Supplementary Material for: Anxiolytic Effects of Chronic Intranasal Oxytocin on Neural Responses to Threat Are Dose-Frequency Dependent

<b><i>Introduction:</i></b> Anxiety disorders are prevalent mental conditions characterized by exaggerated anxious arousal and threat reactivity. Animal and human studies suggest an anxiolytic potential of the neuropeptide oxytocin (OT), yet, while a clinical application will require chronic administration protocols, previous human studies have exclusively focused on single-dose (acute) intranasal OT effects. <b><i>Objective:</i></b> To facilitate the translation of the potential anxiolytic mechanism of OT into clinical application, we determined whether the anxiolytic effects of OT are maintained with repeated (chronic) administration or are influenced by dose frequency and trait anxiety. <b><i>Methods:</i></b> In a pre-registered double-blind randomized placebo-controlled pharmaco-fMRI trial the acute (single dose) as well as chronic effects of two different dose frequencies of OT (OT administered daily for 5 days or every other day) on emotional reactivity were assessed in <i>n</i> = 147 individuals with high versus low trait anxiety (ClinicalTrials.gov ID: NCT03085654). <b><i>Results:</i></b> OT produced valence, dose frequency, and trait anxiety-specific effects, such that the low-frequency (intermittent) chronic dosage specifically attenuated a neural reactivity increase in amygdala-insula-prefrontal circuits observed in the high anxious placebo-treated subjects in response to threatening but not positive stimuli. <b><i>Conclusions:</i></b> The present trial provides the first evidence that low-dose frequency chronic intranasal OT has the potential to alleviate exaggerated neural threat reactivity in subjects with elevated anxiety levels, suggesting a treatment potential for anxiety disorders.

**引言**：焦虑障碍是一类流行广泛的精神疾病，其特征为过度的焦虑唤醒与威胁反应性。动物与人体研究均表明，神经肽催产素（oxytocin, OT）具有抗焦虑潜力；然而临床应用需采用长期给药方案，而既往人体研究仅聚焦于单次给药（急性）的鼻内催产素效应。
**研究目的**：为推动催产素潜在抗焦虑机制向临床应用的转化，本研究旨在明确催产素的抗焦虑效应在重复（长期）给药后是否得以维持，或受给药频率与特质焦虑水平的影响。
**研究方法**：本研究为一项预先注册的双盲随机安慰剂对照药物功能磁共振成像（pharmaco-fMRI）试验，在147名高特质焦虑与低特质焦虑个体中，评估了两种不同给药频率的催产素（每日给药5天，或隔日给药）的急性（单次给药）与长期给药效应，及其对情绪反应性的影响（ClinicalTrials.gov 注册号：NCT03085654）。
**研究结果**：催产素呈现出效价、给药频率与特质焦虑特异性的效应：低频（间歇）长期给药可特异性减弱高特质焦虑安慰剂组受试者在面对威胁性刺激（而非正性刺激）时，杏仁核-脑岛-前额叶环路的神经反应性升高现象。
**研究结论**：本试验首次证实，低频给药的长期鼻内催产素可缓解焦虑水平升高受试者的过度神经威胁反应性，提示其在焦虑障碍治疗中的应用潜力。