Response of Mouse Visual Cortical Neurons to Electric Stimulation of the Retina

Retinal prostheses strive to restore vision to the blind by electrically stimulating the neurons that survive the disease process. Clinical effectiveness has been limited however, and much ongoing effort is devoted toward the development of improved stimulation strategies, especially ones that better replicate physiological patterns of neural signaling. Here, to better understand the potential effectiveness of different stimulation strategies, we explore the responses of neurons in the primary visual cortex to electric stimulation of the retina. A 16-channel implantable microprobe was used to record single unit activities in vivo from each layer of the mouse visual cortex. Layers were identified by electrode depth as well as spontaneous rate. Cell types were classified as excitatory or inhibitory based on their spike waveform and as ON, OFF, or ON-OFF based on the polarity of their light response. After classification, electric stimulation was delivered via a wire electrode placed on the surface of cornea (extraocularly) and responses were recorded from the cortex contralateral to the stimulated eye. Responses to electric stimulation were highly similar across cell types and layers. Responses (spike counts) increased as a function of the amplitude of stimulation, and although there was some variance across cells, the sensitivity to amplitude was largely similar across all cell types. Suppression of responses was observed for pulse rates ≥3 pulses per second (PPS) but did not originate in the retina as RGC responses remained stable to rates up to 5 PPS. Low-frequency sinusoids delivered to the retina replicated the out-of-phase responses that occur naturally in ON vs. OFF RGCs. Intriguingly, out-of-phase signaling persisted in V1 neurons, suggesting key aspects of neural signaling are preserved during transmission along visual pathways. Our results describe an approach to evaluate responses of cortical neurons to electric stimulation of the retina. By examining the responses of single cells, we were able to show that some retinal stimulation strategies can indeed better match the neural signaling patterns used by the healthy visual system. Because cortical signaling is better correlated to psychophysical percepts, the ability to evaluate which strategies produce physiological-like cortical responses may help to facilitate better clinical outcomes

Influence of the sodium channel band on retinal ganglion cell excitation during electric stimulation - A computer simulation : a computer simulation

Retina-Implantate in klinischer Anwendung haben gezeigt dass man blinden Menschen mithilfe von Elektrostimulation visuelle Wahrnehmungen vermitteln kann. Bis solche Implantate jedoch höher-qualitative visuelle Eindrücke erzeugen können müssen noch einige Hürden bewältigt werden.Experimentelle Ergebnisse zeigen dass verschiedene Zelltypen der Retina stimuliert beziehungsweise aktiviert werden können. Diese Arbeit zielt darauf ab einen besseren Einblick über das Verhalten retinaler Nervenzellen während Elektrostimulation zu erhalten.Elektrostimulation mittels der Verwendung von Retina-Implantaten ermöglicht es blinden Menschen eine rudimentäre Art des Sehens wiederzuerlangen. Die erzeugten Eindrücke, auch 'Phosphene' genannt, sind jedoch sehr inkonstant und können deshalb keine hochwertigen visuellen Wahrnehmungen vermitteln. Das bessere Verständnis der Funktionsweise retinaler Nervenzellen, speziell retinaler Ganglienzellen, unter dem Aspekt der Elektrostimulation wird dabei helfen ausgefeiltere Stimulationsstrategien zu entwickeln. Spezielle anatomische und physiologische Eigenschaften wie ein Band mit hoher Natriumkanaldichte könnten dabei helfen eine spezifischere Aktivierung von Zellen zu erreichen.Das nah dem Soma proximal gelegene Axon einer retinal Ganglienzelle zeigt eine spezielle biophysikalische Eigenschaft. Schwellwerte für Elektrodenpositionen nahe dem Band mit hoher Natriumkanaldichte zeigen ein Minimum während Elektrostimulation (Fried et al, 2009). Die (modellierten) Schwellwerte dieser Struktur bestätigen diese Ergebnisse.Der Einfluss auf die Stelle wo ein Aktionspotential im Axon entsteht ist weitreichend. Wenn eine Stimulationselektrode weit außerhalb des Bandes positioniert wird entsteht das resultierende Aktionspotential noch immer im Bereich des Bandes mit hoher Natriumkanaldichte. Diese Erkenntnis unterstützt die weitere Untersuchung der entscheidenden Komponenten auf welchen die Aktivierung retinaler Ganglienzellen beruht. Die fokale Aktivierung ohne die Beeinträchtigung von vorbeiziehenden Axonen weit entfernter Nervenzellen wird die weitere Entwicklung von Retina-Implantaten und die klinischen Resultate verbessern.Retinal implants in clinical trials show that electric stimulation is able to elicit perceptions in patient suffering from blindness. However, there are many obstacles to overcome until such devices will be able to restore vision of higher quality. Experimental studies showed that various cell types within the retina can be stimulated and activated, respectively. To gain a better insight in the behavior of retinal nerve cells during electric stimulation this computational study is performed. Electric stimulation using retinal implants allows blind people to re-experience a rudimentary kind of vision. The elicited percepts or so called 'phosphenes' are highly inconstant and therefore do not restore vision properly. The better knowledge of how retinal neurons, especially retinal ganglion cells, respond to electric stimulation will help to develop more sophisticated stimulation strategies. Special anatomic and physiologic properties like a band of highly dense sodium channels in retinal ganglion cells may help to achieve a focal activation of target cells and as a result better restoration of vision.The very first portion of retinal ganglion cell axons shows a specific biophysical property. Electrode locations close to a band of sodium channels which was identified immunochemically show lowest thresholds during electric stimulation (Fried et al, 2009). The (modeled) thresholds for this kind of structure result in lowest thresholds as well. The influence on the location where action potentials are generated within the axon is far reaching. When a stimulating electrode is positioned far outside the actual band region the site of spike initiation still remains within the sodium channel band. This finding suggests to examine the key mechanisms of activation for retinal ganglion cells because focal activation without influencing passing axons of neurons located far away will improve retinal prostheses and the outcome of electric stimulation.7

Elektronische Zigarette und Kognitive Dissonanz

Manuel WerginzKlagenfurt, Alpen-Adria-Univ., Dipl.-Arb., 2014(VLID)241090

Theresianum Wien, Dachbodenausbau zu neuen Lernräumen

Titelübersetzung des Autors: Theresianum in Vienna - Roof space for new learningZusammenfassung in englischer SpracheDie Diplomarbeit widmet sich der Untersuchung der Baugeschichte der "Favorita auf der Wieden" - das heutige Theresianums. Als Grundlage dient das umfassende Werk von Architekt Dr. Erich Schlöss mit dem Titel 'Die Baugeschichte des Theresianums in Wien', 1998. Ausgehend von der ersten urkundlichen Erwähnung im Mittelalter als Gutshof, ausgebaut zur kaiserlichen Residenz der Favorita, bis hin zur gegenwärtigen Nutzung als Bildungsstätte wird die gesamte Entwicklung des heutigen Gebäudekomplexes dargestellt. Anschließend richtet sich der Blick auf die Bildungsreform durch Maria Theresia. Das dritte Kapitel widmet sich den aktuellen Tendenzen im Schulbau und den damit einhergehenden pädagogischen Konzepten, aus welchen die aktuellen Nutzungsdefizite des Theresianums herausgearbeitet wurden. Anschließend beschäftigt sich die Arbeit mit der Rechtslage zum Thema Dachgeschoßausbau nach der Wiener Bauordnung. Unter Einbeziehung der zuvor behandelten Themen erfolgt der architektonische Entwurf: Ein Ausbau des Dachbodens des zentral gelegenen Reitschulhoftraktes mit dem Ziel, diesen unter Berücksichtigung des historischen und denkmalgeschützen Bestandes, mit belebten Volumina in Form von neuen Lernräumen zu bespielen.The thesis is devoted to the study of the architectural history of the "Favorita auf der Wieden" - today's Theresianum. As a basis serves the comprehensive work of architect Dr. Erich Schlöss called "The architectural history of the Theresianum in Vienna", 1998. Starting from its first mention in the Middle Ages as a farm, the imperial residence of the Favorita constantly expanded until to its current usage as an educational. A short overview on the development of the building complex is represented in this thesis. Furthermore, there is a focus on the educational reforms by Maria Theresia. The third chapter is devoted to current trends in school construction and the associated educational concepts, from which the current deficiencies of the schoolbuilding were identified. In addition, the work deals with the Viennese building codes for Loft extensions. Taking into account the above topics, an architectural design proposal is provided: An expansion of the attic of the central riding school yard tract with the aim of taking into account the historical and landmarked portfolio as well as providing new forms of learning spaces.10

Neuronal activation characteristics in the electrically stimulated retina : a model-based study

Zusammenfassung in deutscher SpracheDie Entwicklung von Netzhautimplantaten ermöglicht es blinden Menschen eine einfache Art des Sehens wiederzuerlangen. Patienten, die an einer Degeneration ihrer Photorezeptoren, Zellen die das einfallende Licht in Nervensignale umwandeln, leiden, können mittels Elektrostimulation rudimentäre Seheindrücke zurückerlangen. Das Ziel der präsentierten Modellierung war es zum Verständnis der Vorgänge in der elektrisch stimulierten Netzhaut beizutragen. Subretinale Implantate im Bereich der degenerierten Photorezeptoren stimulieren in erster Linie Bipolarzellen und können weit entfernte Ganglienzellen nur mit hohen Stimulationsamplituden anregen. Mit epiretinalen Implantaten hingegen wird die Retina von der inneren Seite aus stimuliert und damit werden vorrangig die sensiblen Axone von Ganglienzellen aktiviert. Eine Vielzahl an Erregungs-Phänomenen welche von Stimulusstärke, Polarität, Zellgeometrie, Ionenkanaltypen und anderen geometrischen und elektrischen Parametern abhängen wurde systematisch untersucht. Die neuronale Antwort wurde in einem zweistufigen Verfahren simuliert: i) das elektrische Feld, welches von einer Elektrode hervorgerufen wird, wurde entweder mit der Methode der finiten Elemente oder mit einer einfachen analytischen Lösung für Punktquellen berechnet und ii) die resultierenden elektrischen Potenziale wurden als Eingangsparameter für ein Multi-Kompartment Modell verwendet. Zusätzlich wurde ein einfaches Synapsenmodell entwickelt, welches die Freisetzung von Neurotransmittern an Ribbon-Synapsen an den Enden von Bipolarzellen simuliert. Es wurde gezeigt, dass längerer Axone in ON-Bipolarzellen zu einer stärkere Polarisation der Zellmembrane als in OFF-Bipoalrzellen führen. Depolarisation und die einhergehende Freisetzung von Neurotransmittern an den Enden von Bipolarzellen konnte nur durch anodische Stimulation von subretinaler Seite erzeugt werden. Stimulation von Bipolarzellen über das Nernst-Potenzial von Kalzium hinaus führte zu invertierten Kalziumströmen in den synaptischen Enden. Diese auswärtsgerichteten Ströme waren nicht dazu in der Lage die intrazelluläre Kalziumkonzentration hinreichend zu erhöhen um eine Ausschüttung von Neurotransmittern auszulösen. überraschenderweise führten diese invertierten Kalziumströme bei Stimulation einer Vielzahl von Bipolarzellen im Umkreis von 100x100µm zu einem ausgeprägten Center-Surround Effekt. Dabei konnten drei Stimulationsverläufe unterschieden werden: i) Stimulation mit niedrigen Amplituden war nicht in der Lage Zellen zu aktivieren (unterer Schwelle), ii) Stimulation mit mittleren Amplituden regte nur Zellen an welche nahe an der Stimulationselektrode lagen und iii) Stimulation im Regime der invertierten Ströme verhinderte Aktivität in Bipolarzellen nah an der Elektrode führte jedoch zu einer Freisetzung von neuronalen Botenstoffen in weiter entfernten Zellen (oberer Schwelle). Das große Ziel für eine erhöhte räumliche Auflösung ist eine fokale, d.h. innerhalb eines räumlich begrenzten Gebiets, Anregung von Ganglienzellen. Die Membraneigenschaften wie die spezifische Verteilung von Natriumkanälen verschiedener Sensitivität (Nav1.2 & Nav1.6) wurden im Modell beachtet. Während epiretinaler Stimualtion hatten vorbeiziehende Axone einen um 120% erhöhten Schwellwert gegenüber dem niedrigsten Schwellwert im proximalen Teil des Axons. Der dadurch entstehende Arbeitsbereich konnte dazu genutzt werden um eine kleine Anzahl von Ganglienzellen zu aktivieren ohne eine Co-Aktivierung von weit entfernten Ganglienzellen hervorzurufen. Kathodische Stimulation resultierte generell in niedrigeren Schwellwerten und der Ort der Signalentstehung war einfacher nachzuvollziehen. Für anodische Stimulation ergaben sich komplizierte Aktivierungsmuster die es verhinderten generelle Regeln für den Entstehungsort eines Aktionspotenzials abzuleiten. Zusätzlich wurde festgestellt, dass auch der dendritische Teil von Ganglienzellen während epiretinaler Stimulation zur Signalaktivierung beitragen kann. Faserenden zeigten erniedrigte Schwellwerte und spielten deshalb, unter gewissen Umständen, eine wichtige Rolle in der Entstehung von Aktionspotenzialen. Die Latenzzeit von Aktionspotenzialen wurde außerdem als guter Indikator für den Ort der Signalentstehung bestimmt. Simuliertes Zufallsrauschen des Membranpotenziales erlaubte es die Wahrscheinlichkeit für die Entstehung eines Aktionspotenzials zu berechnen und simulierte Ergebnisse deckten sich mit experimentellen Befunden. Zusammengefasst befasste sich die vorgestellte Arbeit mit den räumlichen und zeitlichen Charakteristika des Antwortverhaltens retinaler Neurone während Elektrostimulation. Spezielles Augenmerk wurde auf die Ausschüttung neuronaler Botenstoffe in Bipolarzellen und dem Ort der Signalentstehung in Ganglienzellen gelegt. Einige der Schlussfolgerungen dieser Arbeit wurden mit vereinfachten Modellneuronen simuliert während andere mittels Geometriedaten aus Experimenten modelliert wurden.Using inner eye prostheses, the restoration of vision to the blind has achieved a low level which hopefully will be enhanced in the future. Patients suffering from degeneration of their photoreceptors, cells which modulate light input to neuronal output, can regain visual perceptions by electrically stimulating the remaining retinal neurons. The aim of the investigated modeling approach was to contribute to the understanding of the responses of extracellularly stimulated bipolar and ganglion cells, the primary target cells of current retinal implants. Related to physiological vision, subretinal implants should primarily cause graded potentials in bipolar cells, whereas higher stimuli are needed to directly excite ganglion cells as they are more distant to the electrodes. Epiretinal implants stimulate the retina from the inner portion of the retina with the sensitively excitable axons of ganglion cells closest to the electrodes. Plenty of stimulus-response phenomena, depending on stimulus strength, polarity, cell geometry, ion channel types and other geometric and electrical parameters were systematically investigated. The neural response was calculated in a two-step procedure: i) the electrical field was either obtained with the finite element method or with a simpler analytical approach for point sources and ii) the response of a model neuron was computed by employing a multi-compartment model with the applied electric field as input parameter. Additionally, a model for neurotransmitter release from ribbon synapses at bipolar cell terminals was developed in order to study the temporal impact of L-type calcium channels. Membrane polarization was shown to be stronger for ON than for OFF bipolar cells because of their longer axonal processes. Depolarization of synaptic terminals and consequent vesicle release was only triggered by anodal subretinal stimulation. Strong depolarization above the Nernst potential of calcium, however, led to reversed calcium currents in synaptic terminals. These outward currents prevented an increase of intracellular calcium concentration and consequently less or no neurotransmitter were released. Surprisingly, by stimulating multiple bipolar cells located within a region of 100x100µm the calcium reversal led to a pronounced center-surround effect of vesicle release. That is, three stimulation regimes could be discriminated: i) stimulation at low amplitudes did not activate bipolar cells at all (lower threshold), ii) stimulation at appropriate amplitudes only activated bipolar cells close to the stimulating electrode and iii) stimulation in the current reversal regime shut down cells located near the electrode but activated distant cells (upper threshold). The major goal for spatial visual performance is to activate ganglion cells focally, i.e. within a closely spaced region on the retina. Membrane-specific properties such as a distinct distribution of sodium channels of different opening sensitivity (Nav1.2 & Nav1.6) were included into the ganglion cell model. During epiretinal cathodic stimulation, passing axons had thresholds approximately 120% higher than lowest thresholds at the proximal portion of the ganglion cell axon. Consequently, the arising operating window could be used to focally activate a number of ganglion cells without co-activating passing axons from ganglion cells located far away. Generally, thresholds were lower during cathodic stimulation and the site of spike initiation was easier to predict. Anodic stimulation, on the other hand, resulted in complicated activation patterns which hindered to derive general rules for determination of the site of spike initiation. Additionally, simulations suggest that the dendritic portion of the target ganglion cell is also of high importance in spike generation, even when stimulation is applied epiretinally. Dendritic edge compartments (i.e. fiber ends) turned out to have lowered thresholds and therefore played an important role in spike generation under certain circumstances, especially during subretinal stimulation. Furthermore, spike latency was shown to reliably act as a good predictor for site of spike initiation. Adding a noisy transmembrane current component allowed to compute spiking probability as a function of stimulus amplitude resulting in sigmoid response curves similar to experimental determined data. In sum, the spatial and temporal response of retinal neurons was monitored during electrical stimulation with a special emphasis on neurotransmitter release in bipolar cells and the site of spike initiation in ganglion cells. Some of the conclusions could even be found using extremely simplified model neurons, others were confirmed simulating the geometric data of real cells.15

Comparison of electrically elicited responses in rabbit and mouse retinal ganglion cells

Retinal implants are currently the only commercially available devices that can restore vision in patients suffering from a wide range of outer retinal degenerations. In order to improve the clinical outcome, i.e. the quality of elicited vision, a large number of in-vitro experiments probing the impact of electric stimulation on activation of the retina have been conducted. In these studies, however, retinas from many different species have been used which impedes comparisons between studies. Therefore, we measured the responses from four major ganglion cell types to light and electric stimulation in rabbit and mouse retina and compared their responses. We found strong similarities between the two species in transient cells whereas responses in sustained cell types typically did not match as well.Fonds zur Förderung der wissenschaftlichen Forschung (FWF)18131816

Electric stimulus duration alters network-mediated responses depending on retinal ganglion cell type

OBJECTIVE: To improve the quality of artificial vision that arises from retinal prostheses, it is important to bring electrically-elicited neural activity more in line with the physiological signaling patterns that arise normally in the healthy retina. Our previous study reported that indirect activation produces a closer match to physiological responses in ON retinal ganglion cells (RGCs) than in OFF cells (Im and Fried 2015 J. Physiol. 593 3677-96). This suggests that a preferential activation of ON RGCs would shape the overall retinal response closer to natural signaling. Recently, we found that changes to the rate at which stimulation was delivered could bias responses towards a stronger ON component (Im and Fried 2016a J. Neural Eng. 13 025002), raising the possibility that changes to other stimulus parameters can similarly bias towards stronger ON responses. Here, we explore the effects of changing stimulus duration on the responses in ON and OFF types of brisk transient (BT) and brisk sustained (BS) RGCs. APPROACH: We used cell-attached patch clamp to record RGC spiking in the isolated rabbit retina. Targeted RGCs were first classified as ON or OFF type by their light responses, and further sub-classified as BT or BS types by their responses to both light and electric stimuli. Spiking in targeted RGCs was recorded in response to electric pulses with durations varying from 5 to100 ms. Stimulus amplitude was adjusted at each duration to hold total charge constant for all experiments. MAIN RESULTS: We found that varying stimulus durations modulated responses differentially for ON versus OFF cells: in ON cells, spike counts decreased significantly with increasing stimulus duration while in OFF cells the changes were more modest. The maximum ratio of ON versus OFF responses occurred at a duration of ~10 ms. The difference in response strength for BT versus BS cells was much larger in ON cells than in OFF cells. SIGNIFICANCE: The stimulation rates preferred by subjects during clinical trials are similar to the rates that maximize the ON/OFF response ratio in in vitro testing (Im and Fried 2016a J. Neural Eng. 13 025002). Here, we determine the stimulus duration that produces the strongest bias towards ON responses and speculate that it will further enhance clinical effectiveness

Differential Responses to High-Frequency Electrical Stimulation in Brisk-Transient and Delta Retinal Ganglion Cells

Retinal microprostheses strive to evoke a sense of vision in individuals blinded by outer retinal degenerative diseases, by electrically stimulating the surviving retina. It is widely suspected that a stimulation strategy that can selectively activate different retinal ganglion cell types will improve the quality of evoked phosphenes. Previous efforts towards this goal demonstrated the potential for selective ON and OFF brisk-transient cell activation using high-rate (2000 pulses per second, PPS) stimulation. Here, we build upon this earlier work by testing an additional rate of stimulation and additional cell populations. We find considerable variability in responses both within and across individual cell types, but show that the sensitivity of a ganglion cell to repetitive stimulation is highly correlated to its single-pulse threshold. Consistent with this, we found thresholds for both stimuli to be correlated to soma size, and thus likely mediated by the properties of the axon initial segment. The ultimate efficacy of high-rate stimulation will likely depend on several factors, chief among which are (a) the residual ganglion types, and (b) the stimulation frequency.Fonds zur Förderung der wissenschaftlichen Forschung (FWF)35293532