First, this study does not speak to the proximal source of the ISe signal. The role mitochondria, as well as other structures in this region,
16 play in producing this signal is still to be determined. Second, as mentioned in Methods, our measurement does not distinguish between bands of lower reflectance versus thinner bands. However, our analyses with thinner ISe segments and visual inspection clearly indicate that while the patients' ISe bands may be thinner, they are also less intense. Third, we cannot be sure that residual cones are not contributing to the ISe band seen in the achromats and cone dystrophy patients. Many achromats have some functioning cones, while patients with cone dystrophy can maintain some cone function as well, although we have shown that the ISe band is present even when cone thresholds are markedly elevated.
11 Fourth, and related to this point, we do not know if the ISe band would have a normal relative intensity if a patient lost all rod receptors, but maintained normal cone function. We have seen a lower relative ISe intensity in regions of the retina in RP. However, we cannot be sure the cones are functioning normally in these regions without further work with two-color threshold measurements.
11 Finally, it remains to be seen if the intensity of the ISe band is affected under other conditions. For example, we are particularly interested in patients with clear functional loss as documented on visual fields and multifocal ERGs, but who have reasonably normal appearing fdOCT scans.
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