1. Visual Development & Amblyopia Adler’s Physiology of the Eye 10th Ed. Chapter 21- Development of Vision in Infancy Chapter 27 - Activity-Dependent Development of Retinogeniculate Projections Chapter 31 - Visual Deprivation Human Amblyopia - Some current issues

2. Visual Development: Hierarchical Model of Vision

3. Visual Development: Development of Contrast Sensitivity VEP DEM FPL Peak temporal frequency (low spatial frequency)

4. Grating Acuity Visual Development: Development of Contrast Sensitivity Peak spatial frequency (low temporal frequency) Sweep VEP

5. Adult Visual Development: Temporal Acuity Precedes Spatial VEP 4 years psychophysically 6 years psychophysically TemporalSpatial

6. Visual Development: Response Latency Shows Rapid Change VEP 50 msec difference in adults 125 msec difference at 5 mo

7. Nasal precedes temporal Visual Development: OKN Asymmetry Improves rapidly over 6 mo VEP DEM

8. Visual Development: Vernier Acuity FPL Sweep VEP (filled)FPL

9. Visual Development: Binocular Vision VEP (solid) FPL (open)

10. Visual Development: Binocular Vision FPL Global stereopsis emerges at 3-5 mo Global stereopsis improves 8 fold in first year Protracted development of adult values

11. Brain Weight:Doubles in 9 mo/90% by 6 yr Cortical Thickness: V1 6 mo/parietal 12 yr/temporal 16 yr Neuronal Density:V1 5 mo/frontal 7 yr Synaptic Density:V1 peaks 4 mo then declines to 11yr frontal peaks 1 yr then declines to 16yr Cortical Metabolism:Peaks 4 yr then declines to 15yr White Matter:Peaks 2 yr and continues to 30 yrs Regionally Specific and Non-Linear Facts and Figures

12. Gross Cortical Development lissencephalic

13. Regionally Specific Growth Sowell ER, Thompson PM, Leonard CM, Welcome SE, Kan E, Toga AW. Longitudinal mapping of cortical thickness and brain growth in normal children. J Neurosci. 2004 Sep 22;24(38):8223-31. gain loss Ages 5-11

14. Visual Behaviors Follow Distinct Time Courses Critical periods

15. Light Visual Cortex Development: Multiple Stages First Binocular Stage

16. Visual Cortex Development: Retinal Waves Serve to fine tune local specificy For eye of origin, retinotopy, on/off

17. Visual Cortex Development: Retinogeniculate Prenatal, uses Spontaneous activity

18. Visual Cortex Development: Geniculocortical Postnatal, experience dependent

19. Visual Cortex Development: Ocular Dominance Layer 4c

20. Visual Cortex Development: Ocular Dominance Columns In normal development each eye acquires an equal amount of territory

21. Visual Cortex Development: Postnatal Development of ODC

22. Visual Cortex Development: Competitive Model Competition, with ‘ a little help from your friends’

23. present at birth Normal DevelopmentMonoc. Deprivation XXX XX Normally, it is useful to be able to fine tune eye alignment after birth Visual Cortex Development: Competitive Model Layer 4c

24. Visual Cortex Development: Three-Eyed Frog Tectum Columns seem to be a general consequence of competition for connections

25. Visual Cortex Development: Spontaneous Activity Correlated neural activity is important

26. Hebb’s Rule ‘winner-take-all’ cooperation between similar inputs in a positive feedback cycle Visual Cortex Development: Cooperative Model

27. Visual Cortex Development: Mechanism for Cooperation/Competition Neurotransmitter Postsynaptic target cell Neural growth factor

28. Developmental Plasticity: Monocular Deprivation * Actually more severe than binocular deprivation * Minimal effect if done to adults * Retina and LGN quite normal

29. ODC sharper than normal No binocular integration Developmental Plasticity: Experimental Strabismus

30. Developmental Plasticity: Cytochrome Oxidase Weak Fixation PreferenceStrong Fixation Preference

31. Developmental Plasticity: Summary for Review This is for layer 4c

32. Human Amblyopia “Lazy Eye” Relatively common developmental visual disorder Reduced visual acuity in an otherwise healthy and properly corrected eye Associated with interruption of normal early visual experience Affects at least 2% of North American population Most common cause of vision loss in children Well characterized behaviorally, not neurologically Treated by patching in children

33. Reduced visual acuity - defining feature –Usually 20/30 - 20/60 – Impaired contrast sensitivity –Prominent at high –spatial frequencies –Central visual field is generally most affected Moderate deficits in object segmentation/recognition and spatial localization Severe deficits in binocular interactions Visual Deficits in Amblyopia Spatial Frequency Contrast Sensitivity

34. Subtypes of Amblyopia Anisometropic –Unequal refractive error between the two eyes Strabismic –Deviated eye that may or may not have unbalanced refraction Deprivation –Congenital cataract; corneal opacity; eyelid masses

35. Mechanisms of Amblyopia 2. Abnormal binocular vision  Binocularity is often changed or lost in amblyopia 1. Form deprivation  Sharp image is not formed at the retina Suppression may be necessary to avoid ‘double vision’

36. Models of Amblyopia Competition hypothesis originated with experiments in kittens in the 1960s by Hubel and Wiesel Monocular deprivation of retinal input during ‘critical’ developmental periods leads to striking abnormalities in the physiology of visual cortical neurons Binocular deprivation actually leads to less severe abnormalities Amblyopia may be a form of activity-dependent deprivation, modulated by competitive interactions

37. Site of abnormality

38. Primary visual cortex and beyond Loss of disparity sensitivity and binocular suppression in V1 (primary visual cortex) Although loss in V1 can’t explain the full abnormality - extrastriate is implicated. Barnes et al. showed with fMRI abnormalities in many visual areas beyond V1. Hypothesized that feedback connections from extrastriate to V1 may be a primary source of abnormality.

39. Abiding debate about how the strabismic and anisometropic subtypes differ from each other. Chicken and egg situation : Is amblyopia a consequence or a cause of strabismus/ anisometropia ? The relationship between performance on monocular versus binocular tests has not been well-studied. Current Issues

40. Hypothesis Impairment in binocular functions may predict the pattern of monocular deficits, and thereby help explain the mechanisms (McKee, Movshon & Levi, 2003).

41. Subjects NAgeYears of education Near acuity normal or fellow Near acuity amblyopia Control725.113.720/18- Strabismics626.313.520/2061*^ Anisometropes72814.920/2361*^ 20 adults (age 19-35) Most Subjects have a history of patch treatment in their childhood. Complete ophthalmologic examination was done to confirm diagnosis

42. General Methods Seven psychophysical Tests Monocular Tests Binocular Tests Amblyopic and fellow eye of amblyopic subjects tested separately Stronger and weaker eye of normal subjects tested separately It is difficult to achieve precise alignment of stimuli in the two eyes, and we pioneered new methods for achieving this using methods that are compatible with fMRI. Both eyes tested simultaneously - required careful stimulus alignment

43. Experiments Monocular tests –Snellen acuity –Grating acuity –Vernier acuity –Contrast sensitivity Binocular tests –Randot stereotest –Binocular motion integration –Binocular contrast integration

44. Summary - Monocular Functions Amblyopic eyes showed a deficit for all the monocular functions tested. Strabismic amblyopes are distinguished from anisometropic amblyopes by their severe loss of Vernier acuity.

45. Vernier acuity Measures the relative position of an object Much finer than Snellen or grating acuity (6-10 arc-sec of visual angle) In our normal subjects Vernier is 12 times better than grating acuity A type of hyperacuity

46. www.cnl.salk.edu/~thomas/ vernier.html Hyperacuity photoreceptor =

47. Binocular Tests - Methods Dichoptic Stimulation with Avotec Eye Tracking with Avotec/SMI System

48. Stimulus Alignment Via Perceptual Report

49. Stimulus Alignment Via Fovea Reflex Dual Eye Tracking Alternate Cover Test

50. Summary - Binocular Functions Stereopsis –Reduced in amblyopes, especially strabismics Binocular motion integration –Binocular perception impaired in amblyopes, especially strabismics

51. Can binocularity predict Vernier acuity?

52. Re-classification We reclassified amblyopes based on binocular properties. A simple pass/fail criterion was used to classify. The subjects who passed both randot stereoacuity test and binocular motion integration were assigned “binocular” (33% strabismics and 57% anisometropes passed the criteria). Those who couldn’t pass were assigned “non-binocular”

53. Result Deficits in Vernier acuity are much more severe in ‘non-binocular’ group as compared to ‘binocular’. Performance in ‘non-binocular’ subgroup can not be predicted the by snellen/grating acuities - suggesting additional factors.

54. Implications Vernier performance is better predicted by residual binocularity than by clinical subtype. Interocular suppression may be an important etiological factor in the development of amblyopia (e.g., Sireteanu, 1980; Agrawal et al., 2006).

55. fMRI experiments that study amblyopic binocular suppression directly, perhaps in comparison with binocular rivalry in normal subjects. Future Directions