Individualized Closed-Loop Neuromodulation Therapy for Alzheimer's Disease

项目摘要/摘要 阿尔茨海默病(AD)是一种神经退行性疾病，影响着500多万美国人。 尽管它对临床和公共卫生有影响，而且在治疗开发上投入了资源，但现有的 治疗仍然只是针对症状(而不是改变疾病)，效果不大。疾病模型有 传统上强调分子(-淀粉样蛋白和tau蛋白的不良适应变化)和细胞 (神经变性)过程。因此，治疗发展的重点是干预措施 这些分子和细胞机制，即药理学和免疫疗法。最近的事态发展 病理生理学、生物标记物的发现和治疗的发展强调了生理学方法。 到AD，重点放在伽马振荡作为治疗目标。关键的是，啮齿类动物的证据表明 用40赫兹的光和声刺激这些异常的生理特征不仅可以恢复 伽玛振荡并改善记忆，但它也激活小胶质细胞，导致淀粉样蛋白减少和 陶先生。因此，这种治疗策略有可能成为一种我们缺乏的疾病修正疗法。 广告。 虽然用40赫兹的光和声音进行伽马振荡是一个可行的策略，但使用电信号 刺激对调制一种电生物现象应该有更大的影响。非侵入式设备 神经调节技术已被用作神经科学工具来探索和研究脑生理学 人类在活体内存在了几十年，并作为诊断程序(例如用于临床神经生理学和 手术前测绘)和神经精神疾病的治疗干预。Tacs是非常安全的，嗯 耐受性好，制造成本低，携带方便，使其有可能成为一种基于家庭的疗法。的能力 TAC参与人脑中的振荡，导致认知、行为和感知的变化 已经成立了。也就是说，考虑到电流的微弱强度(例如2 mA)，TAC可能并不总是 有效地参与或减少大脑中持续的振荡。更精致、更个性化的“智商” 通过读取患者正在进行的脑电活动和使用闭环技术的TACS方法 现在，将刺激与正在进行的患者特定大脑活动同步应用在技术上是可能的，并且 显示出对大脑振荡有更大的影响。我们假设在40赫兹的闭环系统中 AD患者应该采取更有效的策略来处理这些异常节律，如果结果是 正如早期证据显示的那样，啮齿动物可以转化为人类，这可能成为一种亟需的疾病修正 干预措施(或至少是一种安全且成本效益高的对症治疗)。

PROJECT SUMMARY/ABSTRACT Alzheimer’s Disease (AD) is a neurodegenerative disease that affects over 5 million Americans. Despite its clinical and public health impact, and the resources invested in treatment development, existing therapies remain only symptomatic (not disease modifying) and have modest efficacy. Disease models have traditionally emphasized molecular (maladaptive changes in -amyloid and tau proteins) and cellular (neurodegeneration) processes. Therefore, treatment development has focused on interventions that engage these molecular and cellular mechanisms, i.e. pharmacology and immunotherapy. Recent developments in pathophysiology, biomarker discovery and treatment development have emphasized a physiological approach to AD, with a focus on gamma oscillations as treatment targets. Critically, evidence in rodents suggests that engaging these aberrant physiological signatures with 40 Hz light and sound stimulation not only restores gamma oscillations and improves memory, but it also activates microglia leading to a reduction in amyloid and tau. Hence, this treatment strategy has the potential to be a disease-modifying therapy, which we are lacking in AD. While engaging gamma oscillations with 40Hz light and sound is a viable strategy, using electrical stimulation to modulate an electrical biological phenomenon should have greater impact. Noninvasive device neuromodulation technologies have been used as neuroscience tools to probe and study brain physiology in humans in vivo for decades, and as diagnostic procedures (e.g. TMS for clinical neurophysiology and presurgical mapping) and therapeutic interventions for neuropsychiatric conditions. tACS is very safe, well tolerared, cheap to manufacture and portable, making it a potentially home-based therapy. The capacity of tACS to engage oscillations in the human brain leading to changes in cognition, behavior and perception is established. That said, given the weak intensity of the electrical currents (e.g. 2mA), tACS may not always effectively engage or reduce ongoing oscillation in the brain. A more sophisticated and individualized “smart tACS” approach that uses closed-loop technology by reading the ongoing EEG activity of the patient and applying the stimulation in phase with the ongoing patient-specific brain activity is now technically possible, and showing to have greater impact on brain oscillations. We hypothesize that closed-loop tACS at 40 Hz in patients with AD should be a more effective strategy to engage these abnormal rhythms, and if the results in rodents translate to humans as early evidence suggests, it may become a much needed disease-modifying intervention (or at least a safe and cost-effective symptomatic treatment).