Influence of electric field orientation on the effect of ocular current stimulation using full field electroretinogram

Ocular current stimulation (CS) exhibits poten-tial for the treatment of neurodegenerative ocular diseases. For a full field electroretinogram (ffERG) we found no CS effect on the characteristic waves (a-wave, b’-wave, and b-wave). To investigate whether the orientation of the generated electric field has an influence on the CS effect, this study repeated the previous ffERG study with changing one CS electrode posi-tion and compared the results of both studies. In the first study 15 (8m, 27.5±4.5years) and in the second study 17 (7m, 22.0±1.9years) healthy volunteers were stimulated with an anodal, cathodal, and sham direct CS of 800μA for 5min in three sessions (randomized, different days). For both studies, a cut-sized ring rubber electrode was placed around the eye. A square rubber electrode was placed for the first study at the ipsilateral temple and for the second study at thevisual cortex. Before (ERG1) and during (ERG2) the CS, the ffERG was measured. For both studies, the difference between the ERG1 and ERG2measurement(CS effect)for the three characteris-tic waves was analyzed and compared between the studies. For statistical analysis, the Mann-Whitney U test withBonferroni correction was applied (α=0.05). The comparison of the data distribution showed only slight differences between the stud-ies. The Mann-Whitney U test found no significant difference of the CS effect between the studies for all amplitudes and CS groups (p≥0.0055). In the mean, the latency differenceswere smaller than the time resolution, therefore no statements for latency effects werepossible. It can be concluded that the retinal cells generating the ffERG are not affected by ocular CS in either electrode montages tested

Elektrophysiologische Wirkung transokularer Ströme

Die transkranielle Gleichstromstimulation mit schwachen Strömen (≤ 2 mA) ist ein etabliertes Verfahren zur Untersuchung des menschlichen Nervensystems und zur Behandlung psychologisch-neurologischer Erkrankungen. In den letzten Jahren hat die Stimulation des visuellen Systems, speziell der Retina, an Aufmerksamkeit gewonnen, da Hinweise auf positive Einflüsse einer transokularen Stromstimulation zur Behandlung neurodegenerativer retinaler Erkrankungen gefunden wurden. Bis heute fehlt jedoch ein Wirkungskonzept, das den Einfluss der Stromstimulation auf die verschiedenen retinalen Neuronen beschreibt. Aus Studien ist bekannt, dass ein visuell evoziertes Potential durch eine transkranielle Gleichstromstimulation des visuellen Cortex in den charakteristischen Amplituden beeinflusst werden kann. Daraus ergab sich das methodische Verfahren ein evoziertes Potential retinaler Herkunft, welches durch das Elektroretinogramm erfasst wird, in Kombination mit einer transokularen Stromstimulation zu nutzen, um den Einfluss der Stromstimulation auf die retinalen Zellen zu untersuchen. Durch Variation der visuellen Stimulationsparameter zur Generierung des Elektroretinogramms, ist es möglich, unterschiedliche retinale Neuronen in den Fokus zu nehmen. Im ersten Teil der Dissertation wurde ein grundlegendes Studienkonzept auf Basis des Verfahrens der experimentellen Prozessanalyse entwickelt. Aus diesem wurden Anforderungen an einen Mess- und Stimulationsplatz abgeleitet, um eine simultane transokulare Gleichstromstimulation und Aufnahme eines Elektroretinogramms zu ermöglichen. Des Weiteren wurden Anforderungen an das Studiendesign abgeleitet. Im zweiten Teil der Dissertation wurden insgesamt vier aufeinander aufbauende Probandenstudien durchgeführt, analysiert und interpretiert. In diesen wurden sowohl unterschiedliche retinale Neuronen als auch der Einfluss der Position der Stromstimulationselektroden untersucht. Aus den Ergebnissen wurde ein Wirkungskonzept für die transokulare Gleichstromstimulation auf die retinalen Neuronen abgeleitet. Dieses besagt, dass primär die retinalen Ganglienzellen während einer transokularen Gleichstromstimulation in ihrer elektrophysiologischen Aktivität beeinflusst werden. Die Ergebnisse der Dissertation lassen sich weiterführend für die Entwicklung und die Optimierung von Therapieverfahren zur Behandlung neurodegenerativer retinaler Erkrankungen sowie zur Entwicklung objektiver Messmethoden zum Nachweis einer transokularen Stromwirkung verwenden.Transcranial direct current stimulation with weak currents (≤ 2 mA) is an established method for research on the human nervous system and for the treatment of psychological-neuronal disorders. In recent years, stimulation of the visual system and the retina has gained attention, as indications of positive effects of transocular current stimulation for the treatment of neurodegenerative retinal diseases have been found. However, a model describing the influence of transocular current stimulation on different retinal neurons is missing. From studies it is known that a visual evoked potential can be influenced by transcranial direct current stimulation of the visual cortex in the characteristic amplitudes. This resulted in the methodological procedure of using an evoked potential of retinal origin, which is detected by the electroretinogram, in combination with transocular current stimulation to investigate the influence of current stimulation on retinal cells. By varying the visual stimulation parameters used to generate the electroretinogram, it was possible to focus on different retinal neurons. In the first part of the dissertation a study concept, based on the method of experimental process analysis, was developed. From this, requirements for a measurement and stimulation setup were developed, which allowed simultaneous transocular direct current stimulation and recording of an electroretinogram. Furthermore, requirements for the study design were derived. In the second part of the dissertation, a total of four consecutive subject studies were performed, analyzed and interpreted, which investigated different retinal neurons as well as the influence of the position of the current stimulation electrodes. The results were used to derive a model decribing the effects of transocular direct current stimulation on the retinal neurons. This model states that primarily the retinal ganglion cells are influenced in their electrophysiological activity during transocular direct current stimulation. The results of the dissertation can be further applied to the development and optimization of therapeutic methods for the treatment of neurodegenerative, retinal diseases as well as for the development of objective measuring methods for the detection of a transocular current effect

Ocular direct current stimulation affects retinal ganglion cells

Ocular current stimulation (oCS) with weak current intensities (a few mA) has shown positive effects on retinal nerve cells, which indicates that neurodegenerative ocular diseases could be treated with current stimulation of the eye. During oCS, a significant polarity-independent reduction in the characteristic P50 amplitude of a pattern-reversal electroretinogram was found, while no current stimulation effect was found for a full field electroretinogram (ffERG). The ffERG data indicated a trend for a polarity-dependent influence during oCS on the photopic negative response (PhNR) wave, which represents the sum activity of the retinal ganglion cells. Therefore, an ffERG with adjusted parameters for the standardized measurement of the PhNR wave was combined with simultaneous oCS to study the potential effects of direct oCS on cumulative ganglion cell activity. Compared with that measured before oCS, the PhNR amplitude in the cathodal group increased significantly during current stimulation, while in the anodal and sham groups, no effect was visible (α = 0.05, pcathodal = 0.006*). Furthermore, repeated-measures ANOVA revealed a significant difference in PhNR amplitude between the anodal and cathodal groups as well as between the cathodal and sham groups (p* ≤ 0.0167, pcathodal − anodal = 0.002*, pcathodal − sham = 0.011*)

The effects of an ocular direct electrical stimulation on pattern-reversal electroretinogram

Studies on transcranial current stimulation have shown that a direct current stimulation of the occipital cortex can influence the amplitude size of a visual evoked potential (VEP). The current direction (cathodal or anodal) determines whether the VEP amplitudes increase or decrease. The aim of this study was to design a new experimental setup that will enable a simultaneous ocular direct current stimulation and electroretinogram (ERG) recording which will broaden our understanding of current stimulation effects on the visual system. Furthermore, we examined whether a direct current stimulation on the eye has a similar effect on an ERG as on a VEP. The pattern-reversal ERG was measured with sintered Ag/AgCl skin-electrodes, positioned on the lower eyelid (active), the earlobe (reference), and the forehead (ground). Direct current was applied through a ring rubber electrode placed around the eye and a 5 cm 5 cm rubber electrode placed at the ipsilateral temple with a current strength of 500 mA and a duration time of 5 min. Fifty-seven healthy volunteers were divided into three groups depending on the current direction (cathodal, anodal, and sham stimulation, n = 19 each). One ERG measurement (ERG 1) was performed before and another (ERG 2) during the direct current stimulation. The difference between ERG 1 and ERG 2 measurements for the characteristic P50, N95 and N950 (N95 minimum measured from zero line) amplitudes were evaluated by both confidence interval analysis and t-test for related samples (a = 0.05, after Bonferroni correction p = 0.0055). The P50 amplitude was significantly decreased for ERG 2 measurement in the cathodal and anodal stimulation group (cathodal p = 0.001, anodal p = 0.000). No significant changes could be found in the N95 and N950 amplitudes as well as in the sham-stimulation group. Additionally, the latencies did not undergo any significant changes. In conclusion, the newly designed experimental setup enables simultaneous current stimulation and ERG recording. The current influenced P50 amplitude although not the N95 and N950 amplitudes. Furthermore, the amplitude size decreased for both current directions and did not lead to contrary effects as expected

Effects of ocular direct current stimulation on full field electroretinogram

Studies on weak current stimulation (1–2 mA) examine effects on neuronal cells for the treatment of neurological diseases, like depression. Ocular current stimulation showed positive effects on retinal nerve cells which indicate that neurodegenerative ocular diseases, e.g., glaucoma, can be treated with current stimulation of the eye. However, up to now it remains unclear which exact retinal cells can be influenced. During an ocular direct current stimulation, a significant reduction of the characteristic P50 amplitude of a pattern-reversal electroretinogram (PERG) was found for an anodal and a cathodal stimulation. This current stimulation effect could originate from the modulation of pre-ganglion cell activity or by changes in local ON and OFF responses of ganglion cells. For clarification, we investigate acute direct current stimulation effects on a full field electroretinogram (ERG), which represents the activity of pre-ganglion cells (specifically cones and bipolar cells). The ERG from 15 subjects was evaluated before (ERG 1) and during (ERG 2) an ocular direct current stimulation with 800 μA over 5 min. The current was applied through a ring rubber electrode placed around the eye and a 25 cm2 rubber electrode placed at the ipsilateral temple. For ERG measurements, sintered Ag/AgCl skin-electrodes were positioned on the lower eyelid (active), the earlobe (reference), and the forehead (ground). The volunteers were stimulated in three independent sessions, each with a different current application (randomized order): cathodal polarity, anodal polarity (referred to the electrode around the eye), or sham stimulation. The changes between the two ERG measurements of the characteristic full field ERG amplitudes, a-wave, b-wave, and b′-wave (b-wave measured from zero line) were tested with the Wilcoxon signed-rank test (α = 0.05). Comparing before to during the current stimulation for all applications, the ERG waves showed no effects on amplitudes or latencies. Furthermore, no significant difference between the cathodal, anodal, and sham stimulation could be found by a Friedman test. These results indicate an unlikely contribution of pre-ganglion cells to the previously reported stimulation effect on PERG signals

Amplitude changes in the electrophysiological response of retinal cells during simultaneous current stimulation

Purpose : Ocular electrical stimulation exhibit potential for the treatment of neurodegenerative ocular diseases. However, the underlying mechanism in the retinal cells remains subject of research. Studies applying transcranial electrical stimulation show that direct current stimulation (DCS) over the visual cortex manipulates the amplitudes of visual evoked potentials. An anodal DCS leads to increased amplitudes while a cathodal DCS decreased these amplitudes. We hypothesize that the retinal cells show similar reactions. Methods : We stimulated 15 volunteers (8m, 7f, 23.5 ± 1.6 years, one eye) with a cathodal DCS of 500 µA (DC-stimulator MC, neuroConn GmbH, Ilmenau) for 10 minutes. For DCS we used six cup electrodes (diameter: 0.95 cm) placed around one eye . Before, during and after DCS we measured the electrophysiological answer of the retinal ganglion cells using a pattern-reversal stimulus (stimulus field: 1° individual checks, 16° total; reversals per second: 4; Michelson contrast: 99%; mean luminance: 186 cd/m^2). For recording, we used Ag/AgCl ring electrodes located at the lower eyelid and the earlobe. For statistical analysis the Friedman test for paired samples and a confidence interval analysis was performed. Results : The characteristic amplitudes of the the electrophysiological answer (P50 and N95 component) as well as its peak-to-peak difference (PPD) were decreased during the stimulation. The visible trend was statistically not significant (Friedman test P50/N95/PPD: p = 0.527/0.574/0.297). Under consideration of specific volunteers (showed expected reduction of the N95 component, n = 9) we found a significant change of the N95 component for the difference between before and during DCS (confidence interval analysis, lower limit: -2.45 µV; upper limit: -0.38 µV; after Bonferroni correction α = 0.0143). Conclusions : The performed study indicates a trend that a cathodal DCS decreasing electrophysiological activity in the retina

Technical light-field setup for 3D imaging of the human nerve head validated with an eye model

With the new technology of 3D light field (LF) imaging, fundus photography can be expanded to provide depth information. This increases the diagnostic possibilities and additionally improves image quality by digitally refocusing. To provide depth information in the human optic nerve head such as in glaucoma diagnostics, a mydriatic fundus camera was upgraded with an LF imager. The aim of the study presented here was the validation of the technical setup and resulting depth estimations with an appropriate eye model. The technical setup consisted of a mydriatic fundus camera (FF450, Carl Zeiss Meditec AG, Jena, Germany) and an LF imager (R12, Raytrix GmbH, Kiel, Germany). The field of view was set to 30°. The eye model (24.65 mm total length) consisted of a two-lens optical system and interchangeable fundus models with papilla excavations from 0.2 to 1 mm in steps of 0.2 mm. They were coated with red acrylic lacquer and vessels were drawn with a thin brush. 15 images were taken for each papilla depth illuminated with green light (wavelength 520 nm ± 20 nm). Papilla depth was measured from the papilla ground to the surrounding flat region. All 15 measurements for each papilla depth were averaged and compared to the printed depth. It was possible to perform 3D fundus imaging in an eye model by means of a novel LF-based optical setup. All LF images could be digitally refocused subsequently. Depth estimation in the eye model was successfully performed over a 30° field of view. The measured virtual depth and the printed model papilla depth is linear correlated. The presented LF setup allowed high-quality 3D one-shot imaging and depth estimation of the optic nerve head in an eye model

BNDB – The Biochemical Network Database

<p>Abstract</p> <p>Background</p> <p>Technological advances in high-throughput techniques and efficient data acquisition methods have resulted in a massive amount of life science data. The data is stored in numerous databases that have been established over the last decades and are essential resources for scientists nowadays. However, the diversity of the databases and the underlying data models make it difficult to combine this information for solving complex problems in systems biology. Currently, researchers typically have to browse several, often highly focused, databases to obtain the required information. Hence, there is a pressing need for more efficient systems for integrating, analyzing, and interpreting these data. The standardization and virtual consolidation of the databases is a major challenge resulting in a unified access to a variety of data sources.</p> <p>Description</p> <p>We present the Biochemical Network Database (BNDB), a powerful relational database platform, allowing a complete semantic integration of an extensive collection of external databases. BNDB is built upon a comprehensive and extensible object model called BioCore, which is powerful enough to model most known biochemical processes and at the same time easily extensible to be adapted to new biological concepts. Besides a web interface for the search and curation of the data, a Java-based viewer (BiNA) provides a powerful platform-independent visualization and navigation of the data. BiNA uses sophisticated graph layout algorithms for an interactive visualization and navigation of BNDB.</p> <p>Conclusion</p> <p>BNDB allows a simple, unified access to a variety of external data sources. Its tight integration with the biochemical network library BN++ offers the possibility for import, integration, analysis, and visualization of the data. BNDB is freely accessible at <url>http://www.bndb.org</url>.</p

ATP4 and ciliation in the neuroectoderm and endoderm of Xenopus embryos and tadpoles

AbstractDuring gastrulation and neurulation, foxj1 expression requires ATP4a-dependent Wnt/β-catenin signaling for ciliation of the gastrocoel roof plate (Walentek et al. Cell Rep. 1 (2012) 516–527.) and the mucociliary epidermis (Walentek et al. Dev. Biol. (2015)) of Xenopus laevis embryos. These data suggested that ATP4a and Wnt/β-catenin signaling regulate foxj1 throughout Xenopus development. Here we analyzed whether foxj1 expression was also ATP4a-dependent in other ciliated tissues of the developing Xenopus embryo and tadpole. We found that in the floor plate of the neural tube ATP4a-dependent canonical Wnt signaling was required for foxj1 expression, downstream of or in parallel to Hedgehog signaling. In the developing tadpole brain, ATP4-function was a prerequisite for the establishment of cerebrospinal fluid flow. Furthermore, we describe foxj1 expression and the presence of multiciliated cells in the developing tadpole gastrointestinal tract. Our work argues for a general requirement of ATP4-dependent Wnt/β-catenin signaling for foxj1 expression and motile ciliogenesis throughout Xenopus development