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）：胼胝体下扣带回（SCC）区域脑深部电刺激（DBS）的早期临床试验已证明其具有改善难治性抑郁症（TRD）患者生活的真实的潜力。然而，TRD症状的神经生理学基础仍然未知，并且有朝一日可能用于闭环DBS控制系统的电生理学生物标志物的定义仍有待确定。本项目的目标是确定长期记录的局部场电位（LFPs）在SCC的关键电生理特征。我们认为，最近在患者特定建模方面取得的进展，加上能够持续记录LFP的新型临床DBS设备，代表了一个独特的机会，可以增强我们对SCC电生理学和TRD的理解。因此，我们将开发模拟SCC LFP的详细计算机模型，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，调制的theta波段活动在SCC可以与TRD症状缓解DBS，这些LFP信号产生的抑制性和兴奋性输入SCC锥体神经元的相互作用。我们将使用SCC LFP的患者特异性模型来评估我们的假设。本项目的LFP模型将包括植入每个患者大脑的DBS电极的体积导体模型，与产生负责实验记录信号的源和汇的SCC锥体神经元的生物物理模型耦合。我们将分析研究者发起的SCC DBS治疗TRD临床试验中入组的10例患者 (FDA IDE G130107）。该试验将使用新的Medtronic Activa PC+S实验DBS系统，该系统能够记录和遥测植入器械的LFP信号。SCC振荡活动的LFP测量也将伴随着情绪和临床抑郁结果测量的同时采集。这一独特的合作研究机会将整合两位DBS世界专家，独特地融合他们的特定技能和优势，并应用尖端的建模方法来解决真实的临床问题。该项目的结果将扩大我们对人类大脑中LFP信号的基本理解，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：这项建议利用了抑郁症定义和治疗方式的不断发展的范式转变。抑郁症是一种神经系统疾病，具有可量化的神经生理特征（即使我们还不知道确切的细节），这一概念可能会被有学问的学者所接受。然而，整个世界仍然缺乏基本教育和对社会中最常见的痛苦之一的解释。具体而言，本项目中提出的工作具有很大的潜力，可以提供对人类患者情绪调节回路的细胞水平理解。这对未来情绪障碍的定量分类和基于大脑的康复标准具有重要的翻译意义。抑郁症的临床记录和分类的这种范式转变可以代表由科学发现驱动的抑郁症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，必须收集科学数据。这两个中心的合作将促进这一过程，并为计算神经科学和系统神经科学的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，这对于解决新兴的临床神经调节领域的复杂神经工程需求是必要的。