Visceral neural circuits linking childhood threat and deprivation with stress physiology and affective symptoms in a transdiagnostic sample using high-field personalized brain mapping

项目摘要/摘要 儿时的逆境最近被认为是精神病学最大的公共健康挑战，因为它是一种重大的 情绪、焦虑和创伤相关(即情感)障碍的预测因子。童年的逆境也与 有失调的生理应激反应，有情感障碍的个体也表现出来。而当 压力被认为是童年逆境影响身心健康的一种机制，很少有人 研究已经考虑了杏仁皮质和海马区以外与应激相关的脑区。 关于童年的逆境如何影响特定的、近端的应激反应神经，我们知之甚少。 电路。中枢性内脏环路(CVC)与情感性精神病理学有关，并在 控制应激反应。CVC由内脏运动和内脏感觉通路组成，这些通路相互作用 将下丘脑和边缘前脑区与脑干核团联系起来。初步数据显示存在显著的联系 其间：1)童年逆境与CVCs；2)CVCs与情感症状。这些结果还表明 童年“威胁”与“剥夺”对简历的相反影响。“威胁”经历包括虐待和 其他创伤性事件，而“剥夺”包括减少的环境刺激，如儿童期低 社会经济地位或邻里关系被剥夺。有趣的是，有证据表明，威胁是钝化的，而 剥夺会增强生理应激反应(如皮质醇反应)。因此，我们提出这一威胁和 剥夺可能会对最接近应激反应控制的CVCs产生不同的影响，包括 研究不足的区域，如孤束脑干核(NST)、丘脑室旁核 下丘脑(PVN)和终纹床核(BST)。在建议中，较低的场限制 高强度磁共振成像克服了高场磁共振成像改善的信噪比和前所未有的分辨率 在7特斯拉。多模式神经成像将获得特殊的结构，以及静息状态、精神压力和 情绪诱发和脑白质连通性。还将收集应激生理学措施。一致 通过RDoC倡议，我们将招募220名年轻人的持续和跨诊断社区样本 成年人(18-35岁)有儿童时期的各种威胁、剥夺和情感症状可供检查：1) 儿童威胁和剥夺对CVC连通性的影响，2)儿童威胁和剥夺的影响 应激生理和情感症状的剥夺，以及3)CVC连接的程度 调节威胁和剥夺以及生理和情感结果之间的关系。 意义重大。我们的建议与NIMH战略1.3是一致的，即绘制精神疾病的联系， 专注于将CVC作为感兴趣的“连接体”。阐明CVC如何将童年威胁和 使用高场个性化脑地形图剥夺应激生理和情感症状可能 增强我们从临床前模型转化研究结果的能力，并可能通过提供 新的近端应激反应靶点和/或新的或综合的干预方法。

Project Summary/Abstract Childhood adversity was recently posited to be psychiatry's greatest public health challenge, as it is a major predictor of mood, anxiety and trauma-related (i.e., affective) disorders. Childhood adversity is also associated with dysregulated physiological stress reactivity, which individuals with affective disorders also display. While stress is thought to be a mechanism by which childhood adversity influences physical and mental health, few studies have considered stress-related brain regions beyond corticoamygdalar and hippocampal structures and little is known regarding how childhood adversity impacts specific, proximally stress-responsive neural circuits. Central visceral circuits (CVCs) are implicated in affective psychopathology and are critical in the control of stress responses. CVCs comprise visceromotor and viscerosensory pathways that reciprocally connect hypothalamic and limbic forebrain regions to brainstem nuclei. Preliminary data show significant links between: 1) childhood adversity and CVCs and 2) CVCs and affective symptoms. These results also suggest opposing influences of childhood “threat” vs. “deprivation” on CVCs. “Threat” experiences include abuse and other traumatic events, while “deprivation” comprises diminished environmental stimuli, such as low childhood socioeconomic status or neighborhood deprivation. Interestingly, evidence suggests that threat blunts, while deprivation heightens physiological stress reactivity (e.g., cortisol reactivity). Thus, we propose that threat and deprivation may have different effects on the CVCs most proximal to the control of stress responses, including understudied regions such as the brainstem nucleus of the solitary tract (NST), paraventricular nucleus of the hypothalamus (PVN) and bed nucleus of the stria terminalis (BST). In the proposed, limitations of lower field strength MRI are overcome with the improved signal-to-noise and unprecedented resolution of high-field MRI at 7 Tesla. Multimodal neuroimaging will acquire specialized structurals, and resting-state, mental stress and emotion-evoked, and white matter connectivity. Stress physiology measures will also be collected. Consistent with the RDoC initiative, we will recruit a continuous and transdiagnostic community sample of 220 young adults (ages 18-35) with a full range of childhood threat, deprivation and affective symptoms to examine: 1) the effects of childhood threat and deprivation on CVC connectivity, 2) the effects of childhood threat and deprivation on stress physiology and affective symptoms, and 3) the extent to which CVC connectivity mediates the relationship between threat and deprivation, and physiological and affective outcomes. Significance. Our proposal is congruent with NIMH Strategy 1.3, Map the connectomes for mental illnesses, focusing on CVCs as the “connectome” of interest. Elucidating how CVCs may link childhood threat and deprivation to stress physiology and affective symptoms using high-field personalized brain mapping may enhance our ability to translate findings from preclinical models and may guide clinical thinking by providing novel proximally stress-responsive targets and/or novel or integrative approaches for intervention.