Novel itch reduction strategies focusing on pleasant touch brain pathways

瘙痒是一种全球现象，据报告有20-27%的成年人存在。痒会产生挠痒的欲望，这是一种天生的行为反应，在进化上很有用，因为它有助于清除昆虫，因此被认为是愉快的。然而，在病理性瘙痒条件下，随着时间的推移，抓挠反应会引起巨大的痛苦并加剧病情。除了增加痛苦，慢性瘙痒还与其他负面结果有关，如心理健康状况不佳、睡眠不足和情绪低落。目前，药物治疗瘙痒可能会导致负面的副作用，如局部皮质类固醇停药，当长时间使用时，可能会比瘙痒本身更痛苦。还有一个额外的问题是，很大一部分人对治疗有抗药性，导致他们的瘙痒持续存在。因此，需要发展对非药物治疗的需求。皮肤包含几类神经纤维，它们介导躯体感觉的可分离方面。低阈值机械感受器（LTMs）（髓鞘a - β和a - δ传入）向脊髓发送关于无害触摸的快速信息。无髓鞘、传导缓慢的c -纤维传入神经传递疼痛和瘙痒的情感特性。c -触觉（CT）传入为触觉的愉悦特性编码。人们早就知道这些体感受体以一种封闭的方式相互作用。例如，ltm的激活可以减轻疼痛（门控理论Melzack & Wall， 1965），电刺激引起的体感诱发电位可以被另一种体感刺激减少（Jones, 1981）。ct编码一种特定类型的触摸，称为愉快的触摸，这是一种缓慢，温柔，爱抚般的抚摸，在1-10cm/s的速度范围内完成，最佳反应为3cm/s。情感触摸的疼痛减轻效果已在成人和婴儿中得到证实。最近发表的关于大脑对实验诱导的瘙痒反应的荟萃分析（Roberts等人，2019）表明，瘙痒确实激活了与愉快触摸产生的重叠但可分离的大脑区域（例如Morris， 2016）。也有人提出，愉快的触摸打开了通往初级体感皮层的大门（Shirato et al., 2018）。因此，CT介导的愉悦触觉为慢性皮肤病的非药物治疗提供了探索途径（Lloyd等，2015）。关于瘙痒的内源性下行控制知之甚少。然而，最近的功能性磁共振成像（fMRI）实验表明，在执行功能任务中分散瘙痒并不能降低瘙痒的严重程度（Stumpf等人，2017），而疼痛可以诱导瘙痒的中枢下行调节（Andersen等人，2017）。综上所述，这表明体感系统负荷的增加可以调节瘙痒强度。这还有待于探索如何使用舒适的触摸。本博士旨在利用神经成像技术描述对瘙痒的心理和神经心理反应，以及瘙痒和愉快触摸之间的相互作用：-证明实验诱导皮肤瘙痒的主观体验是通过刺激愉快触摸的ct来调节的。-阐明愉快的触摸调节瘙痒相关大脑活动的大脑结构/途径，以确定减少瘙痒的新策略。这些目标将通过行为实验和脑电图等电生理技术来解决。据推测，通过愉快的触摸激活的ct将调节瘙痒的主观体验，与体感门控一致，这将在脑电图波段功率中观察到，以及调节与瘙痒相关的大脑活动。我们的目标是推进我们对瘙痒和愉快触摸的基础生物科学的理解，以改善那些皮肤刺激的人一生的健康，减少医疗干预的需要

Itch is a global phenomenon reported by 20-27% of adults. Itch produces the desire to scratch, an innate behavioural response that is evolutionarily useful as it helps to remove insects and is therefore perceived as pleasurable. However, in pathological itch conditions the scratch response over time causes immense suffering and exacerbates the condition. In addition to increased suffering, chronic itch is also associated with other negative outcomes such as poor mental health, lack of sleep and lower reported mood. Currently, pharmaceutical itch treatments can result in negative side-effects such as topical corticosteroid withdrawal which can become more painful than the itch itself when used for a prolonged period. There is also the additional issue that a significant percentage of individuals are treatment resistant, leading their itch to persist. As a result, the need for non-pharmaceutical treatments needs to be developed. The skin contains several classes of nerve fibres that mediate dissociable aspects of somatosensation. Low threshold mechanoreceptors (LTMs) (myelinated A-beta and A-delta afferents) send rapid information to the spinal cord about innocuous touch. Unmyelinated, slow conducting C-fibre afferents convey emotional properties of pain and itch. C-tactile (CT) afferents encode for the pleasurable properties of touch. These somatosensory receptors have long been known to interact in a gated fashion. E.g. activation of LTMs can attenuate pain (gate control theory Melzack & Wall, 1965), and somatosensory evoked potentials evoked by electrical stimuli can be reduced by another somatosensory stimulus (Jones, 1981). CTs encode for a specific type of touch known pleasant touch which is a slow, gentle, caress-like stroke done within the velocity range of 1-10cm/s with optimal responses at 3cm/s. The pain-attenuating effects of affective touch have been demonstrated in both adults and infants. Recently published meta-analyses of brain responses to experimentally induced itch (Roberts et al., 2019) suggest that itch reliably activates overlapping, but dissociable brain regions to those produced by pleasant touch (e.g Morris, 2016). It has also been proposed that pleasant touch opens the gate to the primary somatosensory cortex (Shirato et al., 2018). Thus, CT mediated pleasant touch provides an avenue of exploration for non-pharmacological treatment of chronic skin conditions (Lloyd et al., 2015).Little is known about endogenous descending control of itch. However, recent functional Magnetic Resonance Imaging (fMRI) experiments suggest that distraction from itch with an executive function task does not reduce itch severity (Stumpf et al., 2017), whereas pain can induce central descending modulation of itch (Andersen et al., 2017). Taken together this suggests that increased load on the somatosensory system can modulate itch intensity. This has yet to be explored using pleasant touch.This PhD aims to characterise the psychological and neuropsychological responses to itch, and the interaction between itch and pleasant touch using neuroimaging techniques: - Demonstrate that the subjective experience of experimentally induced itch on the skin is modulated by stimulating CTs with pleasant touch.- Elucidate the brain architecture/pathways via which pleasant touch modulates itch-related brain activity to identify novel strategies to reduce itch.These objectives will be addressed using behavioural experiments as well as electrophysiological techniques such as electroencephalography. It is hypothesised that activation of CTs by pleasant touch will modulate the subjective experience of itch, in line with somatosensory gating and this will be observable in EEG band power, as well as modulating itch-related brain activity.We aim to advance our understanding of fundamental bioscience of itch and pleasant touch, to improve health across the lifetime for those with skin irritation, reducing the need for medical inter