The speed of sight: Individual variation in critical flicker fusion thresholds.

The critical flicker fusion threshold is a psychophysical measure commonly used to quantify visual temporal resolution; the fastest rate at which a visual system can discriminate visual signals. Critical flicker fusion thresholds vary substantially among species, reflecting different ecological niches and demands. However, it is unclear how much variation exists in flicker fusion thresholds between healthy individuals of the same species, or how stable this attribute is over time within individuals. In this study, we assessed both inter- and intra-individual variation in critical flicker fusion thresholds in a cohort of healthy human participants within a specific age range, using two common psychophysical methods and three different measurements during each session. The resulting thresholds for each method were highly correlated. We found a between-participant maximum difference of roughly 30 Hz in flicker fusion thresholds and we estimated a 95% prediction interval of 21 Hz. We used random-effects models to compare between- and within-participant variance and found that approximately 80% of variance was due to between-individual differences, and about 10% of the variance originated from within-individual differences over three sessions. Within-individual thresholds did not differ significantly between the three sessions in males, but did in females (P<0.001 for two methods and P<0.05 for one method), indicating that critical flicker fusion thresholds may be more variable in females than in males.

Critical flicker fusion in patients with epilepsy under antiseizure medication.

OBJECTIVE: Critical flicker frequency (CFF) and flicker frequency (FF) are used as indicators for the neurotoxic adverse events of drugs in pharmacology. In this pilot study, we investigated whether patients with epilepsy (PWE) treated with various antiseizure medications (ASM) had significantly different CFFs compared with healthy controls. In addition, we investigated the appropriateness of CFF as an objective measurement tool in PWE who reported adverse events according to the adverse event profile (AEP). METHODS: Patients receiving regular antiseizure treatment at our center, along with healthy controls, were included in this study. Clinical neurotoxic symptoms, AEP scores, and serum ASM levels were assessed in the PWE group. We used a CFF device that produced a red-black, green-black, blue-black, or white-black flicker. CFF and FF were compared between PWE and healthy controls. In PWE, the correlation of alterations in CFF and FF with AEP results and through ASM serum concentrations was calculated. RESULTS: A total of 33 PWE and 20 healthy controls participated in the study. Except for two light modalities, CFF and FF were significantly reduced in PWE compared with controls. CFF and FF did not differ significantly between PWE with AEP scores >44 points and those with lower scores. CFF and FF levels did not correlate with changes in AEP scores, serum concentrations, or doses. SIGNIFICANCE: CFF and FF distinguished PWE with ASM from healthy controls. No clinically relevant differentiation was detected in the heterogenous PWE group. To investigate whether CFF and FF may serve as subtle indicators of neurotoxicity or specific modes of action, additional studies are needed in more homogenous PWE groups.

Reply to Mankowska et al. Comment on "Muth et al. Assessing Critical Flicker Fusion Frequency: Which Confounders? A Narrative Review. Medicina 2023, 59, 800".

First and foremost, we like to express our gratitude for the praise bestowed upon our narrative review [...].

Comment on Muth et al. Assessing Critical Flicker Fusion Frequency: Which Confounders? A Narrative Review. Medicina 2023, 59, 800.

We first want to thank the authors of the excellent review for their contributions to summarizing the confounders associated with critical flicker fusion frequency (CFFF) [...].

Retinal Responses to Visual Stimuli in Interphotoreceptor Retinoid Binding-Protein Knock-Out Mice.

Interphotoreceptor retinoid-binding protein (IRBP) is an abundant glycoprotein in the subretinal space bound by the photoreceptor (PR) outer segments and the processes of the retinal pigmented epithelium (RPE). IRBP binds retinoids, including 11-cis-retinal and all-trans-retinol. In this study, visual function for demanding visual tasks was assessed in IRBP knock-out (KO) mice. Surprisingly, IRBP KO mice showed no differences in scotopic critical flicker frequency (CFF) compared to wildtype (WT). However, they did have lower photopic CFF than WT. IRBP KO mice had reduced scotopic and photopic acuity and contrast sensitivity compared to WT. IRBP KO mice had a significant reduction in outer nuclear layer (ONL) thickness, PR outer and inner segment, and full retinal thickness (FRT) compared to WT. There were fewer cones in IRBP KO mice. Overall, these results confirm substantial loss of rods and significant loss of cones within 30 days. Absence of IRBP resulted in cone circuit damage, reducing photopic flicker, contrast sensitivity, and spatial frequency sensitivity. The c-wave was reduced and accelerated in response to bright steps of light. This result also suggests altered retinal pigment epithelium activity. There appears to be a compensatory mechanism such as higher synaptic gain between PRs and bipolar cells since the loss of the b-wave did not linearly follow the loss of rods, or the a-wave. Scotopic CFF is normal despite thinning of ONL and reduced scotopic electroretinogram (ERG) in IRBP KO mice, suggesting either a redundancy or plasticity in circuits detecting (encoding) scotopic flicker at threshold even with substantial rod loss.

Assessing Critical Flicker Fusion Frequency: Which Confounders? A Narrative Review.

The critical flicker fusion frequency (cFFF) refers to the frequency at which a regularly recurring change of light stimuli is perceived as steady. The cFFF threshold is often assessed in clinics to evaluate the temporal characteristics of the visual system, making it a common test for eye diseases. Additionally, it serves as a helpful diagnostic tool for various neurological and internal diseases. In the field of diving/hyperbaric medicine, cFFF has been utilized to determine alertness and cognitive functions. Changes in the cFFF threshold have been linked to the influence of increased respiratory gas partial pressures, although there exist inconsistent results regarding this effect. Moreover, the use of flicker devices has produced mixed outcomes in previous studies. This narrative review aims to explore confounding factors that may affect the accuracy of cFFF threshold measurements, particularly in open-field studies. We identify five broad categories of such factors, including (1) participant characteristics, (2) optical factors, (3) smoking/drug use, (4) environmental aspects, and (5) breathing gases and partial pressures. We also discuss the application of cFFF measurements in the field of diving and hyperbaric medicine. In addition, we provide recommendations for interpreting changes in the cFFF threshold and how they are reported in research studies.

Evaluating a Novel, Portable, Self-Administrable Device ("Beacon") That Measures Critical Flicker Frequency as a Test for Hepatic Encephalopathy.

INTRODUCTION: We compared critical flicker frequency (CFF) thresholds obtained using a novel portable device "Beacon" with thresholds from the commercially available Lafayette Flicker Fusion System (Lafayette-FFS) in patients with cirrhosis. METHODS: One hundred fifty-three participants with chronic liver disease underwent CFF testing using Beacon and Lafayette-FFS with a method-of-limits and/or forced-choice protocol. RESULTS: Beacon demonstrated excellent test-retest reliability (intraclass correlation 0.91-0.97) and good correlation with the Lafayette-FFS values (intraclass correlation 0.77-0.84). Forced-choice CFF were on average 4.1 Hz higher than method-of-limits descending CFFs. DISCUSSION: Beacon can be self-administered by patients with chronic liver disease and cirrhosis to measure CFF, a validated screening test for minimal hepatic encephalopathy.

Is critical flicker-fusion frequency a valid measure of visual fatigue? A post-hoc analysis of a double-masked randomised controlled trial.

PURPOSE: Critical flicker-fusion frequency (CFF) has been used in clinical studies as a measure of visual fatigue. We examine the correlation between CFF and subjective reports of visual fatigue in a group of symptomatic computer users, to consider whether CFF may be used as a surrogate measure of visual fatigue symptoms. METHODS: We analysed data from a previous randomised controlled trial. One hundred and twenty adults, diagnosed with computer vision syndrome, had CFF and visual fatigue symptoms quantified before and after a visually demanding 2-h computer task. Symptoms were assessed using a questionnaire with nine subcomponents that summed to a total score of 900. CFF was measured using a two-interval forced-choice method, with the flicker rate altered by a computer-controlled staircase procedure. For our primary analysis, we determined Spearman correlation coefficients between post-task symptom scores and CFF, and between change from baseline symptom scores and CFF. We also used a bootstrap procedure to consider whether symptom score subcomponents were significantly (Bonferroni-corrected) different from overall scores with regard to their correlations with CFF. RESULTS: Although visual fatigue symptom scores altered significantly post-task (mean change: 92 units; 95% confidence interval [CI]: 11 to 122), CFF did not (mean change -0.7 Hz; 95% CI: -1.7 to 0.3). There was no significant correlation between overall symptom scores and CFF, either for the post-task (r = -0.13; 95% CI: -0.31 to 0.05) or the change from baseline (r = -0.18; 95% CI: -0.35 to 0.01) analysis. Subcomponents of the symptom questionnaire did not show a significant correlation with CFF, either for the post-task or the change from baseline analysis. CONCLUSIONS: We find that CFF is not a useful surrogate for symptoms of visual fatigue, given its low correlation with scores on a visual fatigue symptom questionnaire.

A flashing light may not be that flashy: A systematic review on critical fusion frequencies.

BACKGROUND: Light pollution could represent one of the main drivers behind the current biodiversity erosion. While the effects of many light components on biodiversity have already been studied, the influence of flicker remains poorly understood. The determination of the threshold frequency at which a flickering light is perceived as continuous by a species, usually called the Critical Fusion Frequency (CFF), could thus help further identify the impacts of artificial lighting on animals. OBJECTIVE: This review aimed at answering the following questions: what is the distribution of CFF between species? Are there differences in how flicker is perceived between taxonomic classes? Which species are more at risk of being impacted by artificial lighting flicker? METHODS: Citations were extracted from three literature databases and were then screened successively on their titles, abstracts and full-texts. Included studies were critically appraised to assess their validity. All relevant data were extracted and analysed to determine the distribution of CFF in the animal kingdom and the influence of experimental designs and species traits on CFF. RESULTS: At first, 4881 citations were found. Screening and critical appraisal provided 200 CFF values for 156 species. Reported values of CFF varied from a maximum of between 300 Hz and 500 Hz for the beetle Melanophila acuminata D. to a mean of 0.57 (± 0.08) Hz for the snail Lissachatina fulica B. Insects and birds had higher CFF than all other studied taxa. Irrespective of taxon, nocturnal species had lower CFF than diurnal and crepuscular ones. CONCLUSIONS: We identified nine crepuscular and nocturnal species that could be impacted by the potential adverse effects of anthropogenic light flicker. We emphasize that there remains a huge gap in our knowledge of flicker perception by animals, which could potentially be hampering our understanding of its impacts on biodiversity, especially in key taxa like bats, nocturnal birds and insects.

Usefulness of critical flicker fusion frequency measurement and its laterality for evaluating compressive optic neuropathy due to pituitary neuroendocrine tumors.

Critical flicker fusion frequency (CFF) is a short but sensitive method for evaluating optic nerve function. We measured CFF in patients with pituitary neuroendocrine tumors (Pit-NETs) to assess its usefulness. Data from 184 patients with nonfunctioning Pit-NETs, who had been treated with transsphenoidal surgery and had no medical history of eye diseases, was used in this retrospective study. Visual acuity decline (VAD) was defined as > 0.10 reduction in logMAR visual acuity and CFF decline (CFD) was defined as CFF value < 35 Hz. Visual field defect (VFD) was evaluated by automated perimetry on a Humphrey visual field analyzer. Potential associations between abnormal test results and tumor height from the suprasellar were analyzed. Contact between the optic nerve or chiasma and the tumor was present and absent in 161 and 23 patients, respectively. In patients showing contact, the difference in CFF between the left and right eyes was larger (p = 0.0008), and the optimal cutoff value using the receiver operating characteristic curve was 3 Hz. Therefore, ≥ 3 Hz was considered positive for CFF laterality (CFL), the most prevalent condition. Tumor height was lower in patients with CFL positivity compared to those with VAD or VFD (p < 0.01). The prevalence of test abnormalities was the highest for small tumors compared to those of other tests. Changes in CFL permit early detection of Pit-NETs. Our results indicate that CFF laterality can be seen in the early stages of compressive optic neuropathy due to Pit-NET.

Comment on Mankowska et al. Critical Flicker Fusion Frequency: A Narrative Review. Medicina 2021, 57, 1096.

We have read with great interest the review by Mankowska et al. [...].

Reply to Vrijdag et al. Comment on "Mankowska et al. Critical Flicker Fusion Frequency: A Narrative Review. Medicina 2021, 57, 1096".

Thank you very much for your interest and comments [...].

A reinterpretation of critical flicker-frequency (CFF) data reveals key details about light adaptation and normal and abnormal visual processing.

Our ability to see flicker has an upper frequency limit above which flicker is invisible, known as the "critical flicker frequency" (CFF), that typically grows with light intensity (I). The relation between CFF and I, the focus of nearly 200 years of research, is roughly logarithmic, i.e., CFF âˆ log(I)-a relation called the Ferry-Porter law. However, why this law should occur, and how it relates to the underlying physiology, have never been adequately explained. Over the past two decades we have measured CFF in normal observers and in patients with retinal gene defects. Here, we reanalyse and model our data and historical CFF data. Remarkably, CFF-versus-I functions measured under a wide range of conditions in patients and in normal observers all have broadly similar shapes when plotted in double-logarithmic coordinates, i.e., log (CFF)-versus-log(I). Thus, the entire dataset can be characterised by horizontal and vertical logarithmic shifts of a fixed-shape template. Shape invariance can be predicted by a simple model of visual processing built from a sequence of low-pass filters, subtractive feedforward stages and gain adjustment (Rider, Henning & Stockman, 2019). It depends primarily on the numbers of visual processing stages that approach their power-law region at a given intensity and a frequency-independent gain reduction at higher light levels. Counter-intuitively, the CFF-versus-I relation depends primarily on the gain of the visual response rather than its speed-a conclusion that changes our understanding and interpretation of human flicker perception. The Ferry-Porter "law" is merely an approximation of the shape-invariant template.

An Analysis of Metabolic Changes in the Retina and Retinal Pigment Epithelium of Aging Mice.

Purpose: The purpose of this study was to present our hypothesis that aging alters metabolic function in ocular tissues. We tested the hypothesis by measuring metabolism in aged murine tissues alongside retinal responses to light. Methods: Scotopic and photopic electroretinogram (ERG) responses in young (3-6 months) and aged (23-26 months) C57Bl/6J mice were recorded. Metabolic flux in retina and eyecup explants was quantified using U-13C-glucose or U-13C-glutamine with gas chromatography-mass spectrometry (GC-MS), O2 consumption rate (OCR) in a perifusion apparatus, and quantifying adenosine triphosphatase (ATP) with a bioluminescence assay. Results: Scotopic and photopic ERG responses were reduced in aged mice. Glucose metabolism, glutamine metabolism, OCR, and ATP pools in retinal explants were mostly unaffected in aged mice. In eyecups, glutamine usage in the Krebs Cycle decreased while glucose metabolism, OCR, and ATP pools remained stable. Conclusions: Our examination of metabolism showed negligible impact of age on retina and an impairment of glutamine anaplerosis in eyecups. The metabolic stability of these tissues ex vivo suggests age-related metabolic alterations may not be intrinsic. Future experiments should focus on determining whether external factors including nutrient supply, oxygen availability, or structural changes influence ocular metabolism in vivo.

Critical Flicker Fusion Frequency: A Narrative Review.

This review presents the current knowledge of the usage of critical flicker fusion frequency (CFF) in human and animal model studies. CFF has a wide application in different fields, especially as an indicator of cortical arousal and visual processing. In medicine, CFF may be helpful for diagnostic purposes, for example in epilepsy or minimal hepatic encephalopathy. Given the environmental studies and a limited number of other methods, it is applicable in diving and hyperbaric medicine. Current research also shows the relationship between CFF and other electrophysiological methods, such as electroencephalography. The human eye can detect flicker at 50-90 Hz but reports are showing the possibility to distinguish between steady and modulated light up to 500 Hz. Future research with the use of CFF is needed to better understand its utility and application.

Melanopic stimulation does not alter psychophysical threshold sensitivity for luminance flicker.

In addition to the rod and cone photoreceptors the retina contains intrinsically photosensitive retinal ganglion cells (ipRGCs). These cells express the photopigment melanopsin and are known to be involved in reflexive visual functions such as pupil response and photo-entrainment of the circadian rhythm. It is possible that the ipRGCs contribute to conscious visual perception, either by providing an independent signal to the geniculo-striate pathway, or by interacting with and thus modifying signals arising from "classical" retinal ganglion cells that combine and contrast cone input. Here, we tested for the existence of an interaction by asking if a 350% change in melanopsin stimulation alters psychophysical sensitivity for the detection of luminance flicker. In Experiment 1, we tested for a change in the threshold for detecting luminance flicker in three participants after they adapted to backgrounds with different degrees of tonic melanopsin stimulation. In Experiments 2 and 3, this test was repeated, but now for luminance flicker presented on a transient pedestal of melanopsin stimulation. Across the three experiments, no effect of melanopsin stimulation upon threshold flicker sensitivity was found. Our results suggest that even large changes in melanopsin stimulation do not affect near-threshold, cone-mediated visual perception.

The visual cortex produces gamma band echo in response to broadband visual flicker.

The aim of this study is to uncover the network dynamics of the human visual cortex by driving it with a broadband random visual flicker. We here applied a broadband flicker (1-720 Hz) while measuring the MEG and then estimated the temporal response function (TRF) between the visual input and the MEG response. This TRF revealed an early response in the 40-60 Hz gamma range as well as in the 8-12 Hz alpha band. While the gamma band response is novel, the latter has been termed the alpha band perceptual echo. The gamma echo preceded the alpha perceptual echo. The dominant frequency of the gamma echo was subject-specific thereby reflecting the individual dynamical properties of the early visual cortex. To understand the neuronal mechanisms generating the gamma echo, we implemented a pyramidal-interneuron gamma (PING) model that produces gamma oscillations in the presence of constant input currents. Applying a broadband input current mimicking the visual stimulation allowed us to estimate TRF between the input current and the population response (akin to the local field potentials). The TRF revealed a gamma echo that was similar to the one we observed in the MEG data. Our results suggest that the visual gamma echo can be explained by the dynamics of the PING model even in the absence of sustained gamma oscillations.

Evaluation of cerebral dysfunction in patients with chronic kidney disease using neuropsychometric and neurophysiological tests.

BACKGROUND: Uremic encephalopathy is defined as cerebral dysfunction due to toxin accumulation in patients with chronic kidney disease (CKD). This condition is characterized by subtle to florid symptoms, and its clinical course is always progressive when untreated but partially reversible with renal replacement therapy. While no test exists to measure subclinical uremic encephalopathy, two tests have been validated to measure minimal hepatic encephalopathy: the critical flicker frequency (CFF) test and the psychometric hepatic encephalopathy score (PHES). OBJECTIVE: To use CFF and PHES to measure the prevalence of cerebral dysfunction in individuals with CKD. METHODS: This cross-sectional study included a total of 69 patients with stage-5 CKD. Cutoff points for minimal encephalopathy were established using existing clinical guidelines: ≤39 Hz for CFF and < -4 for PHES. All participants were also screened for cognitive function and depression. RESULTS: Eighteen cases (26.1%) of cerebral dysfunction linked to uremic encephalopathy were detected with CFF, while twelve (17.4%) were detected by PHES; only six cases (8.7%) were diagnosed by both methods. Half of the cases (50%) had diabetes, and 61% were on hemodialysis. Cognitive function scores did not differ significantly between those receiving dialysis, hemodialysis, or no renal replacement therapy. CONCLUSIONS: It is essential to identify cerebral dysfunction when uremic encephalopathy is in early subclinical stages to reduce preventable events as traffic and work accidents.