Introduction
Strabismus is an ocular disease characterized by the inability of both eyes of an individual to gaze at a target simultaneously and the optic axis of both eyes is separated. It can lead to binocular vision impairment, and is often accompanied by amblyopia and loss of stereo vision. The incidence of strabismus in children aged 3–6 years in eastern China is 5.65% (1). There is no ideal classification method for strabismus in clinical practice, and its treatment mainly relies on surgical correction. Dysfunction of the extraocular muscles (EOMs) is an important cause of strabismus. In particular, aberrant EOM development, EOM dystrophy (2) and abnormal position of the EOM (3) can lead to the occurrence of strabismus, while dysfunction of the EOM pulleys has also been associated with the condition (4,5). The eye movement system is underpinned by a complex neural network. The structures in the nucleus of the brain, and the EOMs and nerves that dominate them must all work perfectly and synchronously to ensure normal visual function. For instance, the development of Duane's retraction syndrome has been reported to be associated with mechanical abnormalities of the external rectus muscle (6), aberrant innervation (7) and the absence of an abduction nucleus (8). Neuronal activity in the brain area that is involved in eye movements is also crucial. The frontal eye field (FEF) participates in the control of eye movement (4) and conjugate eye movement (5). A previous study reported that the gray matter volume of the FEF is increased in strabismus patients (9). Therefore, strabismus pathogenesis is directly associated with the EOM and brain function and/or structural alterations.
Amblyopia is caused by abnormal visual experiences (such as monocular strabismus, anisometropia, high ametropia and form-deprivation myopia) during visual development, resulting in decreased monocular and/or binocular best-corrected visual acuity (VA), but no organic lesion is observed on eye examination. The diagnostic criteria for amblyopia include a visual reference value that is below the lower normal limit (which is 0.5 for 3–5-year-old children, and 0.7 for children aged ≥6 years), or the best corrected VA of two eyes differs by ≥0.2, then the eye with poorer VA exhibits amblyopia (10). In China, the prevalence of amblyopia in children is 2–3% (11). At present, early detection and early treatment of amblyopia are important, with standard treatment strategies including accurate glasses and concealment of the dominant eye. According to its etiology, amblyopia can be divided into the strabismus, anisometropic, ametropic and form-deprivation types (12). The pathogenesis of amblyopia is highly complex; the two theories currently recognized involve abnormal binocular interaction and form deprivation (13,14). Simultaneously, abnormal activities in the associated brain regions have also been suggested to contribute to the development of amblyopia. For instance, Wang et al (15) reported that activation of the intraparietal sulcus, FEF and motor sensitive (V5) areas was reduced in patients with amblyopia. Thus, the exploration of brain activity in patients with strabismus and amblyopia (SA) is of practical significance.
Functional magnetic resonance imaging (fMRI) (16) is the primary examination technique used to locate and quantify functional brain areas. Its main advantages over traditional MRI techniques are high spatial resolution and the ability to reveal detailed microscopic structural changes. fMRI technology includes diffusion weighted imaging (DWI), diffusion tensor imaging (DTI), magnetic resonance spectroscopy, and blood oxygen level-dependent (BOLD) fMRI. Among these, DWI can reflect the diffusion movement and limitation of water molecules in tissues and lesions, while DTI reveals the anisotropy of diffusion movement towards water molecules, and can therefore be used to analyze white matter fiber bundles. In addition, BOLD fMRI uses the principle of blood oxygenation level dependence, that is, inconsistencies in the local hemodynamics of neurons following excitation, in order to reveal spontaneous neuronal activity by quantifying alterations in blood oxygen level signals. Thus, the study of brain cognitive activities, and the localization and quantification of brain functional activity areas is facilitated by fMRI. This technology has been widely used to study SA. In addition to these aforementioned studies, the volume of gray matter in the occipital eye field and parietal eye field has been reported to be reduced in patients with strabismus (17), while the functional connectivity between the V1 and V2 regions was decreased in SA monkeys (18). Furthermore, multiple brain areas are reportedly dysfunctional in concomitant strabismus (19).
Resting-state fMRI (rs-fMRI) analysis can be conducted using various methods, among which regional homogeneity (ReHo) is widely used. ReHo is a computational method based on functional differentiation, which was first proposed by the Chinese scholar Professor Yu-Feng Zang. This method can be used to analyze the consistency of brain activity signals and provide information about brain function (20,21). ReHo functions by assuming that the hemodynamics of each voxel in a brain region with the same function is approximately identical, and that the hemodynamics of the brain region may change due to variations in function or task. Thus, the level of consistency of BOLD signals can be represented by evaluating the degree of hemodynamic consistency between voxels in the region of interest and voxels that are adjacent to it simultaneously, which can be expressed using a ReHo value that reveals the consistency of spontaneous neuronal activity. Therefore, changes in ReHo values indicate alterations in brain hemodynamics, that is, changes in the synchrony of spontaneous neuronal activity. An increase in ReHo indicates an increase in the synchrony of spontaneous neuronal activity, whereas a decreased ReHo value suggests reduced synchrony and disordered activity. This method has been successfully applied to the investigation of the etiology of various eye diseases, including concomitant strabismus (19), optic neuritis (22), type 2 diabetes with retinopathy (23), glaucoma (24), open-globe injury (25), late monocular blindness (26) and retinal detachment (27), as well as a number of neurogenic diseases, such as sleep disorders (28) and Parkinson's disease (29).
In the present study, the brain activity of patients with SA was investigated using the ReHo method, in order to confirm alterations in brain function and explore the potential pathophysiological mechanism. To the best of our knowledge, this is the first study to examine SA using this method.
Discussion
rs-fMRI is easier to implement in patients than task-based fMRI, since patients are not required to perform specific tasks during fMRI scans, thus reducing the potential influence of confounding factors on the process (16). rs-fMRI can also provide more functional information, helping to better understand the functional mechanisms underlying specific diseases (16). The ReHo method has been successfully applied in several ophthalmological and neurogenic diseases, and has huge potential for further development (Table IV). To the best of our knowledge, the present study is the first to evaluate resting-state brain activity of patients with SA using the ReHo technique. Compared with the HC individuals, patients with SA exhibited significantly increased ReHo values in the LLG, RMOG/RP, BAC, LMOG and BPG areas, while the ReHo value for the LIFG region was significantly lower compared with that in HCs (Fig. 4).
The occipital lobe is a key brain area for visual processing, which controls eye movements and pupil accommodation reflex activities associated with vision. The lingual gyrus is part of the occipital lobe and an important component of the ventral visual stream, which participates in processing information such as shape, size, color, contour and object recognition. Thus, it is a crucial brain area for visual judgment and visual attention (32). Liang et al (33) used the voxel-mirrored homotopic connectivity (VMHC) method to analyze interhemispheric functional connectivity changes in patients with anisometropic amblyopia. They observed alterations in the lingual gyrus regions of patients with strabismus, amblyopia and anisometropic amblyopia, and the VMHC value of the lingual gyrus was found to be associated with stereoacuity. Furthermore, Qi et al (34) used the surface-based morphological measurement method and DTI to analyze changes in cortical thickness and white matter integrity in children with amblyopia. These researchers observed that the thickness of the lingual gyrus, cuneus and occipital cortex, and the fractional anisotropy (FA) values in the medial lingual cortex were all reduced. Yang et al (35) demonstrated that infants with esotropia exhibited high levels of activation in the lingual gyrus. Huang et al (19) also reported that the ReHo value of the lingual gyrus was increased in patients with concomitant strabismus. Similarly, the present study identified differences in the ReHo value of the LLG in adult patients with SA in comparison with the controls. This can be explained by visual compensation in patients with SA, while functional changes in the lingual gyrus may also cause visual impairment.
The cuneus is also located at the occipital lobe, which forms part of the visual center, and is involved in the processing of visual information in the retina-optic nerve-lateral geniculate pathway. Research by Schraa-Tam et al (36) demonstrated that the cuneus is involved in eye movement reflex that functions to stabilize the image of the retina; therefore, dysfunction of the cuneus causes eye movement disorders. The precuneus also forms an important part of the default mode network (DMN) of the brain, which is associated with cognition, memory, emotion and interaction regulation (37,38). In a study of anisometropic amblyopia, Liang et al (39) reported decreased amplitude of low-frequency fluctuation values in the bilateral precuneus cortex in adults with anisometropic amblyopia, and the degree of reduction was associated with disease severity, suggesting that patients with bilateral precuneus neurons exhibited weaker activity. In addition, Huang et al (40) used DTI technology to analyze changes in whole brain microstructure in patients with strabismus. They found that the FA value of bilateral precuneus was significantly increased, suggesting enhanced fiber bundle integrity in this brain area. In the present study, the ReHo value of the right precuneus of adult SA patients was observed to be increased, which was similar to the results of Huang et al (40), but contrary to the findings presented by Liang et al (39). The differences observed among these studies may be attributed to variations among samples, leading to compensatory alterations to the precuneus. Simultaneously, lesions of the precuneus may also contribute to the SA occurrence.
The middle occipital gyrus and the lingual gyrus are in the V2 region, and the middle occipital gyrus is part of the dorsal visual stream (DVS) in the visual center (41). The DVS functions to analyze spatial information, such as location, direction, motion and action plan. Chan et al (17) used the voxel-based morphometry (VBM) method to analyze the volume of gray matter in patients with concomitant strabismus, and observed that the volume of gray matter in the strabismus group was decreased in the occipital and parietal lobes relative to the HCs. In addition, Yan et al (42) used DTI and VBM techniques to study the white matter structure in 13 patients with concomitant exotropia, and reported that the DVS was abnormal or impaired in these patients. By analyzing visual cortex changes, Jia et al (43) identified that patients with amblyopia exhibited significantly reduced changes in activation in the V2 visual area. In the current study, it was observed that ReHo values of the RMOG and LMOG in adult patients with SA were increased, which was different from the observations of previous studies. This may be due to differences in the samples included. The increased ReHo values observed in the present study can be attributed to visual compensation. According to evidence from earlier studies, changes in the middle occipital gyrus can be considered as one of the pathogenic factors in patients with SA.
The cingulate gyrus is located between the medial cingulate sulcus and the corpus callosum of the cerebral hemispheres (44), and is an important component of the limbic system and Papez circuits (45), as well as the DMN brain region, including the anterior cingulate gyrus, middle cingulate gyrus and posterior cingulate gyrus. The anterior cingulate gyrus has numerous established functions, including in emotion, cognition, movement, visceral movement, maternal behavior and social interactions. In addition, the association between the cingulate gyrus and epilepsy is currently a hot research topic (46,47). A number of studies have noted that the anterior cingulate gyrus receives afferent neurons from the thalamus (48); therefore, it can be speculated that the cingulate gyrus may be associated with visual function. Zhai et al (49) used fMRI technology to analyze the efficacy of perceptual learning in the treatment of amblyopia, and reported that the primary visual cortex, visual junction cortex and right cingulate gyrus were significantly activated in patients receiving this treatment, suggesting that the cingulate gyrus contributes to the occurrence of amblyopia. In the present study, the results revealed that the ReHo value of the BAC gyrus in adult patients with SA was increased in comparison with that in the controls. The current study findings are similar to those reported by Zhai et al (49), suggesting that treatment of patients promotes compensation and that the cingulate gyrus is important in the occurrence of SA. Functional recovery of the cingulate gyrus can serve a compensatory role in treatment, which provides a further basis for the treatment of SA.
The frontal lobe is the most complex part of the brain. It mainly consists of four gyri, including the precentral, superior frontal, middle frontal and inferior frontal gyri. Frontal lobe lesions can cause several disorders, such as voluntary movement, speech, cranial nerve, autonomic nervous function and mental activity disorders. The precentral gyrus is also referred to as the ‘cortical motor area’, which mainly accepts proprioception from the skin, joints, tendons and skeletal muscles, and controls the voluntary movement of the body. However, the frontal lobe is also important to the integrity of visual function. Xiao et al (50) used VBM analysis to investigate changes in the visual cortex of amblyopic children, and identified that the gray matter density of the middle frontal gyrus was decreased. In a study of patients with strabismus, Ouyang et al (51) observed that the volumes of gray matter in the right posterior cingulate gyrus, precentral gyrus and left cuneus were decreased, while the white matter volume of the right precuneus and right anterior motor areas of the patients were significantly decreased. Furthermore, Huang et al (40) used DTI technology to analyze alterations in the whole brain microstructure in patients with strabismus, and reported that the mean diffusion coefficient in the left middle frontal gyrus was significantly decreased. In the current study, the data revealed that the ReHo values were lower in the inferior frontal gyrus of SA patients as compared with those in the HC group, which is consistent with the observations of previous studies, suggesting that the inferior frontal gyrus is important in the occurrence of SA. However, the current study results indicated that the ReHo value of the BPG was higher in SA patients in comparison with that in HCs, which is contrary to the findings of previous studies. This is most likely a result of differences in the study populations. The current study results can be explained by a compensatory mechanism, while other studies have concluded that their findings can be explained by etiology. Nevertheless, all findings reveal that the frontal lobe serves a vital role in visual processing and associated eye movements.
ROC curve analysis in the present study demonstrated the accuracy of the ReHo method for the diagnosis of patients. Accuracy is perceived as excellent when AUC values are 0.7–0.9, values between 0.5 and 0.7 are considered to indicate moderate accuracy, while values <0.5 indicate low discrimination between SA patients and HCs. The ROC curve values generated revealed that the AUC for each brain region was >0.7, indicating that the ReHo values of these changed brain regions exhibited a diagnostic accuracy for the identification of SA. Taken together, it is predicted that the ReHo method may be used for sensitive detection of SA in the future.
The present study also has certain limitations. The sample size was relatively small, and differences among samples may have impacted the results. Furthermore, for certain individuals, the length of the scanning time and small body movements may have affected the scan results.
In conclusion, the data of the present study demonstrated that patients with SA exhibit abnormal spontaneous activities in specific regions of the brain. These abnormal spontaneous activities may be associated with the occurrence of SA and are potentially associated with visual compensation. These findings provide a basis for the study of the pathogenesis of SA and indicate a potential direction for the development of treatment.