A.B., Princeton University, Mathematics (1985)
M.Sc., Stanford University, Mathematics (1992)
Ph.D., Stanford University, Neuroscience (1995)
The goal of our research is to understand how the neural circuitry of the retina encodes visual information, and to use this knowledge in the development of artificial retinas for treating incurable blindness.
In our basic research, we use unique large-scale multi-electrode recordings to study visually evoked activity in hundreds of retinal ganglion cells of multiple types, simultaneously. We ask questions such as these:
• How do patterns of activity in many cells represent the visual scene?
• What distinct aspects of vision are mediated by different cell types?
• How reliably can the brain infer visual stimuli from retinal signals?
• Can we mimic the function of the retina with computational models?
We use this knowledge in the development of advanced artificial retinas. Although artificial retinas exist today, they provide only limited visual function to patients. Our goal is to build a device that can produce a naturalistic visual signal by mimicking the neural code of the retina. We ask questions such as these:
• What patterns of retinal activity can be produced by electrode arrays?
• How can we optimize stimulation to send the most effective visual signal?
• How can we engineer an implanted device that provides effective artificial vision?
In the long run, our understanding of the retinal circuitry and how to interface effectively to it will be relevant for developing many other interfaces to the brain, both for treating disease and for augmenting human capabilities.
Using large-scale multi-electrode recordings to understand how the primate retinal transforms visual information and transmits it to the brain
using multi-electrode recording and stimulation to understand how electrical stimulation of the retina can be used to transmit artificial visual signals to the brain
Sensory receptor noise corrupts sensory signals, contributing to imperfect perception and dictating central processing strategies. For example, noise in rod phototransduction limits our ability to detect light and minimizing the impact of this noise requires precisely tuned nonlinear processing by the retina. But detection sensitivity is only one aspect of night vision: prompt and accurate behavior also requires that rods reliably encode the timing of photon arrivals. We show here that the temporal resolution of responses of primate rods is much finer than the duration of the light response and identify the key limiting sources of transduction noise. We also find that the thermal activation rate of rhodopsin is lower than previous estimates, implying that other noise sources are more important than previously appreciated. A model of rod single-photon responses reveals that the limiting noise relevant for behavior depends critically on how rod signals are pooled by downstream neurons.
View details for DOI 10.1152/jn.00683.2018
View details for PubMedID 30485153
Visual processing is largely organized into ON and OFF pathways that signal stimulus increments and decrements, respectively. These pathways exhibit natural pairings based on morphological and physiological similarities, such as ON and OFF α-ganglion cells in the mammalian retina. Several studies have noted asymmetries in the properties of ON and OFF pathways. For example, the spatial receptive fields (RFs) of OFF α-cells are systematically smaller than ON α-cells. Analysis of natural scenes suggests that these asymmetries are optimal for visual encoding. To test the generality of ON/OFF asymmetries, we measured the spatiotemporal RF properties of multiple RGC types in rat retina. Through a quantitative and serial classification, we identified three functional pairs of ON and OFF RGCs. We analyzed the structure of their RFs and compared spatial integration, temporal integration, and gain across ON and OFF pairs. Similar to previous results from the cat and primate, RGC types with larger spatial RFs exhibited briefer temporal integration and higher gain. However, each pair of ON and OFF RGC types exhibited distinct asymmetric relationships between RF properties, some of which were opposite to the findings of previous reports. These results reveal the functional organization of six RGC types in the rodent retina and indicate that ON/OFF asymmetries are pathway specific.SIGNIFICANCE STATEMENT Circuits that process sensory input frequently process increments separately from decrements, so-called ON and OFF responses. Theoretical studies indicate that this separation, and associated asymmetries in ON and OFF pathways, may be beneficial for encoding natural stimuli. However, the generality of ON and OFF pathway asymmetries has not been tested. Here we compare the functional properties of three distinct pairs of ON and OFF pathways in the rodent retina and show that their asymmetries are pathway specific. These results provide a new view on the partitioning of vision across diverse ON and OFF signaling pathways.
View details for DOI 10.1523/JNEUROSCI.2008-18.2018
View details for Web of Science ID 000449355600011
View details for PubMedID 30249795
View details for PubMedCentralID PMC6222062
Simultaneous electrical stimulation and recording using multi-electrode arrays can provide a valuable technique for studying circuit connectivity and engineering neural interfaces. However, interpreting these measurements is challenging because the spike sorting process (identifying and segregating action potentials arising from different neurons) is greatly complicated by electrical stimulation artifacts across the array, which can exhibit complex and nonlinear waveforms, and overlap temporarily with evoked spikes. Here we develop a scalable algorithm based on a structured Gaussian Process model to estimate the artifact and identify evoked spikes. The effectiveness of our methods is demonstrated in both real and simulated 512-electrode recordings in the peripheral primate retina with single-electrode and several types of multi-electrode stimulation. We establish small error rates in the identification of evoked spikes, with a computational complexity that is compatible with real-time data analysis. This technology may be helpful in the design of future high-resolution sensory prostheses based on tailored stimulation (e.g., retinal prostheses), and for closed-loop neural stimulation at a much larger scale than currently possible.
View details for DOI 10.1371/journal.pcbi.1005842
View details for Web of Science ID 000416838500024
View details for PubMedID 29131818
View details for PubMedCentralID PMC5703587
Epiretinal prostheses for treating blindness activate axon bundles, causing large, arc-shaped visual percepts that limit the quality of artificial vision. Improving the function of epiretinal prostheses therefore requires understanding and avoiding axon bundle activation. This paper introduces a method to detect axon bundle activation based on its electrical signature, and uses the method to test whether epiretinal stimulation can directly elicit spikes in individual retinal ganglion cells without activating nearby axon bundles. Combined electrical stimulation and recording from isolated primate retina were performed using a custom multi-electrode system (512 electrodes, 10 μm diameter, 60 μm pitch). Axon bundle signals were identified by their bi-directional propagation, speed, and increasing amplitude as a function of stimulation current. The threshold for bundle activation varied across electrodes and retinas, and was in the same range as the threshold for activating retinal ganglion cells near their somas. In the peripheral retina, 45% of electrodes that activated individual ganglion cells (17% of all electrodes) did so without activating bundles. This permitted selective activation of 21% of recorded ganglion cells (7% of all ganglion cells) over the array. In the central retina, 75% of electrodes that activated individual ganglion cells (16% of all electrodes) did so without activating bundles. The ability to selectively activate a subset of retinal ganglion cells without axon bundles suggests a possible novel architecture for future epiretinal prostheses.
View details for DOI 10.1152/jn.00750.2016
View details for PubMedID 28566464
View details for Web of Science ID 000394210604007
View details for Web of Science ID 000394210202378
Understanding the function of modulatory interneuron networks is a major challenge, because such networks typically operate over long spatial scales and involve many neurons of different types. Here, we use an indirect electrical imaging method to reveal the function of a spatially extended, recurrent retinal circuit composed of two cell types. This recurrent circuit produces peripheral response suppression of early visual signals in the primate magnocellular visual pathway. We identify a type of polyaxonal amacrine cell physiologically via its distinctive electrical signature, revealed by electrical coupling with ON parasol retinal ganglion cells recorded using a large-scale multi-electrode array. Coupling causes the amacrine cells to fire spikes that propagate radially over long distances, producing GABA-ergic inhibition of other ON parasol cells recorded near the amacrine cell axonal projections. We propose and test a model for the function of this amacrine cell type, in which the extra-classical receptive field of ON parasol cells is formed by reciprocal inhibition from other ON parasol cells in the periphery, via the electrically coupled amacrine cell network.
View details for DOI 10.1016/j.cub.2016.05.051
View details for PubMedID 27397894
View details for Web of Science ID 000362882202117
This study combines for the first time two major approaches to understanding the function and structure of neural circuits: large-scale multielectrode recordings, and confocal imaging of labeled neurons. To achieve this end, we develop a novel approach to the central problem of anatomically identifying recorded cells, based on the electrical image: the spatiotemporal pattern of voltage deflections induced by spikes on a large-scale, high-density multielectrode array. Recordings were performed from identified ganglion cell types in the macaque retina. Anatomical images of cells in the same preparation were obtained using virally transfected fluorescent labeling or by immunolabeling after fixation. The electrical image was then used to locate recorded cell somas, axon initial segments, and axon trajectories, and these signatures were used to identify recorded cells. Comparison of anatomical and physiological measurements permitted visualization and physiological characterization of numerically dominant ganglion cell types with high efficiency in a single preparation.
View details for DOI 10.1523/JNEUROSCI.3675-14.2015
View details for Web of Science ID 000352202300017
View details for PubMedID 25788683
View details for PubMedCentralID PMC4363392
The function of a neural circuit is shaped by the computations performed by its interneurons, which in many cases are not easily accessible to experimental investigation. Here, we elucidate the transformation of visual signals flowing from the input to the output of the primate retina, using a combination of large-scale multi-electrode recordings from an identified ganglion cell type, visual stimulation targeted at individual cone photoreceptors, and a hierarchical computational model. The results reveal nonlinear subunits in the circuity of OFF midget ganglion cells, which subserve high-resolution vision. The model explains light responses to a variety of stimuli more accurately than a linear model, including stimuli targeted to cones within and across subunits. The recovered model components are consistent with known anatomical organization of midget bipolar interneurons. These results reveal the spatial structure of linear and nonlinear encoding, at the resolution of single cells and at the scale of complete circuits.
View details for DOI 10.7554/eLife.05241
View details for PubMedID 26517879
View details for PubMedCentralID PMC4623615
Natural vision relies on spatiotemporal patterns of electrical activity in the retina. We investigated the feasibility of veridically reproducing such patterns with epiretinal prostheses. Multielectrode recordings and visual and electrical stimulation were performed on populations of identified ganglion cells in isolated peripheral primate retina. Electrical stimulation patterns were designed to reproduce recorded waves of activity elicited by a moving visual stimulus. Electrical responses in populations of ON parasol cells exhibited high spatial and temporal precision, matching or exceeding the precision of visual responses measured in the same cells. Computational readout of electrical and visual responses produced similar estimates of stimulus speed, confirming the fidelity of electrical stimulation for biologically relevant visual signals. These results suggest the possibility of producing rich spatiotemporal patterns of retinal activity with a prosthesis and that temporal multiplexing may aid in reproducing the neural code of the retina.
View details for DOI 10.1016/j.neuron.2014.04.044
View details for PubMedID 24910077
Retinal prostheses electrically stimulate neurons to produce artificial vision in people blinded by photoreceptor degenerative diseases. The limited spatial resolution of current devices results in indiscriminate stimulation of interleaved cells of different types, precluding veridical reproduction of natural activity patterns in the retinal output. Here we investigate the use of spatial patterns of current injection to increase the spatial resolution of stimulation, using high-density multielectrode recording and stimulation of identified ganglion cells in isolated macaque retina. As previously shown, current passed through a single electrode typically induced a single retinal ganglion cell spike with submillisecond timing precision. Current passed simultaneously through pairs of neighboring electrodes modified the probability of activation relative to injection through a single electrode. This modification could be accurately summarized by a piecewise linear model of current summation, consistent with a simple biophysical model based on multiple sites of activation. The generalizability of the piecewise linear model was tested by using the measured responses to stimulation with two electrodes to predict responses to stimulation with three electrodes. Finally, the model provided an accurate prediction of which among a set of spatial stimulation patterns maximized selective activation of a cell while minimizing activation of a neighboring cell. The results demonstrate that tailored multielectrode stimulation patterns based on a piecewise linear model may be useful in increasing the spatial resolution of retinal prostheses.
View details for DOI 10.1523/JNEUROSCI.2882-13.2014
View details for PubMedID 24695706
View details for PubMedCentralID PMC3972715
Amacrine cells are the most diverse and least understood cell class in the retina. Polyaxonal amacrine cells (PACs) are a unique subset identified by multiple long axonal processes. To explore their functional properties, populations of PACs were identified by their distinctive radially propagating spikes in large-scale high-density multielectrode recordings of isolated macaque retina. One group of PACs exhibited stereotyped functional properties and receptive field mosaic organization similar to that of parasol ganglion cells. These PACs had receptive fields coincident with their dendritic fields, but much larger axonal fields, and slow radial spike propagation. They also exhibited ON-OFF light responses, transient response kinetics, sparse and coordinated firing during image transitions, receptive fields with antagonistic surrounds and fine spatial structure, nonlinear spatial summation, and strong homotypic neighbor electrical coupling. These findings reveal the functional organization and collective visual signaling by a distinctive, high-density amacrine cell population.
View details for DOI 10.1523/JNEUROSCI.3359-13.2014
View details for PubMedID 24599459
View details for PubMedCentralID PMC3942577
The propagation of visual signals from individual cone photoreceptors through parallel neural circuits was examined in the primate retina. Targeted stimulation of individual cones was combined with simultaneous recording from multiple retinal ganglion cells of identified types. The visual signal initiated by an individual cone produced strong responses with different kinetics in three of the four numerically dominant ganglion cell types. The magnitude and kinetics of light responses in each ganglion cell varied nonlinearly with stimulus strength but in a manner that was independent of the cone of origin after accounting for the overall input strength of each cone. Based on this property of independence, the receptive field profile of an individual ganglion cell could be well estimated from responses to stimulation of each cone individually. Together, these findings provide a quantitative account of how elementary visual inputs form the ganglion cell receptive field.
View details for DOI 10.1016/j.neuron.2013.10.043
View details for PubMedID 24411737
Electrical stimulation of retinal neurons with an advanced retinal prosthesis may eventually provide high-resolution artificial vision to the blind. However, the success of future prostheses depends on the ability to activate the major parallel visual pathways of the human visual system. Electrical stimulation of the five numerically dominant retinal ganglion cell types was investigated by simultaneous stimulation and recording in isolated peripheral primate (Macaca sp.) retina using multi-electrode arrays. ON and OFF midget, ON and OFF parasol, and small bistratified ganglion cells could all be activated directly to fire a single spike with submillisecond latency using brief pulses of current within established safety limits. Thresholds for electrical stimulation were similar in all five cell types. In many cases, a single cell could be specifically activated without activating neighboring cells of the same type or other types. These findings support the feasibility of direct electrical stimulation of the major visual pathways at or near their native spatial and temporal resolution.
View details for DOI 10.1523/JNEUROSCI.4967-12.2013
View details for Web of Science ID 000318419300009
View details for PubMedID 23616529
Sensory neurons have been hypothesized to efficiently encode signals from the natural environment subject to resource constraints. The predictions of this efficient coding hypothesis regarding the spatial filtering properties of the visual system have been found consistent with human perception, but they have not been compared directly with neural responses. Here, we analyze the information that retinal ganglion cells transmit to the brain about the spatial information in natural images subject to three resource constraints: the number of retinal ganglion cells, their total response variances, and their total synaptic strengths. We derive a model that optimizes the transmitted information and compare it directly with measurements of complete functional connectivity between cone photoreceptors and the four major types of ganglion cells in the primate retina, obtained at single-cell resolution. We find that the ganglion cell population exhibited 80% efficiency in transmitting spatial information relative to the model. Both the retina and the model exhibited high redundancy (~30%) among ganglion cells of the same cell type. A novel and unique prediction of efficient coding, the relationships between projection patterns of individual cones to all ganglion cells, was consistent with the observed projection patterns in the retina. These results indicate a high level of efficiency with near-optimal redundancy in visual signaling by the retina.
View details for DOI 10.1523/JNEUROSCI.4036-12.2012
View details for Web of Science ID 000311091000019
View details for PubMedID 23152609
View details for PubMedCentralID PMC3537829
Synchronized spontaneous firing among retinal ganglion cells (RGCs), on timescales faster than visual responses, has been reported in many studies. Two candidate mechanisms of synchronized firing include direct coupling and shared noisy inputs. In neighboring parasol cells of primate retina, which exhibit rapid synchronized firing that has been studied extensively, recent experimental work indicates that direct electrical or synaptic coupling is weak, but shared synaptic input in the absence of modulated stimuli is strong. However, previous modeling efforts have not accounted for this aspect of firing in the parasol cell population. Here we develop a new model that incorporates the effects of common noise, and apply it to analyze the light responses and synchronized firing of a large, densely-sampled network of over 250 simultaneously recorded parasol cells. We use a generalized linear model in which the spike rate in each cell is determined by the linear combination of the spatio-temporally filtered visual input, the temporally filtered prior spikes of that cell, and unobserved sources representing common noise. The model accurately captures the statistical structure of the spike trains and the encoding of the visual stimulus, without the direct coupling assumption present in previous modeling work. Finally, we examined the problem of decoding the visual stimulus from the spike train given the estimated parameters. The common-noise model produces Bayesian decoding performance as accurate as that of a model with direct coupling, but with significantly more robustness to spike timing perturbations.
View details for DOI 10.1007/s10827-011-0376-2
View details for Web of Science ID 000306288900006
View details for PubMedID 22203465
Transduction and synaptic noise generated in retinal cone photoreceptors determine the fidelity with which light inputs are encoded, and the readout of cone signals by downstream circuits determines whether this fidelity is used for vision. We examined the effect of cone noise on visual signals by measuring its contribution to correlated noise in primate retinal ganglion cells. Correlated noise was strong in the responses of dissimilar cell types with shared cone inputs. The dynamics of cone noise could account for rapid correlations in ganglion cell activity, and the extent of shared cone input could explain correlation strength. Furthermore, correlated noise limited the fidelity with which visual signals were encoded by populations of ganglion cells. Thus, a simple picture emerges: cone noise, traversing the retina through diverse pathways, accounts for most of the noise and correlations in the retinal output and constrains how higher centers exploit signals carried by parallel visual pathways.
View details for DOI 10.1038/nn.2927
View details for Web of Science ID 000295254200020
View details for PubMedID 21926983
Retinitis pigmentosa (RP) is a leading cause of degenerative vision loss, yet its progressive effects on visual signals transmitted from the retina to the brain are not well understood. The transgenic P23H rat is a valuable model of human autosomal dominant RP, exhibiting extensive similarities to the human disease pathology, time course, and electrophysiology. In this study, we examined the physiological effects of degeneration in retinal ganglion cells (RGCs) of P23H rats aged between P37 and P752, and compared them with data from wild-type control animals. The strength and the size of visual receptive fields of RGCs decreased rapidly with age in P23H retinas. Light responses mediated by rod photoreceptors declined earlier (∼ P300) than cone-mediated light responses (∼ P600). Responses of ON and OFF RGCs diminished at a similar rate. However, OFF cells exhibited hyperactivity during degeneration, whereas ON cells showed a decrease in firing rate. The application of synaptic blockers abolished about half of the elevated firing in OFF RGCs, indicating that the remodeled circuitry was not the only source of degeneration-induced hyperactivity. These results advance our understanding of the functional changes associated with retinal degeneration.
View details for DOI 10.1152/jn.01061.2010
View details for Web of Science ID 000290710300052
View details for PubMedID 21389304
Retinal ganglion cells exhibit substantial correlated firing: a tendency to fire nearly synchronously at rates different from those expected by chance. These correlations suggest that network interactions significantly shape the visual signal transmitted from the eye to the brain. This study describes the degree and structure of correlated firing among the major ganglion cell types in primate retina. Correlated firing among ON and OFF parasol, ON and OFF midget, and small bistratified cells, which together constitute roughly 75% of the input to higher visual areas, was studied using large-scale multi-electrode recordings. Correlated firing in the presence of constant, spatially uniform illumination exhibited characteristic strength, time course and polarity within and across cell types. Pairs of nearby cells with the same light response polarity were positively correlated; cells with the opposite polarity were negatively correlated. The strength of correlated firing declined systematically with distance for each cell type, in proportion to the degree of receptive field overlap. The pattern of correlated firing across cell types was similar at photopic and scotopic light levels, although additional slow correlations were present at scotopic light levels. Similar results were also observed in two other retinal ganglion cell types. Most of these observations are consistent with the hypothesis that shared noise from photoreceptors is the dominant cause of correlated firing. Surprisingly, small bistratified cells, which receive ON input from S cones, fired synchronously with ON parasol and midget cells, which receive ON input primarily from L and M cones. Collectively, these results provide an overview of correlated firing across cell types in the primate retina, and constraints on the underlying mechanisms.
View details for DOI 10.1113/jphysiol.2010.193888
View details for Web of Science ID 000285760900011
View details for PubMedID 20921200
To understand a neural circuit requires knowledge of its connectivity. Here we report measurements of functional connectivity between the input and ouput layers of the macaque retina at single-cell resolution and the implications of these for colour vision. Multi-electrode technology was used to record simultaneously from complete populations of the retinal ganglion cell types (midget, parasol and small bistratified) that transmit high-resolution visual signals to the brain. Fine-grained visual stimulation was used to identify the location, type and strength of the functional input of each cone photoreceptor to each ganglion cell. The populations of ON and OFF midget and parasol cells each sampled the complete population of long- and middle-wavelength-sensitive cones. However, only OFF midget cells frequently received strong input from short-wavelength-sensitive cones. ON and OFF midget cells showed a small non-random tendency to selectively sample from either long- or middle-wavelength-sensitive cones to a degree not explained by clumping in the cone mosaic. These measurements reveal computations in a neural circuit at the elementary resolution of individual neurons.
View details for DOI 10.1038/nature09424
View details for Web of Science ID 000282572500030
View details for PubMedID 20930838
View details for PubMedCentralID PMC2953734
A characteristic feature of adult retina is mosaic organization: a spatial arrangement of cells of each morphological and functional type that produces uniform sampling of visual space. How the mosaics of visual receptive fields emerge in the retina during development is not fully understood. Here we use a large-scale multielectrode array to determine the mosaic organization of retinal ganglion cells (RGCs) in rats around the time of eye opening and in the adult. At the time of eye opening, we were able to reliably distinguish two types of ON RGCs and two types of OFF RGCs in rat retina based on their light response and intrinsic firing properties. Although the light responses of individual cells were not yet mature at this age, each of the identified functional RGC types formed a receptive field mosaic, where the spacing of the receptive field centers and the overlap of the receptive field extents were similar to those observed in the retinas of adult rats. These findings suggest that, although the light response properties of RGCs may need vision to reach full maturity, extensive visual experience is not required for individual RGC types to form a regular sensory map of visual space.
View details for DOI 10.1152/jn.00896.2009
View details for Web of Science ID 000276555800015
View details for PubMedID 20107116
Retinal implants are intended to help patients with degenerative conditions by electrically stimulating surviving cells to produce artificial vision. However, little is known about how individual retinal ganglion cells respond to direct electrical stimulation in degenerating retina. Here we used a transgenic rat model to characterize ganglion cell responses to light and electrical stimulation during photoreceptor degeneration. Retinas from pigmented P23H-1 rats were compared with wild-type retinas between ages P37 and P752. During degeneration, retinal thickness declined by 50%, largely as a consequence of photoreceptor loss. Spontaneous electrical activity in retinal ganglion cells initially increased two- to threefold, but returned to nearly normal levels around P600. A profound decrease in the number of light-responsive ganglion cells was observed during degeneration, culminating in retinas without detectable light responses by P550. Ganglion cells from transgenic and wild-type animals were targeted for focal electrical stimulation using multielectrode arrays with electrode diameters of approximately 10 microns. Ganglion cells were stimulated directly and the success rate of stimulation in both groups was 60-70% at all ages. Surprisingly, thresholds (approximately 0.05 mC/cm(2)) and latencies (approximately 0.25 ms) in P23H rat ganglion cells were comparable to those in wild-type ganglion cells at all ages and showed no change over time. Thus ganglion cells in P23H rats respond normally to direct electrical stimulation despite severe photoreceptor degeneration and complete loss of light responses. These findings suggest that high-resolution epiretinal prosthetic devices may be effective in treating vision loss resulting from photoreceptor degeneration.
View details for DOI 10.1152/jn.00663.2009
View details for Web of Science ID 000272463200018
View details for PubMedID 19726725
Small bistratified cells (SBCs) in the primate retina carry a major blue-yellow opponent signal to the brain. We found that SBCs also carry signals from rod photoreceptors, with the same sign as S cone input. SBCs exhibited robust responses under low scotopic conditions. Physiological and anatomical experiments indicated that this rod input arose from the AII amacrine cell-mediated rod pathway. Rod and cone signals were both present in SBCs at mesopic light levels. These findings have three implications. First, more retinal circuits may multiplex rod and cone signals than were previously thought to, efficiently exploiting the limited number of optic nerve fibers. Second, signals from AII amacrine cells may diverge to most or all of the approximately 20 retinal ganglion cell types in the peripheral primate retina. Third, rod input to SBCs may be the substrate for behavioral biases toward perception of blue at mesopic light levels.
View details for DOI 10.1038/nn.2353
View details for Web of Science ID 000269317300018
View details for PubMedID 19668201
Synchronized firing among neurons has been proposed to constitute an elementary aspect of the neural code in sensory and motor systems. However, it remains unclear how synchronized firing affects the large-scale patterns of activity and redundancy of visual signals in a complete population of neurons. We recorded simultaneously from hundreds of retinal ganglion cells in primate retina, and examined synchronized firing in completely sampled populations of approximately 50-100 ON-parasol cells, which form a major projection to the magnocellular layers of the lateral geniculate nucleus. Synchronized firing in pairs of cells was a subset of a much larger pattern of activity that exhibited local, isotropic spatial properties. However, a simple model based solely on interactions between adjacent cells reproduced 99% of the spatial structure and scale of synchronized firing. No more than 20% of the variability in firing of an individual cell was predictable from the activity of its neighbors. These results held both for spontaneous firing and in the presence of independent visual modulation of the firing of each cell. In sum, large-scale synchronized firing in the entire population of ON-parasol cells appears to reflect simple neighbor interactions, rather than a unique visual signal or a highly redundant coding scheme.
View details for DOI 10.1523/JNEUROSCI.5187-08.2009
View details for Web of Science ID 000265232000034
View details for PubMedID 19369571
The collective representation of visual space in high resolution visual pathways was explored by simultaneously measuring the receptive fields of hundreds of ON and OFF midget and parasol ganglion cells in isolated primate retina. As expected, the receptive fields of all four cell types formed regular mosaics uniformly tiling the visual scene. Surprisingly, comparison of all four mosaics revealed that the overlap of neighboring receptive fields was nearly identical, for both the excitatory center and inhibitory surround components of the receptive field. These observations contrast sharply with the large differences in the dendritic overlap between the parasol and midget cell populations, revealing a surprising lack of correspondence between the anatomical and functional architecture in the dominant circuits of the primate retina.
View details for DOI 10.1523/JNEUROSCI.5294-08.2009
View details for Web of Science ID 000265009600033
View details for PubMedID 19357292
In the visual system, large ensembles of neurons collectively sample visual space with receptive fields (RFs). A puzzling problem is how neural ensembles provide a uniform, high-resolution visual representation in spite of irregularities in the RFs of individual cells. This problem was approached by simultaneously mapping the RFs of hundreds of primate retinal ganglion cells. As observed in previous studies, RFs exhibited irregular shapes that deviated from standard Gaussian models. Surprisingly, these irregularities were coordinated at a fine spatial scale: RFs interlocked with their neighbors, filling in gaps and avoiding large variations in overlap. RF shapes were coordinated with high spatial precision: the observed uniformity was degraded by angular perturbations as small as 15 degrees, and the observed populations sampled visual space with more than 50% of the theoretical ideal uniformity. These results show that the primate retina encodes light with an exquisitely coordinated array of RF shapes, illustrating a higher degree of functional precision in the neural circuitry than previously appreciated.
View details for DOI 10.1371/journal.pbio.1000063
View details for Web of Science ID 000266500000005
View details for PubMedID 19355787
Statistical dependencies in the responses of sensory neurons govern both the amount of stimulus information conveyed and the means by which downstream neurons can extract it. Although a variety of measurements indicate the existence of such dependencies, their origin and importance for neural coding are poorly understood. Here we analyse the functional significance of correlated firing in a complete population of macaque parasol retinal ganglion cells using a model of multi-neuron spike responses. The model, with parameters fit directly to physiological data, simultaneously captures both the stimulus dependence and detailed spatio-temporal correlations in population responses, and provides two insights into the structure of the neural code. First, neural encoding at the population level is less noisy than one would expect from the variability of individual neurons: spike times are more precise, and can be predicted more accurately when the spiking of neighbouring neurons is taken into account. Second, correlations provide additional sensory information: optimal, model-based decoding that exploits the response correlation structure extracts 20% more information about the visual scene than decoding under the assumption of independence, and preserves 40% more visual information than optimal linear decoding. This model-based approach reveals the role of correlated activity in the retinal coding of visual stimuli, and provides a general framework for understanding the importance of correlated activity in populations of neurons.
View details for DOI 10.1038/nature07140
View details for Web of Science ID 000258591000039
View details for PubMedID 18650810
Synchronized firing in neural populations has been proposed to constitute an elementary aspect of the neural code, but a complete understanding of its origins and significance has been elusive. Synchronized firing has been extensively documented in retinal ganglion cells, the output neurons of the retina. However, differences in synchronized firing across species and cell types have led to varied conclusions about its mechanisms and role in visual signaling. Recent work on two identified cell populations in the primate retina, the ON-parasol and OFF-parasol cells, permits a more unified understanding. Intracellular recordings reveal that synchronized firing in these cell types arises primarily from common synaptic input to adjacent pairs of cells. Statistical analysis indicates that local pairwise interactions can explain the pattern of synchronized firing in the entire parasol cell population. Computational analysis reveals that the aggregate impact of synchronized firing on the visual signal is substantial. Thus, in the parasol cells, the origin and impact of synchronized firing on the neural code may be understood as locally shared input which influences the visual signals transmitted from eye to brain.
View details for DOI 10.1016/j.conb.2008.09.010
View details for Web of Science ID 000261561400008
View details for PubMedID 18832034
Direction selectivity in the retina requires the asymmetric wiring of inhibitory inputs onto four subtypes of On-Off direction-selective ganglion cells (DSGCs), each preferring motion in one of four cardinal directions. The primary model for the development of direction selectivity is that patterned activity plays an instructive role. Here, we use a unique, large-scale multielectrode array to demonstrate that DSGCs are present at eye opening, in mice that have been reared in darkness and in mice that lack cholinergic retinal waves. These data suggest that direction selectivity in the retina is established largely independent of patterned activity and is therefore likely to emerge as a result of complex molecular interactions.
View details for DOI 10.1016/j.neuron.2008.03.013
View details for Web of Science ID 000256120500005
View details for PubMedID 18498732
The development of retinal implants for the blind depends crucially on understanding how neurons in the retina respond to electrical stimulation. This study used multielectrode arrays to stimulate ganglion cells in the peripheral macaque retina, which is very similar to the human retina. Analysis was restricted to parasol cells, which form one of the major high-resolution visual pathways in primates. Individual cells were characterized using visual stimuli, and subsequently targeted for electrical stimulation using electrodes 9-15 microm in diameter. Results were accumulated across 16 ON and 9 OFF parasol cells. At threshold, all cells responded to biphasic electrical pulses 0.05-0.1 ms in duration by firing a single spike with latency lower than 0.35 ms. The average threshold charge density was 0.050 +/- 0.005 mC/cm(2), significantly below established safety limits for platinum electrodes. ON and OFF ganglion cells were stimulated with similar efficacy. Repetitive stimulation elicited spikes within a 0.1 ms time window, indicating that the high temporal precision necessary for spike-by-spike stimulation can be achieved in primate retina. Spatial analysis of observed thresholds suggests that electrical activation occurred near the axon hillock, and that dendrites contributed little. Finally, stimulation of a single parasol cell produced little or no activation of other cells in the ON and OFF parasol cell mosaics. The low-threshold, temporally precise, and spatially specific responses hold promise for the application of high-density arrays of small electrodes in epiretinal implants.
View details for DOI 10.1523/JNEUROSCI.5138-07.2008
View details for Web of Science ID 000255301100019
View details for PubMedID 18434523
The primate visual system consists of parallel pathways initiated by distinct cell types in the retina that encode different features of the visual scene. Small bistratified cells (SBCs), which form a major projection to the thalamus, exhibit blue-ON/yellow-OFF [S-ON/(L+M)-OFF] light responses thought to be important for high-acuity color vision. However, the spatial processing properties of individual SBCs and their spatial arrangement across the visual field are poorly understood. The present study of peripheral primate retina reveals that contrary to previous suggestions, SBCs exhibit center-surround spatial structure, with the (L+M)-OFF component of the receptive field approximately 50% larger in diameter than the S-ON component. Analysis of response kinetics shows that the (L+M)-OFF response in SBCs is slower than the S-ON response and significantly less transient than that of simultaneously recorded OFF-parasol cells. The (L+M)-OFF response in SBCs was eliminated by bath application of the metabotropic glutamate receptor agonist L-APB. These observations indicate that the (L+M)-OFF response of SBCs is not formed by OFF-bipolar cell input as has been suspected and suggest that it arises from horizontal cell feedback. Finally, the receptive fields of SBCs form orderly mosaics, with overlap and regularity similar to those of ON-parasol cells. Thus, despite their distinctive morphology and chromatic properties, SBCs exhibit two features of other retinal ganglion cell types: center-surround antagonism and regular mosaic sampling of visual space.
View details for DOI 10.1523/JNEUROSCI.3437-07.2007
View details for Web of Science ID 000251296700023
View details for PubMedID 18045920
The primate retina communicates visual information to the brain via a set of parallel pathways that originate from at least 22 anatomically distinct types of retinal ganglion cells. Knowledge of the physiological properties of these ganglion cell types is of critical importance for understanding the functioning of the primate visual system. Nonetheless, the physiological properties of only a handful of retinal ganglion cell types have been studied in detail. Here we show, using a newly developed multielectrode array system for the large-scale recording of neural activity, the existence of a physiologically distinct population of ganglion cells in the primate retina with distinctive visual response properties. These cells, which we will refer to as upsilon cells, are characterized by large receptive fields, rapid and transient responses to light, and significant nonlinearities in their spatial summation. Based on the measured properties of these cells, we speculate that they correspond to the smooth/large radiate cells recently identified morphologically in the primate retina and may therefore provide visual input to both the lateral geniculate nucleus and the superior colliculus. We further speculate that the upsilon cells may be the primate retina's counterparts of the Y-cells observed in the cat and other mammalian species.
View details for DOI 10.1523/JNEUROSCI.2836-07.2007
View details for Web of Science ID 000250083300012
View details for PubMedID 17928443
Rules by which V1 neurons combine signals originating in the cone photoreceptors are poorly understood. We measured cone inputs to V1 neurons in awake, fixating monkeys with white-noise analysis techniques that reveal properties of light responses not revealed by purely linear models used in previous studies. Simple cells were studied by spike-triggered averaging that is robust to static nonlinearities in spike generation. This analysis revealed, among heterogeneously tuned neurons, two relatively discrete categories: one with opponent L- and M-cone weights and another with nonopponent cone weights. Complex cells were studied by spike-triggered covariance, which identifies features in the stimulus sequence that trigger spikes in neurons with receptive fields containing multiple linear subunits that combine nonlinearly. All complex cells responded to nonopponent stimulus modulations. Although some complex cells responded to cone-opponent stimulus modulations too, none exhibited the pure opponent sensitivity observed in many simple cells. These results extend the findings on distinctions between simple and complex cell chromatic tuning observed in previous studies in anesthetized monkeys.
View details for DOI 10.1152/jn.00965.2006
View details for Web of Science ID 000247929900045
View details for PubMedID 17303812
The function of any neural circuit is governed by connectivity of neurons in the circuit and the computations performed by the neurons. Recent research on retinal function has substantially advanced understanding in both areas. First, visual information is transmitted to the brain by at least 17 distinct retinal ganglion cell types defined by characteristic morphology, light response properties, and central projections. These findings provide a much more accurate view of the parallel visual pathways emanating from the retina than do previous models, and they highlight the importance of identifying distinct cell types and their connectivity in other neural circuits. Second, encoding of visual information involves significant temporal structure and interactions in the spike trains of retinal neurons. The functional importance of this structure is revealed by computational analysis of encoding and decoding, an approach that may be applicable to understanding the function of other neural circuits.
View details for DOI 10.1146/annurev.neuro.30.051606.094252
View details for Web of Science ID 000248735400001
View details for PubMedID 17335403
Current understanding of many neural circuits is limited by our ability to explore the vast number of potential interactions between different cells. We present a new approach that dramatically reduces the complexity of this problem. Large-scale multi-electrode recordings were used to measure electrical activity in nearly complete, regularly spaced mosaics of several hundred ON and OFF parasol retinal ganglion cells in macaque monkey retina. Parasol cells exhibited substantial pairwise correlations, as has been observed in other species, indicating functional connectivity. However, pairwise measurements alone are insufficient to determine the prevalence of multi-neuron firing patterns, which would be predicted from widely diverging common inputs and have been hypothesized to convey distinct visual messages to the brain. The number of possible multi-neuron firing patterns is far too large to study exhaustively, but this problem may be circumvented if two simple rules of connectivity can be established: (1) multi-cell firing patterns arise from multiple pairwise interactions, and (2) interactions are limited to adjacent cells in the mosaic. Using maximum entropy methods from statistical mechanics, we show that pairwise and adjacent interactions accurately accounted for the structure and prevalence of multi-neuron firing patterns, explaining approximately 98% of the departures from statistical independence in parasol cells and approximately 99% of the departures that were reproducible in repeated measurements. This approach provides a way to define limits on the complexity of network interactions and thus may be relevant for probing the function of many neural circuits.
View details for DOI 10.1523/JNEUROSCI.1282-06.2006
View details for Web of Science ID 000239678800006
View details for PubMedID 16899720
Existing epiretinal implants for the blind are designed to electrically stimulate large groups of surviving retinal neurons using a small number of electrodes with diameters of several hundred micrometers. To increase the spatial resolution of artificial sight, electrodes much smaller than those currently in use are desirable. In this study, we stimulated and recorded ganglion cells in isolated pieces of rat, guinea pig, and monkey retina. We used microfabricated hexagonal arrays of 61 platinum disk electrodes with diameters between 6 and 25 microm, spaced 60 microm apart. Charge-balanced current pulses evoked one or two spikes at latencies as short as 0.2 ms, and typically only one or a few recorded ganglion cells were stimulated. Application of several synaptic blockers did not abolish the evoked responses, implying direct activation of ganglion cells. Threshold charge densities were typically <0.1 mC/cm2 for a pulse duration of 100 micros, corresponding to charge thresholds of <100 pC. Stimulation remained effective after several hours and at high frequencies. To show that closely spaced electrodes can elicit independent ganglion cell responses, we used the multielectrode array to stimulate several nearby ganglion cells simultaneously. From these data, we conclude that electrical stimulation of mammalian retina with small-diameter electrode arrays is achievable and can provide high temporal and spatial precision at low charge densities. We review previous epiretinal stimulation studies and discuss our results in the context of 32 other publications, comparing threshold parameters and safety limits.
View details for DOI 10.1152/jn.01168.2005
View details for Web of Science ID 000237653900003
View details for PubMedID 16436479
Sensory encoding in spiking neurons depends on both the integration of sensory inputs and the intrinsic dynamics and variability of spike generation. We show that the stimulus selectivity, reliability, and timing precision of primate retinal ganglion cell (RGC) light responses can be reproduced accurately with a simple model consisting of a leaky integrate-and-fire spike generator driven by a linearly filtered stimulus, a postspike current, and a Gaussian noise current. We fit model parameters for individual RGCs by maximizing the likelihood of observed spike responses to a stochastic visual stimulus. Although compact, the fitted model predicts the detailed time structure of responses to novel stimuli, accurately capturing the interaction between the spiking history and sensory stimulus selectivity. The model also accounts for the variability in responses to repeated stimuli, even when fit to data from a single (nonrepeating) stimulus sequence. Finally, the model can be used to derive an explicit, maximum-likelihood decoding rule for neural spike trains, thus providing a tool for assessing the limitations that spiking variability imposes on sensory performance.
View details for DOI 10.1523/JNEUROSCI.3305-05.2005
View details for Web of Science ID 000233460400021
View details for PubMedID 16306413
Sensory experience typically depends on the ensemble activity of hundreds or thousands of neurons, but little is known about how populations of neurons faithfully encode behaviorally important sensory information. We examined how precisely speed of movement is encoded in the population activity of magnocellular-projecting parasol retinal ganglion cells (RGCs) in macaque monkey retina. Multi-electrode recordings were used to measure the activity of approximately 100 parasol RGCs simultaneously in isolated retinas stimulated with moving bars. To examine how faithfully the retina signals motion, stimulus speed was estimated directly from recorded RGC responses using an optimized algorithm that resembles models of motion sensing in the brain. RGC population activity encoded speed with a precision of approximately 1%. The elementary motion signal was conveyed in approximately 10 ms, comparable to the interspike interval. Temporal structure in spike trains provided more precise speed estimates than time-varying firing rates. Correlated activity between RGCs had little effect on speed estimates. The spatial dispersion of RGC receptive fields along the axis of motion influenced speed estimates more strongly than along the orthogonal direction, as predicted by a simple model based on RGC response time variability and optimal pooling. on and off cells encoded speed with similar and statistically independent variability. Simulation of downstream speed estimation using populations of speed-tuned units showed that peak (winner take all) readout provided more precise speed estimates than centroid (vector average) readout. These findings reveal how faithfully the retinal population code conveys information about stimulus speed and the consequences for motion sensing in the brain.
View details for DOI 10.1152/jn.01175.2004
View details for Web of Science ID 000230135500013
View details for PubMedID 15625091
Several studies have suggested that the visual system can detect dim lights with a fidelity limited only by Poisson fluctuations in photon absorption and spontaneous activation of rhodopsin. If correct, this implies that neural processing of responses produced by rod photoreceptors is efficient and effectively noiseless. However, experimental uncertainty makes this conclusion tenuous. Furthermore, previous work provided no information about how accurately stimulus timing is represented. Here, the detection sensitivity and temporal resolution of salamander rods and retinal ganglion cells (RGCs) are compared in nearly matched experimental conditions by using recorded responses to identify the time of a flash. At detection threshold, RGCs could reliably signal the absorption of 20-50 photons, but the rods within the RGC receptive field could signal stimuli 3-10 times weaker. For flash strengths 10 times higher than detection threshold, some RGCs could distinguish stimulus timing with a resolution finer than 100 msec, within a factor of 2 of the rod limit. The relationship between RGC and rod sensitivity could not be explained by added noise in the retinal circuitry but could be explained by a threshold acting after pooling of rod signals. Simulations of rod signals indicated that continuous noise, rather than spontaneous activation of rhodopsin or fluctuations in the single-photon response, limited temporal resolution. Thus, detection of dim lights was limited by retinal processing, but, at higher light levels, synaptic transmission, cellular integration of synaptic inputs, and spike generation in RGCs faithfully conveyed information about the time of photon absorption.
View details for DOI 10.1523/JNEUROSCI.2339-04.2005
View details for Web of Science ID 000226271400006
View details for PubMedID 15647475
Recent studies have revealed striking precision in the spike trains of retinal ganglion cells in several species and suggested that this precision could be an important aspect of visual signaling. However, the precision of spike trains has not yet been described in primate retina. The spike time and count variability of parasol (magnocellular-projecting) retinal ganglion cells was examined in isolated macaque monkey retinas stimulated with repeated presentations of high contrast, spatially uniform intensity modulation. At the onset of clearly delineated periods of firing, retinal ganglion cells fired spikes time-locked to the stimulus with a variability across trials as low as 1 ms. Spike count variance across trials was much lower than the mean and sometimes approached the minimum variance possible with discrete counts, inconsistent with Poisson statistics expected from independently generated spikes. Spike time and count variability decreased systematically with stimulus strength. These findings were consistent with a model in which firing probability was determined by a stimulus-driven free firing rate modulated by a recovery function representing the action potential absolute and relative refractory period.
View details for DOI 10.1152/jn.01171.2003
View details for Web of Science ID 000222908200013
View details for PubMedID 15277596
Recent studies have examined the temporal precision of spiking in visual system neurons, but less is known about the time scale that is relevant for behaviorally important visual computations. We examined how spatiotemporal patterns of spikes in ensembles of primate retinal ganglion cells convey information about visual motion to the brain. The direction of motion of a bar was estimated by comparing the timing of responses in ensembles of parasol (magnocellular-projecting) retinal ganglion cells recorded simultaneously, using a cross-correlation approach similar to standard models of motion sensing. To identify the temporal resolution of motion signals, spike trains were low-pass filtered before estimating the direction of motion. The filter time constant that resulted in most accurate motion sensing was in the range of 10-50 msec for a range of stimulus speeds and contrasts and approached a lower limit of approximately 10 msec at high speeds and contrasts. This time constant was, on average, comparable to the length of interspike intervals. These findings suggest that cortical neurons could filter their inputs on a time scale of tens of milliseconds, rather than relying on the precise times of individual input spikes, to sense motion most reliably.
View details for Web of Science ID 000184469200002
View details for PubMedID 12890760
Functional asymmetries in the ON and OFF pathways of the primate visual system were examined using simultaneous multi-electrode recordings from dozens of retinal ganglion cells (RGCs) in vitro. Light responses of RGCs were characterized using white noise stimulation. Two distinct functional types of cells frequently encountered, one ON and one OFF, had non-opponent spectral sensitivity, relatively high response gain, transient light responses, and large receptive fields (RFs) that tiled the region of retina recorded, suggesting that they belonged to the same morphological cell class, most likely parasol. Three principal functional asymmetries were observed. (1) Receptive fields of ON cells were 20% larger in diameter than those of OFF cells, resulting in higher full-field sensitivity. (2) ON cells had faster response kinetics than OFF cells, with a 10-20% shorter time to peak, trough and zero crossing in the biphasic temporal impulse response. (3) ON cells had more nearly linear light responses and were capable of signaling decrements, whereas OFF cells had more strongly rectifying responses that provided little information about increments. These findings suggest specific mechanistic asymmetries in retinal ON and OFF circuits and differences in visual performance on the basis of the activity of ON and OFF parasol cells.
View details for Web of Science ID 000174626000037
View details for PubMedID 11923439
View details for Web of Science ID 000180520100034
We examined the functional microcircuitry of cone inputs to blue-ON/yellow-OFF (BY) ganglion cells in the macaque retina using multielectrode recording. BY cells were identified by their ON responses to blue light and OFF responses to red or green light. Cone-isolating stimulation indicated that ON responses originated in short (S) wavelength-sensitive cones, whereas OFF responses originated in both long (L) and middle (M) wavelength-sensitive cones. Stimulation with fine spatial patterns revealed locations of individual S cones in BY cell receptive fields. Neighboring BY cells received common but unequal inputs from one or more S cones. Inputs from individual S cones differed in strength, indicating different synaptic weights, and summed approximately linearly to control BY cell firing.
View details for Web of Science ID 000083883200014
View details for PubMedID 10491609
Stimuli varying in intensity and chromaticity, presented on numerous backgrounds, were classified into red/green, blue/yellow and white/black opponent color categories. These measurements revealed the shapes of the boundaries that separate opponent colors in three-dimensional color space. Opponent color classification boundaries were generally not planar, but their shapes could be summarized by a piecewise linear model in which increment and decrement color signals are combined with different weights at two stages to produce opponent color sensations. The effect of background light on classification was largely explained by separate gain changes in increment and decrement cone signals.
View details for Web of Science ID 000081693700011
View details for PubMedID 10615508
Color appearance judgments revealed fundamental differences in visual processing of incremental and decremental lights. First, the balance of cone activation required for a light to appear achromatic was different for increments and decrements (Judd, 1940; Helson & Michels, 1948). Second, adaptation--the visual system's adjustment to background light--affected achromatic decrements more than increments. Third, the regulation of adaptation for incremental and decremental stimuli depended differently on background signals from the three cone types. We interpret these asymmetries as differences in mechanisms of adaptation in the ON and OFF pathways, and suggest that they evolved to accommodate the range and physical sources of color signals in the two pathways.
View details for Web of Science ID A1996UH52800020
View details for PubMedID 8782387
Photoreceptor sensitivity changes explained the effect of large uniform backgrounds on the color appearance of small targets in a dichoptic asymmetric color matching experiment. Subjects viewed in each eye a target superimposed on a large background. The backgrounds presented to the two eyes had different spectral compositions. Subjects adjusted the target seen by the right eye to match the appearance of the target seen by the left eye. Receptor sensitivity changes explained the effect of numerous adapting backgrounds on the color appearance of many targets with high precision. Post-receptoral sensitivity changes provided a poorer account of the data. The apparent sensitivity of each receptor class varied inversely with changes in background light absorbed by that receptor class, but did not depend on background light absorbed by the other two receptor classes.
View details for Web of Science ID A1995QA11800005
View details for PubMedID 7839619
We examine two hypotheses about the functional segregation of color and motion perception, using a motion nulling task. The most common interpretation of functional segregation, that motion perception depends only on one of the three dimensions of color, is rejected. We propose and test an alternative formulation of functional segregation: that motion perception depends on a univariate motion signal driven by all three color dimensions, and that the motion signal is determined by the product of the stimulus contrast and a term that depends only on the relative cone excitations. Two predictions of this model are confirmed. First, motion nulling is transitive: when two stimuli null a third they also null another. Second, motion nulling is homogeneous: if two stimuli null one another, they continue to null one another when their contrasts are scaled equally. We describe how to apply our formulation of functional segregation to other behavioral and physiological measurements.
View details for Web of Science ID A1993LQ40900010
View details for PubMedID 8266653