Dry eye (DE) is a term used for a variety of diseases with eye surface tissue damage caused by an abnormal quantity or quality of tears or tear film instability caused by dynamic abnormalities. Eye discomfort is the main complaint and, in some severe cases, visual impairment may occur. Generally, DE can be divided into two types: insufficient tear production and excessive tear evaporation. The former is caused by lacrimal gland dysfunction, which has been termed aqueous tear deficiency (ATD). The latter mainly refers to meibomian gland dysfunction (MGD). DE is more prevalent in women than men and the incidence increases with age (1, 2). According to an epidemiological study, 11.3% of people more than 50 years old were diagnosed with DE, and that percentage increased to 22.8% in women more than 75 years old (1). Since DE not only causes visual impairment, which directly affects daily living, it also brings sociopsychological problems that reduce the quality of life. The increased need for therapy and reduced incomes due to decreasing productivity makes DE a cause of economic burdens (1–5).

The climacteric period, also known as menopause, refers to a period of time that correlates with the age-related decline in ovarian hormone production, usually starting at the ages of 49 to 52 years. Although statements about the climacteric period have been made in the medical literature for centuries, a scientific approach to understanding the climacteric years is a young branch of medicine (6). As mentioned above, DE is more prevalent in females, especially at the age of menopause. This is mainly because of hormonal disorders. Decreased hormonal levels may reduce production of tear film components (7). Several studies have suggested that hormone replacement therapy may have benefits in DE patients during the female climacteric period (8, 9). AlAwlaqi and Hammadeh showed an increased risk of DE symptoms in women taking hormone replacement therapy (10). Thus, the specific mechanism of hormonal disorders and DE remains unclear.

In recent years, research on the clinical diagnosis, treatment, and pathological development of ophthalmic diseases has increasingly proliferated with medical imaging technology. Voxel-based morphometry (VBM), as a new method of magnetic resonance imaging (MRI) analysis, can be used to quantitatively analyze alterations in the density and volume of white and gray matter using each individual voxel in magnetic resonance images, thus reflecting the anatomical structure differences in corresponding regions (11). This may provide an entirely new way to explore neuropathological changes with eye diseases. The VBM technique has already been used widely in many ophthalmic diseases, such as retinal detachment, monocular blindness, concomitant strabismus, optic neuritis, and acute eye pain, as well as other neurogenic diseases (Table 1). In our study, we aimed to determine whether structural changes exist in certain brain regions of female patients with DE during the climacteric period compared to healthy controls (HCs).

This is the first study that investigated changes in brain regions in DE patients during the female climacteric period using a VBM approach. In our study, compared to HCs, significantly decreased VBM values was found in the left putamen, right thalamus, left precuneus, right superior frontal lobe, left middle cingulum, and left middle frontal lobe. Meanwhile, increased VBM values were found in the right superior temporal pole, and right precentral and left insula (Figure 5). ROC curve analysis indicated the potential role of the VBM method for diagnosing DE patients during the climacteric period. Correlation analysis suggested a correlation between the VBM values of certain brain regions in DE patients and their HADS score, but no correlation was found between the duration of the disease and VBM values. Namely, the VBM values of the Putamen_L were negatively correlated with the AS and DS, while a positive correlation was found between VBM values in the Temporal_Pole_Sup_R and the AS. Moreover, VBM values in the Cingulum_Mid_L of DE patients were positively correlated with the AS and DS.

The precuneus is the posterior part of the medial parietal cortex (21). Recent functional imaging findings suggested that the precuneus may participate in visuo-spatial imagery and other highly integrated works (22). The precuneus may also be responsible for self-consciousness (23). In our study, lower VBM values of the Precuneus_L were found in DE patients compared to HCs, suggesting that visual impairment secondary to DE may be correlated with changes in the precuneus lobe.

The thalamus is located in the diencephalon and is comprised of four parts (24). It is a vital relay center for both sensory and motor mechanisms and has several important functions, including sensory and motor functions, sleeping, and emotions (22). Basilious summarized 32 studies and concluded that the prevalence of depression and anxiety are much higher in DE patients (25). In another study, DE patients showed sleep quality reduction (26). In addition, menopausal women with sexual dysfunction also reported a higher prevalence of depression and anxiety (27), as well as sleeping disorders (28). In the present study, the VBM values of Thalamus_R were obviously decreased in DE patients compared to HCs, which corresponded with emotional changes (depression and anxiety) and sleep disorders in DE patients during menopause.

The putamen is part of the lentiform nucleus, which constitutes part of the basal ganglia with other nuclei (29). The putamen is mainly responsible for learning and motor control, as well as cognitive function (30, 31). Kuru found putamen abnormalities in patients with various motor and cognitive dysfunctions (32). In our study, the VBM values of Putamen_L in DE patients were lower and negatively correlated with HADS scores, indicating that these patients may have cognitive disfunction or movement disorders.

The frontal lobe is located anteriorly to the central sulcus and superiorly to the lateral sulcus. The external part of the frontal lobe is divided into three large surfaces (33). In recent years, the middle frontal gyrus (MFG) has been suggested to be part of the language network (34). In addition, Carter's research indicated the role of MFG in stress and cognitive functions (35). The superior frontal gyrus (SFG) has been linked to depression, cognition, and attention (36). Chang and his colleagues found SFG abnormalities in patients with depression (37). Thus, dysfunction of the frontal lobe may result in emotional and cognitive problems. In fact, we found VBM values declined in the frontal lobe, which was in accordance with our previous study (38).

The temporal lobe is a complex region. It has diverse cortical functions. Abnormal activation of these brain regions may cause epilepsy, schizophrenia, and amnesia (39). The insular cortex is buried inside the lateral sulcus of the brain (40). It can be divided into four functional parts with motor, olfactogustatory, socioemotional, and cognitive functions (41). The precentral gyrus is located on the lateral surface of the frontal lobe. It is involved in controlling voluntary motor movement (42). Another study found a correlation between decreased FA values in the precentral gyrus and age processing (43). Brain region alternation and its potential impact was summarized in Table 4. In this study, we demonstrated increased VBM values in the above brain regions in DE patients during menopause. Abnormal activity in these brain regions may be correlated with some excessive symptoms of DE patients, such as anxiety. Given that other functionally-similar brain regions showed contradictory low VBM values, compensation mechanisms may also exist in these brain regions.

A variety of systemic comorbidities has been reported in patients with DE and other ocular diseases, such as problems with memory, depression, cognition, and sleep (44). More severe organic symptoms, sensory and sensorimotor neuropathies, and movement disorders have also been reported (45). We believe that these symptoms may be related to changes in the VBM values of the brain regions mentioned above. Our research demonstrated that the clinical symptoms of DE patients were indeed associated with brain dysfunctions. Thus, we offer two assumptions: 1) DE causes emotional instability, which aggravates endocrine disorders and makes menopausal symptoms more obvious; and 2) abnormal endocrine function in menopause leads to poor lacrimal gland function, meibomian gland dysfunction, and then finally develops to DE.

There are some limitations in our study. First, DE can be divided into many different types, and our sample size was not large enough to subdivide patients into subgroups. Larger sample MRI studies may help increase understanding of the explicit changes in brain activity and DE at different ages or in different categories. Second, both DE and the climacteric period may cause psychological problems, thus impacting brain activity. Whether brain activity changes are secondary to DE, further aggravate symptoms of the climacteric period, or that the climacteric period caused brain activity changes and then contributes to DE remains unknown. In the future, larger more in-depth studies may help to address this question.

In conclusion, our study found significant abnormalities in certain brain regions in patients with DE during the climacteric period. ROC analyses indicated high accuracy of the VBM method for diagnosing DE patients. In the future, further investigations are needed to form a comprehensive understanding of the neuropathological mechanisms of DE.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

The studies involving human participants were reviewed and approved by the committee for medical ethics of the First Affiliated Hospital of Nanchang University. The patients/participants provided their written informed consent to participate in this study.

M-YH, YS, and C-GP designed the current study. MK, M-YH, and L-JZ recruited healthy controls. MK, Y-CP, and L-JZ performed MRI scanning. LY, Q-mG, and Q-yL collected and analyzed the data. M-YH wrote the manuscript. All the authors read and approved the final manuscript.

This research was supported by Key Research Foundation of Jiangxi Province (Nos. 20203BBG73059 and 20181BBG70004), Excellent Talents Development Project of Jiangxi Province (20192BCBL23020), Health Development Planning Commission Science Foundation of Jiangxi Province (20175115), and Education Department Youth Scientific Research Foundation (GJJ160122).

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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