Abstract
The autonomic nervous system (ANS) represents the harmonious relationship between the sympathetic- (SNS) and parasympathetic nervous systems (PNS). Discrepancy in this relationship is associated with the disease pathophysiology of numerous chronic inflammatory disorders. In particular, improving PNS activation, and therefore, increasing vagal tone, is beneficial in the restoration of ANS balance in these disorders. Increased vagal activity is associated with control of the inflammatory reflex which can protect against systemic inflammation. This is of particular interest for patients with chronic inflammatory disorders such as rheumatoid arthritis, Crohn’s disease and inflammatory bowel disease. Increased vagal-parasympathetic activation can also combat the overactive sympathetic tone of the ANS, common in obese and diabetic patients. One method to observe the balance between the two networks of the ANS is to observe sympathovagal tone quantitatively using the electrocardiogram (ECG). ECG can provide measures of heart-rate variability which represents dynamic autonomic modulation.
In recent decades, it has been uncovered that the use of non-invasive, peripheral nerve stimulation of the cranial (olfactory) and spinal (median) nerves could facilitate an increase in parasympathetic-vagal drive of the ANS, and therefore, improve sympathovagal balance. It is understood that both of these peripheral nerve stimulation techniques could indirectly activate the vagal network, reaching vagal brainstem nuclei such as the nucleus tractus solitarius and the dorsal motor nucleus of the vagus. However, frequency effects of median nerve stimulation or odour/concentration-specific influences on olfactory nerve stimulation (ONS) have not been investigated in the literature. Furthermore, the potential effects of sex or the menstrual cycle in these investigations are still lacking, with most studies in the literature using a mixed-sex cohort. The overall aim of this thesis was to observe the effects of non-invasive, peripheral nerve stimulation through the median and olfactory nerves focusing on neuromodulation of the relationship between the olfactory network and the ANS in healthy, adult male and female cohorts. With median nerve stimulation, we investigated several high-frequencies of stimulation previously unexplored in the literature. For the ONS, we focused on the effects of odour concentration and specific role of individual odour delivery using a specialised tool called an olfactometer.
Irrespective of sex, we found that neuromodulation using non-invasive, high-frequency (120 Hz) MNS increased the vagal-parasympathetic activation of the ANS (p-value < 0.001, Cohen-d effect size of 0.76 indicating a medium effect size). There were also menstrual cycle effects where PNS modulation was only present in the luteal stage (p-value = 0.011, Cohen-d effect size of 0.186 indicating a small effect size). The use of ONS found, for the first time in literature, that there were dose- and duration-specific odour effects of odours on the ANS. We also found sex and menstrual cycle effects on this interaction. In the male cohort, olfactory stimulation using a high concentration of rose odour increased the parasympathetic activation of the ANS (p-value = 0.008, Cohen-d effect size of 0.43 indicating a small effect size), whereas, in the female cohort, repetitive presentation of rose odour, irrespective of odour concentration, increased the parasympathetic activation of the ANS (p-value = 0.044, Cohen-d effect size of 0.17 indicating a small effect size). Furthermore, there were also menstrual stage effects on the modulation of the PNS. With the use of an ECG and eye-tracking glasses (measuring pupil dilation) to obtain recordings from vagus-dependent and oculomotor/cervical sympathetic nerves-dependent aspects of the ANS, respectively, we found some distinctions in ANS activation after ONS. In contrast to the results from the ECG, pupil dilation indicated an overall sympathetic activation after ONS using repeated presentations of rose odour for males and all four odours for females. There were also sex differences in SNS activation respective to the mode of odour delivery (acute-single dose versus repetitive presentations). These effects were also odour-specific. Results from the ECG and the eye-tracker highlight the unique roles of the olfactory network on vagus-dependent versus oculomotor/cervical sympathetic nerves-dependent parasympathetic activation of the ANS.
In combination, the use of peripheral nerve stimulation using median and olfactory nerves highlights several promising results in the modulation of the sympathovagal balance on the ANS. Improving sympathovagal balance measured through ECG is reflective of vagal-parasympathetic activation which is important in several chronic inflammatory disorders. Overall, the results from this thesis overall shed light on the efficacy of these neuromodulatory techniques to improve sympathovagal balance through increased vagal-parasympathetic activation. However, emphasis is placed on the focus of sex and menstrual stage when addressing the neuromodulatory effectiveness of these peripheral nerve stimulation techniques on the ANS. Further research into the stimulation frequency of median nerve stimulation and specific odour-concentration interactions with ONS is required to fulfil a deeper understanding of the effectiveness of these peripheral neuromodulatory techniques on the ANS.