Personalised neurostimulation for Parkinson's inspired by neurophysiological improvements observed after physical exercise

帕金森氏症引起的症状范围很广，个体之间差异很大。患者有不同的症状组合，包括震颤、行动迟缓、肌肉痉挛、行走困难和冲动，因此将受益于个性化的治疗方法。目前领先的两种治疗方法是多巴胺能药物和深部脑刺激（DBS），这两种方法在疾病的早期和中期阶段非常有效。然而，在晚期，高剂量的药物会导致副作用，包括幻觉、冲动和过度的无法控制的运动。DBS可以提供个性化的治疗，并最大限度地减少副作用，因为理论上它可以根据症状的波动进行调整。然而，它需要侵入性手术，也会对认知，特别是记忆产生负面影响，因此只有少数患者（约10%）可以使用。非侵入性神经刺激也可以个性化，可能比DBS更具成本效益和更容易获得，因此将是首选-如果方案可以开发出同样有效或能够改善未满足的需求。我的目标是开发新的个性化非侵入性神经刺激方案，以改善帕金森病患者的运动和认知控制能力，超越现有的治疗方法。我将通过详细描述在优化运动控制时大脑区域如何相互交流来实现这一点。我们如何访问“最优调优”？据报道，帕金森氏症患者在进行高强度体育锻炼后的2-4小时内感觉最佳。有些人甚至报告说，他们短暂地觉得自己根本没有患帕金森症。我将充分利用运动的显著益处来确定哪些大脑活动模式应该恢复。然后，我将编制非侵入性神经刺激工具来恢复已识别的模式，并测试它对个体症状的改善程度。我们会得到什么？我们将观察到运动后大脑活动的变化，这将为每位患者设计个性化的神经刺激方案提供信息。从盲目地向所有参与者提供相同的刺激，这是向前迈出的一大步。我们的目标是明确支持与每个个体症状改善相关的大脑活动模式，以解释患者之间症状的巨大差异。为此，我将使用多种刺激工具，包括电刺激和使用振动的感官刺激。我们还将使用计算模型来找到最有效的增产参数。我的方法是及时的，因为现在的新设备能够精确地协调多个部位的刺激，同时也能测量大脑活动。结合多种工具和协调刺激大脑多个区域可能比单独与一个目标区域互动在临床上更有效。此外，我的工作有可能启发改进当前评估治疗成功的实践（例如，在调整药物或DBS参数时）。总之，放弃一刀切的方法，转向以大脑活动为基础的，在这种情况下也是以锻炼为灵感的，个性化的神经刺激可能会彻底改变我们治疗帕金森症和其他运动障碍的方式。

Parkinson's causes a wide range of symptoms that vary strongly between individuals. Patients are burdened with different combinations of symptoms, including tremor, slowness, muscle cramps, walking difficulties and impulsivity, and would thus benefit from a personalized therapeutic approach.The two currently leading therapies are dopaminergic medication and deep brain stimulation (DBS), which can be highly effective in the early and middle stages of the disease. However, high medication doses in later stages can cause side effects including hallucinations, impulsivity, and excessive uncontrollable movements. DBS could deliver personalized therapies and minimize side effects as it can theoretically be programmed to adjust to symptom fluctuations. However, it requires invasive surgery, can also negatively affect cognition, in particular memory, and is thus available to only few patients (~10%). Non-invasive neurostimulation can also be personalized and could be more cost-effective and more accessible than DBS and would thus be preferrable - if protocols could be developed to be similarly effective or were able to improve unmet needs. My aim is to develop novel personalized non-invasive neurostimulation protocols for Parkinson's to improve both motor and cognitive control abilities beyond what existing therapies achieve. I will achieve this by characterizing in detail how brain areas communicate with each other when optimally tuned for movement control. How can we access "optimal tuning"?People with Parkinson's reportedly feel at their best within 2-4 hours after engaging in intense physical exercise. Some even report they briefly feel they do not have Parkinson's at all. I will capitalize on the striking acute benefits of exercise to identify which brain activity patterns should be restored. I will then program non-invasive neurostimulation tools to restore the identified patterns and test how well it improves individual symptoms.What will we gain?The changes in brain activity that we will observe following exercise will inform the design of a personalized neurostimulation protocol for each patient. This is a big step forwards from delivering the same stimulation essentially blindly to all participants. We aim to support specifically the brain activity patterns that are associated with symptom improvements in each individual to account for the large variability of symptoms across patients. To do this I will employ a combination of stimulation tools, including electrical stimulation and sensory stimulation using vibration. We will also use computational modelling to find the maximally effective stimulation parameters. My approach is timely as new devices now have the capability to precisely coordinate stimulation of multiple sites while also measuring brain activity. Combining tools and orchestrating stimulation of multiple brain areas likely will be clinically more effective than interacting with one target area alone. Additionally, my work has the potential to inspire improvements in current practises of assessing treatment success (e.g. when adjusting medication or DBS parameters). In summary, stepping away from a one-fits-all approach towards brain-activity based, and in this case also exercise-inspired, personalization of neurostimulation could revolutionize the way we treat Parkinson's and other movement disorders.