Acute acquired concomitant esotropia (AACE) is a subtype of esotropia characterized by diplopia and a sudden onset of esotropia (Clark et al., 1989). AACE predominantly affects adults or older adolescents, presenting with normal eye movements and equal deviation angles in all direction. Recently, the incidence of AACE has increased, especially during and after the COVID-19 lockdown (Vagge et al., 2020; Neena et al., 2022; Mohan et al., 2021).

The pathogenesis of AACE is multifaceted and not fully understood, with hypotheses suggesting links to accommodation and convergence-divergence dysfunctions (Shanker and Nigam, 2015). Myopic overcorrection and presbyopia-related accommodation decline are implicated, with the latter showing higher AC/A ratios (Fresina et al., 2016; Tong et al., 2020). AACE’s occurrence in aphakic eyes indicates that non-accommodative factors (Ruatta and Schiavi, 2020), such as extraocular muscle abnormalities, may play a role. Our research reveals significant changes in the size and volume of dominant eye muscles, possibly as a compensatory response to binocular diplopia, with the LR muscle potentially enlarging to counteract increased convergence (Chen et al., 2024). Additionally, the anterior positioning of the medial rectus muscle in AACE patients may cause over-concentration, disrupting the balance between convergence and divergence and leading to esotropia (Cai et al., 2019).

Conversely, the emergence of AACE may also be linked to complex neural network within the visual system. Advances in functional magnetic resonance imaging (fMRI) enable precise functional localization of the visual cortex, allowing for the assessment of central visual functions in AACE patients without intracranial lesions. Previous studies have identified functional deficits in the visual cortex associated with various types of strabismus (Guo et al., 2022; Yan et al., 2019). These abnormalities in spontaneous brain activity, which can be attributed to visual compensation, can also be considered as one of the causative factors of such disorders. Notably, using the amplitude of low-frequency fluctuation (ALFF) in resting-state fMRI, one study found deficits in the primary visual cortex and dorsal pathways in AACE patients, with alterations in the fusiform gyrus correlating with deviation angles, suggesting a connection between AACE and visual processing centers (Hu et al., 2023).

Synchronization between cerebral hemispheres is crucial for visual experience. Voxel-mirrored homotopic connectivity (VMHC) accurately and efficiently assesses changes in functional connectivity between hemispheres related to a patient’s behavior and cognition by measuring correlations between hemispheric blood oxygen level-dependent time series that reflect the pattern of information exchange and integration between hemispheres (Mancuso et al., 2019). Recent studies have increasingly focused on VMHC, establishing its associations with a variety of diseases and functional states. It has been applied to analyze numerous ocular conditions, including primary open-angle glaucoma (Wang et al., 2018), monocular blindness (Shao et al., 2018), strabismic amblyopia (Peng et al., 2021; Zhang et al., 2021; Liang et al., 2017), high myopia (Cheng et al., 2022), blepharospasm (Wei et al., 2018), unilateral acute open globe injury (Ye et al., 2018), optic neuritis (Song et al., 2023), concomitant exotropia (Zhang et al., 2018), and congenital nystagmus (Wen et al., 2023).

The objective of our study is to utilize VMHC analysis to detect functional brain changes in patients with AACE. We aim to identify whether these alterations in brain functional connection impact visual quality and overall quality of life, thereby offering novel insights into the neural underpinnings of AACE. This approach is pivotal for advancing our understanding of the condition.

This study first utilized the VMHC method to survey functional network brain activity changes in AACE patients. We observed reduced VMHC values in the SFG and ACG in patients with AACE compared to HC, and these reduced values correlated with time of near vision work, angles of deviation at near and distance and BDI scores.

The frontal lobe is located at the front of the cerebral hemispheres and is the most evolved part of the developing brain (Neulinger et al., 2016). Damage to this area can lead to impairments in voluntary movement, language expression and memory. Among these, supplementary eye field (SEF), located in the medial frontal cortex, is involved in the control of random eye movements and are particularly associated with eye tracking (Purcell et al., 2012). Activity in the frontal eye fields (FEF) was also observed during visual search (Lowe et al., 2022). The superior frontal gyrus (SFG) is located superiorly in the prefrontal cortex and is thought to consist of several cytoarchitecturally distinct subregions, including Brodmann’s zones 6, 8, 9, and 32 (Petrides and Pandya, 1999; Petrides and Pandya, 2002). Functional impairment was found in the above areas in all types of strabismus (Huang et al., 2016a; Tan et al., 2016; Tan et al., 2018; Huang et al., 2018).

One study found significantly higher levels of VMHC in some brain regions in the middle frontal lobe of patients with concomitant exotropia, possibly reflecting abnormal activity in the kinetic eye area due to a compensatory mechanism that may not be the cause of strabismus, but rather a consequence of strabismus (Yan et al., 2019). Besides, another study found that patients with strabismus and amblyopia had significantly lower VMHC values in the bilateral frontal super orbits and bilateral frontal gyrus, which is similar to our findings (Peng et al., 2021). A previous study from our team revealed fusional vergence dysfunction is present in adult AACE cases (Zhao et al., 2022). All of the patients in this study had varying degrees of diplopia symptoms that did not resolve on their own after rest. They had significant abnormalities in fusion function. Since it has been found that the bilateral frontal gyrus regulates normal fusion function in human eyes (Xubo et al., 2014), we hypothesized that a decrease in frontal VMHC, resulting in fusion dysfunction, contributes to the development of AACE. This may be the difference between AACE and other types of strabismus, especially concomitant exotropia.

The cingulate gyrus, situated within the limbic system, has been linked to the formation of mood, the experience of depression and the perception of pain (Ebert and Ebmeier, 1996). The limbic system is intimately associated with memory and emotion. The anterior cingulate gyrus plays a role in a number of established functions, including emotion, cognition, locomotion, visceral movement, maternal behavior and social interaction (Apps et al., 2016; Bliss et al., 2016; Zou et al., 2021). A study utilizing the DTI technique to investigate brain-wide microstructural alterations in individuals with common strabismus revealed that patients with this condition exhibited markedly elevated mean diffusivity values in the left anterior cingulate gyrus, indicating microstructural modifications in this region (Huang et al., 2016a). Patients with common strabismus were also observed to have higher regional homogeneity (ReHo) values were observed in the bilateral cingulate gyrus in the study by Huang et al. (2016b). Additionally, some researchers have discovered that the diffusion coefficient (DC) values in the anterior cingulate cortex (ACC) were markedly elevated in adult patients with common external strabismus in comparison to controls, indicating that it may be a contributing factor to anterior cingulate gyrus dysfunction (Tan et al., 2018). Meanwhile, some researchers have found that optic neuritis patients had reduced VMHC values in the left middle cingulate gyrus, suggesting that functional abnormalities in the cingulate gyrus may lead to cognitive decline or loss in patients (Song et al., 2023).

Numerous studies have found increased signal levels of various indicators in the cingulate gyrus in patients with exotropia, abnormal activation of the cingulate gyrus to compensate for the impairment of fusional function due to exotropia. One study found higher bilateral cingulate VMHC values in strabismic amblyopia than in the HC group, due to a compensatory increase in visual input deficits caused by strabismic amblyopia (Zhang et al., 2021). However, a study of functional brain connectivity in patients with exotropia found no changes in the cingulate gyrus. In the present study, the VMHC values of the cingulate gyrus in AACE patients were significantly lower than those of the normal group, suggesting that our dysfunctional functional connectivity between the bilateral cingulate gyrus may be an important factor affecting the control of the direction and eye position of strabismus.

In our study, the VMHC signal values in the anterior cingulate gyrus were significantly lower in the AACE group compared to the control group and exhibited a negative correlation with BDI depression scores. Prior research has indicated a correlation between olfactory bulb volume and depression (Sabiniewicz et al., 2022). Concurrently, numerous studies have indicated that individuals with strabismus frequently exhibit psychological irregularities, including depressive symptoms (Lin et al., 2014; Lee et al., 2022). Consequently, we postulate that strabismus may be linked to anterior cingulate gyrus dysfunction, which could elucidate the prevalence of depressive symptoms in patients with strabismus. This underscores the necessity for greater emphasis on the psychological well-being and quality of life of patients, in addition to conventional diagnosis and treatment in the clinic.

It is noteworthy that the VMHC values of the left caudate in the AACE group exhibited a positive correlation with the duration of near vision work, the angles of deviation at near and at distance. Additionally, the VMHC values of the bilateral olfactory cortex demonstrated a positive correlation with the duration of near vision work. Excessive near vision work may be a significant contributing factor to the development of AACE (Topcu Yilmaz et al., 2020). It is possible that excessive tension in the medial rectus muscle, caused by near vision work, may result in esotropia if the fusion force is insufficient to overcome this tension. Alternatively, prolonged use of smartphones may stimulate the ciliary muscle, leading to convergence spasms and the development of AACE (Kaur et al., 2019).

Although the present study revealed functional connectivity differences between AACE patients and healthy controls in the resting state by means of fMRI, it remains unclear what association exists between this and the visual impairment associated with strabismus. A more in-depth longitudinal study of brain changes after strabismus correction will be conducted in future investigations.

The VMHC values of the frontal and marginal lobes of AACE patients were changed, suggesting that dysfunction of the medial frontal gyrus and anterior cingulate gyrus may lead to fusion dysfunction, thereby contributing to the development of AACE. This impairment this is related to poor eye habits and the severity of strabismus.