Pierre Lachapelle

Purpose Study the scotopic oscillatory potentials (OPs) in mice over a wide range of flash luminance levels using the Hilbert transform (HT) to extract new features of the high frequency components of the electroretinogram (ERG). Methods Scotopic ERGs [Intensity: − 6.3 to 0.9 log cd∙s∙m⁻²; 12 h of dark-adaptation] were obtained from adult mice (C57BL/6; n = 7). The Hilbert transform (HT) was obtained within 3 consecutive frequency bands (65–90 Hz, 90–115 Hz and 115–140 Hz), with OPs being denoised, automatically identified and analyzed. Measurements included: number of OPs, duration of the OP response, surface-under-the-curve (SUC) of the HT envelopes, implicit times, and instantaneous frequency at the HT envelope peak, mean peak time differences (PTD) between the envelopes of each frequency band (measuring their synchrony), correlation coefficient and lag between consecutive HT envelopes, as well as the number of peaks on the HT envelopes. Results The OP response duration, number of OPs and PTD all peaked for flashes between the level corresponding to the RodVmax (maximal b-wave amplitude of the rod ERG; i.e., the first asymptote of the scotopic luminance-response curve) and K (the flash luminance at which the amplitude of the b-wave is half of that of the RodVmax;), i.e., between -3.9 and -2.4 log cd∙s∙m⁻². The correlation between consecutive envelopes is close to 1 at flashes > -1.2 log cd∙s∙m⁻², with small lags (min. = 1.93 ± 0.45 ms at − 1.2 log cd∙s∙m⁻²), then gradually drops to 0.81 ± 0.02 at the dimmest flash intensity (with a max. lag = 14.76 ± 8.92 ms at − 5.1 log cd∙s∙m⁻²). Finally, we found that the single OP burst (i.e., a single HT envelope peak) seen at flash intensities > − 1.2 log cd∙s∙m⁻² progressively divided in two (or more) OP bursts (i.e., multiple HT envelope peaks) with gradually dimmer flashes. Conclusions Our HT method enabled the analysis of the OP response without the subjective interpretation of the experimenter. Analysis of the scotopic OPs at dim flashes with the HT revealed a novel feature of the OP response not yet reported elsewhere, namely: a split of the OP response into two (or more) distinct bursts. Furthermore, the synchrony peak (measured with the PTD) matched the peak in OP response duration between K and RodVmax, suggesting a disorganization (or dephasing) of the retinal signal in ERGs evoked for weaker flashes. The increased synchronization and correlation of the single burst observed for the strongest flashes could suggest an optimization or saturation of the retinal response. We believe that these novel features of the OP components of the ERG went unnoticed given that previous studies did not use weak enough flashes and failed to recognize the added value that time and frequency domain analysis of the ERG (such as what is achieved with the HT) brings to the interpretation (and our understanding) of the retinal response.

The sub-retina, composed of the choroid and the retinal pigment epithelium (RPE), bears a critical role in proper vision. In addition to phagocytosis of photoreceptor debris, the RPE shuttles oxygen and nutrients to the neuroretina. For their own energy production, RPE cells mainly rely on lactate, a major by-product of glycolysis. Lactate in turn is believed to convey most of its biological effects via the HCAR1 receptor. Here, we show that the lactate-specific receptor, HCAR1, is exclusively expressed in the RPE cells and that Hcar1 ^−/− mice exhibit a substantially thinner choroid vasculature during development. Notably, the angiogenic properties of lactate on the choroid are impacted by the absence of Hcar1 . Hcar1 -deficient mice exhibit elevated endoplasmic reticulum (ER) stress along with eIF2α phosphorylation, a significant decrease in the global protein translation rate, and a lower proliferation rate of choroidal vasculature. Strikingly, inhibition of the Integrated Stress Response using an inhibitor of eIF2α phosphorylation (ISRIB) restores protein translation and rescues choroidal thinning. These results provide evidence that lactate signalling via HCAR1 is important for choroidal development/angiogenesis and highlight the importance of this receptor in establishing mature vision.

Purpose: Our study aimed to determine if ISCEV standard-like ERGs recorded with the LKC RETeval^® portable ERG unit compared to those obtained using the more traditional tabletop unit. Methods: ERGs recorded from normal subjects and patients affected with retinal ON and OFF pathway anomalies were compared. Analysis included peak time and amplitude measurements as well as time–frequency domain analysis with the discrete wavelet transform of waveforms obtained with the two systems. Results: Although both systems were similarly able to record reliable and highly reproducible ERG responses, there were major discrepancies in ERG responses between the portable and tabletop units, pointing toward a weaker stimulation of the retinal OFF pathway with the portable RETeval^® unit. Conclusion: The portable RETeval^® unit appears to be able to record highly reproducible and diagnostically useful clinical ERGs, albeit with some significant differences in waveform composition compared to those obtained with more standard tabletop systems. Given the unknown origin of these waveform discrepancies, if left uncorrected, these differences could potentially lead to erroneous interpretation when used in the clinical context and/or compared to ERGs recorded using more traditional table top units. Clearly, more research is warranted before handheld devices, such as the RETeval^®, can be homologated as a diagnostically sound ERG devices.

Goal: The full-field electroretinogram (ffERG) is an objective tool to assess global retinal function, though as it is currently done, it is unable to localize sources of retinal dysfunction or damage. To overcome this, we have developed a new way to record multiple spatial derivations of the ERG using the rotating capability of the eye, thus creating virtual electrodes. We have termed this the multi-angular ERG (or maERG). With only 3 real electrodes and 11 varying gaze positions, we create 33 virtual electrodes. Methods: We created a realistic electrophysiological and anatomical eye model (i.e. forward model) to reconstruct the retinal activity (i.e. inverse problem) from the 33 virtual electrodes. We simulated 2 pathological scenarios (central and peripheral scotomas), which were compared to their respective theoretical source configurations using an Area under Receiver Operator Characteristic curve metric. Results: Our simulations show that the low-resolution brain electromagnetic tomography algorithm (LORETA) is the best method tested to reconstruct retinal sources when compared to the Minimum Norm Estimate algorithm. Furthermore, a signal to noise ratio of 50dB is needed to accurately reconstruct the retinas functional map. Conclusion: Our proposed maERG recording method, combined with our solution to the electromagnetic inverse problem enables us to reconstruct the functional map of the human retina. Significance: We believe that this new functional retinal imaging technique will permit earlier detection of retinal malfunction and consequently optimize the clinical monitoring of patients affected with retinopathies.

Purpose To demonstrate an organic (retinal) amblyogenic defect in functional amblyopes not responding to treatment. Methods Twenty-four children (Mean age: 5.9 ± 1.8 years; range: 4–10 years) with functional amblyopia were recruited for this study. All these children underwent complete ophthalmic and orthoptic evaluation. In addition, Kinetic Goldman Visual Fields (KGVF), Spectral Domain Optical Coherence Tomography (SD-OCT), full field flash electroretinograms (ffERG) and multifocal electroretinograms (mfERG) were also performed. Ratios were subsequently derived by comparing the amplitudes obtained from the amblyopic eye (AE) to the good eye (GE) for the a- and b-waves of the ffERG, as well as for the ring analysis of the mfERG. Results KGVF showed a central scotoma of varying size (3°–7°) and density (absolute to relative), with increasing target size in 14/24 patients whose best post-treatment vision in the AE ranged from 20/100 to 20/40. The scotoma decreased in size and density with improving vision until a plateau of recovery was reached. The remaining 10/24 patients with a vision ≥ 20/30 showed no scotoma. SD-OCT showed no significant difference between the AE and GE. ffERG and mfERG were obtained in 18/24 patients. The ffERG AE/GE ratio was abnormal in 7 patients, 5 of which had large scotomas on KGVF. The mfERG ring 1 AE/GE ratio was significantly (p < .05) attenuated in 9/18 patients out of which 3 were no longer amblyopic. However, there was no significant difference (p > .05) in ring 1 AE/GE amplitude ratio between those who achieved 20/50–20/40 (.81 ± .26) and those with ≥ 20/25(.86 ± .25). Conclusions The combined findings of central scotoma on KGVF and mfERG anomalies in patients who did not achieve optimal vision with treatment suggest an underlying organic defect impairing macular function.

Purpose: It has been suggested that retinal blood vessel arborization (RBVA) is unique to each individual. We examined this claim in a pedigree that included two pairs of monozygotic twins. Methods: Fundus photographs were taken of subjects belonging to this pedigree to compare the pattern of their RBVA. Pattern prevalence within the general population was estimated from a pre-existing clinical database. Results: The optic nerve head (ONH) RBVA disclosed the following patterns: pattern A, outgrowth, with angle sizes ranging from 12° to 86°, toward the macula, made by the central retinal (CR) vein; pattern O, circular shape delimited by the CR artery on the nasal side and CR vein on the temporal (macula) side; and pattern Y, a double-Y shape (upright in the superior retina and upside down in the inferior retina) made by the four branches—inferior temporal and nasal and superior temporal and nasal—of the CR artery. The prevalence of patterns A, O, and Y was estimated at 11%, 2.8%, and 2.7%, respectively, from our pre-existing clinical database. Pattern A was the most frequently noted in our pedigree, with a prevalence of 26% to 29%, a value significantly larger (P < 0.05) than that measured in our sample of the general population. Of note, familial similarity is progressively lost as we move away from the ONH. Conclusions: Relatives appear to share similar ONH RBVA patterns, suggesting that the ONH RBVA could be genetically transmitted as a familial trait. Arrangement of the more peripheral retinal blood vessels would create individuality. Translational Relevance: Our results suggest the existence of a specific, reproducible, and transmissible retinal identifier, a feature that could potentially be associated with the prevalence of a given disease process, thus offering the possibility of identifying an underlying retinopathy long before its clinical manifestation and consequently optimize its management.

Purpose To investigate the center-periphery distribution of ON and OFF retinal responses in complete congenital stationary night blindness (cCSNB). Methods Photopic full-field flash ERGs (photopic ffERGs) and OPs (photopic ffOPs) and slow m-sequence (to enhance OP prominence) mfERGs (and filtered mfOPs) evoked by a 37 hexagon stimulus array were recorded from normal subjects and cCSNB patients. Discrete wavelet transform (DWT) analysis of photopic ffERGs and mfERGs was also performed in order to assess the contribution of the ON and OFF retinal pathways (i.e., OFF-to-ON ratio) in both cohorts. Results As expected, the photopic ffERG (and ffOPs) responses in cCSNB were devoid of the first two of the three OPs (i.e., OP2 and OP3 and OP4) normally seen on the ascending limb of the b-wave. A similar finding was also noted in the mfERGs (and mfOPs) of ring 4. In contrast, the mfERGs (and mfOPs) of ring 1 included all three OPs. DWT analysis revealed that while in normal subjects, the OFF-to-ON ratio of mfERGs slightly increased from rings 1 to 4 (from 0.61 ± 0.03 to 0.78 ± 0.04; p < 0.05; median: from 0.62 to 0.79; p < 0.05), in cCSNB this ratio increased significantly more [from 0.73 ± 0.13 (ring 1) to 1.18 ± 0.17 (ring 4); p < 0.05; median: 0.78 to 1.22; p < 0.05], hence from a normal ON-dominated ratio (central ring) to an OFF-dominated ratio (peripheral ring). Conclusions Our results show a clear discrepancy of ON and OFF mfOP components in cCSNB. Responses originating from the most central ring (i.e., ring 1) disclosed a near-normal electrophysiological contribution (as revealed with the presence of OP2, OP3 and OP4 as well as with the DWT OFF-to-ON ratio) of the retinal ON and OFF pathways in mfERG (and mfOPs) responses compared to responses from the more peripheral ring (and ffOP) which are devoid of the ON OPs (i.e., OP2 and OP3).