Altered regional brain white matter in dry eye patients: a brain imaging study

Results

Demographic information

No significant differences were found between the groups in body weight (p = 0.853) or age (p = 0.873), while differences were found in monocular BCVA (right p = 0.122; left p = 0.163). Both groups were right-handed. Details are presented in Table 1.

Table 1. Basic information of participants in the study.

Condition	DE	HCs	t	P-value*
Male/Female	7/18	7/18	N/A	>0.99
Age (years)	55.68 ± 8.73	56.29 ± 6.82	0.272	0.873
Weight (kg)	56.92 ± 8.59	57.19 ± 9.16	0.216	0.853
Handedness	25R	25R	N/A	>0.99
Duration of DE (mons)	10.72 ± 3.86	N/A	N/A	N/A
Best-corrected VA-left eye	0.94 ± 0.36	1.12 ± 0.19	−0.915	0.163
Best-corrected VA-right eye	0.91 ± 0.43	1.09 ± 0.22	−0.987	0.122
Independent t-tests comparing two groups (p < 0.05). Abbreviations: HCs: healthy controls; N/A: not applicable; DE: dry eye; VA: visual acuity.

DTI differences

Compared with the HC, the FA value of PAT was significantly lower in the left superior longitudinal fasciculus (LSLF) and corpus callosum (CC) (Figure 1A (blue) and Table 2). Higher DTI values in the brain areas were the LSLF (MD), right posterior limb of the internal capsule (MD), the right posterior thalamic radiation (MD), the genu of CC (AD), right posterior limb of internal capsule (AD) and right splenium of the CC (AD) (Figure 1A (red) and Table 2). The ROI signal values of the two groups were shown in Figure 1B–1D.

Figure 1. Comparison of DTI value of HC and PAT group. Mean DTI values between PAT and HC groups (A–C). (A) ROI1-left superior longitudinal fasciculus; ROI2-body of corpus callosum. (B) ROI1-left superior longitudinal fasciculus; ROI2-right posterior limb of internal capsule. ROI3-right posterior thalamic radiation. (C) ROI1-genu of corpus callosum; ROI2-right posterior limb of internal capsule; ROI3-right splenium of corpus callosum. Significant difference in mean DTI value between HC and PAT group. (D) The red area indicates that the value of PAT is higher than HC and blue areas indicate lower values. Abbreviations: FA: fractional anisotropy; MD: mean diffusivity; AD: axial diffusivity; HC: healthy controls; PAT: patient; ROI: region of interest.

Table 2. Significant differences of DTI values between different brain WM regions of PAT and HC group.

A PAT>HC
Parameter	WM regions (PAT vs. HC)	MNI coordinates			Voxels number	T value	P value	Cluster
		X	Y	Z
MD	Left Superior longitudinal fasciculus	125	121	100	117	7.61	0.00008	ROI1
	Right Posterior limb of internal capsule	80	121	68	125	5.31	0.003	ROI2
	Right Posterior thalamic radiation	59	57	79	94	4.94	0.006	ROI3
AD	Genu of corpus callosum	103	160	79	109	6.37	0.0002	ROI1
	Right Posterior limb of internal capsule	74	120	74	192	5.36	0.002	ROI2
	Right Splenium of corpus callosum	67	76	90	106	5.47	0.001	ROI3
B PAT<HC
Parameter	WM regions (PAT vs. HC)	MNI coordinates			Voxels number	T value	P value	Cluster
		X	Y	Z
FA	Left Superior longitudinal fasciculus	129	116	101	185	−6.78	0.0001	ROI1
	Body of corpus callosum	97	116	101	132	−6.25	0.0003	ROI2
Between-group differences in DTI parameters. Abbreviations: FA: fractional anisotropy; MD: mean diffusivity; AD: axial diffusivity; HC: Healthy controls; PAT: patient; N/A: not applicable.

NODDI differences

Compared with the HCs, DE patients had significantly higher NODDI values in the left anterior corona radiata (ODI), the CC (ODI), LSLF (ODI), the right splenium of CC (FISO), the left posterior corona radiata (FICVF) (Figure 2A (red) and Table 3). Lower NODDI values in the brain areas were LSLF (FICVF) (Figure 2A (blue) and Table 3). The ROI signal values of the two groups were shown in Figure 2B–2D.

Figure 2. Comparison of NODDI value of HC and PAT group. Mean NODDI values between PAT and HC groups (A–C). (A) ROI1-left anterior corona radiata; ROI2-body of corpus callosum; ROI3-left superior longitudinal fasciculus. (B) Right splenium of corpus callosum. (C) ROI1-left posterior corona radiata; ROI2-left superior longitudinal fasciculus. Significant difference in mean NODDI value between HC and PAT group (D) The red area indicates that the value of PAT is higher than HC and blue areas indicate lower values. Abbreviations: ODI: orientation dispersion index; FISO: isotropic volume fraction; FICVF: intra-cellular volume fraction; HC: healthy controls; PAT: patient; ROI: region of interest.

Table 3. Significant differences of NODDI values between different brain WM regions of PAT and HC group.

A PAT>HC
Parameter	WM regions (PAT vs. HC)	MNI coordinates			Voxels number	T value	P value	Cluster
		X	Y	Z
ODI	Left Anterior corona radiata	115	149	91	93	5.17	0.002	ROI1
	Body of corpus callosum	99	107	99	216	4.18	0.011	ROI2
	Left Superior longitudinal fasciculus	132	87	75	87	4.54	0.007	ROI3
FISO	Right Splenium of corpus callosum	67	76	90	132	6.86	0.0005	ROI1
FICVF	Left Posterior corona radiata	118	67	92	83	5.03	0.003	ROI1
B PAT < HC
Parameter	WM regions (PAT vs. HC)	MNI coordinates			Voxels number	T value	P value	Cluster
		X	Y	Z
FICVF	Left Superior longitudinal fasciculus	118	67	92	79	−4.56	0.007	ROI2
Between-group differences in NODDI parameters. Abbreviations: ODI: orientation dispersion index; FISO: isotropic volume fraction; FICVF: intra-cellular volume fraction; HC: Healthy controls; PAT: patient; N/A: not applicable.

Receiver operating characteristic curve

The ROC curve was used to evaluate the value of DTI and NODDI parameters in the two groups for diagnostic. AUC was positively correlated with diagnostic significance. The results showed that the value of DTI and NODDI in different regions of brain were significantly different in the two groups. Hence, as markers, DTI and NODDI values are useful for distinguishing DE from HC. Results of AUC were as follows: DTI: The AUC were 0.976 for LSLF (FA); 0.960 for CC (FA) (Figure 3A, PAT < HC); 0.994 for LSLF (MD); 0.891 for right posterior limb of internal capsule (MD); 0.918 for right posterior thalamic radiation (MD); 0.888 for genu of CC (AD); 0.880 for right posterior limb of internal capsule (AD); and 0.900 for right splenium of CC (AD) (Figure 3B, PAT > HC). NODDI: The AUC was 0.941 for the left anterior corona radiata; 0.867 for CC; 0.874 for the LSLF (ODI); 0.968 for the right splenium of CC; 0.971 for the left posterior corona radiata (Figure 3C, PAT > HC); and 0.880 for the LSLF (FICVF) (Figure 3D, PAT < HC). All p values were < 0.0001 and AUC were over 0.867.

Figure 3. ROC curve analysis of the mean DTI and NODDI values for altered brain regions. (A) The area under the ROC curve were 0.976, (p < 0.0001; 95% CI: 0.941–1.000) for left superior longitudinal fasciculus (FA); body of corpus callosum (FA) 0.960, (p < 0.0001; 95% CI: 0.908–1.000). (B) The area under the ROC curve were 0.994 (p < 0.0001; 95% CI: 0.979–1.000) for left superior longitudinal fasciculus (MD); right posterior limb of internal capsule (MD) 0.891, (p < 0.0001; 95% CI: 0.804–0.979); right posterior thalamic radiation (MD) 0.918, (p < 0.0001; 95% CI: 0.841–0.994); genu of corpus callosum (AD) 0.888, (p < 0.0001; 95% CI: 0.794–0.982); right posterior limb of internal capsule (AD) 0.880, (p < 0.0001; 95% CI: 0.784–0.976); right splenium of corpus callosum (AD) 0.900, (p < 0.0001; 95% CI: 0.816–0.984). (C) The area under the ROC curve were 0.941, (p < 0.0001; 95% CI: 0.879–1.000) for left anterior corona radiata; body of corpus callosum 0.867, (p < 0.0001; 95% CI: 0.765–0.969); left superior longitudinal fasciculus (ODI) 0.874, (p < 0.0001; 95% CI: 0.780–0.967); right splenium of corpus callosum 0.968, (p < 0.0001; 95% CI: 0.916–1.000); left posterior corona radiata 0.971, (p < 0.0001; 95% CI: 0.934–1.000). (D) The area under the ROC curve were 0.880 (p < 0.0001; 95% CI: 0.790–0.970) for left superior longitudinal fasciculus (FICVF). Abbreviations: FA: fractional anisotropy; MD: mean diffusivity; AD: axial diffusivity; RD: radial diffusivity; ODI: orientation dispersion index; FISO: isotropic volume fraction; FICVF: intra-cellular volume fraction; AUC: area under the curve; ROC: receiver operating characteristic.

Correlation analysis

AS and DS values of HC group and PAT group were shown in Figure 4A. In the HC group, AS and DS were not significantly correlated with DTI and NODDI values. In the DE group, the value of FICVF was negatively correlated with DS (r = −0.909, p < 0.01) (Figure 4G) and AS (r = −0.929, p < 0.01) (Figure 4D) While the MD (ROI2) value was positively correlated with DS (r = 0.473, p = 0.017) (Figure 4E) and AS (r = 0.526, p = 0.007) (Figure 4B). The mean value of MD (ROI3) was positively correlated with the DS (r = 0.419, p = 0.037) (Figure 4F) and AS (r = 0.403, p = 0.046) (Figure 4C).

Figure 4. Correlations between the DTI values, NODDI values and AS, DS. (A) The value of AS and DS in two groups. (B–G) In There was a positive correlation with the values of MD and DS, AS. And the mean value of FICVF was negatively correlated with DS and AS. Abbreviations: DS: depression score; AS: anxiety score; MD: mean diffusivity; FICVF: intra-cellular volume fraction; HC: Healthy controls; PAT: patient.

Discussion

Dry eye is one of the most common eye diseases, accounting for 5% to 50% of dry eye cases worldwide [20], seriously affecting patients’ work and life and even causing social-psychological problems such as depression [21], stress [22], anxiety and sleep disorders [23]. However, the multifactorial cycle and pathological mechanism of dry eye has not been fully clarified. The results of this study suggest that there are microstructural changes in WM in DE patients, which may be the basis of mood abnormalities in DE patients.

DTI and NODDI characteristics

DTI is a very useful imaging technique in the clinical diagnosis and study of the microstructure of neural tissues, helping us to better understand the neurophysiological mechanisms of many diseases. DTI can quantitatively analyze the diffusion of water molecules in three-dimensional space within a brain region of interest, thus revealing the structure of WM fiber bundles. The MD in DTI reflects the range of diffusion motion of water molecules per unit time. The increase of MD and AD values may be partly caused by demyelination [24], although other factors such as axon loss, fiber density, axon diameter, and cell membrane integrity may also be responsible. Animal experiments have shown that demyelination after axonal injury often leads to an increase in transverse (short-axis) diffusivity and a decrease in axial (long-axis) diffusivity [25].

FA is very sensitive to white matter changes, reflecting the integrity of myelin sheath, axon density and any changes in diameter [26]. Significant FA decreases in the LSLF and the CC may reflect reduced neural integrity within these regions in DE, due to demyelination or axonal injury [27]. NODDI is an emerging method based on magnetic resonance diffusion imaging [28], which compared with DTI offers more complete and accurate indication of water diffusion behavior in complex brain tissues. ODI is a measure of changes in the direction of nerve processes. In our study, significantly raised ODI values perhaps suggesting a loss of fiber coherence and relatively maintained neuronal fiber density [29, 30].

Application of DTI and NODDI

Previous studies have applied DTI and NODDI in ophthalmology (Table 4), but to our knowledge, the present study is the first to assess WM changes in patients with dry eye using DTI combined with NODDI. Our study found that compared with the HCs, DTI and NODDI values were reduced in some brain regions (Figure 5). ROC results were used to verify DTI and NODDI analysis, and showed areas under the ROC curves greater than 0.7, indicating reliable accuracy. Therefore, it can be concluded that regional brain WM is altered in DE patients compared with HC. In addition, DTI and NODDI values reflect regional changes in white matter, and abnormalities in WM may be the basis for pain and mood disorders in DE patients (Table 5).

Table 4. DTI and NODDI applied in ophthalmologic disease.

	Author	Year	Disease
DTI	Liu et al. [31]	2020	Monocular blindness
	Tian et al. [32]	2019	Neuromyelitis Optic Neuritis
	Wang et al. [33]	2018	Primary Open-Angle Glaucoma
	Lee et al. [34]	2018	Dysthyroid Optic Neuropathy
	Zhong et al. [35]	2017	Monocular blindness
	Gupta et al. [36]	2016	Strabismic amblyopes
	Huang Xin et al. [37]	2016	Comitant strabismus
	Schoemann et al. [38]	2014	Primary open-angle glaucoma
	Schmidt et al. [39]	2014	Primary open-angle glaucoma
	Michelson et al. [40]	2013	Glaucoma
NODDI	Kang et al. [41]	2021	Anterior Visual Pathway Compression
Abbreviations: DTI: diffusion tensor imaging; NODDI: neurite orientation dispersion and density imaging.

Figure 5. The mean DTI and NODOI values of altered brain regions. (A) Compared with the HCs, the DTI values of the following regions were decreased to various extents: 2- left superior longitudinal fasciculus (FA) (t = −6.78), 4- body of corpus callosum (FA) (t = −6.25). Compared with the HCs, the DTI values of the following regions were increased to various extents: 1- left superior longitudinal fasciculus (MD) (t =7.61), 7- right posterior limb of internal capsule (MD) (t = 5.31), 8- right posterior thalamic radiation (MD) (t = 4.94), 3- genu of corpus callosum (AD) (t = 6.37), 6- right posterior limb of internal capsule (AD) (t = 5.36), 5- right splenium of corpus callosum (AD) (t = 5.47). (B) Compared with the HCs, the NODOI values of the following regions were increased to various extents: 2- left anterior corona radiata (t = 5.17), 6- body of corpus callosum (t = 4.18), 5- left superior longitudinal fasciculus (ODI) (t = 4.54), 1- right splenium of corpus callosum (t = 6.86), 3- left posterior corona radiata (t = 5.03). Compared with the HCs, the NODOI values of the following regions were decreased to various extents: 4- left superior longitudinal fasciculus (FICVF) (t = −4.56). Abbreviations: HCs: healthy controls; DTI: diffusion tensor imaging; FA: fractional anisotropy; MD: mean diffusivity; AD: axial diffusivity; ODI: orientation dispersion index; FISO: isotropic volume fraction; FICVF: intracellular volume fraction.

Table 5. Alternation of brain white matter regions and its potential impact.

Brain regions	Experimental results	Brain function	Anticipated results
Thalamic	PAT>HC (MD)	transmit, process and respond visual information and pain information	Visual impairment and persistent pain symptoms
Left Superior longitudinal fasciculus	PAT < HC (FA, FICVF) PAT>HC (MD, ODI)	associated with affective disorders	Depression and anxiety
Right Posterior limb of internal capsule	PAT>HC (MD, AD)	associated with different aspects of emotion, motivation, cognition processing, and decision-making	Social and emotional problems
Corpus callosum (Body, Splenium, Genu)	PAT < HC (FA) PAT>HC (AD, ODI, FISO)	integrate motor, emotional, and cognitive functions; part of the default model network	Social and emotional problems
Corona radiata	PAT>HC (ODI, FICVF)	attentional control	Cognitive impairment
Abbreviations: HC: healthy controls; PAT: patient controls.

Relationship between brain regions, DE and HADS

The thalamus is located around the bilateral third ventricle and is the largest oval mixed nucleus of gray matter in the diencephalon. The thalamus has specific connections with the corresponding cerebral cortex. As a completely functional network, the cerebellum-thalamus can transmit, process and respond to visual and pain information within and beyond the visual brain [42, 43]. In this study, MD values of the right posterior thalamus were significantly different between DE and HC. Pan et al. [44] used the global brain functional connectivity (GFC) method at voxel level to study the differences in functional tissue between DE patients and healthy controls. The GFC changes in the cerebellum-thalamic-cortex network in DE patients may be related to visual impairment and persistent pain symptoms, and reduced GFC may lead to a continuous stress response and reduced pain threshold. The superior longitudinal fasciculus (which contains bidirectional fibers running from the frontal to the parietal, temporal and occipital lobes) is a communication link, connecting the “control network” region of the frontal parietal lobe with other regions. Studies have shown that the FA value of LSLF is decreased in patients with major depression [45, 46], and in affective disorders [47, 48].

The CC is the largest WM fiber bundle, connecting the bilateral cerebral hemispheres. The fibers in the knee of the corpus callosum are mainly connected with the temporal and parietal lobes. Abnormality of WM in schizophrenia or psychosis most commonly occurs in the CC [49]. In the present study, the FA values of the LSLF and CC were decreased in DE patients, while ODI and FISO values were increased, and these findings may be related to the affective disorders caused by DE. The inner capsule is a bundle of fibers that perform primary motor functions. Poulakis [50] found that the knee of the CC, the forelimb of the inner capsule, and the integrity of the coronary fiber bundle after radiation may be used to assess individuals’ risk of future cognitive decline. In addition, the increase in MD and AD values of the right posterior limb of the internal capsule may be related to the social and emotional problems of DE.

HADS is an effective method to evaluate depression and anxiety in patients with DE. Patients with severe symptoms requiring psychological treatment were not included in our study, and HADS in patients with DE was higher than that in the normal group, reflecting the correlation between dry eye and HADS. Persistent eye discomfort and visual impairment caused by DE can lead to anxiety, depression and other mood disorders. Research showed in rats that depression can lead to increased secretion of IL-1B and TNFα and reduced tear secretion [51]. Depressive symptoms are associated with subjective dry eye symptoms, but not with more objective measures (tear break-up time, Schirmer test and corneal staining) [52]. Correlations between mean values MD and FICVF and both AS and DS suggest that the regional changes of WM in DE patients may be related to the patient’s anxiety and depression (Figure 6).

Figure 6. Correlation between DTI and NODDI values and emotional disorder. Compared with HC group, the values of DTI and NODDI in some brain white matter regions were significantly different in PAT group, and patients with dry eye were more prone to depression and anxiety. Abbreviations: HC: healthy controls; PAT: patient controls.

Limitations

This study has some limitations: 1) DTI adopts rapid prototyping technology, is very sensitive to the movement of small molecules, and artifacts caused by physiological movement may affect its results; 2) The small samples limits the credibility of the conclusions, and future studies with larger samples are needed to verify the method and results.

Author Contributions

Yun-Qing Luo and Rong-Bin Liang analyzed the data and draft the manuscript; San-Hua Xu, Yi-Cong Pan and Qiu-Yu Li collected the data; Hui-Ye Shu, Min Kang and Pin Yin assisted in data collation and chart drawing, Li-Juan Zhang final revised the manuscript; Yi Shao conceived, designed and approved the manuscript.

Conflicts of Interest

The authors declare no conflicts of interest related to this study.

Funding

National Natural Science Foundation (No: 82160195); Central Government Guides Local Science and Technology Development Foundation (No: 20211ZDG02003); Key Research Foundation of Jiangxi Province (No: 20181BBG70004, 20203BBG73059); Excellent Talents Development Project of Jiangxi Province (No: 20192BCBL23020; Natural Science Foundation of Jiangxi Province (No: 20181BAB205034; Grassroots Health Appropriate Technology “Spark Promotion Plan” Project of Jiangxi Province (No:20188003); Health Development Planning Commission Science Foundation of Jiangxi Province (No: 20201032,202130210); Health Development Planning Commission Science TCM Foundation of Jiangxi Province (No: 2018A060, 2020A0087); Science and Technology Project of Jiangxi Provincial Health Commission (No: 202210635).

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