Characterizing the Sensory and Affective Neural Components of Persistent Dyspnea

摘要： 在脑干内，呼吸所涉及的神经元回路已经被彻底研究过。近几 多年来，越来越多的证据表明，动物和人类的“高级”大脑结构， 脑干调节呼吸的关键方面，这一发现对设计有效的 为患有某些类型呼吸道疾病的患者提供治疗。这一点尤其适用于 肺部疾病是不可逆的，怀疑有神经或心因性影响，如在一些 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 和新冠肺炎这项提议的总体目标是确定更高级别的大脑区域如何干扰 自动脑干呼吸回路，导致复杂的病理学基础， 人类呼吸道疾病。为了回答这个问题，我们使用一个呼吸困难（呼吸不适）的模型 这是一个主要的症状（相当于慢性疼痛），造成约10%的一般 人口就医。患有持续性呼吸困难的患者选择诸如“感觉”之类的描述符， “感觉空气比水珍贵”。呼吸困难是呼吸道和呼吸道之间失衡的结果。 呼吸的神经驱动和相应的呼吸相关传入。目前的治疗目标是 大脑（而不是肺），以减轻呼吸困难仅限于阿片类药物和/或苯二氮卓类药物，但这些药物 可抑制呼吸驱动，产生依赖性，导致高碳酸血症性呼吸衰竭。我们工作 为了满足寻找减少呼吸困难而不减少呼吸困难的治疗的临床需要， 通过更好地理解调节大脑皮层的机制， 呼吸困难相关的传入神经，并最终形成呼吸困难的主观感觉。 关于人类呼吸困难的神经基础的现有证据来自非侵入性EEG， 功能磁共振成像研究无法提供所需的分辨率水平，以访问涉及呼吸困难的深层来源 也没有解开其不同组成部分（感觉和情感）的时间动态。我们将利用 颅内记录（iEEG）从多个皮层和皮层下区域的患者慢性 由于与本研究无关的原因植入电极（接受癫痫治疗）和杠杆 我们最近的发现，这些区域的神经振荡，使用iEEG记录，跟踪呼吸周期， 呼吸相关脑震荡（RRBO）拟议的实验旨在： 目的1：进一步表征RRBO：确定脑振荡和呼吸周期之间的因果关系。 目的2：RRBO作为呼吸困难的神经标志物：检测记录的RRBO呼吸困难的神经特征 在初级（感觉性呼吸困难维度）和次级（情感性呼吸困难维度）内感受性皮质中。 目的3：使用直接电刺激（DES）探测涉及呼吸困难的皮质部位：减少呼吸困难 通过将DES应用于次级内感受皮层中的关键区域，由呼吸限制诱导。

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.