CRCNS: Patient-Specfic Models of Local Field Potentials in Subcallosal Cingulate

CRCNS：胼胝体下扣带回局部场电位的患者特异性模型

• 批准号: 8926473
• 负责人: Cameron McIntyre
• 金额: $ 39.1万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-15 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8926473
• 关键词: Address; Anatomic Models; Base of the Brain; Behavioral; Biological Markers; Biophysical Process; Brain; Characteristics; Classification; Clinical; Clinical Trials; Collaborations; Complex; Computer Simulation; Coupled; Data; Deep Brain Stimulation; Devices; Disease; Documentation; Education; Electrodes; Electrophysiology (science); Elements; Engineering; Enrollment; Equilibrium; Evolution; Future; Geometry; Goals; Human; Implanted Electrodes; Learning; Life; Location; Magnetic Resonance Imaging; Major Depressive Disorder; Measures; Mental Depression; Methods; Modeling; Mood Disorders; Moods; Movement Disorders; Neurons; Neurosciences; Outcome Measure; Patients; Phase I Clinical Trials; Physiological; Positioning Attribute; Postdoctoral Fellow; Process; Recovery; Research; Research Personnel; Scientist; Signal Transduction; Societies; Source; Synapses; System; Technology; Telemetry; Therapeutic; Training; Training and Infrastructure; Work; base; biophysical model; computational neuroscience; depressive symptoms; graduate student; gray matter; hippocampal pyramidal neuron; implantable device; improved; nervous system disorder; neurophysiology; neuropsychiatry; neuroregulation; next generation; novel; public education; response; skills; treatment-resistant depression

DESCRIPTION (provided by applicant): Early stage clinical trials of deep brain stimulation (DBS) of the subcallosal cingulate (SCC) region has demonstrated real potential to improve the lives of patients with treatment-resistant depression (TRD). However, the neurophysiological basis for TRD symptoms remains unknown and definition of electrophysiological biomarkers that could someday be useful in closed-loop DBS control systems remain to be defined. The goal of this project is to identify the key electrophysiological features of chronically recorded local field potentials (LFPs) in the SCC. We propose that recent advances in patient-specific modeling, coupled with novel clinical DBS devices that enable ongoing LFP recording, represent a unique opportunity to augment our understanding of SCC electrophysiology and TRD. Therefore, we will develop detailed computer models that simulate the SCC LFP and use them to help interpret the clinical longterm recordings acquired from TRD patients. We hypothesize that modulation of theta-band activity in SCC can be correlated with TRD symptom relief from DBS, and these LFP signals arise from the interaction of inhibitory and excitatory inputs on SCC pyramidal neurons. We will use patient-specific models of SCC LFPs to evaluate our hypotheses. The LFP models for this project will consist of volume conductor models of the DBS electrodes implanted in each patient's brain, coupled to biophysical models SCC pyramidal neurons generating the sources and sinks responsible for the experimentally recorded signals. We will analyze 10 patients enrolled in an investigator initiated clinical trial of SCC DBS for TRD (FDA IDE G130107). That trial will use the new Medtronic Activa PC+S experimental DBS system, which enables recording and telemetry of LFP signals from the implanted device. LFP measures of SCC oscillatory activity will also be accompanied by simultaneous acquisition of mood and clinical depression outcome measures. This unique collaborative research opportunity will integrate two DBS world experts, uniquely blending their specific skills and strengths, and apply cutting edge modeling methods to address real life clinical questions. The results of the project will expand our basic understanding of LFP signals in the human brain, and facilitate the evolution of closed-loop DBS technology for the treatment of depression. BROADER IMPACTS: This proposal takes advantage of an evolving paradigm shift in how depression is defined and treated. The concept that depression is a neurological disorder with a quantifiable neurophysiological signature (even though we do not yet know the exact details), may be accepted by learned scholars. However, the world at large is still lacking in basic education and elucidation on one of the most common afflictions in society. Specifically the work proposed in this project has great potential to provide a cellular-level understanding of mood regulatory circuits in human patients. This has important translational implications for future quantitative classification of mood disorders and brain-based criteria for recovery. Such paradigm shifts in the clinical documentation and classification of depression could represent a springboard for public education and enlightenment on depression, driven by scientific discovery. Dr. Mayberg is especially well positioned to facilitate this broader impact goal; however, the scientific data must be assembled. This 2-center collaboration will facilitate that process and provide a unique training opportunity for both graduate students and post-doctoral fellows in both computational neuroscience and systems neuroscience. This project will further provide important infrastructure for training the next generation of interdisciplinary team scientists that will be necessary to address the complex neuro-engineering demands of the burgeoning field of clinical neuromodulation.

描述（由申请人提供）：潜能扣带回（SCC）区域深脑刺激（DB）的早期临床试验（SCC）区域表现出了改善耐药抑郁症患者生活（TRD）的实际潜力。但是，TRD症状的神经生理基础仍然未知，并且有一天可以在闭环DBS控制系统中有助于电生理生物标志物的定义仍有待定义。该项目的目的是确定SCC中长期记录的局部田间电位（LFP）的关键电生理特征。我们建议，最新的特定于患者建模的进步，再加上新型的临床DBS设备，可实现正在进行的LFP记录，这代表了我们对SCC电生理学和TRD的理解的独特机会。因此，我们将开发详细的计算机模型，以模拟SCC LFP并使用它们来解释从TRD患者获得的临床长期记录。我们假设SCC中theta波段活性的调节可以与DBS的TRD症状缓解相关，并且这些LFP信号来自SCC锥体神经元的抑制性和兴奋性输入的相互作用。我们将使用SCC LFP的患者特异性模型来评估我们的假设。该项目的LFP模型将包括植入每个患者大脑中的DBS电极的体积导体模型，并与生物物理模型SCC锥体神经元结合，产生了负责实验记录的信号的来源和下沉。我们将分析10名招募的研究者的患者启动了SCC DBS的临床试验 （FDA IDE G130107）。该试验将使用新的Medtronic Activa PC+S实验DBS系统，该系统可以从植入设备中记录和遥测LFP信号。 SCC振荡活性的LFP度量也将伴随着同时获得情绪和临床抑郁症结果指标。这个独特的协作研究机会将整合两个DBS世界专家，独特地融合了他们的特定技能和优势，并应用最先进的建模方法来解决现实生活中的临床问题。该项目的结果将扩大我们对人脑中LFP信号的基本理解，并促进闭环DBS技术的进化来治疗抑郁症。 更广泛的影响：该提案利用了抑郁症的定义和治疗方式不断发展的范式转变。抑郁症是一种具有可量化的神经生理学特征的神经系统疾病（即使我们还不知道确切细节），也可以被学术学者所接受。但是，整个世界仍然缺乏基础教育和社会上最常见的苦难之一的阐明。具体而言，该项目中提出的工作具有巨大的潜力，可以提供对人类患者情绪调节回路的细胞水平的理解。这对于情绪障碍和基于大脑的恢复标准的未来定量分类具有重要的翻译意义。在科学发现的推动下，临床文件和抑郁症分类的这种范式转变可能代表了公共教育和抑郁症的跳板。梅伯格博士在促进这一更广泛的影响目标方面尤为好；但是，必须组装科学数据。这种2个中心的合作将促进这一过程，并为研究生和博士后研究员提供独特的培训机会。该项目将进一步提供重要的基础设施，以培训下一代跨学科团队科学家，这对于解决临床神经调节蓬勃发展领域的复杂神经工程需求是必不可少的。