Individualized Closed-Loop Neuromodulation Therapy for Alzheimer's Disease

项目总结/摘要 阿尔茨海默病（AD）是一种神经退行性疾病，影响超过500万美国人。 尽管其临床和公共卫生影响，以及在治疗开发方面投入的资源， 治疗仍然仅仅是症状性的（而不是疾病改善）并且具有适度的功效。疾病模型有 传统上强调分子（β-淀粉样蛋白和tau蛋白的适应不良变化）和细胞 （神经变性）过程。因此，治疗开发的重点是干预措施， 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、生物标志物发现和治疗开发强调了生理学方法 以伽马振荡为治疗靶点。重要的是，啮齿类动物的证据表明， 用40 Hz的光和声音刺激这些异常的生理特征，不仅可以恢复 伽马振荡和改善记忆，但它也激活小胶质细胞，导致淀粉样蛋白减少， τ的因此，这种治疗策略有可能成为一种疾病修饰疗法，这是我们缺乏的。 AD. 虽然用40 Hz的光和声音进行伽马振荡是一种可行的策略，但使用电 调节电生物现象的刺激应该具有更大的影响。非侵入性装置 神经调节技术已经被用作神经科学工具来探测和研究脑生理学， 数十年来在人体内，以及作为诊断程序（例如，用于临床神经生理学的TMS和 术前定位）和神经精神疾病的治疗干预。tACS非常安全 耐受性好，制造成本低，便于携带，使其成为一种潜在的家庭治疗。的能力 tACS参与人类大脑的振荡，导致认知，行为和感知的变化， 确立了习也就是说，考虑到电流的弱强度（例如2 mA），tACS可能并不总是 有效地参与或减少大脑中正在进行的振荡。一个更加复杂和个性化的“智能 “tACS”方法，通过阅读患者正在进行的EEG活动使用闭环技术， 与正在进行的患者特异性脑活动同相地施加刺激现在在技术上是可能的，并且 对脑震荡的影响更大。我们假设，在40 Hz的闭环tACS， AD患者应该是一个更有效的策略，从事这些异常的节奏，如果结果， 早期证据表明，啮齿动物转化为人类，它可能成为一种急需的疾病缓解剂， 干预（或至少是安全且具有成本效益的对症治疗）。

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).