Background: Carbon fiber microelectrodes are promising for long-term neural interfaces due to their small size and mechanical compatibility with brain tissue. However, they typically require functional coatings to achieve the electrochemical performance necessary for high-fidelity recording and effective stimulation. Twodimensional MXenes exhibit exceptional electrical properties for neural interfaces, but existing fabrication methods are often complex and hinder translation. Results: Here, we introduce a novel, simplified approach that employs MXene as a counter-ion dopant for in-situ PEDOT polymerization directly on carbon fibers. This MXene-PEDOT composite coating simultaneously reduces electrochemical impedance and significantly enhances charge injection capacity compared to standard PEDOT: PSS. We demonstrate the functional efficacy of these MXene-doped microelectrodes through ex vivo stimulation of retinal ganglion cells and in vivo cortical recording with high signal-to-noise ratios, while also confirming their in vitro biocompatibility. Significance: This work establishes a straightforward method to leverage the advantages of both carbon fibers and MXene for neural interfaces, creating a unified coating that advances both recording and stimulation capabilities for next-generation dual functional neural interfaces.

Millions of adults worldwide experience severe visual impairment due to photoreceptor loss from retinal diseases such as retinitis pigmentosa and macular degeneration. Retinal prostheses that provide artificial vision by stimulating the surviving retinal ganglion cells (RGCs) have emerged as a promising therapy. However, all clinically approved retinal prostheses that use electrical stimulation face the issue of electrical spread. As such, no device has been able to provide vision restoration beyond the threshold of legal blindness. Optogenetic approaches provide greater spatial precision, however, they have poor temporal fidelity compared to electrical stimulation. Questions remain over the safety of the high intensity light required. Here, we developed an opto-electrical hybrid approach that reduced optogenetic activation thresholds and increased the high frequency sensitivity of opsin expressing RGCs. Our findings suggest that incorporating hybrid stimulation in future retinal prostheses could dramatically improve high resolution vision.

Orientation selectivity is a prominent feature of neurons in the mammalian primary visual cortex (V1), yet its emergence along the visual pathway varies across species. In carnivores and primates, neurons with elongated and orientation-selective receptive fields (RFs) emerge in V1, whereas in mice such RFs appear earlier, in the retina or dorsal lateral geniculate nucleus (dLGN). Here, we investigate the RF properties of neurons in the dLGN of a marsupial, the wallaby ( Macropus eugenii) (N=2; Males), using multi-channel electrodes and nonlinear input model (NIM) analysis. Do dLGN RFs resemble those of carnivores and primates or exhibit unique characteristics, particularly regarding orientation selectivity? We found that 82% of neurons have a predominant ON-center response. We identified two main cell types: X-cells (N=15/22), which exhibit linear properties, and Y-cells (N=7/22), which display nonlinear characteristics. Most dLGN RFs were blob-like and lacked the oriented structures seen in cortical neurons but some had slightly elongated central areas. These results indicate that robust orientation selectivity develops fully in V1 (76% of neurons). However, mild orientation biases were observed in 41% of dLGN neurons. This study enhances our understanding of visual processing in marsupials and underscores the evolutionary significance of orientation selectivity in mammalian visual pathways.

The increasing prevalence of neurological and psychiatric diseases, such as Alzheimer disease and schizophrenia, necessitates the development of new research tools to investigate these diseases and develop effective treatments. Thus, in vitro brain models, such as brain-on-a-chip devices, have been developed to mimic in vivo biochemical and mechanobiological interactions and to monitor their electrochemical activity. In this Review, we discuss the technologies to build complex brain models. We discuss progress in microfluidic and semiconductor-based technologies that facilitate in vitro modelling of the blood–brain barrier and neuronal circuits to study pathophysiological processes. We further discuss advances in 3D tissue engineering, electrode strategies and materials that, when combined, could allow simulation of the native complexity of brain regions and the interrogation of their activity at cellular length scales. Furthermore, we explore the engineering challenges and opportunities for complex physiologically relevant brain-on-a-chip devices and their future progress. Brain-on-a-chip models, mimicking brain physiology, hold promise for developing treatments for neurological disorders. This Review discusses the engineering challenges and opportunities for these devices, including the integration of 3D cell cultures and electrodes and scaffold engineering strategies.

Objective: Neurons in primary visual cortex (V1) display a range of sensitivity in their response to translations of their preferred visual features within their receptive field: from high specificity to a precise position through to complete invariance. This visual feature selectivity and invariance is frequently modeled by applying a selection of linear spatial filters to the input image, that define the feature selectivity, followed by a nonlinear function that combines the filter outputs, that defines the invariance, to predict the neural response. We compare two such classes of model, that are both popular and parsimonious, the generalized quadratic model (GQM) and the nonlinear input model (NIM). These two classes of model differ primarily in that the NIM can accommodate a greater diversity in the form of nonlinearity that is applied to the outputs of the filters. Approach: We compare the two model types by applying them to data from multielectrode recordings from cat primary visual cortex in response to spatially white Gaussian noise After fitting both classes of model to a database of 342 single units (SUs), we analyze the qualitative and quantitative differences in the visual feature processing performed by the two models and their ability to predict neural response. Main results: We find that the NIM predicts response rates on a held-out data at least as well as the GQM for 95% of SUs. Superior performance occurs predominantly for those units with above average spike rates and is largely due to the NIMs ability to capture aspects of the model's nonlinear function cannot be captured with the GQM rather than differences in the visual features being processed by the two different models. Significance: These results can help guide model choice for data-driven receptive field modelling.

A fundamental question in sensory neuroscience revolves around how neurons represent complex visual stimuli. In mammalian primary visual cortex (V1), neurons decode intricate visual features to identify objects, with most being selective for edge orientation, but with half of those also developing invariance to edge position within their receptive fields. Position invariance allows cells to continue to code an edge even when it moves around. Combining feature selectivity and invariance is integral to successful object recognition. Considering the marsupial-eutherian divergence 160 million years ago, we explored whether feature selectivity and invariance was similar in marsupials and eutherians. We recovered the spatial filters and non-linear processing characteristics of the receptive fields of neurons in wallaby V1 and compared them with previous results from cat cortex. We stimulated the neurons in V1 with white Gaussian noise and analysed responses using the non-linear input model. Wallabies exhibit the same high percentage of orientation selective neurons as cats. However, in wallabies we observed a notably higher prevalence of neurons with three or more filters compared to cats. We show that having three or more filters substantially increases phase invariance in the V1s of both species, but that wallaby V1 accentuates this feature, suggesting that the species condenses more processing into the earliest cortical stage. These findings suggest that evolution has led to more than one solution to the problem of creating complex visual processing strategies. KEY POINTS: Previous studies have shown that the primary visual cortex (V1) in mammals is essential for processing complex visual stimuli, with neurons displaying selectivity for edge orientation and position. This research explores whether the visual processing mechanisms in marsupials, such as wallabies, are similar to those in eutherian mammals (e.g. cats). The study found that wallabies have a higher prevalence of neurons with multiple spatial filters in V1, indicating more complex visual processing. Using a non-linear input model, we demonstrated that neurons with three or more filters increase phase invariance. These findings suggest that marsupials and eutherian mammals have evolved similar strategies for visual processing, but marsupials have condensed more capacity to build phase invariance into the first step in the cortical pathway.

Degeneration of photoreceptors in the retina is a leading cause of blindness, but commonly leaves the retinal ganglion cells (RGCs) and/or bipolar cells extant. Consequently, these cells are an attractive target for the invasive electrical implants colloquially known as “bionic eyes.” However, after more than two decades of concerted effort, interfaces based on conventional electrical stimulation approaches have delivered limited efficacy, primarily due to the current spread in retinal tissue, which precludes high-acuity vision. The ideal prosthetic solution would be less invasive, provide single-cell resolution and an ability to differentiate between different cell types. Nanoparticle-mediated approaches can address some of these requirements, with particular attention being directed at light-sensitive nanoparticles that can be accessed via the intrinsic optics of the eye. Here we survey the available known nanoparticle-based optical transduction mechanisms that can be exploited for neuromodulation. We review the rapid progress in the field, together with outstanding challenges that must be addressed to translate these techniques to clinical practice. In particular, successful translation will likely require efficient delivery of nanoparticles to stable and precisely defined locations in the retinal tissues. Therefore, we also emphasize the current literature relating to the pharmacokinetics of nanoparticles in the eye. While considerable challenges remain to be overcome, progress to date shows great potential for nanoparticle-based interfaces to revolutionize the field of visual prostheses.

Clinical trials previously demonstrated the notable capacity to elicit visual percepts in blind patients affected with retinal diseases by electrically stimulating the remaining neurons on the retina. However, these implants restored very limited visual acuity and required transcutaneous cables traversing the eyeball, leading to reduced reliability and complex surgery with high postoperative infection risks. To overcome the limitations imposed by cables, a retinal implant architecture in which near-infrared illumination carries both power and data through the pupil to a digital stimulation controller is presented. A high efficiency multi-junction photovoltaic cell transduces the optical power to a CMOS stimulator capable of delivering flexible interleaved sequential stimulation through a diamond microelectrode array. To demonstrate the capacity to elicit a neural response with this approach while complying with the optical irradiance limit at the pupil, fluorescence imaging with a calcium indicator is used on a degenerate rat retina. The power delivered by the laser at the permissible irradiance of 4 mW/mm2 at 850 nm is shown to be sufficient to both power the stimulator ASIC and elicit a response in retinal ganglion cells (RGCs), with the ability to generate of up to 35 000 pulses per second at the average stimulation threshold. This confirms the feasibility of generating a response in RGCs with an infrared-powered digital architecture capable of delivering complex sequential stimulation patterns at high repetition rates, albeit with some limitations.

This study demonstrates the control of neuronal survival and development using nitrogen-doped ultrananocrystalline diamond (N-UNCD). We highlight the role of N-UNCD in regulating neuronal activity via near-infrared illumination, demonstrating the generation of stable photocurrents that enhance neuronal survival and neurite outgrowth and foster a more active, synchronized neuronal network. Whole transcriptome RNA sequencing reveals that diamond substrates improve cellular-substrate interaction by upregulating extracellular matrix and gap junction-related genes. Our findings underscore the potential of conductive diamond as a robust and biocompatible platform for noninvasive and effective neural tissue engineering.

Extracellular recordings were made from 642 units in the primary visual cortex (V1) of a highly visual marsupial, the Tammar wallaby. The receptive field (RF) characteristics of the cells were objectively estimated using the non-linear input model (NIM), and these were correlated with spike shapes. We found that wallaby cortical units had 68% regular spiking (RS), 12% fast spiking (FS), 4% triphasic spiking (TS), 5% compound spiking (CS) and 11% positive spiking (PS). RS waveforms are most often associated with recordings from pyramidal or spiny stellate cell bodies, suggesting that recordings from these cell types dominate in the wallaby cortex. In wallaby, 70–80% of FS and RS cells had orientation selective RFs and had evenly distributed linear and nonlinear RFs. We found that 47% of wallaby PS units were non-orientation selective and they were dominated by linear RFs. Previous studies suggest that the PS units represent recordings from the axon terminals of non-orientation selective cells originating in the lateral geniculate nucleus (LGN). If this is also true in wallaby, as strongly suggested by their low response latencies and bursty spiking properties, the results suggest that significantly more neurons in wallaby LGN are already orientation selective. In wallaby, less than 10% of recorded spikes had triphasic (TS) or sluggish compound spiking (CS) waveforms. These units had a mixture of orientation selective and non-oriented properties, and their cellular origins remain difficult to classify.

Computational modeling helps neuroscientists to integrate and explain experimental data obtained through neurophysiological and anatomical studies, thus providing a mechanism by which we can better understand and predict the principles of neural computation. Computational modeling of the neuronal pathways of the visual cortex has been successful in developing theories of biological motion processing. This review describes a range of computational models that have been inspired by neurophysiological experiments. Theories of local motion integration and pattern motion processing are presented, together with suggested neurophysiological experiments designed to test those hypotheses.

Optogenetics gives us unprecedented power to investigate brain connectivity. The ability to activate neural circuits with single cell resolution and its ease of application has provided a wealth of knowledge in brain function. More recently, optogenetics has shown tremendous utility in prosthetics applications, including vision restoration for patients with retinitis pigmentosa. One of the disadvantages of optogenetics, however, is its poor temporal bandwidth, i.e. the cell’s inability to fire at a rate that matches the optical stimulation rate at high frequencies (>30 Hz). This research proposes a new strategy to overcome the temporal limits of optogenetic stimulation. Using whole-cell current clamp recordings in mouse retinal ganglion cells expressing channelrhodopsin-2 (H134R variant), we observed that randomizing inter-pulse intervals can significantly increase a retinal ganglion cell’s temporal response to high frequency stimulation.Clinical Relevance— A significant disadvantage of optogenetic stimulation is its poor temporal dynamics which prohibit its widespread use in retinal prosthetics. We have shown that randomizing the interval between stimulation pulses reduces adaptation in retinal ganglion cells. This stimulation strategy may contribute to new levels of functional restoration in therapeutics which incorporate optogenetics.

The vision of patients rendered blind by photoreceptor degeneration can be partially restored by exogenous stimulation of surviving retinal ganglion cells (RGCs). Whereas conventional electrical stimulation techniques have failed to produce naturalistic visual percepts, nanoparticle-based optical sensors have recently received increasing attention as a means to artificially stimulate the RGCs. In particular, nanoparticle-enhanced infrared neural modulation (NINM) is a plasmonically mediated photothermal neuromodulation technique that has a demonstrated capacity for both stimulation and inhibition, which is essential for the differential modulation of ON-type and OFF-type RGCs. Gold nanorods provide tunable absorption through the near-infrared wavelength window, which reduces interference with any residual vision. Therefore, NINM may be uniquely well-suited to retinal prosthesis applications but, to our knowledge, has not previously been demonstrated in RGCs. In the present study, NINM laser pulses of 100 μs, 500 μs and 200 ms were applied to RGCs in explanted rat retinae, with single-cell responses recorded via patch-clamping. The shorter laser pulses evoked robust RGC stimulation by capacitive current generation, while the long laser pulses are capable of inhibiting spontaneous action potentials by thermal block. Importantly, an implicit bias toward OFF-type inhibition is observed, which may have important implications for the feasibility of future high-acuity retinal prosthesis design based on nanoparticle sensors.

Neural interfaces are well-established as a tool to understand the behaviour of the nervous system via recording and stimulation of living neurons, as well as serving as neural prostheses. Conventional neural interfaces based on metals and carbon-based materials are generally optimised for high conductivity; however, a mechanical mismatch between the interface and the neural environment can significantly reduce long-term neuromodulation efficacy by causing an inflammatory response. This paper presents a soft composite material made of gelatin methacryloyl (GelMA) containing graphene oxide (GO) conjugated with gold nanorods (AuNRs). The soft hydrogel presents stiffness within the neural environment range of modulus below 5 kPa, while the AuNRs, when exposed to light in the near infrared range, provide a photothermal response that can be used to improve the spatial and temporal precision of neuromodulation. These favourable properties can be maintained at safer optical power levels when combined with electrical stimulation. In this paper we provide mechanical and biological characterization of the optical activity of the GO-AuNR composite hydrogel. The optical functionality of the material has been evaluated via photothermal stimulation of explanted rat retinal tissue. The outcomes achieved with this study encourage further investigation into optical and electrical costimulation parameters for a range of biomedical applications.

Excitation using surface acoustic waves (SAW) has demonstrated efficacy in improving microscale particle/chemical transport due to its ability to generate microscale wavelengths. However, the effects of acoustic stimulation on transport processes along the length of sub-wavelength microchannels and their underlying mechanisms, essential for long-range transport, have not been examined in detail. In this work, we investigate diffusion along the length of subwavelength microchannels using experimental and simulation approaches, demonstrating enhanced transport under SAW excitation. The microchannel-based enhanced diffusion mechanisms are further studied by investigating the acoustic pressure and streaming fields, finding that the degree of enhancement is a function of applied power, microchannel dimensions, and viscosity. This microchannel-based diffusion enhancement approach is applicable to microfluidic and biomedical microscale transport enhancement, with the findings here being relevant to acoustic-based micro-mixing and neurodegenerative therapies.

Primary visual cortices in many mammalian species exhibit modular and periodic orientation preference maps arranged in pinwheel-like layouts. The role of inherited traits as opposed to environmental influences in determining this organization remains unclear. Here, we characterize the cortical organization of an Australian marsupial, revealing pinwheel organization resembling that of eutherian carnivores and primates but distinctly different from the simpler salt-and-pepper arrangement of eutherian rodents and rabbits. The divergence of marsupials from eutherians 160 million years ago and the later emergence of rodents and rabbits suggest that the salt-and-pepper structure is not the primitive ancestral form. Rather, the genetic code that enables complex pinwheel formation is likely widespread, perhaps extending back to the common therian ancestors of modern mammals.

Background The aim of this work is to profile the ocular health and sociodemographic characteristics of Australian College of Optometry service users of all ages and to explore the relationships between key sociodemographic characteristics and eye health. Methods For 3093 eye examinations, best-corrected distance visual acuity and mean spherical equivalent refractive error were tested non-parametrically by clinic category, remoteness area, number of co-morbidities, gender and indigenous status, also correlated against age and socioeconomic advantage/disadvantage. Covariates of interest were entered into linear mixed models of visual acuity and mean spherical equivalent refractive error, controlling for age. Risk estimates are reported for visual impairment (defined as <= 6/12 best-corrected distance visual acuity in one or both eyes) and ocular diagnoses. Results Visual impairment is more prevalent amongst service users examined in domiciliary settings. Increasing co-morbidities were associated with poorer best-corrected distance visual acuity. Aboriginal and Torres Strait Islander service users had lower visual impairment prevalence overall but proportionally fewer aged >= 50 years attended for eye care, compared to non-indigenous. Conclusions Domiciliary eye examinations detect remediable visual impairment. Federal public health interventions delivered by the Australian College of Optometry for Aboriginal and Torres Strait Islander eye care appear effective but may not reach all aged >= 50 years; further research is required. Identification of multiple co-morbidities should prompt optometrists to tailor public health messages and signpost to low vision services earlier.