Development of MRI-compatible Graphene-based Probes for Rodent and Human Electrophysiology

对于严重的耐药癫痫患者，一种常见的治疗方法是通过手术切除导致癫痫复发的异常脑组织，通常被称为癫痫灶。通过使用手术植入的特殊电极记录大脑内的脑波，可以实现对病灶的识别。然而，在许多情况下，仍然不容易发现要移除大脑的哪个部分，部分原因是目前使用的电极是在磁共振成像(MRI)时代之前开发的，并且含有大量金属，这导致植入电极后获取的MRI图像中会出现大量伪影，以验证其位置。这些人工制品模糊了电极的位置，使其周围的脑组织难以可视化，这一限制具有重要的临床意义。磁共振环境中的金属电极也引起了几个安全问题，这些问题是由于探头和磁共振使用的场之间的相互作用而引起的。我们最近表明，一种名为石墨烯(石墨烯溶液门控场效应管，简称gSGFET)电极的新型电极比现有电极有几个优势，包括干扰磁共振的金属量大大减少，以及由于其电子设计，能够以一种全新的方式记录脑波。例如，新的gSGFET能够记录比使用当前金属电极记录的大脑振荡慢得多的大脑振荡。越来越多的证据表明，能够测量这种缓慢的脑电活动是很重要的。到目前为止，新的电极已经用于在小动物身上进行记录，我们现在希望将这项技术应用于临床，承诺为癫痫发作的大脑区域带来新的曙光。建议的发展将确保新的探头技术具有最大的科学影响和临床用途。我们将开发、测试和实施改进的gSGFET探头设计，增加专门设计的功能，使它们在MRI图像中以高精度可见和可定位。我们将进行实验来改进和验证新设计，目的是获得亚毫米级的精度。然后，我们将通过在临床前模型中进行记录来展示探测器在定位、可视化和脑信号质量方面的新能力。最后，我们将建立临床探头的放大原型并对其进行技术测试。这项工作的成功将使未来的首个人类研究成为可能，在这些研究中，新的gSGFET探头改进的脑波记录特性和MR兼容性都可能对癫痫治疗包括手术前规划产生重大影响。除了具体的癫痫考虑因素外，在本提案期间开发的改善探头在MRI图像上的外观的策略将应用于其他神经疾病的研究，并可能适用于考虑用于更复杂的脑机接口的其他非磁性材料，使它们在MRI中可见。例如，使用基于石墨烯的技术制造与MRI兼容的脑深部刺激(DBS)电极用于治疗帕金森氏症等运动障碍的类似方法将允许改进探针的靶向性和可视化，从而实现更有效的治疗。此外，新的电极技术在研究正常大脑活动方面具有重要的潜在应用，因为从大脑留置电极获得的数据也被用来研究脑信号的性质，如功能磁共振和头皮脑电，以及它们之间的相互关系。

A common treatment for patients with severe, drug-resistant epilepsy is to surgically remove the abnormal brain tissue responsible for recurring seizures, often referred to as the epileptic focus. The identification of the focus can be achieved by recording brain waves within the brain using special electrodes implanted surgically. However, in many cases it is still not easy to discover which part of the brain to remove partly because the electrodes currently used were developed prior to the magnetic resonance imaging (MRI) era, and contain a large amount of metal which results in large artefacts in MRI images acquired after their implantation to verify their location. These artefacts obscure the electrodes' location, making it difficult to visualise the brain tissue around them, a limitation with important clinical implications. Metal-based electrodes within the MR environment also pose several safety concerns that arise from interactions between the probe and the fields used in MRI. We recently showed that a new type of electrode, called graphene-based (Graphene Solution-Gated Field-Effect Transistors, or gSGFET) probes, have several advantages over existing electrodes, including a much reduced amount of metal that can interfere with MRI and the ability to record brain waves in a radically new way due to their electronic design. For example, the new gSGFET are able to record brain oscillations that are much slower than those that can be recorded using the current metal electrodes. There is mounting evidence that it is important to be able to measure such slow electrical brain activity. Up to now, the new electrodes have been made for recording in small animals and we now want to move this technology towards the clinic, promising to shed new light on the brain regions responsible for epileptic seizures. The proposed developments will ensure the new probe technology's maximal scientific impact and clinical utility.We will develop, test and implement a modified gSGFET probe design by the addition of features that are specifically conceived to make them visible and localisable with great precision in MRI images. We will perform experiments to improve and validate the new design, with the aim of obtaining sub-millimetric accuracy. We will then demonstrate the probes' new capabilities in terms of localization, visualization and brain signal quality by performing recordings in preclinical models. Finally, we will build upscaled prototypes of clinical probes and subject these to technical tests.Success of this work will allow future first-in-human studies, where both the improved brain wave recording characteristics and MR compatibility of the new gSGFET probes could have a significant impact on epilepsy management including pre-surgical planning. Beyond specific epilepsy considerations, the strategy for improving the appearance of the probes on MRI images developed during this proposal will have applications for the investigation of other neurological conditions, and could be adapted to other nonmagnetic materials considered for more complex brain-machine interfaces to make them visible in MRI. For example, a similar approach to make MRI-compatible deep brain stimulation (DBS) electrodes used to treat movement disorders such as Parkinson's disease with graphene-based technology will allow improved probe targeting and visualisation, and more effective treatment as a result. In addition, the new electrode technology has important potential applications for the study of normal brain activity since data obtained from brain indwelling electrodes is also used to study the nature of brain signals such as functional MRI and scalp EEG, and their inter-relationship.