Systemic lupus erythematosus (SLE) is an autoimmune disease, characterized by the production of multitude of autoantibodies affecting multiple systems, which leads to multiple organ damage. Neuropsychiatric systemic lupus erythematosus (NPSLE) is one of the most serious manifestations of SLE, affecting the peripheral and central nervous systems (CNS), which can occur at any time in the course of SLE. Depression and anxiety are the most common manifestations of diffuse CNS involvement in SLE (1). Genetic factors, immune response and blood brain barrier (BBB) dysfunction are all considered to be involved in the pathogenesis of NPSLE. Alexander et al. firstly found BBB damage in lupus mice (2). A clinical study also found that compared with healthy controls, SLE patients have increased BBB permeability, and patients with NPSLE have more severe BBB damage (3). In some diseases such as traumatic brain injury, epilepsy, and Alzheimer's disease, BBB functional damage has been proven to cause neuronal damage (4–6). Hence, we speculate that BBB damage caused by the influence of pathological changes underlying lupus makes abnormal BBB permeability, allowing inflammatory mediators in the peripheral circulation, such as cytokines, autoantibodies, to pass through the BBB and enter the CNS resulting in neuronal damage and a series of neuropsychiatric symptoms.

The traditionally accepted, reliable indicator for judging BBB damage is the albumin quotient (7). However, lumbar puncture is required to obtain the patient's cerebrospinal fluid (CSF), which is an invasive examination with related risks, so its clinical application is relatively limited. With the invention and development of medical imaging technology, a variety of imaging methods have been applied to the detection of BBB damage. This study used a non-invasive imaging technique that can quantitatively detect BBB dysfunction: dynamic contrast enhanced magnetic resonance imaging (DCE-MRI). The destruction of BBB can lead to the extravasation of low-molecular-weight magnetic resonance imaging contrast agents into the interstitial space outside blood vessels, resulting in increased signal at this site. DCE-MRI technology uses repeated brain scans to capture the changes in signal intensity caused by extravasation of intravenous low-molecular-weight contrast agents from the BBB, and uses the Patlak pharmacokinetic model to obtain the K^trans volume transfer constant, which can quantitatively reflect the destruction of BBB (8). The increase in the K^trans value represents an increase in the leakage of fluid through the BBB into the brain tissue. DCE-MRI technology has been used in the detection of BBB destruction in a variety of diseases, such as multiple sclerosis and brain tumors (9, 10).

Depression and anxiety as common emotional and mental disorders in SLE patients, present significantly higher incidence than which in the general population. Because of the lack of early symptoms and unified diagnostic criteria, depression and anxiety in SLE patients are often ignored in clinical practice. Increasing studies have shown that BBB dysfunction also plays an important role in the pathogenesis of depression. Animal experiments found that destruction of the BBB in mice produces depression-like behaviors (11). In addition, a recent study found that BBB destruction may be related to anxiety. Using DCE-MRI technology, Lyna et al. found that in patients with bipolar disorder, increased BBB permeability was associated with more severe depression and anxiety symptoms as well as the course of the disease (12).

At present, there are few studies that explored the association between BBB permeability changes and depression as well as anxiety in SLE patients. This study used DCE-MRI technology to detect changes in BBB permeability in SLE patients and evaluated depression and anxiety in SLE patients to further analyze their association with BBB dysfunction.

Compared with other invasive methods to evaluate the BBB dysfunction (17, 18), DCE-MRI not only exhibits good specificity and sensitivity but also can analyze the severity of BBB damage quantitatively. And as a non-invasive way, its' low risk will be easier to be accepted by patients.

In this study, the results showed that SLE patients have BBB dysfunction compared with HCs. And the increased BBB permeability was mainly located in the right insular area. In addition, to further explore whether the change of BBB permeability was associated with the emotional disorder of SLE patients, we divided patients into depression/anxiety groups and non-depression/non-anxiety groups to compare the degree of BBB damage in each subset. These results suggested that in SLE patients, the increased K^trans value in the right insula was associated with depression and anxiety.

A study using DCE-MRI technology to analyze the brain imaging of 6 SLE patients, found that the BBB permeability of SLE patients was increased compared with healthy controls (19), which was consistent with our results. And another study using DCE-MRI to assess BBB permeability found that BBB leakage was associated with gray matter loss and cognitive impairment (20), which were similar to the previous study using arterial spin labeling and diffusion-weighted brain MRI with a small sample size (21). Cagnoli et al. used magnetic resonance spectroscopy to study cell-level metabolic changes in several brain regions of SLE patients and HCs and found that compared with healthy controls and SLE patients without neuropsychiatric symptoms, neuron loss or damage was found in the right insular area of NPSLE patients (22). The abnormal brain area of NPSLE found in their study was consistent with the brain area of increased BBB permeability in SLE patients in our study.

Although there were several studies found that change of BBB permeability was associated with neuropsychiatric manifestations in SLE through other invasive methods (23–25), such as acute confusional state and cognitive dysfunction, our study was the first to explore the association between BBB permeability and depression/anxiety through the non-invasive method with relatively big sample size. This study not only provides evidence for extensive application of DCE-MRI to assess BBB damage in clinical management in SLE but also reveals that increased BBB permeability in the right insular region is associated with depression/anxiety in SLE patients.

Insula is a functional brain area involved in somatosensory and visceral sensation, regulating the conduction of pain and emotions, especially negative emotions (26). The anterior insula, as a component of ventral paralimbic regions, is an important part of the complex circuit initiating and regulating behavioral and emotional responses. In normal conditions, when the entire limbic-cortical depression network was activated, blood flow increased in the anterior insula (27). And in many neuropsychiatric diseases, abnormal damage of the insula and its network was found associated with emotional disorders. Frontotemporal dementia patients with damage of the anterior insula were found to present deficits in empathy and emotional reactivity (28). And the damage of insula networks was considered to contribute to depression in Parkinson's Disease (29). In major depression patients, bilateral amygdala and left anterior insula connectivity were found abnormally decreased in an affective network (30). These studies suggest that the destruction of structure in the insula and dysfunction of insular connectivity with other regions both can lead to depression.

Insula also plays an important role in anxiety (31). The severity of anxiety was considered to be positively correlated with central amygdala-insula functional connectivity (32), as well as somatic anxiety severity was found negatively correlated with the resting-state functional connectivity between anterior insula and medial prefrontal gyrus (33). The mechanism of the insula that takes part in anxiety is complex. In rats, the insula was found to have a direct role in anxiety with a regional difference. Medial and caudal regions of the insula exhibit an anxiolytic role, while the rostral region of the insula shows an anxiogenic role (34). Robinson et al. reveal another possible mechanism that anterior insula contributes to the maintenance of anxiety through consisting of a feedback loop with the prelimbic cortex to convey the interoceptive information from visceral change to the prelimbic cortex (35).

Furthermore, besides the direct role in depression/anxiety, the insula also takes part in the brain regulation of immunity. Neurons in the insular cortex can acquire and retrieve specific immune-related information and the insular cortex activity could induce or promote inflammation (36). Hence, we speculate that the high incidence of emotional disorder in SLE patients may not merely result from neuropsychiatric pathogenesis as conventionally known, but also may be associated with its immunity dysfunction and severity of inflammation affecting insula, and the BBB damage of the insular region may be a potential way. But further research is needed to explore the underlying mechanism.

There are also several limitations to our study. Firstly, the influence of various SLE treatment drugs could not be ruled out. For example, it has been reported that glucocorticoids have an impact on cognitive function (37). Recruiting untreated patients and comparing the DCE-MRI before and after treatment with a period of follow-up will be a reliable method to explore the effect of treatments on BBB damage. Secondly, the association of BBB damage with some clinical features could not be explored. Because of the limitation of sample size in this study, the number of patients in some subsets is insufficient to further analyze. Researches based on the larger sample size are needed.

In summary, this study found that SLE patients have increased BBB permeability, mainly in the right insular area. The increased BBB permeability in the right insular region is associated with depression/anxiety in SLE patients.

The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding authors.

The studies involving human participants were reviewed and approved by Institutional Review Board of Kunming Medical University. Written informed consent to participate in this study was provided by the participants' legal guardian/next of kin.

XW, LM, and YL were responsible for the management of the research and drafting the article. YY was responsible for data analysis. BU was responsible for language editing. YC was responsible for the psychiatric assessment of participants. YC, RC, and SL provided invaluable research consultation. YC and JX oversaw the entire research project and the writing of the manuscript. All authors contributed to the article and approved the submitted version.

This work was supported by grants from the National Natural Science Foundation of China (81760296, 82060259, and 81460256), Yunnan Province High-level health technical talents (leading talents) (L-2019004 and L-2019011), Yunnan Province Special Project for Famous Medical Talents of the Ten Thousand Talents Program (YNWR-MY-2018-040 and YNWR-MY-2018-041), the Funding of Yunnan Provincial Health Science and Technology Plan (2017NS051 and 2018NS0133), the Funding of Ministry of Science and Technology of Yunnan Province (2018ZF016), Yunnan Province Clinical Research Center for Skin Immune Diseases (2019ZF012), and Yunnan Province Clinical Center for Skin Immune Diseases (ZX2019-03-02).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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