The effect of voluntary fasting and dehydration on flicker-induced retinal vascular dilation in a healthy individual: a case report

INTRODUCTION: Dynamic retinal vessel analysis represents a well-established method for the assessment of vascular reactivity during both normal conditions and after various provocations. We present a case where the subject showed abnormal retinal vessel reactivity after fasting voluntarily for 20 hours. CASE PRESENTATION: A healthy, 21-year-old man who fasted voluntarily for 20 hours exhibited abnormal retinal vascular reactivity (dilation and constriction) after flicker provocation as measured using the Dynamic Retinal Vessel Analyser (Imedos, Jena, Germany). CONCLUSION: The abnormal vascular reactivity induced by fasting was significant; abnormal levels of important nutrients due to fasting and dehydration could play a role through altering the concentration of vasoactive substances such as nitric oxide. This hypothesis needs further investigation.

Motion, flash, and flicker:A unified spatiotemporal model of perceived edge sharpening

Blurred edges appear sharper in motion than when they are stationary. We proposed a model of this motion sharpening that invokes a local, nonlinear contrast transducer function (Hammett et al, 1998 Vision Research 38 2099-2108). Response saturation in the transducer compresses or 'clips' the input spatial waveform, rendering the edges as sharper. To explain the increasing distortion of drifting edges at higher speeds, the degree of nonlinearity must increase with speed or temporal frequency. A dynamic contrast gain control before the transducer can account for both the speed dependence and approximate contrast invariance of motion sharpening (Hammett et al, 2003 Vision Research, in press). We show here that this model also predicts perceived sharpening of briefly flashed and flickering edges, and we show that the model can account fairly well for experimental data from all three modes of presentation (motion, flash, and flicker). At moderate durations and lower temporal frequencies the gain control attenuates the input signal, thus protecting it from later compression by the transducer. The gain control is somewhat sluggish, and so it suffers both a slow onset, and loss of power at high temporal frequencies. Consequently, brief presentations and high temporal frequencies of drift and flicker are less protected from distortion, and show greater perceptual sharpening.

A reevaluation of achromatic spatio-temporal vision: nonoriented filters are monocular, they adapt, and can be used for decision making at high flicker speeds

Masking, adaptation, and summation paradigms have been used to investigate the characteristics of early spatio-temporal vision. Each has been taken to provide evidence for (i) oriented and (ii) nonoriented spatial-filtering mechanisms. However, subsequent findings suggest that the evidence for nonoriented mechanisms has been misinterpreted: those experiments might have revealed the characteristics of suppression (eg, gain control), not excitation, or merely the isotropic subunits of the oriented detecting mechanisms. To shed light on this, we used all three paradigms to focus on the ‘high-speed’ corner of spatio-temporal vision (low spatial frequency, high temporal frequency), where cross-oriented achromatic effects are greatest. We used flickering Gabor patches as targets and a 2IFC procedure for monocular, binocular, and dichoptic stimulus presentations. To account for our results, we devised a simple model involving an isotropic monocular filter-stage feeding orientation-tuned binocular filters. Both filter stages are adaptable, and their outputs are available to the decision stage following nonlinear contrast transduction. However, the monocular isotropic filters (i) adapt only to high-speed stimuli—consistent with a magnocellular subcortical substrate—and (ii) benefit decision making only for high-speed stimuli (ie, isotropic monocular outputs are available only for high-speed stimuli). According to this model, the visual processes revealed by masking, adaptation, and summation are related but not identical.

Improving the repeatability of heterochromatic flicker photometry for measurement of macular pigment optical density

Background: Heterochromatic flicker photometry (HFP) is a psychophysical technique used to measure macular pigment optical density (MPOD). We used the MPS 9000 (MPS) HFP device. Our aim was to determine if the repeatability of the MPS could be improved to make it more suitable for monitoring MPOD over time. Methods: Intra-session repeatability was assessed in 25 participants (aged 20-50 years). The resulting data was explored in detail, e.g., by examining the effect of removal and adjustment of data with less than optimal quality parameters. A protocol was developed for improved overall reliability, which was then tested in terms of inter-session repeatability in a separate group of 27 participants (aged 19-52 years). Results: Removal and adjustment of data reduced the intra-session coefficient of repeatability (CR) by 0.04, on average, and the mean individual standard deviation by 0.004. Raw data observation offered further insight into ways of improving repeatability. The proposed protocol resulted in an inter-session CR of 0.08. Conclusions: Removal and adjustment of less than optimal data improved repeatability, and is therefore recommended. To further improve repeatability, in brief we propose that each patient perform each part of the test twice, and a third time where necessary (described in detail by the protocol). Doing so will make the MPS more useful in research and clinical settings. © 2012 Springer-Verlag.

Retinal vessel analysis:flicker reproducibility, methodological standardisations and practical limitations

The Retinal Vessel Analyser (RVA) is a commercially available ophthalmoscopic instrument capable of acquiring vessel diameter fluctuations in real time and in high temporal resolution. Visual stimulation by means of flickering light is a unique exploration tool of neurovascular coupling in the human retina. Vessel reactivity as mediated by local vascular endothelial vasodilators and vasoconstrictors can be assessed non-invasively, in vivo. In brief, the work in this thesis • deals with interobserver and intraobserver reproducibility of the flicker responses in healthy volunteers • explains the superiority of individually analysed reactivity parameters over vendorgenerated output • links in static retinal measures with dynamic ones • highlights practical limitations in the use of the RVA that may undermine its clinical usefulness • provides recommendations for standardising measurements in terms of vessel location and vessel segment length and • presents three case reports of essential hypertensives in a -year follow-up. Strict standardisation of measurement procedures is a necessity when utilising the RVA system. Agreement between research groups on implemented protocols needs to be met, before it could be considered a clinically useful tool in detecting or predicting microvascular dysfunction.

Ageing effect on flicker-induced diameter changes in retinal microvessels of healthy individuals

Purpose: To compare flicker-induced retinal vessel diameter changes in varying age groups with low cardiovascular risk. Methods: Retinal vascular reactivity to flicker light was assessed by means of dynamic retinal vessel analysis in 57 participants aged 19-30 years, 75 participants aged 31-50 years and 62 participants aged 51-70 years participants. Other assessments included carotid intima-media thickness (c-IMT), augmentation index (AIx), blood pressure profiles, blood lipid metabolism markers and Framingham risk scores (FRS). Results: Retinal arterial dilation amplitude (DA) and postflicker percentage constriction (MC%) were significantly decreased in the oldest group compared to the middle-aged (p = 0.028; p = 0.021) and youngest group (p = 0.003; p = 0.026). The arterial constriction slope (SlopeAC) was also decreased in the oldest group compared to the youngest group (p = 0.027). On the venous side, MC% was decreased in the middle-aged and oldest groups in comparison with the youngest group (p = 0.015; p = 0.010, respectively). Additionally, men exhibited increased arterial DA (p = 0.007), and percentage dilation (MD%, p < 0.001) in comparison with women, but only in the youngest age group. Both AIx and c-IMT scores increased with age (both p < 0.001); however, no correlations were found between the observed differences in the measured retinal vascular function and systemic parameters. Conclusion: In individuals with low cardiovascular risk, there are age-related differences in flicker-induced retinal vessel diameter changes throughout the entire functional response curve for arteries and veins. Gender differences mainly affect the arterial dilatory phase and are only present in young individuals.

Retinal arteriolar diameter response to flicker light provocation - A useful marker for risk stratification in cardiovascular disease?

Purpose: To to evaluate the benefit of bilinear and linear fitting to characterize the retinal vessel dilation to flicker light stimulation for the purpose of risk stratification in cardiovascular disease. Methods: Forty-five patients (15 with coronary artery disease (CAD), 15 with Diabetes Mellitus (DM) and 15 with CAD and DM) all underwent contact tonometry, digital blood pressure measurement, fundus photography, retinal vessel oximetry, static retinal vessel analysis and continous retinal diameter assessment using the retinal vessel analyser (and flicker light provocation). In addition we measured blood glucose (HbA1c) and keratinin levels in DM patients. Results: With increased severity of cardiovascular disease a more linear reaction profile of retinal arteriolar diameter to flicker light provocation can be observed. Conclusion: Absolute values of vessel dilation provide only limited information on the state of retinal arteriolar dilatory response to flicker light. The approach of bilinear fitting takes into account the immediate response to flicker light provocation as well as the maintained dilatory capacity during prolonged stimulation. Individuals with cardiovascular disease however show a largely linear reaction profile indicating an impairment of the initial rapid dilatory response as usually observed in healty individuals

The time course of changes in retinal vessel diameter in response to differing durations of flicker light provocation

Purpose: To determine the response of retinal vessels to differing durations of flicker light (FL) sitmulation. Methods: We recorded retinal arterial and venous vessel dilation to 12.5 Hz flicker light provocation (Retinal Vessel Analyzer, Imedos Systems) of varying duration (5, 7, 10 and 20 seconds) in twelve healthy young individuals (age range 26-45 yrs). All participants underwent a full ocular examination including intraocular pressure and blood pressure measurements. Results: Maximum dilation (MD) did not show a significant dependence on flicker duration in arteries whereas maximum constriction (MC) did. However, in veins MD significantly increased with flicker duration. Approximately 80-90% of MD in arteries is reached within 10 seconds of flicker light stimulation. Conclusions: The vast majority of arterial dilatory capacity is reached within 10 seconds of flicker light stimulation even though venous dilation continues strongly. Since the MC of arteries shows a significant dependence on flicker duration measurements at two different durations can provide more information about the retinal vascular system than at a single flicker duration alone.

Clinical evaluation of the MPS 9000 Macular Pigment Screener

Background/aims The MPS 9000 uses a psychophysical technique known as heterochromatic flicker photometry to measure macular pigment optical density (MPOD). Our aim was to determine the measurement variability (noise) of the MPS 9000. Methods Forty normally sighted participants who ranged in age from 18 to 50 years (25.4±8.2 years) were recruited from staff and students of Aston University (Birmingham, UK). Data were collected by two operators in two sessions separated by 1 week in order to assess test repeatability and reproducibility. Results The overall mean MPOD for the cohort was 0.35±0.14. There was no significant negative correlation between MPS 9000 MPOD readings and age (r=-0.192, p=0.236). Coefficients were 0.33 and 0.28 for repeatability, and 0.25 and 0.26 for reproducibility. There was no significant correlation between mean and difference MPOD values for any of the four pairs of results. Conclusions When MPOD is being monitored over time then any change less than 0.33 units should not be considered clinically significant as it is very likely to be due to measurement noise. The size of the coefficient appears to be positively correlated with MPOD.

Do lutein, zeaxanthin, and macular pigment optical density differ with age or age-related maculopathy?

Background and aims Current age-related macular disease (ARMD) treatment includes antioxidant supplementation. Lutein (L) and zeaxanthin (Z) are antioxidants that make up macularpigment within the retina and may reduce the risk of developing ARMD. Ageing and smoking are leading risk factors for developing ARMD. We investigated differences in dietary, supplemental and retinal L and Z, and smoking habits in healthy younger eyes (HY), healthy older eyes (HO) and eyes with an early form of ARMD called age-related maculopathy (ARM). Methods HO, HY and ARM groups were assessed for dietary intakes of L and Z using food diaries. Smoking habits and self-administered quantities of L and Z were obtained via questionnaire. Retinal L and Z levels (macularpigmentopticaldensity, or MPOD) were determined using heterochromatic flicker photometry. Results No significant difference was demonstrated for dietary L and Z intake (?2 = 4.983, p = 0.083) or for MPOD between groups (F = 0.40, p = 0.67). There was a significant difference between the HY (mean ± sd: 1.20 ± 2.99), HO (4.51 ± 7.05) ARM groups (9.15 ± 12.28) for pack years smoked (?2 = 11.61, p = 0.03). Conclusions Our results do not support the theory that ARM develops as a result of L and Z deficiency. Higher pack years smoked may be a factor in disease development. Dietary and supplementary L and Z levels must be obtained when assessing MPOD between groups or over time.

Ocular and systemic markers for vascular function in those at risk of type 2 diabetes mellitus and cardiovascular disease

The devastating impact of Type 2 Diabetes Mellitus (T2DM) -related morbidity and mortality on global healthcare is escalating with higher prevalences of obesity, poor diet, and sedentary lifestyles. Therefore, the clinical need for early diagnosis and prevention in groups of high-risk individuals is necessary. The purpose of this thesis was to investigate the use of surrogate markers, namely retinal vascular function, to determine future vascular endothelial dysfunction, atherosclerosis, large vessel disease and cardiovascular risk in certain groups. This namely covered normoglycaemic and normotensive South Asians (SAs), those with Impaired-Glucose Tolerance (IGT) and individuals with a familial history (FH) of T2DM. Additionally the effect of overweight and obesity was studied. The techniques and modified protocols adopted for this thesis involved the investigation of endothelial function by means of vascular reactivity at the ocular and systemic level. Furthermore, the relationships between retinal and systemic function with circulating markers for endothelial cell function and cardiovascular risk markers were explored. The principal studies and findings of the research were: Vascular Function in Normoglycaemic Individuals with and without a FH of T2DM WE FH individuals exhibited higher levels of total cholesterol levels that correlated well with the retinal arterial dilation amplitude to flicker light stimulus. However this did not extend to noticeable differences in markers for endothelial cell damage and impaired retinal and systemic function. Vascular Function in Normoglycaemic South-Asians vs. White-Europeans without a FH and Vascular Disturbances Compared to healthy WEs (normo -glycaemic and -tensive), SA participants exhibited levels of dyslipidaemia and a state of oxidative stress that extended to impaired vascular function as detected by reduced brachial artery flow-mediated dilation, slower retinal arterial vessel dilation reaction times (Appendix 3) and steeper constriction profiles. Furthermore, gender sub-group analysis presented in a sub-chapter shows that SA males demonstrated 24-hour systemic blood pressure (BP) and heart rate variability (HRV) abnormalities and heightened cardiovascular disease (CVD) risk. Vascular Function in Individuals Newly Diagnosed with IGT as compared to Normoglycaemic Healthy Controls Newly-diagnosed WE and SA IGT patients showed a greater risk for CVD and T2DM progression by means of 24-hour BP abnormalities, dyslipidaemia, increased carotid artery intimal-media thickness (c-IMT), Framingham scores and cholesterol ratios. Additionally, pre-clinical markers for oxidative stress and endothelial dysfunction, as evident by significantly lower levels of plasma glutathione and increased levels of von-Willebrand factor in IGT individuals, extended to impaired vascular systemic and retinal function compared to normal controls. This originally shows retinal, systemic and biochemical disturbances in newly-diagnosed IGT not previously reported before. Vascular Function in Normal, Overweight and Obese Individuals of SA and WE Ethnicity In addition to the intended study chapters, the thesis also investigated the influence of obesity and overweight on vascular function. Most importantly, it was found for the first time that compared to lean individuals it was overweight and not obese individuals that exhibited signs of vascular systemic and ocular dysfunction that was evident alongside markers of atherosclerosis, CVD risk and endothelial damage.

Binocular combination at threshold: temporal filtering and summation of signals in separate ON and OFF channels

How does the brain combine spatio-temporal signals from the two eyes? We quantified binocular summation as the improvement in 2AFC contrast sensitivity for flickering gratings seen by two eyes compared with one. Binocular gratings in-phase showed sensitivity up to 1.8 times higher, suggesting nearly linear summation of contrasts. The binocular advantage decreased to 1.4 at lower spatial and higher temporal frequencies (0.25 cycle deg-1, 30 Hz). Dichoptic, antiphase gratings showed only a small binocular advantage, by a factor of 1.1 to 1.2, but no evidence of cancellation. We present a signal-processing model to account for the contrast-sensitivity functions and the pattern of binocular summation. It has linear sustained and transient temporal filters, nonlinear transduction, and half-wave rectification that creates ON and OFF channels. Binocular summation occurs separately within ON and OFF channels, thus explaining the phase-specific binocular advantage. The model also accounts for earlier findings on detection of brief antiphase flashes and the surprising finding that dichoptic antiphase flicker is seen as frequency-doubled (Cavonius et al, 1992 Ophthalmic and Physiological Optics 12 153 - 156). [Supported by EPSRC project GR/S74515/01].

The role of macular pigment assessment in clinical practice:a review

This review compares the results of studies that have investigated the impact of lutein and zeaxanthin supplementation on macular pigment optical density (MPOD) with those that have investigated the reliability of techniques used to measure macular pigment optical density. The review will focus on studies that have used heterochromatic flicker photometry for measurement of macular pigment optical density, as this is the only technique that is currently available commercially to clinicians. We identified articles that reported on supplementation with lutein and/or zeaxanthin and/or meso-zeaxanthin on macular pigment optical density measurement techniques published in peer-reviewed journals, through a multi-staged, systematic approach. Twenty-four studies have investigated the repeatability of MPOD measurements using heterochromatic flicker photometry. Of these, 10 studies provided a coefficient of repeatability or data from which the coefficient could be calculated, with a range in values of 0.06 to 0.58. The lowest coefficient of repeatability assessed on naïve subjects alone was 0.08. These values tell us that, at best, changes greater than 0.08 can be considered clinically significant and at worst, only changes greater than 0.58 can be considered clinically significant. Six studies assessed the effect of supplementation with up to 20 mg/day lutein on macular pigment optical density measured using heterochromatic flicker photometry and the mean increase in macular pigment optical density ranged from 0.025 to 0.09. It seems reasonable to conclude that the chance of eliciting an increase in macular pigment optical density during six months of daily supplementation with between 10 and 20 mg lutein that is of sufficient magnitude to be detected by using heterochromatic flicker photometry on an individual basis is small. Commercially available heterochromatic flicker photometers for macular pigment optical density assessment in the clinical environment appear to demonstrate particularly poor coefficient of repeatability values. Clinicians should exercise caution when considering the purchase of these instruments for potential monitoring of macular pigment optical density in response to supplementation in individual patients.

Fast response static var generator for improving the power system performance of an electric arc furnace (EAF)

Cascaded multilevel inverters-based Static Var Generators (SVGs) are FACTS equipment introduced for active and reactive power flow control. They eliminate the need for zigzag transformers and give a fast response. However, with regard to their application for flicker reduction in using Electric Arc Furnace (EAF), the existing multilevel inverter-based SVGs suffer from the following disadvantages. (1) To control the reactive power, an off-line calculation of Modulation Index (MI) is required to adjust the SVG output voltage. This slows down the transient response to the changes of reactive power; and (2) Random active power exchange may cause unbalance to the voltage of the d.c. link (HBI) capacitor when the reactive power control is done by adjusting the power angle d alone. To resolve these problems, a mathematical model of 11-level cascaded SVG, was developed. A new control strategy involving both MI (modulation index) and power angle (d) is proposed. A selected harmonics elimination method (SHEM) is taken for switching pattern calculations. To shorten the response time and simplify the controls system, feed forward neural networks are used for on-line computation of the switching patterns instead of using look-up tables. The proposed controller updates the MI and switching patterns once each line-cycle according to the sampled reactive power Qs. Meanwhile, the remainder reactive power (compensated by the MI) and the reactive power variations during the line-cycle will be continuously compensated by adjusting the power angles, d. The scheme senses both variables MI and d, and takes action through the inverter switching angle, qi. As a result, the proposed SVG is expected to give a faster and more accurate response than present designs allow. In support of the proposal there is a mathematical model for reactive powered distribution and a sensitivity matrix for voltage regulation assessment, MATLAB simulation results are provided to validate the proposed schemes. The performance with non-linear time varying loads is analysed and refers to a general review of flicker, of methods for measuring flickers due to arc furnace and means for mitigation.

Macular pigment optical density is related to blood glutathione levels in healthy individuals

Purpose. To assess the relationship between macular pigment optical density (MPOD) and blood markers for antioxidant defense in otherwise healthy volunteers. Methods. Forty-seven healthy volunteers were subjected to blood analysis to detect the level of circulating glutathione in its reduced (GSH) and oxidized (GSSG) forms. The level of MPOD was measured using heterochromatic flicker photometry. Systemic blood pressure (BP) parameters, heart rate (HR), body mass index (BMI), and plasma levels of total, HDL, and LDL cholesterol and triglycerides (TGs) were also determined. Results. A simple correlation model revealed that the level of MPOD correlated significantly and positively with both GSH (P < 0.001) and t-GSH (P < 0.001) levels but not with those of GSSG (P > 0.05). Age, sex, systemic BP parameters, HR, BMI, and plasma levels of cholesterol and TGs did not have any influence on either MPOD or glutathione levels (all P > 0.05). In addition, a forward stepwise multiple regression analysis showed MPOD to have a significantly and independent correlation with GSH levels (ß = 0.63; P < 0.001). Conclusions. In otherwise healthy older individuals, there is a positive correlation between local and systemic antioxidant defense mechanisms.