Domain of metamers exciting intrinsically photosensitive retinal ganglion cells (ipRGCs) and rods

Viénot, Françoise; Brettel, Hans; Dang, Tuong-Vi; Rohellec, Jean Le

doi:10.1364/josaa.29.00a366

Cited by 26 publications

(21 citation statements)

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“…[24][25][26] It has been confirmed that the pupil diameter increases when ipRGC and rod excitation is at a minimum. 27 Furthermore, there is strong evidence of an inhibiting influence of S-cones on ipRGCs. 22,28 We speculate that ACHM patients with absence of cone function lack this cone-related inhibition on ipRGCs.…”

Section: Discussionmentioning

confidence: 99%

Development of a Chromatic Pupillography Protocol for the First Gene Therapy Trial in Patients With CNGA3-Linked Achromatopsia

Lisowska

Lisowski

Kelbsch

et al. 2017

Invest. Ophthalmol. Vis. Sci.

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Citation: Lisowska J, Lisowski L, Kelbsch C, et al. Development of a chromatic pupillography protocol for the first gene therapy trial in patients with CNGA3-linked achromatopsia. Invest Ophthalmol Vis Sci. 2017;58:127458: -128258: . DOI:10.1167 PURPOSE. To establish a feasible and sensitive pupillographic protocol to assess outer and inner retinal function for the first gene therapy trial in achromatopsia patients (ACHM) with mutations in CNGA3.METHODS. Twenty-seven CNGA3-ACHM patients and 22 age-matched control subjects were tested using chromatic pupillography. Three different protocols were established to assess the pupillary light reflex parameters and to create the final protocol. In the individual protocols, various stimulus parameters (i.e., intensity, duration, wavelength, adaptation states) were applied to evaluate the impact of these stimuli on the pupillary response in untreated ACHM patients.RESULTS. In the light-adapted conditions, CNGA3-ACHM patients showed significantly reduced maximal amplitudes compared with the control group when using a 1-second high intensity (28-lux corneal illumination) blue or red stimulus (P < 0.005). In the dark-adapted conditions, CNGA3-ACHM patients unexpectedly revealed significantly increased maximal amplitudes when stimulating with red (1 second) or blue (4 ms and 1 second) stimuli of low intensity (0.01-lux corneal illumination; P < 0.05). Pupil responses of CNGA3-ACHM patients after high intensity (28 lux) red and blue 1-second stimuli were within the normal range.CONCLUSIONS. Chromatic pupillography demonstrated significant reduced pupil responses to stimuli addressing primarily cone function, an increased sensitivity to rod-favoring stimuli and evidence for disinhibition of intrinsically photosensitive retinal ganglion cells in CNGA3-ACHM patients. A final protocol was established based on these findings. These conclusions may be useful for the objective assessment of efficacy gained by gene therapy or other innovative interventions in this hereditary retinal disorder.Keywords: chromatic pupillography, achromatopsia, CNGA3, ipRGC A chromatopsia (ACHM) is an inherited autosomal recessive congenital retinal disease, with a prevalence of one in 30,000.1 The most characteristic symptom is the inability to discriminate colors due to the loss of cone photoreceptor function. Achromatopsia patients also suffer from severely reduced visual acuity, nystagmus, and photophobia. 2 Rarely, individuals have incomplete ACHM, in which one or more cone types may be partially functioning. 3 The clinical findings of incomplete ACHM are similar to the complete form, but milder. Fundus examination is usually normal, and electrophysiological testing demonstrates absent cone responses and normal or near-normal rod function. [2][3][4][5] To date, mutations in six genes have been shown to be associated with ACHM: CNGA3 and CNGB3 encode the a and b subunits of the cGMP-gated cation channel, 6 GNAT2 the a subunit of the cone-specific G-protein transducing, 7 PDE6C and PDE6H code for the ...

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Section: Discussionmentioning

confidence: 99%

Development of a Chromatic Pupillography Protocol for the First Gene Therapy Trial in Patients With CNGA3-Linked Achromatopsia

Lisowska

Lisowski

Kelbsch

et al. 2017

Invest. Ophthalmol. Vis. Sci.

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“…Viénot and associates (Viénot & Brettel, 2014;Viénot, Brettel, Dang, & Le Rohellec, 2012) developed a seven-primary system to study the rod and melanopsin inputs to pupil responses using a metameric black framework (Cohen & Kappauf, 1982;Wyszecki, 1958). They maintained cone excitations constant while searching for ''black metamers'' that activated both rods and melanopsin.…”

Section: Discussionmentioning

confidence: 99%

A five-primary photostimulator suitable for studying intrinsically photosensitive retinal ganglion cell functions in humans

2015

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Intrinsically photosensitive retinal ganglion cells (ipRGCs) can respond to light directly through self-contained photopigment, melanopsin. IpRGCs also receive synaptic inputs from rods and cones. Thus, studying ipRGC functions requires a novel photostimulating method that can account for all of the photoreceptor inputs. Here, we introduced an inexpensive LED-based five-primary photostimulator that can control the excitations of rods, S-, M-, L-cones, and melanopsin-containing ipRGCs in humans at constant background photoreceptor excitation levels, a critical requirement for studying the adaptation behavior of ipRGCs with rod, cone, or melanopsin input. We described the theory and technical aspects (including optics, electronics, software, and calibration) of the five-primary photostimulator. Then we presented two preliminary studies using the photostimulator we have implemented to measure melanopsin-mediated pupil responses and temporal contrast sensitivity function (TCSF). The results showed that the S-cone input to pupil responses was antagonistic to the L-, M- or melanopsin inputs, consistent with an S-OFF and (L + M)-ON response property of primate ipRGCs (Dacey et al., 2005). In addition, the melanopsin-mediated TCSF had a distinctive pattern compared with L + M or S-cone mediated TCSF. Other than controlling individual photoreceptor excitation independently, the five-primary photostimulator has the flexibility in presenting stimuli modulating any combination of photoreceptor excitations, which allows researchers to study the mechanisms by which ipRGCs combine various photoreceptor inputs.

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“…Whilst these factors have been established for some time, spectral sensitivity of the pupil reflex response has increasingly become of interest (Adrian, 2003; Vienot et al, 2010), due, basically, to discovery of melanopsin-expressing intrinsically photosensitive ganglion cells (ipRGCs), which contributes significantly to light-evoked pupillary responses (Vienot et al, 2012). …”

Section: Introductionmentioning

confidence: 99%

Pupillary behavior in relation to wavelength and age

Lobato-Rincón

Cabanillas-Campos

Bonnin-Arias

et al. 2014

Front. Hum. Neurosci.

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Pupil light reflex can be used as a non-invasive ocular predictor of cephalic autonomic nervous system integrity. Spectral sensitivity of the pupil's response to light has, for some time, been an interesting issue. It has generally, however, only been investigated with the use of white light and studies with monochromatic wavelengths are scarce. This study investigates the effects of wavelength and age within three parameters of the pupil light reflex (amplitude of response, latency, and velocity of constriction) in a large sample of younger and older adults (N = 97), in mesopic conditions. Subjects were exposed to a single light stimulus at four different wavelengths: white (5600°K), blue (450 nm), green (510 nm), and red (600 nm). Data was analyzed appropriately, and, when applicable, using the General Linear Model (GLM), Randomized Complete Block Design (RCBD), Student's t-test and/or ANCOVA. Across all subjects, pupillary response to light had the greatest amplitude and shortest latency in white and green light conditions. In regards to age, older subjects (46–78 years) showed an increased latency in white light and decreased velocity of constriction in green light compared to younger subjects (18–45 years old). This study provides data patterns on parameters of wavelength-dependent pupil reflexes to light in adults and it contributes to the large body of pupillometric research. It is hoped that this study will add to the overall evaluation of cephalic autonomic nervous system integrity.

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Domain of metamers exciting intrinsically photosensitive retinal ganglion cells (ipRGCs) and rods

Cited by 26 publications

References 44 publications

Development of a Chromatic Pupillography Protocol for the First Gene Therapy Trial in Patients With CNGA3-Linked Achromatopsia

Development of a Chromatic Pupillography Protocol for the First Gene Therapy Trial in Patients With CNGA3-Linked Achromatopsia

A five-primary photostimulator suitable for studying intrinsically photosensitive retinal ganglion cell functions in humans

Pupillary behavior in relation to wavelength and age

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