Increased Concentrations of Circulating Interleukins following Non-Invasive Vagus Nerve Stimulation: Results from a Randomized, Sham-Controlled, Crossover Study in Healthy Subjects.

OBJECTIVE: The vagus nerve constitutes the main component of the parasympathetic nervous system and plays an important role in the regulation of neuro-immune responses. Invasive stimulation of the vagus nerve produces anti-inflammatory effects; however, data on humoral immune responses of transcutaneous vagus nerve stimulation (tVNS) are rare. Therefore, the present study investigated changes in serum cytokine concentrations of interleukin-1ß (IL-1ß), IL-6, IL-8, and tumor necrosis factor α (TNFα) following a short-term, non-invasive stimulation of the vagus nerve. METHODS: Whole blood samples were collected before and after a short-lived application of active tVNS at the inner tragus as well as sham stimulation of the earlobe. Cytokine serum concentrations were determined in two healthy cohorts of younger (n = 20) and older participants (n = 19). Differences between active and sham conditions were analyzed using linear mixed models and post hoc F tests after applying Yeo-Johnson power transformations. This trial was part of a larger study registered on ClinicalTrials.gov (NCT05007743). RESULTS: In the young cohort, IL-6 and IL-1ß concentrations were significantly increased after active stimulation, whereas they were slightly decreased after sham stimulation (IL-6: p = 0.012; IL-1ß: p = 0.012). Likewise, in the older cohort, IL-1ß and IL-8 concentrations were significantly elevated after active stimulation and reduced after sham application (IL-8: p = 0.007; IL-1ß: p = 0.001). In contrast, circulating TNFα concentrations did not change significantly in either group. CONCLUSION: Our results show that active tVNS led to an immediate increase in the serum concentrations of certain pro-inflammatory cytokines such as IL-1ß, IL-6, and/or IL-8 in two independent cohorts of healthy study participants.

Ih contributes to increased motoneuron excitability in restless legs syndrome.

KEY POINTS: Restless legs patients complain about sensory and motor symptoms leading to sleep disturbances. Symptoms include painful sensations, an urge to move and involuntary leg movements. The responsible mechanisms of restless legs syndrome are still not known, although current studies indicate an increased neuronal network excitability. Reflex studies indicate the involvement of spinal structures. Peripheral mechanisms have not been investigated so far. In the present study, we provide evidence of increased hyperpolarization-activated cyclic nucleotide-gated (HCN) channel-mediated inward rectification in motor axons. The excitability of sensory axons was not changed. We conclude that, in restless legs syndrome, an increased HCN current in motoneurons may play a pathophysiological role, such that these channels could represent a valuable target for pharmaceutical intervention. ABSTRACT: Restless legs syndrome is a sensorimotor network disorder. So far, the responsible pathophysiological mechanisms are poorly understood. In the present study, we provide evidence that the excitability of peripheral motoneurons contributes to the pathophysiology of restless legs syndrome. In vivo excitability studies on motor and sensory axons of the median nerve were performed on patients with idiopathic restless legs syndrome (iRLS) who were not currently on treatment. The iRLS patients had greater accommodation in motor but not sensory axons to long-lasting hyperpolarization compared to age-matched healthy subjects, indicating greater inward rectification in iRLS. The most reasonable explanation is that hyperpolarization-activated cyclic nucleotide-gated (HCN) channels open at less hyperpolarized membrane potentials, a view supported by mathematical modelling. The half-activation potential for HCN channels (Bq) was the single best parameter that accounted for the difference between normal controls and iRLS data. A 6 mV depolarization of Bq reduced the discrepancy between the normal control model and the iRLS data by 92.1%. Taken together, our results suggest an increase in the excitability of motor units in iRLS that could enhance the likelihood of leg movements. The abnormal axonal properties are consistent with other findings indicating that the peripheral system is part of the network involved in iRLS.

A randomized vagus nerve stimulation study demonstrates that serum aldosterone levels decrease with age in women, but not in men.

In this randomized, sham-controlled study, we explored the effects of acute transcutaneous vagus nerve stimulation (tVNS) on serum aldosterone in 20 younger (21-26 years) and 19 older (40-70 years) healthy participants. Blood samples were collected on two different days before and after a 20-min application of active tVNS at the inner tragus or sham stimulation of the earlobe. Irrespective of the stimulation mode, aldosterone levels decreased from pre- to post-stimulation in both the young (active: ß = - 1.610 (- 2.855, - 0.365), p = 0.022; sham: ß = - 0.857 (- 2.102, 0.388), p = 0.257) and the old cohort (active: ß = - 1.969 (- 3.234, - 0.703), p = 0.005; sham: ß = - 1.334 (- 2.600, - 0.069), p = 0.063). Although this decline was significant during active tVNS, the difference in estimated ß-coefficients between active and sham stimulation was not statistically significant in either cohort. Nevertheless, aldosterone concentrations showed a significant interaction effect between sex and age (p = 0.001). Among all study participants, younger women (23.3 ± 1.6 years) had the highest mineralocorticoid levels (pre active: 172.1 ± 102.0 pg/ml, pre sham: 214.3 ± 82.3 pg/ml), whereas the lowest were observed in older females (59.4 ± 9.4 years) (pre active: 104.9 ± 85.8 pg/ml, pre sham: 81.1 ± 53.8 pg/ml). This post hoc analysis did not suggest that active auricular tVNS reduces serum aldosterone levels compared to sham stimulation in healthy subjects. However, serum aldosterone levels differed among subjects depending on their age and sex, irrespective of tVNS.

Men Show Reduced Cardiac Baroreceptor Sensitivity during Modestly Painful Electrical Stimulation of the Forearm: Exploratory Results from a Sham-Controlled Crossover Vagus Nerve Stimulation Study.

This paper presents data from a transcutaneous vagus nerve stimulation experiment that point towards a blunted cardiac baroreceptor sensitivity (cBRS) in young males compared to females during electrical stimulation of the forearm and a rhythmic breathing task. Continuous electrocardiography, impedance cardiography and continuous blood-pressure recordings were assessed in a sex-matched cohort of twenty young healthy subjects. Electrical stimulation of the median nerve was conducted by using a threshold-tracking method combined with two rhythmic breathing tasks (0.1 and 0.2 Hz) before, during and after active or sham transcutaneous vagus nerve stimulation. Autonomic and hemodynamic parameters were calculated, and differences were analyzed by using linear mixed models and post hoc F-tests. None of the autonomic and hemodynamic parameters differed between the sham and active conditions. However, compared to females, male participants had an overall lower total cBRS independent of stimulation condition during nerve stimulation (females: 14.96 ± 5.67 ms/mmHg, males: 11.89 ± 3.24 ms/mmHg, p = 0.031) and rhythmic breathing at 0.2 Hz (females: 21.49 ± 8.47 ms/mmHg, males: 15.12 ± 5.70 ms/mmHg, p = 0.004). Whereas vagus nerve stimulation at the left inner tragus did not affect the efferent vagal control of the heart, we found similar patterns of baroreceptor sensitivity activation over the stimulation period in both sexes, which, however, significantly differed in their magnitude, with females showing an overall higher cBRS.