Novel itch reduction strategies focusing on pleasant touch brain pathways

瘙痒是一种全球性现象，有20-27%的成年人报告。瘙痒产生了抓挠的欲望，这是一种天生的行为反应，在进化上是有用的，因为它有助于消除昆虫，因此被认为是令人愉快的。然而，在病理性瘙痒病症中，随着时间的推移，抓挠反应引起巨大的痛苦并使病症恶化。除了增加痛苦，慢性瘙痒还与其他负面结果有关，如精神健康状况不佳，睡眠不足和情绪低落。目前，药物瘙痒治疗可导致负面副作用，例如局部皮质类固醇戒断，当长期使用时，其可变得比瘙痒本身更痛苦。还有一个额外的问题是，相当大比例的人对治疗有抗药性，导致他们的瘙痒持续存在。因此，需要开发非药物治疗的需求。皮肤含有几类神经纤维，它们调节躯体感觉的可分离方面。低阈值机械感受器（LTM）（有髓鞘的A-β和A-δ传入）向脊髓发送有关无害触摸的快速信息。无髓鞘的、传导缓慢的C纤维传入传递疼痛和瘙痒的情感特性。C-触觉（CT）传入编码触觉的愉悦特性。这些躯体感觉受体早已被认为以门控方式相互作用。例如，LTM的激活可以减轻疼痛（门控理论Melzack & Wall，1965），电刺激诱发的体感诱发电位可以被另一种体感刺激降低（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，爱抚般的中风，速度范围为1- 10厘米/秒，最佳反应为3厘米/秒。情感触摸的疼痛减轻效果已在成人和婴儿中得到证实。最近发表的对实验诱导的瘙痒的脑反应的荟萃分析（Roberts等人，2019）表明，瘙痒可靠地激活重叠，但可分离的大脑区域，以产生愉快的触摸（例如Morris，2016）。也有人提出，愉快的触摸打开了通往初级躯体感觉皮层的大门（Shirato等人，2018年）。因此，CT介导的舒适触摸提供了探索慢性皮肤病的非药物治疗的途径（Lloyd等人，2015).对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，用执行功能任务分散对瘙痒的注意力不会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 et al.，2017年）。综上所述，这表明躯体感觉系统的负荷增加可以调节瘙痒强度。这一点还有待于用愉快的触摸来探索。这个博士学位的目的是使用神经成像技术来描述对瘙痒的心理和神经心理学反应，以及瘙痒和愉快的触摸之间的相互作用：-证明实验诱导的皮肤瘙痒的主观体验是通过用愉快的触摸刺激CT来调节的。-阐明大脑结构/路径，通过愉快的触摸调节瘙痒相关的大脑活动，以确定新的策略，以减少瘙痒。这些目标将使用行为实验以及电生理技术，如脑电图。假设愉快的触摸激活CT将调节瘙痒的主观体验，与体感门控一致，这将在EEG频带功率中观察到，并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，改善皮肤刺激者的终生健康，减少对医疗干预的需求

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