The specific alterations of FC in patients with CID will deepen our understanding of the neurobiological mechanism of CID. Based on a previous functional neuroimaging study on LC, we hypothesize that the brain regions showing alterations of LC-based FC in CID are located in DMN regions. The aim of this study is to reveal the relationship between arousal regulation and insomnia by investigating LC-based FC patterns in CID patients and exploring the relationships between the abnormal FC and clinical symptoms. However, it is unclear whether the FC between the LC and DMN is involved in arousal regulation in CID patients. 14 This study showed that the functional connectivity of the LC to the PCC, thalamus, and caudate nucleus is related to the level of arousal. 13 Furthermore, performing FC seed analyses by correlating the average LC time course against the time courses of all voxels in the brain, a study of site-specific pharmacological manipulations in healthy volunteers revealed that the posterior cingulate cortex (PCC, the hub region of the DMN) was disconnected from the LC during the altered arousal state and regained connectivity to the LC during the recovery state. 12 A study comparing the functional connectivity of the LC and ventral tegmental area/substantia nigra pars compacta (VTA/SNc) in a healthy population using seed analysis found that LC and VTA/SNc shared negative connectivity to the precuneus, which was consistent with the function of the default mode network (DMN) inactivated under environmental stimulation. FC can use seed-based analysis to select ROIs and correlate the average blood oxygenation level-dependent (BOLD) time process of voxels in these ROIs with the time process of all other voxels in the brain.

11 Resting-state functional connectivity (FC) analysis is one of the most effective methods for studying the pathophysiological mechanism of neurologic and psychiatric diseases.

Resting-state functional magnetic resonance imaging (rs-fMRI) is superior to other fMRI techniques because of its advantages of simple signal acquisition, small workload of patients, and effective identification of functional areas of different patients. 10 Therefore, the LC, as an indispensable nucleus in arousal regulation, may be a breakthrough point to supplement and explain the neurobiological mechanism underlying insomnia. 9 One study in a chronically implanted stimulating electrode placed in the region of the LC found that electrical stimulation of the LC produced a profound disruption of sleep patterns in contrast to the normal sleep patterns. 8 A recent study based on task-state functional MRI in insomnia found that, from no insomnia complaints to major insomnia symptoms, LC activity (assessed by cortical arousal as a proxy variable) increased gradually. 7 The development of neuroimaging techniques has provided a new avenue of research on detecting neurobiological alterations of the LC in CID. 6 In a recent review on the brain mechanism of insomnia, Van Someren and EJW proposed that the vulnerability to insomnia may exist in the brain circuits regulating emotion and arousal, and speculated that in people with insomnia, the LC is more sensitive to-or receives more inputs the salience network and related circuits. 5 Berridge et al believe that the hyperactivity of LC is incompatible with sleep and may lead to insomnia. The locus coeruleus (LC), a small cluster of Norepinephrine-synthesizing neurons located in the pontine brainstem adjacent to the fourth ventricle, is considered to play a key regulatory role during the transition between sleep and waking. 4 Despite the high prevalence and the negative socio-economic impacts of CID, its neurobiological causes and consequences are still elusive. 3 Persistent insomnia symptoms not only reduce the quality of daily life and affect work efficiency but also lead to depression, anxiety, and even death. 1, 2 CID affects an estimated 5.8 – 20.0% of the population. Chronic insomnia disorder (CID) is an independent psychiatric syndrome that involves difficulties in falling or staying asleep that last for at least three months.

Chronic sleep insomnia