density-fMR-EEG imaging will be used to explore and
define its role in memory and sleep deficits in patients with NREM parasomnia and migraine.