Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.
Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.
PLoS One. 2022 Dec 1;17(12):e0278412. doi: 10.1371/journal.pone.0278412. eCollection 2022.
Non-invasive Gamma ENtrainment Using Sensory stimulation (GENUS) at 40Hz reduces Alzheimer's disease (AD) pathology such as amyloid and tau levels, prevents cerebral atrophy, and improves behavioral testing performance in mouse models of AD. Here, we report data from (1) a Phase 1 feasibility study (NCT04042922, ClinicalTrials.gov) in cognitively normal volunteers (n = 25), patients with mild AD dementia (n = 16), and patients with epilepsy who underwent intracranial electrode monitoring (n = 2) to assess safety and feasibility of a single brief GENUS session to induce entrainment and (2) a single-blinded, randomized, placebo-controlled Phase 2A pilot study (NCT04055376) in patients with mild probable AD dementia (n = 15) to assess safety, compliance, entrainment, and exploratory clinical outcomes after chronic daily 40Hz sensory stimulation for 3 months. Our Phase 1 study showed that 40Hz GENUS was safe and effectively induced entrainment in both cortical regions and other cortical and subcortical structures such as the hippocampus, amygdala, insula, and gyrus rectus. Our Phase 2A study demonstrated that chronic daily 40Hz light and sound GENUS was well-tolerated and that compliance was equally high in both the control and active groups, with participants equally inaccurate in guessing their group assignments prior to unblinding. Electroencephalography recordings show that our 40Hz GENUS device safely and effectively induced 40Hz entrainment in participants with mild AD dementia. After 3 months of daily stimulation, the group receiving 40Hz stimulation showed (i) lesser ventricular dilation and hippocampal atrophy, (ii) increased functional connectivity in the default mode network as well as with the medial visual network, (iii) better performance on the face-name association delayed recall test, and (iv) improved measures of daily activity rhythmicity compared to the control group. These results support further evaluation of GENUS in a pivotal clinical trial to evaluate its potential as a novel disease-modifying therapeutic for patients with AD.
使用 40Hz 的感官刺激进行非侵入性伽马训练（GENUS）可降低阿尔茨海默病（AD）病理，如淀粉样蛋白和tau 水平，防止脑萎缩，并改善 AD 小鼠模型的行为测试表现。在这里，我们报告了来自（1）一项在认知正常志愿者（n=25）、轻度 AD 痴呆患者（n=16）和接受颅内电极监测的癫痫患者（n=2）中进行的 1 期可行性研究（NCT04042922，ClinicalTrials.gov）的数据，以评估单次短暂 GENUS 治疗诱导同步的安全性和可行性，以及（2）一项在轻度可能 AD 痴呆患者中进行的单盲、随机、安慰剂对照的 2A 期试验研究（NCT04055376）的数据，以评估 3 个月慢性每日 40Hz 感觉刺激后的安全性、依从性、同步和探索性临床结果。我们的 1 期研究表明，40Hz GENUS 是安全的，并有效地诱导了皮质区域和其他皮质和皮质下结构（如海马体、杏仁核、脑岛和直回）的同步。我们的 2A 期研究表明，慢性每日 40Hz 光和声 GENUS 耐受性良好，对照组和实验组的依从性同样高，参与者在揭盲前对自己的分组同样不准确。脑电图记录显示，我们的 40Hz GENUS 设备安全有效地诱导了轻度 AD 痴呆患者的 40Hz 同步。经过 3 个月的每日刺激，接受 40Hz 刺激的组显示出（i）较少的脑室扩张和海马体萎缩，（ii）默认模式网络和内侧视觉网络的功能连接增加，（iii）面孔-名字联想延迟回忆测试的表现更好，以及（iv）与对照组相比，日常活动节律性的测量得到改善。这些结果支持在一项关键临床试验中进一步评估 GENUS，以评估其作为 AD 患者新型疾病修饰治疗的潜力。
