Translational approaches to study neural networks in migraine and sleep

睡眠和偏头痛具有共同的病理生理学基础（Holland et al. 2014），其特征仍有待充分表征。我们最近证明，偏头痛患者的睡眠质量较差，睡眠结构改变（Stanyer et al. 2021），这与偏头痛发作时睡眠中断的影响（Kelman. 2007年）。从历史上看，脑干多巴胺能和下丘脑食欲素能系统都参与睡眠/觉醒周期的调节，并且它们类似地涉及觉醒障碍，即所谓的NREM睡眠异常和偏头痛（Holland等人，2006）。NREM异态睡眠是在进入睡眠期间、睡眠中或从睡眠中部分觉醒期间发生的不良身体或行为现象（美国睡眠医学学会，2005），并且包括混乱觉醒、梦游（梦游症）和睡眠恐怖。它们统称为“觉醒障碍”（布劳顿，1968），因为自主和运动觉醒促使患者部分觉醒。大多数发作是由慢波睡眠的突然但不完全的唤醒引起的（Jacobson等人，1965; Kavey等人，1990; Espa等人，2000年）。癫痫通常以错误感知和对外部刺激的相对无反应、精神混乱和紊乱的内感受、自动行为和可变的逆行性遗忘为特征。有趣的是，偏头痛和异睡症都与各种精神疾病有关（Messina et al. 2018），所有这些疾病都与大脑内感受性监测失调有关。现代相关研究进一步表明心脏和呼吸变化与情绪调节之间的联系，包括心脏内感受与焦虑和岛叶皮层功能改变之间的相关性，在生理信号处理和情绪调节中发挥核心作用。重要的是，岛叶皮质也被类似地显示为偏头痛（Borsook et al. 2019）和异眠症（Flamand et al. 2018）的主要皮质下枢纽之一。目前，对偏头痛和异睡症的宏观和微观睡眠结构及其与肾上腺素能和食欲素能系统、岛叶皮层等活动中心以及其他共病精神和认知症状的出现的关系知之甚少。使用临床翻译EEG和潜在的后续成像，该项目将在临床前动物的睡眠/觉醒期间观察大脑活动。然后，我们将探索经验证的偏头痛和转基因小鼠的临床前模型中的改变，这些模型含有改变睡眠生理学的人类突变。探索一组可能导致偏头痛易感性和障碍或觉醒增加的假设机制（第1阶段）。这些发现将有助于进一步模拟病理神经回路，通过化学和/或光遗传学精确靶向脑区域和细胞亚群，可以酌情使用侵入性（例如微型镜/电生理学）和非侵入性（例如fMRI）方法进行询问（第2阶段）。最后一个临床阶段（3期）将以此为基础，同时关注睡眠障碍/异眠症，作为偏头痛的一种被忽视的前驱症状，这可能为治疗干预提供一个令人兴奋的机会。特别关注岛叶皮层作为使用神经刺激/高密度fMR-EEG成像的共享神经中枢，将用于探索和定义其在NREM睡眠异常和偏头痛患者的记忆和睡眠缺陷中的作用。

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.