No / In normal vision, detecting a kink (a change in orientation) in a line is scale invariant: it depends solely on the length/width ratio of the line (D. Whitaker, D. M. Levi, & G. J. Kennedy, 2008). Here we measure detection of a change in the orientation of lines of different length and blur and show that strabismic amblyopia is qualitatively different from normal foveal vision, in that: 1) stimulus blur has little effect on performance in the amblyopic eye, and 2) integration of orientation information follows a different rule. In normal foveal vision, performance improves in proportion to the square root of the ratio of line length to blur (L: B). In strabismic amblyopia improvement is proportional to line length. Our results are consistent with a substantial degree of internal neural blur in first-order cortical filters. This internal blur results in a loss of scale invariance in the amblyopic visual system. Peripheral vision also shows much less effect of stimulus blur and a failure of scale invariance, similar to the central vision of strabismic amblyopes. Our results suggest that both peripheral vision and strabismic amblyopia share a common bottleneck in having a truncated range of spatial mechanisms-a range that becomes more restricted with increasing eccentricity and depth of amblyopia. / Leverhulme Trust, Wellcome Trust, NIH

Yes / Adults with amblyopia ('lazy eye'), long-standing strabismus (ocular misalignment) or both typically do not experience visual symptoms because the signal from weaker eye is given less weight than the signal from its fellow. Here we examine the contribution of the weaker eye of individuals with strabismus and amblyopia with both eyes open and with the deviating eye in its anomalous motor position. The task consisted of a blue-on-yellow detection task along a horizontal line across the central 50 degrees of the visual field. We compare the results obtained in ten individuals with strabismic amblyopia with ten visual normals. At each field location in each participant, we examined how the sensitivity exhibited under binocular conditions compared with sensitivity from four predictions, (i) a model of binocular summation, (ii) the average of the monocular sensitivities, (iii) dominant-eye sensitivity or (iv) non-dominant-eye sensitivity. The proportion of field locations for which the binocular summation model provided the best description of binocular sensitivity was similar in normals (50.6%) and amblyopes (48.2%). Average monocular sensitivity matched binocular sensitivity in 14.1% of amblyopes' field locations compared to 8.8% of normals'. Dominant-eye sensitivity explained sensitivity at 27.1% of field locations in amblyopes but 21.2% in normals. Non-dominant-eye sensitivity explained sensitivity at 10.6% of field locations in amblyopes but 19.4% in normals. Binocular summation provided the best description of the sensitivity profile in 6/10 amblyopes compared to 7/10 of normals. In three amblyopes, dominant-eye sensitivity most closely reflected binocular sensitivity (compared to two normals) and in the remaining amblyope, binocular sensitivity approximated to an average of the monocular sensitivities. Our results suggest a strong positive contribution in habitual viewing from the non-dominant eye in strabismic amblyopes. This is consistent with evidence from other sources that binocular mechanisms are frequently intact in strabismic and amblyopic individuals.

Visual acuity is reduced when optotypes are viewed in the presence of surrounding contours. This reduction in acuity is known as the crowding effect and is thought to be caused by a varying combination of contour interaction, gaze instability and attention. Traditional studies have used single optotypes surrounded by flanking bars to investigate crowding. Such targets may not realistically replicate the crowding effect inherent in clinical vision charts. The aim of this thesis was to systematically investigate the effect of crowding on visual thresholds in subjects with normal vision and in subjects with amblyopia, using specially designed charts. In the 1st and 2nd experiment, contour interaction was assessed using a high (80 %) and low contrast (5.8%) Sheridan Gardiner repeat letter (SGRL) chart in subjects with normal vision. The effect of contour interaction was investigated by varying the inter-letter separation in the SGRL chart. Significant contour interaction was obtained at the abutting condition for both the contrast conditions. In the 3rd experiment the same protocol was repeated but in amblyopes. Significant contour interaction was obtained at 0.2 letter separation and the abutting condition for both the contrast conditions. The effect of contour interaction appears to be less for low contrast than for high contrast letters in normal, non-amblyopic and amblyopic eyes. Finally, in the 4th experiment a Sheridan Gardiner Complex Interaction (SGCI) chart that requires imposed gaze fixations was constructed to measure visual acuity in normal’s and amblyopes. The effect of any gaze instability on crowding was investigated by comparing SGRL thresholds to SGCI thresholds. The SGCI thresholds were higher than the SGRL thresholds at all the separations measured, suggesting an important effect of gaze instability on crowding. In conclusion, this research has shown that gaze instability is an important component of the crowding effect for letter chart acuity measurements. Visual acuity especially when screening for amblyopia should be measured using a whole optotype chart that requires optotype to optotype fixation.

A holy grail in neuroscience is being able to control plasticity to facilitate recovery from insult in the adult brain. Despite success in animal models, few therapies have translated from bench to bedside. This thesis is aimed at addressing 2 major stumbling blocks in translation. The first gap is in our understanding of the mechanisms of plasticity-enhancing therapies, and the second is in our understanding the relevance of those mechanisms for human development. In chapters 2 and 3, I address the first gap by asking whether fluoxetine, a selective serotonin reuptake inhibitor, which reinstates juvenile-like plasticity in adult animals, reinstates a juvenile-like synaptic environment. We found evidence to suggest that fluoxetine is neuroprotective, as it rescued all of the MD-driven changes, but surprisingly we found no evidence that fluoxetine recreated a juvenile-like synaptic environment, with the exception of Ube3A. Ube3A is necessary for critical period plasticity, indicating that Ube3A may play a crucial in enhancing plasticity in the adult cortex. In chapter 4, I address whether D-serine, an amino acid that has similar effects to fluoxetine in terms of both plasticity and anti-depression, shares a common neurobiological signature with fluoxetine. I found that D-serine’s effects were strikingly similar to fluoxetine, with respect to markers of the E/I balance, indicating that it may be an effective alternative to fluoxetine. In chapter 5, I address the second gap by studying the development of 5 glutamatergic proteins in human V1. Some changes occurred early, as would be predicted from animals studies, while other changes were protracted, lasting into the 4th decade. These results will help guide the use of treatments, like fluoxetine, which effect glutamatergic proteins. iv Together the findings in this thesis significantly advances our understanding of the mechanisms involved in restating plasticity in the adult cortex, and their relevance to humans. / Dissertation / Doctor of Philosophy (PhD) / Neurons change to rewire, adapt, and recover. This plasticity is greatest early in development, so much research has focused on bringing it back in adults. There has been amazing progress in animal models, but this has not translated to humans. Two reasons for this are that we do not fully understand the mechanisms of these treatments in animals or whether those mechanisms are relevant for humans. My thesis addresses this by studying how 2 treatments, fluoxetine and D-serine, affect proteins that are important for plasticity, and how those proteins develop in the humans. I found that these treatments are neuroprotective, but do not recreate a younger state. One interesting standout is an increase in Ube3A, which is essential for juvenile plasticity. I also found that much of human development is similar to animals, but the time course for some proteins is uniquely prolonged in humans. These findings have implications for the use of plasticity-enhancing treatments at different ages.

Yes / Purpose: Two binocular sources of information serve motion-in-depth (MID) perception: changes in disparity over time (CD), and interocular velocity differences (IOVD). While CD requires the computation of small spatial disparities, IOVD could be computed from a much lower-resolution signal. IOVD signals therefore might still be available under conditions of binocular vision impairment (BVI) with limited or no stereopsis, e.g. amblyopia. Methods: Sensitivity to CD and IOVD was measured in adults who had undergone therapy to correct optical misalignment or amblyopia in childhood (n=16), as well as normal vision controls with good stereoacuity (n=8). Observers discriminated the interval containing a smoothly-oscillating MID “test” stimulus from a “control” stimulus in a two-interval forced choice (2IFC) paradigm. Results: Of the BVI observers with no static stereoacuity (n=9), one displayed evidence for sensitivity to IOVD only, while there was otherwise no sensitivity for either CD or IOVD in the group. Generally, BVI observers with measurable stereoacuity (n=7) displayed a pattern resembling the control group: showing a similar sensitivity for both cues. A neutral-density (ND) filter placed in front of the fixing eye in a subset of BVI observers did not improve performance. Conclusions: In one BVI observer there was preserved sensitivity to IOVD but not CD, though overall only those BVI observers with at least gross stereopsis were able to detect disparity-based or velocity-based cues to MID. The results imply that these logically distinct information sources are somehow coupled, and in some cases BVI observers with no stereopsis may still retain sensitivity to IOVD. / UK Biotechnology and Biological 498 Sciences Research Council (BBSRC): BB/M002543/1 (Alex R. Wade) BB/M001660/1 (Julie 499 M. Harris) and BB/M001210/1 (Marina Bloj)

PURPOSE: Gait during obstacle negotiation is adapted in visually normal subjects whose vision is temporarily and unilaterally blurred or occluded. This study was conducted to examine whether gait parameters in individuals with long-standing deficient stereopsis are similarly adapted. METHODS: Twelve visually normal subjects and 16 individuals with deficient stereopsis due to amblyopia and/or its associated conditions negotiated floor-based obstacles of different heights (7-22 cm). Trials were conducted during binocular viewing and monocular occlusion. Analyses focused on foot placement before the obstacle and toe clearance over it. RESULTS: Across all viewing conditions, there were significant group-by-obstacle height interactions for toe clearance (P < 0.001), walking velocity (P = 0.003), and penultimate step length (P = 0.022). Toe clearance decreased (approximately 0.7 cm) with increasing obstacle height in visually normal subjects, but it increased (approximately 1.5 cm) with increasing obstacle height in the stereo-deficient group. Walking velocity and penultimate step length decreased with increasing obstacle height in both groups, but the reduction was more pronounced in stereo-deficient individuals. Post hoc analyses indicated group differences in toe clearance and penultimate step length when negotiating the highest obstacle (P < 0.05). CONCLUSIONS: Occlusion of either eye caused significant and similar gait changes in both groups, suggesting that in stereo-deficient individuals, as in visually normal subjects, both eyes contribute usefully to the execution of adaptive gait. Under monocular and binocular viewing, obstacle-crossing performance in stereo-deficient individuals was more cautious when compared with that of visually normal subjects, but this difference became evident only when the subjects were negotiating higher obstacles; suggesting that such individuals may be at greater risk of tripping or falling during everyday locomotion.

PURPOSE: To evaluate whether the Amblyopia and Strabismus Questionnaire (A&SQ) is a suitable instrument for the assessment of vision-related quality-of life (VR-QoL) in individuals with strabismus and/or amblyopia. METHODS: The A&SQ was completed by 102 individuals, all of whom had amblyopia, strabismus, or both. Rasch analysis was used to evaluate the usefulness of individual questionnaire items (i.e., questions); the response-scale performance; how well the items targeted VR-QoL; whether individual items showed response bias, depending on factors such as whether strabismus was present; and dimensionality. RESULTS: Items relating to concerns about the appearance of the eyes were applicable only to those with strabismus, and many items showed large ceiling effects. The response scale showed disordered responses and underused response options, which improved after the number of response options was reduced from five to three. This change improved the discriminative ability of the questionnaire (person separation index increased from 1.98 to 2.11). Significant bias was found between strabismic and nonstrabismic respondents. Separate Rasch analyses conducted for subjects with and without strabismus indicated that all A&SQ items seemed appropriate for individuals with strabismus (Rasch infit values between 0.60 and 1.40), but several items fitted the model poorly in amblyopes without strabismus. The AS&Q was not found to be unidimensional. CONCLUSIONS: The findings highlight the limitations of the A&SQ instrument in the assessment of VR-QoL in subjects with strabismus and especially in those with amblyopia alone. The results suggest that separate instruments are needed to quantify VR-QoL in amblyopes with and without strabismus.

L’amblyopie est un trouble développemental de la vision binoculaire. Elle est typiquement caractérisée par des atteintes de l’acuité visuelle et de la stéréoscopie. Toutefois, de plus en plus d’études indiquent la présence d’atteintes plus étendues telles que les difficultés d’attention visuelle ou de lecture. L’amblyopie est généralement expliquée par une suppression interoculaire au niveau cortical, considérée comme chronique ou permanente à l’extérieur de la période développementale. Or, un nombre croissant d’études suggèrent que des interactions binoculaires normales seraient présentes chez les amblyopes adultes. Dans une première étude, nous avons tenté d’identifier un marqueur électrophysiologique de la vision binoculaire. Nous avons enregistré des potentiels évoqués visuels chez des observateurs normaux à qui l’on a induit une dysfonction binoculaire. Les interactions binoculaires étaient caractérisées à l’aide de patrons (facilitation, moyennage et suppression) en comparant les réponses monoculaires et binoculaires. De plus, ces interactions étaient quantifiées à partir d’index d’intégration continus en soustrayant la somme des réponses monoculaires de la réponse binoculaire. Les résultats indiquaient que les patrons d’interaction n’étaient pas optimaux pour estimer les performances stéréoscopiques. Ces dernières étaient, en revanche, mieux expliquées par notre index d’intégration binoculaire. Ainsi, cette étude suggère que l’électrophysiologie est un bon prédicteur de la vision binoculaire. Dans une deuxième étude, nous avons examiné les corrélats neuronaux et comportementaux de la suppression interoculaire chez des amblyopes adultes et des observateurs normaux. Des potentiels évoqués visuels stationnaires ont été enregistrés en utilisant un paradigme de suppression par flash. La suppression était modulée par un changement de contraste du stimulus flash (10, 20, 30, ou 100%), ou le suppresseur, qui était présenté soit dans l’œil dominant ou non-dominant (ou amblyope). Sur le plan comportemental, la suppression interoculaire était observée indépendamment de l’œil stimulé par le flash chez les contrôles. Au contraire, chez les amblyopes, la suppression était asymétrique (c’est-à-dire supérieure lorsqu’elle provenait de l’œil dominant), ce qui suggérait une suppression chronique. De manière intéressante, l’œil amblyope a supprimé l’œil dominant à haut niveau de contraste. Sur le plan électrophysiologique, l’effet de suppression interoculaire observé à la région occipitale était équivalent dans chaque groupe. Toutefois, les réponses électrophysiologiques à la région frontale chez les amblyopes n’étaient pas modulées comme celles des contrôles; la suppression de l’œil amblyope était manifeste même à bas contraste. Nous résultats supportent ainsi l’existence d’interaction binoculaire fonctionnelle chez les amblyopes adultes ainsi que l’implication d’un réseau cortical étendu dans la suppression interoculaire. En somme, l’amblyopie est une condition complexe dont les atteintes corticales et les déficits fonctionnels semblent globaux. L’amblyopie ne doit plus être considérée comme limitée à une dysfonction de l’aire visuelle primaire. La suppression interoculaire semble un point central de cette problématique, mais encore beaucoup d’études seront nécessaires afin de déterminer l’ensemble des mécanismes impliqués dans celle-ci. / Amblyopia is a developmental dysfunction of binocular vision. It is typically characterized by visual acuity and stereopsis deficits. However, presence of more spread deficits such as problems in visual attention and reading are beginning to be reported in literature. Amblyopia is generally explained by interocular suppression at cortical level, which is considered to be chronic or permanent outside the developmental period. Nevertheless, a growing body of evidence suggests that normal binocular interactions are still present in amblyopic adults. In the first study, we tried to establish an electrophysiological marker of binocular vision. Visual evoked potentials (VEPs) were recorded in normal observers for whom binocular dysfunction was induced. Patterns of binocular interaction were categorized (facilitation, averaging or suppression) by comparing monocular and binocular responses. Quantitative and continuous indexes of binocular integration were also calculated (binocular response minus the sum of monocular responses). Results indicated that patterns of interaction were not optimal to account for stereoscopic performance. The latter was, however, best explained by binocular integration indexes. This study shows evidence of predicting binocular vision based on a novel index that allows continuous quantification of binocular transient-VEP responses. In the second study, we examined the behavioural and neural correlates of interocular suppression in amblyopic adults and controls using a flash suppression paradigm while recording steady-state visual evoked potentials (ssVEP). The strength of suppression was manipulated by changing the contrast (10, 20, 30 or 100%) of the "flash", or the suppressor, and the stimulus was presented either in the dominant (or fellow) or non-dominant (or amblyopic) eye. At the behavioural level, interocular suppression was found regardless the eye origin of the flash for normal observers, but was asymmetric in the amblyopes, so that the suppression from the fellow eye was stronger, supporting a putative chronic suppression. Interestingly, the amblyopic eye suppressed the dominant eye at the highest contrast level. At the electrophysiology level, interocular suppression effects found over the occipital region were equivalent in both groups. However, ssVEP responses over the frontal region in the amblyopic observers were not modulated as those in controls; suppression of the amblyopic eye was manifest even at low contrast levels. Our findings support the existence of functional binocular interaction in adult amblyopia and the implication of a widespread cortical network in interocular suppression. To conclude, amblyopia is a complex condition with widespread cortical and functional deficits. It seems clear that it can’t be limited to a primary visual cortex dysfunction. Interocular suppression seems a core mechanism of the problematic, but more studies are necessary to determine more precise mechanisms implicated.

Submitted by Ana Lúcia Torres (bfmhuap@gmail.com) on 2017-09-19T15:20:57Z No. of bitstreams: 2 license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) COMPARAÇÃO ENTRE O PEVP E O PERG DE CRIANÇAS COM AMBLIOPIA ESTRÁBICA E ANISOMETROPICA 1_3 V5.pdf: 3334834 bytes, checksum: f21a6dfb6b0e7fbc0eb2ef6452f3f4c0 (MD5) / Approved for entry into archive by Ana Lúcia Torres (bfmhuap@gmail.com) on 2017-09-19T15:21:17Z (GMT) No. of bitstreams: 2 license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) COMPARAÇÃO ENTRE O PEVP E O PERG DE CRIANÇAS COM AMBLIOPIA ESTRÁBICA E ANISOMETROPICA 1_3 V5.pdf: 3334834 bytes, checksum: f21a6dfb6b0e7fbc0eb2ef6452f3f4c0 (MD5) / Made available in DSpace on 2017-09-19T15:21:17Z (GMT). No. of bitstreams: 2 license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) COMPARAÇÃO ENTRE O PEVP E O PERG DE CRIANÇAS COM AMBLIOPIA ESTRÁBICA E ANISOMETROPICA 1_3 V5.pdf: 3334834 bytes, checksum: f21a6dfb6b0e7fbc0eb2ef6452f3f4c0 (MD5) Previous issue date: 2017 / Universidade Federal Fluminense. Centro de Ciência Médicas / A ambliopia é uma desordem neurológica do desenvolvimento visual que se manifesta com a redução de capacidades sensoriais em ambos os olhos ou mais comumente de forma monocular, diante da total correção óptica e na ausência de anormalidades do exame clínico. Está associada ao estrabismo e a anisometropia e menos frequentemente à privação visual. As ambliopias estrábica e anisometrópicas apresentam diferenças nas suas fisiopatologias. Comparamos as respostas eletrofisiológicas das ambliopias estrábica e anisometrópicas com o eletroretinograma padrão (PERG) e o potencial evocado visual padrão (PVEP). Cinquenta e seis pacientes, 18 crianças amblíopes anisometrópicas hipermetrópicas (idade média e desviopadrão 9,7 ± 2,5); 19 crianças com ambliopia estrábica esotrópica (idade média e desvio padrão 10,3 ± 2,6) e 19 crianças emétropes normais (idade média e desvio-padrão 10,1 ± 2,2) foram divididos em três grupos. Após o exame oftalmológico de rotina, o eletroretinograma padrão (PERG) e o potencial evocação visual padrão (PVEP) foram registrados em respostas a um estímulo de padrão reverso à taxa de duas reversões/segundo. A diferença entre ambliopia anisometrópica hipermetrópica e ambliopia estrábica em relação às latências das ondas P100 / P50 / N95 (p = 0,055 / 0,855 / 0,132) e as amplitudes P100 / P50 / N95 (p = 0,980 / 0,095 / 0,045) não foi estatisticamente significante. No entanto, houve uma diferença estatística significante entre a ambliopia estrábica e os controles com relação às latências das ondas P100 / P50 / N95 (p = 0,000 / 0,006 / 0,004). Nossos achados indicam que, apesar das diferenças clínicas e fisiopatológicas entre pacientes amblíopes estrábicos esotrópicos e os pacientes com ambliopia anisometrópica hipermetrópica, não foram encontradas diferenças nas respostas de PVEP e PERG. Os componentes anormais do PVEP e PERG em crianças amblíopes podem refletir uma disfunção da retina e da via visual. / Amblyopia is a neurological disorder of visual development manifested by the reduction of sensory abilities in both eyes or more commonly monocular in the face of total optical correction and absence of clinical examination abnormalities. It is associated with strabismus and anisometropia, and less often with visual deprivation. Strabismus amblyopia and anisometropic amblyopia present clinical differences and their pathophysiology. We compared the electrophysiological responses of the strabismic and anisometropic amblyopia with the pattern electroretinogram (PERG) and the pattern visual evoked potential (PVEP). Fifty-six patients, 18 hypermetropic anisometropic amblyopic children (mean age and standard deviation 9.7 ± 2.5); 19 children with esotropic strabismus amblyopia (mean age and standard deviation 10.3 ± 2.6) and 19 normal emetopic children (mean age and standard deviation 10.1 ± 2.2) were divided into three groups. After routine ophthalmologic examination, the pattern electroretinogram (PERG) and standard visual evoked potential (PVEP) were recorded in responses to a reverse pattern stimulus at the rate of two reversions/second. The difference between hypermetropic anisometropic amblyopia and strabismus esotropic amblyopia in relation to P100 / P50 / N95 wave latencies (p = 0.055 / 0.855 / 0.132) and P100 / P50 / N95 amplitudes (p = 0.980 / 0.095 / 0.045) was not statistically significant. However, there was a statistically significant difference between strabismic amblyopia and controls with respect to P100 / P50 / N95 wave latencies (p = 0.000 / 0.006 / 0.004). Our findings indicate that, despite clinical and pathophysiological differences between esotropic strabismus-amblyopic patients and patients with hypermetropic anisometropic amblyopia, no differences in PVEP and PERG responses were found. Abnormal PVEP and PERG components in amblyopic children may reflect retinal and visual pathway dysfunction.

No / PURPOSE: A computer-based interactive binocular treatment system (I-BiT) for amblyopia has been developed, which utilises commercially available 3D 'shutter glasses'. The purpose of this pilot study was to report the effect of treatment on visual acuity (VA) in children with amblyopia. METHODS: Thirty minutes of I-BiT treatment was given once weekly for 6 weeks. Treatment sessions consisted of playing a computer game and watching a DVD through the I-BiT system. VA was assessed at baseline, mid-treatment, at the end of treatment, and at 4 weeks post treatment. Standard summary statistics and an exploratory one-way analysis of variance (ANOVA) were performed. RESULTS: Ten patients were enrolled with strabismic, anisometropic, or mixed amblyopia. The mean age was 5.4 years. Nine patients (90%) completed the full course of I-BiT treatment with a mean improvement of 0.18 (SD=0.143). Six out of nine patients (67%) who completed the treatment showed a clinically significant improvement of 0.125 LogMAR units or more at follow-up. The exploratory one-way ANOVA showed an overall effect over time (F=7.95, P=0.01). No adverse effects were reported. CONCLUSION: This small, uncontrolled study has shown VA gains with 3 hours of I-BiT treatment. Although it is recognised that this pilot study had significant limitations-it was unblinded, uncontrolled, and too small to permit formal statistical analysis-these results suggest that further investigation of I-BiT treatment is worthwhile.