Depression is the third leading cause of disability all over the world, which significantly affects the patients’ life quality and imposes a heavy burden on the community (Vos et al., 2016). Various depressed patients often seek for general hospitalization in outpatient clinics, but in the most cases, they describe their symptoms as dizziness, headache, chest pain, gastrointestinal discomfort, insomnia and other physical symptoms such as main complaints, while emotional symptoms like depressed mood are not prominent. Furthermore, insomnia is the most common physical symptom in depressed patients and invariably emerges as the principal complaint and the first symptom of depressed patients, despite covering up the emotional cause of insomnia and attributing depressed mood to poor sleep. Studies have shown that about 92% of patients with major depression had sleep disorders, and 85.2% of them have insomnia, with most of them presenting with difficulty falling asleep, early awakening or recurrent awakenings (Geoffroy et al., 2018).

It is acknowledged that insomnia is invariably a concomitant symptom of major depressive disorder, evidence involved relationship between amygdala and major depressive disorder (MDD) patient as well as insomnia has been well documented and interpreted (Gong et al., 2021; Li et al., 2019). MDD usually occurs at the same time as insomnia, and insomnia can extend during remission or recovery period. Moreover, insomnia severity is correlated with depression severity, treatment response, suicidal ideation, and risk of recurrence (Li et al., 2012). According to Taylor et al. (Taylor et al., 2005), patients with insomnia were more likely to have clinically severe depression. Insomnia was found to increase the risk of recurrent depressive episodes by two to four times in longitudinal studies of patients with MDD (Breslau et al., 1996; Chang et al., 1997). To some extent, since there exists miscellaneous interaction between insomnia and depression, investigation into particular underlying brain abnormalities associated with insomnia in MDD patients has the potential to provide individualized treatment for patients with severe depression. Nevertheless, the studies of neuropathologic mechanisms underpinning insomnia and MDD comorbidity remain insufficient and unsatisfying. Therefore, research on neural mechanisms of MDD patients with different degrees of insomnia severity would develop a better understanding of the neuropsychopathology for MDD patients with insomnia.

The functional magnetic resonance imaging (fMRI) study discovered that the pathogenesis of depression is associated with functional abnormalities of brain regions involved in emotional processing and regulation, whereby a new path is available to investigate neuropathological mechanisms of mental disorder and predict clinical treatment effectiveness (Wise et al., 2014). To explore neural mechanism of depression and insomnia, applying the use of RSFC method has started bearing fruit. Literature has investigated that dysfunction of the neural network involved amygdala is one of neurobiological mechanism of insomnia (Baglioni et al., 2014a; Huang et al., 2012), which draws a similar conclusion to depression (Bagherzadeh-Azbari et al., 2019). Previous research indicated that the amygdala plays a vital role not only in the emotional circuit of depressive disorders, but also neuropathologic mechanism for insomnia. Cano et al. (Cano et al., 2008) found activation of the limbic system (including the amygdala, hippocampus, etc.) during the period of insomnia. Hyperactivation of the amygdala has been explored in patients with depressive disorders (Baglioni et al., 2014b; Tahmasian et al., 2013). Baglioni et al., 2014aJoo et al., 2014Tahmasian et al., 2013Since the convincing relationship between insomnia and MDD has been established, and neuroimaging functional alteration in amygdala in insomnia and MDD have been proven respectively, we are more likely to assume that patients with combined insomnia and MDD would yield abnormal RSFC change in the specific region of amygdala. It is understood that the brain region of amygdala is a significant anatomical basis for emotional and cognitive processing, as a part of limbic system, supported by study that proved the role of the amygdala in emotional memory and found that the amygdala enhances the experience of pleasant or unpleasant emotions by regulating the coding of emotional memory (Hamann, 2001). In depression, previous studies found that variations in rapid-eye-movement and slow-wave sleep performed association with sleep-related dysfunctional arousal in amygdala, (Nofzinger, 2004), suggesting that alterations in the limbic system function exist in depression and insomnia. Besides, patients with sleep disorder demonstrated amygdala-related FC changes across wakefulness and the whole three nonrapid eye movement sleep stages. (Zou et al., 2021). Since the association between amygdala and MDD was strongly demonstrated, and relationship between amygdala and insomnia was partially detected in literatures as well, we argue that subtype of MDD with impaired sleeping state or concomitant insomnia symptom will revealed altered and different FC changes. Hence, investigation on the neural mechanisms of amygdala for MDD patients with different levels of insomnia severity would improve our understanding of the neuropsychopathology of MDD patients with insomnia.(Gong et al., 2020). Although previous study has identified differences in local amplitude of low-frequency fluctuations (ALFF) (Liu et al., 2018) and global functional connectivity density (gFCD) (Gong et al., 2020) between the insomnia subtype of MDD and healthy controls, differences in functional connectivity of the amygdala have not yet been reported. Thus, the goal of this work was to elucidate these concerns and, as a result, advance our knowledge of the brain processes underlying the insomnia subtype of MDD. By selecting amygdala as the seed region in the RSFC in this study, we used rs-fMRI to record the neuronal activity of target brain regions to identify insomnia-related brain dysfunction in MDD patients. We were intended to address the following questions: 1) shed new light on the changes of resting brain functional connectivity in the amygdala of MDD patients with low insomnia and high insomnia. 2) determine how amygdala RSFC relates to clinical characteristics in MDD patients with insomnia.