Matias I. Maturana

The effect of morphology upon electrophysiological responses of retinal ganglion cells: simulation results

Retinal ganglion cells (RGCs) display differences in their morphology and intrinsic electrophysiology. The goal of this study is to characterize the ionic currents that explain the behavior of ON and OFF RGCs and to explore if all morphological types of RGCs exhibit the phenomena described in electrophysiological data. We extend our previous single compartment cell models of ON and OFF RGCs to more biophysically realistic multicompartment cell models and investigate the effect of cell morphology on intrinsic electrophysiological properties. The membrane dynamics are described using the Hodgkin - Huxley type formalism. A subset of published patch-clamp data from isolated intact mouse retina is used to constrain the model and another subset is used to validate the model. Two hundred morphologically distinct ON and OFF RGCs are simulated with various densities of ionic currents in different morphological neuron compartments. Our model predicts that the differences between ON and OFF cells are explained by the presence of the low voltage activated calcium current in OFF cells and absence of such in ON cells. Our study shows through simulation that particular morphological types of RGCs are capable of exhibiting the full range of phenomena described in recent experiments. Comparisons of outputs from different cells indicate that the RGC morphologies that best describe recent experimental results are ones that have a larger ratio of soma to total surface area.

A Simple and Accurate Model to Predict Responses to Multi-electrode Stimulation in the Retina.

Implantable electrode arrays are widely used in therapeutic stimulation of the nervous system (e.g. cochlear, retinal, and cortical implants). Currently, most neural prostheses use serial stimulation (i.e. one electrode at a time) despite this severely limiting the repertoire of stimuli that can be applied. Methods to reliably predict the outcome of multi-electrode stimulation have not been available. Here, we demonstrate that a linear-nonlinear model accurately predicts neural responses to arbitrary patterns of stimulation using in vitro recordings from single retinal ganglion cells (RGCs) stimulated with a subretinal multi-electrode array. In the model, the stimulus is projected onto a low-dimensional subspace and then undergoes a nonlinear transformation to produce an estimate of spiking probability. The low-dimensional subspace is estimated using principal components analysis, which gives the neuron’s electrical receptive field (ERF), i.e. the electrodes to which the neuron is most sensitive. Our model suggests that stimulation proportional to the ERF yields a higher efficacy given a fixed amount of power when compared to equal amplitude stimulation on up to three electrodes. We find that the model captures the responses of all the cells recorded in the study, suggesting that it will generalize to most cell types in the retina. The model is computationally efficient to evaluate and, therefore, appropriate for future real-time applications including stimulation strategies that make use of recorded neural activity to improve the stimulation strategy.

Prosthetic vision: devices, patient outcomes and retinal research

Retinal disease and its associated retinal degeneration can lead to the loss of photoreceptors and therefore, profound blindness. While retinal degeneration destroys the photoreceptors, the neural circuits that convey information from the eye to the brain are sufficiently preserved to make it possible to restore sight using prosthetic devices. Typically, these devices consist of a digital camera and an implantable neurostimulator. The image sensor in a digital camera has the same spatiotopic arrangement as the photoreceptors of the retina. Therefore, it is possible to extract meaningful spatial information from an image and deliver it via an array of stimulating electrodes directly to the surviving retinal circuits. Here, we review the structure and function of normal and degenerate retina. The different approaches to prosthetic implant design are described in the context of human and preclinical trials. In the last section, we review studies of electrical properties of the retina and its response to electrical stimulation. These types of investigation are currently assessing a number of key challenges identified in human trials, including stimulation efficacy, spatial localisation, desensitisation to repetitive stimulation and selective activation of retinal cell populations.

Retinal ganglion cells: mechanisms underlying depolarization block and differential responses to high frequency electrical stimulation of ON and OFF cells.

OBJECTIVE ON and OFF retinal ganglion cells (RGCs) are known to have non-monotonic responses to increasing amplitudes of high frequency (2 kHz) biphasic electrical stimulation. That is, an increase in stimulation amplitude causes an increase in the cells spike rate up to a peak value above which further increases in stimulation amplitude cause the cell to decrease its activity. The peak response for ON and OFF cells occurs at different stimulation amplitudes, which allows differential stimulation of these functional cell types. In this study, we investigate the mechanisms underlying the non-monotonic responses of ON and OFF brisk-transient RGCs and the mechanisms underlying their differential responses. APPROACH Using in vitro patch-clamp recordings from rat RGCs, together with simulations of single and multiple compartment Hodgkin-Huxley models, we show that the non-monotonic response to increasing amplitudes of stimulation is due to depolarization block, a change in the membrane potential that prevents the cell from generating action potentials. MAIN RESULTS We show that the onset for depolarization block depends on the amplitude and frequency of stimulation and reveal the biophysical mechanisms that lead to depolarization block during high frequency stimulation. Our results indicate that differences in transmembrane potassium conductance lead to shifts of the stimulus currents that generate peak spike rates, suggesting that the differential responses of ON and OFF cells may be due to differences in the expression of this current type. We also show that the length of the axons high sodium channel band (SOCB) affects non-monotonic responses and the stimulation amplitude that leads to the peak spike rate, suggesting that the length of the SOCB is shorter in ON cells. SIGNIFICANCE This may have important implications for stimulation strategies in visual prostheses.

Transient photoresponse of nitrogen-doped ultrananocrystalline diamond electrodes in saline solution

Beyond conventional electrically-driven neuronal stimulation methods, there is a growing interest in optically-driven approaches. In recent years, nitrogen-doped ultrananocrystalline diamond (N-UNCD) has emerged as a strong material candidate for use in electrically-driven stimulation electrodes. This work investigates the electrochemical activity of N-UNCD in response to pulsed illumination, to assess its potential for use as an optically-driven stimulation electrode. Whilst N-UNCD in the as-grown state exhibits a weak photoresponse, the oxygen plasma treated film exhibits two orders of magnitude enhancement in its sub-bandgap open circuit photovoltage response. The enhancement is attributed to the formation of a dense network of oxygen-terminated diamond nanocrystals at the N-UNCD surface. Electrically connected to the N-UNCD bulk via sub-surface graphitic grain boundaries, these diamond nanocrystals introduce a semiconducting barrier between the sub-surface graphitic semimetal and the electrolyte solut...

The effects of temperature changes on retinal ganglion cell responses to electrical stimulation

Little is known about how the retinas response to electrical stimulation is modified by temperatures. In vitro experiments are often used to inform in vivo studies, hence it is important to understand what changes occur at physiological temperature. To investigate this, we recorded from eight RGCs in vitro at three temperatures; room temperature (24°C), 30°C and 34°C. Results show that response latencies and thresholds are reduced, bursting spike rates in response to stimulation increases, and the spiking becomes more consistently locked to the stimulus at higher temperatures.

Predicting the location of the axon initial segment using spike waveform analysis: simulations of retinal ganglion cell physiology

There are 16 morphologically defined classes of rat retinal ganglion cells (RGCs). Most commonly, they are classified on the basis of several criteria including: soma size, dendritic field diameter, the dendritic branching pattern and the depth of stratification in the inner plexiform layer. Recently, it has also been shown that the intrinsic physiological properties of each rat RGC type vary enormously. Using multicompartment models of RGC types we investigated whether the location of the axon initial segment (AIS), the site of greatest sodium channel density and lowest voltage threshold, can be predicted by measurements of spike waveform made at the soma. The action potential waveform in many neurons consists of several components, which can be determined by examining the first and second derivatives of the membrane potential. In this study, we focus on this technique as an objective method to analyze the action potential waveform for different morphological RGC types. In addition, we analyze the features of the phase plot, which shows the rate of change of the membrane potential against the membrane potential itself. Phase plot analysis allows the measurement of subtle differences in the action potential waveform such as the initial segment-soma/dendritic break (ISSD), which corresponds to the early rising phase of the action potential. When the recording is made at the soma, the presence of the ISSD in the phase plot indicates that a low threshold region (i.e. the AIS) is further away from the soma. Rat RGCs were characterized electrophysiologically using standard whole cell patch clamp recording techniques. Data were acquired at 20 kHz using custom software developed in LabView (National Instruments). Spontaneous spikes and spikes evoked by just-threshold current were used for analysis. For each of the recordings, the amplitude and time of the trough between the peaks in the second-order derivatives were analyzed. After three dimensional confocal reconstruction of each recorded cell (Zeiss PASCAL) it was classified morphologically into one of the 16 predefined types. Multicompartment models of real retinal ganglion cells were constructed from 3D rendering confocal reconstructions and their physiology was simulated using the Hodgkin-Huxley formalism in the NEURON environment. Sodium channel density in the AIS and its distance from the soma were systematically varied and the effects on the phase plot analyzed. Simulations showed that the further the AIS was from the soma, the more pronounced the ISSD break, resulting in a larger break with a deeper trough between the two peaks in the phase plot. This result allows us to predict the location of the AIS based on recordings of the impulse waveform. In addition, we found that the density of sodium channels in the AIS affects spike propagation into the soma. We observed that decreasing sodium conductance in the AIS, required two spikes to occur in the AIS in order to evoke a somatic spike. This was also observed experimentally, in particular in C4 cells. Further analysis of individual RGC spike waveforms demonstrated that certain RGC types could be reliably identified using their spike waveforms.

Electrical receptive fields of retinal ganglion cells: Influence of presynaptic neurons

Implantable retinal stimulators activate surviving neurons to restore a sense of vision in people who have lost their photoreceptors through degenerative diseases. Complex spatial and temporal interactions occur in the retina during multi-electrode stimulation. Due to these complexities, most existing implants activate only a few electrodes at a time, limiting the repertoire of available stimulation patterns. Measuring the spatiotemporal interactions between electrodes and retinal cells, and incorporating them into a model may lead to improved stimulation algorithms that exploit the interactions. Here, we present a computational model that accurately predicts both the spatial and temporal nonlinear interactions of multi-electrode stimulation of rat retinal ganglion cells (RGCs). The model was verified using in vitro recordings of ON, OFF, and ON-OFF RGCs in response to subretinal multi-electrode stimulation with biphasic pulses at three stimulation frequencies (10, 20, 30 Hz). The model gives an estimate of each cell’s spatiotemporal electrical receptive fields (ERFs); i.e., the pattern of stimulation leading to excitation or suppression in the neuron. All cells had excitatory ERFs and many also had suppressive sub-regions of their ERFs. We show that the nonlinearities in observed responses arise largely from activation of presynaptic interneurons. When synaptic transmission was blocked, the number of sub-regions of the ERF was reduced, usually to a single excitatory ERF. This suggests that direct cell activation can be modeled accurately by a one-dimensional model with linear interactions between electrodes, whereas indirect stimulation due to summated presynaptic responses is nonlinear.

Irregularly timed electrical pulses reduce adaptation of retinal ganglion cells

OBJECTIVE Retinal prostheses aim to provide visual percepts to blind people affected by diseases caused by photoreceptor degeneration. One of the main challenges presented by current devices is neural adaptation in the retina, which is believed to be the cause of fading-an effect where artificially produced percepts disappear over a short period of time, despite continuous stimulation of the retina. We aim to understand the neural adaptation generated in retinal ganglion cells (RGCs) during electrical stimulation. APPROACH Current visual prostheses use electrical pulses with fixed frequencies and amplitudes modulated over hundreds of milliseconds to stimulate the retina. However, in nature, neuronal spiking occurs with stochastic timing, hence the information received naturally from other neurons by RGCs is irregularly timed. We used a single epiretinal electrode to stimulate and compare rat RGC responses to stimulus trains of biphasic pulses delivered at regular and random inter-pulse intervals (IPI), the latter taken from an exponential distribution. MAIN RESULTS Our observations suggest that stimulation with random IPIs result in lower adaptation rates than stimulation with constant IPIs at frequencies of 50 Hz and 200 Hz. We also found a high proportion of lower amplitude action potentials, or spikelets. The spikelets were more prominent at high stimulation frequencies (50 Hz and 200 Hz) and were less susceptible to adaptation, but it was not clear if they propagated along the axon. SIGNIFICANCE Using random IPI stimulation in retinal prostheses reduces the decay of RGCs and this could potentially reduce fading of electrically induced visual perception.

Feasibility of Nitrogen Doped Ultrananocrystalline Diamond Microelectrodes for Electrophysiological Recording From Neural Tissue

Neural prostheses that can monitor the physiological state of a subject are becoming clinically viable through improvements in the capacity to record from neural tissue. However, a significant limitation of current devices is that it is difficult to fabricate electrode arrays that have both high channel counts and the appropriate electrical properties required for neural recordings. In earlier work, we demonstrated nitrogen doped ultrananocrystalline diamond (N-UNCD) can provide efficacious electrical stimulation of neural tissue, with high charge injection capacity, surface stability and biocompatibility. In this work, we expand on this functionality to show that N-UNCD electrodes can also record from neural tissue owing to its low electrochemical impedance. We show that N-UNCD electrodes are highly flexible in their application, with successful recordings of action potentials from single neurons in an in vitro retina preparation, as well as local field potential responses from in vivo visual cortex tissue. Key properties of N-UNCD films, combined with scalability of electrode array fabrication with custom sizes for recording or stimulation along with integration through vertical interconnects to silicon based integrated circuits, may in future form the basis for the fabrication of versatile closed-loop neural prostheses that can both record and stimulate.