Ultrasonic neuromodulation of deep grey matter structures for the non-invasive treatment of neurological disorders

大脑中央的结构(通常被称为深层灰质结构)对我们执行日常任务的能力至关重要。这包括处理和传递来自我们感官的信息，调节意识和睡眠，以及控制自愿的运动和协调。深部灰质结构的异常可导致广泛的神经疾病。一些例子包括帕金森氏症、亨廷顿氏症、慢性疼痛和特发性震颤。这些疾病使人极度虚弱，并对患者及其照顾者的生活质量产生重大影响。神经疾病也非常常见，就残疾调整生命年而言，这是欧盟发病率的最大单一原因。仅在英国，就有大约1000万人受到影响，其中35万人需要某种形式的全职护理。目前，大多数神经疾病都是通过开出导致大脑功能改变的药物来治疗的。这些药物作用于大脑中传递电信号和化学信号的结构。对于许多患者来说，这会减轻他们的症状。然而，长期治疗往往不是很有效，而且可能会有许多副作用。对于一些患有晚期或耐药障碍的患者，也可以提供一种名为脑深部刺激的外科手术程序。这包括通过在头骨上钻洞将一根小电线插入大脑。这可能是非常有效的，但具有高度侵入性，而且只适用于少数患者。替代药物和手术的一个令人兴奋的选择是使用超声波进行脑刺激。众所周知，超声波是一种诊断成像工具，特别是在怀孕期间。近年来，超声波的治疗应用也越来越多，包括用于刺激大脑。这是可能的，因为超声波引起的机械振动可以产生作用于脑细胞的内力。根据超声脉冲的模式，这可能会导致大脑中电信号的产生或抑制，而这些电信号又可以用来恢复正常的大脑功能。然而，到目前为止，超声波脑刺激只在小动物和人脑的浅表区域进行了演示。这项提议的目的是开发一种新型的超声波设备，将超声波非侵入性地传输到大脑深层灰质结构中，以治疗神经疾病。该设备将包含数百个单独的超声发射器，分布在患者头部的环形阵列中。发射器的布置将得到优化，以确保超声波可以聚焦到大脑深处，而不会影响大脑电路的其他区域。超声波设备将与计算机规划系统相结合，该系统使用关于超声波如何通过头骨和大脑传播的详细数学模型。这将被用来根据患者的解剖图像精确地定位超声束。开发完成后，该系统将在实验室使用3D打印的头骨模型进行严格测试，然后在成人志愿者身上进行测试。该项目的成功将是神经疾病治疗方面的重大突破。开发的系统将是完全非侵入性的，并允许以前所未有的准确性和灵活性刺激、抑制和调制深部灰质结构中的神经回路。这最终将提高我们对大脑深层功能和相关神经退行性疾病的理解，并为突破性的新临床治疗方法的开发奠定基础。这项技术的低成本和可扩展的性质也意味着它可以被广泛部署，极大地增加了可以获得非药物治疗的患者数量。

The structures in the centre of the brain (often referred to as the deep grey matter structures) are vitally important to our ability to perform everyday tasks. This includes processing and passing on information from our senses, regulating consciousness and sleep, and the control of voluntary movement and coordination. Abnormalities in the deep grey matter structures can lead to a wide range of neurological disorders. Some examples are Parkinson's disease, Huntington's disease, chronic pain, and essential tremor. These disorders are extremely debilitating, and have a significant impact on quality of life for patients and their carers. Neurological conditions are also very common, and form the largest single cause of morbidity in the EU in terms of disability adjusted life years. In the UK alone, approximately 10 million people are affected, with 350,000 needing some form of full time care. Currently, most neurological disorders are treated by the prescription of drugs that cause alterations in brain function. These drugs act on the structures that transmit electrical and chemical signals in the brain. For many patients, this causes a reduction in their symptoms. However, long-term treatment is often not very effective, and there can be many side-effects. For some patients with advanced or drug-resistant disorders, a surgical procedure known as deep brain stimulation may also be offered. This involves putting a small wire into the brain via holes drilled through the skull. This can be very effective, but is highly invasive, and only available to a small number of patients. An exciting alternative to drugs and surgery is brain stimulation using ultrasound. Ultrasound is well known as a diagnostic imaging tool, particularly during pregnancy. In recent years, a growing number of therapeutic applications of ultrasound have also been demonstrated, including for stimulating the brain. This is possible because the mechanical vibrations caused by ultrasound waves can generate internal forces that act on the brain cells. Depending on the pattern of the ultrasound pulses, this can cause the generation or suppression of electrical signals in the brain, which in turn can be used to restore normal brain function. However, until now, ultrasound brain stimulation has only been demonstrated on small animals and in superficial areas of the human brain.The aim of this proposal is to develop a new type of ultrasound device to deliver ultrasound waves non-invasively into the deep grey matter structures of the brain to treat neurological disorders. The device will contain hundreds of individual ultrasound transmitters distributed in a ring array positioned on the patient's head. The arrangement of the transmitters will be optimised to ensure ultrasound can be focused into the deep brain without affecting other areas of brain circuitry. The ultrasound device will be coupled with a computer planning system that uses a detailed mathematical model of how ultrasound waves propagate through the skull and brain. This will be used to position the ultrasound beam precisely based on images of the patient's anatomy. After development, the system will be rigorously tested in the laboratory using 3D printed skull phantoms, before being tested on adult human volunteers.Success in this project will be a major breakthrough in the treatment of neurological disorders. The developed system will be completely non-invasive, and allow the stimulation, suppression, and modulation of the neural circuitry in deep grey matter structures with unprecedented accuracy and flexibility. This will ultimately improve our understanding of deep brain function and associated neurodegenerative diseases, as well as underpin the development of ground-breaking new clinical treatments. The low-cost and scalable nature of the technology also means it could be widely deployed, greatly increasing the number of patients that have access to non-pharmacological treatments.