Activity dependent degeneration explains hub vulnerability in Alzheimer's disease.
Activity dependent degeneration explains hub vulnerability in Alzheimer's disease.
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DOI：
10.1371/journal.pcbi.1002582
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发表时间：
2012
影响因子：
4.3
通讯作者：
Stam CJ
中科院分区：
文献类型：
--
作者：
de Haan W;Mott K;van Straaten EC;Scheltens P;Stam CJ
大脑连接研究表明，高度连接的“枢纽”区域特别容易受到阿尔茨海默病的影响：它们在早期阶段显示出明显的淀粉样蛋白-β沉积。最近，过度的局部神经元活动已被证明会增加淀粉样蛋白沉积。在这项研究中，我们使用一个计算模型来测试的假设，枢纽地区拥有最高水平的活动和枢纽的脆弱性，阿尔茨海默氏病是由于这一功能。大脑皮层区域被建模为神经块，每个神经块描述大量相互连接的兴奋性和抑制性神经元的平均活动（尖峰密度和频谱功率）。大规模网络由78个神经块组成，根据基于人类DTI的皮层拓扑结构连接。尖峰密度和光谱功率与结构和功能节点程度呈正相关，证实了枢纽区域的高活性，也为高静息状态默认模式网络活性提供了可能的解释。通过降低作为主要兴奋性神经元的尖峰密度的函数的突触强度来模拟“活动依赖性退化”（ADD），并与随机退化进行比较。结果结构和功能网络的变化进行了评估与图论分析。ADD的影响包括振荡减慢，频谱功率和远程同步的损失，枢纽的脆弱性，并中断功能网络拓扑结构。在轻度认知障碍（MCI）患者中观察到的棘波密度和功能连接的短暂增加与报告相匹配，可能不是代偿性的，而是病理性的。总之，过度的神经元活动导致变性的假设提供了一个可能的解释枢纽脆弱性阿尔茨海默氏病，支持观察到的连接和活动之间的关系和再现的几个神经生理学标志。神经元活动可能在阿尔茨海默病中发挥因果作用的见解可能对早期检测和干预策略产生影响。最近一个有趣的观察结果是，淀粉样β蛋白的沉积是阿尔茨海默病的标志之一，主要发生在与其他区域高度连接的大脑区域。为了验证这一假设，即这些“枢纽”区域由于更高的神经元活动水平而更脆弱，我们在人脑的计算模型中研究了大脑连接和活动之间的关系。此外，我们根据大脑区域的活动水平模拟了对大脑区域的渐进性损伤，并研究了其对剩余大脑网络的结构和动力学的影响。我们发现大脑中枢区域确实是最活跃的区域，通过根据区域活动水平破坏网络，我们不仅可以重现中枢脆弱性，还可以重现阿尔茨海默病患者的实际神经生理数据中遇到的一系列现象：阿尔茨海默病患者的大脑活动丧失和减缓，区域之间失去同步，以及功能网络组织的类似变化。这项研究的结果表明，过度的连接依赖性神经元活动在阿尔茨海默病的发展中起着重要作用，并且进一步研究调节区域脑活动的因素可能有助于检测，阐明和对抗疾病机制。
Brain connectivity studies have revealed that highly connected ‘hub’ regions are particularly vulnerable to Alzheimer pathology: they show marked amyloid-β deposition at an early stage. Recently, excessive local neuronal activity has been shown to increase amyloid deposition. In this study we use a computational model to test the hypothesis that hub regions possess the highest level of activity and that hub vulnerability in Alzheimer's disease is due to this feature. Cortical brain regions were modeled as neural masses, each describing the average activity (spike density and spectral power) of a large number of interconnected excitatory and inhibitory neurons. The large-scale network consisted of 78 neural masses, connected according to a human DTI-based cortical topology. Spike density and spectral power were positively correlated with structural and functional node degrees, confirming the high activity of hub regions, also offering a possible explanation for high resting state Default Mode Network activity. ‘Activity dependent degeneration’ (ADD) was simulated by lowering synaptic strength as a function of the spike density of the main excitatory neurons, and compared to random degeneration. Resulting structural and functional network changes were assessed with graph theoretical analysis. Effects of ADD included oscillatory slowing, loss of spectral power and long-range synchronization, hub vulnerability, and disrupted functional network topology. Observed transient increases in spike density and functional connectivity match reports in Mild Cognitive Impairment (MCI) patients, and may not be compensatory but pathological. In conclusion, the assumption of excessive neuronal activity leading to degeneration provides a possible explanation for hub vulnerability in Alzheimer's disease, supported by the observed relation between connectivity and activity and the reproduction of several neurophysiologic hallmarks. The insight that neuronal activity might play a causal role in Alzheimer's disease can have implications for early detection and interventional strategies. An intriguing recent observation is that deposition of the amyloid-β protein, one of the hallmarks of Alzheimer's disease, mainly occurs in brain regions that are highly connected to other regions. To test the hypothesis that these ‘hub’ regions are more vulnerable due to a higher neuronal activity level, we examined the relation between brain connectivity and activity in a computational model of the human brain. Furthermore, we simulated progressive damage to brain regions based on their level of activity, and investigated its effect on the structure and dynamics of the remaining brain network. We show that brain hub regions are indeed the most active ones, and that by damaging networks according to regional activity levels, we can reproduce not only hub vulnerability but a range of phenomena encountered in actual neurophysiological data of Alzheimer patients as well: loss and slowing of brain activity in Alzheimer, loss of synchronization between areas, and similar changes in functional network organization. The results of this study suggest that excessive, connectivity dependent neuronal activity plays a role in the development of Alzheimer, and that the further investigation of factors regulating regional brain activity might help detect, elucidate and counter the disease mechanism.
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影响因子：
5.7
作者：
Bassett, Danielle S.;Nelson, Brent G.;Mueller, Bryon A.;Camchong, Jazmin;Lim, Kelvin O.
通讯作者：
Lim, Kelvin O.
影响因子：
4.3
作者：
Deco, Gustavo;Jirsa, Viktor K.;Robinson, Peter A.;Breakspear, Michael;Friston, Karl J.
通讯作者：
Friston, Karl J.
DOI：
10.1523/jneurosci.3189-09.2009
发表时间：
2009-10-07
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Hedden T;Van Dijk KR;Becker JA;Mehta A;Sperling RA;Johnson KA;Buckner RL
通讯作者：
Buckner RL
DOI：
10.1073/pnas.0811168106
发表时间：
2009-02-10
影响因子：
11.1
作者：
Honey, C. J.;Sporns, O.;Hagmann, P.
通讯作者：
Hagmann, P.
影响因子：
9.9
作者：
Dickerson, BC;Salat, DH;Sperling, RA
通讯作者：
Sperling, RA