Defining the microstructural basis of tremor in vivo to identify novel therapeutic targets

震颤，身体部分无法控制的颤抖，是一种影响许多人的常见和致残的情况。震颤的常见原因包括特发性震颤综合征(ET)、帕金森氏病(PD)和一种较为罕见的肌张力障碍。它可以显著影响日常活动和生活质量，并且患者之间的差异很大，对诊断和治疗都构成了挑战。一半的震颤患者对目前可用的任何药物都没有反应。在这些患者中，更具侵入性的治疗通常被认为是更具侵入性的治疗，如脑深部刺激(DBS)或聚焦超声，它们会中断携带异常震颤信号的大脑电路，通常针对的是被称为丘脑腹侧中间核(Vim)的深层区域。然而，还有许多其他的脑膜区域和网络参与了地震的产生和传播。更好地了解这些可能会在未来实现非侵入性的“神经调节”治疗，使用有针对性的电刺激来抑制异常的大脑信号。为了开发更好的震颤治疗方法，需要对支撑人体震颤的神经回路有更深入的了解。这需要绘制出震颤患者大脑局部区域以及这些区域之间的联系是如何改变的，以更好地了解这些结构的不同损伤模式是如何改变震颤特性的，如身体受影响的区域、严重程度或对治疗的反应。已知受震颤影响的大脑部分，如Vim，在常规MRI上看不到。先进的磁共振成像技术，使用定量磁共振成像(QMRI)，不仅可以定义这些区域，还可以提供反映脑组织不同属性的测量结果，并允许绘制区域之间的联系。此外，现在可以使用公开可用的“大数据”资源，如英国生物库，将大脑区域的焦点变化与与这些大脑结构相关的基因联系起来(“注释”)，这样做使我们能够确定可能的生化途径，这些途径可能代表未来治疗的途径。这项研究将集中于ET和PD，这是震颤最常见的原因，目标如下1。使用qMRI绘制与不同震颤特性相关的脑组织变化图2。绘制大脑局部变化之间的联系图，并识别与这些大脑结构相关的基因3。使用这些地图来确定潜在的治疗方案，使用神经调节或药物，针对特定的震颤亚型/特性这项研究将持续三年，使用来自40名帕金森氏病震颤患者和70名正常人的数据，来自Lambert博士(帕金森病解剖表型定量磁共振成像)领导的现有研究。我们将增加40名有震颤症状的参与者，他们将接受与qMAP-PD研究相同的评估。我们将使用标准化的震级和先进的地震视频记录来表征地震，并使用类似智能手表的设备来生成详细的地震记录。详细的QMRI将使我们能够识别和绘制引起不同震颤特征的结构和网络。一旦我们确定了大脑区域，我们将根据现有的资源将这些区域与基因联系起来(英国生物库)。在这个过程中，我们将在大脑区域标记或注释这些基因(基因注释)。利用现有的知识，我们将确定影响这些地区功能的因素。这将允许从现有的知识资源中确定潜在的新的医疗选择。这种结合的方法将提供三个关键的输出，广泛应用于指导震颤的精确治疗：(1)支撑震颤特征的大脑区域的地图(2)通过电刺激或聚焦超声进行调制的潜在靶点和(3)震颤的新治疗选择

Tremor, a shaking or trembling in part the body that cannot be controlled, is a common and disabling condition that affects many people. Common causes of tremor include Essential Tremor Syndrome (ET), Parkinson's disease (PD) and a rarer condition called dystonia. It can significantly impact day to day activities and quality of life, and is highly variable between sufferers, posing a challenge both with diagnosis and treatment. Half of all tremor patients do not respond to any of the medication currently available. In these individuals, more invasive treatments are often considered such as deep brain stimulation (DBS) or focused ultrasound, that interrupt the brain circuits that carry the abnormal tremor signals, often targeting a deep region known as ventralis intermedius nucleus of the thalamus (Vim). However, there are many other bran areas and networks involved in the generation and propagation of tremor. A better understanding of these could allow non-invasive "neuromodulation" treatments in the future, using targeted electrical stimulation to dampen the abnormal brain signals. To develop better treatments for tremor, a greater understanding of the neural circuits that underpin tremor in humans is required. This requires mapping how focal brain regions, and the connections between these, are altered in tremor sufferers, to better understand how different patterns of damage to these structures modify tremor properties such as body regions affected, severity or response to treatment.Some parts of the brain known to be affected in tremor, such as Vim, cannot be seen on routine MRI. Advanced MRI techniques, using quantitative MRI (qMRI), not only allow these areas to be defined but also provide measurements that reflect different properties of brain tissue and allow the connections between region to be mapped. Furthermore, it is now possible to use openly available "big data" resources, such as the UK Biobank, to link ("annotate") focal changes in brain regions to the genes that are related to these brain structures, and in doing so allow us to identify possible biochemical pathways that may represent avenues for future treatments. This study will focus on ET and PD, the most common causes of tremor with the following objectives1. To map the changes in brain tissue associated with different tremor properties using qMRI 2. To map connections between regional brain changes and identify genes associated with these brain structures3. To use these maps to identify potential treatment options, using either neuromodulation or drugs, that are targeted to specific tremor subtypes/propertiesThe study will run over three years and use data from 40 people with PD tremor and 70 normal people, from an existing study led by Dr Lambert(Quantitative MRI for Anatomical Phenotyping in Parkinson's disease (qMAP-PD). We will add 40 additional participants with tremor who will undergo the same assessments as qMAP-PD study. We will characterize the tremor using standardized scales and advanced video recording of tremors with a smart watch like device to generate detailed tremor recordings. Detailed qMRI of will allow us to identify and map the structures and networks that give rise to the different tremor characteristics. Once we have identified brain regions, we will link these to genes based on an existing resource (UK biobank). In this process we will mark or annotate these genes on brain regions (gene annotation). Using existing knowledge, we will identify factors that influence function in these regions. This will allow identification of potential new medical treatment options from existing knowledge resources. This combined approach will deliver three key outputs with wide applications to direct precision therapies for tremor: (1) Maps of the brain regions that underpin tremor characteristics (2) Potential targets for modulation through electrical stimulation or focused ultrasound and (3) New treatment options for tremor