In this study, a positive correlation was observed between the severity of insomnia and the severity of anxiety. In other words, the more times an individual experience insomnia, the more anxious they will become. Through voxel-based morphologic analysis, we found a decrease in gray matter volume in the cerebellar region and the left insular regions of the patients. The decrease in cerebellar gray matter volume was negatively correlated with the severity of insomnia, while the decrease in gray matter volume in the left insula was negatively correlated with the severity of anxiety and insomnia. In addition, functional connectivity analysis showed decreased connections between the left cerebellum and the left cingulate gyrus, the left cerebellum and the left superior frontal gyrus, the left insula and the left posterior central gyrus, and the increased connections between the left cerebellum and the right angular gyrus, the left insula and the left cingulate gyrus. Moreover, some of these abnormal functional connections were associated with insomnia and anxiety severity scores, indicating that they may be involved in the pathogenesis of insomnia comorbidity anxiety.
Insomnia comorbidity anxiety was selected as the study object due to its commonality in clinical practice. Many insomnia patients who come to the hospital for help suffer from anxiety disorders. Similarly, most anxiety individuals with also suffer from insomnia, which is fully demonstrated in our correlation analysis. In our study, patients' PSQI scores and ISI scores were positively correlated with anxiety severity scores, and their HAMA scores and SAS scores were positively correlated with insomnia severity scores, suggesting that insomnia and anxiety seem to be twin brothers. Actually, insomnia and anxiety are often found to be comorbidities in many previous studies. According to a large-scale study, there is a causal relationship between insomnia and anxiety(Gibson et al, 2023). Insomnia can trigger anxiety. In addition, several longitudinal studies on insomnia have found that chronic insomnia can be a predictor of anxiety(Hertenstein et al, 2019). Anxiety can be alleviated under the condition that insomnia is actively treated and sleep quality is improved(Scott et al, 2021). For Individuals with anxiety is typically accompanied with insomnia, resulting in shortened sleep duration and interrupted sleep continuity(Cox & Olatunji, 2020). The results suggest that close attention should be paid to the patients' insomnia symptoms when dealing with their anxiety. Insomnia and anxiety are both highly prevalent mental disorders. Researchers have found that the morbidity of insomnia and anxiety almost tripled during the COVID-19 epidemic. Additionally, many people suffered from both insomnia and anxiety. Undoubtedly, there are a large number of people suffering from insomnia and anxiety(Shi et al, 2020), emphasizing the significance to investigate their pathogenesis.
According to many researchers, their initial understanding of insomnia lies in the fact that the brain is in a state of hyperarousal. They believe that abnormalities in the brainstem ascending reticular activation system may contribute to insomnia. However, with the deepening of study, researchers found abnormalities in the brain stem ascending reticular activation system resulted not only in sleep disorders, but also in emotional regulation disorders. For example, abnormalities in the brain stem ascending reticular activation system will not only lead to insomnia, but also anxiety(Gong et al, 2023). In other studies, abnormalities were found in the emotional regulation and arousal circuits of insomnia patients, which may indicate the potentially important role of the locus coeruleus. In other words, insomnia can cause excessive activity of the locus coeruleus at night, making it difficult to relieve anxiety at night, which will exacerbate anxiety and ultimately result in the occurrence of insomnia comorbidity anxiety(Van Someren, 2021). People's regulation of emotions and sleep cannot be separated from the role of hormones, among which norepinephrine plays an important role in keeping the body in a state of excitement and anxiety. Some researchers have found that abnormalities in the locus coeruleus-norepinephrine system are closely related to insomnia and anxiety(Gong et al, 2021a). Some special neuronal abnormalities can also lead to the occurrence of insomnia comorbidity anxiety. For example, glutaminergic neurons is involved in the regulation of both emotions and sleep. Abnormalities in the glutaminergic neurons-cingulate cortex neural circuit will lead to anxiety. Abnormalities in the glutaminergic neuron- paraventricular thalamic nucleus neural circuit will lead to insomnia(Liu et al, 2022). Briefly, insomnia comorbidity anxiety may be attributed to their similar pathological mechanisms, which is consisted with our finding. From the perspective of brain morphological structure and functional connectivity, we tried to discover the mechanism of insomnia comorbidity anxiety.
In our study, the decreased volume of grey matter in the cerebellar region was negative correlated with the severity of insomnia, suggesting that the cerebellum may be involved in the pathogenesis of insomnia, and play a role in sleep regulation, which has been found in some previous studies. The cerebellum is not just for maintaining body balance, regulating muscle tone, and coordinating voluntary movement. A cat will become drowsy during the day if its cerebellum is removed(JD. & I., 1982). In addition, when recording the electrophysiological activity of the cerebellum in mice, changes in neuronal activity occurred when the sleep and wake states were switched(Zhang et al, 2020). Through in-depth study, the cerebellum was found to have extensive associations with other regions of the brain during sleep. The cerebellum can interfere with the activity of some brain regions associated with sleep. For example, during some sleep periods, the electrophysiological activity of the cerebellum is similar to that of the hippocampus. The cerebellum may regulate sleep together with the hippocampus(Torres-Herraez et al, 2022). In addition, some clinicians have observed that patients with cerebellar damage typically have sleep disorders(Song & Zhu, 2022), suggesting a close link between the cerebellum and sleep. So far, many studies have found that the cerebellum is involved in sleep regulation(DelRosso & Hoque, 2014). The cerebellum seems to act as a relay station for sleep regulation. It can receive sleep instructions from some brain regions, and subsequently affect some brain regions(Canto et al, 2017). Our study demonstrated that insomnia could lead to a decrease in cerebellar gray matter volume from a morphological point of view.
The decrease in gray matter volume in insula appears to be the result of insomnia comorbidity anxiety. We found that the decrease in gray matter volume in the left insula was negatively correlated with ISI scale scores (r=-0.45) and HAMA scale scores (r=-0.35). As is well known, an important function of the insula is involved in the regulation of human emotions. It regulate emotions together with brain regions such as the amygdala, thalamus, and prefrontal lobe. Moreover, the mechanisms involved in emotional regulation are varied. Insula can not only affect the effects of hormones and neurotransmitters, but also change the functional status of certain brain regions(Gehrlach et al, 2019). Abnormalities in the insula are found in many mental disorders(Nord et al, 2021). Anxiety plays a significant and persistent role on insular gray matter volume. The volume of insular gray matter gradually decreases as the anxiety severity increases(Chen et al, 2020). But it's not just anxiety that causes atrophy of the insula. Studies have found that abnormal changes in brain structure in anxious patients are also negatively correlated with their insomnia severity(Zhang et al, 2022), suggesting that insomnia can also lead to abnormal changes in the insula. Actually, some studies have shown that the insula mediates the onset of both anxiety and insomnia. When facing great pressure, the functional state of insula is usually abnormal, eventually resulting in anxiety, as well as insomnia(Predatu et al, 2023). Other researchers have found that when the insular activity is artificially triggered, anxiety and sleep disorders will be induced(Kim et al, 2022). However, it remains unclear whether anxiety or insomnia first triggers the abnormal changes in the insula at the current stage. Therefore some mediation analysis experiments were conducted on this basis. However, no valuable conclusions have been drawn. We prefer to believe that insomnia comorbidity anxiety is responsible for the loss of gray matter volume in the insula.
We also found abnormalities in functional connectivity, which may reflect changes in patients' functional brain activity. The connections between left cerebellum and left cingulate gyrus, left cerebellum and left superior frontal gyrus were reduced, which were negatively associated with the severity of insomnia and anxiety in patients. In addition, the connection between the left insula and the left cingulate gyrus was increased. These abnormal functional connections may be a manifestation of abnormal emotional and sleep regulation in patients. The cingulate gyrus and the superior frontal gyrus are important neural nodes in the emotional regulation mechanism of the human body, and they are also related to sleep. Researchers have found that long-term poor sleep quality may lead to a decrease in the volume of gray matter in the cingulate gyrus(Jalbrzikowski et al, 2021). Other researchers have reviewed numerous studies and found the important role of prefrontal lobe in sleep arousal(Mashour et al, 2022). Insomnia can not only cause abnormalities in the superior frontal gyrus and cingulate gyrus, but also reduce the level of myelin in the cortex(Toschi et al, 2021) and cause abnormal levels of neurotransmitters. Long-term insomnia can also cause abnormalities in the human body's default network, negative emotional network, and reward network(Anastasiades et al, 2022). These abnormal brain networks are closely related to superior frontal gyrus and cingulate gyrus. Eventually, abnormalities in the superior frontal gyrus and cingulate gyrus may lead to anxiety. Some previous studies have also made similar findings. They found that abnormalities in the functional connectivity of the superior frontal, cingulate gyrus and were associated with insomnia and anxiety(Kim & Kim, 2021; Zhu et al, 2021). We suggest that abnormal functional connections between the superior frontal gyrus and the cingulate gyrus may be valuable imaging markers. We must consider whether there are abnormalities in both emotional and sleep regulation when observing these connections. In addition, this also suggests that the mechanism of insomnia comorbidity anxiety may be related to their altered functional activities.
The connection between the left insula and the left upper posterior central gyrus was reduced, which was negatively correlated with the severity of anxiety. The increased connections between the left cerebellum and the right angular gyrus were negatively correlated with the severity of insomnia, which may be related to complications in patients with insomnia or anxiety. We have observed that many patients experience symptoms of fatigue, tension, muscle soreness, memory loss, and concentration loss(Reeve et al, 2019). The posterior central gyrus is an area of the brain responsible for somatosensory function. Impaired function of this brain region is typically accompanied by numbness, heaviness, and weak sensory dysfunction. Anxiety patients usually have abnormal functional connections in the posterior central gyrus, which has been proved to be related their physical symptoms in some studies. The abnormal function of the posterior central gyrus may mediate the transition from anxiety to depression(Kong et al, 2022), indicating that we cannot simply assume that the posterior central gyrus has only somatosensory functions. It is also related to emotional regulation. Previously, patients with posterior central gyrus injury have been found to experience emotional regulation dysfunction, which may be due to the close neural connections between the posterior central gyrus and the amygdala and insula(Kropf et al, 2019). However, the exact mechanism remains unclear. As the visual language center, the angular gyrus is responsible for a range of advanced brain functions, such as understanding written and vocal information. Abnormal angular gyrus function can be manifested as reduced understanding of information and situations(Humphreys et al, 2021), which may be associated with memory loss, attention loss and other symptoms caused by long-term insomnia. However, imaging studies have shown the overactive angular gyrus function. According to a study of diffusion-weighted imaging, the angular gyrus in insomnia patients has enhanced nerve fiber connections to other brain regions(Wei et al, 2019), suggesting that further research is needed on the role of the angular gyrus in insomnia.
Our study also has several limitations. Firstly, all participants underwent only one MRI scan, which is a cross-sectional study and may not be able to document the evolution of the disease. Secondly, it would be valuable to associate participants' hormone levels, electrical brain activity, and genetic information with image features, on which we hope to carry out further research. Finally, increasing the number of participants helps to improve the credibility of the experimental results. More experimental groups can be designed as the number of participants increases. Our research group is planning further research.