**9. Occupational stress-related sleep disorders in frontline healthworkers during COVID-19 pandemic: Roles of emotional perturbations**

Studies provide evidence that COVID-19 caused emotional perturbation in frontline healthcare workers. Serrano-Ripoll et al. [77] in a systematic review noted that the prevalence of anxiety in frontline healthcare workers during COVID-19 pandemic stood at 30%. Mrklas et al. [78] conducted a six-week cross-sectional investigation to ascertain the prevalence of anxiety and depression in frontline healthcare workers during COVID-19 pandemic. They found that the prevalence of anxiety and depression was 47 and 46%, respectively. Using a structured internet-based questionnaire method, Ghio et al. [79] documented that there was a rise in the quanta of depression and anxiety with values of 62 and 61%, respectively in frontline health workers during COVID-19. Saragih et al. [80] indicated that the prevalence of depression and anxiety in Doctors and Nurses stood at 40 and 37%, respectively during COVID-19 pandemic. In a review by Sofia et al. [81] about 23.2 and 22.8% of healthcare professionals who faced COVID-19 patients experienced anxiety and depression in India, respectively. Ching et al. [82] showed in their review that 37.5 and 39.7% of healthcare workers suffered from depression and anxiety, respectively during COVID-19 pandemic in Asia. Health Professionals managing COVID-19 were studied by Magnavita et al. [83]. The result of the study showed that 27.8% of the respondents experienced anxiety and 51.1% had depression in Italy.

Emotional arousal induced sleep disorders may be mediated through increased sympathetic activation [84]. In the rat model, an increase in sympathetic nervous system index has been documented [85]. Activation of noradrenergic neurons and sympatho-adrenal axis by anxiety leads to increased secretion of epinephrine and norepinephrine, neurotransmitters which stimulate reticular activating system, and result in increased wakefulness. For many years, interruption of upper thoracic sympathetic ganglions has been reported to lead to elevated perspiration occurring in the arms and palms, blushing, and trembling [86]. Activation of the sympathetic nervous system results in increased expression of Cannabinoid type-1 (CB1) receptors [87]. CB1 receptors are expressed in the brain where they modulate GABA release. Wilkinson et al. [88] showed an increase in muscle sympathetic activity and plasma epinephrine in panic patients. Reduction in basal forebrain brain-derived neurotrophic factor (BDNF) and adenosine and a rise in nitric oxide in animal models have been linked with emotional disorder-related alteration in sleep pattern [89].

Apart from the involvement of brain derived neurotrophic factor, nitric oxide, adenosine, and sympathoadrenal axis, occupational stress-related sleep disorders in frontline health workers during COVID-19 pandemic may be due to elevation in glucocorticoid and corticotropin releasing hormone profile. CRH and cortisol are integrated through ACTH. ADH from parvocellular hypothalamic neuro-secretory cells induces the secretion of ACTH by binding V1bR of hypophyseal corticotroph. ACTH acts on its receptors on the adrenal cortex. A study by D'Angelo et al. [90] showed that there was marked disruption of sleep in Cushing Syndrome patients. However, the study found no correlation between urinary free cortisol and sleep impairment. In another development, there is increasing evidence that occupational stress-induced sleep disorders may be characterized by changes in EEG. Holsboer et al. [91] investigated the electroencephalographic effects of exogenous corticotropin-releasing hormone (CRH) and reported a reduction in slow wave sleep and an increase in wakefulness. The possibility that sleep disorders associated with frontline health workers might be due to glucocorticoid-induced changes in hippocampal glycogen is increasing. Gip et al. [92] reported that sleep-deprived rats, characterized by elevated glucocorticoid, exhibited decreased hippocampal glycogen and brain glycogen. Depression in hippocampal glycogen and brain glycogen has been linked with EEG waves [93]. Bradbury et al. [94] demonstrated the possible role of CRH and glucocorticoids on hypnotic EEG. Suppression of adrenal glucocorticoid secretion via adrenal gland removal led to decreased delta waves but alpha waves increased. While reversion occurs with physiological glucocorticoid treatment, the quantity of non-rapid eye movement was depressed with extra-physiological glucocorticoid administration. Furthermore, administration of REM-prolonging peptide secreted by the intermediate lobe of the hypophysis known as corticotropinlike intermediate lobe peptide raised the latency of sleep [95, 96]. Another way through which CRH may disrupt sleep is the inhibition of spontaneous reticular thalamic discharge implicated in synchronizing NREM waves (**Figure 1**). Injection of CRH has been reported to suppress NREM waves in C57BL/67 and CRH-R1 CL mice [97].
