Introduction

Intermittent exotropia（IXT）is one of the most common eye movement disorders in children and adolescents. Its main symptom is the involuntary outward movement of the eyes. Because the exact pathophysiology of IXT is not fully understood yet, and the outcome of common-used extraocular muscle surgery and no-surgery therapies are not satisfying[2], there’s still no consensus about how to treat those patients. Some recent studies have revealed several brain cortical structure changes in IXT patients. [3] [4] However, these studies lack screening for different subtypes of IXT. Therefore, this study enrolled only subjects with basic type of IXT for a more targeted investigation. SBM (Surface-based morphometry) is used to quantify and compare cerebral cortex features between IXT patients and HCs. Based on our findings, some new neuroimaging evidence for the etiology of basic-type IXT in children and adolescents were found and a new hypothesis regarding its pathogenesis is proposed.

Materials and Methods

31 pediatric and adolescent patients diagnosed with basic type IXT (10.94 ± 1.69 years old), along with 37 age-matched (11.14 ± 2.06 years old) healthy controls (HCs) were enrolled.
3D T1WI sequence (MPRAGE) was scanned for all subjects with a 3.0 T MRI scanner (Siemens Healthineers, Erlangen, Germany), with below-listed parameters: TR = 2000ms, TE = 2.25 ms, TI= 900ms, matrix = 256 × 256, FOV = 256mm×256mm, 192 slices, voxel size = 1 mm× 1 mm× 1 mm.
FreeSurfer 6.0 software was employed for post-processing of the T1WI images to generate SBM cortical features including cortical volume, cortical thickness, surface area and curvature.
The obtained cortical features were compared between IXT and HC groups with a vertex-level P value set at <0.01, and cluster-level threshold P<0.05.

Results

Compared to HCs, IXT patients demonstrated significantly decreased cortical thickness on a cluster located in the right rostral middle frontal cortex (Table 1 and Figure 1) and increased cortical curvature on a cluster located in left precuneus cortex (Table 1 and Figure 2). No significant differences were found in surface area and cortical volume between the two groups.

Discussion and Conclusion

The cluster that shows a decrease in cortical thickness is located in the rostral middle frontal gyrus, and the functions that have been found to be associated with vision and eye movements at this location are mainly eye movement control and visual search. [5] Another cluster that showed changes in cortical curvature is in the posterior part of the precuneus, and according to previous findings, brain function of this region is mainly about visuospatial imagery and visuospatial associative memory. [6] [7] And based on our findings, there’s a more significant statistically difference in the cortical thickness changes in the rostral middle frontal gyrus.
Studies have demonstrated that surgery early in the course of this disease results in more satisfactory surgical outcomes, which may be related to the fact that binocular visual functions are not yet significantly involved early in the course of the disease and that younger patients have greater neuroplasticity and resilience, so that once ocular deviation is surgically corrected, the binocular visual function can be somehow restored or even improved after proper training. [8, 9] It has also been demonstrated that surgical treatment alone leads to a higher recurrence rate, while the efficacy of visual function training alone is not convincing either, but combined visual function training after surgery can lead to a more satisfactory outcome. [2] [10] This also implies that the clinical symptoms of IXT are not only affected by abnormal ocular motor function but are also related to the impaired function of the higher visual cortex.
Accordingly, we proposed a new hypothesis for the pathogenesis of this disease: firstly, the abnormality of rostral middle frontal gyrus leads to ocular deviation, which results in the inability of the incoming visual signals to be processed properly in the primary visual cortex, and then further involves the higher visual centers and causes binocular visual function loss. This hypothesis is not only consistent with the current consensus on the function of the two brain regions, but also explains the differences in efficacy of different treatment regimens in previous studies, which may further contribute to provide a new rationale for treatment design for those patients.

Acknowledgements

Ren-zhi Wang, Zhaohui Liu, and Xiang Wan are the corresponding authors of this article.

References

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