Characterizing the Sensory and Affective Neural Components of Persistent Dyspnea

持续性呼吸困难的感觉和情感神经成分的特征

• 批准号: 10419096
• 负责人: Jose Luis Herrero Rubio
• 金额: $ 41.47万
• 依托单位: FEINSTEIN INSTITUTE FOR MEDICAL RESEARCH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-05 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10419096
• 关键词: Affective; Air; Animals; Anterior; Area; Asthma; Awareness; Benzodiazepines; Brain; Brain Stem; Brain region; Breathing; COVID-19; COVID-19 pandemic; Cardiac; Caring; Chronic; Chronic Obstructive Pulmonary Disease; Clinical; Complex; Conscious; Coronavirus; Coupled; Coupling; Dependence; Descriptor; Detection; Dimensions; Distress; Dyspnea; Electric Stimulation; Electrical Stimulation of the Brain; Electroencephalography; Electrophysiology (science); Epilepsy; Esthesia; Etiology; Feeling; Foundations; Frequencies; Fright; Functional Magnetic Resonance Imaging; Future; General Population; Heart Diseases; Human; Hypercapnic respiratory failure; Implanted Electrodes; Interstitial Lung Diseases; Intervention; Lead; Link; Lung; Lung diseases; Medical; Methods; Modeling; Monitor; Neuromuscular Diseases; Neurons; Opioid; Pain; Palliative Care; Participant; Pathology; Patients; Perception; Persons; Pharmaceutical Preparations; Physiology; Population; Prevalence; Resolution; Resort; Respiration; Respiratory Disease; Respiratory Signs and Symptoms; Respiratory physiology; Rodent; Sensory; Severe Acute Respiratory Syndrome; Shapes; Signal Transduction; Site; Sleep Stages; Source; Structure; Symptoms; Syndrome; Therapeutic Intervention; Time; Visual; Water; Work; Work of Breathing; alternative treatment; analog; chronic pain; cingulate cortex; design; effective therapy; experience; experimental study; feature detection; improved; machine learning method; mechanical load; meetings; neuronal circuitry; pulmonary rehabilitation; relating to nervous system; respiratory; scaffold; targeted treatment; tool

Abstract: The neuronal circuitry underlying respiration has been investigated thoroughly within the brainstem. In recent years, mounting evidence in animals and humans has revealed that ‘higher-level’ brain structures above the brainstem modulate key aspects of respiration, a finding that has important implications to design effective treatments for patients suffering from certain types of respiratory disease. This is especially relevant for cases where lung disease is not reversible and where neural or psychogenic influences are suspected, as in some forms of COPD, asthma, interstitial lung disease, cardiac and neuromuscular diseases, as well as palliative care and COVID-19. The overall aim of this proposal is to determine how higher-level brain regions interfere with automatic brainstem respiratory circuits to give rise to the complex pathology underlying respiratory disease in humans. To answer this question, we use a model of dyspnea (breathing discomfort) which is one of the leading symptoms (rivaling chronic pain) that cause approximately 10% of the general population to seek medical care. Patients suffering from persistent dyspnea choose descriptors such as “feeling suffocated” and “feeling like air is more precious than water”. Dyspnea is the result of an imbalance between the neural drive to breathe and the corresponding respiratory-related afferents. Current treatments that target the brain (rather than the lungs) to alleviate dyspnea are limited to opioids and/or benzodiazepines, but these drugs can suppress ventilatory drive, produce dependence and contribute to hypercapnic respiratory failure. We work towards meeting the clinical need of finding a treatment that reduces dyspnea without reducing ventilatory drive, by providing a better understanding of the cortical mechanisms that modulate respiratory-related afferents and ultimately shape the subjective sensations of dyspnea. Available evidence on the neural substrates of dyspnea in humans comes from noninvasive EEG and fMRI studies which do not afford the level of resolution required to access the deep sources involved in dyspnea nor disentangle the temporal dynamics of its different components (sensory and affective). We will utilize intracranial recordings (iEEG) from multiple cortical and subcortical regions in patients with chronically implanted electrodes for reasons unrelated to the present study (undergoing epilepsy treatment) and leverage on our recent finding that neural oscillations in these regions, recorded using iEEG, track the respiratory cycle, the so called Respiratory-Related Brain Oscillations (RRBO). The proposed experiments aim to: Aim 1: Further characterize RRBO: Determining causality between brain oscillations and the breathing cycle. Aim 2: Validate RRBO as neural marker of dyspnea: Detecting neural features of dyspnea in RRBO recorded in the primary (sensory dyspnea dimension) and secondary (affective dyspnea dimension) interoceptive cortex. Aim 3: Using direct electrical stimulation (DES) to probe cortical sites involved in dyspnea: Reducing dyspnea induced by the respiratory constrains by applying DES to key regions in the secondary interoceptive cortex.

摘要： 在脑干内，已经对呼吸的神经回路进行了彻底的研究。在最近 多年来，越来越多的证据表明，在动物和人类身上，位于大脑 脑干调节呼吸的关键方面，这一发现对设计有效的呼吸具有重要意义 治疗患有某些类型呼吸系统疾病的患者。这一点在案件中尤其重要 肺部疾病不可逆转的，怀疑有神经或心理影响的，如在某些情况下 各种形式的慢性阻塞性肺病、哮喘、间质性肺病、心脏和神经肌肉疾病以及姑息治疗 还有新冠肺炎。这项提议的总体目标是确定较高级别的大脑区域如何干扰 与自动脑干呼吸回路一起引起复杂的病理基础 人类中的呼吸系统疾病。为了回答这个问题，我们使用了一个呼吸困难(呼吸不适)的模型。 这是导致大约10%的全身疼痛的主要症状之一(与慢性疼痛相当) 人口寻求医疗保健。患有持续性呼吸困难的患者会选择描述符，如“感觉 “窒息”和“感觉空气比水更珍贵”。呼吸困难是由于呼吸不平衡造成的 呼吸的神经驱动和相应的呼吸相关传入。目前的治疗方法是针对 缓解呼吸困难的大脑(而不是肺)仅限于阿片类药物和/或苯二氮卓类药物，但这些药物 会抑制呼吸动力，产生依赖，并导致高碳酸血症呼吸衰竭。我们工作 朝着满足临床需要寻找一种既减少呼吸困难又不减少呼吸困难的治疗方法 通气性驱动，通过更好地了解调节 呼吸相关的传入，并最终形成呼吸困难的主观感觉。 有关人类呼吸困难神经底物的现有证据来自非侵入性脑电和 无法获得与呼吸困难有关的深层来源所需的分辨率水平的功能磁共振研究 也不能理清其不同组成部分(感官和情感)的时间动态。我们将利用 慢性阻塞性肺疾病患者多个皮质和皮质下区的脑电研究 植入电极的原因与本研究无关(正在接受癫痫治疗)和杠杆作用 根据我们最近的发现，使用iEEG记录的这些区域的神经振荡跟踪呼吸周期， 所谓的呼吸相关脑振荡(RRBO)。拟议的实验旨在： 目标1：进一步描述RRBO：确定大脑振荡和呼吸周期之间的因果关系。 目的2：验证RRBO作为呼吸困难的神经标志物：检测RRBO记录的呼吸困难的神经特征 在初级(感觉性呼吸困难)和次级(情感呼吸困难)感觉皮层。 目的3：使用直接电刺激(DES)探测与呼吸困难有关的皮质部位：减少呼吸困难 通过将DES应用于次级感觉间皮层的关键区域来诱导呼吸抑制。