Abstract：
BACKGROUND: Pain thresholds and primary headaches, including cluster headache attacks, have circadian rhythmicity. Thus, they might share a common neuronal mechanism.
OBJECTIVE: This study aimed to elucidate how the modulation of nociceptive input in the brainstem changes from noon to midnight. Insights into the mechanism of these fluctuations could allow for new hypotheses about the pathophysiology of cluster headache.
METHODS: This repeated measure observational study was conducted at the University Hospital Zurich from December 2019 to November 2022. Healthy adults between 18 and 85 years of age were eligible. All participants were examined at noon and midnight. We tested the pain threshold on both sides of the foreheads with quantitative sensory testing, assessed tiredness levels, and obtained high-field (7 Tesla) and high-resolution functional magnetic resonance imaging (MRI) at each visit. Functional connectivity was assessed at the two visits by performing a region-of-interest analysis. We defined nuclei in the brainstem implicated in processing nociceptive input as well as the thalamus and suprachiasmatic nucleus as the region-of-interest.
RESULTS: Ten people were enrolled, and seven participants were included. First, we did not find statistically significant differences between noon and midnight of A-delta-mediated pain thresholds (median mechanical pain threshold at noon: left 9.2, right 9.2; at night: left 6.5, right 6.1). Second, after correction for a false discovery rate, we found changes in the mechanical pain sensitivity to have a statistically significant effect on changes in the functional connectivity between the left parabrachial nucleus and the suprachiasmatic nucleus (T = -40.79).
CONCLUSIONS: The MRI data analysis suggested that brain stem nuclei and the hypothalamus modulate A-delta-mediated pain perception; however, these changes in pain perception did not lead to statistically significantly differing pain thresholds between noon and midnight. Hence, our findings shed doubt on our hypothesis that the physiologic circadian rhythmicity of pain thresholds could drive the circadian rhythmicity of cluster headache attacks.
OBJECTIVE: This study aimed to elucidate how the modulation of nociceptive input in the brainstem changes from noon to midnight. Insights into the mechanism of these fluctuations could allow for new hypotheses about the pathophysiology of cluster headache.
METHODS: This repeated measure observational study was conducted at the University Hospital Zurich from December 2019 to November 2022. Healthy adults between 18 and 85 years of age were eligible. All participants were examined at noon and midnight. We tested the pain threshold on both sides of the foreheads with quantitative sensory testing, assessed tiredness levels, and obtained high-field (7 Tesla) and high-resolution functional magnetic resonance imaging (MRI) at each visit. Functional connectivity was assessed at the two visits by performing a region-of-interest analysis. We defined nuclei in the brainstem implicated in processing nociceptive input as well as the thalamus and suprachiasmatic nucleus as the region-of-interest.
RESULTS: Ten people were enrolled, and seven participants were included. First, we did not find statistically significant differences between noon and midnight of A-delta-mediated pain thresholds (median mechanical pain threshold at noon: left 9.2, right 9.2; at night: left 6.5, right 6.1). Second, after correction for a false discovery rate, we found changes in the mechanical pain sensitivity to have a statistically significant effect on changes in the functional connectivity between the left parabrachial nucleus and the suprachiasmatic nucleus (T = -40.79).
CONCLUSIONS: The MRI data analysis suggested that brain stem nuclei and the hypothalamus modulate A-delta-mediated pain perception; however, these changes in pain perception did not lead to statistically significantly differing pain thresholds between noon and midnight. Hence, our findings shed doubt on our hypothesis that the physiologic circadian rhythmicity of pain thresholds could drive the circadian rhythmicity of cluster headache attacks.
摘要：
背景：疼痛阈值和原发性头痛，包括丛集性头痛发作，有昼夜节律。因此，它们可能有共同的神经元机制.
目的：本研究旨在阐明脑干伤害性输入的调节如何从中午到午夜变化。对这些波动机制的见解可能会为丛集性头痛的病理生理学提供新的假设。
方法：这项重复测量观察性研究于2019年12月至2022年11月在苏黎世大学医院进行。18至85岁的健康成年人符合资格。所有参与者都在中午和午夜进行检查。我们用定量感官测试测试了额头两侧的疼痛阈值，评估疲劳程度，并在每次访问时获得高场（7特斯拉）和高分辨率功能磁共振成像（MRI）。在两次访问中通过执行感兴趣区域分析来评估功能连通性。我们定义了脑干中与处理伤害性输入有关的核，以及丘脑和视交叉上核作为感兴趣的区域。
结果：登记了10人，包括七名参与者。首先,我们没有发现A-delta介导的疼痛阈值在中午和午夜之间有统计学显著差异(中午时的机械性疼痛阈值中位数:左9.2,右9.2;晚上:左6.5,右6.1).第二,在纠正错误发现率后，我们发现机械性疼痛敏感性的变化对左臂旁核和视交叉上核之间功能连接的变化有统计学意义的影响(T=-40.79).
结论：MRI数据分析提示脑干核和下丘脑调节A-delta介导的疼痛感知；然而，这些疼痛感知的变化并没有导致中午和午夜之间疼痛阈值的统计学差异.因此，我们的研究结果对我们的假设产生了怀疑，即疼痛阈值的生理昼夜节律可以驱动丛集性头痛发作的昼夜节律。
目的：本研究旨在阐明脑干伤害性输入的调节如何从中午到午夜变化。对这些波动机制的见解可能会为丛集性头痛的病理生理学提供新的假设。
方法：这项重复测量观察性研究于2019年12月至2022年11月在苏黎世大学医院进行。18至85岁的健康成年人符合资格。所有参与者都在中午和午夜进行检查。我们用定量感官测试测试了额头两侧的疼痛阈值，评估疲劳程度，并在每次访问时获得高场（7特斯拉）和高分辨率功能磁共振成像（MRI）。在两次访问中通过执行感兴趣区域分析来评估功能连通性。我们定义了脑干中与处理伤害性输入有关的核，以及丘脑和视交叉上核作为感兴趣的区域。
结果：登记了10人，包括七名参与者。首先,我们没有发现A-delta介导的疼痛阈值在中午和午夜之间有统计学显著差异(中午时的机械性疼痛阈值中位数:左9.2,右9.2;晚上:左6.5,右6.1).第二,在纠正错误发现率后，我们发现机械性疼痛敏感性的变化对左臂旁核和视交叉上核之间功能连接的变化有统计学意义的影响(T=-40.79).
结论：MRI数据分析提示脑干核和下丘脑调节A-delta介导的疼痛感知；然而，这些疼痛感知的变化并没有导致中午和午夜之间疼痛阈值的统计学差异.因此，我们的研究结果对我们的假设产生了怀疑，即疼痛阈值的生理昼夜节律可以驱动丛集性头痛发作的昼夜节律。
