The Circadian Response of Intrinsically Photosensitive Retinal Ganglion Cells

Intrinsically photosensitive retinal ganglion cells (ipRGC) signal environmental light level to the central circadian clock and contribute to the pupil light reflex. It is unknown if ipRGC activity is subject to extrinsic (central) or intrinsic (retinal) network-mediated circadian modulation during light entrainment and phase shifting. Eleven younger persons (18–30 years) with no ophthalmological, medical or sleep disorders participated. The activity of the inner (ipRGC) and outer retina (cone photoreceptors) was assessed hourly using the pupil light reflex during a 24 h period of constant environmental illumination (10 lux). Exogenous circadian cues of activity, sleep, posture, caffeine, ambient temperature, caloric intake and ambient illumination were controlled. Dim-light melatonin onset (DLMO) was determined from salivary melatonin assay at hourly intervals, and participant melatonin onset values were set to 14 h to adjust clock time to circadian time. Here we demonstrate in humans that the ipRGC controlled post-illumination pupil response has a circadian rhythm independent of external light cues. This circadian variation precedes melatonin onset and the minimum ipRGC driven pupil response occurs post melatonin onset. Outer retinal photoreceptor contributions to the inner retinal ipRGC driven post-illumination pupil response also show circadian variation whereas direct outer retinal cone inputs to the pupil light reflex do not, indicating that intrinsically photosensitive (melanopsin) retinal ganglion cells mediate this circadian variation

Peripheral refraction in orthokeratology patients

Purpose. The purpose of this study is to measure refraction across the horizontal central visual field in orthokeratology patients before and during treatment.\ud \ud Methods. Refractions were measured out to 34[degrees] eccentricity in both temporal and nasal visual fields using a free-space autorefractor (Shin-Nippon SRW5000) for the right eyes of four consecutively presenting myopic adult patients. Measurements were made before orthokeratology treatment and during the course of treatment (usually 1 week and 2 weeks into treatment). Refractions were converted into mean sphere (M), 90[degrees] to 180[degrees] astigmatism (J180), and 45[degrees] to 135[degrees] astigmatism (J45) components.\ud \ud Results. Before treatment, subjects had either a relatively constant mean sphere refraction across the field or a relative hypermetropia in the periphery as compared with the central refraction. As a result of treatment, myopia decreased but at reduced rate out into the periphery. Most patients had little change in mean sphere at 30[degrees] to 34[degrees]. In all patients, the refraction pattern altered little after the first week.\ud \ud Conclusion. Orthokeratology can correct myopia over the central +/- 10[degrees] of the visual field but produces only minor changes at field angles larger than 30[degrees]. If converting relative peripheral hypermetropia to relative peripheral myopia is a good way of limiting the axial elongation that leads to myopia, orthokeratology is an excellent option for achieving this

Diurnal cone photoreceptor contributions to the human pupil light reflex.

<p>(A) Baseline pupil diameter of 11 participants (mean ± s.e.m) viewing a uniform photopic screen, recorded over 20–24 hours (linear model, line R²>1.00). (B) Average maximum pupil constriction (488 nm) for 11 participants (±s.e.m) analysed as for <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0017860#pone-0017860-g001" target="_blank">Fig. 1A</a>. Insets; Coloured lines show baseline pupil diameter (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0017860#pone-0017860-g001" target="_blank">Fig. 1A</a>) and maximum constriction of one participant (19,F) at circadian times of 3.5 h and 15.4 h (from <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0017860#pone-0017860-g002" target="_blank">Fig. 2A</a>). Lines show linear regression; R²>0.47. (C) Average maximum pupil constriction (610 nm) for 11 participants (± s.e.m). Direct outer retinal cone photoreceptor contributions to the pupil do not vary diurnally (R²>0.64).</p

Circadian variation of the ipRGC controlled post-illumination pupil response of the pupil light reflex.

<p>Left and right columns show pupil light reflex data for two participants (19yo F, 18yo M). Left ordinates show pupil diameter (% baseline), right ordinates show pupil diameter (mm). (A) Post-illumination pupil responses at three circadian times were 75.0% (3.5 h), 83.2% (9.4 h) and 92.5% (15.4 h) of the mean baseline pupil diameter of 7.77 mm. The pupil light reflex (thin lines) was described by best-fitting linear and exponential functions (thick lines). (B) Post-illumination pupil responses of 71.4% (5.4 h), 77.0% (10.4 h) and 99.6% (15.4 h) of the mean baseline pupil diameter of 6.68 mm. (C) The post-illumination component of the pupil light reflex fitted with a skewed baseline cosine function (Eq 1) (data show mean ± s.d; filled circles; model, line) (R² = 079). (D) As for panel (C) for participant 2 (18 yo M) (R² = 0.71). Post-illumination pupil response (blue lines) from <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0017860#pone-0017860-g002" target="_blank">Figure 2B</a> at 5.4 h and 15.4 h. Insets in panel (C) and (D) show the post-illumination pupil response (blue lines) from panel (A) at 3.5 and 15.4 h.</p

Circadian testing protocol.

<p>The flowchart identifies the order of measurements conducted each hour during the 24 h test period.</p

Comparison of the circadian response of intrinsic ipRGC and cone inputs to the post-illumination pupil response (PIPR) with salivary melatonin.

<p>Symbols (n = 11 participants; mean ± s.e.m) and lines (mean skewed baseline cosine function; Eq 1) encode intrinsic ipRGC (blue) and cone inputs (red) to the ipRGC controlled PIPR and salivary melatonin (black). Arrows indicate threshold change in activity based on the group model. (A) PIPR diameter (488 nm stimulus) began to increase at 10:50 h and peaked at 14:58 h (blue arrows) (R² = 0.65). (B) PIPR diameter (688 nm stimulus) began to increase at 9:16 h and peaked at 15:18 h (red arrows) (R² = 0.80). (C) Salivary melatonin began to increase at 13:30 h and peaked at 18:40 circadian hours (red arrows) (R² = 0.96), 2:40 hours after PIPR (488 nm) began to increase. For the best-fitting salivary melatonin curve (Eq 1), <i>(b)</i> = 4.54 pM; peak amplitude above baseline <i>(H)</i> = 65.40 pM; width <i>(c)</i> = −0.091; phase <i>(Φ)</i> = 11.46 radians and skewness <i>(v)</i> = 0.302. (D) Re-dilation kinetics (mm.s⁻¹) derived from the time-constant of the best-fitting exponential functions to the 488 nm PIPR. (E) Re-dilation kinetics (mm.s⁻¹) for the 610 nm PIPR. Change in post-illumination pupil response amplitude and kinetics independent of the constant external illumination demonstrates circadian control of ipRGC activity.</p

Aberrations of emmetropic subjects at different ages

We made on-axis aberrations and horizontal peripheral refraction measurements of emmetropic subjects (spherical equivalent -0.88 D to +0.75 D) aged between 19 and 70 years. We found smaller changes in on-axis aberrations with age than has previously been reported, possibly because of the small refractive error range of our subject group. Higher order root-mean-squared aberrations increased by 26% across the age range (5 mm pupils), with significant age related changes in 4th- and 6th-order aberrations. The only aberration co-efficient to change significantly was horizontal coma co-efficient C(3, 1). Several aberration co-efficients were significantly different from zero across the group of subjects. The only changes in peripheral refraction with increase in age were shifts in the turning points of the spherical equivalent and horizontal/vertical astigmatism towards less temporal visual field angles

Intrinsically photosensitive melanopsin retinal ganglion cell contributions to the pupillary light reflex and circadian rhythm

Recently discovered intrinsically photosensitive melanopsin retinal ganglion cells contribute to the maintenance of pupil diameter, recovery and post-illumination components\ud of the pupillary light reflex and provide the primary environmental light input to the suprachiasmatic nucleus for photoentrainment of the circadian rhythm. This review\ud summarises recent progress in understanding intrinsically photosensitive ganglion cell histology and physiological properties in the context of their contribution to the pupillary and circadian functions and introduces a clinical framework for using the pupillary light reflex to evaluate inner retinal (intrinsically photosensitive melanopsin ganglion cell) and outer retinal (rod and cone photoreceptor) function in the detection of retinal\ud eye disease