GOALI: Collaborative - Magnetoelectric Nanodevices for Wireless Repair of Neural Circuits Deep in the Brain

工程和医学交叉的GOALI项目旨在解决神经退行性疾病广泛领域的以下差距。电场刺激神经网络可以修复导致各种神经退行性疾病（如阿尔茨海默病（AD）和许多其他疾病）的异常神经活动。此外，最近已经证明电场对细胞命运和神经发生有根本影响。然而，现有的方法，如(1)通过与神经网络建立直接电接触的直接深部脑刺激（DBS）和(2)侵入性较小的间接经颅磁刺激（TMS），不能提供在细胞水平上充分控制神经网络所需的空间和时间分辨率，从而在不造成任何破坏性副作用的情况下有效地利用电治愈这些疾病。该项目通过实施纳米技术方法填补了这一空白，根据该方法，磁电纳米粒子（MENs）被用来结合电场和磁场的主要优势，使无线控制的高效、高特异性和高选择性刺激大脑的选择性区域，以治疗特定的神经退行性疾病，而没有任何副作用。潜在的应用是深远的工程电磁和多铁纳米粒子驱动系统，可能影响个性化精密医学，认知神经科学，神经影像学，临床神经病学和精神病学等新兴领域。所提出的系统可以帮助对大脑进行逆向工程，从而为从根本上理解大脑开辟了一条道路。该项目的一个重要组成部分是激励未被充分代表的少数民族在工程和医学交叉领域攻读跨学科学位。将特别强调吸引当地K-12和本科生继续在FIU和印第安纳大学进行研究。GOALI提案旨在进行全面的研究，以设计基于磁电纳米粒子（MENs）的系统，用于无线刺激大脑深处的局部区域，以修复疾病的特定障碍。MENs可以将大脑深处的局部固有电场与磁场连接起来，从而实现局部电刺激的外部控制，从而修复局部神经回路。与传统的磁性纳米颗粒一样，MENs可以用作磁共振成像中的图像造影剂，并通过应用磁场梯度穿越血脑屏障。此外，与传统的纳米颗粒不同，由于存在非零磁电（ME）效应，MENs显示出全新的特性。由于磁致伸缩和压电元件的耦合，ME效应可以有效地将大脑深处的固有电场与磁场耦合在一起，从而可以从头骨外部无线控制磁场。因此，MENs允许使用直流和交流磁场来分离两种功能，(i)应用直流磁场梯度使MENs通过血脑屏障进行图像引导导航并进入特定疾病的局部区域，以及（ii）应用交流磁场分别通过感应局部交流电场局部刺激该局部区域。基于亚稳态系统的物理特性，使用电磁铁系统，纳米颗粒可以有效地保持在准抗磁状态，从而通过交流磁场的应用移动到大脑深处的任何点，进一步进行局部电刺激。由于mes效应，MENs提供的图像不仅包含结构信息，还反映了由于神经元活动而产生的局部电场。所有这些效应将在体外和体内通过动物模型进行研究，以了解MENs对神经元和突触激活、皮层神经元活动、神经元兴奋性和突触传递的场控制局部效应的潜在机制。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

The GOALI project at the intersection of engineering and medicine aims to address the following gap in the broad area of neurodegenerative diseases. Stimulation of the neural network by electric fields can repair the abnormal neural activity responsible for various neurodegenerative diseases such as Alzheimer's Disease (AD) and many others. Further, recently it has been shown that electric fields have fundamental effects on cell fate and neurogenesis. However, the existing approaches such as (1) direct deep-brain stimulation (DBS) by establishing direct electrical contact to the neural network and (2) less-invasive indirect transcranial magnetic stimulation (TMS) don't provide spatial and temporal resolutions required for adequate control of the neural network at the cellular level to effectively cure these diseases using electricity, without causing any devastating side effects. This project fills this gap by implementing a nanotechnology approach, according to which magnetoelectric nanoparticles (MENs) are used to combine the main advantages of electric and magnetic fields to enable wirelessly controlled high-efficacy, high-specificity and high-selectivity stimulation of selective regions in the brain to treat specific neurodegenerative diseases without any side effects. The potential applications are far-reaching into engineering electromagnetic and multiferroic nanoparticle-driven systems which could impact the emerging field of personalized precision medicine, cognitive neuroscience, neuroimaging, clinical neurology, and psychiatry. The proposed system can help reverse engineer the brain and thus open a pathway to fundamental understanding of the brain. An important component of the project is to motivate underrepresented minorities to pursue cross-disciplinary degrees at the intersection of engineering and medicine. A special emphasis will be made to attract local K-12 and undergraduate students to continue their research at FIU and Indiana University.The GOALI proposal aims to conduct comprehensive studies to engineer magnetoelectric nanoparticles (MENs) based system for wireless stimulation of local regions deep in the brain to repair disease specific impediments. MENs can bridge local intrinsic electric fields deep in the brain with magnetic fields and thus enable an external control of local electric stimulation for repairing neural circuits locally. Like traditional magnetic nanoparticles, MENs can be used as image contrast agents in magnetic resonance imaging and navigated across the blood-brain barrier via application of magnetic field gradients. In addition, unlike traditional nanoparticles, MENs display an entirely new property due to the presence of a non-zero magnetoelectric (ME) effect. The ME effect, which exists due to coupled magnetostrictive and piezoelectric components, allows to efficiently couple intrinsic electric fields deep in the brain to magnetic fields which in turn can be wirelessly controlled from outside the skull. Thus, MENs allow to use d.c. and a.c magnetic fields for separating the two functions, (i) application of a d.c. magnetic field gradient for image-guided navigation of MENs across BBB and into a disease-specific local region(s) and (ii) application of an a.c. magnetic field to stimulate this local region(s) locally via inducing local a.c. electric fields, respectively. Based on the physics of metastable systems, using a system of electromagnets, the nanoparticles can be effectively maintained in a quasi-diamagnetic state and thus moved to any point deep in the brain for further local electric stimulation via application of a.c. magnetic fields. Due to the ME effect, the image provided by MENs not only contains structural information but also reflects a local electric field due to the neuronal activity. All these effects will be studied in vitro and in vivo using animal models to understand field-controlled local effects of MENs on the underlying mechanisms of activation of neurons and synapses, the cortical neuronal activity, neuronal excitability, and synaptic transmission.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.