Abstract
Transcutaneous auricular vagus nerve stimulation (taVNS) has been reported to be effective in the treatment of primary insomnia (PI); however, its efficacy varies considerably across individuals for reasons that are unclear. In order to clarify the underlying mechanisms, this study investigated the effects of taVNS on spontaneous neuronal activity and autonomic nervous system function by functional magnetic resonance imaging (fMRI) and measurement of heart rate variability (HRV), respectively, in patients with PI. Forty patients with PI were divided into effective (group A) and ineffective (group B) groups based on their response to taVNS as determined by Pittsburgh Sleep Quality Index score reduction rate (group A ≥ 25% and group B < 25%). Spontaneous neuronal activity was measured by fractional amplitude of low-frequency fluctuations (fALFF) and HRV values and was compared between the two groups as well as before vs after taVNS. We then analyzed the correlations among efficacy of taVNS for 4 weeks, the fALFF and HRV values during continuous taVNS state. The results showed that the HRV parameter values (i.e., root mean square of successive differences, percentage of adjacent NN intervals differing by >50 ms, and high frequency) of group A were higher than those of group B during continuous taVNS state. In the fMRI scan, the fALFF values of the right cerebellum, right medial superior frontal gyrus, and bilateral supplementary motor area—which belong to the sensorimotor network (SMN)—were lower in group A than in group B during continuous taVNS state. The correlation analysis revealed that the efficacy of continuous taVNS and HRV and fALFF values were interrelated. These findings demonstrate that differential regulation of the SMN by the autonomic nervous system may be responsible for inter-individual variations in the efficacy of taVNS and suggest that HRV and fALFF are potential biomarkers for predicting PI patients’ response to taVNS treatment.
Highlights
Primary insomnia (PI) is a common chronic disease that is mainly treated by cognitive behavioral therapy for insomnia (CBT-I) and sedative–hypnotic drugs (Patel et al, 2018)
The values of the heart rate variability (HRV) parameters HF and PNN50 were higher for group A than for group B (P < 0.05) during continuous Transcutaneous auricular vagus nerve stimulation (taVNS) state; there was no significant difference between the two groups in terms of the value of rMSSD, there was a trend of a higher value for group A (P = 0.05)
Neuronal activity as reflected by the fractional amplitude of low-frequency fluctuations (fALFF) value was significantly decreased in the right cerebellum, right medial superior frontal gyrus, and bilateral supplementary motor area (SMA) during continuous taVNS state in group A (Figure 4 and Table 2)
Summary
Primary insomnia (PI) is a common chronic disease that is mainly treated by cognitive behavioral therapy for insomnia (CBT-I) and sedative–hypnotic drugs (Patel et al, 2018). CBT-I has shortcomings, including limited efficacy in preventing sleep attacks, inconvenience, long treatment duration, and high cost (Kay-Stacey and Attarian, 2016), whereas drugs have adverse effects such as delirium, endocrine disorder, anterograde memory disorder, and daytime sleepiness (KayStacey and Attarian, 2016). There is an urgent need for new therapies for insomnia that have minimal side effects and can be used over a long term. Transcutaneous auricular vagus nerve stimulation (taVNS) is known to be effective in the treatment of insomnia (Luo et al, 2017; Jiao et al, 2020; Zhao et al, 2020). TaVNS directly attenuates autonomic nerve imbalance (Laborde et al, 2019), activates the cholinergic neuron system, and inhibits the release of inflammatory mediators (De Couck et al, 2014). Imaging studies have revealed that taVNS modulates neuronal activity in the periaqueductal gray, hypothalamus, thalamus, and hippocampus, which are brain areas that are closely related to sleep disorders (Badran et al, 2018a)
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