Two Novel Disease-Causing Variants in the PDE6C Gene Underlying Achromatopsia

We report the clinical phenotype and genetic findings of two variants in PDE6C underlying achromatopsia (ACHM). Four patients with the variant c.1670G&#x3e;A in exon 13 of the PDE6C gene were identified. Additionally, one had compound heterozygous genotype, with two variants in the <i>PDE6C</i> gene, a variant of c.2192G&#x3e;A in exon 18 and c.1670G&#x3e;A in exon 13. All patients presented the symptomatic triad of decreased visual acuity, severe photophobia, and colour vision disturbances. SD-OCT showed an absence of the ellipsoid zone, creating an optically empty cavity at the fovea in three patients. The patient with the compound heterozygous genotype presented a more severe subfoveal outer retina atrophy. ERG recordings showed extinguished responses under photopic and 30-Hz flicker stimulation, with a normal rod response. We identified two new variants in the <i>PDE6C</i> gene that leads to ACHM.

Retinal Vessel Responses to Flicker Stimulation Are Impaired in Cav2.3-Deficient Mice—An in-vivo Evaluation Using Retinal Vessel Analysis (RVA)

Objective: Metabolic demand increases with neuronal activity and adequate energy supply is ensured by neurovascular coupling (NVC). Impairments of NVC have been reported in the context of several diseases and may correlate with disease severity and outcome. Voltage-gated Ca2+-channels (VGCCs) are involved in the regulation of vasomotor tone. In the present study, we compared arterial and venous responses to flicker stimulation in Cav2.3-competent (Cav2.3[+/+]) and -deficient (Cav2.3[−/−]) mice using retinal vessel analysis.Methods: The mice were anesthetized and the pupil of one eye was dilated by application of a mydriaticum. An adapted prototype of retinal vessel analyzer was used to perform dynamic retinal vessel analysis. Arterial and venous responses were quantified in terms of the area under the curve (AUCart/AUCven) during flicker application, mean maximum dilation (mMDart/mMDven) and time to maximum dilation (tMDart/tMDven) during the flicker, dilation at flicker cessation (DFCart/DFCven), mean maximum constriction (mMCart/mMCven), time to maximum constriction (tMCart/tMCven) after the flicker and reactive magnitude (RMart/RMven).Results: A total of 33 retinal scans were conducted in 22 Cav2.3[+/+] and 11 Cav2.3[−/−] mice. Cav2.3[−/−] mice were characterized by attenuated and partially reversed arterial and venous responses, as reflected in significantly lower AUCart (p = 0.031) and AUCven (p = 0.047), a trend toward reduced DFCart (p = 0.100), DFCven (p = 0.100), mMDven (p = 0.075), and RMart (p = 0.090) and a trend toward increased tMDart (p = 0.096).Conclusion: To our knowledge, this is the first study using a novel, non-invasive analysis technique to document impairment of retinal vessel responses in VGCC-deficient mice. We propose that Cav2.3 channels could be involved in NVC and may contribute to the impairment of vasomotor responses under pathophysiological conditions.

SSVEP phase synchronies and propagation during repetitive visual stimulation at high frequencies

Steady-state visual evoked potentials (SSVEPs), the brain response to visual flicker stimulation, have proven beneficial in both research and clinical applications. Despite the practical advantages of stimulation at high frequencies in terms of visual comfort and safety, high frequency-SSVEPs have not received enough attention and little is known about the mechanisms behind their generation and propagation in time and space. In this study, we investigated the origin and propagation of SSVEPs in the gamma frequency band (40–60 Hz) by studying the dynamic properties of EEG in 32 subjects. Using low-resolution brain electromagnetic tomography (sLORETA) we identified the cortical sources involved in SSVEP generation in that frequency range to be in the primary visual cortex, Brodmann areas 17, 18 and 19 with minor contribution from sources in central and frontal sites. We investigated the SSVEP propagation as measured on the scalp in the framework of the existing theories regarding the neurophysiological mechanism through which the SSVEP spreads through the cortex. We found a progressive phase shift from posterior parieto-occipital sites over the cortex with a phase velocity of approx. 8–14 m/s and wavelength of about 21 and 24 cm. The SSVEP spatial properties appear sensitive to input frequency with higher stimulation frequencies showing a faster propagation speed.

Plexus-specific effect of flicker-light stimulation on the retinal microvasculature assessed with optical coherence tomography angiography

We present vessel density alterations in response to flicker stimulation using optical coherence tomography angiography and identified the superficial capillary plexus as the layer with the most pronounced effect. This points out the physiological importance of the microvasculature in mediating functional hyperemia and suggests a fine-tuned plexus-specific mechanism to meet cellular metabolic demands.

Longitudinal stability of retinal blood flow regulation in response to flicker stimulation and systemic hyperoxia in mice assessed with laser speckle flowgraphy

This study aimed to evaluate longitudinal changes in retinal blood flow in response to flicker stimulation and systemic hyperoxia in mice using a laser speckle flowgraphy (LSFG-Micro). The retinal blood flow in vascular area surrounding the optic nerve head was measured in 8-week-old male mice every 2 weeks until age 20-week. The coefficient of variation of retinal blood flow under resting condition was analyzed every 2 weeks to validate the consistency of the measurement. On day 1 of the experiment, retinal blood flow was assessed every 20 s for 6 min during and after 3 min flicker light (12 Hz) stimulation; on day 2, retinal blood flow was measured every minute for 20 min during and after 10 min systemic hyperoxia; and on day 3, electroretinography (ERG) was performed. Body weight, systemic blood pressure, and ocular perfusion pressure increased significantly with age, but the resting retinal blood flow and ERG parameters remained unchanged. Retinal blood flow significantly increased with flicker stimulation and decreased with systemic hyperoxia, independent of age. The LSFG-Micro provides consistent and reproducible retinal blood flow measurement in adult mice. Longitudinal assessments of retinal blood flow in response to flicker stimulation and systemic hyperoxia may be useful indexes for noninvasive monitoring of vascular function in retinas.

THE ROLE OF OCULAR BLOOD FLOW IN THE PATHOGENESIS OF GLAUCOMA

Glaucoma is currently the second leading cause of blindness worldwide and the prevalence is expected to increase. Despite lowering of IOP, vascular risk factors, genetics, and other systemic conditions could progress the glaucoma damage. Ocular blood flow has emerged as an increasingly prevalent glaucoma risk factor in large population-based trials. Abnormal perfusion and the subsequent ischemia of the ONH play a major role in the glaucomatous damage. Ocular Blood flow is unstable if IOP fluctuates on a high enough or blood pressure on a low enough level to exceed temporarily the autoregulation capacity. IOP fluctuation is also related to both an increase in scotomas and an increase in diffuse visual fields damage. OBF is unstable if autoregulation itself is disturbed. In glaucoma the response of retinal and optic nerve head blood flow to flicker stimulation is reduced. Primary vascular dysregulation appears to be associated with abnormal retinal neurovascular coupling, because vasospastic subjects show a reduced response to flicker stimulation.Keywords: ocular blood flow, glaucoma