Noninvasive Targeted Neuromodulation

摘要 神经和精神疾病占医疗保健总支出的三分之一；超过癌症、心血管疾病和糖尿病的总和。平均而言，大约三分之一的患者对药物治疗没有反应或有无法忍受的副作用ff等。神经调节，旨在从神经源治疗大脑疾病，为ff和个性化治疗提供了一条新的途径。不幸的是，现有的侵入性神经调节方法目前仅限于特殊的fic患者和脑靶点，而非侵入性方法没有必要的空间分辨率。因此，很大一部分患者没有得到适当的治疗。为了解决这个问题，我们开发了一种非侵入性方法和硬件，使非侵入性和靶向神经调节成为可能。该工具根据命令以高空间和时间分辨率调制特定的fic大脑目标。该方法具有植入电极的精度，但应用范围很远，完全是非侵入性的。为了实现这一点，该方法结合了两种形式的非侵入性能量-聚焦超声波和磁fi场。这些fi区的产物产生局部电刺激(“Lstim”)。超声波使Lstim具有清晰的焦点和靶向fl的灵活性。刺激区域可以小到人脑深处的一粒米那么小。为了实现这种方法的潜力，我们开发了一种可编程的换能器阵列，可以根据需要快速定位特定的脑区，从而能够连续或协同地刺激多个脑靶点。我们在18名受试者的周围神经系统中验证了Lstim的神经调节作用。我们现在建议开发ff安全的Lstim协议来调制大脑中的深层电路，从而充分利用这一方法的力量。我们将在非人类灵长类动物身上进行这项工作，以最大限度地提高临床相关性并加快翻译速度。具体地说，我们将确定哪些Lstim参数最能刺激和抑制神经元fi(目标1)。我们将以大脑深部视觉区域为目标，并使用已建立的电生理读数来评估神经调制E-ff效应的大小和极性。我们将通过敏感的行为任务、对比增强的MRI和脑切片的组织学检查来验证Lstim的安全性(目标2)。这两个目标的实现将最大限度地发挥一种新的、非侵入性的、靶向的神经调节技术的ff效率，并验证其安全性。这种方法有可能为大量耐药患者提供治疗选择。我们将传播开发的硬件和有效的协议，以造福于临床医生、患者和研究人员。

Summary Neurological and psychiatric disorders absorb one-third of the total health care expenditures; more than cancer, cardiovascular diseases, and diabetes combined. On average, approximately one in three patients fails to respond to medication treatments or has intolerable side effects. Neuromodulation, which aims to treat brain disorders at their neural source, provides a new path to effective and personalized treatments. Unfortunately, existing invasive neuromodulation approaches are currently limited to specific patients and brain targets, and noninvasive approaches do not have the necessary spatial resolution. As a consequence, a large proportion of patients do not receive adequate treatment. To address this issue, we have developed a non-invasive approach and hardware that enable noninvasive and targeted neuromodulation. The tool modulates specific brain targets on command and at high spatial and temporal resolution. The approach has the precision of implanted electrodes but is applied remotely and entirely noninvasively. To achieve this, the approach combines two forms of noninvasive energies—focused ultrasonic and magnetic fields. The product of these fields generates localized electrical stimulation (“Lstim”). The ultrasound bestows Lstim with sharp focus and targeting flexibility. The stimulated regions can be as small as a grain of rice deep in the human brain. To realize the potential of the method, we have developed a programmable transducer array that can target specified brain regions rapidly on demand, enabling the stimulation of multiple brain targets in succession or concert. We have validated the neuromodulatory effects of Lstim in the peripheral nervous system of 18 human subjects. We now propose to develop effective and safe Lstim protocols for modulating deep circuits in the brain and thus harness the full power of the approach. We will perform the work in non-human primates to maximize clinical relevance and accelerate translation. Specifically, we will determine which Lstim parameters excite and inhibit neurons most effectively (Aim 1). We will target deep brain visual regions and assess the magnitude and polarity of the neuromodulatory effects using an established electrophysiological readout. We will validate the safety of Lstim using a sensitive behavioral task, contrast-enhanced MRI, and histological examination of brain slices (Aim 2). The completion of these two aims will maximize the effectiveness of a new, non-invasive and targeted neuromodulation technique and validate its safety. The approach has the potential to provide treatment options for a large number of medication-resistant patients. We will disseminate the developed hardware along with the effective protocols for the benefit of clinicians, patients, and researchers.