Brain Mechanisms for Autonomic Outflow and Nausea in Cyclic Vomiting Syndrome

描述(申请人提供)：虽然恶心的感觉在人类体验中是普遍存在的，但这种知觉状态背后的大脑活动并没有被很好地理解。恶心的典型症状是上腹部不适，有呕吐的冲动，自主神经系统(ANS)外流的特点是交感神经占优势。恶心是周期性呕吐综合征(CVS，罗马III定义)患者的一种特别虚弱的症状。CVS患者会出现极度恶心和呕吐的发作，并交替出现相对无症状的时期。虽然对CVS的病理生理学知之甚少，但交感迷走神经功能障碍和脑生理改变被认为起着重要作用。我们团队已经成功地引入了源于静息或内在脑连接的功能磁共振(FMRI)测量的指标，作为慢性疼痛患者疼痛的客观神经生物学相关性。我们的目标是扩展我们的方法，以更好地描述一种不同的令人厌恶的主观感觉-恶心。我们最近对健康成年人进行的研究表明，恶心背后的大脑电路包括已知的处理内感的区域，以及边缘和前额叶皮质较高的区域。这些区域在晕动病期间表现出与视觉运动处理区域更强的连接性。我们的初步数据还表明，来自前额叶和边缘皮质脑区的fMRI信号服务于恶心的认知和情感成分，与晕动病期间的自主神经调节更相关。因此，我们假设CVS患者，即使在他们的发作间歇期，也会在健康成年人的运动病期间发现的相同的感觉、情感和认知处理区域之间表现出静息性大脑连接的增加。这种增强的连通性可能使这些患者对中枢呕吐信号产生高反应性。我们的总体目标是通过对比CVS患者和健康成年人的内在脑连接来评估支持恶心的大脑回路，无论是在休息时还是在晕动病引起的恶心状态下。我们的目标将评估与健康成年人晕动病引起的恶心相关的脑功能连接，并调查CVS静息脑连接的改变及其与交感优势的关系。一旦完成，我们的长期目标是利用恶心和CVS背后的大脑回路的特征来建立客观的神经成像生物标志物，这些生物标志物可以用于CVS和其他慢性恶心患者的亚型，并定义新疗法开发中纵向试验的结果衡量标准。

DESCRIPTION (provided by applicant): While the sensation of nausea is universal in the human experience, the brain activity underlying this perceptual state is not well understood. Nausea is typified by epigastric discomfort with the urge to vomit, and autonomic nervous system (ANS) outflow characterized by sympathetic dominance. Nausea is a particularly debilitating symptom for patients with Cyclic Vomiting Syndrome (CVS, ROME III definition). CVS patients suffer from episodes of extreme nausea and vomiting, alternating with relatively symptom-free periods. While the pathophysiology of CVS is poorly understood, sympathovagal dysfunction and altered brain physiology have been proposed to play a significant role. Our group has successfully introduced metrics derived from functional MRI (fMRI) measures of resting, or intrinsic, brain connectivity as objective neurobiological correlates of pain in chroni pain patients. Our goal is to extend our approach to better characterize a different aversive subjective sensation - nausea. Our recent studies in healthy adults using combined visually-induced vection with concurrent fMRI and autonomic monitoring has suggested that the brain circuitry underlying nausea includes areas known to process interoception, as well as limbic and higher prefrontal cortical brain regions. These regions demonstrate greater connectivity to visual motion processing regions during motion sickness. Our preliminary data also suggests that fMRI signal from prefrontal and limbic cortical brain regions subserving the cognitive and affective components of nausea is more correlated with autonomic modulation during motion sickness. Hence, we hypothesize that CVS patients, even during their inter-episodic state, will demonstrate increased resting brain connectivity between the same interoceptive, affective, and cognitive processing regions identified during motion sickness in healthy adults. Such enhanced connectivity may predispose these patients to be hyper-responsive to central emetic signaling. Our overall goal is to evaluate the brain circuitry supporting nausea by contrasting intrinsic brai connectivity in CVS patients with that of healthy adults, both at rest and during a motion sickness-induced nausea state. Our Aims will evaluate functional brain connectivity associated with motion sickness-induced nausea in healthy adults, and investigate altered resting brain connectivity in CVS and its relationship to sympathetic dominance. Once completed, our long-term goal is to use the characterization of brain circuitry underlying nausea and CVS to establish objective neuroimaging biomarkers, which can be used to sub-phenotype CVS and other chronic nausea patients, and to define outcome measures for longitudinal trials in the development of novel therapies.