Investigating central brain circuits contributing to migraine and pain pathophysiology

偏头痛是50岁以下残疾的主要原因，全球有超过10亿患者。尽管取得了进展，但目前的疗法通常无效，或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至关重要。发作的特征是反复发作的头痛和相关的多感官超敏反应，对光（恐惧症），声音（恐惧症），嗅觉（恐惧症）和触觉（异常性疼痛），这表明丘脑的关键作用。丘脑神经元在不同的调节机制下控制信息流向皮层。这一系列的调节信号可以改变丘脑皮层中继神经元的活动，并提供了一个潜在的基础，状态依赖性（如不吃饭，睡眠中断）偏头痛的易感性。这些丘脑皮层回路在偏头痛患者中功能失调，并且增加的丘脑皮层活动与偏头痛相关的多模态感觉障碍（例如异常疼痛和视觉处理）和皮层过度兴奋有关。为了支持这一点，我们和其他人已经确定了偏头痛患者和实验模型对伤害性和视觉刺激的过度活跃的丘脑反应。此外，抗偏头痛治疗剂在中枢给药时可调节丘脑皮质活动。与此一致，我们最近已经证明，丘脑皮质调制是一个潜在的机制，单脉冲经颅磁刺激的疗效，这是一个既定的神经调节偏头痛的方法。目前的项目旨在确定丘脑在偏头痛相关的多感觉信息的异常处理的作用。该研究预测，感觉信息的异常丘脑门控导致不同的丘脑皮层网络的异常激活，从而引起偏头痛的不同病理学。该项目将使用最先进的病毒追踪技术（0-12个月）在体内绘制多感觉和三叉神经头痛网络之间的相互作用。使用光遗传学/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）模型的组合，该项目将验证其调节的功能后果（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），并在适当的情况下将其转化为临床。学生将发展体内技能，包括手术，光遗传学/化学遗传学，电生理学和行为方法，掌握一些非常理想的专业技能，超越标准实验室程序。

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.