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Chromatic pupil responses: preferential activation of the melanopsin-mediated versus outer photoreceptor-mediated pupil light reflex
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2009 (English)In: Ophthalmology (Rochester, Minn.), ISSN 0161-6420, E-ISSN 1549-4713, Vol. 116, no 8, 1564-1573 p.Article in journal (Refereed) Published
Abstract [en]

OBJECTIVE: To weight the rod-, cone-, and melanopsin-mediated activation of the retinal ganglion cells, which drive the pupil light reflex by varying the light stimulus wavelength, intensity, and duration.

DESIGN: Experimental study.

PARTICIPANTS: Forty-three subjects with normal eyes and 3 patients with neuroretinal visual loss.

METHODS: A novel stimulus paradigm was developed using either a long wavelength (red) or short wavelength (blue) light given as a continuous Ganzfeld stimulus with stepwise increases over a 2 log-unit range. The pupillary movement before, during, and after the light stimulus was recorded in real time with an infrared illuminated video camera.

MAIN OUTCOME MEASURES: The percent pupil contraction of the transient and sustained pupil response to a low- (1 cd/m(2)), medium- (10 cd/m(2)), and high-intensity (100 cd/m(2)) red- and blue-light stimulus was calculated for 1 eye of each subject. From the 43 normal eyes, median and 25th, 75th, 5th, and 95th percentile values were obtained for each stimulus condition.

RESULTS: In normal eyes at lower intensities, blue light evoked much greater pupil responses compared with red light when matched for photopic luminance. The transient pupil contraction was generally greater than the sustained contraction, and this disparity was greatest at the lowest light intensity and least apparent with bright (100 cd/m(2)) blue light. A patient with primarily rod dysfunction (nonrecordable scotopic electroretinogram) showed significantly reduced pupil responses to blue light at lower intensities. A patient with achromatopsia and an almost normal visual field showed selective reduction of the pupil response to red-light stimulation. A patient with ganglion cell dysfunction owing to anterior ischemic optic neuropathy demonstrated global loss of pupil responses to red and blue light in the affected eye.

CONCLUSIONS: Pupil responses that differ as a function of light intensity and wavelength support the hypothesis that selected stimulus conditions can produce pupil responses that reflect phototransduction primarily mediated by rods, cones, or melanopsin. Use of chromatic pupil responses may be a novel way to diagnose and monitor diseases affecting either the outer or inner retina.

Place, publisher, year, edition, pages
2009. Vol. 116, no 8, 1564-1573 p.
National Category
Ophthalmology
Identifiers
URN: urn:nbn:se:umu:diva-79626DOI: 10.1016/j.ophtha.2009.02.007PubMedID: 19501408OAI: oai:DiVA.org:umu-79626DiVA: diva2:643353
Available from: 2013-08-27 Created: 2013-08-27 Last updated: 2017-12-06Bibliographically approved
In thesis
1. Selective wavelength pupillometry to evaluate outer and inner retinal photoreception
Open this publication in new window or tab >>Selective wavelength pupillometry to evaluate outer and inner retinal photoreception
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Purpose

Intrinsically photosensitive retinal ganglion cells (ipRGCs) express a unique photopigment called melanopsin. Capable of direct phototransduction, the ipRGCs are also influenced by rods and cones via synaptic inputs.  Thus, the photoinput that mediates the pupil light reflex derives from both outer (rods and cones) and inner (melanopsin-mediated) retinal photoreception. This thesis has aimed to develop a pupillometric test that provides quantitative information about the functional status of outer and inner retinal photoreception in healthy eyes and in eyes with retinal degeneration. In addition to regulating the pupil light reflex, the ipRGCs signal light information for the circadian rhythm, thus, these two non-visual physiologic responses to inner retinal photoreception were examined simultaneously.

Methods

Pupil responses to a long and short wavelength light over a range of intensities (under conditions of light, mesopic and dark adaptation) were recorded using a customized infrared computerized pupillometer. Results were compared for two groups: patients with retinitis pigmentosa and controls. The response function threshold intensity and a half-max intensity was determined from the rod-weighted and cone-weighted pupil responses and correlated to extent of visual loss. The pupil response to light offset was assessed as a measure of direct melanopsin activation. Lastly, pupil responses to red and blue light at equal photo flux were recorded hourly during a 24-hour period and correlated to salivary melatonin concentrations in healthy subjects.

Results

In normal eyes, the blue light evoked greater pupil responses compared to equiluminant red light. With increasing intensity, pupil contraction became more sustained which was most apparent with the brightest blue light. In patients with retinitis pigmentosa, the pupil responses mediated predominantly by rod and cone activation were significantly reduced compared to controls, (p<0.001) and the relative decrease in their contribution resulted in a greater influence of melanopsin on the post-stimulus response. Even at endstage retinal degeneration, pupil responses that derived predominantly from residual cone activity were detectable. The threshold intensity of the rod-mediated, but not cone-mediated, pupil response was also significantly reduced (p=0.006) in patients and the half-maximal intensity of rods correlated with severity of visual loss (r2=0.7 and p=0.02). In healthy controls, the melanopsin-mediated pupil response demonstrated a circadian modulation whereas the cone-mediated pupil response did not.

Conclusion

Early and progressive loss of rod function in mild-moderate stages of retinitis pigmentosa is detectable and quantifiable as a progressive loss of pupillary sensitivity to extremely dim blue lights obtained under conditions of dark adaptation. In advanced stages of retinal degeneration, chromatic pupillometry is more sensitive than standard electroretinography for detecting residual levels of rod and especially cone activity. In addition, selective wavelength pupillometry can assess non-visual light-dependent functions. The timing of the post-stimulus pupil response to blue light is in phase with melatonin secretion, suggesting a circadian regulation of this pupil parameter.

Abstract [sv]

Bakgrund

Jätteganglieceller (intrinsically photosensitive retinal ganglion cells, ipRGCs) är en klass av fotoreceptorer som utnyttjar ett unikt vitamin-A-baserat fotopigment som kallas melanopsin. Utöver deras direkta ljuskänslighet, mottar ipRGCs stimulerande och hämmande synaptiska signaler från andra fotoreceptorer (tappar och stavar) som därigenom kan modulera aktiviteten hos ipRGCs. Ögats pupillreflex medieras alltså av ljus både via yttre (stavar och tappar) och inre (melanopsin-medierad) retinal fotoreception, och den gemensamma afferenta pupillomotor-signalen leds till den pretectala nucleus olivarius via axoner från ipRGCs.

Arbetet i denna avhandling syftar till att utveckla ett kliniskt pupilltest som ger kvantitativ information om yttre och inre retinala fotoreceptorers funktionella status hos friska försökspersoner och patienter med retinal degeneration. Förutom att styra pupillreflexen, skickar ipRGCs även impulser som påverkar kroppens dygnsrytm. Därför ingår även en delstudie i vilken ipRGCs aktivitet studeras genom att avläsa icke-visuella fysiologiska reaktioner på inre retinal fotoreception.

Metoder

Ljus av lång (röd) respektive kort (blå) våglängd presenterades med stegvis ökad ljusstyrka för att selektivt stimulera stavar, tappar eller melanopsin. Pupillreaktionerna registrerades med en infraröd datoriserad pupillometer och jämfördes mellan friska kontroller och patienter med retinitis pigmentosa. I uppföljande experiment gjordes mer noggranna tester i syfte att isolera aktiveringen av varje ljusmottagande element. Tröskelintensiteten för stav- eller tapp-medierad pupillreaktion bestämdes med linjär regressionsanalys. Reaktionskurvan för stavmedierad pupillreflex kvantifierades (halv-maximal intensitet) och jämfördes med svårighetsgraden av sjukdomen i två familjer med samma sjukdomsframkallande mutation för retinitis pigmentosa. För att undersöka icke-visuella reaktioner på inre fotoreception från ipRGCs, undersöktes pupillreaktion på rött och blått ljus varje timme under en 24-timmarsperiod och korrelerades till melatoninkoncentration i saliv hos friska personer med normal syn.

Resultat

I normala ögon, gav blått ljus en kraftigare pupillreaktion jämfört med rött ljus av samma ljusstyrka. Med ökande intensitet, blev pupillkontraktionen mer ihållande, vilket var tydligast med starkt blått ljus. Hos patienter med retinitis pigmentosa, var både tapp- och stav-medierad pupillreaktion signifikant reducerad jämfört med kontroller, (p<0,001). Patienter med avancerad sjukdom och icke-reaktivt elektro-retinogram hade fortfarande mätbar pupillreflex, huvudsakligen härrörande från kvarvarande stavaktivitet. I två familjer med retinitis pigmentosa beroende på en enda missense-mutation av NR2E3 genen, var tröskelvärdet för stavmedierad pupillreflex signifikant reducerat (p= 0,006) och korrelerade till sjukdomens svårighetsgrad. Tappmedierad pupillreflex hos dessa patienter skilde sig dock inte signifikant från kontroller, trots att fotopiskt (tapp) elektroretinogram var klart avvikande. Hos friska kontroller visade melanopsinmedierat pupillsvar en dygnsvariation medan tapp-medierat pupillsvar inte gjorde det.

Slutsatser

Som tillägg till standardundersökningar kan selektiv våglängds-pupillometri (kromatisk pupillometri) vara användbart för utvärdering av funktionen hos stavar och tappar. Denna avhandling visar att tidig och gradvis förlust av stav-funktion i milt-måttligt stadium av retinitis pigmentosa är detekterbar och mätbar som en progressiv förlust av pupillens känslighet för mycket svagt blått ljus, efter mörkeradaptation. I avancerade stadier av retinal degeneration är kromatisk pupillometri känsligare än standardelektroretinografi för att detektera kvarvarande nivåer av stav- och speciellt tapp-aktivitet. Hos unga patienter, där elektroretinografi kan vara tekniskt svårt, är pupillometri en lovande teknik för att värdera yttre retinal fotoreception relaterad till synfunktion. Dessutom kan selektiv våglängdspupillometri ge information om icke-visuella ljusberoende funktioner. Pupillreaktionen på blått ljus varierar med melatoninsekretionen, vilket tyder på en cirkadisk reglering. Ytterligare studier krävs för att undersöka om selektiv våglängds-pupillometri även kan användas i samband med sjukdomar relaterade till störd dygnsrytm, som sömnlöshet och årstidsbunden depression.

Place, publisher, year, edition, pages
Umeå: Umeå University, 2013. 41 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1588
Keyword
pupil, pupil light reflex, melanopsin, photoreceptor, intrinsically photosensitive retinal ganglion cell
National Category
Ophthalmology
Research subject
Ophtalmology
Identifiers
urn:nbn:se:umu:diva-79628 (URN)978-91-7459-708-0 (ISBN)
Public defence
2013-09-26, Hörsal 135, Unod X 1, Norrlands universitetssjukhus, Umeå, 13:00 (English)
Opponent
Supervisors
Available from: 2013-09-05 Created: 2013-08-27 Last updated: 2013-09-05Bibliographically approved

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