A pilot study assessing neurophysiological and cardiovascular effects of non-invasive vagus nerve stimulation in healthy subjects and patients with restless legs syndrome
by Elisabeth Veiz
Date of Examination:2023-08-22
Date of issue:2023-08-31
Advisor:Prof. Dr. Thomas Meyer
Referee:Prof. Dr. Thomas Meyer
Referee:Prof. Dr. Manuela Schmidt
Persistent Address:
http://dx.doi.org/10.53846/goediss-10081
Files in this item
Name:Dissertation Elisabeth Veiz.pdf
Size:3.13Mb
Format:PDF
The following license files are associated with this item:
Abstract
English
Background: Transcutaneous auricular vagus nerve stimulation (taVNS) is an auspicious neurostimulation technique intensively investigated for its potential antidepressant, anticonvulsive, anti-inflammatory and analgesic effects. Although the exact mechanisms of action are unknown, data suggest the involvement of several neurotransmitter systems modulated via direct and indirect projections from the brainstem to the limbic system and cerebral cortex. Despite promising study results, the clinical translation of taVNS is aggravated by the lack of suitable biomarkers indicating successful stimulation. Therefore, in this pilot study the usefulness of heart rate variability (HRV) parameters as potential biomarkers for taVNS was evaluated. Furthermore, based on its proposed mechanistic pathway, it was explored whether taVNS reduces sympathetic activity and circulating concentrations of cytokines and the mineralocorticoid aldosterone. Methods: Two groups of younger (n=20, 23.4 ± 1.5 years) and middle-aged (n=19, 58.0 ± 8.9 years) healthy participants underwent continuous electrocardiography and blood pressure recordings before, during, and after either 20-min of active taVNS treatment at the left tragus or sham intervention at the left earlobe. From these data the root mean square of successive RR interval differences (RMSSD), the standard deviation of RR intervals (SDNN), the normalized high-frequency component of heart rate variability (HF-HRV), and total cardiac baroreceptor sensitivity (cBRS) were calculated. In addition, median nerve excitability was measured in young subjects using the threshold-tracking technique and serum levels of aldosterone, interleukin-6 (IL-6) and tumor necrosis factor α (TNFα) were determined from blood samples collected before and after the experiment. Processed data were analyzed using linear mixed models and post-hoc F-tests. During a second trial, 39 patients with RLS (55.1 ± 13.7 years) were randomized to self-administrate either one week of daily active taVNS treatment or sham intervention. Before and after the stimulation week, HRV parameters and serum cytokine levels were assessed, as described above for the healthy cohort. Additionally, symptom severity in RLS patients was quantified using standardized questionnaires and their sudomotor function at palms and soles was measured using the Sudoscan device. Differences in outcome measures before and after the stimulation week were compared between the two groups using robust linear regression models. Results: Active taVNS did not affect RMSSD, SDNN, HF-HRV and cBRS in the healthy cohorts and in RLS patients. Likewise, taVNS treatment had no effect on the chronaxie of the median nerve in younger healthy participants. However, serum IL-6 levels in younger subjects increased significantly from pre- to post-stimulation after active taVNS treatment (pre: 9.91 ± 8.21 pg/ml, post: 13.07 ± 9.22 pg/ml, p=0.016), but not after sham intervention (pre: 13.74 ± 9.47 pg/ml, post: 12.39 ± 9.48 pg/ml, p=0.220), while there was neither a significant effect in older healthy probands nor in the patient cohort. Similarly, concentrations of TNFα and aldosterone were not significantly different. Nevertheless, irrespective of stimulation condition, serum aldosterone levels were significantly dependent on age and gender (p=0.001), with younger women showing higher aldosterone levels compared to men (βmale=-2.412 (-4.258, -0.566), p= 0.022), and older females having lower levels com-pared to their male peers (βmale=3.600 (1.497, 5.702), p=0.002). Furthermore, younger women showed a significantly higher cBRS of 14.96 ± 5.67 ms/mmHg compared to younger men (cBRS=11.89 ± 3.24 ms/mmHg, p=0.031), whereas in the older cohort only a non-significant trend was found (women=11.14 ± 6.53, men=7.47 ± 2.49 ms/mmHg, p=0.067). Similarly, both younger and older females had significantly higher HF-HRV values compared to their male peers (younger women=33.62 ± 15.42%, younger men=21.34 ± 8.46%, p=0.016; older women=29.56 ± 12.74%, older men=18.95 ± 9.11%, p=0.011). Active taVNS treatment in the RLS patients resulted in no significant change in symptom severity scores compared to sham intervention. However, sudomotor function at patients’ hands (βsham=-5.823 (-10.285, -1.361), p=0.011) and feet (βsham=-9.513 (-17.433, -1.593), p=0.019) were significantly different between the active taVNS and the sham intervention group. In particular, electrochemical skin conductance at the soles of the feet improved in the active taVNS group. Additionally, at baseline there was a significant association between more severe RLS symptoms and reduced electrochemical skin conductance at the feet (ρ=-0.418, p=0.008), but not the hands (ρ=-0.246, p=0.131). Conclusion: This pilot study provides further evidence that HRV parameters are unlikely to be suitable biomarkers for taVNS treatments. Furthermore, taVNS had no attenuating effects on humoral cytokine levels in both healthy volunteers and RLS patients. However, cardiovascular control and serum aldosterone concentrations in healthy subjects were significantly dependent on gender, emphasizing the importance of examining differences between female and male physiology not only in taVNS research. In addition, severe RLS symptoms were associated with higher electrochemical skin conductance in the feet, suggesting a potential new autonomic disease biomarker.
Keywords: Non-invasive vagus nerve stimulation; Restless legs syndrome; Heart rate variability; Biomarker; vagus nerve; gender effects; Aldosterone; Cytokine
