Linkage analysis identifies an isolated strabismus locus at 14q12 overlapping with FOXG1 syndrome region.

Strabismus is a common condition, affecting 1%-4% of individuals. Isolated strabismus has been studied in families with Mendelian inheritance patterns. Despite the identification of multiple loci via linkage analyses, no specific genes have been identified from these studies. The current study is based on a seven-generation family with isolated strabismus inherited in an autosomal dominant manner. A total of 13 individuals from a common ancestor have been included for linkage analysis. Among these, nine are affected and four are unaffected. A single linkage signal has been identified at an 8.5 Mb region of chromosome 14q12 with a multipoint LOD (logarithm of the odds) score of 4.69. Disruption of this locus is known to cause FOXG1 syndrome (or congenital Rett syndrome; OMIM #613454 and *164874), in which 84% of affected individuals present with strabismus. With the incorporation of next-generation sequencing and in-depth bioinformatic analyses, a 4 bp non-coding deletion was prioritised as the top candidate for the observed strabismus phenotype. The deletion is predicted to disrupt regulation of FOXG1, which encodes a transcription factor of the Forkhead family. Suggestive of an autoregulation effect, the disrupted sequence matches the consensus FOXG1 and Forkhead family transcription factor binding site and has been observed in previous ChIP-seq studies to be bound by Foxg1 in early mouse brain development. Future study of this specific deletion may shed light on the regulation of FOXG1 expression and may enhance our understanding of the mechanisms contributing to strabismus and FOXG1 syndrome.

Evaluating visuomotor coordination in children with amblyopia.

Past research has reported deficits on reaching and grasping tasks in adults with amblyopia and degraded stereoacuity, but less is known about visuomotor deficits in children-specifically, for complex tasks that require movement sequencing. This study therefore compared the visuomotor performance in 21 children with abnormal binocular vision (patient group) due to amblyopia and/or strabismus to that of 236 children with normal binocular vision development (control group) ages 5-14 years. Visual acuity, stereoacuity, and hand-movement kinematics on a bead-threading task were assessed. The patient group showed significantly longer durations than the control group on grasp, thread, and total movement durations. Both groups of participants were then split into immature (ages 5-9 years) and mature (ages 10-14 years) groups based on the maturation age for these parameters in control children. Grasp duration was longer in both mature and immature patient groups; thread and total movement durations were longer in the mature patient group only. Grasp duration was the most disrupted kinematic parameter in children with disrupted binocular vision due to amblyopia and/or strabismus, regardless of age. The level of stereoacuity loss rather than the depth of visual acuity loss was associated with the severity of visuomotor deficits.

Continuous theta burst TMS of area MT+ impairs attentive motion tracking.

Attentive motion tracking deficits measured using multiple object tracking (MOT) tasks have been identified in a number of neurodevelopmental disorders such as amblyopia and autism. These deficits are often attributed to the abnormal development of high-level attentional networks. However, neuroimaging evidence from amblyopia suggests that reduced MOT performance can be explained by impaired function in motion-sensitive area MT+ alone. To test the hypothesis that a subtle disruption of MT+ function could cause MOT impairment, we assessed whether continuous theta burst stimulation (cTBS) of MT+ influenced MOT task accuracy in individuals with normal vision. The MOT stimulus consisted of four target and four distractor dots and was presented at ±10° eccentricity (right/left hemifield). fMRI-guided cTBS was applied to left MT+. Participants (n = 13, age: 27 ± 3) attended separate active and sham cTBS sessions where the MOT task was completed before, 5-min post- and 30-min post-cTBS. Active cTBS significantly impaired MOT task accuracy relative to baseline for the right (stimulated) hemifield 5-min (10 ± 2% reduction) and 30-min (14 ± 3% reduction) post-stimulation. No impairment occurred within the left (control) hemifield after active cTBS or for either hemifield after sham cTBS. These results highlight the importance of lower level motion processing for MOT, suggesting that a minor disruption of MT+ function alone is sufficient to cause a deficit in MOT performance.

White matter but not grey matter predicts change in reading skills after intervention.

This study examined changes in white matter microstructure and grey matter volume, cortical thickness, and cortical surface area before and after reading intervention. Participants included 22 average readers and 13 dyslexic readers (8-9 years old in third grade); the dyslexic readers were enrolled in reading intervention programs at their elementary school. Participants completed scans of diffusion tensor imaging and T1-weighted MRI before and after 3 months of instruction. An a priori region of interest (ROI) analysis was used. Dyslexic readers, compared to average readers, showed higher mean diffusivity in white matter ROIs including bilateral inferior frontal, bilateral insula, left superior temporal, and right supramarginal gyri across time points. Dyslexic readers also had thicker cortex in left fusiform and bilateral supramarginal gyri; whereas, average readers had greater surface area in right fusiform across time. There were no significant changes in white or grey matter following intervention; however, mean diffusivity in the right hemisphere was associated with reading gains over time. White matter organization in the right hemisphere predicts reading changes, and dyslexic readers may have persistent differences in white and grey matter due to ongoing reading deficits.

Effect of Visual Field Location on Global Motion Perception: A Developmental Study.

Previous work has shown that motion perception in school-age children is similar to that of adults for fast speeds but is immature at slow speeds for stimuli presented in the central visual field. This study examined whether visual field location affects this developmental pattern. We measured left/right and up/down global motion direction discrimination for fast and slow speeds in 7- to 10-year-old children and in adults with stimuli presented to upper, central, or lower visual fields. For left/right direction discrimination, children showed significantly higher (worse) coherence thresholds than adults for slow, but not fast, speeds in the central visual field. In the upper and lower visual fields, children showed significantly higher coherence thresholds than adults for both speeds. For up/down direction discrimination, children showed similar performance to adults for the central visual field. In the upper and lower visual fields, children performed significantly worse than adults; this finding was speed-tuned only for the lower visual field. Thus, children show immature global motion perception in the periphery even when performance in central vision is adult-like. These results enrich our understanding of motion perception development in children with typical vision.

Concurrent maturation of visuomotor skills and motion perception in typically-developing children and adolescents.

Perceptual and visuomotor skills undergo considerable development from early childhood into adolescence; however, the concurrent maturation of these skills has not yet been examined. This study assessed visuomotor function and motion perception in a cross-section of 226 typically-developing children between 4 and 16 years of age. Participants were tested on three tasks hypothesized to engage the dorsal visual stream: threading a bead on a needle, marking dots using a pen, and discriminating form defined by motion contrast. Mature performance was reached between 8 and 12 years, with youngest maturation for kinematic measures for a reach-to-grasp task, and oldest maturation for a precision tapping task. Performance on the motion perception task shared no association with motor skills after controlling for age.

Longitudinal outcomes of an individualized and intensive reading intervention for third grade students.

Early intervention is known to reduce reading disabilities; however, treatment response is variable, and some students have persistent deficits that require intensive supports. This study examined the immediate and 1-year outcomes of an individualized and intensive reading program for third grade students, which was delivered throughout the school day for an average of 189 hr of instruction over 3 months. These students' performances were compared with two comparison groups, including poor readers who received small group supports and good readers who did not have additional reading instruction. The intensive group showed an improvement in word recognition and decoding fluency immediately after the program and 1 year later, and there was a decrease in significant reading impairments from 62% before intervention to 35% at follow-up. Furthermore, baseline reading, spelling, phonological awareness, and rapid naming skills were predictive of persistent reading deficits at a later time point. Although improvements in reading skills were shown, a significant gap between poor and good readers persisted in the third and fourth grades. This study illustrates the importance of a tertiary intensive reading program, but also the need for continuing supports.

Neural Correlates of Speed-Tuned Motion Perception in Healthy Adults.

It has been suggested that slow and medium-to-fast speeds of motion may be processed by at least partially separate mechanisms. The purpose of this study was to establish the cortical areas activated during motion-defined form and global motion tasks as a function of speed, using functional magnetic resonance imaging. Participants performed discrimination tasks with random dot stimuli at high coherence, at coherence near their own thresholds, and for random motion. Stimuli were moving at 0.1 or 5 deg/s. In the motion-defined form task, lateral occipital complex, V5/MT+ and intraparietal sulcus showed greater activation by high or near-threshold coherence than by random motion stimuli; V5/MT+ and intraparietal sulcus demonstrated greater activation for 5 than 0.1 deg/s dot motion. In the global motion task, only high coherence stimuli elicited significant activation over random motion; this activation was primarily in nonclassical motion areas. V5/MT+ was active for all motion conditions and showed similar activation for coherent and random motion. No regions demonstrated speed-tuning effects for global motion. These results suggest that similar cortical systems are activated by slow- and medium-speed stimuli during these tasks in healthy adults.

Motion-Defined Form Perception in Deprivation Amblyopia.

Purpose: The purpose of this study was to assess motion-defined form perception, including the association with clinical and sensory factors that may drive performance, in each eye of children with deprivation amblyopia due to unilateral cataract. Methods: Coherence thresholds for orientation discrimination of motion-defined form were measured using a staircase procedure in 30 children with deprivation amblyopia and 59 age-matched controls. Visual acuity, stereoacuity, fusion, and interocular suppression were also measured. Fixation stability and fellow-eye global motion thresholds were measured in a subset of children. Results: Motion-defined form coherence thresholds were elevated in 90% of children with deprivation amblyopia when viewing with the amblyopic eye and in 40% when viewing with the fellow eye. The deficit was similar in children with a cataract that had been visually significant at birth (congenital) and in children for whom the cataract appeared later in infancy or childhood (developmental). Poorer motion-defined form perception in amblyopic eyes was associated with poorer visual acuity, poorer binocular function, greater interocular suppression, and the presence of nystagmus. Fellow-eye deficits were not associated with any of these factors, but a temporo-nasal asymmetry for global motion perception in favor of nasalward motion suggested a general disruption in motion perception. Conclusions: Deficits in motion-defined form perception are common in children with deprivation amblyopia and may reflect a problem in motion processing that relies on binocular mechanisms.

Sparing of coarse stereopsis in stereodeficient children with a history of amblyopia.

Stereoscopic depth perception may be obtained from small retinal disparities that can be fused for single vision (fine stereopsis), but reliable depth information is also obtained from larger disparities that produce double vision (coarse stereopsis). Here we assess the possibility that the early development of coarse stereopsis makes it resilient to the factors that cause amblyopia by comparing performance in children with a history of strabismic, anisometropic, or aniso-strabismic amblyopia and age-matched controls (5-12 years). The task was to indicate whether a cartoon character was nearer or farther away than a zero-disparity reference frame. Test disparities were grouped into fine and coarse ranges based on preliminary assessment of diplopia thresholds. In the fine range, accuracy increased with disparity for both groups, but children in the amblyopia group performed significantly worse than children in the control group, particularly when their amblyopia was associated with strabismus. In the coarse range, accuracy was constant across all disparities for both groups although performance appeared to be poorer in the aniso-strabismic group. These results suggest that, under some conditions, stereopsis for large disparities may be spared when stereopsis for small disparities is disrupted by early visual deprivation. This undetected residual binocular function has important clinical implications given recent efforts to improve amblyopia treatment outcomes by employing binocular treatment protocols.

The reverse motion illusion in random dot motion displays and implications for understanding development.

Across two independent developmental labs, we have been puzzled by the observation that a small proportion of our child and adult participants consistently report perceiving motion in the direction opposite to that presented in random-dot motion displays, sometimes even when the motion is at 100% coherence. In this review, we first draw together existing reports of misperceptions of motion direction in random dot displays across observers in a small percentage of trials, before reporting evidence of consistent reverse motion perception in a minority of observers, including previously unreported observations from our own studies of visual development. We consider possible explanations for this reverse motion illusion, including motion induction, motion energy, correspondence noise and spatial undersampling. However, more work is required to understand the individual differences relating to this percept. We suggest that errors in perceived motion direction are likely to be more widespread than can be currently gleaned from the literature and explain why systematic study is needed, especially in children. Finally, we list some remaining open questions and call for collaborative efforts to document this phenomenon and stimulate future investigation.

The Curve Visible on the Campbell-Robson Chart Is Not the Contrast Sensitivity Function.

The Campbell-Robson chart is a highly popular figure used in psychophysics and visual perception textbooks to illustrate the Contrast Sensitivity Function (CSF). The chart depicts a grating which varies logarithmically in spatial frequency (SF) from left to right and in contrast from bottom to top. Campbell and Robson's (1964) intuition was that the boundary between the grating and the homogeneous gray area (below threshold) would trace the shape of the observer's own CSF. In this paper, we tested this intuition. A total of 170 participants (96 adults and 74 children) adjusted the four parameters of a truncated log-parabola directly onto a Campbell-Robson chart rendition and completed a gold-standard CSF evaluation. We hoped that this procedure which requires a mere three clicks on the computer mouse, would speed up the measurement of the CSF to under a minute. Unfortunately, the only parameter of the truncated log-parabola fitted to the gold-standard CSF data that could be predicted from the Campbell-Robson chart data was the peak sensitivity for the adult participants. We conclude that the curve visible on the Campbell-Robson chart cannot be used practically to measure the CSF.

The relationship between reflex eye realignment and the percept of single vision in young children.

Effective binocular vision is dependent on both motor and perceptual function. Young children undergo development of both components while interacting with their dynamic three-dimensional environment. When this development fails, eye misalignment and double vision may result. We compared the range of image disparities over which young children display reflex motor realignment of their eyes with the range over which they report a single versus double percept. In response to step changes in the disparity of a 2.2° wide stimulus, 5-year-olds generated an adult-like reflex vergence velocity tuning function peaking at 2° of disparity, with a mean latency of 210 ms. On average, they reported double vision for stimulus disparities of 3° and larger, compared to 1° in adult reports. Three-year-olds also generated reflex vergence tuning functions peaking at approximately 2° of disparity, but their percepts could not be assessed. These data suggest that, by age 5, reflex eye realignment responses and percepts driven by these brief stimuli are tightly coordinated in space and time to permit robust binocular function around the point of fixation. Importantly, the plastic neural processes maintaining this tight coordination during growth control the stability of visual information driving learning during childhood.

Combined functional MRI and diffusion tensor imaging analysis of visual motion pathways.

BACKGROUND: Motion perception may be preserved after damage to striate cortex (primary visual cortex, area V1). Awareness and normal discrimination of fast-moving stimuli have been observed even in the complete absence of V1. These facts suggest that motion-sensitive cortex (the V5/MT complex or V5/MT+) may be activated by direct thalamic or collicular inputs that bypass V1. Such projections have been identified previously in monkeys but have not been shown in humans using neuroimaging techniques. METHODS: We used diffusion tensor imaging (DTI) tractography to visualize white matter fiber tracts connecting with V5/MT+ in 10 healthy volunteers. V5/MT+ was localized for each subject using functional MRI (fMRI). Functional activity maps were overlaid on high-resolution anatomical images and registered with the diffusion-weighted images to define V5/MT+ as the region of interest (ROI) for DTI tractography analysis. Fibers connecting to V1 were excluded from the analysis. RESULTS: Using conservative tractography parameters, we found connections between the V5/MT+ region and the posterior thalamus and/or superior colliculus in 4 of 10 subjects. CONCLUSIONS: Connections between the V5/MT+ region and the posterior thalamus and/or superior colliculus may explain visual motion awareness in the absence of a functioning V1.

The Effect of Stimulus Area on Global Motion Thresholds in Children and Adults.

Performance on random-dot global motion tasks may reach adult-like levels before 4 or as late as 16 years of age, depending on the specific parameters used to create the stimuli. Later maturation has been found for slower speeds, smaller spatial displacements, and sparser dot arrays. This protracted development on global motion tasks may depend on limitations specific to spatial aspects of a motion stimulus rather than to motion mechanisms per se. The current study investigated the impact of varying stimulus area (9, 36, and 81 deg2) on the global motion coherence thresholds of children 4-6 years old and adults for three signal dot displacements (∆x = 1, 5, and 30 arcmin). We aimed to determine whether children could achieve mature performance for the smallest displacements, a condition previously found to show late maturation, when a larger stimulus area was used. Coherence thresholds were higher in children compared to adults in the 1 and 5 arcmin displacement conditions, as reported previously, and this did not change as a function of stimulus area. However, both children and adults performed better with a larger stimulus area in the 30 arcmin displacement condition only. This suggests that immature spatial integration, as measured by stimulus area, cannot account for immaturities in global motion perception.

Fellow Eye Deficits in Amblyopia.

Amblyopia is a neurodevelopmental disorder of the visual system, as a result of discordant visual experience during infancy or early childhood. Because amblyopia is typically defined as monocularly reduced visual acuity accompanied by one or more known amblyogenic factors, it is often assumed that the fellow eye is normal and sufficient for tasks like reading and eye-hand coordination. Recent scientific evidence of ocular motor, visual, and visuomotor deficits that are present with fellow eye monocular viewing and with binocular viewing calls this assumption into question. This clinical update reviews the research that has revealed fellow ocular motor and visual deficits and the effect that these deficits have on an amblyopic child's visuomotor and visuocognitive skills. We need to understand how to prevent and rehabilitate the effects of amblyopia not only on the nonpreferred eye but also on the fellow eye.

Reading ability of children treated for amblyopia.

Previous studies have reported compromised reading ability in children with amblyopia. Standardized psychoeducational test norms have not been used; therefore, the practical consequences of poor reading ability, such as eligibility for reading supports at school, have not been assessed. Furthermore, several studies have used atypical reading conditions such as monocular or distant viewing. It is also not clear how amblyopia treatment impacts reading ability. Thus, the goal of this study was to use standardized tests to compare binocular reading performance in children treated for amblyopia to that of a large normative sample, as well as to the types of control groups used in previous studies. Children treated for strabismic or anisometropic amblyopia (N = 14) were compared to children treated for strabismus without amblyopia (N = 12) and to children with healthy vision (N = 39). Visual acuity, stereoacuity, interocular suppression, intellectual functioning, oral single-word reading (TOWRE-2), and oral paragraph reading (GORT-5) were assessed. The control group showed significantly higher single-word reading accuracy than the amblyopia and strabismus groups. However, mean performance for all groups was within the average range of the normative sample. While mean scores were in the average range, six children (four amblyopia, two strabismus) performed below average on the single-word reading task; four of these children also showed below average paragraph reading. Reading scores were not correlated with visual acuity in the patient groups. The results raise the possibility that both strabismus and amblyopia can disrupt reading ability, even following successful treatment, to an extent that might benefit from reading supports at school.

Effect of reading intervention and task difficulty on orthographic and phonological reading systems in the brain.

Children with poor reading skills have differences in brain function when compared to typically-developing readers, and there may also be changes in the brain following reading intervention. However, most functional imaging studies focus on phonological reading tasks with one level of task difficulty. The purpose of this study was to compare good and poor readers on functional magnetic resonance imaging (fMRI) tasks of orthography (spelling) and phonology (rhyming) before and after 3 months of school-based intervention. These tasks were also modulated by task difficulty based on printed word frequency. The results showed that primarily left hemisphere regions were activated for the spelling and rhyming tasks, and poor readers showed a pattern of increased activation in bilateral inferior frontal, bilateral insula, right parietal, and left cerebellum following intervention. Activity in left pars triangularis and right parietal regions were associated with gains in decoding skills. Intervention effects appeared across blocks of easy and difficult words, except for the right parietal cortex. In this region, poor readers had greater activity on the easy word blocks after intervention, which indicates that there was increased recruitment of the right parietal cortex for relatively easy words. These results indicate that effects of intervention may be more evident on phonological tasks in comparison to orthographic tasks, and some of these effects may be modulated by relative task difficulty.

Impaired Fellow Eye Motion Perception and Abnormal Binocular Function.

Purpose: Binocular discordance due to strabismus, anisometropia, or both may result in not only monocular visual acuity deficits, but also in motion perception deficits. We determined the prevalence of fellow-eye deficits in motion-defined form (MDF) perception, the ability to identify a two-dimensional (2D) shape defined by motion rather than luminance contrast. We also examined the following: the causative role of reduced visual acuity and binocularity, associations with clinical and sensory factors, and effectiveness of binocular amblyopia treatment in alleviating deficits. Methods: Participants included 91 children with residual amblyopia (strabismic, anisometropic, or both; age, 9.0 ± 1.7 years), 79 nonamblyopic children with treated strabismus or anisometropia (age, 8.5 ± 2.1 years), and 20 controls (age, 8.6 ± 1.5 years). MDF coherence thresholds, visual acuity, stereoacuity, and interocular suppression were measured. Results: MDF deficits, relative to controls, were present in the fellow eye of 23% of children with residual amblyopia and 20% of nonamblyopic children. Stereoacuity and age first patched were correlated with MDF threshold (r = 0.29, 95% CI: 0.09-0.47; r = -0.33, 95% CI: -0.13 to -0.50, respectively). MDF deficits were more common in children treated with patching alone than in those receiving contrast-rebalanced binocular treatment with games or movies (t89 = 3.46; P = 0.0008). The latter was associated with a reduction in mean fellow eye MDF threshold (t26 = 6.32, P < 0.0001). Conclusions: Fellow eye MDF deficits are common and likely reflect abnormalities in binocular cortical mechanisms that result from early discordant visual experience. Binocular amblyopia treatment, which is effective in improving amblyopic eye visual acuity, appears to provide a benefit for the fellow eye.

Navigational skills correlate with hippocampal fractional anisotropy in humans.

Individuals vary widely in their ability to orient within the environment. We used diffusion tensor imaging to investigate whether this ability, as measured by navigational performance in a virtual environment, correlates with the anatomic structural properties of the hippocampus, i.e., fractional anisotropy. We found that individuals with high fractional anisotropy in the right hippocampus are (a) faster in forming a cognitive map of the environment, and (b) more efficient in using this map for the purpose of orientation, than individuals with low fractional anisotropy. These results are consistent with the role of the hippocampus in navigation, and suggest that its microstructural properties may contribute to the intersubject variability observed in spatial orientation.