Abstract
Sleep is an evolutionarily conserved process with almost all organisms partaking in sleep or a state akin to it, periodically. It is a crucial component of overall health and wellbeing, yet poor sleep is a pervasive problem throughout the modern world. Insufficient sleep quality or quantity negatively affects almost every aspect of physical and cognitive functioning. The prevalence of sleep disorders increases with age, as does the incidence of many diseases. This correlational relationship may be, in part, due to declining levels of circulating melatonin, a hormone predominantly produced by the pineal gland. Melatonin is a potent antioxidant and free-radical scavenger and if pineal melatonin levels could be increased, this may provide therapeutic benefit to a number of clinical populations through the improvement of sleep.
A number of studies have shown that neuromodulation of the pineal gland in animals is possible via invasive stimulation its sympathetic pathway. However, no studies to date have explored whether this can be achieved via non-invasive stimulation methods and, if possible, how this affects sleep in humans. Therefore, the aim of this thesis was to investigate whether neuromodulation of the pineal gland, and subsequent changes in measures of sleep, are possible via non-invasive, electrical stimulation of dermatomes that share anatomical connections with the pineal gland’s sympathetic pathway.
To answer this question, we first needed to demonstrate whether such non-invasive stimulation was capable of a direct effect on pineal gland activity. First, we delivered noninvasive, electrical stimulation to either the C2 or T1 dermatome of rats at frequencies of either 10 Hz or 80 Hz, with sham stimulation serving as an experimental control. We then employed real-time quantitative polymerase chain reaction to measure changes in the expression of genes associated with the synthesis, regulation, and signalling of melatonin. This was examined within the pineal, salivary, and lacrimal glands due to them sharing similar sources of innervation. Upregulation of gene expression was apparent for the pineal and salivary glands with different frequencies exerting specific effects when delivered at the C2 dermatome only. No changes in gene expression were observed with T1 dermatome stimulation. These results demonstrate that modulation of the pineal and salivary glands is possible via non-invasive stimulation of the C2 dermatome. Moreover, they show that such modulation imparts effects that are frequency-specific, as is consistent with the literature.
We then progressed to human studies and utilised stimulation of the C2 dermatome only, as no modulatory effects were apparent with T1 dermatome stimulation in rats. A combination of objective and subjective methods were used to examine sleep changes following non-invasive 10 Hz or 80 Hz stimulation in both the day- and night-time. We also explored changes in salivary melatonin levels via enzyme-linked immunosorbent assay, sedation via electroencephalography, and used various measures to examine changes in autonomic nervous system (ANS) activity. In humans, unlike animals, significant effects were apparent following 10 Hz stimulation only, highlighting interspecies differences in neuromodulatory effects. Actigraphy revealed a reduction in sleep onset latency (SOL) following night-time stimulation and a reduction in sedation and decrease in interhemispheric cortical asymmetry were observed during daytime stimulation. Finally, no effects on salivary melatonin levels or ANS activity were observed with any variable suggesting that the effects on sedation and SOL are mediated independently of the ANS. From the findings in this thesis, we hypothesise that 10 Hz C2 dermatome stimulation generates a sedative effect on the brain, allowing sleep onset to occur given the proper environmental cues. Such an effect may be mediated via modulation of brain networks involved in arousal regulation.
Difficulties with sleep initiation are symptomatic of a wide range of diseases but may also be induced by many medications used to treat such diseases. Prolonged SOL is also a common complaint of healthy individuals, and can be exacerbated with stress. Additionally, increased interhemispheric cortical asymmetry is characteristic of major depressive disorder (MDD) or attention hyperactivity deficit disorder (ADHD), and a reduction in such asymmetry may improve symptoms. This thesis provides evidence for the capability of non-invasive, electrical stimulation to modulate activity of the pineal gland, sedation levels, and sleep metrics. These may confer therapeutic benefits for those who suffer with prolonged sleep onset, and individuals with disorders characterised by increased cortical asymmetry such as ADHD and MDD.