CAREER: Enhancing perception and cognition while minimizing side effects through closed-loop peripheral neural stimulation

职业：通过闭环周围神经刺激增强感知和认知，同时最大限度地减少副作用

• 批准号: 1847315
• 负责人: Qi Wang
• 金额: $ 50万
• 依托单位: Columbia University
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1847315&HistoricalAwards=false
• 关键词: CAREER; Enhancing; perception; cognition; while

Perception, cognition, and behavioral performance are heavily influenced by arousal level. For example, a student will likely perform much better on exams when alert than when drowsy or overly anxious. Arousal is regulated by several neuromodulatory systems, including the locus coeruleus (LC), which is a cluster of neurons in the brainstem whose damage often leads to neurodegenerative diseases. Thus, from an engineering standpoint, it is plausible that control of LC activity could maximize behavioral performance in healthy individuals and treat LC related disorders. However, the small size and deep location of the LC in the brainstem makes it challenging to access and manipulate. To overcome this challenge, this project will use peripheral vagus nerve stimulation (VNS) to control LC activity. The vagus nerve, which runs from the brainstem to the colon area, is easy to access non-invasively, and the LC is the main brain structure that mediates the effect of VNS on brain activity. Using cutting-edge machine learning and nonlinear control theory, this project aims to develop an engineering framework for controlling LC activity via periphery VNS and measuring pupil size, which is also an indicator of arousal level. The success of this project will lead to the development of non-invasive methods to enhance human perception and cognition and treat LC-related brain disorders, e.g., Alzheimer's disease, bipolar disorder, depression and Attention Deficit Hyperactivity Disorder (ADHD). Research activities in the planned studies will enrich the undergraduate curriculum and provide interdisciplinary research opportunities for undergraduates and graduate students, who will contribute to the national highly-qualified workforce in the rapidly-growing biotechnology and biomedical engineering field. Moreover, the project is expected to broaden the participation in STEM of under-represented minority and female students with social-economically disadvantaged backgrounds. The proposed educational curriculum and outreach activities will also engage the general public to increase their awareness of how STEM disciplines can be applied to solve problems in the nervous system.The PI's long-term career research goal is to enhance human perception and cognition through control of population activities within the nervous system. Toward this goal, this project is to develop an engineering framework that uses peripheral nerve stimulation to control neural population activity to achieve optimal behavioral performance while minimizing unintended side effects and to functionally validate this technology in an animal model. The vagus nerve-to-locus coeruleus (LC) pathway will be used as a model system to develop and test the technology. This pathway was chosen because an FDA approved non-invasive vagus nerve stimulator exists and the LC plays a pivotal role in modulating brain functions through regulation of arousal levels. Studies will include assessment of LC spiking activity and pupil size, which is a noninvasive proxy of LC activity that will be useful in future translation of the technology developed. The Research Plan is organized under three objectives. The FIRST OBJECTIVE is to identify the optimal parameter space of VNS (vagus nerve stimulation) for selectively modulating LC activity/pupil size while minimizing side effects on heart rate using Bayesian active learning. A cohort of animals will be implanted with electrodes for left VNS at the level of the carotid artery (blunt dissection) and with a wireless electrocardiography (ECG) transmitter to monitor heart rate. A genetically-encoded calcium indicator will be selectively expressed in LC neurons using viral vectors, enabling calcium imaging of the activity of LC populations of neurons. The average spiking activity of the LC neurons will then be inferred from the fluorescence signals. Bayesian active learning will be used to discover the VNS parameter spaces in which VNS has high efficacy in driving LC activity/pupil size while leaving minimal effects on heart rate. Stimulation will be presented in the form of bursts of charge-balanced bi-phasic current pulses with short inter-pulse intervals. The parameter space will include current amplitude of the higher amplitude phase of the pulses, pulse width of the higher amplitude phase, pulse polarity (i.e. cathode-leading or anode-leading), pulse waveform, asymmetry ratio, inter-pulse interval, number of pulses per burst, and inter-burst interval. The SECOND OBJECTIVE is to synthesize a nonlinear closed-loop controller for control of LC population activity/pupil size while minimizing changes in heart rate through VNS. Non-parametric Gaussian Process (GP) models will be used to model the nonlinear synamics of the vagus nerve-to-LC and vagus nerve-to-pupil circuitry. A nonlinear predictive model controller based on the GP models will be synthesized to control LC population activity/pupil size through VNS in a closed-loop fashion. Different nonlinear optimization methods will be tested in the controller, and extensive simulations will be conducted to evaluate its performance. The THIRD OBJECTIVE is to functionally validate the technology in awake behaving animals. The extent to which the controller is able to maintain optimal behavioral performance while producing minimal side effects for animals in real-world applications will be examined. Rats instrumented for monitoring the spiking performance of neurons in the LC will be trained to perform a tactile detection task, e.g., licking a water spout in response to a whisker deflection. Their behavioral performance will be quantitatively evaluated from the probabilities of their correct and incorrect responses to sensory stimuli. The behavioral performance and heart rate of animals in sessions with the stimulator on will be compared to those in sessions with the stimulator off. Different firing rates will be tested to determine which firing rate results in optimal behavior performance. The successful completion of the above objectives will provide, for the first time, an engineering framework to guide the design and validation of optimal, closed-loop stimulation for enhancing behavior.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

感知、认知和行为表现很大程度上受到唤醒水平的影响。例如，学生在警觉时的考试成绩可能比昏昏欲睡或过度焦虑时好得多。觉醒受到多种神经调节系统的调节，包括蓝斑 (LC)，它是脑干中的一组神经元，其损伤通常会导致神经退行性疾病。 因此，从工程学的角度来看，控制 LC 活性可以最大限度地提高健康个体的行为表现并治疗 LC 相关疾病是合理的。 然而，脑干中的 LC 体积小且位置深，使其难以访问和操作。 为了克服这一挑战，该项目将使用外周迷走神经刺激 (VNS) 来控制 LC 活动。 迷走神经从脑干延伸到结肠区域，很容易无创地到达，LC是介导VNS对大脑活动影响的主要大脑结构。 该项目旨在利用尖端的机器学习和非线性控制理论，开发一个工程框架，用于通过外围 VNS 控制 LC 活动并测量瞳孔大小（这也是唤醒水平的指标）。该项目的成功将促进非侵入性方法的开发，以增强人类的感知和认知，并治疗与 LC 相关的脑部疾病，例如阿尔茨海默病、双相情感障碍、抑郁症和注意力缺陷多动障碍 (ADHD)。 计划研究中的研究活动将丰富本科生课程，并为本科生和研究生提供跨学科研究机会，他们将为快速发展的生物技术和生物医学工程领域的国家高素质劳动力做出贡献。此外，该项目预计将扩大代表性不足的少数族裔和社会经济弱势背景的女学生对 STEM 的参与。拟议的教育课程和推广活动还将吸引公众提高他们对如何应用 STEM 学科来解决神经系统问题的认识。 PI 的长期职业研究目标是通过控制神经系统内的群体活动。 为了实现这一目标，该项目旨在开发一种工程框架，利用周围神经刺激来控制神经群体活动，以实现最佳行为表现，同时最大限度地减少意外副作用，并在动物模型中对这项技术进行功能验证。 迷走神经到蓝斑（LC）通路将被用作开发和测试该技术的模型系统。 选择这条通路是因为 FDA 批准了一种非侵入性迷走神经刺激器，并且 LC 在通过调节唤醒水平来调节大脑功能方面发挥着关键作用。 研究将包括对 LC 尖峰活动和瞳孔大小的评估，这是 LC 活动的非侵入性代表，将有助于未来开发技术的转化。 该研究计划根据三个目标进行组织。第一个目标是确定 VNS（迷走神经刺激）的最佳参数空间，用于选择性调节 LC 活动/瞳孔大小，同时使用贝叶斯主动学习最大限度地减少对心率的副作用。 一组动物将在颈动脉水平（钝性解剖）植入左 VNS 电极，并植入无线心电图 (ECG) 发射器以监测心率。 基因编码的钙指示剂将使用病毒载体选择性地在 LC 神经元中表达，从而能够对 LC 神经元群的活动进行钙成像。 然后将从荧光信号推断出 LC 神经元的平均尖峰活动。 贝叶斯主动学习将用于发现 VNS 参数空间，其中 VNS 在驱动 LC 活动/瞳孔大小方面具有高效能，同时对心率的影响最小。 刺激将以具有短脉冲间隔的电荷平衡双相电流脉冲突发的形式呈现。 参数空间将包括脉冲的较高振幅相位的电流振幅、较高振幅相位的脉冲宽度、脉冲极性（即阴极领先或阳极领先）、脉冲波形、不对称率、脉冲间间隔、脉冲数量。每个突发的脉冲数和突发间的间隔。第二个目标是合成一个非线性闭环控制器，用于控制 LC 群体活动/瞳孔大小，同时通过 VNS 最大限度地减少心率变化。 非参数高斯过程 (GP) 模型将用于模拟迷走神经到 LC 和迷走神经到瞳孔电路的非线性同义词。 将合成基于 GP 模型的非线性预测模型控制器，以通过 VNS 以闭环方式控制 LC 群体活动/瞳孔大小。 将在控制器中测试不同的非线性优化方法，并进行广泛的仿真来评估其性能。第三个目标是在清醒的动物身上验证该技术的功能。 将检查控制器在现实应用中能够在多大程度上保持最佳行为性能，同时对动物产生最小的副作用。 用于监测 LC 中神经元尖峰性能的大鼠将被训练执行触觉检测任务，例如，舔水管以响应胡须偏转。 他们的行为表现将根据他们对感官刺激的正确和错误反应的概率进行定量评估。 动物在刺激器打开时的行为表现和心率将与刺激器关闭时的行为表现和心率进行比较。 将测试不同的放电率以确定哪种放电率会产生最佳的行为表现。上述目标的成功完成将首次提供一个工程框架来指导设计和验证最佳闭环刺激以增强行为。该奖项反映了 NSF 的法定使命，并通过评估被认为值得支持利用基金会的智力优势和更广泛的影响审查标准。

项目成果

The Neuromodulatory Role of the Noradrenergic and Cholinergic Systems and Their Interplay in Cognitive Functions: A Focused Review

去甲肾上腺素能和胆碱能系统的神经调节作用及其在认知功能中的相互作用：重点回顾

• DOI: 10.3390/brainsci12070890
• 发表时间: 2022-07-07
• 期刊: Brain Sciences
• 影响因子: 3.3
• 作者: Cody Slater;Yuxiang Liu;Evan Weiss;Kunpeng Yu;Qi Wang
• 通讯作者: Qi Wang

Rapid Effects of Vagus Nerve Stimulation on Sensory Processing Through Activation of Neuromodulatory Systems

迷走神经刺激通过激活神经调节系统对感觉处理的快速影响

• DOI: 10.3389/fnins.2022.922424
• 发表时间: 2022
• 期刊: Frontiers in Neuroscience
• 影响因子: 4.3
• 作者: Rodenkirch, Charles;Carmel, Jason B.;Wang, Qi
• 通讯作者: Wang, Qi

Rapid and transient enhancement of thalamic information transmission induced by vagus nerve stimulation

迷走神经刺激引起丘脑信息传递的快速和短暂增强

• DOI: 10.1088/1741-2552/ab6b84
• 发表时间: 2020-04
• 期刊: Journal of Neural Engineering
• 影响因子: 4
• 作者: Rodenkirch, Charles;Wang, Qi
• 通讯作者: Wang, Qi

Neuromodulation of Neural Oscillations in Health and Disease

健康和疾病中神经振荡的神经调节

• DOI: 10.3390/biology12030371
• 发表时间: 2023-02-26
• 期刊: Biology
• 影响因子: 4.2
• 作者: Evan Weiss;Michael Kann;Qi Wang
• 通讯作者: Qi Wang

Alzheimer's disease: An evolving understanding of noradrenergic involvement and the promising future of electroceutical therapies

阿尔茨海默病：对去甲肾上腺素能参与的不断发展的理解和电疗法的光明前景

• DOI: 10.1002/ctm2.397
• 发表时间: 2021-04
• 期刊: Clinical and Translational Medicine
• 影响因子: 10.6
• 作者: Slater C;Wang Q
• 通讯作者: Wang Q