Translational approaches to study neural networks in migraine and sleep

睡眠和偏头痛有一个共同的病理生理基础（Holland et al. 2014），这仍有待充分表征。我们最近证明偏头痛患者睡眠质量较差，睡眠结构改变（Stanyer et al. 2021），这与提出的睡眠中断对偏头痛发作的影响一致（Kelman. 2007）。从历史上看，脑干的5 -羟色胺能系统和下丘脑的食欲能系统都参与睡眠/觉醒周期的调节，它们也同样涉及觉醒障碍，即所谓的NREM睡眠异常和偏头痛（Holland et al. 2006）。非快速眼动睡眠异常是在进入睡眠、睡眠中或睡眠部分觉醒期间发生的不受欢迎的身体或行为现象（美国睡眠医学学会，2005年），包括混乱觉醒、梦游（梦游症）和睡眠恐怖。它们被统称为“觉醒障碍”（Broughton, 1968），因为自主神经和运动觉醒会将患者推向部分清醒。大多数发作源于慢波睡眠中突然但不完全的觉醒（Jacobson et al., 1965; Kavey et al., 1990; Espa et al., 2000）。发作的一般特征是误解和对外部刺激的相对无反应，精神混乱和内感受障碍，自动行为和可变逆行性遗忘。有趣的是，偏头痛和睡眠异常都与多种精神疾病有关（Messina et al. 2018），所有这些疾病都与大脑的内感受性监测失调有关。现代相关研究进一步表明，心脏和呼吸变化与影响调节之间存在联系，包括心脏内感受与焦虑和岛叶皮质功能改变之间的相关性，在生理信号处理和情绪调节中起核心作用。重要的是，岛叶皮层同样被证明是偏头痛（Borsook et al. 2019）和睡眠异常（Flamand et al. 2018）的主要皮质下中枢之一。目前，对于偏头痛和睡眠异常的宏观和微观睡眠结构，以及它们与血清素能和食欲能系统、活动中枢（如岛皮质）以及其他精神和认知共病症状的关系知之甚少。利用临床转化脑电图和潜在的后续成像，该项目将表征临床前动物睡眠/清醒期间的大脑活动。然后，我们将在偏头痛的临床前模型和转基因小鼠中探索改变，这些小鼠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紊乱或觉醒增加的假设机制（第一阶段）。这些发现将有助于进一步建立病理神经回路模型，通过化学和/或光学遗传学精确定位大脑区域和细胞亚群，这些区域和细胞亚群可以酌情使用侵入性（例如显微镜/电生理学）和非侵入性（例如功能磁共振成像）方法进行查询（第二阶段）。最后的临床阶段（第三阶段）将以此为基础，同时关注睡眠障碍/睡眠异常，作为偏头痛的一个被忽视的前驱症状，这可能为治疗干预提供一个令人兴奋的机会。特别关注作为共享神经中枢的岛叶皮层，将使用神经刺激/高密度fmr - eeg成像来探索和定义其在非快速眼动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.