Dynamic Neuromodulation

据估计，英国4%的人口患有原发性震颤，而大约127,000人患有帕金森病，这使得这些疾病的长期治疗成为医疗保健系统面临的主要挑战之一。脑深部刺激是一种常用的治疗干预，它涉及对大脑关键区域的电刺激。最先进的刺激模式减弱了驱动疾病症状并导致症状抑制的大脑活动。然而，刺激也会抑制与帕金森病和原发性震颤的运动症状无关的大脑活动，在接受深部脑刺激治疗的患者中，高达50%的患者会产生副作用。我相信开发治疗策略，选择性地针对大脑活动驱动的疾病症状，可以减少刺激引起的副作用，并显着提高患者的生活质量。这一建议源于临床需要提高刺激特异性，以减少患者所经历的副作用，并将这种强大的治疗干预扩大到其他难以治疗的神经系统疾病。该提议的第一个目标是通过仔细选择刺激时间来选择性地抑制与疾病相关的大脑活动。关键的是，我的目标是实现状态依赖的深部脑刺激，它根据患者的症状严重程度动态调整治疗的关键方面（例如，提供多少刺激和刺激模式）。神经调节不仅可以抑制驱动疾病症状的大脑活动，还可以增强在控制我们日常行为中起关键作用的神经活动。我的目标是开发刺激技术，以选择性地增强被认为有助于行为的神经过程，如反应抑制和行动选择。促进神经活动来补偿损伤的可能性，可能在未来治疗难治性疾病（如强迫症和冲动性）方面发挥重要作用。该提案的第二个目的是从基本的神经过程中学习，以便设计更“自然”的治疗干预。驱动帕金森病和原发性震颤的运动症状的大脑活动可以自发抑制。例如，当震颤患者做一个动作时，震颤幅度明显减小。从我们大脑中甚至在疾病期间发生的自然过程中获得灵感的治疗干预可能提供一种有效的方法来减少疾病症状，同时保留与疾病过程无关的大脑活动。这个研究项目将产生令人兴奋的理论和实验工具，可以用来理解不同的大脑区域如何交流和控制行为。至关重要的是，模仿我们的大脑通过刺激控制疾病相关神经活动的方式是一条创新之路，它不仅可以用于帕金森病和特发性震颤，还可以用于由类似大脑活动驱动的其他运动和精神疾病的新型治疗干预。

It is estimated that 4% of UK's population suffer from essential tremor while approximately 127,000 people live with Parkinson's disease, making long-term treatment of these conditions one of the key challenges facing the healthcare system. Deep brain stimulation is a commonly used therapeutic intervention, which involves electrical stimulation of key brain regions. State of the art stimulation patterns attenuate brain activity that drives disease symptoms and lead to symptom suppression. However, stimulation also suppresses brain activity not linked with motor symptoms of Parkinson's disease and essential tremor, inducing side effects in up to 50 % of the patients treated with deep brain stimulation. I believe developing therapeutic strategies that selectively target brain activity driving disease symptoms could reduce stimulation-induced side effects and significantly improve patients' quality of life. This proposal emerges from a clinical need to improve stimulation specificity in order to reduce side effects experienced by patients, and to expand the use of this powerful therapeutic intervention to other difficult to treat neurological disorders. The first aim of the proposal is to selectively suppress disease related brain activity by carefully timing stimulation. Critically, I aim to achieve state-dependent deep brain stimulation, which adjusts key aspects of the therapy (e.g. how much stimulation is delivered and pattern of stimulation) dynamically according to patients' symptom severity. Neuromodulation can be used not only to suppress brain activities driving disease symptoms but also to enhance neural activity that play a critical role in controlling our every day actions. I aim to develop stimulation techniques in order to selectively enhance neural processes believed to contribute to behaviors such as response inhibition and action selection. The possibility of promoting neural activity to compensate for impairment may play an important role in the future for managing treatment-refractory disorders such as obsessive-compulsive disorder and impulsivity. The second aim of the proposal is to learn from fundamental neural processes in order to design more "natural" therapeutic interventions. Brain activity driving motor symptoms of Parkinson's disease and essential tremor can be spontaneously suppressed. For instance, when patients with tremor make a movement, tremor amplitude reduces significantly. Therapeutic interventions inspired by natural processes that take place in our brains even during disease, may provide an effective method for reducing disease symptoms while sparing brain activity not linked to disease processes. This research programme will generate exciting theoretical and experimental tools, which could be used to understand how different brain regions communicate and control behavior. Critically, the notion of mimicking the way our brains readily control disease related neural activity through stimulation is an innovative path that could lead to the development of new types of therapeutic interventions not only for Parkinson's disease and essential tremor but also for other movement and psychiatric disorders driven by similar types of brain activity.