New evidence for the sensorimotor mismatch theory of weight perception and the size-weight illusion.

The size-weight illusion is a phenomenon where a smaller object is perceived heavier than an equally weighted larger object. The sensorimotor mismatch theory proposed that this illusion occurs because of a mismatch between efferent motor commands and afferent sensory feedback received when lifting large and small objects (i.e., the application of too little and too much lifting force, respectively). This explanation has been undermined by studies demonstrating a separation between the perceived weight of objects and the lifting forces that are applied on them. However, this research suffers from inconsistencies in the choice of lifting force measures reported. Therefore, we examined the contribution of sensorimotor mismatch in the perception of weight in the size-weight illusion and in non-size-weight illusion stimuli and evaluated the use of a lifting force aggregate measure comprising the four most common lifting force measures used in previous research. In doing so, the sensorimotor mismatch theory was mostly supported. In a size-weight illusion experiment, the lifting forces correlated with weight perception and, contrary to some earlier research, did not adapt over time. In a non-size-weight illusion experiment, switches between lifting light and heavy objects resulted in perceiving the weight of these objects differently compared to no switch trials, which mirrored differences in the manner participants applied forces on the objects. Additionally, we reveal that our force aggregate measure can allow for a more sensitive and objective examination of the effects of lifting forces on objects.

The Influence of Light Wavelength on Human HPA Axis Rhythms: A Systematic Review.

Environmental light entrains many physiological and behavioural processes to the 24 h solar cycle. Such light-driven circadian rhythms are centrally controlled by the suprachiasmatic nucleus (SCN), which receives information from the short-wavelength-sensitive intrinsically photosensitive retinal ganglion cells. The SCN synchronizes local clocks throughout the body affecting sleep/wake routines and the secretion of neuroendocrine-linked hormones such as melatonin from the pineal gland and cortisol via the hypothalamic pituitary adrenal (HPA) axis. Although the effects of light parameters on melatonin have been recently reviewed, whether the experimental variation of the spectral power distribution and intensity of light can induce changes in cortisol rhythms remains unclear. Thus, this systematic review evaluated the effects of daytime exposure to lights of different spectral wavelength characteristics and luminance intensity on the cortisol levels in healthy individuals. A search of the PubMed, Web of Science, EMBASE, CINAHL, Medline, PsycINFO and Cochrane Library databases on 19 June 2023 identified 3418 articles, of which 12 studies (profiling 337 participants) met the inclusion and risk of bias criteria. An analysis of the literature indicated that exposure to bright lights of any colour during the late night or early morning can induce significant increases in cortisol secretion relative to time-matched dim light comparison conditions. Furthermore, exposure to bright lights with stronger short-wavelength (blue/green) components in the early morning typically induced greater increases in cortisol relative to lights with stronger long-wavelength (red) components. Thus, the circadian regulation of cortisol is sensitive to the wavelength composition of environmental lighting, in line with the more commonly studied melatonin. As such, wavelength characteristics should be optimized and reported in light intervention studies (particularly for the investigation of cortisol-associated disorders and HPA axis function), and exposure to short-wavelength light during sensitive periods should be carefully considered in constructed environments (e.g., bedroom and classroom lighting and device screens).

Sex and stress hormone dysregulation as clinical manifestations of hypothalamic function in migraine disorder: A meta-analysis.

Migraine is a leading cause of disability in young adults. It occurs more frequently in females, often comorbidly with stress disorders, suggesting an association with hypothalamic sex and stress hormonal function and a likely interaction with autonomic nervous system activation. Thus, this study aimed to meta-analyse current literature pertaining to female and male sex hormones (estrogen, progesterone and testosterone concentration), hypothalamic-pituitary-adrenal axis (HPA axis) cortisol responses and heart rate variability (HRV) in migraineurs and controls aged 13-65 years. A systematic search of MEDLINE, Embase, PsycINFO, PubMed, CINAHL and Web of Science databases on 29/08/2022 identified 29 studies for meta-analysis (encompassing 719 migraineur and 592 control participants) that met inclusion and NHLBI risk of bias criteria. Results demonstrated that estrogen concentrations of female migraineurs were reduced (g = -.60, 95% CI [-.91, -.29], p < .001) in the luteal phase of the menstrual cycle, compared to controls. No differences were found in progesterone levels overall in female migraineurs, nor in testosterone levels in male migraineurs compared to controls. Further, early diurnal cortisol concentrations were elevated (g = .32, 95% CI [.00, .63], p = .036) in female and male migraineurs compared to controls, though no differences were found in HRV of female or male migraineurs compared to controls. These findings of dysregulation of estrogen in females and cortisol dysregulation in female and male migraineurs indicate perturbed hypothalamic function and highlight the association of migraine with stress and the need for further rigorous investigation of hypothalamic neuroendocrine functions in migraineurs of both sexes.

Visual Motor Reaction Times Predict Receptive and Expressive Language Development in Early School-Age Children.

Proficiency of multisensory processing and motor skill are often associated with early cognitive, social, and language development. However, little research exists regarding the relationship between multisensory motor reaction times (MRTs) to auditory, visual and audiovisual stimuli, and classical measures of receptive language and expressive vocabulary development in school-age children. Thus, this study aimed to examine the concurrent development of performance in classical tests of receptive (Peabody Picture Vocabulary Test; abbreviated as PPVT) and expressive vocabulary (Expressive Vocabulary Test; abbreviated as EVT), nonverbal intelligence (NVIQ) (determined with the aid of Raven's Colored Progressive Matrices; abbreviated as RCPM), speed of visual-verbal processing in the Rapid Automatic Naming (RAN) test, Eye-Hand Co-ordination (EHC) in the SLURP task, and multisensory MRTs, in children (n = 75), aged between 5 and 10 years. Bayesian statistical analysis showed evidence for age group differences in EVT performance, while PPVT was only different for the youngest group of children aged 5-6, supporting different developmental trajectories in vocabulary acquisition. Bayesian correlations revealed evidence for associations between age, NVIQ, and vocabulary measures, with decisive evidence and a higher correlation (r = 0.57 to 0.68) between EVT, MRT tasks, and EHC visuomotor processing. This was further supported by regression analyses indicating that EVT performance was the strongest unique predictor of multisensory MRTs, EHC, and RAN time. Additionally, visual MRTs were found to predict both receptive and expressive vocabulary. The findings of the study have important implications as accessible school-based assessments of the concurrent development of NVIQ, language, and multisensory processing; and hence as rapid and timely measures of developmental and neurodevelopmental status.

Flash Electroretinography as a Measure of Retinal Function in Myopia and Hyperopia: A Systematic Review.

Refractive errors (myopia and hyperopia) are the most common visual disorders and are severe risk factors for secondary ocular pathologies. The development of refractive errors has been shown to be associated with changes in ocular axial length, suggested to be induced by outer retinal elements. Thus, the present study systematically reviewed the literature examining retinal function as assessed using global flash electroretinograms (gfERGs) in human clinical refractive error populations. Electronic database searching via Medline, PubMed, Web of Science, Embase, Psych INFO, and CINAHL retrieved 981 unique records (last searched on the 29 May 2022). Single case studies, samples with ocular comorbidities, drug trials, and reviews were excluded. Demographic characteristics, refractive state, gfERG protocol details, and waveform characteristics were extracted for the eight studies that met the inclusion criteria for the review and were judged to have acceptable risk of bias using the OHAT tool (total N = 552 participants; age 7 to 50). Study synthesis suggests that myopia in humans involves attenuation of gfERG photoreceptor (a-wave) and bipolar cell (b-wave) function, consistent with the animal literature. Meaningful interpretation of the overall findings for hyperopia was limited by inconsistent reporting, highlighting the need for future studies to report key aspects of gfERG research design and outcomes more consistently for myopic and hyperopic refractive errors.

The Contribution of Visual and Auditory Working Memory and Non-Verbal IQ to Motor Multisensory Processing in Elementary School Children.

Although cognitive abilities have been shown to facilitate multisensory processing in adults, the development of cognitive abilities such as working memory and intelligence, and their relationship to multisensory motor reaction times (MRTs), has not been well investigated in children. Thus, the aim of the current study was to explore the contribution of age-related cognitive abilities in elementary school-age children (n = 75) aged 5-10 years, to multisensory MRTs in response to auditory, visual, and audiovisual stimuli, and a visuomotor eye-hand co-ordination processing task. Cognitive performance was measured on classical working memory tasks such as forward and backward visual and auditory digit spans, and the Raven's Coloured Progressive Matrices (RCPM test of nonverbal intelligence). Bayesian Analysis revealed decisive evidence for age-group differences across grades on visual digit span tasks and RCPM scores but not on auditory digit span tasks. The results also showed decisive evidence for the relationship between performance on more complex visually based tasks, such as difficult items of the RCPM and visual digit span, and multisensory MRT tasks. Bayesian regression analysis demonstrated that visual WM digit span tasks together with nonverbal IQ were the strongest unique predictors of multisensory processing. This suggests that the capacity of visual memory rather than auditory processing abilities becomes the most important cognitive predictor of multisensory MRTs, and potentially contributes to the expected age-related increase in cognitive abilities and multisensory motor processing.

Visual Processing During the Interictal Period Between Migraines: A Meta-Analysis.

Migraine is a poorly understood neurological disorder and a leading cause of disability in young adults, particularly women. Migraines are characterized by recurring episodes of severe pulsating unilateral headache and usually visual symptoms. Currently there is some disagreement in the electrophysiological literature regarding the universality of all migraineurs exhibiting physiological visual impairments also during interictal periods (i.e., the symptom free period between migraines). Thus, this meta-analysis investigated the evidence for altered visual function as measured electrophysiologically via pattern-reversal visual evoked potential (VEP) amplitudes and habituation in adult migraineurs with or without visual aura and controls in the interictal period. Twenty-three studies were selected for random effects meta-analysis which demonstrated slightly diminished VEP amplitudes in the early fast conducting P100 component but not in N135, and substantially reduced habituation in the P100 and the N135 in migraineurs with and without visual aura symptoms compared to controls. No statistical differences were found between migraineurs with and without aura, possibly due to inadequate studies. Overall, insufficient published data and substantial heterogeneity between studies was observed for all latency components of pattern-reversal VEP, highlighting the need for further electrophysiological experimentation and more targeted temporal analysis of visual function, in episodic migraineurs.

Age-related decrease in motor contribution to multisensory reaction times in primary school children.

Traditional measurement of multisensory facilitation in tasks such as speeded motor reaction tasks (MRT) consistently show age-related improvement during early childhood. However, the extent to which motor function increases with age and hence contribute to multisensory motor reaction times in young children has seldom been examined. Thus, we aimed to investigate the contribution of motor development to measures of multisensory (auditory, visual, and audiovisual) and visuomotor processing tasks in three young school age groups of children (n = 69) aged (5-6, n = 21; 7-8, n = 25.; 9-10 n = 18 years). We also aimed to determine whether age-related sensory threshold times for purely visual inspection time (IT) tasks improved significantly with age. Bayesian results showed decisive evidence for age-group differences in multisensory MRT and visuo-motor processing tasks, though the evidence showed that threshold time for visual identification IT performance was only slower in the youngest age group children (5-6) compared to older groups. Bayesian correlations between performance on the multisensory MRT and visuo-motor processing tasks indicated moderate to decisive evidence in favor of the alternative hypothesis (BF10 = 4.71 to 91.346), though not with the threshold IT (BF10 < 1.35). This suggests that visual sensory system development in children older than 6 years makes a less significant contribution to the measure of multisensory facilitation, compared to motor development. In addition to this main finding, multisensory facilitation of MRT within race-model predictions was only found in the oldest group of children (9-10), supporting previous suggestions that multisensory integration is likely to continue into late childhood/early adolescence at least.

Faster social attention disengagement in individuals with higher autism traits.

INTRODUCTION: Atypical visual and social attention has often been associated with clinically diagnosed autism spectrum disorder (ASD), and with the broader autism phenotype. Atypical social attention is of particular research interest given the importance of facial expressions for social communication, with faces tending to attract and hold attention in neurotypical individuals. In autism, this is not necessarily so, where there is debate about the temporal differences in the ability to disengage attention from a face. METHOD: Thus, we have used eye-tracking to record saccadic latencies as a measure of time to disengage attention from a central task-irrelevant face before orienting to a newly presented peripheral nonsocial target during a gap-overlap task. Neurotypical participants with higher or lower autism-like traits (AT) completed the task that included central stimuli with varied expressions of facial emotion as well as an inverted face. RESULTS: High AT participants demonstrated faster saccadic responses to detect the nonsocial target than low AT participants when disengaging attention from a face. Furthermore, faster saccadic responses were recorded when comparing disengagement from upright to inverted faces in low AT but not in high AT participants. CONCLUSIONS: Together, these results extend findings of atypical social attention disengagement in autism and highlight how differences in attention to faces in the broader autism phenotype can lead to apparently superior task performance under certain conditions. Specifically, autism traits were linked to faster attention orienting to a nonsocial target due to the reduced attentional hold of the task irrelevant face stimuli. The absence of an inversion effect in high AT participants also reinforces the suggestion that they process upright or inverted faces similarly, unlike low AT participants for whom inverted faces are thought to be less socially engaging, thus allowing faster disengagement.

The Age-Related Changes in Speed of Visual Perception, Visual Verbal and Visuomotor Performance, and Nonverbal Intelligence During Early School Years.

Speed of sensory information processing has long been recognized as an important characteristic of global intelligence, though few studies have concurrently investigated the contribution of different types of information processing to nonverbal IQ in children, nor looked at whether chronological age vs. months of early schooling plays a larger role. Thus, this study investigated the speed of visual information processing in three tasks including a simple visual inspection time (IT) task, a visual-verbal processing task using Rapid Automatic Naming (RAN) of objects as an accepted preschool predictor of reading, and a visuomotor processing task using a game-like iPad application, (the "SLURP" task) that requires writing like skills, in association with nonverbal IQ (Raven's Coloured Progressive Matrices) in children (n = 100) aged 5-7 years old. Our results indicate that the rate and accuracy of information processing for all three tasks develop with age, but that only RAN and SLURP rates show significant improvement with years of schooling. RAN and SLURP also correlated significantly with nonverbal IQ scores, but not with IT. Regression analyses demonstrate that months of formal schooling provide additional contributions to the speed of dual-task visual-verbal (RAN) and visuomotor performance and Raven's scores supporting the domain-specific hypothesis of processing speed development for specific skills as they contribute to global measures such as nonverbal IQ. Finally, RAN and SLURP are likely to be useful measures for the early identification of young children with lower intelligence and potentially poor reading.

Action video game training improves text reading accuracy, rate and comprehension in children with dyslexia: a randomized controlled trial.

Dynamic visual attention training using Action Video Games (AVGs) is a promising intervention for dyslexia. This study investigated the efficacy of 5 h (10 × 30 min) of AVG training in dyslexic children (aged 8-13) using 'Fruit Ninja', while exploring whether increasing attentional and eye movement demands enhanced AVG effectiveness. Regular (AVG-R; n = 22) and enhanced AVG training (AVG+; n = 23) were compared to a treatment-as-usual comparison group (n = 19) on reading, rapid naming, eye movements and visuo-temporal processing. Playing 'Fruit Ninja' for only 5 h significantly improved reading accuracy, rate, comprehension and rapid naming of both AVG groups, compared to the comparison group, though increasing attentional demands did not enhance AVG efficacy. Participants whose low contrast magnocellular-temporal processing improved most following training also showed significantly greater improvement in reading accuracy. The findings demonstrate a clear role for visual attention in reading and highlight the clinical applicability of AVGs as a fun, motivational and engaging intervention for dyslexia.

Long-Wavelength-Filtered Light Transiently Inhibits Negative Lens-Induced Axial Eye Growth in the Chick Myopia Model.

Purpose: Eye growth and myopia development in chicks, and some other animal models, can be suppressed by rearing under near-monochromatic, short-wavelength blue light. We aimed to determine whether similar effects could be achieved using glass filters that transmit a broader range of short and middle wavelengths. Methods: On day 6 or 7 post-hatch, 169 chicks were assigned to one of three monocular lens conditions (-10 D, +10 D, plano) and reared for 7 or 10 days under one of four 201-lux lighting conditions: (1) B410 long-wavelength-filtered light, (2) B460 long-wavelength-filtered light, (3) Y48 short-wavelength-filtered light, or (4) HA50 broadband light. Results: At 7 days, B410 (but not B460) long-wavelength-filtered light had significantly inhibited negative lens induced axial growth relative to Y48 short-wavelength-filtered light (mean difference in experimental eye = -0.249 mm; P = 0.006) and HA50 broadband light (mean difference = -0.139 mm; P = 0.038). B410 filters also inhibited the negative lens-induced increase in vitreous chamber depth relative to all other filter conditions. Corresponding changes in refraction did not occur, and biometric measurements in a separate cohort of chicks suggested that the axial dimension changes were transient and not maintained at 10 days. Conclusions: Chromatic effects on eye growth can be achieved using filters that transmit a broad range of wavelengths even in the presence of strong cues for myopia development. Translational Relevance: Broad-wavelength filters that provide a more "naturalistic" visual experience relative to monochromatic light have potential to alter myopia development, although the effects shown here were modest and transient and require exploration in further species.

Electroretinography and Gene Expression Measures Implicate Phototransduction and Metabolic Shifts in Chick Myopia and Hyperopia Models.

The Retinal Ion-Driven Fluid Efflux (RIDE) model theorizes that phototransduction-driven changes in trans-retinal ion and fluid transport underlie the development of myopia (short-sightedness). In support of this model, previous functional studies have identified the attenuation of outer retinal contributions to the global flash electroretinogram (gfERG) following weeks of myopia induction in chicks, while discovery-driven transcriptome studies have identified changes to the expression of ATP-driven ion transport and mitochondrial metabolism genes in the retina/RPE/choroid at the mid- to late-induction time-points. Less is known about the early time-points despite biometric analyses demonstrating changes in eye growth by 3 h in the chick lens defocus model. Thus, the present study compared gfERG and transcriptome profiles between 3 h and 3 days of negative lens-induced myopia and positive lens-induced hyperopia in chicks. Photoreceptor (a-wave and d-wave) and bipolar (b-wave and late-stage d-wave) cell responses were suppressed following negative lens-wear, particularly at the 3-4 h and 3-day time-points when active shifts in the rate of ocular growth were expected. Transcriptome measures revealed the up-regulation of oxidative phosphorylation genes following 6 h of negative lens-wear, concordant with previous reports at 2 days in this model. Signal transduction pathways, with core genes involved in glutamate and G-protein coupled receptor signalling, were down-regulated at 6 h. These findings contribute to a growing body of evidence for the dysregulation of phototransduction and mitochondrial metabolism in animal models of myopia.

Temporal whole field sawtooth flicker without a spatial component elicits a myopic shift following optical defocus irrespective of waveform direction in chicks.

PURPOSE: Myopia (short-sightedness) is the commonest visual disorder and greatest risk factor for sight threatening secondary pathologies. Myopia and hyperopia can be induced in animal models by rearing with optical lens defocus of opposite sign. The degree of refractive compensation to lens-induced defocus in chicks has been shown to be modified by directionally drifting sawtooth spatio-temporal luminance diamond plaids, with Fast-ON sawtooth spatio-temporal luminance profiles inhibiting the myopic shift in response to negative lenses, and Fast-OFF profiles inhibiting the hyperopic shift in response to positive lenses. What is unknown is whether similar sign-of-defocus dependent results produced by spatio-temporal modulation of sawtooth patterns could be achieved by rearing chicks under whole field low temporal frequency sawtooth luminance profiles at 1 or 4 Hz without a spatial component, or whether such stimuli would indiscriminately elicit a myopic shift such as that previously shown with symmetrical (or near-symmetrical) low frequency flicker across a range of species. METHODS: Hatchling chicks (n = 166) were reared from days five to nine under one of three defocus conditions (No Lens, +10D lens, or -10D lens) and five light conditions (No Flicker, 1 Hz Fast-ON/Slow-OFF sawtooth flicker, 4 Hz Fast-ON/Slow-OFF sawtooth flicker, 1 Hz Fast-OFF/Slow-ON sawtooth flicker, or 4Hz Fast-OFF/Slow-ON sawtooth flicker). The sawtooth flicker was produced by light emitting diodes (white LEDs, 1.2 -183 Lux), and had no measurable dark phase. Biometrics (refraction and ocular axial dimensions) were measured on day nine. RESULTS: Both 1 Hz and 4 Hz Fast-ON and Fast-OFF sawtooth flicker induced an increase in vitreous chamber depth that was greater in the presence of negative compared to positive lens defocus. Both sawtooth profiles at both temporal frequencies inhibited the hyperopic shift in response to +10D lenses, whilst full myopic compensation (or over-compensation) in response to -10D lenses was observed. CONCLUSIONS: Whole field low temporal frequency Fast-ON and Fast-OFF sawtooth flicker induces a generalized myopic shift, similar to that previously shown for symmetrical sine-wave and square-wave flicker. Our findings highlight that temporal modulation of retinal ON/OFF pathways per se (without a spatial component) is insufficient to produce strong sign-of-defocus dependent effect.

Pathway analysis identifies altered mitochondrial metabolism, neurotransmission, structural pathways and complement cascade in retina/RPE/ choroid in chick model of form-deprivation myopia.

PURPOSE: RNA sequencing analysis has demonstrated bidirectional changes in metabolism, structural and immune pathways during early induction of defocus induced myopia. Thus, the aim of this study was to investigate whether similar gene pathways are also related to the more excessive axial growth, ultrastructural and elemental microanalytic changes seen during the induction and recovery from form-deprivation myopia (FDM) in chicks and predicted by the RIDE model of myopia. METHODS: Archived genomic transcriptome data from the first three days of induction of monocularly occluded form deprived myopia (FDMI) in chicks was obtained from the GEO database (accession # GSE6543) while data from chicks monocularly occluded for 10 days and then given up to 24 h of normal visual recovery (FDMR) were collected. Gene set enrichment analysis (GSEA) software was used to determine enriched pathways during the induction (FDMI) and recovery (FDMR) from FD. Curated gene-sets were obtained from open access sources. RESULTS: Clusters of significant changes in mitochondrial energy metabolism, neurotransmission, ion channel transport, G protein coupled receptor signalling, complement cascades and neuron structure and growth were identified during the 10 days of induction of profound myopia and were found to correlate well with change in axial dimensions. Bile acid and bile salt metabolism pathways (cholesterol/lipid metabolism and sodium channel activation) were significantly upregulated during the first 24 h of recovery from 10 days of FDM. CONCLUSIONS: The gene pathways altered during induction of FDM are similar to those reported in defocus induced myopia and are established indicators of oxidative stress, osmoregulatory and associated structural changes. These findings are also consistent with the choroidal thinning, axial elongation and hyperosmotic ion distribution patterns across the retina and choroid previously reported in FDM and predicted by RIDE.

Ouabain inhibition of Na/K-ATPase across the retina prevents signed refractive compensation to lens-induced defocus, but not default ocular growth in young chicks.

PURPOSE: The relevance of retinal integrity and energy pathways to ocular growth and induction of refractive errors has seldom been investigated. Thus, we used ouabain to target the channels that are essential for the maintenance of membrane potentials in cells, sodium potassium ATPase (Na/K-ATPase), to examine refractive compensation and ocular growth in response to lens-induced defocus in the chick. METHODS:  A single intravitreal injection of 1 mM ouabain in dimethyl sulfoxide (DMSO) carrier or DMSO alone was followed by monocular defocus with positive or negative 10 D lens (or no lens) from post-hatching days 5-9 under 12/12 hr light/dark conditions. Biometry and dark-adapted flash and electroretinography (ERG) were conducted on day 9, followed by immunohistological analyses. RESULTS: Ouabain inhibited differential ocular growth and refractive compensation to signed defocus compared to DMSO. By 4-days post-ouabain injection all components of the typical ERG responses to light had been eliminated, and widespread histological damage was apparent, though some 'default state' ocular growth was measurable. Immunohistochemistry demonstrated reduction in the specialized water channel Aquaporin 4 (AQP4) expression and increased evidence of caspase 3 expression (a cell death associated protein) in ouabain-treated eyes compared with DMSO alone. CONCLUSION: The current study demonstrates that blockade of photoreceptor and inner retinal responses to light onset and offset by ouabain inhibits differential refractive compensation to optical blur, but does not prevent ocular growth.

Light modulation, not choroidal vasomotor action, is a regulator of refractive compensation to signed optical blur.

BACKGROUND AND PURPOSE: The nitric oxide system has two proposed sites and mechanisms of action within the ocular growth/refractive compensation platform-neuromodulatory effects on retinal physiology, and vascular/smooth muscle effects in the choroid. The relative contribution of these mechanisms are tested here with drugs that perturb the nitric oxide system and with slow flicker modulation of the ON and OFF pathways of the retina. EXPERIMENTAL APPROACH: Intravitreal injection of saline or 900 nmol N(G) -nitro-L-arginine methyl ester or L-arginine in saline was followed by monocular defocus with ±10 D lens (or no lens), from days 5-9 under standard diurnal (SD) or daytime 1 Hz ramped flicker conditions. Biometric, electrophysiological and histological analyses were conducted. KEY RESULTS: After 4 days of SD conditions, both drugs enhanced electroretinogram (ERG) b-wave cf. d-wave amplitudes compared with saline and reduced refractive compensation to -10 D lenses. Under flicker conditions compensation to +10 D lenses was suppressed. Choroidal thinning was observed in the drug, no lens groups under SD conditions, whereas choroidal thickening was seen in most groups under flicker conditions, irrespective of refractive outcomes. CONCLUSIONS AND IMPLICATIONS: As choroidal thickness was not predictive of final refractive compensation across any of the variables of drug, defocus sign or light condition, it is unlikely that choroidal thickness is a primary mechanism underlying refractive compensation across the range of parameters of this study. Rather, the changes in refractive compensation observed under these particular drug and light conditions are more likely due to a neuromodulatory action on retinal ON and OFF pathways.

Spatial and temporal dissociation of AQP4 and Kir4.1 expression during induction of refractive errors.

PURPOSE: Spatial co-localization of aquaporin water channels (AQP4) and inwardly rectifying potassium ion channels (Kir4.1) on the endfeet regions of glial cells has been suggested as the basis of functionally interrelated mechanisms of osmoregulation in brain edema. The aim of this study was to investigate the spatial and temporal changes in the expression of AQP4 and Kir4.1 channels in an avascular retina during the first week of the optical induction of refractive errors. METHODS: Three-day-old hatchling chicks were randomly assigned to three groups and either did not wear lenses or were monocularly goggled with +/-10D lenses for varying times up to 7 days before biometric assessment. Retinal tissue was prepared either for western blot analysis to show the presence of the AQP4 and Kir4.1 protein in the chick retina or for immunolocalization using AQP4 and Kir4.1 antibodies to determine the regional distribution and intensity of labeling during the induction of refractive errors. RESULTS: As expected, ultrasonography demonstrated that all eyes showed rapid elongation post hatching. Negative lens-wearing eyes elongated faster than fellow eyes or normal non goggled eyes and became progressively more myopic with time post lensing. Positive lens-wearing eyes showed reduced ocular growth compared to normal controls and developed a hyperopic refraction. Quantitative immunohistochemistry revealed the upregulation of AQP4 channel expression on Müller cells in the retinal nerve fiber layer during the first 2 days of negative lens wear. Kir4.1 channel upregulation in the inner plexiform layer was only found on day 4 of positive lens wear during the development of refractive hyperopia. CONCLUSIONS: These results indicate that the expression of AQP4 and Kir4.1 channels on Müller cells is associated with the changes in ocular volume seen during the induction of refractive errors. However, the sites of greatest expression and the temporal pattern of the upregulation of AQP4 and Kir4.1 were dissimilar, indicating a dissociation of AQP4 and Kir4.1 function during refractive error development. Increased AQP4 expression in the nerve fiber layer is suggested to contribute to the rapid axial elongation and movement of fluid into the vitreous cavity in the presence of minus lenses; whereas, upregulation of Kir4.1 channels appears to play a role in limiting axial elongation in the presence of plus lenses.

Potassium channel and NKCC cotransporter involvement in ocular refractive control mechanisms.

Myopia affects well over 30% of adult humans globally. However, the underlying physiological mechanism is little understood. This study tested the hypothesis that ocular growth and refractive compensation to optical defocus can be controlled by manipulation of potassium and chloride ion-driven transretinal fluid movements to the choroid. Chicks were raised with +/-10D or zero power optical defocus rendering the focal plane of the eye in front of, behind, or at the level of the retinal photoreceptors respectively. Intravitreal injections of barium chloride, a non-specific inhibitor of potassium channels in the retina and RPE or bumetanide, a selective inhibitor of the sodium-potassium-chloride cotransporter were made, targeting fluid control mechanisms. Comparison of refractive compensation to 5 mM Ba(2+) and 10(-5) M bumetanide compared with control saline injected eyes shows significant change for both positive and negative lens defocus for Ba(2+) but significant change only for negative lens defocus with bumetanide (Rx(SAL)(-10D) = -8.6 +/- .9 D; Rx(Ba2+)(-10D) = -2.9 +/- .9 D; Rx(Bum)(-10D) = -2.9 +/- .9 D; Rx(SAL)(+10D) = +8.2 +/- .9 D; Rx(Ba2+)(+10D) = +2.8 +/- 1.3 D; Rx(Bum)(+10D) = +8.0 +/- .7 D). Vitreous chamber depths showed a main effect for drug conditions with less depth change in response to defocus shown for Ba(2+) relative to Saline, while bumetanide injected eyes showed a trend to increased depth without a significant interaction with applied defocus. The results indicate that both K channels and the NKCC cotransporter play a role in refractive compensation with NKCC blockade showing far more specificity for negative, compared with positive, lens defocus. Probable sites of action relevant to refractive control include the apical retinal pigment epithelium membrane and the photoreceptor/ON bipolar synapse. The similarities between the biometric effects of NKCC inhibition and biometric reports of the blockade of the retinal ON response, suggest a possible common mechanism. The selective inhibition of refractive compensation to negative lens in chick by loop diuretics such as bumetanide suggests that these drugs may be effective in the therapeutic management of human myopia.

A role for aquaporin-4 during induction of form deprivation myopia in chick.

PURPOSE: Aquaporins (AQP) form a family of specialized water channels known to transport water across cell membranes and reduce osmotic gradients. The isoform AQP4 is highly expressed in the astroglia of the brain and Müller cells in the retina. In the brain, AQP4 play a role in the control of cerebral edema by shunting excess fluid into blood vessels and by upregulating during conditions of hyperosmolarity. Thus, on the basis of the hyperosmolarity seen across the retina and choroid of hatchling chickens made myopic by form deprivation (FD), we predicted an upregulation of retinal AQP4 expression during induction of myopia. METHODS: Two-day-old hatchling chicks were monocularly form-deprived for 48, 72, or 96 h, and then after biometric assessment, the eyes of these animals and the normal controls of the same age were enucleated. Retinal tissue was prepared either for western blot analysis to show the presence of the AQP4 protein in the chick retina or for immunolocalization using polyclonal AQP4 antibodies to determine regional distribution and intensity of labeling during the induction of form deprivation myopia (FDM). RESULTS: As expected, ultrasonography demonstrated that all post hatchling eyes showed rapid elongation with occluded eyes elongating faster than fellow eyes or normal controls and becoming progressively more myopic with the duration of visual deprivation. Western blot analyses revealed an approximately 30 kDa band immunoreactive for AQP4 protein and confirmed the presence of AQP4 in chicks. Immunohistochemical staining showed the greatest positive immunoreactivity for antibodies to AQP4 in the inner retina along the vitreoretinal interface, nerve fiber layer, ganglion cell layer, and inner plexiform layer in all animals. The control eyes showed relatively constant levels of AQP4 expression until day 5 after which the level appeared to decrease. By comparison, positive AQP4 immunoreactivity in the nerve fiber layer increased significantly over the first 48 h in form-deprived eyes and in fellow eyes and then decreased over the next 48 h but not to the level of expression in the normal untreated eyes. CONCLUSIONS: This is the first study to demonstrate the presence of AQP4 protein in the chick retina and to associate AQP4 expression in the inner retina with the initiation of form deprivation and the period of fastest axial elongation. This increased expression of AQP4 channels near the vitread border during the time of rapid growth suggests a role for AQP4 as a conduit for movement of retinal fluid into the vitreous in form-deprived chicks.