In previous attempts to correlate retinal function and structure, visual acuity was correlated with central retinal thickness derived from OCT measurements, e.g. in diabetic macular edema. However, the relationship was found to be poor and it was concluded that retinal thickness is a poor surrogate for visual acuity 
. Using SD-OCT and an automated segmentation technique, it was recently shown that the correlation between visual acuity and specifically the outer retinal thickness is considerably stronger than for full macular thickness suggesting that detailed image analysis is essential to find a correlation 
. Since visual acuity testing exclusively reveals foveal function but does not provide a functional map of the retina, kinetic or automated static perimetry has been used to reveal and quantify functional defects of the visual field. Using these techniques, there was a consistent relationship between the thickness of the photoreceptor layers as determined by SD-OCT and retinal sensitivity in retinitis pigmentosa, which is genetically heterogeneous group of photoreceptor degeneration 
However, these techniques do not provide an accurate correlation between retinal structural pathology and functional defects. Co-registration of microperimetry-, cSLO- and SD-OCT datasets now provides an exact overlay of functional and structural exams and reveals the functional impact of microstructural alterations in vivo.
The cross sectional data show that there can be remarkable functional preservation if the pathology spares the outer neurosensory retina that accommodates the process of phototransduction, highlighting the eminent importance of photoreceptor layer integrity for maintaining visual function 
. Notably, anti-VEGF-A therapy appeared to be ineffective to prevent such functional loss in the longitudinal interventional clinical trial. Actually, recent studies showed that VEGF-inhibition can cause dysfunction and damage of the murine retina 
There has long been the fundamental question about whether morphological changes in the neurosensory system precede functional alterations or vice versa. Our data may suggest that high-resolution imaging can detect very early retinal pathology before its progression causes functional loss as detected by functional mapping. It cannot unequivocally be decided whether there are compensatory functional mechanisms when there are sufficiently small morphological defects or whether microperimetry is methodologically limited to detect the earliest functional deficits, or both. In either case, high-resolution OCT appears superior to functional mapping to detect relevant damage of the central retina early in the disease process.
cSLO topographic imaging of the retina provides approximately 15 µm transversal resolution 
. However, if aberrations are compensated using adaptive optics, the transversal resolution of a cSLO could be improved to less than 3 µm 
. Zawadzki et al. using spectral/Fourier domain detection and a closed loop adaptive optics system achieved improved lateral resolution (~ 4 µm) of retinal images, while maintaining the high axial resolution (~6 µm) of OCT. Their instrument enabled the three-dimensional visualization of different retinal structures, e.g., microscopic blood vessels, and an en face view of the cone photoreceptor mosaic 
. Simultaneous cSLO and SD-OCT in combination with adaptive optics may have the potential to provide researchers and clinicians with near cellular-resolution information on intraretinal morphology 
Although there has been progress correlating single cone photoreceptors to the response of central visual neurons anatomical maps 
or relating retinal nerve fiber layer distribution with visual fields in glaucoma 
, this is the first report of a high-resolution structure-function correlation of pathology within the central human retina. Such a methodology is capable of revealing an unprecedented pathophysiological context in retinal disease that is highly relevant for therapeutic decision. In diseases such as X-linked retinoschisis where gene therapy has been shown to work in animal models 
, future therapeutic trials should aim to preserve the outer retinal morphology that, if still intact, may provide the patient with relatively good visual function.
A robust correlation between structural abnormalities of the retina and functional deficits may have to be established for every individual disease entity. For enhanced S-cone syndrome due to mutations in the NR2E3 gene, it has recently been shown that both increased and decreased retinal thickness are associated with retinal sensitivity loss 
. While an increase in retinal thickness was due to a foveal schisis, a decrease was due to neurodegeneration of the retina. This study shows that retinal thickness per se is a poor predictor of retinal function and it underscores the importance to correlate individual retinal layers with retinal function as performed in our study.
Current clinical practice emphasizes the development of techniques to diagnose disease in its early stages, when treatment is most effective and irreversible damage can be prevented or delayed. There is a strong need to define surrogate endpoints which may serve as a substitute for a true clinical endpoint (such as functional loss) but are more efficient 
. Since our data indicate consistent associations between high-resolution imaging and visual function and since such imaging techniques are becoming more widely available, high-resolution imaging of the retina may have a high potential to serve as surrogate endpoints in future clinical trials.