Publications by authors named "Hamish Meffin"

72 Publications

Neural activity shaping utilizing a partitioned target pattern.

J Neural Eng 2021 Mar 8. Epub 2021 Mar 8.

Australian College of Optometry, Parkville, Carlton, Victoria, 3010, AUSTRALIA.

Electrical stimulation of neural tissue is used in both clinical and experimental devices to evoke a desired spatiotemporal pattern of neural activity. These devices induce a local field that drives neural activation, referred to as an activating function or generator signal. In visual prostheses, the spread of generator signal from each electrode within the neural tissue results in a spread of visual perception, referred to as a phosphene. In cases where neighboring phosphenes overlap, it is desirable to use current steering or neural activity shaping strategies to manipulate the generator signal between the electrodes to provide greater control over the total pattern of neural activity. Applying opposite generator signal polarities in neighboring regions of the retina forces the generator signal to pass through zero at an intermediate point, thus inducing low neural activity that may be perceived as a high-contrast line. This approach provides a form of high contrast visual perception, but it requires partitioning of the target pattern into those regions that use positive or negative generator signals. This discrete optimization is an NP-hard problem that is subject to being trapped in detrimental local minima. This investigation proposes a new partitioning method using image segmentation to determine the most beneficial positive and negative generator signal regions. Utilizing a database of 1000 natural images, the method is compared to alternative approaches based upon the mean squared error of the outcome. Under nominal conditions and with a set computation limit, partitioning provided improvement for 32% of these images. This percentage increased to 89% when utilizing image pre-processing to emphasize perceptual features of the images. The percentage of images that were dealt with most effectively with image segmentation increased as lower computation limits were imposed on the algorithms.
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http://dx.doi.org/10.1088/1741-2552/abecc4DOI Listing
March 2021

Learning receptive field properties of complex cells in V1.

PLoS Comput Biol 2021 Mar 2;17(3):e1007957. Epub 2021 Mar 2.

Department of Biomedical Engineering, The University of Melbourne, Melbourne, Australia.

There are two distinct classes of cells in the primary visual cortex (V1): simple cells and complex cells. One defining feature of complex cells is their spatial phase invariance; they respond strongly to oriented grating stimuli with a preferred orientation but with a wide range of spatial phases. A classical model of complete spatial phase invariance in complex cells is the energy model, in which the responses are the sum of the squared outputs of two linear spatially phase-shifted filters. However, recent experimental studies have shown that complex cells have a diverse range of spatial phase invariance and only a subset can be characterized by the energy model. While several models have been proposed to explain how complex cells could learn to be selective to orientation but invariant to spatial phase, most existing models overlook many biologically important details. We propose a biologically plausible model for complex cells that learns to pool inputs from simple cells based on the presentation of natural scene stimuli. The model is a three-layer network with rate-based neurons that describes the activities of LGN cells (layer 1), V1 simple cells (layer 2), and V1 complex cells (layer 3). The first two layers implement a recently proposed simple cell model that is biologically plausible and accounts for many experimental phenomena. The neural dynamics of the complex cells is modeled as the integration of simple cells inputs along with response normalization. Connections between LGN and simple cells are learned using Hebbian and anti-Hebbian plasticity. Connections between simple and complex cells are learned using a modified version of the Bienenstock, Cooper, and Munro (BCM) rule. Our results demonstrate that the learning rule can describe a diversity of complex cells, similar to those observed experimentally.
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http://dx.doi.org/10.1371/journal.pcbi.1007957DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7954310PMC
March 2021

Analysis of extracellular spike waveforms and associated receptive fields of neurons in cat primary visual cortex.

J Physiol 2021 Jan 27. Epub 2021 Jan 27.

National Vision Research Institute, Australian College of Optometry, Carlton, Victoria, 3053, Australia.

Key Points: Extracellular spikes recorded in the visual cortex (Area 17/18, V1) are commonly classified into either regular-spiking (RS) or fast-spiking (FS). Using multi-electrode arrays positioned in cat V1 and a broadband stimulus, we show that there is also a distinct class with positive-spiking (PS) waveforms. PS units were associated mainly with non-oriented receptive fields while RS and FS units had orientation-selective receptive fields. We suggest that PS units are recordings of axons originating from the thalamus. This conclusion was reinforced by our finding that we could record PS units after cortical silencing, but not record RS and FS units. The importance of our findings is that we were able to correlate spike shapes with receptive field characteristics with high precision using multi-electrode extracellular recording techniques. This allows considerable increases in the amount of information that can be extracted from future cortical experiments.

Abstract: Extracellular spike waveforms from recordings in the visual cortex have been classified into either regular-spiking (RS) or fast-spiking (FS) units. While both these types of spike waveforms are negative-dominant, we show that there are also distinct classes of spike waveforms in visual Area 17/18 (V1) of anaesthetised cats with positive-dominant waveforms, which are not regularly reported. The spatial receptive fields (RFs) of these different spike waveform types were estimated, which objectively revealed the existence of oriented and non-oriented RFs. We found that units with positive-dominant spikes, which have been associated with recordings from axons in the literature, had mostly non-oriented RFs (84%), which are similar to the centre-surround RFs observed in the dorsal lateral geniculate nucleus (dLGN). Thus, we hypothesise that these positive-dominant waveforms may be recordings from dLGN afferents. We recorded from V1 before and after the application of muscimol (a cortical silencer) and found that the positive-dominant spikes (PS) remained while the RS and FS cells did not. We also noted that the PS units had spiking characteristics normally associated with dLGN units (i.e. higher response spike rates, lower response latencies and higher proportion of burst spikes). Our findings show quantitatively that it is possible to correlate the RF properties of cortical neurons with particular spike waveforms. This has implications for how extracellular recordings should be interpreted and complex experiments can now be contemplated that would have been very challenging previously, such as assessing the feedforward connectivity between brain areas in the same location of cortical tissue.
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http://dx.doi.org/10.1113/JP280844DOI Listing
January 2021

In vivo feasibility of epiretinal stimulation using ultrananocrystalline diamond electrodes.

J Neural Eng 2020 08 5;17(4):045014. Epub 2020 Aug 5.

Graduate School of Biomedical Engineering, University of New South Wales, Kensington, NSW 2033, Australia. The Bionics Institute of Australia, East Melbourne, VIC 3002, Australia.

Objective: Due to their increased proximity to retinal ganglion cells (RGCs), epiretinal visual prostheses present the opportunity for eliciting phosphenes with low thresholds through direct RGC activation. This study characterised the in vivo performance of a novel prototype monolithic epiretinal prosthesis, containing Nitrogen incorporated ultrananocrystalline (N-UNCD) diamond electrodes.

Approach: A prototype implant containing up to twenty-five 120 × 120 µm N-UNCD electrodes was implanted into 16 anaesthetised cats and attached to the retina either using a single tack or via magnetic coupling with a suprachoroidally placed magnet. Multiunit responses to retinal stimulation using charge-balanced biphasic current pulses were recorded acutely in the visual cortex using a multichannel planar array. Several stimulus parameters were varied including; the stimulating electrode, stimulus polarity, phase duration, return configuration and the number of electrodes stimulated simultaneously.

Main Results: The rigid nature of the device and its form factor necessitated complex surgical procedures. Surgeries were considered successful in 10/16 animals and cortical responses to single electrode stimulation obtained in eight animals. Clinical imaging and histological outcomes showed severe retinal trauma caused by the device in situ in many instances. Cortical measures were found to significantly depend on the surgical outcomes of individual experiments, phase duration, return configuration and the number of electrodes stimulated simultaneously, but not stimulus polarity. Cortical thresholds were also found to increase over time within an experiment.

Significance: The study successfully demonstrated that an epiretinal prosthesis containing diamond electrodes could produce cortical activity with high precision, albeit only in a small number of cases. Both surgical approaches were highly challenging in terms of reliable and consistent attachment to and stabilisation against the retina, and often resulted in severe retinal trauma. There are key challenges (device form factor and attachment technique) to be resolved for such a device to progress towards clinical application, as current surgical techniques are unable to address these issues.
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http://dx.doi.org/10.1088/1741-2552/aba560DOI Listing
August 2020

Minimizing axon bundle activation of retinal ganglion cells with oriented rectangular electrodes.

J Neural Eng 2020 06 29;17(3):036016. Epub 2020 Jun 29.

National Vision Research Institute, Australian College of Optometry, Carlton, VIC, Australia. School of Physics, The University of Melbourne, Parkville, VIC, Australia. Department of Vision Science and Optometry, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Parkville, VIC, Australia.

Objective: Retinal prostheses aim to restore vision in patients with retinal degenerative diseases, such as age-related macular degeneration and retinitis pigmentosa. By implanting an array of microelectrodes, such a device creates percepts in patients through electrical stimulation of surviving retinal neurons. A challenge for retinal prostheses when trying to return high quality vision is the unintended activation of retinal ganglion cells through the stimulation of passing axon bundles, which leads to patients reporting large, elongated patches of light instead of focal spots.

Approach: In this work, we used calcium imaging to record the responses of retinal ganglion cells to electrical stimulation in explanted retina using rectangular electrodes placed with different orientations relative to the axon bundles.

Main Results: We showed that narrow, rectangular electrodes oriented parallel to the axon bundles can achieve focal stimulation. To further improve the strategy, we studied the impact of different stimulation waveforms and electrode configurations. We found the selectivity for focal stimulation to be higher when using short (33 μs), anodic-first biphasic pulses, with long electrode lengths and at least 50 μm electrode-to-retinal separation. Focal stimulation was, in fact, less selective when the electrodes made direct contact with the retinal surface due to unwanted preferential stimulation of the proximal axon bundles.

Significance: When employed in retinal prostheses, the proposed stimulation strategy is expected to provide improved quality of vision to the blind.
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http://dx.doi.org/10.1088/1741-2552/ab909eDOI Listing
June 2020

Mechanisms of Feature Selectivity and Invariance in Primary Visual Cortex.

Cereb Cortex 2020 Jul;30(9):5067-5087

National Vision Research Institute, Australian College of Optometry, Carlton VIC 3053, Australia.

Visual object identification requires both selectivity for specific visual features that are important to the object's identity and invariance to feature manipulations. For example, a hand can be shifted in position, rotated, or contracted but still be recognized as a hand. How are the competing requirements of selectivity and invariance built into the early stages of visual processing? Typically, cells in the primary visual cortex are classified as either simple or complex. They both show selectivity for edge-orientation but complex cells develop invariance to edge position within the receptive field (spatial phase). Using a data-driven model that extracts the spatial structures and nonlinearities associated with neuronal computation, we quantitatively describe the balance between selectivity and invariance in complex cells. Phase invariance is frequently partial, while invariance to orientation and spatial frequency are more extensive than expected. The invariance arises due to two independent factors: (1) the structure and number of filters and (2) the form of nonlinearities that act upon the filter outputs. Both vary more than previously considered, so primary visual cortex forms an elaborate set of generic feature sensitivities, providing the foundation for more sophisticated object processing.
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http://dx.doi.org/10.1093/cercor/bhaa102DOI Listing
July 2020

Stimulation Strategies for Improving the Resolution of Retinal Prostheses.

Front Neurosci 2020 26;14:262. Epub 2020 Mar 26.

National Vision Research Institute, Australian College of Optometry, Carlton, VIC, Australia.

Electrical stimulation using implantable devices with arrays of stimulating electrodes is an emerging therapy for neurological diseases. The performance of these devices depends greatly on their ability to activate populations of neurons with high spatiotemporal resolution. To study electrical stimulation of populations of neurons, retina serves as a useful model because the neural network is arranged in a planar array that is easy to access. Moreover, retinal prostheses are under development to restore vision by replacing the function of damaged light sensitive photoreceptors, which makes retinal research directly relevant for curing blindness. Here we provide a progress review on stimulation strategies developed in recent years to improve the resolution of electrical stimulation in retinal prostheses. We focus on studies performed with explanted retinas, in which electrophysiological techniques are the most advanced. We summarize achievements in improving the spatial and temporal resolution of electrical stimulation of the retina and methods to selectively stimulate neurons with different visual functions. Future directions for retinal prostheses development are also discussed, which could provide insights for other types of neuromodulatory devices in which high-resolution electrical stimulation is required.
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http://dx.doi.org/10.3389/fnins.2020.00262DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7135883PMC
March 2020

Hybrid diamond/ carbon fiber microelectrodes enable multimodal electrical/chemical neural interfacing.

Biomaterials 2020 02 22;230:119648. Epub 2019 Nov 22.

School of Physics, University of Melbourne, Parkville, Victoria, Australia. Electronic address:

Implantable medical devices are now in regular use to treat or ameliorate medical conditions, including movement disorders, chronic pain, cardiac arrhythmias, and hearing or vision loss. Aside from offering alternatives to pharmaceuticals, one major advantage of device therapy is the potential to monitor treatment efficacy, disease progression, and perhaps begin to uncover elusive mechanisms of diseases pathology. In an ideal system, neural stimulation, neural recording, and electrochemical sensing would be conducted by the same electrode in the same anatomical region. Carbon fiber (CF) microelectrodes are the appropriate size to achieve this goal and have shown excellent performance, in vivo. Their electrochemical properties, however, are not suitable for neural stimulation and electrochemical sensing. Here, we present a method to deposit high surface area conducting diamond on CF microelectrodes. This unique hybrid microelectrode is capable of recording single-neuron action potentials, delivering effective electrical stimulation pulses, and exhibits excellent electrochemical dopamine detection. Such electrodes are needed for the next generation of miniaturized, closed-loop implants that can self-tune therapies by monitoring both electrophysiological and biochemical biomarkers.
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http://dx.doi.org/10.1016/j.biomaterials.2019.119648DOI Listing
February 2020

Determination of the electrical impedance of neural tissue from its microscopic cellular constituents.

J Neural Eng 2020 01 24;17(1):016037. Epub 2020 Jan 24.

Department of Electrical and Electronic Engineering, The University of Melbourne, Parkville, Victoria, Australia. Department of Biomedical Engineering, The University of Melbourne, Parkville, Victoria, Australia.

The electrical properties of neural tissue are important in a range of different applications in biomedical engineering and basic science. These properties are characterized by the electrical admittivity of the tissue, which is the inverse of the specific tissue impedance.

Objective: Here we derived analytical expressions for the admittivity of various models of neural tissue from the underlying electrical and morphological properties of the constituent cells.

Approach: Three models are considered: parallel bundles of fibers, fibers contained in stacked laminae and fibers crossing each other randomly in all three-dimensional directions.

Main Results: An important and novel aspect that emerges from considering the underlying cellular composition of the tissue is that the resulting admittivity has both spatial and temporal frequency dependence, a property not shared with conventional conductivity-based descriptions. The frequency dependence of the admittivity results in non-trivial spatiotemporal filtering of electrical signals in the tissue models. These effects are illustrated by considering the example of pulsatile stimulation with a point source electrode. It is shown how changing temporal parameters of a current pulse, such as pulse duration, alters the spatial profile of the extracellular potential. In a second example, it is shown how the degree of electrical anisotropy can change as a function of the distance from the electrode, despite the underlying structurally homogeneity of the tissue. These effects are discussed in terms of different current pathways through the intra- and extra-cellular spaces, and how these relate to near- and far-field limits for the admittivity (which reduce to descriptions in terms of a simple conductivity).

Significance: The results highlight the complexity of the electrical properties of neural tissue and provide mathematical methods to model this complexity.
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http://dx.doi.org/10.1088/1741-2552/ab560aDOI Listing
January 2020

Improved visual acuity using a retinal implant and an optimized stimulation strategy.

J Neural Eng 2019 12 23;17(1):016018. Epub 2019 Dec 23.

National Vision Research Institute, Australian College of Optometry, Carlton, Victoria, Australia. School of Physics, The University of Melbourne, Parkville, Victoria, Australia. Department of Optometry and Vision Sciences, The University of Melbourne, Parkville, Victoria, Australia.

Objective: Retinal prosthetic devices hold great promise for the treatment of retinal degenerative diseases such as retinitis pigmentosa and age-related macular degeneration. Through electrical stimulation of the surviving retinal neurons, these devices evoke visual signals that are then relayed to the brain. Currently, the visual prostheses used in clinical trials have few electrodes, thus limiting visual acuity. Electrode arrays with high electrode densities have been developed using novel technologies, including diamond growth and laser machining, and these may provide a more promising route to achieve high visual acuity in blind patients.

Approach: Here, we studied the potential spatial resolution of electrical stimulation using diamond electrodes. We did this by labeling retinal ganglion cells in whole mount retina with a calcium indicator in wild-type rats and those with retinal degeneration. We imaged the ganglion cell responses to a range of stimulation parameters, including pulse duration and return electrode configuration.

Main Results: With sub-retinal stimulation, in which electrodes were in contact with the intact or degenerated photoreceptor layer, we found that biphasic pulses of 0.1 ms phase duration and a local return configuration was the most effective in confining the retinal ganglion cell activation patterns, while also remaining within the safety limits of the materials and providing the best power efficiency.

Significance: These results provide an optimized stimulation strategy for retinal implants, which if implemented in a retinal prosthetic is expected to improve the achievable visual acuity.
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http://dx.doi.org/10.1088/1741-2552/ab5299DOI Listing
December 2019

Synaptic Basis for Contrast-Dependent Shifts in Functional Identity in Mouse V1.

eNeuro 2019 Mar-Apr;6(2). Epub 2019 Apr 9.

National Vision Research Institute, Australian College of Optometry, Carlton, Victoria 3053, Australia.

A central transformation that occurs within mammalian visual cortex is the change from linear, polarity-sensitive responses to nonlinear, polarity-insensitive responses. These neurons are classically labelled as either simple or complex, respectively, on the basis of their response linearity (Skottun et al., 1991). While the difference between cell classes is clear when the stimulus strength is high, reducing stimulus strength diminishes the differences between the cell types and causes some complex cells to respond as simple cells (Crowder et al., 2007; van Kleef et al., 2010; Hietanen et al., 2013). To understand the synaptic basis for this shift in behavior, we used whole-cell recordings while systematically shifting stimulus contrast. We find systematic shifts in the degree of complex cell responses in mouse primary visual cortex (V1) at the subthreshold level, demonstrating that synaptic inputs change in concert with the shifts in response linearity and that the change in response linearity is not simply due to the threshold nonlinearity. These shifts are consistent with a visual cortex model in which the recurrent amplification acts as a critical component in the generation of complex cell responses (Chance et al., 1999).
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http://dx.doi.org/10.1523/ENEURO.0480-18.2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6464514PMC
February 2020

Toward a Biologically Plausible Model of LGN-V1 Pathways Based on Efficient Coding.

Front Neural Circuits 2019 14;13:13. Epub 2019 Mar 14.

Department of Biomedical Engineering, The University of Melbourne, Melbourne, VIC, Australia.

Increasing evidence supports the hypothesis that the visual system employs a sparse code to represent visual stimuli, where information is encoded in an efficient way by a small population of cells that respond to sensory input at a given time. This includes simple cells in primary visual cortex (V1), which are defined by their linear spatial integration of visual stimuli. Various models of sparse coding have been proposed to explain physiological phenomena observed in simple cells. However, these models have usually made the simplifying assumption that inputs to simple cells already incorporate linear spatial summation. This overlooks the fact that these inputs are known to have strong non-linearities such the separation of ON and OFF pathways, or separation of excitatory and inhibitory neurons. Consequently these models ignore a range of important experimental phenomena that are related to the emergence of linear spatial summation from non-linear inputs, such as segregation of ON and OFF sub-regions of simple cell receptive fields, the push-pull effect of excitation and inhibition, and phase-reversed cortico-thalamic feedback. Here, we demonstrate that a two-layer model of the visual pathway from the lateral geniculate nucleus to V1 that incorporates these biological constraints on the neural circuits and is based on sparse coding can account for the emergence of these experimental phenomena, diverse shapes of receptive fields and contrast invariance of orientation tuning of simple cells when the model is trained on natural images. The model suggests that sparse coding can be implemented by the V1 simple cells using neural circuits with a simple biologically plausible architecture.
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http://dx.doi.org/10.3389/fncir.2019.00013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6427952PMC
January 2020

Global activity shaping strategies for a retinal implant.

J Neural Eng 2019 04 13;16(2):026008. Epub 2018 Nov 13.

Department of Biomedical Engineering, The University of Melbourne, Parkville, Victoria, Australia.

Objective: Retinal prostheses provide visual perception via electrical stimulation of the retina using an implanted array of electrodes. The retinal activation resulting from each electrode is not point-like; instead each electrode introduces a spread of retinal activation that may overlap with activations from other electrodes. With most conventional stimulation strategies this overlap leads to image blur. Here we propose a 'shaping' algorithm that uses multiple electrodes to manipulate the current between electrodes in a desired way.

Approach: We assume a forward model for the conversion of electrode strengths to retinal activation. Three alternative global shaping algorithms are developed by calculating reverse models under different assumptions: linear inversion using singular value decomposition to produce the pseudoinverse, a linearly constrained quadratic program, and a binary quadratic program to partition the target pattern. The algorithms were assessed using both the mean squared error between the resulting images and desired images, as well as their adherence to the maximum allowed electrode currents.

Main Results: Under wide activation spreads the linear inversion algorithm gave improved solutions but faced two limitations: under low-noise conditions the electrode amplitudes exceeded their set limit; the set of solutions did not include the possibility of using negative local currents to induce retinal activation. The linearly constrained quadratic program and binary quadratic program respectively addressed these problems, but required much greater computation time.

Significance: This provides a framework for improving the resolution of future retinal implants, especially those with high density electrode arrays.
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http://dx.doi.org/10.1088/1741-2552/aaf071DOI Listing
April 2019

Bistability in Hodgkin-Huxley-type equations.

Annu Int Conf IEEE Eng Med Biol Soc 2018 Jul;2018:4728-4731

We study how initial conditions of the Hodgkin-Huxley model affect the dynamics of simulated neurons. We systematically vary the amplitudes of depolarization currents in order to bring neuron dynamics to stable equilibrium. Our results demonstrate that simulated neurons can have spontaneous spiking or a silent state, depending on the initial conditions. We propose the methodology to study the circumstances under which Purkinje cells transit between hyperpolarized quiescent state (down state) and a depolarized spiking state (up state). We show that results derived using the Hodgkin-Huxley methodology should be carefully analyzed before suggesting a direct relevance to neuroprosthetic implants.
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http://dx.doi.org/10.1109/EMBC.2018.8513233DOI Listing
July 2018

Neuroprostheses: method to evaluate the information content of stimulation strategies.

Annu Int Conf IEEE Eng Med Biol Soc 2018 Jul;2018:4724-4727

We propose a framework to evaluate the information content of different stimulation strategies used in neuroprosthetic implants. We analyze the responses of retinal ganglion cells to electrical stimulation using an information theory framework. This methodology allows us to calculate the information content by looking at the consistency of neural responses generated across multiple repetitions of the same stimulation protocol.
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http://dx.doi.org/10.1109/EMBC.2018.8513122DOI Listing
July 2018

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

Front Bioeng Biotechnol 2018 22;6:85. Epub 2018 Jun 22.

Department of Biomedical Engineering, University of Melbourne, Melbourne, VIC, Australia.

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 retina preparation, as well as local field potential responses from 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.
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http://dx.doi.org/10.3389/fbioe.2018.00085DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6024013PMC
June 2018

Compensation for Traveling Wave Delay Through Selection of Dendritic Delays Using Spike-Timing-Dependent Plasticity in a Model of the Auditory Brainstem.

Front Comput Neurosci 2018 5;12:36. Epub 2018 Jun 5.

NeuroEngineering Laboratory, Department of Biomedical Engineering, University of Melbourne, Melbourne, VIC, Australia.

Asynchrony among synaptic inputs may prevent a neuron from responding to behaviorally relevant sensory stimuli. For example, "octopus cells" are monaural neurons in the auditory brainstem of mammals that receive input from auditory nerve fibers (ANFs) representing a broad band of sound frequencies. Octopus cells are known to respond with finely timed action potentials at the onset of sounds despite the fact that due to the traveling wave delay in the cochlea, synaptic input from the auditory nerve is temporally diffuse. This paper provides a proof of principle that the octopus cells' dendritic delay may provide compensation for this input asynchrony, and that synaptic weights may be adjusted by a spike-timing dependent plasticity (STDP) learning rule. This paper used a leaky integrate and fire model of an octopus cell modified to include a "rate threshold," a property that is known to create the appropriate onset response in octopus cells. Repeated audio click stimuli were passed to a realistic auditory nerve model which provided the synaptic input to the octopus cell model. A genetic algorithm was used to find the parameters of the STDP learning rule that reproduced the microscopically observed synaptic connectivity. With these selected parameter values it was shown that the STDP learning rule was capable of adjusting the values of a large number of input synaptic weights, creating a configuration that compensated the traveling wave delay of the cochlea.
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http://dx.doi.org/10.3389/fncom.2018.00036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5996126PMC
June 2018

Biophysical basis of the linear electrical receptive fields of retinal ganglion cells.

J Neural Eng 2018 10 11;15(5):055001. Epub 2018 Jun 11.

NeuroEngineering Laboratory, Department of Biomedical Engineering, The University of Melbourne, Australia.

Responses of retinal ganglion cells to direct electrical stimulation have been shown experimentally to be well described by linear-nonlinear models. These models rely on the simplifying assumption that retinal ganglion cell responses to stimulation with an array of electrodes are driven by a simple linear weighted sum of stimulus current amplitudes from each electrode, known as the 'electrical receptive field'.

Objective: This paper aims to demonstrate the biophysical basis of the linear-nonlinear model and the electrical receptive field to facilitate the development of improved stimulation strategies for retinal implants.

Approach: We compare the linear-nonlinear model of subretinal electrical stimulation with a multi-layered, biophysical, volume conductor model of retinal stimulation.

Main Results: Our results show that the linear electrical receptive field of the linear-nonlinear model matches the transmembrane currents induced by electrodes (the activating function) at the site of the high-density sodium channel band with only minor discrepancies. The discrepancies are mostly eliminated by including axial current flow originating from adjacent cell compartments. Furthermore, for cells where a single linear electrical receptive field is insufficient, we show that cell responses are likely driven by multiple sites of action potential initiation with multiple distinct receptive fields, each of which can be accurately described by the activating function.

Significance: This result establishes that the biophysical basis of the electrical receptive field of the linear-nonlinear model is the superposition of transmembrane currents induced by different electrodes at and near the site of action potential initiation. Together with existing experimental support for linear-nonlinear models of electrical stimulation, this provides a firm basis for using this much simplified model to generate more optimal stimulation patterns for retinal implants.
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http://dx.doi.org/10.1088/1741-2552/aacbaaDOI Listing
October 2018

In vitro assessment of the differences in retinal ganglion cell responses to intra- and extracellular electrical stimulation.

J Neural Eng 2018 08 8;15(4):046022. Epub 2018 May 8.

National Vision Research Institute, Australian College of Optometry, Melbourne, Australia.

Objective: To compare responses of retinal ganglion cells (RGCs) to intracellular and extracellular electrical stimulation of varying frequency and amplitude.

Approach: In vitro patch clamp was used to record the responses of RGCs to sinusoidal current stimulation of varying frequency and amplitude. The results were simulated using the Neuron software package.

Main Results: The stimulation frequency yielding the greatest response was higher for extracellular stimulation compared to intracellular stimulation in the same cells (256 Hz versus 64 Hz). In fact, at the high end of the frequency range, where extracellular stimulation was highly efficacious, no responses could be generated using intracellular stimulation. A region in the amplitude-frequency stimulation space was identified where OFF-RGCs could be preferentially stimulated over ON-RGCs. We found that the inability of RGCs to respond at high frequencies of intracellular stimulation is likely the result of the axon acting as a low pass filter.

Significance: There is no direct translation of the results obtained with intracellular stimulation to those that employ extracellular stimulation.
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http://dx.doi.org/10.1088/1741-2552/aac2f7DOI Listing
August 2018

Upper stimulation threshold for retinal ganglion cell activation.

J Neural Eng 2018 08 4;15(4):046012. Epub 2018 Apr 4.

National Vision Research Institute, Australian College of Optometry, Australia. Department of Biomedical Engineering, The University of Melbourne, Australia.

Objective: The existence of an upper threshold in electrically stimulated retinal ganglion cells (RGCs) is of interest because of its relevance to the development of visual prosthetic devices, which are designed to restore partial sight to blind patients. The upper threshold is defined as the stimulation level above which no action potentials (direct spikes) can be elicited in electrically stimulated retina.

Approach: We collected and analyzed in vitro recordings from rat RGCs in response to extracellular biphasic (anodic-cathodic) pulse stimulation of varying amplitudes and pulse durations. Such responses were also simulated using a multicompartment model.

Main Results: We identified the individual cell variability in response to stimulation and the phenomenon known as upper threshold in all but one of the recorded cells (n  =  20/21). We found that the latencies of spike responses relative to stimulus amplitude had a characteristic U-shape. In silico, we showed that the upper threshold phenomenon was observed only in the soma. For all tested biphasic pulse durations, electrode positions, and pulse amplitudes above lower threshold, a propagating action potential was observed in the distal axon. For amplitudes above the somatic upper threshold, the axonal action potential back-propagated in the direction of the soma, but the soma's low level of hyperpolarization prevented action potential generation in the soma itself.

Significance: An upper threshold observed in the soma does not prevent spike conductance in the axon.
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http://dx.doi.org/10.1088/1741-2552/aabb7dDOI Listing
August 2018

Minimizing activation of overlying axons with epiretinal stimulation: The role of fiber orientation and electrode configuration.

PLoS One 2018 1;13(3):e0193598. Epub 2018 Mar 1.

Department of Biomedical Engineering, The University of Melbourne, Parkville, Victoria, Australia.

Currently, a challenge in electrical stimulation of the retina with a visual prosthesis (bionic eye) is to excite only the cells lying directly under the electrode in the ganglion cell layer, while avoiding excitation of axon bundles that pass over the surface of the retina in the nerve fiber layer. Stimulation of overlying axons results in irregular visual percepts, limiting perceptual efficacy. This research explores how differences in fiber orientation between the nerve fiber layer and ganglion cell layer leads to differences in the electrical activation of the axon initial segment and axons of passage.

Approach: Axons of passage of retinal ganglion cells in the nerve fiber layer are characterized by a narrow distribution of fiber orientations, causing highly anisotropic spread of applied current. In contrast, proximal axons in the ganglion cell layer have a wider distribution of orientations. A four-layer computational model of epiretinal extracellular stimulation that captures the effect of neurite orientation in anisotropic tissue has been developed using a volume conductor model known as the cellular composite model. Simulations are conducted to investigate the interaction of neural tissue orientation, stimulating electrode configuration, and stimulation pulse duration and amplitude.

Main Results: Our model shows that simultaneous stimulation with multiple electrodes aligned with the nerve fiber layer can be used to achieve selective activation of axon initial segments rather than passing fibers. This result can be achieved while reducing required stimulus charge density and with only modest increases in the spread of activation in the ganglion cell layer, and is shown to extend to the general case of arbitrary electrode array positioning and arbitrary target volume.

Significance: These results elucidate a strategy for more targeted stimulation of retinal ganglion cells with experimentally-relevant multi-electrode geometries and achievable stimulation requirements.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0193598PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5833203PMC
June 2018

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

PLoS Comput Biol 2018 02 12;14(2):e1005997. Epub 2018 Feb 12.

National Vision Research Institute, Australian College of Optometry, Carlton, Victoria, Australia.

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.
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http://dx.doi.org/10.1371/journal.pcbi.1005997DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5825175PMC
February 2018

Neural Responses to Multielectrode Stimulation of Healthy and Degenerate Retina.

Invest Ophthalmol Vis Sci 2017 07;58(9):3770-3784

Bionics Institute, East Melbourne, Victoria, Australia 10Department of Medical Bionics, The University of Melbourne, Victoria, Australia.

Purpose: Simultaneous stimulation of multiple retinal electrodes in normally sighted animals shows promise in improving the resolution of retinal prostheses. However, the effects of simultaneous stimulation on degenerate retinae remain unknown. Therefore, we investigated the characteristics of cortical responses to multielectrode stimulation of the degenerate retina.

Methods: Four adult cats were bilaterally implanted with retinal electrode arrays in the suprachoroidal space after unilateral adenosine triphosphate (ATP)-induced retinal photoreceptor degeneration. Functional and structural changes were characterized by using electroretinogram a-wave amplitude and optical coherence tomography. Multiunit activity was recorded from both hemispheres of the visual cortex. Responses to single- and multielectrode stimulation of the ATP-injected and fellow control eyes were characterized and compared.

Results: The retinae of ATP-injected eyes displayed structural and functional changes consistent with mid- to late-stage photoreceptor degeneration and remodeling. Responses to multielectrode stimulation of the ATP-injected eyes exhibited shortened latencies, lower saturated spike counts, and higher thresholds, compared to stimulation of the fellow control eyes. Electrical receptive field sizes were significantly larger in the ATP-injected eye than in the control eye, and positively correlated with the extent of degeneration.

Conclusions: Significant differences exist between cortical responses to stimulation of healthy and degenerate retinae. Our results highlight the importance of using a retinal degeneration model when evaluating the efficacy of novel stimulation paradigms.
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http://dx.doi.org/10.1167/iovs.16-21290DOI Listing
July 2017

A computational model of orientation-dependent activation of retinal ganglion cells.

Annu Int Conf IEEE Eng Med Biol Soc 2016 Aug;2016:5447-5450

Currently, a challenge in electrical stimulation for epiretinal prostheses is the avoidance of stimulation of axons of passage in the nerve fiber layer that originate from distant regions of the ganglion cell layer. A computational model of extracellular stimulation that captures the effect of neurite orientation in anisotropic tissue is developed using a modified version of the standard volume conductor model, known as the cellular composite model, embedded in a four layer model of the retina. Simulations are conducted to investigate the interaction of neural tissue orientation, electrode placement, and stimulation pulse duration and amplitude. Using appropriate multiple electrode configurations and higher frequency stimulation, preferential activation of the axon initial segment is shown to be possible for a range of realistic electrode-retina separation distances. These results establish a quantitative relationship between the time-course of stimulation and physical properties of the tissue, such as fiber orientation.
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http://dx.doi.org/10.1109/EMBC.2016.7591959DOI Listing
August 2016

Diamond Devices for High Acuity Prosthetic Vision.

Adv Biosyst 2017 Feb 5;1(1-2):e1600003. Epub 2016 Dec 5.

School of Physics, University of Melbourne, Victoria, 3010, Australia.

Retinal implants restore a sense of vision, for a growing number of users worldwide. Nevertheless, visual acuities provided by the current generation of devices are low. The quantity of information transferable to the retina using existing implant technologies is limited, far below receptor cells' capabilities. Many agree that increasing the information density deliverable by a retinal prosthesis requires devices with stimulation electrodes that are both dense and numerous. This work describes a new generation of retinal prostheses capable of upscaling the information density conveyable to the retina. Centered on engineered diamond materials, the implant is very well tolerated and long-term stable in the eye's unique physiological environment and capable of delivering highly versatile stimulation waveforms - both key attributes in providing useful vision. Delivery of high-density information, close to the retina with the flexibility to alter stimulation parameters in situ provides the best chance for success in providing high acuity prosthetic vision.
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http://dx.doi.org/10.1002/adbi.201600003DOI Listing
February 2017

Single-compartment models of retinal ganglion cells with different electrophysiologies.

Network 2017 ;28(2-4):74-93

a Department of Biomedical Engineering , The University of Melbourne , Melbourne , Australia.

There are more than 15 different types of retinal ganglion cells (RGCs) in the mammalian retina. To model responses of RGCs to electrical stimulation, we use single-compartment Hodgkin-Huxley-type models and run simulations in the Neuron environment. We use our recently published in vitro data of different morphological cell types to constrain the model, and study the effects of electrophysiology on the cell responses separately from the effects of morphology. We find simple models that can match the spike patterns of different types of RGCs. These models, with different input-output properties, may be used in a network to study retinal network dynamics and interactions.
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http://dx.doi.org/10.1080/0954898X.2018.1455993DOI Listing
January 2019

Prediction of cortical responses to simultaneous electrical stimulation of the retina.

J Neural Eng 2017 02 30;14(1):016006. Epub 2016 Nov 30.

NeuroEngineering Laboratory, Department of Electrical & Electronic Engineering, The University of Melbourne, VIC 3010, Australia. National ICT Australia, Victoria Research Lab, The University of Melbourne, VIC 3010, Australia. Bionics Institute, 384-388 Albert St, East Melbourne, VIC 3002, Australia.

Objective: Simultaneous electrical stimulation of multiple electrodes has shown promise in diversifying the responses that can be elicited by retinal prostheses compared to interleaved single electrode stimulation. However, the effects of interactions between electrodes are not well understood and clinical trials with simultaneous stimulation have produced inconsistent results. We investigated the effects of multiple electrode stimulation of the retina by developing a model of cortical responses to retinal stimulation.

Approach: Electrical stimuli consisting of temporally sparse, biphasic current pulses, with amplitudes sampled from a bi-dimensional Gaussian distribution, were simultaneously delivered to the retina across a 42-channel electrode array implanted in the suprachoroidal space of anesthetized cats. Visual cortex activity was recorded using penetrating microelectrode arrays. These data were used to identify a linear-nonlinear model of cortical responses to retinal stimulation. The ability of the model to generalize was tested by predicting responses to non-white patterned stimuli.

Main Results: The model accurately predicted two cortical activity measures: multi-unit neural responses and evoked potential responses to white noise stimuli. The model also provides information about electrical receptive fields, including the relative effects of each stimulating electrode on every recording site.

Significance: We have demonstrated a simple model that accurately describes cortical responses to simultaneous stimulation of a suprachoroidal retinal prosthesis. Overall, our results demonstrate that cortical responses to simultaneous multi-electrode stimulation of the retina are repeatable and predictable, and that interactions between electrodes during simultaneous stimulation are predominantly linear. The model shows promise for determining optimal stimulation paradigms for exploiting interactions between electrodes to shape neural activity, thereby improving outcomes for patients with retinal prostheses.
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http://dx.doi.org/10.1088/1741-2560/14/1/016006DOI Listing
February 2017

Optimizing growth and post treatment of diamond for high capacitance neural interfaces.

Biomaterials 2016 10 6;104:32-42. Epub 2016 Jul 6.

School of Physics, University of Melbourne, Victoria 3010, Australia. Electronic address:

Electrochemical and biological properties are two crucial criteria in the selection of the materials to be used as electrodes for neural interfaces. For neural stimulation, materials are required to exhibit high capacitance and to form intimate contact with neurons for eliciting effective neural responses at acceptably low voltages. Here we report on a new high capacitance material fabricated using nitrogen included ultrananocrystalline diamond (N-UNCD). After exposure to oxygen plasma for 3 h, the activated N-UNCD exhibited extremely high electrochemical capacitance greater than 1 mF/cm(2), which originates from the special hybrid sp(2)/sp(3) structure of N-UNCD. The in vitro biocompatibility of the activated N-UNCD was then assessed using rat cortical neurons and surface roughness was found to be critical for healthy neuron growth, with best results observed on surfaces with a roughness of approximately 20 nm. Therefore, by using oxygen plasma activated N-UNCD with appropriate surface roughness, and considering the chemical and mechanical stability of diamond, the fabricated neural interfaces are expected to exhibit high efficacy, long-term stability and a healthy neuron/electrode interface.
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http://dx.doi.org/10.1016/j.biomaterials.2016.07.006DOI Listing
October 2016

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

PLoS Comput Biol 2016 Apr 1;12(4):e1004849. Epub 2016 Apr 1.

National Vision Research Institute, Australian College of Optometry, Carlton, Victoria, Australia.

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.
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http://dx.doi.org/10.1371/journal.pcbi.1004849DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4818105PMC
April 2016

Spectral distribution of local field potential responses to electrical stimulation of the retina.

J Neural Eng 2016 06 30;13(3):036003. Epub 2016 Mar 30.

NeuroEngineering Laboratory, Electrical and Electronic Engineering, The University of Melbourne, VIC 3010, Australia. National Vision Research Institute, Australian College of Optometry, Carlton, VIC 3053, Australia.

Objective: Different frequency bands of the local field potential (LFP) have been shown to reflect neuronal activity occurring at varying cortical scales. As such, recordings of the LFP may offer a novel way to test the efficacy of neural prostheses and allow improvement of stimulation strategies via neural feedback. Here we use LFP measurements from visual cortex to characterize neural responses to electrical stimulation of the retina. We aim to show that the LFP is a viable signal that contains sufficient information to optimize the performance of sensory neural prostheses.

Approach: Clinically relevant electrode arrays were implanted in the suprachoroidal space of one eye in four felines. LFPs were simultaneously recorded in response to stimulation of individual electrodes using penetrating microelectrode arrays from the visual cortex. The frequency response of each electrode was extracted using multi-taper spectral analysis and the uniqueness of the responses was determined via a linear decoder.

Main Results: We found that cortical LFPs are reliably modulated by electrical stimulation of the retina and that the responses are spatially localized. We further characterized the spectral distribution of responses, with maximum information being contained in the low and high gamma bands. Finally, we found that LFP responses are unique to a large range of stimulus parameters (∼40) with a maximum conveyable information rate of 6.1 bits.

Significance: These results show that the LFP can be used to validate responses to electrical stimulation of the retina and we provide the first steps towards using these responses to provide more efficacious stimulation strategies.
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http://dx.doi.org/10.1088/1741-2560/13/3/036003DOI Listing
June 2016