Dual-focus contact lenses for myopia control modify central retinal electrophysiology in humans.

INTRODUCTION: Dual-focus contact lenses create two focal planes, one providing a clear retinal image while the other imposes myopic defocus on the retina to slow myopia progression. This study used global-flash multifocal electroretinogram (gmfERG) response amplitudes to compare central versus peripheral retinal responses under dual-focus conditions and to assess the optimal degree of myopic defocus compared with a single-vision control lens. METHODS: Twenty participants each underwent three gmfERG trials, wearing a spectacle correction over dual-focus contact lenses with plano central power and peripheral secondary focal powers of either +2.00D, +4.00D or a plano single-vision lens. We compared amplitudes and latencies of the gmfERG direct and induced components (DC and IC) within participants, between the three different contact lens powers and at different retinal eccentricities (gmfERG ring). RESULTS: We observed significant differences in the gmfERG responses between the single-vision and dual-focus contact lenses. Overall, DC amplitudes peaked between zero and +2.00D secondary power, while IC amplitudes were maximal between +2.00D and +4.00D. Compared with the single-vision control, the greatest increase in DC and IC amplitudes while wearing dual-focus lenses occurred within the central 10° of the retina. There was no interaction effect between gmfERG ring (eccentricity) and secondary power, and no difference in the latency of the gmfERG responses between different powers. CONCLUSION: We found that dual-focus contact lenses with a +2.00D secondary power are close to that expected to induce the greatest increase in gmfERG responses relative to a single-vision lens. Dual-focus lenses produced the highest DC and IC response amplitudes relative to a single-vision lens in the central 10° of the retina. This suggests that dual-focus contact lenses slow myopia progression by modifying central rather than peripheral retinal activity.

Global-flash mfERG responses to local differences in spherical and astigmatic defocus across the human retina.

PURPOSE: Emmetropisation is essentially a visually guided, within-eye process. We investigated differences in global-flash multifocal electroretinogram (gmfERG) responses to naturally occurring differences in spherical and astigmatic defocus across the retina, which might provide a basis for guiding eye growth. METHODS: Experiment 1: The gmfERG responses (direct, DC, and induced, IC, amplitudes and latencies) recorded simultaneously from six retinal areas (15° eccentricity, spaced at 60°, areas 3.2°2 ) were correlated with the uncorrected retinal defocus measured at the six corresponding retinal locations in 20 adults with foveal refractive errors (-4.75 to +1.25D). No correcting lenses were used to avoid introduction of lens-induced aberrations and magnification. Experiment 2 investigated the effect of superimposing astigmatic defocus (+2.00/-4.00D Jackson Cross Cylinder presented at four orientations) on gmfERG responses. RESULTS: Experiment 1: DC and IC response amplitudes were greater in retinal regions naturally exposed to more hyperopic spherical defocus (DC: rho = 0.26, p = 0.005; IC: rho = 0.29, p = 0.001), but response latencies were unaffected by sign or magnitude of spherical defocus (DC: p = 0.34; IC: p = 0.40). Response amplitudes and latencies were unaffected by astigmatic defocus. Experiment 2: Rotating the JCC axis to four different orientations had no effect on the gmfERG responses (DC amplitude, p = 0.39; DC latency, p = 0.10; IC amplitude, p = 0.51; IC latency, p = 0.64). CONCLUSION: The gmfERG responses from discrete retinal areas varied with the sign and magnitude of local spherical defocus, but we found no evidence that retinal responses were affected by astigmatic defocus. Therefore, local astigmatism is unlikely to provide cues for controlling eye growth, whereas differences in response to spherical defocus between different retinal regions could potentially provide cues for controlling eye growth in emmetropisation.

Classical Short-Delay Eyeblink Conditioning in One-Year-Old Children.

Classical eyeblink conditioning (EBC) refers to the learned association between a conditioned stimulus (an auditory tone) and an unconditioned stimulus (a puff of air to the cornea). Eyeblink conditioning is often used experimentally to detect abnormalities in cerebellar-dependent learning and memory that underlies this type of associative learning. While experiments in adults and older children are relatively simple to administer using commercial equipment, eyeblink conditioning in infants is more challenging due to their poor compliance, which makes correct positioning of the equipment difficult. To achieve conditioning in one-year-old infants, a custom-made or an adapted commercial system can be used to deliver the air puff to the infant's cornea. The main challenge lies in successfully detecting and classifying the behavioral responses. We report that automated blink detection methods are unreliable in this population, and that conditioning experiments should be analyzed using frame-by-frame analysis of supplementary video camera recordings. This method can be applied to study developmental changes in eyeblink conditioning and to examine whether this paradigm can detect children with neurological disorders.

Fluoxetine Does Not Enhance Visual Perceptual Learning and Triazolam Specifically Impairs Learning Transfer.

The selective serotonin reuptake inhibitor fluoxetine significantly enhances adult visual cortex plasticity within the rat. This effect is related to decreased gamma-aminobutyric acid (GABA) mediated inhibition and identifies fluoxetine as a potential agent for enhancing plasticity in the adult human brain. We tested the hypothesis that fluoxetine would enhance visual perceptual learning of a motion direction discrimination (MDD) task in humans. We also investigated (1) the effect of fluoxetine on visual and motor cortex excitability and (2) the impact of increased GABA mediated inhibition following a single dose of triazolam on post-training MDD task performance. Within a double blind, placebo controlled design, 20 healthy adult participants completed a 19-day course of fluoxetine (n = 10, 20 mg per day) or placebo (n = 10). Participants were trained on the MDD task over the final 5 days of fluoxetine administration. Accuracy for the trained MDD stimulus and an untrained MDD stimulus configuration was assessed before and after training, after triazolam and 1 week after triazolam. Motor and visual cortex excitability were measured using transcranial magnetic stimulation. Fluoxetine did not enhance the magnitude or rate of perceptual learning and full transfer of learning to the untrained stimulus was observed for both groups. After training was complete, trazolam had no effect on trained task performance but significantly impaired untrained task performance. No consistent effects of fluoxetine on cortical excitability were observed. The results do not support the hypothesis that fluoxetine can enhance learning in humans. However, the specific effect of triazolam on MDD task performance for the untrained stimulus suggests that learning and learning transfer rely on dissociable neural mechanisms.

Excitatory binocular interactions in two cases of alternating strabismus.

PURPOSE: Individuals with alternating fixation due to strabismus have often been considered prime examples of monocular visual function. A growing body of evidence suggests, however, that, at least in the case of a fixed-angle strabismus, excitatory binocular function is possible in the strabismic visual cortex if interocular suppression is taken into account. We investigated whether excitatory binocular function might also be possible for patients with alternating strabismus. METHODS: Suprathreshold binocular interaction was tested in two individuals with alternating fixation and no amblyopia using a dichoptic motion coherence paradigm that can measure and account for interocular suppression. RESULTS: Both participants exhibited strong interocular suppression when stimuli of the same contrast were presented to each eye, whereas no such suppressive interactions were present for controls; however, in significantly reducing the contrast of the stimuli presented to the fixing eye, excitatory binocular interactions were demonstrated in both participants similar to those measured in controls without the contrast imbalance. CONCLUSIONS: The cortical mechanisms necessary for combining information from the two eyes seem to have been present but suppressed in our 2 participants with alternating fixation, just as they have been shown to be present in patients with fixed-angle strabismus.

Effect of CYP3A and ABCB1 single nucleotide polymorphisms on the pharmacokinetics and pharmacodynamics of calcineurin inhibitors: Part I.

The calcineurin inhibitors ciclosporin (cyclosporine) and tacrolimus are immunosuppressant drugs used for the prevention of organ rejection following transplantation. Both agents are metabolic substrates for cytochrome P450 (CYP) 3A enzymes--in particular, CYP3A4 and CYP3A5--and are transported out of cells via P-glycoprotein (ABCB1). Several single nucleotide polymorphisms (SNPs) have been identified in the genes encoding for CYP3A4, CYP3A5 and P-glycoprotein, including CYP3A4 -392A>G (rs2740574), CYP3A5 6986A>G (rs776746), ABCB1 3435C>T (rs1045642), ABCB1 1236C>T (rs1128503) and ABCB1 2677G>T/A (rs2032582). The aim of this review is to provide the clinician with an extensive overview of the recent literature on the known effects of these SNPs on the pharmacokinetics of ciclosporin and tacrolimus in solid-organ transplant recipients. Literature searches were performed, and all relevant primary research articles were critiqued and summarized. Influence of the CYP3A4 -392A>G SNP on the pharmacokinetics of either ciclosporin or tacrolimus appears limited. Variability in CYP3A4 expression due to environmental factors is likely to be more important than patient genotype. Influence of the CYP3A5 6986A>G SNP on the pharmacokinetics of ciclosporin is also uncertain and likely to be small. CYP3A4 may play a more dominant role than CYP3A5 in the metabolism of ciclosporin. The CYP3A5 6986A>G SNP has a well established influence on the pharmacokinetics of tacrolimus. Several studies in kidney, heart and liver transplant recipients have reported an approximate halving of tacrolimus dose-adjusted trough concentrations and doubling of tacrolimus dose requirements in heterozygous or homozygous carriers of a CYP3A5*1 wild-type allele compared with homozygous carriers of a CYP3A5*3 variant allele. Carriers of a CYP3A5*1 allele take a longer time to reach target blood tacrolimus concentrations. Influence of ABCB1 3435C>T, 1236C>T and 2677G>T/A SNPs on the pharmacokinetics of ciclosporin and tacrolimus remains uncertain, with inconsistent results. Genetic linkage between the three variant genotypes suggests that the pharmacokinetic effects are complex and not related to any one ABCB1 SNP. It is likely that these polymorphisms exert a small but combined effect, which is additive to the effects of the CYP3A5 6986A>G SNP. In liver transplant patients, recipient and donor liver genotypes may act together in determining overall drug disposition, hence the importance of assessing both. Studies with low patient numbers may account for many inconsistent results to date. Meta-analyses of the current data should help resolve some discrepancies. The majority of studies have only evaluated the effects of individual SNPs; however, multiple polymorphisms may interact to produce a combined effect. Further haplotype analyses are likely to be useful. It is not yet clear whether pharmacogenetic profiling of calcineurin inhibitors will be a useful clinical tool for personalizing immunosuppressant therapy.

Effect of CYP3A and ABCB1 single nucleotide polymorphisms on the pharmacokinetics and pharmacodynamics of calcineurin inhibitors: Part II.

The calcineurin inhibitors ciclosporin (cyclosporine) and tacrolimus are immunosuppressant drugs used for the prevention of organ rejection following transplantation. Both agents are metabolic substrates for cytochrome P450 (CYP) 3A enzymes - in particular, CYP3A4 and CYP3A5 - and are transported out of cells via P-glycoprotein (ABCB1). Several single nucleotide polymorphisms (SNPs) have been identified in the genes encoding for CYP3A4, CYP3A5 and P-glycoprotein, including CYP3A4 -392A>G (rs2740574), CYP3A5 6986A>G (rs776746), ABCB1 3435C>T (rs1045642), ABCB1 1236C>T (rs1128503) and ABCB1 2677G>T/A (rs2032582). The aim of this review is to provide the clinician with an extensive overview of the recent literature on the known effects of these SNPs on the pharmacodynamics of ciclosporin and tacrolimus in solid-organ transplant recipients. Literature searches were performed and all relevant primary research articles were critiqued and summarized. There is no evidence that the CYP3A4 -392A>G SNP has an effect on the pharmacodynamics of either ciclosporin or tacrolimus; however, studies have been limited. For patients prescribed ciclosporin, the CYP3A5 6986A>G SNP may influence long-term survival, possibly because of a different metabolite pattern over time. This SNP has no clear association with acute rejection during ciclosporin therapy. Despite a strong association between the CYP3A5 6986A>G SNP and tacrolimus pharmacokinetics, there is no consistent evidence of organ rejection as a result of genotype-related under-immunosuppression. This is likely to be explained by the practice of performing tacrolimus dose adjustments in the early phase after transplantation. The effect of the CYP3A5 6986A>G SNP on ciclosporin- and tacrolimus-related nephrotoxicity and development of hypertension is unclear. Similarly, the ABCB1 SNPs exert no clear influence on either ciclosporin or tacrolimus pharmacodynamics, with studies showing conflicting results in regard to the main parameters of acute rejection and nephrotoxicity. In kidney transplant patients, consideration of the donor kidney genotype rather than the recipient genotype may be more important when assessing development of nephrotoxicity. Studies with low patient numbers may account for many inconsistent results to date. The majority of studies have only evaluated the effects of individual SNPs; however, multiple polymorphisms may interact to produce a combined effect. Further haplotype analyses are likely to be useful, particularly ones that consider both donor and recipient genotype. The effects of polymorphisms associated with the pregnane X receptor, organic anion transporting polypeptides, calcineurin inhibitor target sites and immune response pathways need to be further investigated. A large standardized clinical trial is now required to evaluate the relationship between the pharmacokinetics and pharmacodynamics of CYP3A5-mediated tacrolimus metabolism, particularly in regard to the outcomes of acute rejection and nephrotoxicity. It is not yet clear whether pharmacogenetic profiling of calcineurin inhibitors will be a useful clinical tool for personalizing immunosuppressant therapy.