Investigating central brain circuits contributing to migraine and pain pathophysiology

偏头痛是50岁以下人群致残的主要原因，全球有超过10亿患者。尽管取得了进展，但目前的治疗方法通常是无效的，或者在大多数情况下耐受性差。因此，为了开发更有效的治疗方法，详细了解偏头痛的潜在机制是必不可少的。发作的特征是反复发作的头痛和相关的对光（恐光）、声音（恐音）、气味（恐渗透）和触觉（异常性疼痛）的多感官超敏反应，这表明丘脑起着关键作用。丘脑神经元通过多种调节机制控制信息流向皮层。这一系列调节信号可以改变丘脑皮质中继神经元的活动，并为状态依赖性（如不吃饭、睡眠中断）偏头痛易感性提供了潜在的基础。偏头痛患者的这些丘脑皮质回路功能失调，丘脑皮质活动增加与偏头痛相关的多模态感觉障碍（如异常疼痛和视觉处理）和皮质亢进有关。为了支持这一点，我们和其他人已经在偏头痛患者和实验模型中发现了对伤害性和视觉刺激的过度活跃的丘脑反应。此外，抗偏头痛治疗可以调节丘脑皮质活动时，集中施用。与此一致，我们最近证明了丘脑皮质调节是单脉冲经颅磁刺激的潜在机制，这是一种已建立的偏头痛神经调节方法。目前的项目旨在确定丘脑在偏头痛相关的多感觉信息异常处理中的作用。它预测感觉信息的异常丘脑门控导致不同丘脑皮质网络的异常激活，从而引起偏头痛的不同症状。该项目将利用最先进的病毒追踪技术绘制体内多感官和三叉神经头部疼痛网络之间的相互作用图（0-12个月）。将光遗传学/化学遗传学方法与偏头痛的临床前行为和电生理（丘脑多通道电极记录）模型相结合，该项目将描述其调节的功能后果（10-24个月）。最后，我们将探索新的治疗靶点来调节这些功能失调的网络（24-36个月），并在适当的时候将这些靶点转化为临床。学生将发展包括外科、光遗传学/化学遗传学、电生理学和行为方法在内的体内技能，掌握标准实验室程序之外的一些非常理想的专业技能。

Migraine is the leading cause of disability in the under 50's with over one billion sufferers globally. Despite advances, current therapies are routinely ineffective, or poorly tolerated in most cases. Therefore, to develop more effective therapies, a detailed understanding of the mechanisms underlying migraine is essential. Attacks are characterised by repeated bouts of headache and associated multisensory hypersensitivity to light (photophobia), sound (phonophobia), smell (osmophobia) and touch (allodynia) that indicate a key role for the thalamus.Thalamic neurons control the flow of information to the cortex under diverse regulatory mechanisms. This array of modulatory signalling can alter the activity of thalamocortical relay neurons and provides a potential basis for state-dependent (e.g. skipping meals, disrupted sleep) migraine susceptibility. These thalamocortical circuits are dysfunctional in migraine patients and increased thalamocortical activity has been linked to migraine-related multimodal sensory disturbances (e.g. abnormal pain and visual processing) and cortical hyperexcitability. In support of this, we and others have identified hyperactive thalamic responses to nociceptive and visual stimuli in migraineurs and experimental models. Further, anti-migraine therapeutics can modulate thalamocortical activity when administered centrally. In agreement, we have recently demonstrated that thalamocortical modulation is a potential mechanism for the efficacy of single pulse transcranial magnetic stimulation that is an established neuromodulatory approach for migraine.The current project aims to determine the role of the thalamus in the abnormal processing of migraine-related multisensory information. It predicts that abnormal thalamic gating of sensory information results in aberrant activation of diverse thalamocortical networks giving rise to the diverse symptomatology of migraine.The project will map the interactions between multisensory and trigeminal head pain networks in-vivo using state of the art viral tracing techniques (0-12 months). Using a combination of optogenetic/chemogenetic approaches with preclinical behavioural and electrophysiological (thalamic multi-channel electrode recording) models of migraine, the project will characterise the functional consequences of their modulation (10-24 months). Finally, we will explore novel therapeutic targets to modulate these dysfunctional networks (24-36 months) and where appropriate these will be translated into the clinic. The student will develop in-vivo skills including surgical, optogenetic/chemogenetic, electrophysiology and behavioural approaches, mastering a number of highly desirable specialist skills above and beyond standard laboratory procedures.