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非侵入性多感官刺激治疗在阿尔茨海默病认知功能治疗中的应用进展

萌宠菠菠乐园
2024-10-16 05:15

阿尔茨海默病（Alzheimer's disease，AD）是一类起病隐匿、进行性发展的中枢神经系统变性疾病，是老年人最常见的痴呆类型[1-2]，其临床表现主要为认知功能下降，精神行为症状及生活能力减退，即ABC症候群[3]。目前，AD已成为威胁人类健康的主要疾病之一，在2022年度更新的AD流行病学数据中，AD依然是65岁以上中国及美国人的第五大死亡原因。如若在预防、延缓及治愈方面没有突破性进展，到2050年这一数字可能增长至1380万[4]。据世界卫生组织估计2019年全球AD社会成本高达1.3万亿美元[5]。阿尔茨海默病是涉及多种病理生理变化的慢性复杂疾病，其发病机制非常多元化，根据目前的研究进展，AD的主要病理特征是淀粉样（Amyloid-β，Aβ）斑块和神经纤维缠结(Neurofibrillary tangles, NFTs) [6-7]，以及相关的星形胶质细胞增生、小胶质细胞激活和脑淀粉样血管病变等[8]，这些病理改变使神经元兴奋性和抑制性突触传递失衡[9]，进而导致神经元之间活动不平衡，神经网络功能不良，进而影响脑内Gamma 振荡的发生[10-11]。近几十年来，针对阿尔茨海默病的药物研发进展缓慢且困难重重，临床治疗效果不佳[4]。因此，许多科研人员将目光投向了非化学疗法对AD患者的影响。近年来，非侵入性多感官刺激治疗作为一种新兴的治疗手段，引起了越来越多的关注和研究。非侵入性多感官刺激治疗（non-invasive multisensory stimulation therapy，NIMST）是指通过对大脑的不同感觉区域（如视觉、听觉、触觉等）施加特定频率和强度的刺激，调节大脑的神经活动，改善神经元和突触的功能，从而影响认知和情绪等高级神经功能的一种治疗方法，非侵入性多感官刺激治疗技术也许可作为AD的替代治疗途径，成为一种新的选择方案[12-13]。

1 Gamma 振荡在认知障碍中的作用

神经振荡（Neural oscillations）是一种脑部活动的节律性波动，产生于局部神经元群或多个脑区神经元的协同活动，并随时间而变化[14]。这些振荡的频率范围包括Delta（1-4 Hz）、Theta（4-8 Hz）、Alpha（8-12 Hz）、Beta（15-30 Hz）、Gamma（30-90 Hz）以及高Gamma（>50 Hz）[15-16]。Gamma振荡作为一种快速的神经振荡，其频带范围相对较宽，介于25~100 Hz，由Gamma- 氨基丁酸A型受体(GABA受体) 抑制性中间神经元发放的抑制性突触后电位引发，可使神经网络中的兴奋信号暂时摆脱抑制信号的影响，进而增强不同脑区间信息传递的效率、精确性和选择性。目前大量研究表明，Gamma振荡与认知功能密切相关，当大脑执行需要高度认知控制和信息整合的任务时，Gamma振荡的强度和同步性会增加，在记忆编码、工作记忆、记忆检索等认知过程中发挥着重要作用，实现更复杂更高级的认知功能[17-18]。Iaccarino等人[19]通过使用AD的5xFAD小鼠模型进行实验，证明了在疾病早期，与野生型小鼠相比，5xFAD小鼠海马区的 Gamma神经振荡水平显著降低，并且这一Gamma振荡降低是出现在淀粉样斑块积聚等病理变化之前的。在人源 ApoE4 基因敲入的小鼠模型中的研究发现，这些小鼠在尚未出现认知障碍时即存在明显的慢gamma振荡减少，Gillespie等人[20-21]进一步使用该动物模型研究证明，增强慢gamma振荡可改善这些小鼠的学习障碍和记忆缺陷。此外，Jafari等人[22-23]在人类AD患者的一般静息脑电图（rs EEG）中发现，Gamma神经振荡存在异常，表现为快节律振荡（Alpha、Beta和Gamma频率）的减少和慢节律（Delta和Theta频率）的普遍增强。综合以上研究，gamma振荡的异常可能是引起认知障碍的一种机制，甚至可能在神经变性病变的前驱症状出现之前就存在，并且有理由相信Gamma振荡可作为AD潜在的早期电生理标志[24]。因此，研究Gamma振荡在神经系统疾病中的角色可能有助于我们更好地理解这些疾病的病理生理学，并且改善阿尔茨海默病患者的 Gamma 节律活性可能有助于改善AD患者认知功能。

2 40 Hz声光联合刺激对AD动物模型的影响

近年来，有大量研究指出，通过40 Hz的感官刺激（例如声音、可见光等）可以改善AD动物模型的脑部病理结构，从而提高其认知功能。根据Iaccarino等人[19]进行的一项重要研究表明，以特定频率闪烁的光刺激方案对5xFAD小鼠模型的神经振荡进行调控，研究结果表明，40 Hz光闪烁刺激能够特异性诱导视觉皮层中40 Hz神经振荡的功率，调节峰电位的发放频率，并且可以降低大约50%的Aβ淀粉样沉积和海马CA1区域的斑块负荷，然而，在20 Hz或者80 Hz的光刺激下不会产生相同甚至更好的效果。Adaikkan等人[25]还在Tau P301S AD和CK-p25小鼠模型中也报告了类似结果，并且实验还表明，40 Hz光照不仅能有效改善神经元及突触功能，还能改善神经小胶质细胞的“免疫吞噬”功能。

随后，Martorell 等人[26]在此研究基础上扩展到听觉系统，他们让5xFAD小鼠连续1周每天1小时的一系列听觉刺激（8 Hz, 40 Hz, 80 Hz，随机刺激和无刺激），结果发现，只有40 Hz声音刺激对AD小鼠产生显著影响，导致其听觉皮层和海马区域的Aβ淀粉样沉积显著减少，tau蛋白磷酸化水平降低。在认知功能测试中，接受40 Hz声音刺激的小鼠表现出更好的结果，其物体识别和空间记忆能力高于其他频率刺激组的小鼠。此外，研究者还发现，40 Hz声音刺激导致AD小鼠的小胶质细胞和星型胶质细胞数量增多，这些细胞具有更强的清除Aβ淀粉样物质清除能力，进而缓解AD相关的血管病理结构改变。在此基础上，Martorell 等人[26]进一步将40 Hz声光刺激结合起来，连续1周每天1小时作用于5xFAD小鼠，结果显示，与单独的听觉或视觉刺激相比，40 Hz声光联合刺激( gamma entrainment using sensory stimulation, GENUS )对Aβ淀粉样蛋白的清除效果更显著，并且40 Hz声光联合刺激进一步扩大了其影响范围，在大脑内侧前额叶皮层中也发现了数量增加的小胶质细胞，这些细胞聚集在蛋白质斑块周围，发挥其清除功能，联合刺激1周后，与未接受刺激的小鼠相比，前额叶皮层总斑块体积减少了37 %，数量减少了34 % 。基于以上AD动物模型的相关研究结果，40 Hz GENUS能够改善AD小鼠模型中Aβ淀粉样斑块沉积，神经纤维缠结，神经元突触功能丧失等关键病理变化，因此，这为进一步探索40 Hz多感觉刺激能否在AD患者中提供有效的治疗效果奠定了坚实的理论基础。

3 40 Hz声光联合刺激对AD患者的认知功能影响

多感官刺激在AD小鼠模型上已取得了显著效果。接下来，研究者们将多感官刺激治疗在健康人群和AD患者中的治疗效果展开临床试验。之前的研究表明，当人类大脑感觉区域受到几秒钟的到几小时的刺激时，连接会增强，这可能需要长时间的gamma感觉刺激来治疗阿尔茨海默病[27⇓⇓⇓-31]。目前，一些初期研究已经揭示了多感觉刺激治疗对于AD患者的潜在疗效。

目前多项研究表明40 Hz的光闪烁刺激能引起大脑更强的振荡活动，同时多个脑区的振荡活动也显著提升，但是在AD病理进展的最关键区域，即颞叶较少显示夹带效应[32-33]。另外，也有研究表明，长期暴露于40 Hz光闪烁刺激会对具有特殊神经系统疾病的患者带来一些潜在风险，Hermes等人[34]报道，在视觉皮层中引发的神经振荡可能引发光敏性癫痫患者的癫痫发作或癫痫前活动。基于这个问题，听觉刺激可能是能解决此类问题的一种选择。Chuanliang Han 等人[35]表明40 Hz正弦波的听觉刺激在前额叶区域引起的神经振荡反应最强，同时还发现40 Hz方波会抑制前额叶区域α节律，但是40 Hz的听觉刺激也并未引起颞叶的振荡活动。以上基于单种刺激均未引起颞叶有效的振荡活动，仍需进一步探索更有效的方法。

在临床试验中，以蔡理慧团队使用的40 Hz GENUS为例，Annabelle C. Singer团队进行了一项应用GENUS的小规模可能性研究，他们招募了10位轻度认知损伤的AD患者，随机分成两组，一组患者在8周内每天1小时接受40 Hz声光闪烁刺激，另一组在实验延迟4周后进行了4周治疗，试验结果显示，40 Hz声光闪烁刺激安全性及耐受性方面表现良好，所有患者均诱导出广泛的脑波夹带，并且经过8周的治疗，大脑网络连接得到了加强。与AD小鼠研究一样，40 Hz声光闪烁治疗也在人体中得到了免疫应答，经过8周后的声光刺激后，脑脊液中的细胞因子和免疫因子表现出下调的趋势[36]。类似地，Cimenser A等人[37]招募了22名轻中度AD患者，随机将他们分为积极治疗组和假手术组，并在两组中均持续进行了为期6个月的疗程。在此期间，每天都会给患者进行1小时的40 Hz声光闪烁刺激，研究结果表明，与假手术组相比，积极治疗组的夜间睡眠显著改善，而日常生活能力没有进一步下降。最近还有一项随机对照临床试验在15名轻度AD患者中进行，志愿者接受了GENUS装置的治疗，连续4个月每天接受1小时40 Hz声光刺激。结果表明，GENUS装置能安全有效地在皮层和皮层下引起神经振荡，并且还能影响之前的研究中单独使用听觉或视觉刺激没有引起Gamma振荡的区域，而安慰剂治疗无效。与安慰剂对照组相比，治疗组在GENUS刺激治疗后3个月内，显示出了一系列正面效应，这包括在默认模式网络(DMN)和内侧视觉网络(MVN)中表现出网络功能连接增强，海马体积保持稳定和心室扩大程度减小，昼夜节律和认知功能(即面孔-名字回忆测试)均得到改善，脑脊液中的细胞因子和免疫因子也有所变化[38]。值得一提的是，40 Hz声光刺激被证明是一种安全的技术，即使在癫痫患者样本中也不会引发癫痫样活动，并且在AD患者组和对照组中不会引起任何严重的不良反应。总之，这些有关GENUS的临床试验研究表明，GENUS可能有助于改善AD患者的认知功能和昼夜节律模式。

4 40 Hz振动触觉刺激对AD动物模型和AD患者的影响

以上多个研究小组已经在AD小鼠和人类患者身上用40 Hz的光和/或声音多感官刺激，证明可以改善认知功能。现在，已将研究继续延伸到触觉振动刺激上，Ho-Jun Suk 等人[39]在Tau-p 301S小鼠和CK-p25小鼠上进行了这项实验，在这项实验中，实验组小鼠被置于播放40 Hz声音的扬声器产生的振动中，而对照组小鼠则被放置在同一房间的笼子里，没有接受刺激。因此，刺激小鼠和对照小鼠之间的差异是通过增加振动触觉刺激来实现的。该实验主要关注大脑的两个区域：初级躯体感觉皮层（SSp）和初级运动皮层（MOp）。研究结果显示，在接受3周的振动刺激后，实验组Tau-p 301S小鼠SSp区域中tau含量显著降低，并且在Mop中表现出相似的趋势。对于实验组CK-p25小鼠接受6周的振动刺激后，它们的大脑SSp和Mop两个区域均显示出更高水平的突触蛋白标记物，并且DNA的损伤程度也有所降低。另外，暴露在振动触觉中的两种小鼠模型都表现出能在旋转杆上停留更长的时间，具有更强的运动能力。

在AD患者的研究中，Clements-Cortés等人[40]在2016年通过将40 Hz振动触觉刺激与低频声音刺激相结合（RSS），对18名不同严重程度的AD患者（6名轻度AD患者，6名中度AD患者，6名重度AD患者）进行评估，实验组接受40 Hz RSS治疗，对照组接受视觉刺激，均为每周2次，持续6周。结果表明，40 Hz RSS能够导致认知能力（SLUMS）的进行性改善，并且能提升轻中度AD患者的行为能力。2022年，Clements-Cortés等人[41]随后使用多感官刺激Sound Oasis VTS 1000设备对2名 AD患者和1名 MCI患者进行了长达1年时间的调控。SLUMS结果表明，这3 例患者的认知功能水平在一年内保持稳定，这也初步证明 40 Hz 听觉伴随触觉刺激有望改善 AD 患者的病情进展。以上实验均表明40 Hz听觉伴随触觉刺激能有效缓解AD患者疾病的进展、改善认知功能、心理功能的可能性。

5 总结与展望

近年来，针对阿尔茨海默病的多感官刺激非侵入性治疗手段正受到越来越多的关注。现有的证据表明，40 Hz gamma 振荡具有潜在的神经保护作用，能诱导神经胶质细胞反应促进神经保护，减轻AD相关的病理变化[16,42]。此外，gamma刺激能改善AD患者的脑血流灌注，调控突触的可塑性，增强神经元之间的同步性和连接性的潜力[43-44]，为治疗AD带来了新的希望[45]。尽管前述一系列成功的研究为这一治疗方法铺平了道路，但最近一项研究成果却与之前的发现相矛盾，对之前的研究成果发出了质疑和挑战。Soula等人[46]在2023年的研究中调查了急性和慢性40 Hz 刺激在APP/PS1和5xFAD动物模型中的作用。他们的研究结果表明，40 Hz的闪烁光并不能降低新皮质或海马体中的Aβ蛋白水平。相反，研究发现小鼠会避免40 Hz光闪烁刺激，并且只有一小部分海马和内嗅神经元对光刺激有反应，但对于Gamma振荡没有观察到显著的影响。目前这项实验对之前的研究成果提出了挑战，但也需要考虑到动物模型的个体差异以及可能存在的未知实验干扰因素，并且还未有其他更多的相关研究对此研究成果进一步证实。因此，对于40 Hz光刺激对神经疾病的确切作用还需要进一步的研究和验证。

目前，多种用于临床治疗的40 Hz多感觉刺激治疗设备正在开发中，例如GENUS，虚拟现实（VR）技术，Sound Oasis VTS 1000和音乐疗法设备等，这些设备应用在临床和家庭中都有广泛的潜力。多感官刺激治疗具有高度扩散的特性，与以前的非侵入性脑刺激技术[如经颅磁刺激(TMS)和经颅直流电刺激(tDCS)]不同，它们不需要直接作用于颅骨，因此影响范围更广泛，涵盖多个脑区域[47⇓-49]。此外，与需要手术植入的深部脑刺激(DBS)相比，多感官刺激治疗更为便捷[50]。研究表明，在动物模型中，多感官刺激治疗通常从感觉（听觉或视觉）皮层起始，然后扩散到其他大脑区域，包括内侧前额叶皮层(mPFC)和海马CA1区[25-26]，甚至可能影响到更深层的脑区域。这一特性使多感官刺激治疗在治疗阿尔茨海默病等神经疾病时具有潜在的优势。然而，关于多感官刺激治疗在治疗阿尔茨海默病的研究仍处于起步阶段，且在AD患者中的具体作用机制尚不清楚，目前开展的相关临床试验样本量都较少，仍需要进行进一步的实验研究和更大样本中展开纵向临床试验，以确定这种多感官刺激方法在治疗阿尔茨海默病中的有效性和安全性。

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Karaman R

. Comprehensive review on alzheimer's disease: causes and treatment[J]. Molecules, 2020, 25(24):5789.

Alzheimer’s disease (AD) is a disorder that causes degeneration of the cells in the brain and it is the main cause of dementia, which is characterized by a decline in thinking and independence in personal daily activities. AD is considered a multifactorial disease: two main hypotheses were proposed as a cause for AD, cholinergic and amyloid hypotheses. Additionally, several risk factors such as increasing age, genetic factors, head injuries, vascular diseases, infections, and environmental factors play a role in the disease. Currently, there are only two classes of approved drugs to treat AD, including inhibitors to cholinesterase enzyme and antagonists to N-methyl d-aspartate (NMDA), which are effective only in treating the symptoms of AD, but do not cure or prevent the disease. Nowadays, the research is focusing on understanding AD pathology by targeting several mechanisms, such as abnormal tau protein metabolism, β-amyloid, inflammatory response, and cholinergic and free radical damage, aiming to develop successful treatments that are capable of stopping or modifying the course of AD. This review discusses currently available drugs and future theories for the development of new therapies for AD, such as disease-modifying therapeutics (DMT), chaperones, and natural compounds.

Singh A

, Ekavali, et al. A review on Alzheimer's disease pathophysiology and its management:an update[J]. Pharmacol Rep, 2015, 67(2): 195-203.

Alzheimer's disease acknowledged as progressive multifarious neurodegenerative disorder, is the leading cause of dementia in late adult life. Pathologically it is characterized by intracellular neurofibrillary tangles and extracellular amyloidal protein deposits contributing to senile plaques. Over the last two decades, advances in the field of pathogenesis have inspired the researchers for the investigation of novel pharmacological therapeutics centered more towards the pathophysiological events of the disease. Currently available treatments i.e. acetylcholinesterase inhibitors (rivastigmine, galantamine, donepezil) and N-methyl d-aspartate receptor antagonist (memantine) contribute minimal impact on the disease and target late aspects of the disease. These drugs decelerate the progression of the disease, provide symptomatic relief but fail to achieve a definite cure. While the neuropathological features of Alzheimer's disease are recognized but the intricacies of the mechanism have not been clearly defined. This lack of understanding regarding the pathogenic process may be the likely reason for the non-availability of effective treatment which can prevent onset and progression of the disease. Owing to the important progress in the field of pathophysiology in the last couple of years, new therapeutic targets are available that should render the underlying disease process to be tackled directly. In this review, authors will discusses the different aspects of pathophysiological mechanisms behind Alzheimer's disease and its management through conventional drug therapy, including modern investigational therapeutic strategies, recently completed and ongoing. Copyright © 2014 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

Selkoe DJ

. Neurotoxicity of amyloid β-protein: synaptic and network dysfunction[J]. Cold Spring Harb Perspect Med, 2012, 2(7): a006338.

Yamazaki T

Citron M

, et al. The role of APP processing and trafficking pathways in the formation of amyloid beta-protein[J]. Ann N Y Acad Sci, 1996, 777: 57-64.

Mann EO

Hang GB

, et al. Inhibitory interneuron deficit links altered network activity and cognitive dysfunction in Alzheimer model[J]. Cell, 2012, 149(3): 708-721.

Alzheimer's disease (AD) results in cognitive decline and altered network activity, but the mechanisms are unknown. We studied human amyloid precursor protein (hAPP) transgenic mice, which simulate key aspects of AD. Electroencephalographic recordings in hAPP mice revealed spontaneous epileptiform discharges, indicating network hypersynchrony, primarily during reduced gamma oscillatory activity. Because this oscillatory rhythm is generated by inhibitory parvalbumin (PV) cells, network dysfunction in hAPP mice might arise from impaired PV cells. Supporting this hypothesis, hAPP mice and AD patients had decreased levels of the interneuron-specific and PV cell-predominant voltage-gated sodium channel subunit Nav1.1. Restoring Nav1.1 levels in hAPP mice by Nav1.1-BAC expression increased inhibitory synaptic activity and gamma oscillations and reduced hypersynchrony, memory deficits, and premature mortality. We conclude that reduced Nav1.1 levels and PV cell dysfunction critically contribute to abnormalities in oscillatory rhythms, network synchrony, and memory in hAPP mice and possibly in AD.Copyright © 2012 Elsevier Inc. All rights reserved.

Dulewicz M

Kulczyńska-przybik A

, et al. Biochemical markers in Alzheimer's disease[J]. Int J Mol Sci, 2020, 21(6):222-234.

The microbiome is able to modulate immune responses, alter the physiology of the human organism, and increase the risk of viral infections and development of diseases such as cancer. In this review, we address changes in the cervical microbiota as potential biomarkers to identify the risk of cervical intraepithelial neoplasia (CIN) development and invasive cervical cancer in the context of human papillomavirus (HPV) infection. Current approaches for clinical diagnostics and the manipulation of microbiota with the use of probiotics and through microbiota transplantation are also discussed.

Penney J

Tsai LH

, et al. The road to restoring neural circuits for the treatment of Alzheimer's disease[J]. Nature, 2016, 539(7628): 187-196.

Colgin LL

. Gamma oscillations in cognitive disorders[J]. Curr Opin Neurobiol, 2018, 52: 182-187.

Gamma oscillations (∼25-100 Hz) are believed to play a role in cognition. Accordingly, aberrant gamma oscillations have been observed in several cognitive disorders, including Alzheimer's disease and Fragile X syndrome. Here, we review how recent results showing abnormal gamma rhythms in Alzheimer's disease and Fragile X syndrome help reveal links between cellular disturbances and cognitive impairments. We also discuss how gamma results from rodent models of Alzheimer's disease and Fragile X syndrome may provide insights about unique functions of distinct slow (∼25-50 Hz) and fast gamma (∼55-100 Hz) subtypes. Finally, we consider studies employing brain stimulation paradigms in Alzheimer's disease and discuss how such studies may reveal causal relationships between gamma impairments and memory disturbances.Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.

Femir B

Emek-savaş DD

, et al. Increased long distance event-related gamma band connectivity in Alzheimer's disease[J]. Neuroimage Clin, 2017, 14: 580-590.

Rossi S

Koch G

, et al. Toward noninvasive brain stimulation 2.0 in Alzheimer's disease[J]. Ageing Res Rev, 2022, 75: 101555.

Konstantinou N

. Gamma oscillations in alzheimer's disease and their potential therapeutic role[J]. Front Syst Neurosci, 2021, 15: 782399.

Despite decades of research, Alzheimer’s Disease (AD) remains a lethal neurodegenerative disorder for which there are no effective treatments. This review examines the latest evidence of a novel and newly introduced perspective, which focuses on the restoration of gamma oscillations and investigates their potential role in the treatment of AD. Gamma brain activity (∼25–100 Hz) has been well-known for its role in cognitive function, including memory, and it is fundamental for healthy brain activity and intra-brain communication. Aberrant gamma oscillations have been observed in both mice AD models and human AD patients. A recent line of work demonstrated that gamma entrainment, through auditory and visual sensory stimulation, can effectively attenuate AD pathology and improve cognitive function in mice models of the disease. The first evidence from AD patients indicate that gamma entrainment therapy can reduce loss of functional connectivity and brain atrophy, improve cognitive function, and ameliorate several pathological markers of the disease. Even though research is still in its infancy, evidence suggests that gamma-based therapy may have a disease-modifying effect and has signified a new and promising era in AD research.

Semenova A

Sakata S

, et al. Mutual interactions between brain states and alzheimer's disease pathology: a focus on gamma and slow oscillations[J]. Biology (Basel), 2021, 10(8).

Sohal VS

. Neural oscillations and synchrony in brain dysfunction and neuropsychiatric disorders: it's about time[J]. JAMA Psychiatry, 2015, 72(8): 840-844.

Neural oscillations are rhythmic fluctuations over time in the activity or excitability of single neurons, local neuronal populations or "assemblies," and/or multiple regionally distributed neuronal assemblies. Synchronized oscillations among large numbers of neurons are evident in electrocorticographic, electroencephalographic, magnetoencephalographic, and local field potential recordings and are generally understood to depend on inhibition that paces assemblies of excitatory neurons to produce alternating temporal windows of reduced and increased excitability. Synchronization of neural oscillations is supported by the extensive networks of local and long-range feedforward and feedback bidirectional connections between neurons. Here, we review some of the major methods and measures used to characterize neural oscillations, with a focus on gamma oscillations. Distinctions are drawn between stimulus-independent oscillations recorded during resting states or intervals between task events, stimulus-induced oscillations that are time locked but not phase locked to stimuli, and stimulus-evoked oscillations that are both time and phase locked to stimuli. Synchrony of oscillations between recording sites, and between the amplitudes and phases of oscillations of different frequencies (cross-frequency coupling), is described and illustrated. Molecular mechanisms underlying gamma oscillations are also reviewed. Ultimately, understanding the temporal organization of neuronal network activity, including interactions between neural oscillations, is critical for elucidating brain dysfunction in neuropsychiatric disorders.

Voytek B

. Brain Oscillations and the Importance of Waveform Shape[J]. Trends Cogn Sci, 2017, 21(2): 137-149.

Oscillations are a prevalent feature of brain recordings. They are believed to play key roles in neural communication and computation. Current analysis methods for studying neural oscillations often implicitly assume that the oscillations are sinusoidal. While these approaches have proven fruitful, we show here that there are numerous instances in which neural oscillations are nonsinusoidal. We highlight approaches to characterize nonsinusoidal features and account for them in traditional spectral analysis. Instead of being a nuisance, we discuss how these nonsinusoidal features may provide crucial and so far overlooked physiological information related to neural communication, computation, and cognition.Copyright © 2016 Elsevier Ltd. All rights reserved.

Wang S

Huang A

, et al. The role of gamma oscillations in central nervous system diseases:mechanism and treatment[J]. Front Cell Neurosci, 2022, 16: 962957.

Gamma oscillation is the synchronization with a frequency of 30–90 Hz of neural oscillations, which are rhythmic electric processes of neuron groups in the brain. The inhibitory interneuron network is necessary for the production of gamma oscillations, but certain disruptions such as brain inflammation, oxidative stress, and metabolic imbalances can cause this network to malfunction. Gamma oscillations specifically control the connectivity between different brain regions, which is crucial for perception, movement, memory, and emotion. Studies have linked abnormal gamma oscillations to conditions of the central nervous system, including Alzheimer’s disease, Parkinson’s disease, and schizophrenia. Evidence suggests that gamma entrainment using sensory stimuli (GENUS) provides significant neuroprotection. This review discusses the function of gamma oscillations in advanced brain activities from both a physiological and pathological standpoint, and it emphasizes gamma entrainment as a potential therapeutic approach for a range of neuropsychiatric diseases.

Peylo C

Biel AL

, et al. Does cross-frequency phase coupling of oscillatory brain activity contribute to a better understanding of visual working memory?[J]. Br J Psychol, 2019, 110(2):245-255.

Singer AC

Martorell AJ

, et al. Gamma frequency entrainment attenuates amyloid load and modifies microglia[J]. Nature, 2016, 540(7632): 230-235.

Jones EA

Lin YH

, et al. Apolipoprotein E4 Causes Age-Dependent Disruption of Slow Gamma Oscillations during Hippocampal Sharp-Wave Ripples[J]. Neuron, 2016, 90(4): 740-751.

Apolipoprotein (apo) E4 is the major genetic risk factor for Alzheimer's disease (AD), but the mechanism by which it causes cognitive decline is unclear. In knockin (KI) mice, human apoE4 causes age-dependent learning and memory impairments and degeneration of GABAergic interneurons in the hippocampal dentate gyrus. Here we report two functional apoE4-KI phenotypes involving sharp-wave ripples (SWRs), hippocampal network events critical for memory processes. Aged apoE4-KI mice had fewer SWRs than apoE3-KI mice and significantly reduced slow gamma activity during SWRs. Elimination of apoE4 in GABAergic interneurons, which prevents learning and memory impairments, rescued SWR-associated slow gamma activity but not SWR abundance in aged mice. SWR abundance was reduced similarly in young and aged apoE4-KI mice; however, the full SWR-associated slow gamma deficit emerged only in aged apoE4-KI mice. These results suggest that progressive decline of interneuron-enabled slow gamma activity during SWRs critically contributes to apoE4-mediated learning and memory impairments. VIDEO ABSTRACT.Copyright © 2016 Elsevier Inc. All rights reserved.

Bien-ly N

Xu Q

, et al. Apolipoprotein E4 causes age- and Tau-dependent impairment of GABAergic interneurons, leading to learning and memory deficits in mice[J]. J Neurosci, 2010, 30(41): 13707-13717.

Apolipoprotein E4 (apoE4) is the major genetic risk factor for Alzheimer's disease. However, the underlying mechanisms are unclear. We found that female apoE4 knock-in (KI) mice had an age-dependent decrease in hilar GABAergic interneurons that correlated with the extent of learning and memory deficits, as determined in the Morris water maze, in aged mice. Treating apoE4-KI mice with daily peritoneal injections of the GABA(A) receptor potentiator pentobarbital at 20 mg/kg for 4 weeks rescued the learning and memory deficits. In neurotoxic apoE4 fragment transgenic mice, hilar GABAergic interneuron loss was even more pronounced and also correlated with the extent of learning and memory deficits. Neurodegeneration and tauopathy occurred earliest in hilar interneurons in apoE4 fragment transgenic mice; eliminating endogenous Tau prevented hilar GABAergic interneuron loss and the learning and memory deficits. The GABA(A) receptor antagonist picrotoxin abolished this rescue, while pentobarbital rescued learning deficits in the presence of endogenous Tau. Thus, apoE4 causes age- and Tau-dependent impairment of hilar GABAergic interneurons, leading to learning and memory deficits in mice. Consequently, reducing Tau and enhancing GABA signaling are potential strategies to treat or prevent apoE4-related Alzheimer's disease.

Fang Y

Wang X

, et al. Enhanced gamma activity and cross-frequency interaction of resting-state electroencephalographic oscillations in patients with Alzheimer's disease[J]. Front Aging Neurosci, 2017, 9: 243.

Cognitive impairment, functional decline and behavioral symptoms that characterize Alzheimer's disease (AD) are associated with perturbations of the neuronal network. The typical electroencephalographic (EEG) features in AD patients are increased delta or theta rhythm and decreased alpha or beta rhythm activities. However, considering the role of cross-frequency couplings in cognition, the alternation of cross-frequency couplings in AD patients is still obscure. This study aims to explore the interaction dynamics between different EEG oscillations in AD patients. We recorded the resting eye-closed EEG signals in 8 AD patients and 12 healthy volunteers. By analyzing the wavelet power spectrum and bicoherence of EEG, we found enhanced gamma rhythm power in AD patients in addition to the increased delta and decreased alpha power. Furthermore, an enhancement of the cross-frequency coupling strength between the beta/gamma and low-frequency bands was observed in AD patients compared to healthy controls (HCs). We propose that the pathological increase of ongoing gamma-band power might result from the disruption of the GABAergic interneuron network in AD patients. Furthermore, the cross-frequency overcouplings, which reflect the enhanced synchronization, might indicate the attenuated complexity of the neuronal network, and AD patients have to use more neural resources to maintain the resting brain state. Overall, our findings provide new evidence of the disturbance of the brain oscillation network in AD and further deepen our understanding of the central mechanisms of AD.

Manikandan K

Kumar WS

, et al. Gamma oscillations weaken with age in healthy elderly in human EEG[J]. Neuroimage, 2020, 215: 116826.

Nielsen MS

Musaeus JS

, et al. Electroencephalographic cross-frequency coupling as a sign of disease progression in patients with mild cognitive impairment: a pilot study[J]. Front Neurosci, 2020, 14: 790.

Middleton SJ

Marco A

, et al. Gamma entrainment binds higher-order brain regions and offers neuroprotection[J]. Neuron, 2019, 102(5): 929-43.e8.

Neuronal and synaptic loss is characteristic in many neurodegenerative diseases, such as frontotemporal dementia and Alzheimer's disease. Recently, we showed that inducing gamma oscillations with visual stimulation (gamma entrainment using sensory stimuli, or GENUS) reduced amyloid plaques and phosphorylated tau in multiple mouse models. Whether GENUS can affect neurodegeneration or cognitive performance remains unknown. Here, we demonstrate that GENUS can entrain gamma oscillations in the visual cortex, hippocampus, and prefrontal cortex in Tau P301S and CK-p25 mouse models of neurodegeneration. Tau P301S and CK-p25 mice subjected to chronic, daily GENUS from the early stages of neurodegeneration showed a preservation of neuronal and synaptic density across multiple brain areas and modified cognitive performance. Our transcriptomic and phosphoproteomic data suggest that chronic GENUS shifts neurons to a less degenerative state, improving synaptic function, enhancing neuroprotective factors, and reducing DNA damage in neurons while also reducing inflammatory response in microglia.Copyright © 2019 Elsevier Inc. All rights reserved.

Paulson AL

Suk HJ

, et al. Multi-sensory gamma stimulation ameliorates alzheimer's-associated pathology and improves cognition[J]. Cell, 2019, 177(2): 256-71.e22.

We previously reported that inducing gamma oscillations with a non-invasive light flicker (gamma entrainment using sensory stimulus or GENUS) impacted pathology in the visual cortex of Alzheimer's disease mouse models. Here, we designed auditory tone stimulation that drove gamma frequency neural activity in auditory cortex (AC) and hippocampal CA1. Seven days of auditory GENUS improved spatial and recognition memory and reduced amyloid in AC and hippocampus of 5XFAD mice. Changes in activation responses were evident in microglia, astrocytes, and vasculature. Auditory GENUS also reduced phosphorylated tau in the P301S tauopathy model. Furthermore, combined auditory and visual GENUS, but not either alone, produced microglial-clustering responses, and decreased amyloid in medial prefrontal cortex. Whole brain analysis using SHIELD revealed widespread reduction of amyloid plaques throughout neocortex after multi-sensory GENUS. Thus, GENUS can be achieved through multiple sensory modalities with wide-ranging effects across multiple brain areas to improve cognitive function.Copyright © 2019 Elsevier Inc. All rights reserved.

Makeig S

Talmachoff PJ

, et al. A 40-Hz auditory potential recorded from the human scalp[J]. Proc Natl Acad Sci U S A, 1981, 78(4): 2643-2647.

Computer techniques readily extract from the brainwaves an orderly sequence of brain potentials locked in time to sound stimuli. The potentials that appear 8 to 80 msec after the stimulus resemble 3 or 4 cycles of a 40-Hz sine wave; we show here that these waves combined to form a single, stable, composite wave when the sounds are repeated at rates around 40 per sec. This phenomenon, the 40-Hz event-related potential (ERP), displays several properties of theoretical and practical interest. First, it reportedly disappears with surgical anesthesia, and it resembles similar phenomena in the visual and olfactory system, facts which suggest that adequate processing of sensory information may require cyclical brain events in the 30- to 50-Hz range. Second, latency and amplitude measurements on the 40-Hz ERP indicate it may contain useful information on the number and basilar membrane location of the auditory nerve fibers a given tone excites. Third, the response is present at sound intensities very close to normal adult thresholds for the audiometric frequencies, a fact that could have application in clinical hearing testing.

Appelbaum LG

Ales JM

, et al. The steady-state visual evoked potential in vision research: A review[J]. J Vis, 2015, 15(6): 4.

Linden D

Suffield JB

, et al. Human auditory steady state potentials[J]. Ear Hear, 1984, 5(2): 105-113.

Vuurman EF

, et al. Van Kranen-mastenbroek VH,40-Hz steady state response in Alzheimer's disease and mild cognitive impairment[J]. Neurobiol Aging, 2011, 32(1): 24-30.

The 40-Hz steady state response (SSR) reflects early sensory processing and can be measured with electroencephalography (EEG). The current study compared the 40-Hz SSR in groups consisting of mild Alzheimer's disease patients (AD) (n=15), subjects with mild cognitive impairment (MCI) (n=20) and healthy elderly control subjects (n=20). All participants were naïve for psychoactive drugs. Auditory click trains at a frequency of 40-Hz evoked the 40-Hz SSR. To evaluate test-retest reliability (TRR), subjects underwent a similar assessment 1 week after the first. The results showed a high TRR and a significant increase of 40-Hz SSR power in the AD group compared to MCI and controls. Furthermore a moderate correlation between 40-Hz SSR power and cognitive performance as measured by ADAS-cog was shown. The results suggest that 40-Hz SSR might be an interesting candidate marker of disease progression.Copyright © 2009. Published by Elsevier Inc.

Park Y

Suh SW

, et al. Optimal flickering light stimulation for entraining gamma waves in the human brain[J]. Sci Rep, 2021, 11(1): 16206.

Although light flickering at 40 Hz reduced Alzheimer's disease (AD) pathologies in mice by entraining gamma waves, it failed to reduce cerebral amyloid burden in a study on six patients with AD or mild cognitive impairment. We investigated the optimal color, intensity, and frequency of the flickering light stimulus for entraining gamma waves in young adults. We compared the event-related synchronization (ERS) values of entrained gamma waves between four different light colors (white, red, green, and blue) in the first experiment and four different luminance intensities in the second experiment. In both experiments, we compared the ERS values of entrained gamma waves between 10 different flickering frequencies from 32 to 50 Hz. We also examined the severity of six adverse effects in both experiments. We compared the propagation of gamma waves in the visual cortex to other brain regions between different luminance intensities and flickering frequencies. We found that red light entrained gamma waves most effectively, followed by white light. Lights of higher luminance intensities (700 and 400 cd/m) entrained stronger gamma waves than those of lower luminance intensities (100 and 10 cd/m). Lights flickering at 34-38 Hz entrained stronger and more widely spread beyond the visual cortex than those flickering at 40-50 Hz. Light of 700 cd/m resulted in more moderate-to-severe adverse effects than those of other luminance intensities. In humans, 400 cd/m white light flickering at 34-38 Hz was most optimal for gamma entrainment.© 2021. The Author(s).

Lee K

Park J

, et al. Optimal flickering light stimulation for entraining gamma rhythms in older adults[J]. Sci Rep, 2022, 12(1): 15550.

With aging, optimal parameters of flickering light stimulation (FLS) for gamma entrainment may change in the eyes and brain. We investigated the optimal FLS parameters for gamma entrainment in 35 cognitively normal old adults by comparing event-related synchronization (ERS) and spectral Granger causality (sGC) of entrained gamma rhythms between different luminance intensities, colors, and flickering frequencies of FLSs. ERS entrained by 700 cd/m FLS and 32 Hz or 34 Hz FLSs was stronger than that entrained by 400 cd/m at Pz (p < 0.01) and 38 Hz or 40 Hz FLSs, respectively, at both Pz (p < 0.05) and Fz (p < 0.01). Parieto-occipital-to-frontotemporal connectivities of gamma rhythm entrained by 700 cd/m FLS and 32 Hz or 34 Hz FLSs were also stronger than those entrained by 400 cd/m at Pz (p < 0.01) and 38 Hz or 40 Hz FLSs, respectively (p < 0.001). ERS and parieto-occipital-to-frontotemporal connectivities of entrained gamma rhythms did not show significant difference between white and red lights. Adverse effects were comparable between different parameters. In older adults, 700 cd/m FLS at 32 Hz or 34 Hz can entrain a strong gamma rhythm in the whole brain with tolerable adverse effects.© 2022. The Author(s).

Kasteleijn-nolst Trenité DGA

WINAWER J

, et al. Gamma oscillations and photosensitive epilepsy[J]. Curr Biol, 2017, 27(9): R336-R338.

Zhao X

Li M

, et al. Enhancement of the neural response during 40 Hz auditory entrainment in closed-eye state in human prefrontal region[J]. Cogn Neurodyn, 2023, 17(2): 399-410.

Colon-motas KM

Pybus AF

, et al. A feasibility trial of gamma sensory flicker for patients with prodromal Alzheimer's disease[J]. Alzheimers Dement (N Y), 2021, 7(1): e12178.

Hempel E

Travers T

, et al. Sensory-evoked 40-hz gamma oscillation improves sleep and daily living activities in Alzheimer's disease patients[J]. Front Syst Neurosci, 2021, 15: 746859.

Pathological proteins contributing to Alzheimer’s disease (AD) are known to disrupt normal neuronal functions in the brain, leading to unbalanced neuronal excitatory-inhibitory tone, distorted neuronal synchrony, and network oscillations. However, it has been proposed that abnormalities in neuronal activity directly contribute to the pathogenesis of the disease, and in fact it has been demonstrated that induction of synchronized 40 Hz gamma oscillation of neuronal networks by sensory stimulation reverses AD-related pathological markers in transgenic mice carrying AD-related human pathological genes. Based on these findings, the current study evaluated whether non-invasive sensory stimulation inducing cortical 40 Hz gamma oscillation is clinically beneficial for AD patients. Patients with mild to moderate AD (n = 22) were randomized to active treatment group (n = 14; gamma sensory stimulation therapy) or to sham group (n = 8). Participants in the active treatment group received precisely timed, 40 Hz visual and auditory stimulations during eye-closed condition to induce cortical 40 Hz steady-state oscillations in 1-h daily sessions over a 6-month period. Participants in the sham group were exposed to similar sensory stimulation designed to not evoke cortical 40 Hz steady-state oscillations that are observed in the active treatment patients. During the trial, nighttime activities of the patients were monitored with continuous actigraphy recordings, and their functional abilities were measured by Alzheimer’s Disease Cooperative Study – Activities of Daily Living (ADCS-ADL) scale. Results of this study demonstrated that 1-h daily therapy was well tolerated throughout the 6-month treatment period by all subjects. Patients receiving gamma sensory stimulation showed significantly reduced nighttime active periods, in contrast, to deterioration in sleep quality in sham group patients. Patients in the sham group also showed the expected, significant decline in ADCS-ADL scores, whereas patients in the gamma sensory stimulation group fully maintained their functional abilities over the 6-month period. These findings confirm the safe application of 40 Hz sensory stimulation in AD patients and demonstrate a high adherence to daily treatment. Furthermore, this is the first time that beneficial clinical effects of the therapy are reported, justifying expanded and longer trials to explore additional clinical benefits and disease-modifying properties of gamma sensory stimulation therapy.

Suk HJ

Jackson BL

, et al. Gamma frequency sensory stimulation in mild probable Alzheimer's dementia patients: Results of feasibility and pilot studies[J]. PLoS One, 2022, 17(12): e0278412.

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.

Buie N

Xu G

, et al. Vibrotactile stimulation at gamma frequency mitigates pathology related to neurodegeneration and improves motor function[J]. Front Aging Neurosci, 2023, 15: 1129510.

The risk for neurodegenerative diseases increases with aging, with various pathological conditions and functional deficits accompanying these diseases. We have previously demonstrated that non-invasive visual stimulation using 40 Hz light flicker ameliorated pathology and modified cognitive function in mouse models of neurodegeneration, but whether 40 Hz stimulation using another sensory modality can impact neurodegeneration and motor function has not been studied. Here, we show that whole-body vibrotactile stimulation at 40 Hz leads to increased neural activity in the primary somatosensory cortex (SSp) and primary motor cortex (MOp). In two different mouse models of neurodegeneration, Tau P301S and CK-p25 mice, daily exposure to 40 Hz vibrotactile stimulation across multiple weeks also led to decreased brain pathology in SSp and MOp. Furthermore, both Tau P301S and CK-p25 mice showed improved motor performance after multiple weeks of daily 40 Hz vibrotactile stimulation. Vibrotactile stimulation at 40 Hz may thus be considered as a promising therapeutic strategy for neurodegenerative diseases with motor deficits.

Ahonen H

Evans M

, et al. Short-term effects of rhythmic sensory stimulation in alzheimer's disease: an exploratory pilot study[J]. J Alzheimers Dis, 2016, 52(2): 651-660.

This study assessed the effect of stimulating the somatosensory system of Alzheimer's disease (AD) patients at three stages of their illness with 40 Hz sound. In this AB cross-over study design, 18 participants (6 mild, 6 moderate, 6 severe) each participated in 13 sessions: one intake and 12 treatment. Treatment A consisted of 40 Hz sound stimulation and Treatment B consisted of visual stimulation using DVDs, each provided twice a week over 6 weeks for a total of 6 times per treatment. Outcome measures included: St. Louis University Mental Status Test (SLUMS), Observed Emotion Rating Scale, and behavioral observation by the researcher. Data were submitted to regression analysis for the series of 6 SLUMS scores in treatment A and 6 scores in B with comparison by group. The slopes for the full sample and subgroups in the 40 Hz treatment were all significant beyond alpha = 0.05, while those for the DVD were not. A thematic analysis of qualitative observations supported the statistical findings. 40 Hz treatment appeared to have the strongest impact on persons with mild and moderate AD. Results are promising in terms of a potential new treatment for persons with AD, and further research is needed.

Bartel L

. Long-term multi-sensory gamma stimulation of dementia patients: a case series report[J]. Int J Environ Res Public Health, 2022, 19(23):15553.

Dementia prevalence is increasing globally, and symptom management and treatment strategies require further investigation. Music-based interventions have demonstrated some efficacy with respect to quality of life and symptom reduction, though limited with respect to cognition. This study reports on three case studies where the use of gamma stimulation over one year contributed to maintenance of cognition and increases in mood for participants with Alzheimer’s disease or mild cognitive impairment. Auditory stimulation with isochronous sound at 40 Hz was delivered to participants via a commercially available vibroacoustic chair device five times per week for 30 min with assistance from caregivers. Further research is needed to assess the integration of this therapy in the overall care for persons with dementia.

. A mechanism for cognitive dynamics: neuronal communication through neuronal coherence[J]. Trends Cogn Sci, 2005, 9(10): 474-480.

At any one moment, many neuronal groups in our brain are active. Microelectrode recordings have characterized the activation of single neurons and fMRI has unveiled brain-wide activation patterns. Now it is time to understand how the many active neuronal groups interact with each other and how their communication is flexibly modulated to bring about our cognitive dynamics. I hypothesize that neuronal communication is mechanistically subserved by neuronal coherence. Activated neuronal groups oscillate and thereby undergo rhythmic excitability fluctuations that produce temporal windows for communication. Only coherently oscillating neuronal groups can interact effectively, because their communication windows for input and for output are open at the same times. Thus, a flexible pattern of coherence defines a flexible communication structure, which subserves our cognitive flexibility.

Ioannides AA

Singh KD

, et al. Magnetic field tomography of coherent thalamocortical 40-Hz oscillations in humans[J]. Proc Natl Acad Sci U S A, 1991, 88(24): 11037-11041.

This paper introduces the use of magnetic field tomography (MFT), a noninvasive technique based on distributed source analysis of magnetoencephalography data, which makes possible the three-dimensional reconstruction of dynamic brain activity in humans. MFT has a temporal resolution better than 1 msec and a spatial accuracy of 2-5 mm at the cortical level, which deteriorates to 1-3 cm at depths of 6 cm or more. MFT is used here to visualize the origin of a spatiotemporally organized pattern of coherent 40-Hz electrical activity. This coherence, initially observed during auditory input, was proposed to be generated by recurrent corticothalamic oscillation. In support of this hypothesis, we illustrate well-defined 40-Hz coherence between cortical-subcortical sites with a time shift that is consistent with thalamocortical conduction times. Studies on Alzheimer patients indicate that, while a similar activity pattern is present, the cortical component is reduced in these subjects.

Traub RD

Whittington MA

, et al. Neuronal networks for induced '40 Hz' rhythms[J]. Trends Neurosci, 1996, 19(5): 202-208.

A fast, coherent EEG rhythm, called a gamma or a '40 Hz' rhythm, has been implicated both in higher brain functions, such as the 'binding' of features that are detected by sensory cortices into perceived objects, and in lower level processes, such as the phase coding of neuronal activity. Computer simulations of several parts of the brain suggest that gamma rhythms can be generated by pools of excitatory neurones, networks of inhibitory neurones, or networks of both excitatory and inhibitory neurones. The strongest experimental evidence for rhythm generators has been shown for: (1) neocortical and thalamic neurones that are intrinsic '40 Hz' oscillators, although synchrony still requires network mechanisms; and (2) hippocampal and neocortical networks of mutually inhibitory interneurones that generate collective 40 Hz rhythms when excited tonically.

Frisoni GB

Fracassi C

, et al. MCI patients' EEGs show group differences between those who progress and those who do not progress to AD[J]. Neurobiol Aging, 2011, 32(4): 563-571.

The theta/gamma and alpha3/alpha2 ratio were investigated as early markers for prognosticating of progression to dementia. 76 subjects with mild cognitive impairment (MCI) underwent EEG recording, MRI scans and neuropsychological (NPS) tests. After 3 years of follow-up, three subgroups were characterized as converters to Alzheimer's disease (AD, N=18), converters to non-AD dementia (N=14) and non-converters (N=44). The theta/gamma and alpha3/alpha2 ratio, performance on cognitive tests and hippocampal volume, as evaluated at the time of initial MCI diagnosis, were studied in the three groups. As expected, MCI to AD converters had the smallest mean hippocampal volume and poorest performance on verbal learning tests, whereas MCI to non-AD converters had poorest cognitive performance in non-verbal learning tests, abstract thinking, and letter fluency. Increased theta/gamma ratio was associated with conversion to both AD and non-AD dementia; increased alpha3/alpha2 ratio was only associated with conversion to AD. Theta/gamma and alpha3/alpha2 ratio could be promising prognostic markers in MCI patients. In particular, the increase of high alpha frequency seems to be associated with conversion in AD. EEG markers allow a mean correct percentage of correct classification up to 88.3%. Future prospective studies are needed to evaluate the sensitivity and specificity of these measures for predicting an AD outcome.Copyright © 2009 Elsevier Inc. All rights reserved.

Martín-ávila A

Zhang Y

, et al. Forty-hertz light stimulation does not entrain native gamma oscillations in Alzheimer's disease model mice[J]. Nat Neurosci, 2023, 26(4): 570-578.

There is a demand for noninvasive methods to ameliorate disease. We investigated whether 40-Hz flickering light entrains gamma oscillations and suppresses amyloid-β in the brains of APP/PS1 and 5xFAD mouse models of Alzheimer's disease. We used multisite silicon probe recording in the visual cortex, entorhinal cortex or the hippocampus and found that 40-Hz flickering simulation did not engage native gamma oscillations in these regions. Additionally, spike responses in the hippocampus were weak, suggesting 40-Hz light does not effectively entrain deep structures. Mice avoided 40-Hz flickering light, associated with elevated cholinergic activity in the hippocampus. We found no reliable changes in plaque count or microglia morphology by either immunohistochemistry or in vivo two-photon imaging following 40-Hz stimulation, nor reduced levels of amyloid-β 40/42. Thus, visual flicker stimulation may not be a viable mechanism for modulating activity in deep structures.© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.

Qin Y

Xie L

, et al. High-frequency repetitive transcranial magnetic stimulation combined with cognitive training improves cognitive function and cortical metabolic ratios in Alzheimer's disease[J]. J Neural Transm (Vienna), 2019, 126(8): 1081-1094.

Liu T

Dou M

, et al. Repetitive transcranial magnetic stimulation reverses aβ1-42-induced dysfunction in gamma oscillation during working memory[J]. Curr Alzheimer Res, 2018, 15(6): 570-577.

Alzheimer's disease (AD) is a neurodegenerative disease that gradually induces cognitive deficits in the elderly and working memory impairment is typically observed in AD. Amyloid-β peptide (Aβ) is a causative factor for the cognitive impairments in AD. Gamma oscillations have been recognized to play important roles in various cognitive functions including working memory. Previous study reported that Aβ induces gamma oscillation dysfunction in working memory.Although repetitive transcranial magnetic stimulation (rTMS) represents a technique for noninvasive stimulation to induce cortical activity and excitability changes and has been accepted for increasing brain excitability and regulating cognitive behavior, the question whether rTMS can reserve the Aβ-induced gamma oscillation dysfunction during working memory remains unclear. The present study aims to investigate the effect of rTMS to the Aβ-induced gamma oscillation dysfunction during working memory.The present study investigates the rTMS-modulated gamma oscillation in Aβ1-42-induced memory deficit. Adult SD rats were divided into four groups: Aβ, Con, Aβ+rTMS and Con+rTMS. 16-channel local field potentials (LFPs) were recorded from rat medial prefrontal cortex while the rats performed a Y-maze working memory task. Gamma oscillation among LFPs was measured by coherence.The results show that rTMS improved the behavior performance and enhanced gamma oscillation for the Aβ-injected subjects.These results indicate that rTMS may reserve the Aβ-induced dysfunction in gamma oscillation during working memory and thus result in potential benefits for working memory.Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Li K

Zhao S

, et al. Early-stage dysfunction of hippocampal theta and gamma oscillations and its modulation of neural network in a transgenic 5xFAD mouse model[J]. Neurobiol Aging, 2020, 94: 121-129.

Alzheimer's disease (AD) is pathologically characterized by amyloid-β (Aβ) accumulation, which induces Aβ-dependent neuronal dysfunctions. We focused on the early-stage disease progression and examined the neuronal network functioning in the 5xFAD mice. The simultaneous intracranial recordings were obtained from the hippocampal perforant path (PP) and the dentate gyrus (DG). Concomitant to Aβ accumulation, theta power was strongly attenuated in the PP and DG regions of 5xFAD mice compared to those in nontransgenic littermates. For either theta rhythm or gamma oscillation, the phase synchronization on the PP-DG pathway was impaired, evidenced by decreased phase locking value and diminished coherency index. To alleviate the neural oscillatory deficits in early-stage AD, a neural modulation approach (rTMS) was used to activate gamma oscillations and strengthen the synchronicity of neuronal activity on the PP-DG pathway. In brief, there was a significant neuronal network dysfunction at an early-stage AD-like pathology, which preceded the onset of cognitive deficits and was likely driven by Aβ accumulation, suggesting that the neural oscillation analysis played an important role in early AD diagnosis.Copyright © 2020 Elsevier Inc. All rights reserved.

Tseng P

. Gamma sensory entrainment for cognitive improvement in neurodegenerative diseases: opportunities and challenges ahead[J]. Front Integr Neurosci, 2023, 17: 1146687.

Neural oscillations have been categorized into various frequency bands that are mechanistically associated with different cognitive functions. Specifically, the gamma band frequency is widely implicated to be involved in a wide range of cognitive processes. As such, decreased gamma oscillation has been associated with cognitive declines in neurological diseases, such as memory dysfunction in Alzheimer’s disease (AD). Recently, studies have attempted to artificially induce gamma oscillations by using 40 Hz sensory entrainment stimulation. These studies reported attenuation of amyloid load, hyper-phosphorylation of tau protein, and improvement in overall cognition in both AD patients and mouse models. In this review, we discuss the advancements in the use of sensory stimulation in animal models of AD and as a therapeutic strategy in AD patients. We also discuss future opportunities, as well as challenges, for using such strategies in other neurodegenerative and neuropsychiatric diseases.

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