Parkinson’s disease (PD) is a neurodegenerative condition characterized by a host of motor and non-motor symptoms affecting about 10 million individuals worldwide. Visual impairments in PD are far more common than appreciated and include blepharospasm, dry eyes, reduced blinking, visual hallucinations, decreased visual acuity, and contrast sensitivity (Repka et al., 1996; Biousse et al., 2004; Almer et al., 2012; Anderson and MacAskill, 2013; Borm et al., 2020). On the oculomotor level, the deficits comprise abnormal rapid gaze shifts (i.e., saccades) with increased saccadic intrusions causing difficulties in reading and scanning the visual surroundings (Lepore, 2006; Almer et al., 2012; Urwyler et al., 2014; Antoniades et al., 2015; Armstrong, 2015; Beylergil et al., 2022). Up to 70% of PD patients experience some form of visual impairment as per the self-reported visual function and non-motor symptom questionnaires (Schindlbeck et al., 2017; Visser et al., 2019; Borm et al., 2020; Smilowska et al., 2020; Hamedani et al., 2021; Naumann et al., 2021). Vergence insufficiency, the disconjugate movement of the eyes in response to a target jump from far to near and vice versa, has been reported in PD (Racette et al., 1999; Biousse et al., 2004; Lepore, 2006; Urwyler et al., 2014; Armstrong, 2015). Ocular misalignment is described as both a consequence of convergence insufficiency (Repka et al., 1996; Kang et al., 2018) as well as a more nuanced subcortical deficit in Parkinson’s disease (Almer et al., 2012; Searle and Rowe, 2016; Naumann et al., 2021).

There are two key sensory drives for inducing vergence while looking at targets at different depths, which are (1) visual blur under monocular viewing that induces accommodative vergence; and (2) retinal disparity under binocular viewing, i.e., differences in the spatial position of the image on two retinas that induces disparity-driven vergence. There are two key motor components of disparity-driven vergence, which are (1) the fusion initiation component, i.e., the open loop or pulse of neural activity facilitating the initial movement responsible for vergence, and (2) the fusion maintenance component driven by visual or internal feedback to align the eyes accurately to maintain a fusion of the binocular image of the target (Semmlow et al., 2019, 2021). A handful of studies have quantified vergence in PD and have reported increased latency with variable effects on convergence velocity and gain (Hanuška et al., 2015; Gupta et al., 2021a,b). None of the studies to date have examined eye alignment and disparity-driven vergence using eye movement recordings in the same cohort. The overarching goal of this study is to examine the relationship between the impairments in fusion-initiating and fusion-maintaining components of vergence and eye misalignment, i.e., strabismus in PD. We hypothesize that the time-based control of eye alignment and increased eye deviation under binocular viewing will be related to the fusion-initiating and fusion-maintaining component deficits of disparity-driven vergence in PD.

We recruited 33 PD patients (age: 69.16 ± 8.2 years) and 10 healthy controls (age: 65.14 ± 6.8 years) with no significant difference in age between the two groups (U = 65, p = 0.36). The goal of our study was to test the hypothesis that the eye misalignment, which causes diplopia, is correlated with the vergence insufficiency seen in PD. The results validating this hypothesis first outline the eye alignment during gaze holding and subsequently summarize binocular coordination in the vergence task. We applied DBSCAN to eye deviation obtained in all controls and PD subjects under MV and BV in the gaze-holding task. For control subjects, the Good Time (%) under BV was 98.3 ± 2.2. We grouped PD subjects into three groups based on the Good Time (%) under BV as follows: PD Group 1: Good Time (%) > 80% (n = 15); PD Group 2: Good Time (%) between 5% and 80% (n = 10); and PD Group 3: Good Time (%) < 5% (n = 8).

Here, we detail the results of the parameters of eye alignment and vergence performance of each group.

Oculomotor abnormalities are frequently seen in PD (Repka et al., 1996; Biousse et al., 2004; Almer et al., 2012; Anderson and MacAskill, 2013; Kang et al., 2018; Borm et al., 2020). The majority of the studies describe saccadic and gaze-holding abnormalities in PD. These include increased frequency and amplitude of saccadic intrusions and square wave jerks (Averbuch-Heller et al., 1999; Leigh and Riley, 2000; Beh et al., 2017; Otero-Millan et al., 2018; Beylergil et al., 2022). Patients with PD have increased saccadic latencies, hypometric, slow and staircase saccades, and more frequent errors during anti-saccade tasks (Zee et al., 1992; Antoniades et al., 2015; Ghasia and Shaikh, 2015; Shaikh and Ghasia, 2017, 2019; Otero-Millan et al., 2018; Beylergil et al., 2022). Eye movement abnormalities affecting binocular alignment (strabismus) and vergence deficits are not uncommon in PD (Hanuška et al., 2015; Kang et al., 2018; Borm et al., 2020; Smilowska et al., 2020; Gupta et al., 2021a). Clinical studies have speculated a causal relationship between vergence insufficiency and strabismus in PD with variable reports of improvement of deficits with medical treatment (Racette et al., 1999; Almer et al., 2012; Kang et al., 2018). Recent studies have increasingly recognized that diplopia is common in PD ranging from 20 to 30% (Schindlbeck et al., 2017; Visser et al., 2019; Smilowska et al., 2020; Santos-García et al., 2021). There is some evidence to support that the presence of diplopia could be associated with cognitive decline and apathy and a worse prognosis (Santos-García et al., 2010; Naumann et al., 2021). It is also increasingly recognized that diplopia in PD is under-reported and under-recognized as the majority of studies use self-reported questionnaires to study the prevalence of diplopia (Ekker et al., 2017). In our study, all PD patients exhibited increased near point of convergence (NPC > 10 cm). Out of 33 patients, only 2 had no measurable strabismus or eye deviation based on the results of the ophthalmological examination; however, both of those PD patients also had eye deviation under monocular viewing conditions along with reduced convergence gain and prolonged latency of gaze shift compared to controls.

Strabismus or eye misalignment interferes with visual-motor coordination of eye movements, resulting in disconjugate and cross-axis eye movements during visually guided saccades, variable and subnormal vergence responses, and fixation instability (Bucci et al., 1997; Kapoula et al., 1997; Fu et al., 2007; Ghasia et al., 2015, 2018). In our study, eye movement recordings were used to quantify time-based control of eye alignment under binocular viewing. Vergence is elicited either by retinal disparity or accommodative blur. When one eye is occluded under monocular viewing, the occluded eye position can decay and become heterophoric. Heterophoria is dependent upon accommodative convergence (SCHROEDER et al., 1996; Lee et al., 2009). We found that more than 50% of PD subjects had intermediate to poor control of eye alignment under binocular viewing and all of them had some increase in exodeviation under monocular viewing (exophoria). At first glance, this might indicate that reduced convergence abilities further hinder monocular control and increase misalignment under monocular viewing, since the accommodation (blur-driven) circuit is cross-coupled with the vergence (retinal disparity-driven) circuit (Gupta et al., 2021a). However, it is equally probable that the inherent retinal disparity cue (binocular viewing) allows for better control of eye alignment which when taken away results in poor monocular control (Horwood and Riddell, 2014; Ooi and He, 2015). This perspective is further supported by our data, in that control subjects, who do not have convergence insufficiency, still exhibit worse eye alignment in monocular viewing as compared to binocular viewing conditions. Only a handful of studies have quantified vergence in PD and have reported increased latency with variable effects on convergence velocity and gain (Hanuška et al., 2015; Gupta et al., 2021a,b). Our vergence results revealed a similar overall trend, and controls had higher vergence gain and lower latencies than PD patients. PD Group 1 showed a greater frequency of vergence-leading strategies and lower saccadic compensation along with higher vergence gain and lower latencies than Groups 2 and 3. PD subjects with good eye alignment under binocular viewing were less likely to exhibit saccadic responses to disparity-driven vergence, whereas those with poor control and worse eye alignment under binocular viewing were more likely to exhibit saccadic responses or had minimal eye movement responses to pure symmetrical step stimuli located at different initial vergence angle. PD Group 3 patients who exhibited pure vergence or combined vergence/saccade responses to disparity-driven vergence exhibited deficits of both fusion-initiating (prolonged latencies, reduced gain, and peak vergence velocities) and fusion-maintaining components (increased eye position variance). We also found that PD subjects can have abnormalities in convergence such as prolonged latencies and reduced gain despite having relatively good eye alignment.

There was no correlation between disease severity and eye alignment abnormalities. The majority of the studies evaluating diplopia in PD are based on results obtained from subjective self-reported questionnaires (Davidsdottir et al., 2005; Borm et al., 2020; Naumann et al., 2021; Santos-García et al., 2021; van der Lijn et al., 2022). PD subjects can have CI without symptoms of diplopia per se; thus, binocular dysfunction is frequently overlooked (Lepore, 2006; Sauerbier and Ray Chaudhuri, 2013; Ekker et al., 2017). A handful of studies have evaluated convergence insufficiency and eye alignment in PD using standard ophthalmic clinical examination. These studies have found no differences between the prevalence of CI and the duration of disease, with patients with early PD also likely to have CI. Furthermore, no systematic differences were observed between disease severity and extent of exodeviation at near or convergence insufficiency (Repka et al., 1996; Biousse et al., 2004; Almer et al., 2012; Visser et al., 2019). We have used eye movement recordings to quantify binocular dysfunction in PD including time-based variability of eye deviation and vergence abnormalities. It allows quantification of the control of eye deviation over time and quantification of latencies, gain of vergence, and ability to maintain eyes on the target at the end of vergence. These parameters cannot be precisely quantified or are limited by subjectivity in measurements when evaluated by standard clinical exam techniques alone. Quantification of these parameters would be critical particularly while evaluating treatment outcomes.

Non-human primate (NHP) studies have provided important insights into the neural correlates of oculomotor abnormalities observed in strabismus. Cells within the rostral superior colliculus have been shown to modulate vergence (Jiang, 1996; Chaturvedi and Van Gisbergen, 1999, 2000; Krauzlis, 2003; Van Horn et al., 2013; Pallus et al., 2018). Electrical micro-stimulation of the superior colliculus in strabismic NHPs has been shown to evoke disconjugate saccades (both in direction and amplitude) (Fleuriet et al., 2016). The cells within the rostral superior colliculus have also been shown to carry signals related to horizontal eye misalignment and fixation preference in strabismic NHPs (Van Horn et al., 2013; Upadhyaya et al., 2017; Upadhyaya and Das, 2019). The midbrain houses neurons critical to controlling the vergence position (Judge and Cumming, 1986; Shook et al., 1990; Buttner-Ennever, 2006) and velocity (May et al., 1992) in the mesencephalic reticular formation, in a region called the supra-oculomotor area (SOA). Neurons within the SOA, encoding vergence responses in normal animals, were found to encode horizontal misalignment in strabismic monkeys (Das, 2011, 2012; Walton et al., 2017). The SOA receives inputs from the deep cerebellar nuclei (fastigial nucleus and interpositus nucleus) which in turn project to the ocular motor neurons innervating slow extraocular muscle fibers (Mays, 1984; Judge and Cumming, 1986; Stanton et al., 1988).

PD is a progressive neurodegenerative disorder caused due to degeneration of dopaminergic projections between the substantia nigra pars compacta (SNc) and the remaining basal ganglia circuitry. There is increasing evidence that the subthalamic nucleus, one of the key regions demonstrating abnormal neural discharge in PD, has visuo-oculomotor neurons (Matsumura et al., 1992). The eye movement cells in monkeys and human PD subjects were primarily in the ventral portion of the subthalamic nucleus (STN) and comprised 20% of the share (Matsumura et al., 1992; Hikosaka et al., 2000; Fawcett et al., 2005, 2007; Sieger et al., 2013). They receive inputs from the prefrontal association cortex (Monakow et al., 1978), the frontal eye field (FEF) (Stanton et al., 1988; Huerta and Kaas, 1990), or the supplementary eye field (SEF) (Huerta and Kaas, 1990). Human and non-human primate physiologic and anatomic studies suggest that STN plays a role in processing information related to eye movements (Matsumura et al., 1992; Hikosaka et al., 2000). The oculomotor neurons in STN in PD patients showed task-specific responses to cued versus self-paced saccades and responded to both passive limb movement and voluntary eye movement and scanning eye movements. There is increasing anatomic and neurophysiologic evidence that STN is connected with brainstem and cerebellar circuitry, particularly areas intricately involved with driving vergence and strabismus. Two possible pathways by which STN could modulate vergence are as follows: The first pathway involves the substantia nigra pars reticulata (SNr)—one of the output stations of the basal ganglia (Hopkins and Niessen, 1976; Jayaraman et al., 1977; Graybiel, 1978). SNr receives inputs from the STN and projects to the SOA via superior colliculus (Shaikh et al., 2004). Thus, impairment in SNr output as seen in PD could affect vergence. The second pathway directly involves the cerebellum (Hill et al., 2013). This pathway involves subthalamo-ponto-cerebellar projections to the deep cerebellar nuclei via precerebellar pontine nuclei (Jenkinson et al., 2009). Further downstream from the subthalamo-ponto-cerebellar projections, the cerebello-pontine fibers connect the deep cerebellar nuclei to the strabismus angle-sensitive neurons in SOA (Das, 2011, 2012; Joshi and Das, 2013).

Debates exist in the literature concerning the neural control of binocular coordination of eye movements (Ramat et al., 2006; Cullen and Van Horn, 2011; King, 2011). Previous studies have demonstrated complex, non-linear interactions between the saccade (conjugate) and vergence (disconjugate) subsystems (Zee et al., 1992; van Leeuwen et al., 1998). Although saccadic and vergence eye movements are thought to be generated by different neural subsystems, the occurrence of a saccade during a vergence movement increases vergence velocity (Enright, 1984). In addition, Collewijin et al. have shown that for saccades that occur during vergence, the peak velocity of the saccades is reduced and the saccadic duration is increased (Collewijn et al., 1995). Studies have shown that the crux of the interaction between saccades and vergence movements is within the omnipause neurons (OPNs). Electrical micro-stimulation of the OPNs has been shown to increase the tonic inhibition of vergence and saccadic velocity neurons slowing both the vergence and saccade components (Zee and Levi, 1989; Ramat et al., 2005). Thus, the release of OPN inhibition during a saccade allows the vergence velocity neurons to fire more vigorously, thereby increasing the vergence velocity. The motor neurons receive both saccadic pulse-step signals and the vergence velocity and vergence position signals. Thus, the occurrence of a horizontal saccade during a vergence movement results in combination of the vergence and saccadic signals producing a net pulse-step signal which is larger in one eye than the other resulting in saccades of unequal size.

Our results demonstrate that the vergence abnormalities in PD subjects systematically correlate with both the angle and control of eye alignment. The target stimuli within our study were pure vergence stimuli with no retinal stimulation to the saccadic system. Yet, saccades were observed, especially within the slower vergence responses. We speculate, based upon the neurophysiology studies, that the responses to symmetrical vergence stimuli (along the midline) will evoke the near response cells (Mays et al., 1991; Zhang et al., 1992), and when the vergence velocity is below a preferred threshold, a saccade may be initiated by (1) the excitation of burst neurons, (2) the inhibition of OPNs, or (3) both the excitation and inhibition of burst neurons and OPNs. Our data support an interaction exists between the vergence and saccade subsystems in PD patients. Thus, convergence abnormalities in PD may be the result of the direct effects of the disease on vergence motor control, coupled with disturbances in the saccadic pathway. Fast vergence eye movements are disrupted in PD which comprise both convergence and divergence abnormalities (Hanuška et al., 2015; Gupta et al., 2021a,b). Future studies evaluating whether divergence insufficiency is associated with esotropia or esophoria in PD will provide a deeper understanding of issues related to vergence abnormalities and eye misalignment in Parkinson’s disease. Future neurophysiology and behavioral studies are needed to further understand the interaction between saccade and vergence eye movements.

Our PD patient cohort was referred by neurologists, based on their PD diagnosis. On further ophthalmological examination and eye movement recordings, it was discovered that all of them had some binocular dysfunction deficit, implying that these are severely under-reported or under-recognized. In addition, similar to previous studies, we found that eye deviation and vergence abnormalities are frequently seen in PD subjects with no systematic correlation with the severity of PD (Wu et al., 2018; Alhassan et al., 2020). Video-oculography was used to quantify eye movements and report deficits that are frequently not recognized with standard clinical assessments, for example, variability of the angle of ocular misalignment under different viewing conditions or precise measures of vergence abnormalities including latencies and saccadic compensation seen in neurodegenerative disorders (Gupta et al., 2021a,b). Thus, our study describes objective measures to evaluate vergence abnormalities and quantify eye deviation in PD parameters that may be of interest to assess treatment response. Further studies on early-stage and pre-symptomatic PD subjects are also needed to determine whether vergence abnormalities and strabismus can serve as a biomarker of the disease.

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

The studies involving humans were approved by Cleveland Clinic Institutional Review Board. The studies were conducted in accordance with the local legislation and institutional requirements. The participants provided their written informed consent to participate in this study.

PG, AS, and FG: study design and manuscript drafting. PG, JM, JJ, AS, and FG: experiment design. PG, SB, AS, CK, and FG: data acquisition. PG and FG: data analysis and statistical analysis. PG, JM, SB, JJ, CK, AS, and FG: manuscript editing. All authors contributed to the article and approved the submitted version.