Enhancing the spatial control of non-invasive brain stimulation by magnetic temporal interference

项目总结/摘要 电磁脑刺激是一种安全且经过验证的非侵入性控制神经活动的方法， 植入硬件或注入生化试剂。经颅磁刺激（TMS）是FDA批准的 用于治疗耐药性抑郁症和强迫症， 正在调查的申请。近年来，它在神经科学研究中的应用也迅速扩大 因为它能够通过非侵入性地扰乱神经活动来测试因果关系。 TMS最关键的限制是它无法以空间选择性的方式聚焦深度刺激; 电场（E场）在最接近刺激线圈的表面区域中总是最大的。这是一个重大 考虑到皮质下结构在健康和疾病中发挥的关键作用，利用叠加原理， 或“时间干扰”，在不同频率振荡的E场产生调幅（AM） 在皮层下的给定目标处的最大值已经被建议作为该问题的解决方案。当E- 场仍然是最强的浅表区域，神经元的时间锁定AM振荡，而不是 振荡的个别E场，产生增强的刺激，在皮层下叠加区。一 最近的研究证明了这一概念在小鼠模型中的可行性， 通过头骨两侧的两个电极对。虽然这些临床前动物数据非常有希望， 头皮电极的使用对于人的平移将是有问题的 头皮和颅骨组织，使电流分流，导致人类颅骨内的电场非常弱。 在这个F32项目中，我们建议开发一种使用磁刺激（TiMS）的时间干扰方法。 这可能是一种比电刺激更适合人类的技术。与电刺激不同， 磁场有效地穿过人的头骨，在大脑中诱导明显的阈上电场， 可以直接去神经元。首先，在理论上的可行性，所提出的技术方面， 将通过计算建模来研究增产效率和安全极限。理论结果将 然后使用通常用于MRI匀场的低功率系统在体模头部模型中进行验证， 目前在我们的实验室里。最后，基于这些计算结果和实验验证， 根据这一想法，我们将设计、建造和验证一种能够提供有效颅内TiMS的原型装置。 通过将定制的TMS线圈连接到内部MRI梯度放大器系统。项目的最终目标 是要有一个新的设备原型，能够非侵入性脑刺激，是可操纵的沿着深度 尺寸和准备用于非人类灵长类动物模型的临床前测试，并最终在人类。

Project Summary/Abstract Electromagnetic brain stimulation is a safe and proven way of controlling neural activity non-invasively with no implanted hardware or injected biochemical agents. Transcranial magnetic stimulation (TMS) is FDA approved for treatment of drug resistant depression and obsessive compulsory disorder with a range of other clinical applications under investigation. Its use in neuroscience research has also seen rapid expansion in recent years due to its ability to test causality by non-invasively perturbing neural activity. The most critical limitation of TMS is its inability to focus the stimulation depth-wise in a spatially selective manner; the electric field (E-field) is always maximal in the superficial region, closest to the stimulating coil. This is a major limitation given the critical role that subcortical structures play in both health and disease. Using the superposition, or “temporal interference”, of E-fields oscillating at different frequencies to create an amplitude modulation (AM) maximum at a given target in the subcortex has been suggested as a work-around to this problem. While the E- fields are still strongest in the superficial region, the neurons time-lock to the AM oscillation rather than the oscillations of the individual E-fields, yielding enhanced stimulation in the subcortical superposition zone. A recent study demonstrated the feasibility of this concept in a mouse model using electrical stimulation delivered via two electrode pairs at opposing sides of the skull. Although these pre-clinical animal data were very promising, the use of scalp electrodes will be problematic for human translation due to the high conductivity ratio between the scalp and skull tissues that shunts the current and leads to very weak E-fields inside the cranium of humans. In this F32 project, we propose developing a temporal interference approach using magnetic stimulation (TiMS) which could be a more translatable technique to humans than electrical stimulation. Unlike electrical stimulation, magnetic fields efficiently pass through the human skull inducing clearly suprathreshold E-fields in the brain that can directly depolarize neurons. Firstly, the theoretical feasibility of the proposed technique in terms of stimulation efficiency and safety limits will be investigated by computational modeling. The theoretical results will then be validated in a phantom head model using a low-power system usually used for MRI shimming that is currently in place in our lab. Finally, based on these computational results and the experimental verification of the idea, we will design, build, and validate a prototype device capable of delivering effective intracranial TiMS by connecting custom made TMS coils to an in-house MRI gradient amplifier system. The end goal of the project is to have a novel device prototype capable of non-invasive brain stimulation that is steerable along the depth dimension and ready to be used in non-human primate models for pre-clinical testing and ultimately in humans.