Investigating central brain circuits contributing to migraine and pain pathophysiology

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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.