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The amyloid precursor protein (APP) is linked to the genetics and pathogenesis of Alzheimer's disease (AD). It is the parent protein of the β-amyloid (Aβ) peptide, the main constituent of the amyloid plaques found in an AD brain. The pathways from APP to Aβ are intensively studied, yet the normal functions of APP itself have generated less interest. We report here that glutamate stimulation of neuronal activity leads to a rapid increase inAppgene expression. In mouse and human neurons, elevated APP protein changes the structure of the axon initial segment (AIS) where action potentials are initiated. The AIS is shortened in length and shifts away from the cell body. The GCaMP8f Ca2+reporter confirms the predicted decrease in neuronal activity. NMDA antagonists or knockdown ofAppblock the glutamate effects. The actions of APP on the AIS are cell-autonomous; exogenous Aβ, either fibrillar or oligomeric, has no effect. In culture, APPSwe(a familial AD mutation) induces larger AIS changes than wild type APP. Ankyrin G and βIV-spectrin, scaffolding proteins of the AIS, both physically associate with APP, more so in AD brains. Finally, in humans with sporadic AD or in the R1.40 AD mouse model, both females and males, neurons have elevated levels of APP protein that invade the AIS.In vivoasin vitro, this increased APP is associated with a significant shortening of the AIS. The findings outline a new role for the APP and encourage a reconsideration of its relationship to AD.SIGNIFICANCE STATEMENTWhile the amyloid precursor protein (APP) has long been associated with Alzheimer's disease (AD), the normal functions of the full-length Type I membrane protein have been largely unexplored. We report here that the levels of APP protein increase with neuronal activity.In vivoandin vitro, modest amounts of excess APP alter the properties of the axon initial segment. The β-amyloid peptide derived from APP is without effect. Consistent with the observed changes in the axon initial segment which would be expected to decrease action potential firing, we show that APP expression depresses neuronal activity. In mouse AD models and human sporadic AD, APP physically associates with the scaffolding proteins of the axon initial segment, suggesting a relationship with AD dementia.

Optical flow is a crucial component of the feature space for early visual processing of dynamic scenes especially in new applications such as self-driving vehicles, drones and autonomous robots. The dynamic vision sensors are well suited for such applications because of their asynchronous, sparse and temporally precise representation of the visual dynamics. Many algorithms proposed for computing visual flow for these sensors suffer from the aperture problem as the direction of the estimated flow is governed by the curvature of the object rather than the true motion direction. Some methods that do overcome this problem by temporal windowing under-utilize the true precise temporal nature of the dynamic sensors. In this paper, we propose a novel multi-scale plane fitting based visual flow algorithm that is robust to the aperture problem and also computationally fast and efficient. Our algorithm performs well in many scenarios ranging from fixed camera recording simple geometric shapes to real world scenarios such as camera mounted on a moving car and can successfully perform event-by-event motion estimation of objects in the scene to allow for predictions of upto 500 ms i.e. equivalent to 10 to 25 frames with traditional cameras., Pre-print version, 12 pages, 12 figures. Accepted in IEEE tPAMI July 2020

Event-based vision sensors produce asynchronous event streams with high temporal resolution based on changes in the visual scene. The properties of these sensors allow for accurate and fast calculation of optical flow as events are generated. Existing solutions for calculating optical flow from event data either fail to capture the true direction of motion due to the aperture problem, do not use the high temporal resolution of the sensor, or are too computationally expensive to be run in real time on embedded platforms. In this research, we first present a faster version of our previous algorithm, ARMS (Aperture Robust Multi-Scale flow). The new optimized software version (fARMS) significantly improves throughput on a traditional CPU. Further, we present hARMS, a hardware realization of the fARMS algorithm allowing for real-time computation of true flow on low-power, embedded platforms. The proposed hARMS architecture targets hybrid system-on-chip devices and was designed to maximize configurability and throughput. The hardware architecture and fARMS algorithm were developed with asynchronous neuromorphic processing in mind, abandoning the common use of an event frame and instead operating using only a small history of relevant events, allowing latency to scale independently of the sensor resolution. This change in processing paradigm improved the estimation of flow directions by up to 73% compared to the existing method and yielded a demonstrated hARMS throughput of up to 1.21 Mevent/s on the benchmark configuration selected. This throughput enables real-time performance and makes it the fastest known realization of aperture-robust, event-based optical flow to date., 18 pages, 16 figures, 4 tables

Restoring vision using optogenetics is an ideal medical application because the eye offers a direct window to access and stimulate the pathological area: the retina. Optogenetic therapy could be applied to diseases with photoreceptor degeneration such as retinitis pigmentosa. Here, we select the specific optogenetic construct that is now used in the clinical trial and assess the opsin functional efficacy on non-human primate’s retinal ganglion cells (RGCs).We chose the microbial opsin ChrimsonR and showed that the vector AAV2.7m8 produced greater transfection in RGCs compared to AAV2, and that ChrimsonR attached to tdTomato (ChR-tdT) is more efficiently expressed than ChrimsonR. The 600 nm light activates the RGCs transfected with the vector AAV2.7m8-ChR-tdT from an irradiance of 1015 photons.cm-2.s-1. Vector doses of 5.1010 and 5.1011 vg/eye transfect up to 7000 RGCs/mm2 in the perifovea, with no significant immune reaction. Furthermore, using a multielectrode array we recorded RGCs responses starting from 1ms stimulus duration. Using the recorded activity we were able to decode stimulus information and estimate a theoretical visual acuity of 20/249, above legal blindness. Altogether, our results pave the way for the ongoing clinical trial with the AAV2.7m8-ChrimsonR-tdT vector for vision restoration in patients affected by retinitis pigmentosa.One Sentence SummaryWe select here the vector and genetic construct best suited to provide vision restoration in patients suffering from retinopathies, we demonstrate temporal resolution compatible with high dynamic visual scenes and a visual acuity above legal blindness.

Vision restoration is an ideal medical application for optogenetics, because the eye provides direct optical access to the retina for stimulation. Optogenetic therapy could be used for diseases involving photoreceptor degeneration, such as retinitis pigmentosa or age-related macular degeneration. We describe here the selection, in non-human primates, of a specific optogenetic construct currently tested in a clinical trial. We used the microbial opsin ChrimsonR, and showed that the AAV2.7m8 vector had a higher transfection efficiency than AAV2 in retinal ganglion cells (RGCs) and that ChrimsonR fused to tdTomato (ChR-tdT) was expressed more efficiently than ChrimsonR. Light at 600 nm activated RGCs transfected with AAV2.7m8 ChR-tdT, from an irradiance of 1015 photons.cm−2.s−1. Vector doses of 5 × 1010 and 5 × 1011 vg/eye transfected up to 7000 RGCs/mm2 in the perifovea, with no significant immune reaction. We recorded RGC responses from a stimulus duration of 1 ms upwards. When using the recorded activity to decode stimulus information, we obtained an estimated visual acuity of 20/249, above the level of legal blindness (20/400). These results lay the groundwork for the ongoing clinical trial with the AAV2.7m8 - ChR-tdT vector for vision restoration in patients with retinitis pigmentosa., Gauvain et al demonstrate that optogenetic therapy using the AAV2.7m8- ChR-tdT construct can partially restore vision in non-human primates to levels above those considered legally-blind. This study enables the identification of the most suitable construct for ongoing clinical trials attempting vision restoration in patients with retinitis pigmentosa.

This letter introduces a study to precisely measure what an increase in spike timing precision can add to spike-driven pattern recognition algorithms. The concept of generating spikes from images by converting gray levels into spike timings is currently at the basis of almost every spike-based modeling of biological visual systems. The use of images naturally leads to generating incorrect artificial and redundant spike timings and, more important, also contradicts biological findings indicating that visual processing is massively parallel, asynchronous with high temporal resolution. A new concept for acquiring visual information through pixel-individual asynchronous level-crossing sampling has been proposed in a recent generation of asynchronous neuromorphic visual sensors. Unlike conventional cameras, these sensors acquire data not at fixed points in time for the entire array but at fixed amplitude changes of their input, resulting optimally sparse in space and time—pixel individually and precisely timed only if new, (previously unknown) information is available (event based). This letter uses the high temporal resolution spiking output of neuromorphic event-based visual sensors to show that lowering time precision degrades performance on several recognition tasks specifically when reaching the conventional range of machine vision acquisition frequencies (30–60 Hz). The use of information theory to characterize separability between classes for each temporal resolution shows that high temporal acquisition provides up to 70% more information that conventional spikes generated from frame-based acquisition as used in standard artificial vision, thus drastically increasing the separability between classes of objects. Experiments on real data show that the amount of information loss is correlated with temporal precision. Our information-theoretic study highlights the potentials of neuromorphic asynchronous visual sensors for both practical applications and theoretical investigations. Moreover, it suggests that representing visual information as a precise sequence of spike times as reported in the retina offers considerable advantages for neuro-inspired visual computations.

Brain 31P-neurometabolites play an important role in energy and membrane metabolism. Unambiguous identification and quantification of these neurochemicals in different brain regions would be a great aid in advancing the understanding of metabolic processes in the nervous system. Phosphomonoester (PME), consisting of phosphoethanolamine (PE) and phosphocholine (PC), is the “building block” for membranes, while phosphodiesters (PDE), consisting of glycerophosphocholine (GPC) and glycerophosphoethanolamine (GPE) metabolites are involved in the membrane breakdown process. In the clinical setting, generating well-resolved spectra for PC, PE, GPC, and GPE could be crucial phospholipids in providing information regarding membrane metabolism. We present here a new experimental approach for generating well-resolved 31P spectra for PC and PE as well as for GPC, GPE, and other 31P metabolites. Our results (based on uni-dimensional (1D) and multi-voxel 31P studies) indicate that an intermediate excitation pulse angle (35°) is best suited to obtain well-resolved PC/PE and GPC/GPE resonance peaks. Our novel signal processing scheme allows generating metabolite maps of different phospholipids include PC/PE and GPC/GPE using the ‘time-domain–frequency-domain’ method as referred to in the MATLAB programming language.

The emergence of Address-Event Representation (AER) as a general communications method across a large variety of neural devices suggests that they might be made interoperable. If there were a standard AER interface, systems could communicate using native AER signalling, allowing the construction of large-scale, real-time, heterogeneous neural systems. We propose a transport-agnostic AER protocol that permits direct bidirectional event communications between systems over Ethernet, and demonstrate practical implementations that connect a neuromimetic chip: SpiNNaker, both to standard host PCs and to real-time robotic systems. The protocol specifies a header and packet format that supports a variety of different possible packet types while coping with questions of data alignment, time sequencing, and packet compression. Such a model creates a flexible solution either for real-time communications between neural devices or for live spike I/O and visualisation in a host PC. With its standard physical layer and flexible protocol, the specification provides a prototype for AER protocol standardisation that is at once compatible with legacy systems and expressive enough for future very-large-scale neural systems.

Brain (31)P-neurometabolites play an important role in energy and membrane metabolism. Unambiguous identification and quantification of these neurochemicals in different brain regions would be a great aid in advancing the understanding of metabolic processes in the nervous system. Phosphomonoester (PME), consisting of phosphoethanolamine (PE) and phosphocholine (PC), is the "building block" for membranes, while phosphodiesters (PDE), consisting of glycerophosphocholine (GPC) and glycerophosphoethanolamine (GPE) metabolites are involved in the membrane breakdown process. In the clinical setting, generating well-resolved spectra for PC, PE, GPC, and GPE could be crucial phospholipids in providing information regarding membrane metabolism. We present here a new experimental approach for generating well-resolved (31)P spectra for PC and PE as well as for GPC, GPE, and other (31)P metabolites. Our results (based on uni-dimensional (1D) and multi-voxel (31)P studies) indicate that an intermediate excitation pulse angle (35°) is best suited to obtain well-resolved PC/PE and GPC/GPE resonance peaks. Our novel signal processing scheme allows generating metabolite maps of different phospholipids include PC/PE and GPC/GPE using the 'time-domain-frequency-domain' method as referred to in the MATLAB programming language.

This paper deals with the optimal design and control of an exoskeleton robot. First, the motion data from the thumb of a normal subject was captured by a vision system. As the human finger joints cannot be modeled by single revolute joints due to changing instantaneous centre of rotation, we have used 4-bar mechanisms to model each joint. Optimal 4-bars have been designed using genetic algorithms, by minimizing the error between a coupler point and points traced by the finger links. It is shown that the designed 4-bars can accurately track the motion of the human fingers. The exoskeleton is controlled by using the EMG signals obtained from the subject's muscles. The relation between the EMG and finger motion is first learned, using a neural net. Based on the learned parameters, the subjects EMG signal is used to control a simulation of the exoskeleton joint motion.

This paper deals with the optimal design and control of an exoskeletal robot. First, the motion data from the fingers of a normal subject was captured by a vision system. As the human finger joints cannot be modeled by single revolute joints due to changing instantaneous centre of rotation, we have used 4-bar mechanisms to model each joint. Optimal 4-bars have been designed using genetic algorithms, by minimizing the error between a coupler point and points traced by the finger links. It is shown that the designed 4-bars can accurately track the motion of the human fingers. The exoskeleton is controlled by using the EMG signals obtained from the subject's muscles. The relation between the EMG and finger motion is first learned, using a neural net. Based on the learned parameters, the subjects EMG signal is used to control a simulation of the exoskeleton joint motion. A comparison between Recurrent Neural Network and Multi Layer Perceptron for classifying and mapping the EMG to finger position was also carried out.

Retinal dystrophies and age-related macular degeneration related to photoreceptor degeneration can cause blindness. In blind patients, although the electrical activation of the residual retinal circuit can provide useful artificial visual perception, the resolutions of current retinal prostheses have been limited either by large electrodes or small numbers of pixels. Here we report the evaluation, in three awake non-human primates, of a previously reported near-infrared-light-sensitive photovoltaic subretinal prosthesis. We show that multipixel stimulation of the prosthesis within radiation safety limits enabled eye tracking in the animals, that they responded to stimulations directed at the implant with repeated saccades and that the implant-induced responses were present two years after device implantation. Our findings pave the way for the clinical evaluation of the prosthesis in patients affected by dry atrophic age-related macular degeneration. A near-infrared-light-sensitive photovoltaic subretinal prosthesis triggers behavioural responses in awake macaques, even two years after device implantation.