Altered Large-Scale Resting-State Functional Network Connectivity in Convergence Insufficiency Young Adults Compared With Binocularly Normal Controls.

Purpose: To investigate the underlying resting-state functional connectivity (RSFC) of symptomatic convergence insufficiency (CI) compared with binocularly normal controls (BNC) using functional magnetic resonance imaging (fMRI) under The Convergence Insufficiency Neuro­mechanism Adult Population Study (NCT03593031). Methods: A total of 101 participants were eligible for this study. After removing datasets with motion artifacts, 49 CI and 47 BNC resting-state functional magnetic resonance imaging datasets were analyzed. CI was diagnosed with the following signs: (1) receded near point of convergence of 6 cm or greater, (2) decreased positive fusional vergence of less than 15∆ or failing Sheard's criteria of twice the near phoria, (3) near phoria of at least 4∆ more exophoric compared with the distance phoria, and (4) symptoms using the Convergence Insufficiency Symptom Survey (score of ≥21). RSFC was assessed using a group-level independent components analysis and dual regression. A behavioral correlation analysis using linear regression method was performed between clinical measures and RSFC using the significant difference between the CI and BNC. Results: On average, a decreased RSFC was observed within the frontoparietal network, default mode network and visual network in patients with CI, compared with the participants with BNC (P < 0.05, corrected for multiple comparisons). The default mode network RSFC strength was significantly correlated with the PFV, near point of convergence, and difference between the horizontal phoria at near compared with far (P < 0.05). Conclusions: Results support altered RSFC in patients with CI compared with participants with BNC and suggest that these differences in underlying neurophysiology may in part be in connection with the differences in optometric visual function used to diagnose CI.

Convergence Insufficiency Neuro-Mechanism Adult Population Study: Phoria Adaptation Results.

Purpose: The purpose of this study was to compare changes in phoria adaptation between young adult binocularly normal controls (BNCs) and participants with symptomatic convergence insufficiency (CI), who were randomized to either office-based vergence accommodative therapy (OBVAT) or office-based placebo therapy (OBPT). Methods: In the double-masked randomized clinical trial, 50 BNC and 50 CI participants were randomized to the following therapeutic interventions: OBVAT or OBPT with home reinforcement for 12 one-hour office sessions. A 6∆ base-out and 6∆ base-in phoria adaptation experiment at near (40 cm) was conducted using the flashed Maddox rod technique at baseline and at outcome. Measurements included the rate and the magnitude of phoria adaptation. Results: At baseline, BNC and CI participants had significantly different rates and magnitudes of base-in and base-out phoria adaptation (P < 0.001). When comparing the outcome to baseline measurements, significant main effect differences in longitudinal measurements were observed for the magnitude and the rate of phoria adaptation for both base-out and base-in experiments (P < 0.05). For the magnitude and rate of phoria adaptation, post hoc analyses using paired t-tests revealed that the CI group administered the OBVAT intervention exhibited a significant increase in the magnitude and rate of phoria adaptation compared to baseline for both base-in and base-out phoria adaptation (P < 0.01) but not for those administered OBPT. Conclusions: Phoria adaptation is significantly different at baseline between those with normal binocular vision and symptomatic CI participants. OBVAT significantly improves the rate and magnitude of both base-out and base-in phoria adaptation at near compared to OBPT. Results have clinical implications for new therapeutic interventions.

Underlying neurological mechanisms associated with symptomatic convergence insufficiency.

Convergence insufficiency (CI) is the most common binocular vision problem, associated with blurred/double vision, headaches, and sore eyes that are exacerbated when doing prolonged near work, such as reading. The Convergence Insufficiency Neuro-mechanism Adult Population Study (NCT03593031) investigates the mechanistic neural differences between 50 binocularly normal controls (BNC) and 50 symptomatic CI participants by examining the fast and slow fusional disparity vergence systems. The fast fusional system is preprogrammed and is assessed with convergence peak velocity. The slow fusional system optimizes vergence effort and is assessed by measuring the phoria adaptation magnitude and rate. For the fast fusional system, significant differences are observed between the BNC and CI groups for convergence peak velocity, final position amplitude, and functional imaging activity within the secondary visual cortex, right cuneus, and oculomotor vermis. For the slow fusional system, the phoria adaptation magnitude and rate, and the medial cuneus functional activity, are significantly different between the groups. Significant correlations are observed between vergence peak velocity and right cuneus functional activity (p = 0.002) and the rate of phoria adaptation and medial cuneus functional activity (p = 0.02). These results map the brain-behavior of vergence. Future therapeutic interventions may consider implementing procedures that increase cuneus activity for this debilitating disorder.

Convergence Insufficiency Neuro-mechanism in Adult Population Study Randomized Clinical Trial: Clinical Outcome Results.

SIGNIFICANCE: These data confirm the effectiveness of office-based vergence/accommodative therapy for improving the near point of convergence and positive fusional vergence in young adults with symptomatic convergence insufficiency within a double-masked longitudinal randomized clinical trial. PURPOSE: This study aimed to report changes in clinical signs and symptoms of convergence insufficiency from a randomized clinical trial evaluating the effectiveness of office-based vergence/accommodative therapy for young adults with symptomatic convergence insufficiency. METHODS: In this double-masked, randomized clinical trial, convergence insufficiency patients (n = 50; average age, 21 ± 3 years; range, 18 to 32 years) were randomized to either office-based vergence/accommodative therapy or office-based placebo therapy. Improvements in (1) near point of convergence, (2) positive fusional vergence, and (3) self-reported symptoms (Convergence Insufficiency Symptom Survey [CISS] score) were evaluated after twelve 1-hour sessions of treatment within the office comparing the results from the vergence/accommodative therapy and the placebo therapy groups. RESULTS: The mean near point of convergence improved by 6.0 and 3.1 cm in the vergence/accommodative and placebo therapy groups, respectively (mean difference of -2.9 cm; 95% confidence interval [CI], -4.6 to -1.0 cm; P < .01). The mean positive fusional vergence increased by 17.3 and 7.4Δ in the vergence/accommodative and placebo therapy groups, respectively (mean difference of 9.9Δ; 95% CI, 4.9 to 16.0Δ; P < .001). The mean CISS score improved by 12.4 and 10.1 points in the vergence/accommodative and placebo therapy groups, respectively (mean difference of 2.3 points; 95% CI, -8.3 to +4.6 points; P = .56). CONCLUSIONS: Our results demonstrate that office-based vergence/accommodative therapy is effective for improving the near point of convergence and positive fusional vergence in young adults with symptomatic convergence insufficiency. However, given that both treatment groups had a similar reduction in self-reported symptoms, we recommend that the CISS be revised if it is to be used as an outcome measure in future studies of convergence insufficiency.

Test-retest of a phoria adaptation stimulus-induced functional MRI experiment.

This study was designed to identify the neural substrates activated during a phoria adaptation task using functional magnetic resonance imaging (MRI) in young adults with normal binocular vision and to test the repeatability of the fMRI measurements for this protocol. The phoria adaptation task consisted of a block protocol of 90 seconds of near visual crossed fixation followed by 90 seconds of far visual uncrossed fixation, repeated three times; the data were collected during two different experimental sessions. Results showed that the oculomotor vermis, cuneus, and primary visual cortex had the greatest functional activity within the regions of interest studied when stimulated by the phoria adaptation task. The oculomotor vermis functional activity had an intraclass correlation coefficient (ICC) of 0.3, whereas the bilateral cuneus and primary visual cortex had good ICC results of greater than 0.6. These results suggest that the sustained visual fixation task described within this study reliably activates the neural substrates of phoria adaptation. This protocol establishes a methodology that can be used in future longitudinal studies investigating therapeutic interventions that may modify phoria adaptation.

The Convergence Insufficiency Neuro-mechanism in Adult Population Study (CINAPS) Randomized Clinical Trial: Design, Methods, and Clinical Data.

Purpose: To describe the design and methodology of the Convergence Insufficiency Neuro-mechanism in Adult Population Study (CINAPS), the first randomized clinical trial (RCT) studying young adults with symptomatic convergence insufficiency (CI) using a combination of traditional clinical tests, objective eye movement recordings, and functional brain activities as outcome measures.Methods: In this double-masked RCT, binocularly normal controls (BNC) (N = 50) and CI patients (N = 50) are randomized into office-based vergence/accommodative therapy (OBVAT) or office-based placebo therapy (OBPT). Outcome measures included clinical signs and symptoms, phoria adaptation, forced fixation disparity curves, binocular rivalry, vergence and saccadic objective eye movements, and task-induced functional brain activities. This study is registered on ClinicalTrials.gov NCT03593031.Results: No significant baseline differences are observed between the BNC (p > .4) or CI (p > .3) participants assigned to OBVAT or OBPT for age, near point of convergence (NPC), positive fusional vergence (PFV), phoria at distance and near, amplitude of accommodation, or the Convergence Insufficiency Symptom Survey (CISS). Significant differences are observed between the CI and BNC cohorts at baseline measurements for NPC, PFV, difference in phoria from far to near, amplitude of accommodation, and CISS (p < .001). For the CI patients, 26% had a comorbidity of accommodation insufficiency, and 16% self-reported ADHD.Conclusion: Features of the study design include the following: standardized diagnostic and office-based therapeutic intervention, placebo treatment arm, masked clinical outcome examinations, objective eye movement recordings, functional imaging, phoria adaptation, fixation disparity curves and binocular rivalry measurements.

Test-Retest Reliability of Functional Magnetic Resonance Imaging Activation for a Vergence Eye Movement Task.

Vergence eye movements are the inward and outward rotation of the eyes responsible for binocular coordination. While studies have mapped and investigated the neural substrates of vergence, it is not well understood whether vergence eye movements evoke the blood oxygen level-dependent signal reliably in separate experimental visits. The test-retest reliability of stimulus-induced vergence eye movement tasks during a functional magnetic resonance imaging (fMRI) experiment is important for future randomized clinical trials (RCTs). In this study, we established region of interest (ROI) masks for the vergence neural circuit. Twenty-seven binocularly normal young adults participated in two functional imaging sessions measured on different days on the same 3T Siemens scanner. The fMRI experiments used a block design of sustained visual fixation and rest blocks interleaved between task blocks that stimulated eight or four vergence eye movements. The test-retest reliability of task-activation was assessed using the intraclass correlation coefficient (ICC), and that of spatial extent was assessed using the Dice coefficient. Functional activation during the vergence eye movement task of eight movements compared to rest was repeatable within the primary visual cortex (ICC = 0.8), parietal eye fields (ICC = 0.6), supplementary eye field (ICC = 0.5), frontal eye fields (ICC = 0.5), and oculomotor vermis (ICC = 0.6). The results demonstrate significant test-retest reliability in the ROIs of the vergence neural substrates for functional activation magnitude and spatial extent using the stimulus protocol of a task block stimulating eight vergence eye movements compared to sustained fixation. These ROIs can be used in future longitudinal RCTs to study patient populations with vergence dysfunctions.

Predictive Smooth Pursuit Eye Movements.

Smooth pursuit eye movements maintain the line of sight on smoothly moving targets. Although often studied as a response to sensory motion, pursuit anticipates changes in motion trajectories, thus reducing harmful consequences due to sensorimotor processing delays. Evidence for predictive pursuit includes (a) anticipatory smooth eye movements (ASEM) in the direction of expected future target motion that can be evoked by perceptual cues or by memory for recent motion, (b) pursuit during periods of target occlusion, and (c) improved accuracy of pursuit with self-generated or biologically realistic target motions. Predictive pursuit has been linked to neural activity in the frontal cortex and in sensory motion areas. As behavioral and neural evidence for predictive pursuit grows and statistically based models augment or replace linear systems approaches, pursuit is being regarded less as a reaction to immediate sensory motion and more as a predictive response, with retinal motion serving as one of a number of contributing cues.

Clinical and Functional Imaging Changes Induced from Vision Therapy in Patients with Convergence Insufficiency.

Office-Based Vergence/Accommodative Therapy (OBVAT) is an effective treatment for convergence insufficiency (CI) and remediates symptoms in about 75% of patients. Hence, the study of CI patients can serve as a systems-level model to understand the neural mechanisms evoked from rehabilitation. Symptomatic young adult CI patients (N=25) participated in 12 hours of OBVAT and were compared to 25 binocularly normal controls (BNC) using unpaired t-tests. CI patients have significantly lower near point of convergence and positive fusional vergence and were more symptomatic compared to BNC (p<; 0.0001). Using paired t-tests, significant differences (p<; 0.0001) were observed between CI patients' baseline and post-OBVAT measurements where the near point of convergence decreased, positive fusional vergence increased, and the results from the Convergence Insufficiency Symptom Survey (CISS) decreased. Using paired t-tests, the mean beta weights of the functional activity significantly increased for the frontal eye fields (p<; 0.01) and the oculomotor vermis (p<; 0.05) for CI patients post-OBVAT compared to baseline measurements. These data demonstrate that OBVAT increases functional activity within the brain and improves clinical function and visual symptoms in CI patients.

Effects of visual distractors on vergence eye movements.

Visual attention is an important aspect of everyday life, which can be incorporated in the assessment of many diagnoses. Another important characteristic of visual attention is that it can be improved via therapeutic interventions. Fifteen subjects with normal binocular vision were presented with visual distractor stimuli at various spatial locations while initiating disparity vergence eye movements (inward or outward rotation of eyes) within a haploscope system. First, a stationary distractor stimulus was presented in either the far, middle, or near visual spaces while the subjects were instructed to follow a target stimulus that was either stationary, converging (moving toward subject), or diverging (moving away from subject). For the second experiment, a dynamic distractor stimulus within the far, middle, or near visual space that was converging or diverging was presented while the target stimulus was also converging or diverging. The subjects were instructed to visually follow the target stimulus and ignore the distractor stimulus. The vergence responses had a final vergence angle between the target and distractor stimuli which has been termed a center of gravity (CoG) effect. Statistically significant differences were observed between the convergence peak velocities (p < 0.001) and response amplitudes (p < 0.001) comparing responses without distractors to responses with the presence of a vergence distractor. The results support that vergence eye movements are influenced by visual distractors, which is similar to how distractors influence saccadic eye movements. The influence of visual distractors within vergence eye movements may be useful to assess binocular dysfunction and visual distraction which are common post brain injury.

Comparison of symmetrical prism adaptation to asymmetrical prism adaptation in those with normal binocular vision.

This study sought to determine whether symmetrical compared to asymmetrical horizontal prisms (base-out or base-in) evoked different rates of phoria adaptation. Sixteen young adults with normal binocular vision participated in a symmetrical phoria adaptation experiment using a 3Δ base-out or 3Δ base-in binocular prism flipper and an asymmetrical phoria adaptation experiment using a 6Δ base-out or 6Δ base-in monocular wedge prism. The experiments were randomized and counterbalanced to reduce the influence of the prism stimulation order. Asymmetrical base-out prism adaptation was significantly faster than symmetrical prism adaptation for subjects with normal binocular vision. Asymmetrical phoria adaptation with base-in prism was not significantly different from symmetrical phoria adaptation implying that there are directional asymmetries (convergent versus divergent eye movements) in the slow fusional component of vergence. Data suggest that a potential interaction between the version system and the slow fusional vergence system may exist. Results have clinical relevance because patients with convergence or divergence insufficiency/excess may potentially show more pronounced differences between symmetrical and asymmetrical phoria adaptation compared to binocularly normal controls. These differences might also be relevant to clinical measurements such as vergence fusional range, which can be measured symmetrically (with Risley prisms in a phoroptor) or asymmetrically (with prism bar).

Anticipatory smooth pursuit eye movements evoked by probabilistic cues.

Anticipatory smooth eye movements (ASEM; smooth eye movements in the direction of anticipated target motion) are elicited by cues that signal the direction of future target motion with high levels of certainty. Natural cues, however, rarely convey information with perfect certainty, and responses to uncertainty provide insights about how predictive behaviors are generated. Subjects smoothly pursued targets that moved to the right or left with varying cued probabilities. ASEM strength in a given direction increased with the probability level. The type of cue also played a role. ASEM elicited by symbolic visual cues tended to underweight low probabilities and overweight high probabilities. Cues based on memory (varying the proportion of trials with left or right motion) produced the opposite pattern, overweighting low probabilities and underweighting high probabilities. Finally, cues whose perceptual structure depicted the motion path produced a bias in ASEM in the depicted direction that was maintained across levels of cue congruency. The results show that the smooth pursuit system relies on a combination of signals, including memory for recent target motions, interpretation of cues, and prior beliefs about the relationship between the perceptual configuration and the motion path to determine the anticipatory response in the presence of uncertainty.

Davida Teller Award Lecture 2013: the importance of prediction and anticipation in the control of smooth pursuit eye movements.

The ability of smooth pursuit eye movements to anticipate the future motion of targets has been known since the pioneering work of Dodge, Travis, and Fox (1930) and Westheimer (1954). This article reviews aspects of anticipatory smooth eye movements, focusing on the roles of the different internal or external cues that initiate anticipatory pursuit.We present new results showing that the anticipatory smooth eye movements evoked by different cues differ substantially, even when the cues are equivalent in the information conveyed about the direction of future target motion. Cues that convey an easily interpretable visualization of the motion path produce faster anticipatory smooth eye movements than the other cues tested, including symbols associated arbitrarily with the path, and the same target motion tested repeatedly over a block of trials. The differences among the cues may be understood within a common predictive framework in which the cues differ in the level of subjective certainty they provide about the future path. Pursuit may be driven by a combined signal in which immediate sensory motion, and the predictions about future motion generated by sets of cues, are weighted according to their respective levels of certainty. Anticipatory smooth eye movements, an overt indicator of expectations and predictions, may not be operating in isolation, but may be part of a global process in which the brain analyzes available cues, formulates predictions, and uses them to control perceptual, motor, and cognitive processes.

Anticipatory smooth eye movements in autism spectrum disorder.

Smooth pursuit eye movements are important for vision because they maintain the line of sight on targets that move smoothly within the visual field. Smooth pursuit is driven by neural representations of motion, including a surprisingly strong influence of high-level signals representing expected motion. We studied anticipatory smooth eye movements (defined as smooth eye movements in the direction of expected future motion) produced by salient visual cues in a group of high-functioning observers with Autism Spectrum Disorder (ASD), a condition that has been associated with difficulties in either generating predictions, or translating predictions into effective motor commands. Eye movements were recorded while participants pursued the motion of a disc that moved within an outline drawing of an inverted Y-shaped tube. The cue to the motion path was a visual barrier that blocked the untraveled branch (right or left) of the tube. ASD participants showed strong anticipatory smooth eye movements whose velocity was the same as that of a group of neurotypical participants. Anticipatory smooth eye movements appeared on the very first cued trial, indicating that trial-by-trial learning was not responsible for the responses. These results are significant because they show that anticipatory capacities are intact in high-functioning ASD in cases where the cue to the motion path is highly salient and unambiguous. Once the ability to generate anticipatory pursuit is demonstrated, the study of the anticipatory responses with a variety of types of cues provides a window into the perceptual or cognitive processes that underlie the interpretation of events in natural environments or social situations.

Anticipatory smooth eye movements with random-dot kinematograms.

Anticipatory smooth eye movements were studied in response to expectations of motion of random-dot kinematograms (RDKs). Dot lifetime was limited (52-208 ms) to prevent selection and tracking of the motion of local elements and to disrupt the perception of an object moving across space. Anticipatory smooth eye movements were found in response to cues signaling the future direction of global RDK motion, either prior to the onset of the RDK or prior to a change in its direction of motion. Cues signaling the lifetime of the dots were not effective. These results show that anticipatory smooth eye movements can be produced by expectations of global motion and do not require a sustained representation of an object or set of objects moving across space. At the same time, certain properties of global motion (direction) were more sensitive to cues than others (dot lifetime), suggesting that the rules by which prediction operates to influence pursuit may go beyond simple associations between cues and the upcoming motion of targets.