Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv-Yafo 69978, Israel.
Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv-Yafo 69978, Israel.
J Neurosci. 2021 Jan 13;41(2):320-330. doi: 10.1523/JNEUROSCI.1361-20.2020. Epub 2020 Nov 19.
Vagus nerve stimulation (VNS) is widely used to treat drug-resistant epilepsy and depression. While the precise mechanisms mediating its long-term therapeutic effects are not fully resolved, they likely involve locus coeruleus (LC) stimulation via the nucleus of the solitary tract, which receives afferent vagal inputs. In rats, VNS elevates LC firing and forebrain noradrenaline levels, whereas LC lesions suppress VNS therapeutic efficacy. Noninvasive transcutaneous VNS (tVNS) uses electrical stimulation that targets the auricular branch of the vagus nerve at the cymba conchae of the ear. However, the extent to which tVNS mimics VNS remains unclear. Here, we investigated the short-term effects of tVNS in healthy human male volunteers ( = 24), using high-density EEG and pupillometry during visual fixation at rest. We compared short (3.4 s) trials of tVNS to sham electrical stimulation at the earlobe (far from the vagus nerve branch) to control for somatosensory stimulation. Although tVNS and sham stimulation did not differ in subjective intensity ratings, tVNS led to robust pupil dilation (peaking 4-5 s after trial onset) that was significantly higher than following sham stimulation. We further quantified, using parallel factor analysis, how tVNS modulates idle occipital alpha (8-13Hz) activity identified in each participant. We found greater attenuation of alpha oscillations by tVNS than by sham stimulation. This demonstrates that tVNS reliably induces pupillary and EEG markers of arousal beyond the effects of somatosensory stimulation, thus supporting the hypothesis that tVNS elevates noradrenaline and other arousal-promoting neuromodulatory signaling, and mimics invasive VNS. Current noninvasive brain stimulation techniques are mostly confined to modulating cortical activity, as is typical with transcranial magnetic or transcranial direct/alternating current electrical stimulation. Transcutaneous vagus nerve stimulation (tVNS) has been proposed to stimulate subcortical arousal-promoting nuclei, though previous studies yielded inconsistent results. Here we show that short (3.4 s) tVNS pulses in naive healthy male volunteers induced transient pupil dilation and attenuation of occipital alpha oscillations. These markers of brain arousal are in line with the established effects of invasive VNS on locus coeruleus-noradrenaline signaling, and support that tVNS mimics VNS. Therefore, tVNS can be used as a tool for studying how endogenous subcortical neuromodulatory signaling affects human cognition, including perception, attention, memory, and decision-making; and also for developing novel clinical applications.
迷走神经刺激(VNS)广泛用于治疗耐药性癫痫和抑郁症。虽然介导其长期治疗效果的确切机制尚未完全解决,但它们可能涉及通过孤束核刺激蓝斑,孤束核接收传入的迷走神经输入。在大鼠中,VNS 可提高蓝斑放电和前脑去甲肾上腺素水平,而蓝斑损伤可抑制 VNS 的治疗效果。非侵入性经皮迷走神经刺激(tVNS)使用电刺激,刺激耳甲腔的迷走神经耳支。然而,tVNS 模拟 VNS 的程度尚不清楚。在这里,我们在健康男性志愿者(n = 24)中使用高分辨率脑电图和瞳孔测量法,在休息时进行视觉固定,研究了 tVNS 的短期影响。我们将短(3.4 秒)的 tVNS 试验与耳屏(远离迷走神经分支)的假电刺激进行了比较,以控制躯体感觉刺激。尽管 tVNS 和假刺激在主观强度评分上没有差异,但 tVNS 导致的瞳孔扩张(在试验开始后 4-5 秒达到峰值)明显高于假刺激。我们进一步使用平行因子分析量化了 tVNS 如何调节每个参与者识别的空闲枕部α(8-13Hz)活动。我们发现 tVNS 比假刺激更能抑制α 振荡。这表明 tVNS 可靠地诱导了除躯体感觉刺激之外的警觉性的瞳孔和 EEG 标志物,从而支持了 tVNS 升高去甲肾上腺素和其他促觉醒神经调制信号的假设,并模拟了侵入性 VNS。目前的非侵入性脑刺激技术主要局限于调节皮质活动,这是经颅磁刺激或经颅直流电/交流电刺激的典型特征。经皮迷走神经刺激(tVNS)已被提议用于刺激促觉醒的皮质下核,但以前的研究结果不一致。在这里,我们显示在健康男性志愿者中,短暂(3.4 秒)的 tVNS 脉冲会引起短暂的瞳孔扩张和枕部α 振荡的衰减。这些大脑觉醒的标志物与侵入性 VNS 对蓝斑-去甲肾上腺素信号的既定影响一致,并支持 tVNS 模拟 VNS。因此,tVNS 可用于研究内源性皮质下神经调制信号如何影响人类认知,包括感知、注意力、记忆和决策;并为开发新的临床应用提供了一种工具。
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