Bioinspired closed-loop deep brain stimulation for disorders of decision-making

历史上，帕金森病（PD）被概念化为运动障碍。然而，越来越清楚的是，神经精神症状的发生既是基础疾病的结果，也是治疗的结果。例如，丘脑底核脑深部电刺激（STN-DBS）与冲动控制失调有关，导致冲动和强迫行为（ICB）。实验1在高冲突决策过程中，反应抑制是关键的，这被认为是通过内侧前额叶皮层（mPFC）和前额叶皮层的θ-波段（4-8Hz）耦合发生的。在治疗频率（60- 150 Hz）下，STN-DBS破坏了这种mPFC-神经刺激耦合，减少了反应时间，增加了高冲突决策的错误率。为了验证这一假设，即电生理学相关的行为可以告知刺激范例，这些电生理学特征编码的大脑区域之间的双向通信，调节行为，我将进行一项研究的θ-频率STN-DBS。以前的研究已经证明了这种方法的安全性，但尚未研究过全脑网络效应。在高冲突决策任务期间，将有内置STN-DBS植入物的有和无ICB的PD患者招募到θ频率STN-DBS试验中。将行为结局与治疗频率STN-DBS和STN-DBS关闭进行比较。同时电生理记录（MEG/EEG），以确定mPFC θ-连贯性在任务和全脑建模管道将确定更广泛的决策网络effects.Experiment 2在人类中，决策行动启动网络已确定从功能磁共振成像数据，在非人类灵长类动物的相关性。值得注意的是，这些包括DBS靶点，例如脚桥核。经颅超声刺激（TUS）已证明对非人类灵长类动物的决策网络具有可重复的影响，但尚未在人类中进行测试。为了检验这个决策网络中的网络节点的TUS可以导致人类可再现和可逆的行为变化的假设，我将在健康志愿者和PD患者中进行一项研究，调查这个网络中目标的TUS。参与者将在TUS期间使用安全参数完成高冲突决策任务，并将接受fMRI成像以检测网络调制。实验3根据观察到的发现，这些目标的一个子集将用于识别决策网络调制的电生理相关性。为了检验这些网络效应是双向的并与观察到的任务表现相关的假设，将在TUS/DBS研究中招募植入DBS器械的PD患者。这将利用现代DBS设备在内化后记录和遥测读出局部场电位（LFP）的能力：第1阶段：在关键网络节点的TUS期间记录决策的LFP信号。这些LFP记录将与行为结果相关。第2阶段：相关LFP特征将用于定义刺激设置。植入的DBS器械将被程控为这些设置，参与者将在没有TUS的情况下重复决策任务。将行为结局与TUS期间的行为结局进行比较。第三阶段：这些决策的LFP特征将用于概念验证闭环刺激范例，以证明个体内的再现性。

Historically, Parkinson's disease (PD) was conceptualised as a movement disorder. However it is increasingly clear that neuropsychiatric symptoms occur both as a result of the underlying disease and its treatment. For example, subthalamic nucleus deep brain stimulation (STN-DBS) has been implicated in the dysregulation of impulse control, leading to impulsive and compulsive behaviours (ICBs). Experiment 1 The STN is pivotal in response inhibition during high-conflict decision-making and this is thought to occur through theta-band (4-8Hz) coupling of the medial prefrontal cortex (mPFC) and the STN. At therapeutic frequencies (60-150Hz) STN-DBS disrupts this mPFC-STN coupling, reducing reaction time and increasing error rates in high-conflict decision-making. To test the hypothesis that electrophysiological correlates of behaviour can inform stimulation paradigms, and that these electrophysiological signatures encode bidirectional communication between brain regions that modulate behaviour, I will conduct a study of theta-frequency STN-DBS. Previous studies have demonstrated the safety of this but whole-brain network effects have not been investigated. PD patients with and without ICBs who have internalised STN-DBS implants will be recruited into a trial of theta-frequency STN-DBS during a high-conflict decision-making task. Behavioural outcomes will be compared against therapeutic-frequency STN-DBS and STN-DBS off. Simultaneous electrophysiological recordings will be taken (MEG/EEG) to identify mPFC theta-coherence during task and a whole-brain modelling pipeline will identify the wider decision-network effects.Experiment 2 In humans, a decision-making action initiation network has been identified from fMRI data, with correlates in non-human primates. Notably, these include DBS targets such as the pedunculopontine nucleus. Transcranial Ultrasound Stimulation (TUS) has demonstrated reproducible effects on this decision-making network in non-human primates but this has not yet been tested in humans. To test the hypothesis that TUS of network nodes in this decision-making network can lead to reproducible and reversible behavioural change in humans, I will conduct a study investigating TUS of targets within this network in healthy volunteers and PD patients. Participants will complete high-conflict decision-making tasks during TUS using safe parameters, and will undergo fMRI imaging to detect network modulation. Experiment 3 Based on the observed findings, a subset of these targets will be used to identify electrophysiological correlates of decision network modulation. To test the hypothesis that these network effects are bidirectional and correlate with observed task performance, PD patients with implanted DBS devices will be recruited into a TUS/DBS study. This will utilise the capacity of modern DBS devices to record and telemetrically readout local field potentials (LFPs) after internalisation: Phase 1: LFP signals of decision-making will be recorded during TUS of key network nodes. These LFP recordings will be correlated with behavioural outcomes. Phase 2: Correlated LFP signatures will be used to define stimulation settings. Implanted DBS devices will be programmed to these settings and participants will repeat the decision-making tasks without TUS. Behavioural outcomes will be compared to those during TUS. Phase 3: These LFP signatures of decision-making will be used in a proof-of-concept closed-loop stimulation paradigm to demonstrate reproducibility within individuals.