Project #3 In vivo microneurography recordings of sensory afferents

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Migraine, one of the most common primary headache disorders, affects 1 in 4 US households. This complex neurologic disorder is mediated in part by alterations in trigeminal somatosensation, which manifests as head/fa- cial pain and/or trigeminal allodynia. Effective treatments for migraine are still limited, and our knowledge about human trigeminal system at baseline and migraine conditions are sparse. In response to RFA-NS-22-018, HEAL Initiative: Discovery and Functional Evaluation of Human Pain-associated Genes & Cells, we propose to form the Penn Human Precision Pain Center (Penn HPPC) to elucidate molecular, cellular, epigenetic, and physiological profiles of human trigeminal ganglion (TG) sensory neurons at baseline and migraine conditions. The Penn HPPC will be composed of Penn and international investigators with multidisciplinary expertise. The PI, two MPIs, and two co-Is are currently collaborating on a single-soma deep RNA-seq of human dorsal root ganglion (DRG) neuron project, which form a strong foundation for this application. Specifically, the Penn HPPC will contain three cores and perform three projects. Project 3 will be led by the PI, Dr. Olausson, and the Co- I, Dr. Nagi, who are internationally renowned human sensory afferent electrophysiologists, and supported by Dr. Li, PI of the data core. In aim 1, we will recruit migraine patients and control subjects to conduct pain question- naires, somatosensory tests, and blink reflex to evaluate their sensory and motor functions. In aim 2, we will perform In vivo ultrasound-guided microneurography recordings of trigeminal and spinal sensory afferents with these migraine patients and controls, using a newly developed stimulus protocol. Our ultrasound guided micro- neurography technique greatly improves the experimental yield. The new stimulus protocol is designed accord- ing to the human DRG neuron single-soma deep RNA-seq data, allowing for sophisticated characterizations of primary sensory afferents and comparison between migraine patients and controls. In short, the anticipated re- sults from project 3, the electrophysiological and sensory results of migraineurs and controls, will generate novel functional datasets regarding human primary sensory afferents at baseline and migraine conditions. Together with results from projects 1 and 2, our proposed Penn HPPC will generate comprehensive, multi-dimensional molecular and functional datasets of human TGs at baseline and migraine conditions.