Abnormal 8-Hz flicker electroretinograms in carriers of X-linked retinoschisis.
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ABSTRACT:
SUBMITTER: McAnany JJ
PROVIDER: S-EPMC5556686 | biostudies-other | 2016 Aug
REPOSITORIES: biostudies-other
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Project description:Humans perceive a stable average intensity image without flicker artifacts when a television or monitor updates at a sufficiently fast rate. This rate, known as the critical flicker fusion rate, has been studied for both spatially uniform lights, and spatio-temporal displays. These studies have included both stabilized and unstablized retinal images, and report the maximum observable rate as 50-90 Hz. A separate line of research has reported that fast eye movements known as saccades allow simple modulated LEDs to be observed at very high rates. Here we show that humans perceive visual flicker artifacts at rates over 500 Hz when a display includes high frequency spatial edges. This rate is many times higher than previously reported. As a result, modern display designs which use complex spatio-temporal coding need to update much faster than conventional TVs, which traditionally presented a simple sequence of natural images.
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Project description:Rhythmic visual stimulation ("flicker") is primarily used to "tag" processing of low-level visual and high-level cognitive phenomena. However, preliminary evidence suggests that flicker may also entrain endogenous brain oscillations, thereby modulating cognitive processes supported by those brain rhythms. Here we tested the interaction between 10 Hz flicker and endogenous alpha-band (?10 Hz) oscillations during a selective visuospatial attention task. We recorded EEG from human participants (both genders) while they performed a modified Eriksen flanker task in which distractors and targets flickered within (10 Hz) or outside (7.5 or 15 Hz) the alpha band. By using a combination of EEG source separation, time-frequency, and single-trial linear mixed-effects modeling, we demonstrate that 10 Hz flicker interfered with stimulus processing more on incongruent than congruent trials (high vs low selective attention demands). Crucially, the effect of 10 Hz flicker on task performance was predicted by the distance between 10 Hz and individual alpha peak frequency (estimated during the task). Finally, the flicker effect on task performance was more strongly predicted by EEG flicker responses during stimulus processing than during preparation for the upcoming stimulus, suggesting that 10 Hz flicker interfered more with reactive than proactive selective attention. These findings are consistent with our hypothesis that visual flicker entrained endogenous alpha-band networks, which in turn impaired task performance. Our findings also provide novel evidence for frequency-dependent exogenous modulation of cognition that is determined by the correspondence between the exogenous flicker frequency and the endogenous brain rhythms.SIGNIFICANCE STATEMENT Here we provide novel evidence that the interaction between exogenous rhythmic visual stimulation and endogenous brain rhythms can have frequency-specific behavioral effects. We show that alpha-band (10 Hz) flicker impairs stimulus processing in a selective attention task when the stimulus flicker rate matches individual alpha peak frequency. The effect of sensory flicker on task performance was stronger when selective attention demands were high, and was stronger during stimulus processing and response selection compared with the prestimulus anticipatory period. These findings provide novel evidence that frequency-specific sensory flicker affects online attentional processing, and also demonstrate that the correspondence between exogenous and endogenous rhythms is an overlooked prerequisite when testing for frequency-specific cognitive effects of flicker.
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Project description:Previous studies showed that entrainment of light flicker at low gamma frequencies provided neuroprotection in mouse models of Alzheimer's disease (AD) and stroke. The current study was set to explore the feasibility of using 40 Hz light flicker for human brain stimulation for future development as a tool for brain disease treatment. The effect of 40 Hz low gamma frequency light on a cohort of healthy human brains was examined using 64 channel electroencephalography (EEG), followed by microstate analyses. A random frequency light flicker was used as a negative control treatment. Light flicker at 40 Hz significantly increased the corresponding band power in the O1, Oz, and O3 electrodes covering the occipital areas of both sides of the brain, indicating potent entrainment with 40 Hz light flicker in the visual cortex area. Importantly, the 40 Hz light flicker significantly altered microstate coverage, transition duration, and the Lempel-Ziv complexity (LZC) compared to the rest state. Microstate metrics are known to change in the brains of Alzheimer's disease, schizophrenia, and stroke patients. The current study laid the foundation for the future development of 40 Hz light flicker as therapeutics for brain diseases.
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Project description:Sirtuin 1 (SIRT1) is a protein deacetylase with important cellular functions, as it regulates numerous processes, including the circadian rhythm in peripheral tissues. Efforts are ongoing to reveal how Sirt1 can be used to treat diseases, such as alcoholic liver disease (ALD), Alzheimer's disease, and liver fibrosis. We have recently shown that noninvasive exposure to 40-Hz light flicker activates hypothalamic SIRT1 gene expression, thereby regulating the central circadian clock. This study investigated the effects of 40-Hz light flicker in a mouse model of ALD. RNA sequencing (RNA-seq) analysis was performed to explore the potential pathways affected by 40-Hz light flicker. We found that 40-Hz light flicker significantly decreased the acute ethanol-induced increases in serum alanine aminotransferase (ALT) and serum triglyceride (TG) levels and reduced fat-droplet accumulation in mouse livers. Additionally, 40-Hz light flicker significantly suppressed ethanol-induced increases in sterol regulatory element binding protein 1 (SREBP-1) and fatty acid synthase (Fasn) levels. Furthermore, the ethanol induced significant decreases in both Sirt1 levels and phosphorylation of adenosine monophosphate-activated protein kinase subunit (AMPK?), compared with those in the control group. Strikingly, pretreatment with 40-Hz light flicker ameliorated such ethanol-induced decreases in SIRT1 levels and AMPK? phosphorylation. In addition, ethanol-induced increases in levels of brain and muscle arnt-like protein-1 (BMAL1), circadian locomotor output cycles kaput (CLOCK), and period 2 (PER2) were reversed by 40-Hz light flicker. RNA-seq analysis revealed significant differences in expression of genes related to the AMPK signalling. Moreover, ethanol consumption altered mRNA levels of Sirt1 and circadian genes in the suprachiasmatic nucleus (SCN), indicating that ethanol influenced central pacemaker genes; however, 40-Hz light flicker reversed these ethanol-induced changes. Taken together, our findings demonstrate that 40-Hz light flicker rapidly influence the SCN and exhibits inhibitory properties on hepatic lipogenesis, indicating that 40-Hz light flicker has therapeutic potential for preventing alcoholic liver steatosis.
| S-EPMC7109315 | biostudies-literature
Project description:Alzheimer's disease (AD) patients often exhibit perturbed circadian rhythm with fragmented sleep before disease onset. This study was designed to evaluate the effect of a 40-Hz light flicker on circadian rhythm in an AD mouse model (APP/PS1). Locomotor rhythms recordings were conducted to examine the circadian clock rhythm in APP/PS1 mice. Molecular biology analyses, including western blot and real-time qPCR assays, were conducted to assess the changes in circadian locomotor output cycles kaput (CLOCK), brain and muscle arnt-like protein-1 (BMAL1), and period 2 (PER2). In addition to determining the direct effect of a 40-Hz light flicker on hypothalamic central clock, whole-cell voltage-clamp electrophysiology was employed to record individual neurons of suprachiasmatic nucleus (SCN) sections. The results reported herein demonstrate that a 40-Hz light flicker relieves circadian rhythm disorders in APP/PS1 mice and returns the expression levels of key players in the central circadian clock, including Clock, Bmal1, and Per2, to baseline. Moreover, the frequency of spontaneous inhibitory postsynaptic currents (sIPSCs) in SCN neurons is significantly lower in APP/PS1 mice than in the control, and the amplitude of sIPSCs is decreased. Exposure to a 40-Hz light flicker significantly increases the sIPSC frequency in SCN neurons of APP/PS1 mice, with little effect on the amplitude. However, the frequency and amplitude of spontaneous excitatory postsynaptic currents (sEPSCs) are both unaffected by a 40-Hz light flicker. The data suggest that a 40-Hz light flicker can ameliorate AD-associated circadian rhythm disorders, presenting a new type of therapeutic treatment for rhythm disorders caused by AD.
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Project description:BackgroundDistal neuropathy is part of the clinical phenotype in most males with the fragile X-associated tremor/ataxia syndrome (FXTAS) caused by the 55 to 200 CGG repeat expansion.MethodsWe performed nerve conduction studies in 16 male carriers with FXTAS, 11 non-FXTAS carriers, and 11 control subjects and assessed the outcomes with respect to the fragile X mental retardation 1 genotype (FMR1) (Online Mendelian Inheritance in Man [OMIM] 309550; NT011681) and messenger RNA expression.ResultsMen with FXTAS had slower tibial nerve conduction velocities and prolonged F-wave latencies compared with controls (z = 2.06, P = .04; and z = 2.73, P = .005) and unaffected premutation males (z = 1.98, P = .04; and z = 2.00, P = .04). Compound muscle action potential amplitudes were smaller in the FXTAS group relative to controls. Sural nerve action potential amplitudes were reduced in the FXTAS group compared with controls. After controlling for age, there was a significant relationship between the longer CGG repeat number and tibial nerve conduction velocity slowing (r = -0.42, P = .04) and between elevated messenger RNA levels and reduction of the tibial compound muscle action potential velocity (r = -0.52, P = .01) in the permutation group.ConclusionsMale premutation carriers had significant conduction abnormalities of motor and sensory nerves that correlated with molecular measures, suggesting that the premutation FMR1 genotype is a causal factor. There was also evidence of nerve conduction abnormalities in non-FXTAS carriers compared with controls, which suggests that the neuropathy can occur without the full clinical presentation of FXTAS.
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Project description:ObjectiveThe huntingtin gene is critical for the formation and differentiation of the CNS, which raises questions about the neurodevelopmental effect of CAG expansion mutations within this gene (mHTT) that cause Huntington disease (HD). We sought to test the hypothesis that child and adolescent carriers of mHTT exhibit different brain growth compared to peers without the mutation by conducting structural MRI in youth who are at risk for HD. We also explored whether the length of CAG expansion affects brain development.MethodsChildren and adolescents (age 6-18) with a parent or grandparent diagnosed with HD underwent MRI and blinded genetic testing to confirm the presence or absence of mHTT. Seventy-five individuals were gene-expanded (GE) and 97 individuals were gene-nonexpanded (GNE). The GE group was estimated to be on average 35 years from clinical onset. Following an accelerated longitudinal design, age-related changes in brain regions were estimated.ResultsAge-related striatal volume changes differed significantly between the GE and GNE groups, with initial hypertrophy and more rapid volume decline in GE. This pattern was exaggerated with CAG expansion length for CAG > 50. A similar age-dependent group difference was observed for the globus pallidus, but not in other major regions.ConclusionOur results suggest that pathogenesis of HD begins with abnormal brain development. An understanding of potential neurodevelopmental features associated with mHTT may be needed for optimized implementation of preventative gene silencing therapies, such that normal aspects of neurodevelopment are preserved as neurodegeneration is forestalled.
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Project description:To determine whether retinal dysfunction in obligate carriers of X-linked retinoschisis (XLRS) could be observed in local electroretinographic responses obtained with the multifocal electroretinogram (mfERG).Nine obligate carriers of XLRS (mean age, 46.2 years) were examined for the study. Examination of each carrier included an ocular examination and mfERG testing. For the mfERG, we used a 103-scaled hexagonal stimulus array that subtended a retinal area of approximately 40 degrees in diameter. The amplitudes and implicit times in each location for the mfERG were compared with the corresponding values determined for a group of 34 normally-sighted, age-similar control subjects.Mapping of 103 local electroretinographic response amplitudes and implicit times within a central 40 degrees area with the mfERG showed regions of reduced mfERG amplitudes and delayed implicit times in two of nine carriers.The mfERG demonstrated areas of retinal dysfunction in two carriers of XLRS. When present, retinal dysfunction was evident in the presence of a normal-appearing fundus. Multifocal ERG testing can be useful for identifying some carriers of XLRS.
| S-EPMC1784540 | biostudies-other
Project description:ObjectiveWe performed a genome-wide brain expression study to reveal the underpinnings of diseases linked to a repeat expansion in chromosome 9 open reading frame 72 (C9ORF72).MethodsThe genome-wide expression profile was investigated in brain tissue obtained from C9ORF72 expansion carriers (n = 32), patients without this expansion (n = 30), and controls (n = 20). Using quantitative real-time PCR, findings were confirmed in our entire pathologic cohort of expansion carriers (n = 56) as well as nonexpansion carriers (n = 31) and controls (n = 20).ResultsOur findings were most profound in the cerebellum, where we identified 40 differentially expressed genes, when comparing expansion carriers to patients without this expansion, including 22 genes that have a homeobox (e.g., HOX genes) and/or are located within the HOX gene cluster (top hit: homeobox A5 [HOXA5]). In addition to the upregulation of multiple homeobox genes that play a vital role in neuronal development, we noticed an upregulation of transthyretin (TTR), an extracellular protein that is thought to be involved in neuroprotection. Pathway analysis aligned with these findings and revealed enrichment for gene ontology processes involved in (anatomic) development (e.g., organ morphogenesis). Additional analyses uncovered that HOXA5 and TTR levels are associated with C9ORF72 variant 2 levels as well as with intron-containing transcript levels, and thus, disease-related changes in those transcripts may have triggered the upregulation of HOXA5 and TTR.ConclusionsIn conclusion, our identification of genes involved in developmental processes and neuroprotection sheds light on potential compensatory mechanisms influencing the occurrence, presentation, and/or progression of C9ORF72-related diseases.
| S-EPMC5479438 | biostudies-literature
Project description:Flickering lights can be uncomfortable to look at and can induce seizures in observers with photosensitive epilepsy. However, the temporal characteristics contributing to these effects are not fully known. In the spatial domain, one identified source of visual discomfort is when images have Fourier amplitude spectra that deviate from the natural (?1/frequency, 1/f) statistical characteristics of natural scenes, especially if they contain excess energy at the medium frequencies at which the visual system is most sensitive. We tested for analogous effects in the temporal domain, manipulating both the amplitude and phase spectra of the flicker. Participants judged the relative discomfort of temporal luminance variations in a pair of uniform 17° fields with different temporal modulations. In general, discomfort increased with deviations from natural amplitude spectra, particularly those with excess energy at medium frequencies or biased toward sharper spectra. These ratings of discomfort were also consistent with ratings of how natural the modulations appeared. However, the temporal discomfort judgments were also strongly affected by the phase spectra of the flicker, with fixed vs. random spectra producing very different responses. This was not due to the perceived regularity or predictability of the flicker, but could arise from a number of other potential factors. Our findings suggest that, like spatial patterns, visual discomfort in time-varying patterns depends in part on how similar they are to the amplitude spectra of temporal variations in the natural visual environment, but also point to the critical role of the phase spectrum in the perceived discomfort of flicker.
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