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Single administration of low-dose ketamine has both acute and sustained anti-depressant effects. Sustained effect is associated with restoration of glutamatergic synapses in medial prefrontal cortic (mFPC) neurons. Ketamine induced profound changes in a number of molecular pathways in a mouse model for chronic stress. Cell-cell communication analyses predicted that planar-cell-polarity (PCP) signaling was decreased after chronic administration of corticosterone but increased following ketamine administration in most of the excitatory neurons. Similar decrease of PCP signaling in excitatory neurons was predicted in dorsolateral prefrontal cortical (dl-PFC) neurons of patients with major depressive disorder (MDD). We showed that the basolateral amygdala (BLA)-projecting infralimbic prefrontal cortex (IL PFC) neurons regulate immobility time in the tail suspension test and food consumption. Conditionally knocking out Celsr2 and Celsr3 or Prickle2 in the BLA-projecting IL PFC neurons abolished ketamine-induced synapse restoration and behavioral remission. Therefore, PCP proteins in IL PFC-BLA neurons mediate synapse restoration induced by of low-dose ketamine.

There are known individual differences in both the ability to learn the layout of novel environments and the flexibility of strategies for navigating known environments. However, it is unclear how navigational abilities are impacted by high-stress scenarios. Here we used immersive virtual reality (VR) to develop a novel behavioral paradigm to examine navigation under dynamically changing situations. We recruited 48 participants (24 female; ages 17-32) to navigate a virtual maze (7.5 m × 7.5 m). Participants learned the maze by moving along a fixed path past the mazes landmarks (paintings). Subsequently, participants experienced either a non-stress condition, or a high-stress condition tasking them with navigating the maze. In the high-stress condition, their initial path was blocked, the environment was darkened, threatening music was played, fog obstructed more distal views of the environment, and participants were given a time limit of 20 s with a countdown timer displayed at the top of their screen. On trials where the path was blocked, we found self-reported stress levels and distance traveled increased while trial completion rate decreased (as compared to non-stressed control trials). On unblocked stress trials, participants were less likely to take a shortcut and consequently navigated less efficiently compared to control trials. Participants with more trait spatial anxiety reported more stress and navigated less efficiently. Overall, our results suggest that navigational abilities change considerably under high-stress conditions.

PurposeRetinal implants use electrical stimulation to elicit perceived flashes of light ("phosphenes"). Single-electrode phosphene shape has been shown to vary systematically with stimulus parameters and the retinal location of the stimulating electrode, due to incidental activation of passing nerve fiber bundles. However, this knowledge has yet to be extended to paired-electrode stimulation.MethodsWe retrospectively analyzed 3548 phosphene drawings made by three blind participants implanted with an Argus II Retinal Prosthesis. Phosphene shape (characterized by area, perimeter, major and minor axis length) and number of perceived phosphenes were averaged across trials and correlated with the corresponding single-electrode parameters. In addition, the number of phosphenes was correlated with stimulus amplitude and neuroanatomical parameters: electrode-retina and electrode-fovea distance as well as the electrode-electrode distance to ("between-axon") and along axon bundles ("along-axon"). Statistical analyses were conducted using linear regression and partial correlation analysis.ResultsSimple regression revealed that each paired-electrode shape descriptor could be predicted by the sum of the two corresponding single-electrode shape descriptors (p

ObjectiveRetinal prostheses evoke visual precepts by electrically stimulating functioning cells in the retina. Despite high variance in perceptual thresholds across subjects, among electrodes within a subject, and over time, retinal prosthesis users must undergo `system fitting', a process performed to calibrate stimulation parameters according to the subject's perceptual thresholds. Although previous work has identified electrode-retina distance and impedance as key factors affecting thresholds, an accurate predictive model is still lacking.ApproachTo address these challenges, we 1) fitted machine learning (ML) models to a large longitudinal dataset with the goal of predicting individual electrode thresholds and deactivation as a function of stimulus, electrode, and clinical parameters (`predictors') and 2) leveraged explainable artificial intelligence (XAI) to reveal which of these predictors were most important.Main resultsOur models accounted for up to 76% of the perceptual threshold response variance and enabled predictions of whether an electrode was deactivated in a given trial with F1 and AUC scores of up to 0.730 and 0.910, respectively. Our models identified novel predictors of perceptual sensitivity, including subject age, time since blindness onset, and electrode-fovea distance.SignificanceOur results demonstrate that routinely collected clinical measures and a single session of system fitting might be sufficient to inform an XAI-based threshold prediction strategy, which has the potential to transform clinical practice in predicting visual outcomes..

Abstract Fundus images allow for non-invasive assessment of the retinal vasculature whose features provide important information on health. Using a fully automated image processing pipeline, we extract 17 different morphological vascular phenotypes, including median vessels diameter, diameter variability, main temporal angles, vascular density, central retinal equivalents, the number of bifurcations, and tortuosity, from over 130,000 fundus images of close to 72,000 UK Biobank subjects. We perform genome-wide association studies of these phenotypes. From this, we estimate their heritabilities, ranging between 5 and 25%, and genetic cross-phenotype correlations, which mostly mirror the corresponding phenotypic correlations, but tend to be slightly larger. Projecting our genetic association signals onto genes and pathways reveals remarkably low overlap suggesting largely decoupled mechanisms modulating the different phenotypes. We find that diameter variability, especially for the veins, associates with diseases including heart attack, pulmonary embolism, and age of death. Mendelian Randomization analysis suggests a causal influence of blood pressure and body mass index on retinal vessel morphology, among other results. We validate key findings in two independent smaller cohorts. Our analyses provide evidence that large-scale analysis of image-derived vascular phenotypes has sufficient power for obtaining functional and causal insights into the processes modulating the retinal vasculature.

Abstract Single administration of low-dose ketamine has both acute and sustained anti-depressant effects. Sustained effect is associated with restoration of glutamatergic synapses in medial prefrontal cortic (mFPC) neurons. Ketamine induced profound changes in a number of molecular pathways in a mouse model for chronic stress. Cell-cell communication analyses predicted that planar-cell-polarity (PCP) signaling was decreased after chronic administration of corticosterone but increased following ketamine administration in most of the excitatory neurons. Similar decrease of PCP signaling in excitatory neurons was predicted in dorsolateral prefrontal cortical (dl-PFC) neurons of patients with major depressive disorder (MDD). We showed that the basolateral amygdala (BLA)-projecting infralimbic prefrontal cortex (IL PFC) neurons regulate immobility time in the tail suspension test and food consumption. Conditionally knocking out Celsr2 and Celsr3 or Prickle2 in the BLA-projecting IL PFC neurons abolished ketamine-induced synapse restoration and behavioral remission. Therefore, PCP proteins in IL PFC-BLA neurons mediate synapse restoration induced by of low-dose ketamine.

Over the past decade, extended reality (XR) has emerged as an assistive technology not only to augment residual vision of people losing their sight but also to study the rudimentary vision restored to blind people by a visual neuroprosthesis. A defining quality of these XR technologies is their ability to update the stimulus based on the user's eye, head, or body movements. To make the best use of these emerging technologies, it is valuable and timely to understand the state of this research and identify any shortcomings that are present. Here we present a systematic literature review of 227 publications from 106 different venues assessing the potential of XR technology to further visual accessibility. In contrast to other reviews, we sample studies from multiple scientific disciplines, focus on technology that augments a person's residual vision, and require studies to feature a quantitative evaluation with appropriate end users. We summarize prominent findings from different XR research areas, show how the landscape has changed over the past decade, and identify scientific gaps in the literature. Specifically, we highlight the need for real-world validation, the broadening of end-user participation, and a more nuanced understanding of the usability of different XR-based accessibility aids.

Deep neural networks have surpassed human performance in key visual challenges such as object recognition, but require a large amount of energy, computation, and memory. In contrast, spiking neural networks (SNNs) have the potential to improve both the efficiency and biological plausibility of object recognition systems. Here we present a SNN model that uses spike-latency coding and winner-take-all inhibition (WTA-I) to efficiently represent visual stimuli using multi-scale parallel processing. Mimicking neuronal response properties in early visual cortex, images were preprocessed with three different spatial frequency (SF) channels, before they were fed to a layer of spiking neurons whose synaptic weights were updated using spike-timing-dependent-plasticity. We investigate how the quality of the represented objects changes under different SF bands and WTA-I schemes. We demonstrate that a network of 200 spiking neurons tuned to three SFs can efficiently represent objects with as little as 15 spikes per neuron. Studying how core object recognition may be implemented using biologically plausible learning rules in SNNs may not only further our understanding of the brain, but also lead to novel and efficient artificial vision systems.

Abstract There are known individual differences in both the ability to learn the layout of novel environments and the flexibility of strategies for navigating known environments. However, it is unclear how navigational abilities are impacted by high-stress scenarios. Here we used immersive virtual reality (VR) to develop a novel behavioral paradigm to examine navigation under dynamically changing situations. We recruited 48 participants (24 female; ages 17–32) to navigate a virtual maze (7.5 m × 7.5 m). Participants learned the maze by moving along a fixed path past the maze’s landmarks (paintings). Subsequently, participants experienced either a non-stress condition, or a high-stress condition tasking them with navigating the maze. In the high-stress condition, their initial path was blocked, the environment was darkened, threatening music was played, fog obstructed more distal views of the environment, and participants were given a time limit of 20 s with a countdown timer displayed at the top of their screen. On trials where the path was blocked, we found self-reported stress levels and distance traveled increased while trial completion rate decreased (as compared to non-stressed control trials). On unblocked stress trials, participants were less likely to take a shortcut and consequently navigated less efficiently compared to control trials. Participants with more trait spatial anxiety reported more stress and navigated less efficiently. Overall, our results suggest that navigational abilities change considerably under high-stress conditions.

IntroductionUnderstanding the retina in health and disease is a key issue for neuroscience and neuroengineering applications such as retinal prostheses. During degeneration, the retinal network undergoes complex and multi-stage neuroanatomical alterations, which drastically impact the retinal ganglion cell (RGC) response and are of clinical importance. Here we present a biophysically detailed in silico model of the cone pathway in the retina that simulates the network-level response to both light and electrical stimulation.MethodsThe model included 11, 138 cells belonging to nine different cell types (cone photoreceptors, horizontal cells, ON/OFF bipolar cells, ON/OFF amacrine cells, and ON/OFF ganglion cells) confined to a 300 × 300 × 210μm patch of the parafoveal retina. After verifying that the model reproduced seminal findings about the light response of retinal ganglion cells (RGCs), we systematically introduced anatomical and neurophysiological changes (e.g., reduced light sensitivity of photoreceptor, cell death, cell migration) to the network and studied their effect on network activity.ResultsThe model was not only able to reproduce common findings about RGC activity in the degenerated retina, such as hyperactivity and increased electrical thresholds, but also offers testable predictions about the underlying neuroanatomical mechanisms.DiscussionOverall, our findings demonstrate how biophysical changes typified by cone-mediated retinal degeneration may impact retinal responses to light and electrical stimulation. These insights may further our understanding of retinal processing and inform the design of retinal prostheses.

Climate change is associated with adverse mental and emotional health outcomes. Social and economic factors are well-known drivers of mental health, yet comparatively few studies examine the social and economic pathways through which climate change affects mental health. There is additionally a lack of research on climate change and mental health in sub-Saharan Africa. This qualitative study aimed to identify potential social and economic pathways through which climate change impacts mental and emotional wellbeing, focusing on a vulnerable population of Kenyan smallholder farmers living with HIV. We conducted in-depth, semi-structured interviews with forty participants to explore their experience of climate change. We used a thematic analytical approach. We find that among our study population of Kenyan smallholder farmers living with HIV, climate change is significantly affecting mental and emotional wellbeing. Respondents universally report some level of climate impact on emotional health including high degrees of stress; fear and concern about the future; and sadness, worry, and anxiety from losing one's home, farm, occupation, or ability to support their family. Climate-related economic insecurity is a main driver of emotional distress. Widespread economic insecurity disrupts systems of communal and family support, which is an additional driver of worsening mental and emotional health. Our study finds that individual adaptive strategies used by farmers in the face of economic and social volatility can deepen economic insecurity and are likely insufficient to protect mental health. Finally, we find that agricultural policies can worsen economic insecurity and other mental health risk factors. Our proposed conceptual model of economic and social pathways relevant for mental health can inform future studies of vulnerable populations and inform health system and policy responses to protect health in a changing climate.

Objective.How can we return a functional form of sight to people who are living with incurable blindness? Despite recent advances in the development of visual neuroprostheses, the quality of current prosthetic vision is still rudimentary and does not differ much across different device technologies.Approach.Rather than aiming to represent the visual scene as naturally as possible, aSmart Bionic Eyecould provide visual augmentations through the means of artificial intelligence-based scene understanding, tailored to specific real-world tasks that are known to affect the quality of life of people who are blind, such as face recognition, outdoor navigation, and self-care.Main results.Complementary to existing research aiming to restore natural vision, we propose a patient-centered approach to incorporate deep learning-based visual augmentations into the next generation of devices.Significance.The ability of a visual prosthesis to support everyday tasks might make the difference between abandoned technology and a widely adopted next-generation neuroprosthetic device.

Uncertainties on the intensive care unit (ICU) regarding the eligibility of a patient to be a potential deceased organ donor may prevent their referral and enrolment in the pathway for organ donation. Healthcare staff may exclude potential donors for medical reasons, which are no longer applicable. Hence, Swisstransplant implemented a digital donor evaluation tool (DET) in 2021, which allows the local hospital’s organ donation coordinator to send a direct request to medical advisors (MA) of the organ procurement organization before excluding potential donors. All 156 requests entered in 2022 were analyzed. 117 patients (75.0%) were primarily accepted by the MA as potential donors. Of those 60 patients (51.3%) became actual organ donors. Main reasons for using the DET were questions regarding malignancies (n = 33, 21.2%), infectious diseases (n = 35, 22.4%) and age/co-morbidities (n = 34, 21.8%). The average age of the actual “DET donor” compared to the regularly enrolled, actual “Non-DET donor” was 65.3 ± 15.8 vs. 56.8 ± 17.5 years, respectively (p = 0.008). On average 1.9 ± 1.1 organs compared to 3.2 ± 1.3 organs were retrieved from DET vs. Non-DET donors. In summary, this new digital donor evaluation tool supports reporting and facilitates eligibility decisions in uncertain, complex donor cases, potentially increasing the number of organ donations.

The nervous system is under tight energy constraints and must represent information efficiently. This is particularly relevant in the dorsal part of the medial superior temporal area (MSTd) in primates where neurons encode complex motion patterns to support a variety of behaviors. A sparse decomposition model based on a dimensionality reduction principle known as non-negative matrix factorization (NMF) was previously shown to account for a wide range of monkey MSTd visual response properties. This model resulted in sparse, parts-based representations that could be regarded as basis flow fields, a linear superposition of which accurately reconstructed the input stimuli. This model provided evidence that the seemingly complex response properties of MSTd may be a by-product of MSTd neurons performing dimensionality reduction on their input. However, an open question is how a neural circuit could carry out this function. In the current study, we propose a spiking neural network (SNN) model of MSTd based on evolved spike-timing-dependent plasticity and homeostatic synaptic scaling (STDP-H) learning rules. We demonstrate that the SNN model learns compressed and efficient representations of the input patterns similar to the patterns that emerge from NMF, resulting in MSTd-like receptive fields observed in monkeys. This SNN model suggests that STDP-H observed in the nervous system may be performing a similar function as NMF with sparsity constraints, which provides a test bed for mechanistic theories of how MSTd may efficiently encode complex patterns of visual motion to support robust self-motion perception.SIGNIFICANCE STATEMENT The brain may use dimensionality reduction and sparse coding to efficiently represent stimuli under metabolic constraints. Neurons in monkey area MSTd respond to complex optic flow patterns resulting from self-motion. We developed a spiking neural network model that showed MSTd-like response properties can emerge from evolving spike-timing-dependent plasticity with STDP-H parameters of the connections between then middle temporal area and MSTd. Simulated MSTd neurons formed a sparse, reduced population code capable of encoding perceptual variables important for self-motion perception. This model demonstrates that complex neuronal responses observed in MSTd may emerge from efficient coding and suggests that neurobiological plasticity, like STDP-H, may contribute to reducing the dimensions of input stimuli and allowing spiking neurons to learn sparse representations.

IntroductionRetinal implants provide artificial vision to blind individuals through electrically stimulating remaining non-photoreceptor retinal cells. For epiretinal implants, placed over the ganglion cell layer, individual electrodes produce elongated 'streaks' due to the unselective stimulation of underlying ganglion axons (Beyeler, 2019). Here, to examine whether these axonal streaks explain the poor spatial acuity of prosthetic patients, we measured two-point discrimination performance in three patients implanted with an Argus 2 epiretinal implant (Second Sight Medical Products Inc).MethodsOn each trial two electrodes were simultaneously stimulated (0.45 um pulse width, 6-20 Hz pulse train, 250-500ms duration, current amplitude 2x threshold). Participants verbally reported the number of distinct percepts they saw.ResultsA regression analysis found that current amplitude, physical distance, distance along the axon, and distance between axons all played a significant role in determining whether participants saw one or two percepts.ConclusionsParticipants were less likely to see two distinct percepts when electrodes were physically close or lay close to the same axon bundle. Electrodes with high stimulation thresholds were also less likely to produce distinct percepts. Thus electrode pairs can merge into a single percept when (1) current fields overlap, (2) their current fields stimulate the same axonal bundle, or (3) the elongated percepts overlap.

Two of the main obstacles to the development of epiretinal prosthesis technology are electrodes that require current amplitudes above safety limits to reliably elicit percepts, and a failure to consistently elicit pattern vision. Here, we explored the causes of high current amplitude thresholds and poor spatial resolution within the Argus II epiretinal implant. We measured current amplitude thresholds and two-point discrimination (the ability to determine whether one or two electrodes had been stimulated) in 3 blind participants implanted with Argus II devices. Our data and simulations show that axonal stimulation, lift and retinal damage all play a role in reducing performance in the Argus 2, by either limiting sensitivity and/or reducing spatial resolution. Understanding the relative role of these various factors will be critical for developing and surgically implanting devices that can successfully subserve pattern vision.

Many forms of artificial sight recovery, such as electronic implants and optogenetic proteins, generally cause simultaneous, rather than complementary firing of on- and off-center retinal cells. Here, using virtual patients-sighted individuals viewing distorted input-we examine whether plasticity might compensate for abnormal neuronal population responses. Five participants were dichoptically presented with a combination of original and contrast-reversed images. Each image (I) and its contrast-reverse (I') was filtered using a radial checkerboard (F) in Fourier space and its inverse (F'). [I * F'] + [I' * F] was presented to one eye, and [I * F] + [I' * F'] was presented to the other, such that regions of the image that produced on-center responses in one eye produced off-center responses in the other eye, and vice versa. Participants continuously improved in a naturalistic object discrimination task over 20 one-hour sessions. Pre-training and post-training tests suggest that performance improvements were due to two learning processes: learning to recognize objects with reduced visual information and learning to suppress contrast-reversed image information in a non-eye-selective manner. These results suggest that, with training, it may be possible to adapt to the unnatural on- and off-cell population responses produced by electronic and optogenetic sight recovery technologies.