Sensory system abnormalities in childhood dystonia / dystonic cerebral palsy - are sensory networks modulated by Deep Brain Stimulation?

肌张力障碍是一种严重致残和疼痛的运动障碍，其中人们遭受不自主的肌肉收缩，导致扭曲运动，异常姿势和疼痛痉挛。它影响了至少70000人在英国（类似于多发性硬化症）。有很多原因，但我们还不完全了解大脑中发生了什么，产生这些异常的运动。成人发作的肌张力障碍通常涉及身体的单个部位，而儿童发作的肌张力障碍通常是广泛的，并且如此严重，以至于人们发现不可能控制他们的身体。这可能会阻止智力相对正常的儿童实现成人独立。这些人的长期护理需求对国家卫生服务和社会来说是非常昂贵的。肌张力障碍无法治愈，但症状可以通过一种名为深部脑刺激（DBS）的技术得到改善。这涉及到使用称为电极的细线将电脉冲传递到大脑深处的一组特定神经细胞，称为苍白球（GPi）。在神经外科医生进行手术期间，电极被植入大脑。在手术过程中，我们可以使用特殊的记录电极记录GPi中神经细胞的活动。DBS对某些类型的肌张力障碍比其他类型更有效，但我们不知道为什么，因为a）我们还不知道DBS是如何工作的，B）我们还不了解不同类型肌张力障碍的机制，特别是婴儿期脑损伤导致的肌张力障碍（肌张力障碍性脑瘫）。这种知识上的差距限制了我们开发和应用有效疗法的能力。大多数研究肌张力障碍机制的研究都是在患有遗传性肌张力障碍的成人中进行的。这些研究表明，“抑制”，即身体“抑制”神经系统活动的机制，在肌张力障碍患者中减少。也有证据表明大脑处理感官信息的方式异常。因此，肌张力障碍的一种可能机制是感觉输入的异常感知导致扭曲或过度运动。然而，这些机制都没有在肌张力障碍性脑瘫中进行过研究。研究哪些机制是常见的，哪些机制在不同类型的肌张力障碍之间有所不同，这是了解原因和提高我们治疗这种致残性疾病的能力的关键。我自己的工作已经确定了不同类型的肌张力障碍之间GPi神经细胞活性的差异，并表明这些细胞的活性与DBS手术的结果有关。我还发现了一些肌张力障碍儿童感觉通路异常的证据，特别是在肌张力障碍性脑瘫中。我的数据表明，这种感觉缺陷可能与DBS的结果有关，但仍然需要更强大的结果标志物。我计划通过调查不同类型的肌张力障碍患者大脑内感觉处理的措施是否异常以及这些措施是否与DBS的结果有关来推进这一点。为了调查感觉处理，我将使用频率分析方法来检测EEG（脑电波）活动与感觉刺激和运动任务相关的变化。我将比较这些措施在儿童与不同类型的肌张力障碍和儿童与良好和不良的结果后DBS。我还将分析DBS手术时记录的GPi细胞的活性，并将其与不同类型的肌张力障碍进行比较。最后，我将通过使用植入的刺激器来唤起皮层的活动，评估连接GPi和皮层（大脑的外层）的通路。这些数据将确定张力障碍性脑瘫的感觉处理是否异常，以及感觉处理的测量是否与DBS的结果相关。这对预测结果，选择最合适的手术候选人以及为患者和家属提供咨询具有重要意义。

Dystonia is a severely disabling and painful motor disorder in which people suffer involuntary muscle contractions causing twisting movements, abnormal postures and painful spasms. It affects at least 70 000 people in the UK (similar to Multiple Sclerosis). There are many causes but we don't yet fully understand what happens within the brain to produce these abnormal movements. Adult-onset dystonia usually involves a single part of the body, whereas childhood-onset dystonia is often widespread and so severe that people find it impossible to control their bodies. This can prevent children with relatively normal intellect from achieving adult independence. The long-term care needs of these individuals are hugely expensive to the National Health Service and society.Dystonia has no cure but symptoms can be improved by a technique called Deep Brain Stimulation (DBS). This involves using fine wires, called electrodes, to deliver electrical pulses to a specific group of nerve cells deep within the brain, called the Globus Pallidus interna (GPi). The electrodes are implanted in the brain during an operation performed by a neurosurgeon. During the surgery, we can record the activity of nerve cells in the GPi using special recording electrodes.DBS is more effective in some types of dystonia than others but we do not know why because a) we don't yet know how DBS works and b) we don't yet understand the mechanisms responsible for different types of dystonia, especially dystonia resulting from brain injury during infancy (dystonic cerebral palsy). This gap in our knowledge limits our ability to develop and apply effective therapies.Most studies investigating the mechanisms of dystonia have been in adults with genetic forms of dystonia. These studies have shown that "inhibition", the mechanism by which the body "damps down" activity within the nervous system, is reduced in people with dystonia. There is also evidence of abnormalities in the way the brain processes sensory information. Thus one possible mechanism of dystonia is that abnormal perception of sensory inputs leads to distorted or excessive movements. However, none of these mechanisms have been investigated in dystonic cerebral palsy.Studying which mechanisms are common and which differ between different types of dystonia is key to understanding the causes and improving our ability to treat this disabling condition. My own work has identified differences in the activity of GPi nerve cells between different types of dystonia and has shown that the activity of these cells is related to outcome from DBS surgery. I have also found evidence of abnormal sensory pathways in some children with dystonia, particularly in dystonic cerebral palsy. My data suggest that such sensory deficits may be linked to outcome from DBS, but more powerful markers of outcome are still needed. I plan to take this forward by investigating whether measures of sensory processing within the brain are abnormal in different types of dystonia and whether these measures relate to outcome from DBS.To investigate sensory processing I will use frequency analysis methods to detect changes in EEG (brainwave) activity in relation to a sensory stimulus and a motor task. I will compare these measures in children with different types of dystonia and in children with good and poor outcome following DBS. I will also analyse the activity of GPi cells recorded at the time of DBS surgery and compare these across different types of dystonia. Finally I will assess the pathway linking the GPi and the cortex (the outer layer of the brain) by using the implanted stimulator to evoke activity in the cortex. These data will determine whether sensory processing is abnormal in dystonic cerebral palsy and whether measures of sensory processing relate to outcome from DBS. This has important implications for predicting outcome, selecting the most appropriate candidates for surgery and in counselling patients and families.