Harnessing sensorimotor cortical plasticity to improve outcomes in children with dystonia and dystonic cerebral palsy

肌张力障碍是一种无法治愈的严重致残性运动障碍，患者会遭受疼痛的肌肉痉挛，导致扭曲运动和异常姿势。原因有很多，包括遗传疾病和脑损伤。后者包括张力障碍脑瘫（CP），其损伤发生在出生前后，全世界约有250万人受到影响。而成人发病的肌张力障碍往往涉及一个身体区域，儿童发病的肌张力障碍往往影响整个身体。这些儿童无法控制自己的身体，难以接受教育或参加活动，需要昂贵的终身护理。肌张力障碍通常对药物无反应。症状可以通过深部脑刺激（DBS）得到改善，这种方法是将细导线植入大脑深处的神经细胞。电线传送电脉冲来调节大脑活动，减少不必要的运动。DBS对某些类型的肌张力障碍非常有效，但对其他类型的肌张力障碍效果较差。预测益处是困难的，因为产生异常运动的机制尚不完全清楚。越来越多的证据表明，其中一种机制涉及大脑对感觉信息的异常处理（例如，从我们的触觉和身体位置传递给大脑的信号）：对这些信号的扭曲感知反过来又扰乱了大脑产生计划和执行动作指令的方式。这一领域的大多数研究涉及的是患有肌张力障碍的成年人，他们只影响身体的一个部位。儿童肌张力障碍，特别是肌张力障碍CP的研究很少，尽管这些患者有最大的临床需求：他们的肌张力障碍影响全身，非常严重，对治疗反应较差。了解导致不同类型肌张力障碍的机制以及它们如何影响发育中的大脑是至关重要的，如果我们要改善结果和时间干预，以利用大脑最能做出反应的发育时间窗口。我自己的研究表明，超过40%的肌张力障碍儿童（尤其是肌张力障碍CP）通向大脑的感觉通路是异常的。我还通过使用记录EEG（脑电图-脑电波信号）和/或EMG（肌电图-肌肉电信号）的方法，证明了患有肌张力障碍和肌张力障碍CP的儿童大脑处理与运动相关的感觉信息的方式是异常的。我们的脑电波显示出与我们的活动相关的特征模式。例如，在感觉运动皮层（大脑负责处理感觉和运动信息的外层）上，一种被称为“mu”的特定大脑节律通常会在感觉刺激或运动的反应中减少。这种mu活动的变化反映了大脑对感觉信息的处理，对儿童运动技能的发展很重要。我对患有肌张力障碍/肌张力障碍性脑瘫的儿童的研究表明，这种与运动相关的mu活动变化受到损害，与运动相关的感觉刺激会触发大脑中的许多细胞以低频率相互同步放电。这两种异常的大脑活动模式可能是相互联系的，它们也可能与异常的肌肉活动有关。这个项目将会。测试这些联系以及DBS对这些异常脑模式的影响，从而提高对肌张力障碍/肌张力障碍CP机制的认识；探讨脑电以电脑游戏的形式反馈是否可以增强肌张力障碍/肌张力障碍CP患儿的mu活动的运动相关变化；以及增强的mu活动是否与改善的运动控制有关。这些发现将告诉我们mu活性的生物反馈是否具有治疗作用；研究健康婴儿和有发生肌张力障碍CP风险的婴儿的mu活动的运动相关变化的早期发展，从而显示可能的最佳治疗干预时间窗。

Dystonia is a severely disabling movement disorder with no cure, in which people suffer painful muscle spasms causing twisting movements and abnormal postures. There are many causes, including genetic conditions and brain injury. The latter includes dystonic cerebral palsy (CP) in which the injury occurs around birth and which affects around 2.5 million people worldwide. Whilst adult-onset dystonia tends to involve a single body region, childhood-onset dystonia often affects the whole body. These children find it impossible to control their bodies, have difficulties accessing education or activities, and require costly life-long care. Dystonia is often unresponsive to drugs. Symptoms can be improved by Deep Brain Stimulation (DBS), in which fine wires are implanted into nerve cells deep in the brain. The wires deliver electrical pulses to modulate brain activity and reduce unwanted movements. DBS is very effective in some types of dystonia but less so in others. Predicting benefit is difficult, as the mechanisms that produce the abnormal movements are not fully understood. There is growing evidence that one mechanism involves abnormal brain processing of sensory information (eg signals to the brain from our senses of touch and body position): the distorted perception of these signals in turn disrupts the way the brain produces instructions for planning and performing movements. Most research in this field involves adults with dystonias affecting a single part of the body. Research in childhood dystonia, especially dystonic CP is sparse, despite these patients having the greatest clinical need: their dystonia affects the whole body, is very severe, and less responsive to therapy. Understanding the mechanisms that lead to different types of dystonia and how they affect the developing brain is critical if we are to improve outcomes and time interventions to exploit developmental time-windows when the brain is most able to respond. My own work shows that sensory pathways to the brain are abnormal in over 40% of children with dystonia (especially dystonic CP). I have also shown that the way the brain processes sensory information related to movement is abnormal in children with dystonia and dystonic CP, by using methods that record the EEG (electroencephalogram - brain wave signals) and/or EMG (electromyogram - electrical signal from muscles). Our brain waves show characteristic patterns in relation to our activities. For example, a particular brain rhythm known as "mu", which is seen over sensorimotor cortex (the outer layer of the brain responsible for processing sensory and movement information), is typically reduced in response to sensory stimulation or movement. This change in mu activity reflects the brain's processing of sensory information and is important in the development of motor skills in children. My research in children with dystonia/dystonic CP, shows that this movement-related change in mu activity is impaired, and that sensory stimuli related to movement trigger many cells across the brain to fire in synchrony with each other at a low frequency. It is possible that these two abnormal patterns of brain activity are linked and that they also relate to abnormal muscle activity.This project will 1. test these links and the effect of DBS on these abnormal brain patterns, thereby advancing knowledge of the mechanisms underlying dystonia/dystonic CP;2. investigate whether movement-related changes in mu activity can be enhanced in children with dystonia/dystonic CP by using EEG feedback in the form of a computer game; and whether enhanced mu activity is associated with improved movement control. These findings will tell us whether biofeedback of mu activity could have a therapeutic role;3. study the early development of movement-related changes in mu activity in healthy infants and those at risk of developing dystonic CP, thus demonstrating likely optimal time windows for therapeutic intervention.