This study shows the pronounced change in human foveal morphology in both the inner and outer layers of the retina from midgestion to early adulthood. Because assignment of layers is critical to SDOCT interpretation18, 19
, understanding these qualitiative and quantitative changes allows us to establish a standard reference for pediatric SDOCT. This correlation will be presented in the following paper. The second point that emerges is the marked similarity in human foveal development compared to Old World Macaca
and New World marmoset monkeys (reviewed in12, 21–23
). Human late fetal and infant necropsy retinas are scarce, especially with maximal preservation which allows detailed analysis of cellular development. There also is a marked similarity between adult monkey and human in SDOCT/histology24
. This allows us to draw inferences about human development from well-preserved monkey fetal and infant retinas of known age. It also suggests that research into neonatal development versus SDOCT images would be feasible in monkeys.
This study documents the marked changes that occur within the central human retina after midgestation. Starting at Fwk25, outward displacements of the inner retinal layers begin to form the foveal pit. Molecular analysis of the macular region beginning at Fwk8 indicates the presence of axon guidance molecules such as pigment epithelium derived factor, natriuretic peptide precursor B, collagen type IV alpha 2 and ephrin A625, 26
. These factors probably act first to repel axons and later blood vessels to form the foveal avascular zone20, 27–29
. Pit formation begins shortly after Fwk24–25 when the foveal avascular zone is formed29
, Modeling and quantitative morphology15, 16, 30
underscore the importance of the foveal avascular zone in pit development, with intraocular pressure acting on it to initiate invagination. By 13–15 months, pit formation appears complete with a single, broken layer of neurons in the pit center.
This paper documents the dramatic changes in the outer retina which mainly occur after birth. The foveal ONL contains a single layer of cones until after birth but then attains 10–12 deep thickness by 6–8 years9, 31, 32
. Cone elongation and packing are mainly postnatal events, and it is just this period in which the pit shape changes from narrow and deep to wide and shallow, presumably due to retinal stretch during eye growth16
. Cone density is 18,472 cones/mm2
at Fwk 22 before a pit is apparent, doubles to 36,294 at birth when the pit is narrow, rises to 52,787 at 15 months and at 108,439 cones/mm2
is within the Bottom end of the adult range at 3.8 years10
. Thus pit remodeling may influence early phases of cone packing16, 33
, but the cause for doubling of density between 15 months and 3.8 years is not obvious. A correlation of fibroblast growth factor expression and cone packing has been described34
, but its exact role is unclear.
Of direct interest to SDOCT imaging is the observation that from Fwk22 to birth foveal cones have short thick IS and very short OS while cones at 1–2mm have longer IS and OS. This pattern was verified in vivo through 3D mapping of premature infant photoreceptor OS on SDOCT volumes19
. This was first shown by Bach and Seefelder31
who provided the first description of human foveal development, and has been noted subsequently for monkeys8, 15, 20
and humans9, 32, 35
. This pattern is unexpected in that all descriptions of expression of opsin, synaptic proteins and other photoreceptor molecules in humans2, 5–7, 36
find expression first in and around the fovea with a subsequent progression into the periphery. Thus photoreceptor differentiation begins very early in the fovea, but further maturation is delayed until well after birth.
At birth peripheral cone IS/OS are twice as long as foveal, by 15 months foveal and peripheral IS/OS are about the same length, and by 13 years foveal OS are 4× longer than at 2mm. IS and OS growth might be suppressed to facilitate cone displacement into the fovea. However, cone density rises 1.5× between birth and 15 months when elongation begins, and then doubles between 15 months and 13 years when it finishes10
, demonstrating that very long IS and OS do not inhibit most cone packing.
An additional change within the outer retina is the postnatal elongation of cone and central rod axons. This changes the OPL from a thin layer of synaptic terminals to a layer as thick or thicker than the ONL. Photoreceptor axons are formed as a result of neuronal displacements in foveal development8, 13, 23
. Foveal photoreceptors form synapses before midgestation36
; (also see Top far right) with INL neurons. As these neurons are displaced peripherally by pit formation, photoreceptor axons elongate to keep contact. Axons must elongate further after birth when photoreceptors are displaced centrally to raise cone density. Thus photoreceptor axons form to retain synaptic integrity during these two opposing neuronal movements.
This paper expands the existing literature and shows that the human fovea develops over a very long period. Morphologically the incipient fovea can be identified at Fwk11–12 by its characteristic lamination. In the last half of gestation the pit forms by GCL, IPL and INL displacement which is finished by 1–2 years. Foveal cones change little in late gestation but in the first year after birth, they become elongated cells with long IS, OS and axons, and by 4–6 years develop the longest IS and OS in the retina. Concurrently, cones are packed into the fovea to raise cone density 10×. These processes are completed before 10 years when the fovea has its adult characteristics.
Now that technical advances in SDOCT imaging have made it possible to study pre-and neonatal human eyes, the data presented here will be critical in interpreting clinical images of retinal microstructures in young infants. These histological data provide a reference of normal development which will aid in the diagnosis of abnormal development detected in SDOCT imaging.