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

基本信息

批准号：
9501771
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
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-15 至 2020-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9501771
关键词：
Address Anatomic Models Base of the Brain Behavioral Biological Markers Biophysical Process Brain Characteristics Chronic Classification Clinical Clinical Trials Collaborations Complex Computer Simulation Coupled Data Deep Brain Stimulation Devices Documentation Education Electrodes Electrophysiology (science)Elements Engineering Enrollment Equilibrium Evolution Future Geometry Goals Human Implanted Electrodes 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 and Infrastructure Work biophysical model computational neuroscience depressive symptoms graduate student gray matter hippocampal pyramidal neuron implantable device improved nervous system disorder neurophysiology neuropsychiatric disorder neuroregulation next generation novel public education reduce symptoms response skills training opportunity treatment-resistant depression

项目摘要

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）：胼胝体下扣带回（SCC）区域的深部脑刺激（DBS）的早期临床试验已经证明了改善难治性抑郁症（TRD）患者生活的真正潜力。然而，TRD 症状的神经生理学基础仍然未知，并且有朝一日可用于闭环 DBS 控制系统的电生理生物标志物的定义仍有待定义。该项目的目标是确定 SCC 中长期记录的局部场电位 (LFP) 的关键电生理特征。我们认为，患者特异性建模的最新进展，加上能够持续进行 LFP 记录的新型临床 DBS 设备，为增强我们对 SCC 电生理学和 TRD 的理解提供了独特的机会。因此，我们将开发详细的计算机模型来模拟 SCC LFP，并使用它们来帮助解释从 TRD 患者获得的临床长期记录。我们假设 SCC 中 θ 带活动的调节可能与 DBS 的 TRD 症状缓解相关，并且这些 LFP 信号源自 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，与生物物理模型 SCC 锥体神经元相结合，生成负责实验记录信号的源和汇。我们将分析 10 名参与研究者发起的 SCC DBS 治疗 TRD 临床试验的患者（FDA IDE G130107）。该试验将使用新的美敦力 Activa PC+S 实验 DBS 系统，该系统能够记录和遥测来自植入设备的 LFP 信号。 SCC 振荡活动的 LFP 测量还将伴随着情绪和临床抑郁结果测量的同步采集。这一独特的合作研究机会将整合两位 DBS 世界专家，以独特的方式融合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。该项目的成果将扩大我们对人脑LFP信号的基本了解，并促进用于治疗抑郁症的闭环DBS技术的发展。更广泛的影响：该提案利用了抑郁症定义和治疗方式不断演变的范式转变。抑郁症是一种神经系统疾病，具有可量化的神经生理学特征（尽管我们尚不知道确切的细节），这一概念可能会被博学的学者所接受。然而，整个世界仍然缺乏基础教育和对社会最常见疾病之一的阐明。具体来说，该项目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理解。这对于未来情绪障碍的定量分类和基于大脑的恢复标准具有重要的转化意义。抑郁症临床记录和分类的这种范式转变可以成为在科学发现的推动下对抑郁症进行公共教育和启蒙的跳板。梅伯格博士特别适合促进这一更广泛的影响目标；然而，必须汇总科学数据。这项两中心合作将促进这一过程，并为计算神经科学和系统神经科学领域的研究生和博士后提供独特的培训机会。该项目将进一步为培训下一代跨学科团队科学家提供重要的基础设施，这对于满足新兴的临床神经调节领域的复杂神经工程需求是必要的。