Strabismus and amblyopia are two common visual developmental disorders that can occur in infancy and persist into adulthood if treatment is not successful (Tarczy-Hornoch et al., 2013; Chen et al., 2014). Strabismus is an optical manifestation disorder associated with the coordination of the external eye muscles. Different conditions of extraocular muscle incongruity may result in different types of diplopic images (Figure 1). Strabismus is generally considered to be associated with maldevelopment of the visual pathways in the brain that mediate eye movement (Min et al., 2018), and inimically affects stereopsis, binocularity, and depth perception (Gunton et al., 2015). Hyperopia, muscle dysfunction, trauma, brain disease, and infection are all important causes of strabismus, and risk factors include premature birth and cerebral palsy. Diagnosis can be made by the observation of light reflected from the anterior eye offset from the center of the pupil. Treatments, including refractive correction and eye alignment surgery, address the impact on vision and are good choices for patients. The incidence rate of adult-onset strabismus is reportedly 54.2 per 100,000 individuals (Mohney et al., 2012), and in adults strabismus is often associated with undiagnosed amblyopia in early childhood and symptoms associated with aging (Chan et al., 2004).

Amblyopia, also known as lazy eye, is a visual disorder with causes which affect cooperation between the eyes and brain (National Eye Institute, 2016). Because the condition is associated with changes in the brain, visual impairment such as ametropia cannot be fully treated after surgery (Schwartz et al., 2002; Levi, 2013). Early detection can improve the rate of successful treatment (Jefferis et al., 2015) and glasses may be an important part of treatment for children (Jefferis et al., 2015; Maconachie and Gottlob, 2015). Many patients with amblyopia, especially mild cases, are unaware of their condition because one eye is affected and the vision of the fellow eye is normal. However, because two eyes are needed for stereo vision (which is usually lacking for the patients), patients with amblyopia may have relatively poor vision, and relatively low sensitivity to contrast and movement in the affected eye (Fazzi and Bianchi, 2016). Amblyopia features reduced stereopsis, visual acuity (VA), visual sensitivity, and impaired spatial vision and binocular summation (Webber and Wood, 2005).

Diplopia refers to the abnormal phenomenon of one object being perceived as two identical but separated images. There are many causes of diplopia, some of which reflect anomalies of the brain (Cerulli Irelli et al., 2021). Diplopia may occur when one or more of the six muscles that control eye movement become inflamed, injured, or neurologically impaired, and the muscles in both eyes do not accurately coordinate (Goseki et al., 2021). Because strabismus causing diplopia and confusion (perceived superposition of two different images) can make the patient feel unwell, the image from the macula of the strabismic eye may be suppressed for a sustained period, and the amblyopia that accompanies this situation is known as strabismic amblyopia (Peña Urbina et al., 2021).

Magnetic resonance imaging (MRI) has been widely used in various pretreatment imaging diagnoses recently. As a non-invasive neuroimaging method, it is mainly used to evaluate the functional and structural changes of the human brain (Brown et al., 2016). Functional Magnetic Resonance Imaging (fMRI) is a technology with precise spatial resolution and is used for the analysis of brain function (Goodyear and Menon, 2001). This imaging method helps to reveal the mechanism underpinning eye diseases (Conner et al., 2007; Wang et al., 2012; Liang et al., 2017). Repetitive transcranial magnetic stimulation (rTMS) mainly achieve excitation or inhibition of local cerebral cortical function by changing the stimulation frequency, with the aim of effective treatment of disease. Thompson’s present data show that rTMS of the visual cortex can temporarily improve contrast sensitivity in the adult amblyopic visual cortex (Thompson et al., 2008). Spiegel have shown that a-tDCS to the visual cortex would improve contrast sensitivity in adult patients with amblyopia by enhancing the cortical response to inputs from the amblyopic eye (Spiegel et al., 2013). Rehn found that rTMS could improve the symptoms of patients with obsessive-compulsive disorder (Rehn et al., 2018). Chou demonstrated the effect of rTMS on Alzheimer’s disease (Chou et al., 2020). TMS can be used to stimulate the cerebral cortex, such as the visual cortex and somatosensory cortex, to induce local excitatory or inhibitory effects and affect the function of the system. In addition, TMS can also be used in learning, memory, language, and emotional research (Brunoni et al., 2017; Sebastianelli et al., 2017; McClintock et al., 2018; Arns et al., 2019; Yang et al., 2019; Chou et al., 2020; Malkani and Zee, 2020).

Studies suggested the neural networks modulating aspects of emotional behavior to be implicated in the pathophysiology of mood disorders. These networks involve the prefrontal cortex (Rigucci et al., 2010). AhmedA Abdelrahman’s findings revealed that HF-rTMS over L-DLPCF for 10 days reduced cigarette consumption, craving, dependence, and improved associated symptoms of anxiety and depression (Abdelrahman et al., 2021). The abnormal activity of dorsolateral prefrontal cortex (DLPFC) is related to the occurrence of anxiety and depression.

Amplitude of low-frequency fluctuation (ALFF) is a commonly used clinical method which reflects changes in spontaneous brain activity and has been applied in the investigation of several ophthalmological diseases. Amplitude of low-frequency fluctuation is used to measure spontaneous fluctuations in blood oxygen level-dependent fMRI-signal intensity for nervous activity, reflecting the intensity of regional spontaneous brain activity at rest. The increase of ALFF indicated increased blood oxygen dependence level and increased activity in this brain region, on the contrary, activity of the brain area decreased. We used the ALFF sequence to compare the activity of different brain regions in POT and PRT. Our study is the first to determine whether there are ALFF differences in brain regions before and after transcranial magnetic stimulation within SA patients after surgery, and to identify those regions. Functional MRI is one of the most widely used functional brain imaging techniques. ALFF has been applied in ophthalmologic and neurogenic diseases, and in this study (Table 3) we demonstrated that the intrinsic patterns of activity in different brain regions of POT were changed after rTMS.

We collected information on the brain regions where ALFF changed after rTMS treatment, including areas unrelated to visual processing (Table 4). There were significant differences in ALFF values in several brain areas between POT and PRT stages. Values were decreased in the FR and FIL regions, but increased in the AR, PIL, and CMR regions. These results demonstrate bidirectional changes in ALFF values between the POT and PRT stages. The ROC curve shows the clinical diagnostic significance of both the left parietal inferior, right cingulum middle, right angular, right fusiform, and left frontal inferior orb regions. The AUCs of all these brain areas are high, indicating that ALFF may be used in clinical diagnosis of other brain diseases in SA patients after surgery.

Of these areas, the fusiform gyrus is located at the middle inferior part of the visual association cortex. The fusiform gyrus is not only used for face recognition, it is also responsible for the recognition of subcategories of objects (SparkNotes, 2007). In the fusiform face area, most studies have shown that the right hemisphere is more important for face recognition than the left. The face recognition area is located in the right fusiform gyrus, but it is involved in the recognition of a variety of complex stimuli and is a key brain region for acquiring the skills to distinguish similar objects (Tordesillas-Gutierrez et al., 2018). In patients with strabismic amblyopia, rTMS treatment significantly improved the condition of postoperative visual recovery, which may be related to the changes in the activity of the fusiform gyrus.

The angular gyrus, above Wernicke’s area, at the parietal-occipital junction, is an important association area in the back of the brain. If the angular gyrus is removed, the visual and auditory perception of words will lose connection, causing dyslexia (a reading and writing disorder) and audio-visual aphasia. In the latter, the sufferer loses the connection between what is seen and what is heard and is unable to understand the meaning of the words (Tordesillas-Gutierrez et al., 2018; Palejwala et al., 2020).

The middle part of the right cingulate is the gyrus between the cingulate sulcus of the medial part of the brain hemisphere and the sulcus of the corpus callosum, belonging to the cortical part of the limbic system (Creel, 2012). This brain region transmits nerve impulses to the anterior cingulate gyrus and striatum and receives output from the amygdala, orbitofrontal gyrus, and medial frontal gyrus (Li et al., 2017). It has long been understood as an important part of the emotional circuit, involved in processes such as emotion and self-evaluation, and is closely associated with depressive symptoms. Audiovisual hallucinations, sensory illusions, and emotional symptoms caused by diplopia onset usually occur after surgery and accompanied by a slow recovery period of 12 months. After rTMS treatment, the condition will be greatly reduced (Sasaki et al., 2016; Craciun et al., 2018). Primary epileptic seizures in the cingulate gyrus are mainly complex partial seizures with characteristic automaticity, autonomic nervous dysfunction, affective changes, and urinary incontinence. We speculate that rTMS can effectively control epilepsy in part of the cingulate gyrus brain region. SA may cause abnormalities in cerebral blood flow and metabolism in the brain, resulting in hypofunction, which in turn leads to depression in patients (Craciun et al., 2018).

The lower and upper parietal gyrus contain visual segmentation groups, which can be distinguished according to structural or connection standards, topographic organization, or other functional standards. The conventional view that this brain area is a type of visual sensory area and contains numerous optic motor neurons and parietal visual function focuses on its role in spatial perception, so the lesions in this area will cause abnormalities in the relevant visual field. Therefore, our research showing a decreased ALFF of the left parietal inferior region may manifest as a defect in the visual field, and this pathological change will seriously affect the daily life of the patient (Hilbert et al., 2019).

Previous studies have demonstrated a link between the frontal cortex and emotion. The occurrence and development of the clinical symptoms of schizophrenia, major depression, and anxiety depend on the frontal cortex system. Evidence suggests that affective function, experience, expression, and load information processing have different neural representations in the frontal cortex (Wang and Luo, 2004; Makris et al., 2013; Bocca et al., 2015). Therefore, it is reasonable to infer that the effect of rTMS on the activity of the frontal cortex may be useful for the treatment of patients with schizophrenia, major depression, and anxiety disorders.

We believe that ALFF has clinical significance, it can detect abnormal changes in the brain activity of patients through fMRI in advance of this factor, and provide timely interventions to effectively reduce the sequelae and complications of SA such as diplopia. It is worth noting that the limitations of the current study, including differences in measurement standards and other factors, require further unification of measurement scales in in-depth studies to verify the findings. The clinical features we used in this study were not rigorous. For example, different SA patients have different degrees of visual acuity recovery after surgery, some of which were not significantly different from the preoperative stage. Therefore, attention should be paid to these problems in future studies and the sample size should be expanded to accurately evaluate the changes of brain ALFF indexes in SA patients after surgery. In addition, the control group of patients treated with rTMS after SA surgery was not included in this study, changes in ALFF values generated by longitudinal brain recombination after SA surgery were not measured. As a result, in the results obtained in this study, the difference in ALFF value is not solely affected by rTMS treatment, and part of the difference may be related to longitudinal brain reorganization, the specific differences need to be further studied. Despite these deficiencies, this study revealed specific changes and effects of rTMS on ALFF in the brain regions of SA patients.

In summary, we confirmed that within SA patients ALFF changes significantly in some brain regions after rTMS. Changes in ALFF reflect increases or decreases in activity within brain regions and may partly reflect the degree of improvement in visual dysfunction caused by postoperative complications in patients with SA. ALFF may be used for clinical diagnosis and evaluation of postoperative rehabilitation in patients with SA.

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

All research methods were approved by the Committee of the Medical Ethics of the First Affiliated Hospital of Nanchang University and were in accordance with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. All subjects were explained the purpose, method, potential risks and signed an informed consent form. Written informed consent to participate in this study was provided by the participants’ legal guardian/next of kin. Written informed consent was obtained from the individual(s), and minor(s)’ legal guardian/next of kin, for the publication of any potentially identifiable images or data included in this article.

Y-NW and Y-CP analyzed the data and drafted the manuscript. H-YS, Q-MG, and Y-CP assisted with data interpretation and figure composing. L-JZ, R-BL, and Q-YL collected the data. YS conceived, designed, and directed the study and finally revised and approved the manuscript.

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.

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.