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

对严重的耐药性癫痫患者的一种常见治疗方法是手术切除导致复发性癫痫发作的异常脑组织，通常被称为癫痫灶。通过手术植入的特殊电极记录脑内的脑电波，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，并且包含大量的金属，这导致在植入后获取的MRI图像中出现大的伪影以验证其位置。这些伪影模糊了电极的位置，使其难以可视化周围的脑组织，这是一个具有重要临床意义的限制。MR环境中的金属基电极也会引起几个安全问题，这些问题是由探头与MRI中使用的场之间的相互作用引起的。我们最近表明，一种新型电极，称为石墨烯基（石墨烯溶液门控场效应晶体管，或gSGFET）探针，与现有电极相比具有几个优点，包括可以干扰MRI的金属量大大减少，以及由于其电子设计而以全新的方式记录脑电波的能力。例如，新的gSGFET能够记录比使用当前金属电极记录的慢得多的脑振荡。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，新的电极已经用于记录小动物，我们现在希望将这项技术推向临床，有望为癫痫发作的大脑区域提供新的线索。我们将开发、测试和实施一种改进的gSGFET探头设计，增加专门设计的功能，使其在MRI图像中能够以极高的精度可见和定位。我们将进行实验来改进和验证新的设计，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针在定位、可视化和脑信号质量方面的新功能。最后，我们将建立临床探针的升级原型，并对其进行技术测试。这项工作的成功将允许未来的首次人体研究，其中新gSGFET探针的改进的脑电波记录特性和MR兼容性可能对癫痫管理（包括术前计划）产生重大影响。除了特定的癫痫考虑之外，在该提案期间开发的改善MRI图像上探针外观的策略将应用于其他神经系统疾病的研究，并且可以适用于其他被认为是更复杂的脑机接口的可植入材料，以使它们在MRI中可见。例如，一种类似的方法，使MRI兼容的深部脑刺激（DBS）电极用于治疗运动障碍，如帕金森病与石墨烯为基础的技术将允许改善探针的目标和可视化，并因此更有效的治疗。此外，新的电极技术对于正常脑活动的研究具有重要的潜在应用，因为从脑留置电极获得的数据也用于研究脑信号的性质，例如功能性MRI和头皮EEG，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.