Bioinspired closed-loop deep brain stimulation for disorders of decision-making: Using non-invasive methods for predictive neurosurgery

帕金森病（PD）的特点是运动缓慢、僵硬和震颤。PD是由多巴胺分泌减少引起的，因此一线治疗是多巴胺替代疗法。随着时间的推移，这种药物的效果越来越差，深部脑刺激（DBS）可能被认为是治疗运动症状的方法。最常见的大脑目标是丘脑下核（STN）。高达16%的PD患者还会出现冲动控制障碍，如强迫性赌博和药物滥用，这对患者及其家人来说是毁灭性的。以前的研究已经确定了STN在决策中的关键作用，特别是在存在相互矛盾的信息时。STN被认为通过低频电信号（振荡）在前额皮质之间传递信息，从而对决策施加控制。在STN-DBS后，一些患者会出现新的冲动控制障碍，而另一些患者可能会好转。该项目的目的是通过三个实验阶段来理解其中的原因，并将这种理解转化为治疗决策障碍的新方法。在实验1中，这些低频振荡将通过DBS重现，试图重现在之前的实验中观察到的对决策的影响。将招募已经在STN中植入DBS电极的患者，并将其分为两组。一组术前冲动得分高，另一组术前冲动得分低。然后，这两组人将在不同的实验条件下进行两项计算机化的认知任务。在这些任务中，将使用非侵入性方法（脑电图（EEG）和脑磁图（MEG））记录大脑电信号，以将大脑特征与任务表现和自我报告的冲动行为联系起来。根据之前的研究，这些任务将在三种实验条件下完成(1)无刺激(2)高频刺激（临床常规）和(3)低频刺激。在实验2中，除了年龄匹配的对照组外，还将招募两个相似的组（在实验1中描述，但在手术前）。这些参与者将接受非侵入性经颅聚焦超声（FUS）刺激，刺激特定的大脑区域，这些区域与最近确定的决策网络有关。刺激对大脑的影响将通过功能性核磁共振扫描记录下来，对决策的影响将通过与实验1相同的认知任务进行评估。这个实验将通过单独刺激这些特定的大脑区域来确定它们对决策的影响。这将使我们能够使用非侵入性刺激预测决策网络调制的行为反应。在实验3中，将招募植入具有遥测记录功能的DBS电极的PD患者。目的是将实验1和2的结果转化为概念验证闭环系统。为了达到这个目的，在进行认知任务时，大脑的一部分区域将受到FUS的刺激。然后将从植入的电极上记录振荡，以表征大脑深处这种行为变化的相关特征。在第二个实验阶段，DBS将以复制这些大脑信号的频率进行，以测试对决策的影响是否与用FUS非侵入性刺激时相同。本实验的最后一步是在概念验证研究中证明，非侵入性脑刺激可用于预测对侵入性DBS的反应，并告知闭环刺激程序，该程序以正确的频率和时间提供刺激，而无需额外的侵入性电极放置。这些实验将导致闭环DBS治疗PD患者冲动控制障碍的临床试验。

Parkinson's disease (PD) is characterised by slow movement, rigidity, and tremor. PD is caused by reduced dopamine production and first-line treatment is therefore dopamine replacement therapy. This medication becomes less effective over time and deep brain stimulation (DBS) may be considered to treat motor symptoms. The most common brain target is the subthalamic nucleus (STN). Up to 16% of patients with PD also develop impulse control disorders such as compulsive gambling and medication abuse which are devastating for the patient and their family. Previous studies have identified the critical role of the STN in decision-making, especially in the presence of conflicting information. The STN is thought to exert control on decision-making through low-frequency electrical signals (oscillations) that carry information to and from the prefrontal cortex. After STN-DBS, some patients develop new impulse control disorders whilst others may get better. The aim of this project is to understand why and translate this understanding into new treatments for disorders of decision-making through three experimental phases.In experiment 1, these low-frequency oscillations will be replicated through DBS in an attempt to reproduce the observed effects on decision-making seen in previous experiments. Patients who have had an operation to implant DBS electrodes into the STN will be recruited and separated into two groups. One group will have high preoperative impulsivity scores and the other group will have low scores. These two groups will then undertake two computerised cognitive tasks under different experimental conditions. During these tasks, the electrical signals of the brain will be recorded using non-invasive methods (electroencephalography (EEG) and magnetoencephalography (MEG)) to correlate brain signatures with task performance and self-reported impulsive behaviour. Informed by previous studies, these tasks will be done under three experimental conditions (1) no stimulation (2) high-frequency stimulation (clinically routine) and (3) low-frequency stimulation. In experiment 2, two similar groups (described in experiment 1 but before surgery) will be recruited in addition to age-matched controls. These participants will receive non-invasive transcranial focused ultrasound (FUS) stimulation to particular brain regions known to be involved within a recently identified decision network. Stimulation effects on the brain will then be recorded using functional MRI scans and the effect on decision-making will be assessed using the same cognitive tasks as experiment 1. This experiment will identify the effects of these specific brain regions on decision-making by stimulating them individually. This will allow us to predict the behavioural response of decision network modulation using non-invasive stimulation.In experiment 3, PD patients with implanted DBS electrodes that have telemetric recording capabilities will be recruited. The aim will be to translate the results of experiment 1 and 2 into a proof-of-concept closed loop system. To achieve this, a subset of brain regions will be stimulated with FUS during a cognitive task. Oscillations will then be recorded from the implanted electrodes to characterise the correlates of this behavioural change deep in the brain. In a second experimental session, DBS will be delivered at a frequency that replicates these brain signals to test the hypothesis that the effect on decision-making will be the same as when stimulating non-invasively with FUS. The final step of this experiment is to demonstrate, in proof-of-concept study, that non-invasive brain stimulation can be used to predict response to invasive DBS and inform a closed-loop stimulation program that delivers stimulation at the correct frequency and time without the need for additional invasive electrode placement. These experiments will lead to a clinical trial of closed-loop DBS for impulse control disorders in PD.