Response Characteristics and Retinal Origin of the Photopic Negative Response of the Electroretinogram in Dogs.

PURPOSE: To investigate the response characteristics and retinal origin of the photopic negative response (PhNR) of the electroretinograms (ERGs) in dogs. METHODS: Photopic ERGs were elicited by white flash stimuli of different intensities under a steady white background illumination in four anesthetized dogs. These ERGs were also recorded in the same manner after intravitreal injection of tetrodotoxin (TTX). Additionally, retinal localization of voltage-gated sodium channel Nav 1.6 was assessed by immunohistochemistry. RESULTS: The amplitude of the a-wave and the PhNR was increased as the stimulus intensity was raised, while the amplitude of the b-wave was peaked at the moderate stimulus intensity of 3.09 cd·s/m2. TTX greatly attenuated the PhNR, while the reduction in the b-waves and a-wave was mild or insignificant. Nav 1.6-expression was specifically detected on the retinal ganglion cells (RGCs). CONCLUSIONS: Our results are consistent with the PhNR primarily derived from the inner retina including RGCs in dogs, suggesting that the PhNR can be used to monitor function of these retinal components in dogs.

Comparison of photopic negative response (PhNR) between focal macular and full-field electroretinograms in monkeys.

PURPOSE: To compare the characteristics of the photopic negative response (PhNR) between the focal macular and full-field electroretinograms (ERGs) in monkeys. METHODS: Both focal macular and full-field photopic ERGs were recorded in four cynomolgus monkeys under identical stimulus and recording conditions except for which area of the retina was illuminated. The luminance and duration of red flash stimuli were varied in the presence of steady blue background illumination. These ERGs were recorded before and after intravitreal injection of tetrodotoxin (TTX). RESULTS: Several differences were identified between the focal macular and full-field ERGs, including: (1) The PhNR/b-wave amplitude ratio was higher in the focal macular than in the full-field ERGs, and (2) the stimulus threshold of the focal macular PhNR was lower than that of the full-field PhNR. For both macular and full-field stimulation conditions, (1) PhNR amplitude generally increased with increasing stimulus luminance; (2) PhNR implicit time was independent of the stimulus luminance; (3) PhNR amplitude and implicit time increased with increasing stimulus duration up to 50 ms, while a further increase in stimulus duration produced no change in amplitude or implicit time; and (4) PhNR amplitude was selectively attenuated by TTX. CONCLUSIONS: Both the focal macular and full-field PhNRs reflect the functional properties of the inner retina including the retinal ganglion cells (RGCs). Relative to the b-wave, the contribution is weighted more heavily in the focal macular than in the full-field PhNR. Furthermore, these results support the idea that the focal macular PhNR can be an indicator of the function of the macular RGCs.

N-Methyl-N-Nitrosourea-Induced Acute Alteration of Retinal Function and Morphology in Monkeys.

PURPOSE: The purpose of this study was to investigate both functional and morphologic alteration of the retina acutely induced by N-methyl-N-nitrosourea (MNU) in monkeys. METHODS: The MNU was administered intravenously at a single dose of 40 mg/kg to six cynomolgus monkeys, and standard full-field electroretinograms (ERGs) were recorded 1, 3, and 7 days after dosing. In addition, the rod and cone a-waves in response to high-intensity flashes were analyzed by the a-wave fitting model (a-wave analysis). The photopic negative response (PhNR) was also recorded at the same time points. Furthermore, the retinas of two animals each were examined histopathologically 1, 3, or 7 days after dosing. RESULTS: The MNU attenuated all the standard full-field ERGs including the rod-driven and cone-driven responses; in the combined rod-cone response, the b-wave was more affected than the a-wave. In the a-wave analysis, the sensitivity parameters (S) of the rod and cone a-waves had decreased on the day after dosing and remained unchanged thereafter. The maximum response parameter (Rmax) of the rod a-wave gradually decreased. On the other hand, the Rmax in the cone a-wave transiently increased on the day after dosing and decreased thereafter; the PhNR amplitude showed a similar time course change. Histopathologically, the retinal lesion on the day after dosing mainly consisted of pyknosis and karyorrhexis in the photoreceptor nucleus. Depletion of some photoreceptor nuclei, and shortening and disorientation of the photoreceptor segments became prominent at 3 and 7 days after dosing. Localization of degenerated photoreceptors was consistent with that of rhodopsin-positive photoreceptors, resulting in a well-preserved central fovea. CONCLUSIONS: Our results indicated that MNU acutely induced rod-dominant photoreceptor degeneration in monkey retinas, but the photoreceptor function was impaired in both the rods and cones. Functional involvement of the postreceptoral components was also indicated.

Sildenafil-induced reversible impairment of rod and cone phototransduction in monkeys.

PURPOSE: To investigate functional alteration of the retina induced by sildenafil in monkeys. METHODS: Sildenafil was administered intravenously to cynomolgus monkeys at dose levels of 0, 1, 3, and 10 mg/kg, and standard full-field electroretinograms (ERGs) were recorded. The rod and cone a-waves in response to high-intensity flashes were also analyzed by the a-wave fitting model (a-wave analysis). Additionally, the photopic negative responses were recorded. RESULTS: Sildenafil at 3 mg/kg or more induced the following alterations in the standard full-field ERGs immediately after dosing: delayed b-wave in the rod response; delayed a-wave in the combined rod-cone response; and attenuated b-waves in the single-flash cone response and in the 30 Hz flicker. Additionally, the following changes were observed in the 10 mg/kg group: attenuated b-wave in the rod response; attenuated a-wave and delayed b-wave in the combined rod-cone response; delayed oscillatory potentials; and attenuated and delayed a-wave in the single-flash cone response. In the a-wave analysis immediately after dosing, sildenafil selectively decreased the sensitivity parameter (S) in the cone a-wave at 3 mg/kg, and in both the rod and cone a-waves at 10 mg/kg. The S value was highly correlated with plasma sildenafil concentration. The above changes fully recovered 24 hours after dosing. CONCLUSIONS: Sildenafil produced reversible impairment of the rod and cone phototransduction in monkeys. Meanwhile, involvement of the postreceptoral retinal components was suggested. These findings contribute to the clarification of sildenafil-induced visual disturbances. It is suggested that the photoreceptors are predominantly, but not exclusively, affected in the retina of humans with sildenafil-induced visual disturbances.

Exploring a new regime for processing optical qubits: squeezing and unsqueezing single photons.

We implement the squeezing operation as a genuine quantum gate, deterministically and reversibly acting "online" upon an input state no longer restricted to the set of Gaussian states. More specifically, by applying an efficient and robust squeezing operation for the first time to non-Gaussian states, we demonstrate a two-way conversion between a particlelike single-photon state and a wavelike superposition of coherent states. Our squeezing gate is reliable enough to preserve the negativities of the corresponding Wigner functions. This demonstration represents an important and necessary step towards hybridizing discrete and continuous quantum protocols.

Digoxin-induced reversible dysfunction of the cone photoreceptors in monkeys.

PURPOSE: To investigate functional alteration of the retina induced by digoxin in monkeys. METHODS: Digoxin was intravenously administered to cynomolgus monkeys and standard full-field electroretinograms (ERGs) were serially recorded. In other digoxin-treated monkeys, the rod and cone a-waves to high-intensity flashes were obtained and analyzed by the a-wave fitting model (a-wave analysis). The following responses were also recorded: dark- and light-adapted responses to flashes of different intensities (dark- and light-adapted luminance responses), photopic ERG elicited by long-duration stimulus (ON-OFF response), and the photopic negative response (PhNR). RESULTS: Delayed b-wave was observed in all responses of the standard full-field ERGs; amplitude of the b-wave was increased in the rod response, but was decreased in the single-flash cone response and the 30-Hz flicker. These changes recovered gradually after elimination of digoxin from the blood. Digoxin enhanced and delayed the b-wave in the dark-adapted luminance-response analysis regardless of stimulus intensity. In the light-adapted luminance-response analysis, digoxin attenuated the a- and b-waves only at high and middle stimulus intensity, respectively. The a-wave analysis revealed selective decrease in the maximum response parameter (Rmax) in the cone a-wave. Both the b- and d-waves of the ON-OFF response were delayed. CONCLUSIONS: The selectively reduced Rmax in the cone a-wave indicated dysfunction of the cone photoreceptors in digoxin-treated monkeys. Meanwhile, the enhanced and delayed rod response suggested alteration of retinal components other than the cone photoreceptors. These results may contribute to the understanding of digoxin-induced visual disturbances in humans. It is suggested that the cone function is markedly, but not exclusively, affected in the retina of such patients.

Retinal function and morphology in monkeys with ethambutol-induced optic neuropathy.

PURPOSE: Ethambutol-induced optic neuropathy is a well recognized adverse ocular event. However, abnormalities of the retina in this optic neuropathy are not fully understood. Therefore, the purpose of the present study was to investigate both functional and morphological alterations of the retina induced by ethambutol in monkeys. METHODS: Ethambutol was orally administered to three cynomolgus monkeys, initially at 400 mg/kg/day followed by 800 mg/kg/day, for a maximum of 39 weeks. Full-field electroretinograms (ERGs) were recorded at intervals of approximately one month. The protocol included standard ERG responses to white flashes obtained under dark-adapted conditions (rod, combined rod-cone, oscillatory potentials) or with a white background (single-flash cone, 30 Hz flicker). In addition, we measured the ERG elicited with red flashes under blue background light (single-flash cone response [R/B]). All the ethambutol-treated monkeys were euthanized, and the retinae and various other nervous system tissues were examined histopathologically. RESULTS: No obvious changes were observed in the standard full-field ERGs. On the other hand, selective attenuation of the photopic negative response (PhNR) of the single-flash cone response (R/B) was observed in two out of three ethambutol-treated monkeys at week 22 or 28. Histopathology of these two monkeys revealed single cell necrosis of the retinal ganglion cells (RGCs), decreased RGCs in the parafovea and increased microglial cells in the nerve fiber layer in the retina, in addition to demyelination and glial reaction in the optic nerve, chiasm and tracts. CONCLUSIONS: The attenuated PhNR and histopathology of the retina indicated that RGCs were markedly damaged, both functionally and morphologically in monkeys with ethambutol-induced optic neuropathy. These results implied that RGCs are predominantly affected in the retina of patients with ethambutol-induced optic neuropathy.

Demonstration of unconditional one-way quantum computations for continuous variables.

One-way quantum computation is a very promising candidate to fulfill the capabilities of quantum information processing. Here we demonstrate an important set of unitary operations for continuous variables using a linear cluster state of four entangled optical modes. These operations are performed in a fully measurement-controlled and completely unconditional fashion. We implement three different levels of squeezing operations and a Fourier transformation, all of which are accessible by selecting the correct quadrature measurement angles of the homodyne detections. Though not sufficient, these linear transformations are necessary for universal quantum computation.

Mechanism of voriconazole-induced transient visual disturbance: reversible dysfunction of retinal ON-bipolar cells in monkeys.

PURPOSE: To investigate the mechanism of voriconazole-induced transient visual disturbance in humans. METHODS: andard full-field electroretinograms (ERGs) were recorded from monkeys treated intravenously with voriconazole. In addition, photopic ERGs elicited by long-duration stimuli (ON-OFF response) were also recorded from monkeys receiving intravenous voriconazole or intravitreal 2-amino-4-phosphonobutyric acid (APB). RESULTS: aracteristic changes were observed in the waveform of the standard full-field ERGs obtained immediately after dosing of voriconazole as follows: electronegative combined rod-cone response (markedly attenuated b-wave and oscillatory potentials), undetectable rod response (eliminated b-wave); slightly abnormal single-flash cone response (flattened appearance in the bottom of the a-wave, mildly attenuated b-wave); and slightly abnormal 30 Hz flicker (mildly attenuated b-wave). The above changes fully recovered to baseline 24 hours after each dosing, along with a decrease in plasma voriconazole concentration. In addition, the change in the waveform of the ON-OFF response recorded in voriconazole-treated monkeys was quite similar to that recorded in APB-treated monkeys as follows: the b-wave was eliminated or prominently attenuated; and the a- and d-waves were not apparently attenuated. CONCLUSIONS: The results strongly suggest that voriconazole induces selective and reversible dysfunction of the retinal ON-bipolar cells in both the rod and cone pathways in monkeys. From the results obtained in monkeys in this study, it is suggested that the function of the retinal ON-bipolar cells was selectively and reversibly affected in voriconazole-treated humans who complained of transient visual disturbances.