Synaptic Transmission in Energy Homeostasis Group, Max Planck Institute for Metabolism Research, Gleueler Strasse 50, 50931, Cologne, Germany; Translational Neurocircuitry Group, Max Planck Institute for Metabolism Research, Gleueler Strasse 50, 50931, Cologne, Germany; Center for Anatomy II, Neuroanatomy, University Hospital Cologne, Joseph-Stelzmann Str. 9, 50937, Cologne, Germany.
Translational Neurocircuitry Group, Max Planck Institute for Metabolism Research, Gleueler Strasse 50, 50931, Cologne, Germany; Translational Neuromodeling Unit, Institute for Biomedical Engineering, Swiss Federal Institute of Technology, Wilfriedstrasse 6, 8032, Zurich, Switzerland.
Neuroimage. 2021 Dec 1;244:118566. doi: 10.1016/j.neuroimage.2021.118566. Epub 2021 Sep 10.
Our increasing knowledge about gut-brain interaction is revolutionising the understanding of the links between digestion, mood, health, and even decision making in our everyday lives. In support of this interaction, the vagus nerve is a crucial pathway transmitting diverse gut-derived signals to the brain to monitor of metabolic status, digestive processes, or immune control to adapt behavioural and autonomic responses. Hence, neuromodulation methods targeting the vagus nerve are currently explored as a treatment option in a number of clinical disorders, including diabetes, chronic pain, and depression. The non-invasive variant of vagus nerve stimulation (VNS), transcutaneous auricular VNS (taVNS), has been implicated in both acute and long-lasting effects by modulating afferent vagus nerve target areas in the brain. The physiology of neither of those effects is, however, well understood, and evidence for neuronal response upon taVNS in vagal afferent projection regions in the brainstem and its downstream targets remain to be established. Therefore, to examine time-dependent effects of taVNS on brainstem neuronal responses in healthy human subjects, we applied taVNS during task-free fMRI in a single-blinded crossover design. During fMRI data acquisition, we either stimulated the left earlobe (sham), or the target zone of the auricular branch of the vagus nerve in the outer ear (cymba conchae, verum) for several minutes, both followed by a short 'stimulation OFF' period. Time-dependent effects were assessed by averaging the BOLD response for consecutive 1-minute periods in an ROI-based analysis of the brainstem. We found a significant response to acute taVNS stimulation, relative to the control condition, in downstream targets of vagal afferents, including the nucleus of the solitary tract, the substantia nigra, and the subthalamic nucleus. Most of these brainstem regions remarkably showed increased activity in response to taVNS, and these effect sustained during the post-stimulation period. These data demonstrate that taVNS activates key brainstem regions, and highlight the potential of this approach to modulate vagal afferent signalling. Furthermore, we show that carry-over effects need to be considered when interpreting fMRI data in the context of general vagal neurophysiology and its modulation by taVNS.
我们对肠道-大脑相互作用的认识不断增加，正在彻底改变我们对消化、情绪、健康甚至日常生活中决策之间联系的理解。为了支持这种相互作用，迷走神经是一种至关重要的途径，它可以将各种源自肠道的信号传递到大脑，以监测代谢状态、消化过程或免疫控制，从而适应行为和自主反应。因此，目前正在探索靶向迷走神经的神经调节方法，作为包括糖尿病、慢性疼痛和抑郁症在内的多种临床疾病的治疗选择。迷走神经刺激（VNS）的非侵入性变体，经皮耳迷走神经刺激（taVNS），通过调节大脑中迷走神经传入靶区，已经涉及到急性和长期的影响。然而，这些影响的生理学都还没有得到很好的理解，并且 taVNS 在脑干中迷走神经传入投射区及其下游靶区的神经元反应的证据仍然有待建立。因此，为了研究 taVNS 在健康人体中对脑干神经元反应的时间依赖性影响，我们在一项单盲交叉设计的任务自由 fMRI 中应用 taVNS。在 fMRI 数据采集期间，我们要么刺激左耳廓（假刺激），要么刺激外耳迷走神经耳支的靶区（耳甲腔，真刺激）几分钟，之后进行短暂的“刺激关闭”期。通过在基于 ROI 的脑干分析中对连续 1 分钟的时间依赖性效应进行平均，评估时间依赖性效应。我们发现，与对照条件相比，急性 taVNS 刺激在下游迷走神经传入的靶区中产生了显著的反应，包括孤束核、黑质和丘脑底核。这些脑干区域中的大多数在 taVNS 刺激下表现出显著的活性增加，并且这些效应在刺激后持续存在。这些数据表明 taVNS 激活了关键的脑干区域，并强调了这种方法调节迷走神经传入信号的潜力。此外，我们还表明，在解释与一般迷走神经生理学及其通过 taVNS 调节相关的 fMRI 数据时，需要考虑延续效应。
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