Peripheral direct current reduces naturally evoked nociceptive activity at the spinal cord in rodent models of pain.

Objective.Electrical neuromodulation is an established non-pharmacological treatment for chronic pain. However, existing devices using pulsatile stimulation typically inhibit pain pathways indirectly and are not suitable for all types of chronic pain. Direct current (DC) stimulation is a recently developed technology which affects small-diameter fibres more strongly than pulsatile stimulation. Since nociceptors are predominantly small-diameter Aδand C fibres, we investigated if this property could be applied to preferentially reduce nociceptive signalling.Approach.We applied a DC waveform to the sciatic nerve in rats of both sexes and recorded multi-unit spinal activity evoked at the hindpaw using various natural stimuli corresponding to different sensory modalities rather than broad-spectrum electrical stimulus. To determine if DC neuromodulation is effective across different types of chronic pain, tests were performed in models of neuropathic and inflammatory pain.Main results.We found that in both pain models tested, DC application reduced responses evoked by noxious stimuli, as well as tactile-evoked responses which we suggest may be involved in allodynia. Different spinal activity of different modalities were reduced in naïve animals compared to the pain models, indicating that physiological changes such as those mediated by disease states could play a larger role than previously thought in determining neuromodulation outcomes.Significance.Our findings support the continued development of DC neuromodulation as a method for reduction of nociceptive signalling, and suggests that it may be effective at treating a broader range of aberrant pain conditions than existing devices.

Neural activity of retinal ganglion cells under continuous, dynamically-modulated high frequency electrical stimulation.

Objective.Current retinal prosthetics are limited in their ability to precisely control firing patterns of functionally distinct retinal ganglion cell (RGC) types. The aim of this study was to characterise RGC responses to continuous, kilohertz-frequency-varying stimulation to assess its utility in controlling RGC activity.Approach.We usedin vitropatch-clamp experiments to assess electrically-evoked ON and OFF RGC responses to frequency-varying pulse train sequences. In each sequence, the stimulation amplitude was kept constant while the stimulation frequency (0.5-10 kHz) was changed every 40 ms, in either a linearly increasing, linearly decreasing or randomised manner. The stimulation amplitude across sequences was increased from 10 to 300µA.Main results.We found that continuous stimulation without rest periods caused complex and irreproducible stimulus-response relationships, primarily due to strong stimulus-induced response adaptation and influence of the preceding stimulus frequency on the response to a subsequent stimulus. In addition, ON and OFF populations showed different sensitivities to continuous, frequency-varying pulse trains, with OFF cells generally exhibiting more dependency on frequency changes within a sequence. Finally, the ability to maintain spiking behaviour to continuous stimulation in RGCs significantly reduced over longer stimulation durations irrespective of the frequency order.Significance.This study represents an important step in advancing and understanding the utility of continuous frequency modulation in controlling functionally distinct RGCs. Our results indicate that continuous, kHz-frequency-varying stimulation sequences provide very limited control of RGC firing patterns due to inter-dependency between adjacent frequencies and generally, different RGC types do not display different frequency preferences under such stimulation conditions. For future stimulation strategies using kHz frequencies, careful consideration must be given to design appropriate pauses in stimulation, stimulation frequency order and the length of continuous stimulation duration.

Probing the Contribution of Vertical Processing Layers of the Retina to White-Noise Electrical Stimulation Responses.

Optimal stimulus parameters for epiretinal prostheses have been investigated by analyzing retinal ganglion cell (RGC) spiking responses to white-noise electrical stimulation, through a spike-triggered average (STA) analysis technique. However, it is currently unknown as to activation of which retinal cells contribute to features of the STA. We conducted whole-cell patch clamping recordings in ON and OFF RGCs in response to white-noise epiretinal electrical stimulation by using different inhibitors of synaptic transmission in a healthy retina. An mGluR6 agonist, L-AP4, was firstly used to selectively block the output of photoreceptors (PRs) to ON bipolar cells (BCs). We subsequently fully blocked all synaptic inputs to RGCs using a combination of pharmacological agents. Our data shows that PRs dominate the ability of ON RGCs to integrate electrical pulses and form a unique STA shape, while BCs do not contribute in any way. In addition, our results demonstrate that the ability of OFF RGCs to integrate pulses is consistently impaired after blocking the PR to ON BC pathway. We hypothesise that the mechanisms underlying this co-effect are related to the narrow field AII amacrine cells connecting ON and OFF pathways.Clinical Relevance-Recent retinal studies recorded mirror-inverted STAs in ON and OFF retinal pathways, thus raising the possibility of designing a stimulation approach that can differentially activate ON and OFF pathways with electrical stimulation. However, the detailed contribution of three major retinal cell layers in forming characteristic STAs is still unclear. It is of great clinical relevance to investigate the isolated contribution of PRs to the electrically driven STA since PRs progressively degenerate in the course of retinal disease.

Modulating functionally-distinct vagus nerve fibers using microelectrodes and kilohertz frequency electrical stimulation.

Modulation of functionally distinct nerve fibers with bioelectronic devices provides a therapeutic opportunity for various diseases. In this study, we began by developing a computational model including four major subtypes of myelinated fibers and one unmyelinated fiber. Second, we used an intrafascicular electrode to perform kHz-frequency electric stimulation to preferentially modulate a population of fibers. Our model suggests that fiber physical properties and electrode-to-fascicle distance severely impacts stimulus-response relationships. Large diameter fibers (Aα- and Aß-) were only minimally influenced by the fascicle size and electrode location, while smaller diameter fibers (Aδ-, B- and C-) indicated a stronger dependency.Clinical Relevance- Our findings support the possibility of selectively modulating functionally-distinct nerve fibers using electrical stimulation in a small, localized region. Our model provides an effective tool to design next-generation implantable devices and therapeutic stimulation strategies toward minimizing off-target effects.

Development of a rabbit model of Adenosine triphosphate-induced monocular retinal degeneration for optimization of retinal prostheses.

Optimization of retinal prostheses requires preclinical animal models that mimic features of human retinal disease, have appropriate eye sizes to accommodate implantable arrays, and provide options for unilateral degeneration so as to enable a contralateral, within-animal control eye. In absence of a suitable non-human primate model and shortcomings of our previous feline model generated through intravitreal injections of Adenosine Triphosphate (ATP), we aimed in the present study to develop an ATP induced degeneration model in the rabbit. Six normally sighted Dutch rabbits were monocularly blinded with this technique. Subsequent retinal degeneration was assessed with optical coherence tomography, electroretinography, and histological assays. Overall, there was a 42% and 26% reduction in a-wave and oscillatory potential amplitudes in the electroretinograms respectively, along with a global decrease in retinal thickness, with increased variability. Qualitative inspection also revealed that there were variable levels of retinal degeneration and remodeling both within and between treated eyes, mimicking the disease heterogeneity observed in retinitis pigmentosa. These findings confirm that ATP can be utilized to unilaterally induce blinding in rabbits and, potentially present an ideal model for future cortical recording experiments aimed at optimizing vision restoration strategies.Clinical Relevance- A rapid, unilaterally induced model of retinal degeneration in an animal with low binocular overlap and large eyes will allow for clinically valid recordings of downstream cortical activity following retinal stimulation. Such a model would be highly beneficial for the optimization of clinically appropriate vision restoration approaches.

The direct influence of retinal degeneration on electrical stimulation efficacy: Significant implications for retinal prostheses.

Photoreceptor loss and inner retinal network remodeling severely impacts the ability of retinal prosthetic devices to create artificial vision. We developed a computational model of a degenerating retina based on rodent data and tested its response to retinal electrical stimulation. This model includes detailed network connectivity and diverse neural intrinsic properties, capable of exploring how the degenerated retina influences the performance of electrical stimulation during the degeneration process. Our model suggests the possibility of quantitatively modulating retinal ON and OFF pathways between phase II and III of retinal degeneration without requiring any differences between ON and OFF RGC intrinsic cellular properties. The model also provided insights about how remodeling events influence stage-dependent differential electrical responses of ON and OFF pathways.Clinical Relevance-This data-driven model can guide future development of retinal prostheses and stimulation strategies that may benefit patients at different stages of retinal disease progression, particularly in the early and mid-stages, thus increasing their global acceptance.

Loss of Müller cell glutamine synthetase immunoreactivity is associated with neuronal changes in late-stage retinal degeneration.

Introduction: A hallmark of photoreceptor degenerations is progressive, aberrant remodeling of the surviving retinal neurons and glia following photoreceptor loss. The exact relationship between neurons and glia remodeling in this late stage of retinal degeneration, however, is unclear. This study assessed this by examining Müller cell dysfunction via glutamine synthetase immunoreactivity and its spatial association with retinal neuron subpopulations through various cell markers. Methods: Aged Rd1 mice retinae (P150 - P536, n = minimum 5 per age) and control heterozygous rd1 mice retinae (P536, n = 5) were isolated, fixed and cryosectioned. Fluorescent immunolabeling of glutamine synthetase was performed and retinal areas quantified as having low glutamine synthetase immunoreactivity if proportion of labeled pixels in an area was less than two standard deviations of the mean of the total retina. Other Müller cell markers such as Sox9 and Glial fibrillary acidic protein along with neuronal cell markers Calbindin, Calretinin, recoverin, Protein kinase C-α, Glutamic acid decarboxylase 67, and Islet-1 were then quantified within areas of low and normal synthetase immunoreactivity. Results: Glutamine synthetase immunoreactivity was lost as a function of age in the rd1 mouse retina (P150 - P536). Immunoreactivity of other Müller cell markers, however, were unaffected suggesting Müller cells were still present in these low glutamine synthetase immunoreactive regions. Glutamine synthetase immunoreactivity loss affected specific neuronal populations: Type 2, Type 8 cone, and rod bipolar cells, as well as AII amacrine cells based on reduced recoverin, protein kinase Ca and parvalbumin immunoreactivity, respectively. The number of cell nuclei within regions of low glutamine synthetase immunoreactivity was also reduced suggesting possible neuronal loss rather than reduced cell marker immunoreactivity. Conclusion: These findings further support a strong interplay between glia-neuronal alterations in late-stage degeneration and highlight a need for future studies and consideration in intervention development.

Estimating Phosphene Locations Using Eye Movements of Suprachoroidal Retinal Prosthesis Users.

Purpose: Accurate mapping of phosphene locations from visual prostheses is vital to encode spatial information. This process may involve the subject pointing to evoked phosphene locations with their finger. Here, we demonstrate phosphene mapping for a retinal implant using eye movements and compare it with retinotopic electrode positions and previous results using conventional finger-based mapping. Methods: Three suprachoroidal retinal implant recipients (NCT03406416) indicated the spatial position of phosphenes. Electrodes were stimulated individually, and the subjects moved their finger (finger based) or their eyes (gaze based) to the perceived phosphene location. The distortion of the measured phosphene locations from the expected locations (retinotopic electrode locations) was characterized with Procrustes analysis. Results: The finger-based phosphene locations were compressed spatially relative to the expected locations all three subjects, but preserved the general retinotopic arrangement (scale factors ranged from 0.37 to 0.83). In two subjects, the gaze-based phosphene locations were similar to the expected locations (scale factors of 0.72 and 0.99). For the third subject, there was no apparent relationship between gaze-based phosphene locations and electrode locations (scale factor of 0.07). Conclusions: Gaze-based phosphene mapping was achievable in two of three tested retinal prosthesis subjects and their derived phosphene maps correlated well with the retinotopic electrode layout. A third subject could not produce a coherent gaze-based phosphene map, but this may have revealed that their phosphenes were indistinct spatially. Translational Relevance: Gaze-based phosphene mapping is a viable alternative to conventional finger-based mapping, but may not be suitable for all subjects.

Simulating the impact of photoreceptor loss and inner retinal network changes on electrical activity of the retina.

Objective.A major reason for poor visual outcomes provided by existing retinal prostheses is the limited knowledge of the impact of photoreceptor loss on retinal remodelling and its subsequent impact on neural responses to electrical stimulation. Computational network models of the neural retina assist in the understanding of normal retinal function but can be also useful for investigating diseased retinal responses to electrical stimulation.Approach.We developed and validated a biophysically detailed discrete neuronal network model of the retina in the software package NEURON. The model includes rod and cone photoreceptors, ON and OFF bipolar cell pathways, amacrine and horizontal cells and finally, ON and OFF retinal ganglion cells with detailed network connectivity and neural intrinsic properties. By accurately controlling the network parameters, we simulated the impact of varying levels of degeneration on retinal electrical function.Main results.Our model was able to reproduce characteristic monophasic and biphasic oscillatory patterns seen in ON and OFF neurons during retinal degeneration (RD). Oscillatory activity occurred at 3 Hz with partial photoreceptor loss and at 6 Hz when all photoreceptor input to the retina was removed. Oscillations were found to gradually weaken, then disappear when synapses and gap junctions were destroyed in the inner retina. Without requiring any changes to intrinsic cellular properties of individual inner retinal neurons, our results suggest that changes in connectivity alone were sufficient to give rise to neural oscillations during photoreceptor degeneration, and significant network connectivity destruction in the inner retina terminated the oscillations.Significance.Our results provide a platform for further understanding physiological retinal changes with progressive photoreceptor and inner RD. Furthermore, our model can be used to guide future stimulation strategies for retinal prostheses to benefit patients at different stages of disease progression, particularly in the early and mid-stages of RD.

A Second-Generation (44-Channel) Suprachoroidal Retinal Prosthesis: Long-Term Observation of the Electrode-Tissue Interface.

Purpose: To report the long-term observations of the electrode-tissue interface and perceptual stability in humans after chronic stimulation with a 44-channel suprachoroidal retinal implant. Methods: Four subjects (S1-4) with end-stage retinitis pigmentosa received the implant unilaterally (NCT03406416). Electrode impedances, electrode-retina distance (measured using optical coherence tomography imaging), and perceptual thresholds were monitored up to 181 weeks after implantation as the subjects used the prosthesis in the laboratory and in daily life. Stimulation charge density was limited to 32 µC/cm2 per phase. Results: Electrode impedances were stable longitudinally. The electrode-retina distances increased after surgery and then stabilized, and were well-described by an asymptotic exponential model. The stabilization of electrode-retina distances was variable between subjects, stabilizing after 45 weeks for S1, 63 weeks for S2, and 24 weeks for S3 (linear regression; Pgradient > 0.05). For S4, a statistically significant increase in electrode-retina distance persisted (P < 0.05), but by the study end point the rate of increase was clinically insignificant (exponential model: 0.33 µm/wk). Perceptual electrical thresholds were stable in one subject, decreased over time in two subjects (linear model; P < 0.05), and increased slightly in one subject but remained within the predefined charge limits (P = 0.02). Conclusions: Chronic stimulation with the suprachoroidal retinal prosthesis over 3 years resulted in stable impedances, small individual changes in perceptual electrical thresholds, and no clinically significant increase in electrode-retina distances after a period of settling after surgery. Translational Relevance: Chronic stimulation with the 44-channel suprachoroidal retinal implant with a charge density of up to 32 µC/cm2 per phase is suitable for long-term use in humans.

Anin-silicoanalysis of electrically evoked responses of midget and parasol retinal ganglion cells in different retinal regions.

Objective. Visual outcomes provided by present retinal prostheses that primarily target retinal ganglion cells (RGCs) through epiretinal stimulation remain rudimentary, partly due to the limited knowledge of retinal responses under electrical stimulation. Better understanding of how different retinal regions can be quantitatively controlled with high spatial accuracy, will be beneficial to the design of micro-electrode arrays and stimulation strategies for next-generation wide-view, high-resolution epiretinal implants.Approach. A computational model was developed to assess neural activity at different eccentricities (2 mm and 5 mm) within the human retina. This model included midget and parasol RGCs with anatomically accurate cell distribution and cell-specific morphological information. We then performedin silicoinvestigations of region-specific RGC responses to epiretinal electrical stimulation using varied electrode sizes (5-210µm diameter), emulating both commercialized retinal implants and recently developed prototype devices.Main results. Our model of epiretinal stimulation predicted RGC population excitation analogous to the complex percepts reported in human subjects. Following this, our simulations suggest that midget and parasol RGCs have characteristic regional differences in excitation under preferred electrode sizes. Relatively central (2 mm) regions demonstrated higher number of excited RGCs but lower overall activated receptive field (RF) areas under the same stimulus amplitudes (two-way analysis of variance (ANOVA),p< 0.05). Furthermore, the activated RGC numbers per unit active RF area (number-RF ratio) were significantly higher in central than in peripheral regions, and higher in the midget than in the parasol population under all tested electrode sizes (two-way ANOVA,p< 0.05). Our simulations also suggested that smaller electrodes exhibit a higher range of controllable stimulation parameters to achieve pre-defined performance of RGC excitation. An empirical model:I=a· exp (b·D) +cof the stimulus amplitude (I)-electrode diameter (D) relationship was constructed to achieve the pre-defined objective function values in different retinal regions, indicating the ability of controlling retinal outputs by fine-tuning the stimulation amplitude with different electrode sizes. Finally, our multielectrode simulations predicted differential neural crosstalk between adjacent electrodes in central temporal and peripheral temporal regions, providing insights towards establishing a non-uniformly distributed multielectrode array geometry for wide-view retinal implants.Significance.Stimulus-response properties in central and peripheral retina can provide useful information to estimate electrode parameters for region-specific activation by retinal stimulation. Our findings support the possibility of improving the performance of epiretinal prostheses by exploring the influence of electrode array geometry on activation of different retinal regions.

Classifying Retinal Degeneration in Histological Sections Using Deep Learning.

Purpose: Artificial intelligence (AI) techniques are increasingly being used to classify retinal diseases. In this study we investigated the ability of a convolutional neural network (CNN) in categorizing histological images into different classes of retinal degeneration. Methods: Images were obtained from a chemically induced feline model of monocular retinal dystrophy and split into training and testing sets. The training set was graded for the level of retinal degeneration and used to train various CNN architectures. The testing set was evaluated through the best architecture and graded by six observers. Comparisons between model and observer classifications, and interobserver variability were measured. Finally, the effects of using less training images or images containing half the presentable context were investigated. Results: The best model gave weighted-F1 scores in the range 85% to 90%. Cohen kappa scores reached up to 0.86, indicating high agreement between the model and observers. Interobserver variability was consistent with the model-observer variability in the model's ability to match predictions with the observers. Image context restriction resulted in model performance reduction by up to 6% and at least one training set size resulted in a model performance reduction of 10% compared to the original size. Conclusions: Detecting the presence and severity of up to three classes of retinal degeneration in histological data can be reliably achieved with a deep learning classifier. Translational Relevance: This work lays the foundations for future AI models which could aid in the evaluation of more intricate changes occurring in retinal degeneration, particularly in other types of clinically derived image data.

Laminin coated diamond electrodes for neural stimulation.

The performance of many implantable neural stimulation devices is degraded due to the loss of neurons around the electrodes by the body's natural biological responses to a foreign material. Coating of electrodes with biomolecules such as extracellular matrix proteins is one potential route to suppress the adverse responses that lead to loss of implant functionality. Concurrently, however, the electrochemical performance of the stimulating electrode must remain optimal to continue to safely provide sufficient charge for neural stimulation. We have previously found that oxygen plasma treated nitrogen included ultrananocrystalline diamond coated platinum electrodes exhibit superior charge injection capacity and electrochemical stability for neural stimulation (Sikder et al., 2019). To fabricate bioactive diamond electrodes, in this work, laminin, an extracellular matrix protein known to be involved in inter-neuron adhesion and recognition, was used as an example biomolecule. Here, laminin was covalently coupled to diamond electrodes. Electrochemical analysis found that the covalently coupled films were robust and resulted in minimal change to the charge injection capacity of diamond electrodes. The successful binding of laminin and its biological activity was further confirmed using primary rat cortical neuron cultures, and the coated electrodes showed enhanced cell attachment densities and neurite outgrowth. The method proposed in this work is versatile and adaptable to many other biomolecules for producing bioactive diamond electrodes, which are expected to show reduced the inflammatory responses in vivo.

A Computational Model of Functionally-distinct Cervical Vagus Nerve Fibers.

Cervical vagus nerve stimulation (VNS) is a neuromodulation therapy used in the treatment of several chronic disorders. In order to maximize the therapeutic effectiveness of VNS, it has become increasingly important to deliver fiber-specific neurostimulation, so that undesired effects can be minimized. Assessing the activation of different vagal fiber types through electrical stimulation is therefore essential for developing fiber-selective VNS therapies. Towards this goal, we conducted in silico investigations using a generic model of functionally distinct nerve fibers and clinically relevant cuff electrodes using COMSOL. Our model is constrained by histological observations from rat cervical vagus nerves and its outputs are validated against averaged compound nerve action potentials (CNAPs) obtained from rat vagus nerve recordings. We propose this model as an effective tool to design fiber-specific stimulation protocols before testing them in experimental animals.

Towards Controlling Functionally-Distinct Retinal Ganglion Cells In Degenerate Retina.

Present retinal neuroprostheses have limited performance capabilities due to indiscriminate activation of different neural pathways. Based on our success in differentially activating ON and OFF cells using high frequency stimuli in a healthy retina, in this study we explored whether we could achieve similar differential activation between these two cell types but in degenerate retina. We found that after blocking the synaptic network, ON retinal ganglion cells (RGCs) could be differentially activated at higher frequencies (4 - 6 kHz) and amplitudes (200 - 240 µA), and OFF RGCs at relatively lower amplitudes (80 - 160 µA) across all tested frequencies. We further found that both cell types could be controlled by quickly modulating the frequency using short stimulation bursts. This work takes us one step closer to reducing the likelihood of indiscriminate activation of RGCs by accurately controlling the activation of functionally-distinct neural pathways.

Creation of virtual channels in the retina using synchronous and asynchronous stimulation-a modelling study.

Objective.The spatial resolution of an implantable neural stimulator can be improved by creation of virtual channels (VCs). VCs are commonly achieved through synchronized stimulation of multiple electrodes. It remains unknown whether asynchronous stimulation is able to generate comparable VC performance in retinal stimulation, and how VC can be optimized by re-designing stimulation settings. This study begins with exploring the feasibility of creating VCs using synchronous and asynchronous epiretinal stimulation, and ending with predicting the possible VC performance with a thorough exploration of stimulation parameter space.Approach.A computational model of epiretinal dual-electrode stimulation is developed to simulate the neural activity of a population of retinal ganglion cells (RGCs) under both synchronous and asynchronous stimulation conditions. The interaction between the electrode and RGCs under a range of stimulation parameters are simulated.Main results.Our simulation based on direct RGC activation suggests that VCs can be created using asynchronous stimulation. Two VC performance measures: 1) linearity in the change in centroid location of activated RGC populations, and 2) consistency in the size of activated RGC populations, have comparable performance under asynchronous and synchronous stimulation with appropriately selected stimulation parameters.Significance.Our findings support the possibility of creating VCs by directly activating RGCs under synchronous and asynchronous stimulation conditions. This study establishes the fundamental capability of VC creation based on temporal interactions within the RGC population alone and does not include the effects of potential indirect activation of any surviving inner retinal network neurons. Our results provide theoretical evidence for designing next-generation retinal prosthesis with higher spatial resolution.

In vivo feasibility of epiretinal stimulation using ultrananocrystalline diamond electrodes.

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.

Tapping Into the Language of Touch: Using Non-invasive Stimulation to Specify Tactile Afferent Firing Patterns.

The temporal pattern of action potentials can convey rich information in a variety of sensory systems. We describe a new non-invasive technique that enables precise, reliable generation of action potential patterns in tactile peripheral afferent neurons by brief taps on the skin. Using this technique, we demonstrate sophisticated coding of temporal information in the somatosensory system, that shows that perceived vibration frequency is not encoded in peripheral afferents as was expected by either their firing rate or the underlying periodicity of the stimulus. Instead, a burst gap or silent gap between trains of action potentials conveys frequency information. This opens the possibility of new encoding strategies that could be deployed to convey sensory information using mechanical or electrical stimulation in neural prostheses and brain-machine interfaces, and may extend to senses beyond artificial encoding of aspects of touch. We argue that a focus on appropriate use of effective temporal coding offers more prospects for rapid improvement in the function of these interfaces than attempts to scale-up existing devices.

Neural activity of functionally different retinal ganglion cells can be robustly modulated by high-rate electrical pulse trains.

OBJECTIVE: This study focused on characterising the response of four major functionally-different retinal ganglion cells (RGCs) to a high frequency stimulus (HFS) paradigm. APPROACH: We used in vitro patch clamp experiments to assess the viability of evoking a differential response between different RGC types-OFF-Sustained, OFF-Transient, ON-Sustained and ON-Transient-under a wide range of HFS and stimulation amplitude combinations. MAIN RESULTS: Of the four types, we found that the OFF-Sustained, OFF-Transient and ON-Transient RGCs could be differentially activated at various frequency and amplitude combinations, in particular, OFF-Sustained cells can be differentially targeted between 20-100 µA at all frequencies, OFF-Transient cells between 150-240 µA at 1 kHz and ON-Transient between 180-240 µA and 4-6 kHz. We further found that this differential activation held true when the stimulus duration was reduced from 300 ms to 50 ms. Finally, we found that the cell spiking response was not primarily dependent on total charge contained in the pulse train or current amplitude alone, but a combination of amplitude and frequency. SIGNIFICANCE: These results indicate that HFS may be a promising method to target functionally-distinct neural pathways in the retina in an effort to improve the vision quality with retinal prostheses.