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author:("like, Alan M.")
1.  Properties and application of a multichannel integrated circuit for low-artifact, patterned electrical stimulation of neural tissue 
Journal of neural engineering  2012;9(6):066005.
Objective
Modern multielectrode array (MEA) systems can record the neuronal activity from thousands of electrodes, but their ability to provide spatio-temporal patterns of electrical stimulation is very limited. Furthermore, the stimulus-related artifacts significantly limit the ability to record the neuronal responses to the stimulation. To address these issues, we designed a multichannel integrated circuit for patterned MEA-based electrical stimulation and evaluated its performance in experiments with isolated mouse and rat retina.
Approach
The Stimchip includes 64 independent stimulation channels. Each channel comprises an internal digital-to-analog converter that can be configured as a current or voltage source. The shape of the stimulation waveform is defined independently for each channel by the real-time data stream. In addition, each channel is equipped with circuitry for reduction of the stimulus artifact.
Main results
Using a high-density MEA stimulation/recording system, we effectively stimulated individual retinal ganglion cells (RGCs) and recorded the neuronal responses with minimal distortion, even on the stimulating electrodes. We independently stimulated a population of RGCs in rat retina and, using a complex spatio-temporal pattern of electrical stimulation pulses, we replicated visually-evoked spiking activity of a subset of these cells with high fidelity.
Significance
Compared with current state-of-the-art MEA systems, the Stimchip is able to stimulate neuronal cells with much more complex sequences of electrical pulses and with significantly reduced artifacts. This opens up new possibilities for studies of neuronal responses to electrical stimulation, both in the context of neuroscience research and in the development of neuroprosthetic devices.
doi:10.1088/1741-2560/9/6/066005
PMCID: PMC3551622  PMID: 23160018
2.  Focal Electrical Stimulation of Major Ganglion Cell Types in the Primate Retina for the Design of Visual Prostheses 
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.
doi:10.1523/JNEUROSCI.4967-12.2013
PMCID: PMC3735130  PMID: 23616529
3.  Efficient Coding of Spatial Information in the Primate Retina 
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.
doi:10.1523/JNEUROSCI.4036-12.2012
PMCID: PMC3537829  PMID: 23152609
4.  Extending Transfer Entropy Improves Identification of Effective Connectivity in a Spiking Cortical Network Model 
PLoS ONE  2011;6(11):e27431.
Transfer entropy (TE) is an information-theoretic measure which has received recent attention in neuroscience for its potential to identify effective connectivity between neurons. Calculating TE for large ensembles of spiking neurons is computationally intensive, and has caused most investigators to probe neural interactions at only a single time delay and at a message length of only a single time bin. This is problematic, as synaptic delays between cortical neurons, for example, range from one to tens of milliseconds. In addition, neurons produce bursts of spikes spanning multiple time bins. To address these issues, here we introduce a free software package that allows TE to be measured at multiple delays and message lengths. To assess performance, we applied these extensions of TE to a spiking cortical network model (Izhikevich, 2006) with known connectivity and a range of synaptic delays. For comparison, we also investigated single-delay TE, at a message length of one bin (D1TE), and cross-correlation (CC) methods. We found that D1TE could identify 36% of true connections when evaluated at a false positive rate of 1%. For extended versions of TE, this dramatically improved to 73% of true connections. In addition, the connections correctly identified by extended versions of TE accounted for 85% of the total synaptic weight in the network. Cross correlation methods generally performed more poorly than extended TE, but were useful when data length was short. A computational performance analysis demonstrated that the algorithm for extended TE, when used on currently available desktop computers, could extract effective connectivity from 1 hr recordings containing 200 neurons in ∼5 min. We conclude that extending TE to multiple delays and message lengths improves its ability to assess effective connectivity between spiking neurons. These extensions to TE soon could become practical tools for experimentalists who record hundreds of spiking neurons.
doi:10.1371/journal.pone.0027431
PMCID: PMC3216957  PMID: 22102894
5.  Uniform signal redundancy of parasol and midget ganglion cells in primate retina 
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 an unexpected relationship between the anatomical and functional architecture in the dominant circuits of the primate retina.
doi:10.1523/JNEUROSCI.5294-08.2009
PMCID: PMC3202971  PMID: 19357292
6.  Functional connectivity in the retina at the resolution of photoreceptors 
Nature  2010;467(7316):673-677.
To understand a neural circuit requires knowing its connectivity. This paper reports measurements of functional connectivity between the input and ouput layers of the retina at single cell resolution and its implications for color vision. Multi-electrode technology was employed to record simultaneously from complete populations of the retinal ganglion cell types (midget, parasol, 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 exhibited 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.
doi:10.1038/nature09424
PMCID: PMC2953734  PMID: 20930838
7.  Spatial-Temporal Patterns of Retinal Waves Underlying Activity-Dependent Refinement of Retinofugal Projections 
Neuron  2009;64(2):200-212.
During development, retinal axons project coarsely within their central visual targets before refining to form precisely organized synaptic connections. Spontaneous retinal activity, in the form of acetylcholine-driven retinal waves, is widely proposed to be necessary for establishing these precise projection patterns. In particular, both axonal terminations of retinal ganglion cells (RGCs) and the size of receptive fields of neurons in visual areas of the brain are larger in mice that lack the β2 subunit of the nicotinic acetylcholine receptor (β2KO). Here, using a large-scale, high-density multi-electrode array to record single-unit activity from hundreds of RGCs simultaneously, we present analysis of early post-natal retinal activity from both wild type (WT) and β2KO retinas. We find that β2KO retinas have correlated patterns of activity, but many aspects of these patterns differ from those of WT retina. Quantitative analysis of these differences suggests that wave directionality, coupled with short-distance correlated bursting patterns of RGCs, work together to drive refinement of retinofugal projections.
doi:10.1016/j.neuron.2009.09.021
PMCID: PMC2771121  PMID: 19874788
8.  High sensitivity rod photoreceptor input to the blue-yellow color opponent pathway in macaque retina 
Nature neuroscience  2009;12(9):1159-1164.
Small bistratified cells (SBCs) in the primate retina carry a major blue-yellow opponent signal to the brain. Here we show that SBCs also carry signals from rod photoreceptors, with the same sign as S cone input. SBCs exhibited robust responses under low scotopic conditions (<0.01 P*/rod/s). 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. We discuss three implications of these findings. First, more retinal circuits than previously thought may multiplex rod and cone signals, efficiently exploiting the limited number of optic nerve fibers. Second, signals from AII amacrine cells may diverge to most or all of the <20 RGC 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.
doi:10.1038/nn.2353
PMCID: PMC2789108  PMID: 19668201
9.  The structure of large-scale synchronized firing in primate retina 
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 ~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.
doi:10.1523/JNEUROSCI.5187-08.2009
PMCID: PMC2678680  PMID: 19369571
Retinal Ganglion Cell; Synchrony; Information Theory; Sensory Neurons; Network; Correlated variability
10.  Direction selectivity in the retina is established independent of visual experience and early cholinergic retinal waves 
Neuron  2008;58(4):499-506.
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.
doi:10.1016/j.neuron.2008.03.013
PMCID: PMC2474739  PMID: 18498732
11.  Spatio-temporal correlations and visual signalling in a complete neuronal population 
Nature  2008;454(7207):995-999.
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 dependencies1–3, 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 responses4,5. 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 decoding6. 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.
doi:10.1038/nature07140
PMCID: PMC2684455  PMID: 18650810
12.  Receptive Fields in Primate Retina Are Coordinated to Sample Visual Space More Uniformly 
PLoS Biology  2009;7(4):e1000063.
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°, 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.
Author Summary
All visual information reaching the brain is transmitted by retinal ganglion cells, each of which is sensitive to a small region of space known as its receptive field. Each of the 20 or so distinct ganglion cell types is thought to transmit a complete visual image to the brain, because the receptive fields of each type form a regular lattice covering visual space. However, within each regular lattice, individual receptive fields have jagged, asymmetric shapes, which could produce “blind spots” and excessive overlap, degrading the visual image. To understand how the visual system overcomes this problem, we used a multielectrode array to record from hundreds of ganglion cells in isolated patches of peripheral primate retina. Surprisingly, we found that irregularly shaped receptive fields fit together like puzzle pieces, with high spatial precision, producing a more homogeneous coverage of visual space than would be possible otherwise. This finding reveals that the representation of visual space by neural ensembles in the retina is functionally coordinated and tuned, presumably by developmental interactions or ongoing visual activity, producing a more precise sensory signal.
Receptive fields in primate retina have irregular shapes, but they interlock like puzzle pieces to provide highly uniform coverage of visual space.
doi:10.1371/journal.pbio.1000063
PMCID: PMC2672597  PMID: 19355787
13.  Modeling the impact of common noise inputs on the network activity of retinal ganglion cells 
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.
doi:10.1007/s10827-011-0376-2
PMCID: PMC3560841  PMID: 22203465
Retina; Generalized linear model; State-space model; Multielectrode; Recording; Random-effects model

Results 1-13 (13)