Interocular suppression occurs during the dominance competition between two eyes and potentially contributes to the pathological processes of visual function impairment experienced by patients with amblyopia or strabismus (Maehara et al., 2011; Dorr et al., 2019; Webber et al., 2020). For strabismus, visual suppression has been proposed as the most important indicator for determining the intervention strategies in clinical practice (Kim et al., 2019; Yoo et al., 2019). However, the assessment of suppression in patients with intermittent exotropia (IXT) could be challenging because IXT patients sometimes are able to maintain ocular alignment and still have a certain degree of binocular visual function (Wakayama et al., 2013).

IXT is the most common type of divergent strabismus, occurring in more than half of patients with exotropia (Mohney and Huffaker, 2003; Bergholz and Salchow, 2015), and it has been well recognized as variable and unstable (Hatt et al., 2008; Bergholz and Salchow, 2015; Economides et al., 2016). These intrinsic characteristics of IXT make it difficult for eye care professionals to determine the ideal treatment strategy and intervention timing for patients. It is well recognized that surgical intervention decisions should be made more by the reference of a patient’s suppression depth rather than divergent degree alone, especially for children whose visual function is still developing. Normally, longer duration of deviation results in stronger visual suppression in patients with strabismus (Adams et al., 2017; Cadet et al., 2018). However, the situation is much more complicated in IXT patients, as their visual suppression condition is unstable and varies with eye position (Serrano-Pedraza et al., 2011; Wakayama et al., 2013). Patients with IXT can switch the fixating eye spontaneously according to the object position (Adams et al., 2017; Ramachandran and Das, 2020). Thus, suppression can change between eyes depending on fixation. Moreover, the deviated eyes are believed to be suppressed in the clinical practice. However, accumulating evidence shows that the foveal function of the deviated eye is not completely suppressed and still has perceptual functions (Economides et al., 2014, 2017; Agaoglu et al., 2015). Yet, visually dissimilar targets for the two eyes were used in these studies, which might cause fixation switch and result in incorrect measurement of suppression. Thus, an accurate objective quantification of visual suppression in patients with IXT is warranted.

Clinically, the most commonly used assessments for visual suppression are Bagolini glasses and Worth 4-dot tests. Though these tests are easy to operate, they are in fact subjective qualitative assessments to evaluate visual suppression from the foveal region of the fixating eye to the non-foveal region of the deviated eye in IXT patients when they exhibit exodeviation (Baker et al., 2008; Wen et al., 2018), thus the foveal-foveal suppression remains unknown. Meanwhile, electrophysiological (Brown et al., 1999; Zheng et al., 2019) and neuroimage (Lygo et al., 2021) methods as well as several established psychophysical paradigms, including the global motion coherence threshold, orientation coherence, and interocular phase combination (Narasimhan et al., 2012; Ding et al., 2013; Zhou et al., 2013; Wang et al., 2019; Zheng et al., 2019; Gong et al., 2020; Lygo et al., 2021), have been devised to quantify suppression. These subjective assessments require attention and certain responses from patients during evaluation, making them more difficult for young children. Moreover, in patients with strabismus, fixation switch would frequently occur because of the dichoptic stimulation (Barboni et al., 2020), and ocular position cannot be monitored in real time during these tests, thereby affecting the reliability of the results. Currently, there is no recognized objective quantification method for foveal-foveal visual suppression in IXT.

Optokinetic nystagmus (OKN) is an involuntary rhythmic ocular reaction elicited by moving patterns across the visual field (Lewis et al., 2000; Valmaggia et al., 2003). This visual field-motion response minimizes retinal slip and stabilizes retinal images, which can be quantified objectively and proposed as a good predictor for visual function. For example, it has been employed by eye care professionals to evaluate visual acuity in infants or applied for contrast function measurements (Hyon et al., 2010; Agaoglu et al., 2015; Wen et al., 2018; Doustkouhi et al., 2020). Also, during grating stimulations, subjects with interocular visual suppression exhibit asymmetric OKN movement, as the suppressed eye has difficulty in tracking moving gratings (Knapp et al., 2013; Agaoglu et al., 2015). Schor and Levi (1980) indicated that OKN motion was significantly decreased in the amblyopic eyes compared with the normal eyes, and the degree of decline was particularly related to the depth of visual suppression. Moreover, Wen et al. (2018) suggested that dichoptic OKN assessment could provide objective and reliable quantification of interocular suppression in patients with amblyopia. In OKN movement, there is a slow phase called pursuit in which the ocular moves toward the same direction as the stimulus, and a fast phase called saccade in which the ocular moves to the opposite direction (Knapp et al., 2013). During interocular rivalry, the OKN direction in the slow phase indicates the perceived direction of dominant motion, which is biased toward the stimulus with higher contrast (Knapp et al., 2013). Hence, by analyzing the OKN pattern, the dominance relationship between two eyes and the depth of interocular visual suppression could be calculated.

With the advent of an eye tracker using a desktop eye movement recorder, the dichoptic OKN motion can be measured and quantified objectively and easily and, more importantly, not restricted by the patient’s eye position. On this basis, in the present study, we sought to develop an objective quantification method for visual suppression in IXT subjects during the state of orthotropia and exodeviation, by assessing OKN behavior with an eye tracker. These observations might provide a new way to assess visual suppression and offer clinical guidance for patients with IXT.

Visual suppression has been proposed as an important anti-diplopia mechanism in patients with IXT (Serrano-Pedraza et al., 2011; Adams et al., 2017). Whether for clinical diagnosis, intervention strategy guidance, or postoperative visual function evaluation, the measurement of visual suppression is of great clinical importance. It helps to determine the surgical intervention timing, assess postoperative visual function re-establishment, etc. However, there is no clinically accepted objective quantitative assessment of visual suppression, especially in patients with strabismus. In the present study, our data suggest that, with the assistance of eye trackers, the dOKN test can objectively quantify the changes in intraocular suppression not only in healthy controls but also in IXT patients under various viewing conditions, which effectively complement the conventional suppression tests and provide intuitive evaluation to ophthalmologists and optometrists.

In healthy controls with ND filters, the visual suppression measured by the dOKN test showed a good concordance with those of the phase and the motion tests. Also, the variation trend of interocular suppression in healthy subjects induced by different ND filters could be reflected by the dOKN test accurately. Interestingly, we noticed that the dOKN test measured the smallest ECR value, thus showing the deepest visual suppression among the three tests. Several reasons may account for this observation. First, there were different cortical areas responsible for these three tests. The phase test was thought to reflect the function of the primary visual cortex V1, while the motion and the OKN tests (Lewis et al., 2000) might indicate the function of the middle temporal V5 region (Hess et al., 2014). Second, the inspection processes are quite different. For example, there is no time limit for the phase test, thus, subjects can allocate attention continuously and choose to proceed by themselves, while the dOKN and motion tests require subjects to make judgments within a short time. Third, the difference in inspection principles may also lead to different detection accuracies. The suppression mechanisms might differ between dynamic and static images, for instance. In addition, we could not rule out the possibility that different methodologies could have confounded the interpretation of our results.

As described above, for IXT patients with aligned eye position, dOKN, phase, and motion tests could complement one another. However, for IXT patients with large angle of ocular deviation, neither phase nor motion test is easy to perform, as the ocular deviation angle needs to be compensated, and the bi-foveal presentation of stimuli cannot be guaranteed because of the lack of continuous eye position monitoring. Besides, both the phase and the motion tests require attention and response from subjects, making these psychophysical tests difficult to carry out in young children. In contrast, the dOKN test is available and relatively easy to perform, regardless of the viewing state of subjects. More importantly, this paradigm is designed based on an involuntary ocular motion that requires a minimal response from subjects, making it more applicable during clinical practice. These observations are consistent with a previous study (Wen et al., 2018).

In patients with strabismus, interocular suppression is elicited to avoid diplopia (de Graaf et al., 2017). Consequently, the retina region that corresponds to the overlapping areas is suppressed. Though the foveal region in the deviated eye was once believed to be suppressed (Pratt-Johnson and Tillson, 1984), recent studies have revealed a different scenario. Economides et al. (2012) found that regardless of which eye is fixed, the foveal and temporal visual field in the deviated eye could still perceive visual signals. Agaoglu et al. (2015) also showed that in macaques with exotropia, OKN could be induced even when the stimulus pattern was presented only in the deviation visual field. Consistently, in the present study, typical OKN motion was induced in both eyes of IXT subjects regardless of the current eye position, as long as the visual stimulation was strong enough. When the moving visual stimuli were strong for the deviated eye and weak for the dominant eye, the deviated eye of IXT subjects could functionally respond to it, further indicating that the foveal region of the deviated eye is not totally suppressed. Generally, the results of the dOKN test follows the same general properties as other suppression measurement tests, but we further confirm that visual suppression is not binary. Not only that, we also observed much stronger visual suppression in the foveal region of the deviated eye in the IXT subjects during the state of exodeviation, compared with the state of normal alignment. Our results support the clinical knowledge that suppression can change with ocular alignment, and that alignment state needs to be considered when measuring suppression.

Moreover, the results of dOKN are in line with the categorization of binocular function measured by synoptophore, and this correlation was not observed in either the phase or the motion test (Figure 7A), further suggesting the potential clinical significance of the dOKN test. On one hand, this observation is consistent with the variability nature of IXT (Wakayama et al., 2013). On the other hand, the difference of intraocular suppression between the two subgroups was only evident when their deviation was manifested, thus the phase and motion tests might fail to capture this feature. Additionally, the depth of suppression measured with dOKN did not show any correlation with the deviation angle, and neither did the phase nor the motion tests. This evidence indicates that the deviation angle might not be a good indicator of binocular function in patients with IXT. Clinically, it is not rare to see the patients with small deviation degree have poor vision function. These patients need surgical intervention, by which to restore or maintain their visual function (Willshaw and Keenan, 1991). Thus, quantify interocular suppression in IXT patients objectively might help in the clinical decision of optical or surgical intervention for IXT patients in the future. Yet, further investigation is warranted.

This study had several limitations. First, as most adult IXT patients do not wish to receive clinical intervention, most IXT subjects in the present study were teenagers who needed surgical intervention, which might have caused selection bias. Second, the sample size was relatively small. The correlation between deviation angle and the depth of visual suppression was not observed. Third, though the dOKN test is easy to implement, it still needs subjects to focus and trace the grating targets as instructed, which is not suitable for young infants and patients with cognitive dysfunction. Hence, the clinical application of the dOKN test requires further investigation.

In conclusion, our study shows that, with the assistance of an eye tracker, the dOKN test allows the objective and effective quantification of visual suppression for IXT patients, regardless of during the periods of orthotropia or exotropia. This test could not only complement the conventional suppression tests and provide a more comprehensive evaluation for strabismus patients but also provide an approach to explore the disease progression of IXT from another perspective.

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

The studies involving human participants were reviewed and approved by the Ethics Committee of Sun Yat-sen University, Zhongshan Ophthalmic Center. Written informed consent to participate in this study was provided by the participants’ legal guardian/next of kin.

XC, ZC, YL, and DD collected and analyzed the data. XC, DD, and MY interpreted the data. XC, ZC, and MY were the major contributors in writing the manuscript. All authors read and approved the final 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.