CRCNS: Effects of Weak Applied Currents on Memory Consolidation During Sleep

CRCNS：弱施加电流对睡眠期间记忆巩固的影响

• 批准号: 8055164
• 负责人: LUCAS C PARRA
• 金额: $ 12.56万
• 依托单位: CITY COLLEGE OF NEW YORK
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-29 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8055164
• 关键词: Acute; Address; Adverse effects; Affect; Area; Basic Science; Brain; Chemosensitization; Clinical; Code; Cognition; Cognitive; Communication; Computer Simulation; Data; Dependence; Development; Electric Stimulation; Electrodes; Equilibrium; Exhibits; Experimental Models; Frequencies; German population; Germany; Hippocampus (Brain); Human; In Vitro; Injection of therapeutic agent; International; Ion Channel; Kale - dietary; Learning; Light; Link; Literature; Long-Term Effects; Machine Learning; Marshal; Measures; Mediating; Membrane; Memory; Mental Depression; Modeling; Neocortex; Nerve Tissue; Neurons; Pattern; Perceptual learning; Performance; Phase; Plastics; Play; Positioning Attribute; Predictive Value; Preparation; Principal Investigator; Process; Property; Protocols documentation; Pyramidal Cells; Rattus; Research; Research Personnel; Role; Scalp structure; Signal Transduction; Site; Sleep; Sleep Stages; Slice; Slide; Slow-Wave Sleep; Stimulus; Stroke; Surface; Synapses; Synaptic Potentials; Synaptic plasticity; System; Techniques; Testing; Thalamic structure; Theoretical model; Time; Training; Visual; Wakefulness; Work; awake; base; computational network modeling; computational neuroscience; data modeling; density; electric field; human subject; imprint; improved; memory trace reactivation; motor learning; neocortical; painful neuropathy; receptive field; research study; response; tool; voltage

DESCRIPTION (provided by applicant): Intellectual Merit: There is compelling evidence that the distinct stages of sleep play an essential role in the long-term consolidation of memories (Marshall & Born 2007). Specifically, slow-wave sleep (SWS), which is hallmarked by slow oscillatory activity (< 1 Hz) in the human electro-encephalogram (EEG), has been implicated in memory consolidation. We demonstrated that weak electric currents (<1mA, <1Hz and DC) applied to the scalp during SWS modulate these endogenous EEG rhythms and can improve human memory performance (Marshall 2006a). Moreover, application of the same weak currents during learning modulates ongoing EEG rhythms that are typical for the awake state in humans and boosts immediate performance in some learning tasks (Kirov 2009). Yet, despite these remarkable phenomenological findings, the question of how weak currents can modulate brain oscillations and induce plastic changes in brain function remains fundamentally unaddressed. Here we propose to quantitatively address this question through the development of computational models that are tightly constrained by specialized brain-slice experiments and validated through targeted human subject experiments. A central question is: how can weak electric currents, that appear insufficient to modulate excitability or plasticity in quiescent neurons, exert such a powerful effect on oscillations and learning? Our central hypothesis is that weak currents couple into ongoing slow oscillatory activity that then boost their modulatory effect on synaptic plasticity. Preliminary data from our group and others already provides strong evidence for modulation of endogenous rhythmic network activity by applied currents - at intensities considered too weak to affect single neuron function. Concurrently, we and other groups have investigated links between slow wave activity and memory consolidation, including by application of weak currents in human. But a specific connection between the effects of applied weak currents on slow-wave rhythms and plasticity has so far not been explored. Guided by computational models, the crucial empirical link between the two will be sought by probing lasting changes resulting from weak-current stimulation of an in vitro cortical preparation that exhibits SWA. Targeted human experiments will directly test if applied currents also enhance the consolidation of other SWS-mediated learning as the hypothesis would suggest, or rather, if the effect is limited to hippocampus-related learning, thus providing significant constraints to the computational models. Broader Impacts: Weak applied currents are being explored in a number of empirical studies for their potential benefits to treat depression and neuropathic pain, to assist motor learning after stroke, or more generally, to enhance cognitive performance and to improve learning. The promise of this technique is that weak currents can be applied non-invasively with a potentially broad range of applications and minimal side effects. The enigma in this potentially transformative clinical tool, however, is that the electric field strengths generated by these currents in most studies are two orders of magnitude below what is required to activate an otherwise silent neuron. Currently, research in this area is almost entirely phenomenological and the few mechanistic explanations for the promising phenomenological observations are superficial (e.g. describing all brain function as a "sliding scale of excitability") and do not address plasticity - as such, there is no rational basis for improving and targeting stimulation protocols. This work is the first attempt at establishing the mechanistic link between applied currents on endogenous rhythms and the associated SWS-related learning enhancements. Evidently, such an analysis will address basic science questions about the link between endogenous SWS and learning, add to the set of experimental tools which can be used to study cognition, and, shed light on the functional and causal role of the ubiquitous endogenous rhythms generated by the brain. Consistent with present call for US/German Collaborative Research in Computational Neuroscience this project will combined the expertise of international researchers in the areas of: (1) effects of noninvasive electrical stimulation on nervous tissue (Bikson, US), EEG signal analysis and computational network models (Parra, US), human sleep and learning with applied currents (Marshall, Germany), and dynamical systems and machine learning (Claussen/Martinetz, Germany; Parra, US).

描述（由申请人提供）： 智力优点：有令人信服的证据表明，睡眠的不同阶段在记忆的长期巩固中发挥着重要作用（Marshall & Born 2007）。具体来说，慢波睡眠 (SWS) 的特点是人类脑电图 (EEG) 中的缓慢振荡活动 (< 1 Hz)，与记忆巩固有关。我们证明，在 SWS 期间施加到头皮的微弱电流（<1mA、<1Hz 和直流电）可以调节这些内源性脑电图节律，并可以提高人类的记忆能力 (Marshall 2006a)。此外，在学习过程中应用相同的弱电流可以调节人类清醒状态下典型的持续脑电图节律，并提高某些学习任务的即时表现（Kirov 2009）。然而，尽管有这些引人注目的现象学发现，弱电流如何调节大脑振荡并引起大脑功能可塑性变化的问题仍然没有从根本上得到解决。在这里，我们建议通过开发计算模型来定量解决这个问题，这些模型受到专门的大脑切片实验的严格约束，并通过有针对性的人体实验进行验证。一个核心问题是：似乎不足以调节静止神经元的兴奋性或可塑性的微弱电流如何对振荡和学习产生如此强大的影响？我们的中心假设是，弱电流耦合到持续的缓慢振荡活动，然后增强它们对突触可塑性的调节作用。我们小组和其他人的初步数据已经为通过施加电流调节内源节律网络活动提供了强有力的证据——强度被认为太弱而无法影响单个神经元功能。同时，我们和其他小组研究了慢波活动和记忆巩固之间的联系，包括在人体中应用弱电流。但迄今为止，所施加的弱电流对慢波节律和可塑性的影响之间的具体联系尚未被探索。在计算模型的指导下，通过探测表现出 SWA 的体外皮质制剂的弱电流刺激所产生的持久变化，来寻找两者之间的关键经验联系。有针对性的人体实验将直接测试所施加的电流是否也增强了其他 SWS 介导的学习的巩固，或者更确切地说，效果是否仅限于海马体相关的学习，从而为计算模型提供了显着的约束。 更广泛的影响：许多实证研究正在探索弱外加电流的潜在益处，以治疗抑郁症和神经性疼痛，协助中风后的运动学习，或更广泛地说，增强认知能力和改善学习。这项技术的前景是可以非侵入性地施加弱电流，具有潜在的广泛应用和最小的副作用。然而，这种潜在变革性临床工具的谜团在于，在大多数研究中，这些电流产生的电场强度比激活原本沉默的神经元所需的电场强度低两个数量级。目前，这一领域的研究几乎完全是现象学的，对有希望的现象学观察结果的少数机械解释是肤浅的（例如，将所有大脑功能描述为“兴奋性的滑动尺度”），并且没有解决可塑性 - 因此，没有合理的解释改进和瞄准刺激方案的基础。这项工作是首次尝试建立内源节律应用电流与相关 SWS 相关学习增强之间的机械联系。显然，这样的分析将解决有关内源性 SWS 与学习之间联系的基本科学问题，增加可用于研究认知的实验工具集，并阐明所产生的普遍存在的内源节律的功能和因果作用。通过大脑。 与目前美国/德国计算神经科学合作研究的号召一致，该项目将结合国际研究人员在以下领域的专业知识：(1) 无创电刺激对神经组织的影响（美国比克森）、脑电图信号分析和计算网络模型（帕拉，美国）、人类睡眠和应用电流学习（马歇尔，德国）以及动力系统和机器学习（克劳森/马丁内茨，德国；帕拉，美国）。