bioRxiv Subject Collection: Neuroscience's Journal

Loss of age-associated increase in m6A-modified RNA contributes to GABAergic dysregulation in Alzheimer's disease
Dysregulated RNA metabolism is a significant feature of Alzheimers disease (AD), yet how post-transcriptional RNA modifications like

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Dysregulated RNA metabolism is a significant feature of Alzheimers disease (AD), yet how post-transcriptional RNA modifications like <IN/I><SUB6/SUB>-methyladenosine (m<SUB6/SUB>A) are altered in AD is unknown. Here, we performed deamination adjacent to RNA modification targets (DART-seq) on human dorsolateral prefrontal cortices to assess changes in m<SUB6/SUB>A with nucleotide resolution. In non-AD brains, m<SUB6/SUB>A sites increased with age, predominantly within the 3UTR of transcripts encoding tripartite synapse proteins. In contrast, AD brains lost the age-associated m<SUB6/SUB>A site increase and exhibited global hypomethylation of transcripts, including MAPT and APP. Hypomethylated genes involved with GABAergic signaling, glutamate transport, and ubiquitin-mediated proteolysis exhibited reduced expression, connecting m<SUB6/SUB>A to synaptic excitotoxicity and disrupted proteostasis in AD. Site-specific m<SUB6/SUB>A levels were linked with GABRA1 expression and protein levels, but this relationship was abolished in AD. Our findings provide insight into post-transcriptional mechanisms of dysregulated RNA metabolism in AD that are related to aging and GABAergic regulation.

Structural Interactions of Ankyrin B with NrCAM and β2 Spectrin
Ank2 is a high confidence autism spectrum disorder (ASD) gene encoding the spectrin-actin scaffold protein Ankyrin B (AnkB). The 220 kDal isoform of AnkB has multiple functions including developmental spine pruning through L1 family cell adhesion molecules (L1-CAMs) and class 3 Semaphorins on dendrites of pyramidal neurons to achieve an appropriate excitatory balance in the neocortex. Molecular modeling employing AlphaFold was used to predict the structure and interactions of AnkB with the cytoplasmic domain of Neuron-glial Related L1-CAM (NrCAM), and with {beta}2-Spectrin. The validity of the models was assessed by analyzing protein-protein interactions by co-immunoprecipitation from HEK293 cell lysates after mutating key residues in AnkB predicted to impair these associations. Results revealed a pocket with critical residues in the AnkB membrane-binding domain that engages NrCAM at the conserved cytoplasmic motif FIGQY. Alphafold modeling of the AnkB/{beta}2-Spectrin complex also identified key interactions between the AnkB spectrin-binding domain and {beta}2-Spectrin repeats 14-15. Selected ASD-linked mutations in AnkB predicted to impact binding to NrCAM or {beta}2-Spectrin were then assayed for protein interactions. Maternally inherited ASD missense mutations AnkB A368G located in the NrCAM binding pocket and AnkB R977Q in the Zu51 subdomain disrupted associations with NrCAM and {beta}2-Spectrin, respectively. Moreover, AnkB A368G impaired the neuronal function of 220 kDal AnkB in Semaphorin 3F-induced spine pruning in mouse cortical neuron cultures. These new findings provide structural insights into the L1-CAM/AnkB complex and the molecular basis of ASD etiology associated with AnkB missense mutations.

Synaptic vesicles that store monoamines and glutamate differ in protein composition.
Neuromodulators such as the monoamines are known to differ from classical neurotransmitters like glutamate in the time scale of signaling due to activation of slower G protein-coupled receptors. Recent work has suggested that the mode of release also differs between classical and modulatory transmitters. Although many components of neurotransmitter release machinery have been identified, we still understand little about the mechanisms responsible for differences in release. In this study, we address the differences between release of dopamine and glutamate by comparing the composition of synaptic vesicles (SVs) that contain the vesicular monoamine transporter 2 (VMAT2) versus vesicular glutamate transporter 2 (VGLUT2). Previous work has shown that these SV populations differ in frequency dependence, recycling kinetics and biogenesis. Taking advantage of a CRISPR-generated knock-in mouse with a cytoplasmic hemagglutinin (HA) tag at the N-terminus of VMAT2 to immunoisolate monoamine SVs, we find differences in the abundance and isoform expression of many SV protein families. Validation in primary neurons and in brain tissue confirms these differences in SV protein abundance between dopamine and glutamate release sites. Functional analysis reveals that the loss of differentially expressed SCAMP5 selectively impairs the recycling of VGLUT2 SVs, sparing VMAT2 vesicles in the same neuronal population. These findings provide new insights into the molecular diversity of SVs and the mechanisms that regulate the release of dopamine and glutamate, with implications for the physiological role of these transmitters and behavior.

EGFR activation correlates with intracranial pressure and outcome in a mixed intracranial bleeding porcine model
The pig model is an advanced system for studying human brain injury due to its anatomical similarities with the brain, such as brain size, gyrencephalic structure, skull shape, and white-to-gray matter ratio. Brain hemorrhage increases intracranial pressure through blood accumulation and brain swelling, leading to impaired cerebral blood flow, ischemia, and potentially, secondary injury, thus further exacerbating neurological damage. This study investigates the role of receptor tyrosine kinases (RTKs) in the injury response and clinical outcomes, focusing on their potential as therapeutic targets for intracranial pressure control after injury. To this end, we developed a sustained, resuscitated pig model of acute mixed intracranial bleeding with ICP and hemorrhagic shock. Multimodal brain monitoring and neurological assessments offered insights into the progression of the injury. Our findings showed that 36-48 hours post-injury, animals exhibited signs of cerebral tissue hypoxia, neuroinflammation, and extensive tissue damage. Elevated HIF1- expression in the injured hemisphere confirmed local hypoperfusion. Inflammatory markers such as TNF-, CD68, and MMP-9 were upregulated in both hemispheres, reflecting a generalized neuroinflammatory response. Gene expression analysis revealed increased markers of vascular, astrocytic, and neuroimmune activation, particularly related to endothelial integrity and astrocyte activation. RTK expression analysis showed increased levels of VEGFR1, VEGFR2, Tie-2, EGFR, and Axl in the injured cortex, with activation of EGFR/ErbB4 and HGFR/Met pathways. Hierarchical clustering of our transcriptional analysis revealed distinct patterns of activation, highlighting the direct relationship between severity of ICP increase and astrocyte response. In particular, EGFR phosphorylation correlated with i) severity of ICP increase, ii) neurological evaluation using a modified Glasgow Coma Scale, and iii) survival. These findings suggest that modulating EGFR signaling may offer a therapeutic approach for managing ICP and improving outcome in traumatic brain injury.

Diverse and Flexible Strategies Enable Successful Cooperation in Marmoset Dyads
In humans, cooperation relies on advanced social cognition, but the extent to which these mechanisms support cooperation in nonhuman primates remains unclear. To investigate this, we examined freely moving marmoset dyads in a cooperative lever-pulling task. Marmosets successfully coordinated actions, relying on social vision rather than environmental cues. Blocking visual access or replacing the partner with an automated agent disrupted coordination. Causal dependencies between social gaze and pull actions revealed both gaze-dependent and gaze-independent strategies. Cooperation depended on social relationships, including dominance, kinship, and sex. Remarkably, marmosets adapted strategies based on partner identity, indicating rapid social learning and memory. Altogether, these findings show that flexible, cognitively driven cooperation extends more broadly across primates than previously recognized, informing our understanding of cooperative behavior mechanisms and evolution.

Neural and behavioral signatures of policy compression in cognitive control
Making context-dependent decisions incurs cognitive costs. Cognitive control studies have investigated the nature of such costs from both computational and neural perspectives. In this paper, we offer an information-theoretic account of the costs associated with context-dependent decisions. According to this account, the brain's limited capacity to store context-dependent policies necessitates "compression" of policies into internal representations with an upper bound on code length, quantified by an information-theoretic measure (policy complexity). These representations are decoded into actions by sequentially inspecting each bit, such that longer codes take more time to decode. When a response deadline is imposed, the account predicts that policy complexity should increase with the deadline. Higher policy complexity is associated with several behavioral signatures: (i) higher accuracy; (ii) lower variability; and (iii) lower perseveration. Analyzing data from a rule-based action selection task, we found evidence supporting all of these predictions. We further hypothesized that complex policies require higher neural dimensionality (which constrains the code space). Consistent with this hypothesis, we found that policy complexity correlates with a measure of neural dimensionality in a rule-based decision task. This finding brings us a step closer to understanding the neural implementation of policy compression and its implications for cognitive control.

Complement biosynthesis in human brain: Insights from single-nucleus transcriptomics of hippocampus.
Complement is a key contributor to neuroinflammation, driving pathology in neurodegenerative diseases (NDDs); however, little is known about the source of complement in the brain. Effective targeting of complement in NDDs requires understanding of its source - in particular, which brain cells express complement genes, how expression is regulated, and how expression changes in disease. To address this knowledge gap, we identified and integrated single-nucleus RNA sequencing (snRNAseq) datasets from 398,097 nuclei across 48 hippocampal samples from non-demented brains to create a comprehensive transcriptomic atlas of complement gene expression (the complementome) in the healthy brain. Expression levels of genes encoding complement components, receptors, and regulators were analysed across different brain cell types, and the impact of sex and age on complement gene expression was tested. To test the impact of disease, we generated a further atlas from datasets comprising 11 non-demented and 12 Alzheimer's disease (AD) patient hippocampi to assess changes in complement gene expression in AD. All glial cells in the non-demented hippocampus expressed complement genes. C1QA/B/C genes were exclusively expressed in microglia, while C3 was highly expressed in microglia and astrocytes. Notably, C3 expression defined a subset of pro-inflammatory microglia. Complement receptor-encoding genes (C3AR1, C5AR2, ITGAM, ITGAX, ITGB2, VSIG4) were predominantly expressed in microglia, while neurons expressed a set of brain-specific putative receptors (NPTX1/2, NPTXR, NRP1). Endothelial cells abundantly expressed key regulators (CD46, CD55, CD59, CFH), while neurons and OPCs expressed a set of putative regulators (CSMD1/2/3 and SUSD4). Astrocytes abundantly expressed CLU. Cell type-specific gender differences included higher expression of C1QA/B/C, C1R, and C1S in female microglia, and higher expression of ITGAM and ITGAX in male microglia. Generally, higher complement gene expression was seen in older donors. Compared to controls, AD microglia showed higher expression of C1QB and C3, and AD astrocytes showed higher C1S and C3 expression. Expression of ITGAX was elevated in AD microglia compared to controls, while many AD cell types demonstrated reduced expression of brain-specific putative receptors. Defining the complementome in the non-demented hippocampus provides a baseline for exploring brain complement expression. Complement expression is upregulated in AD, likely contributing to neuroinflammation and highlighting its potential as a therapeutic target.

A novel approach to map the causal impact of brain stimulation on semantic processing with language models
Non-invasive brain stimulation (NIBS) studies on semantic cognition hold the promise of revealing the functional relevance of brain areas through causal intervention. A primary challenge, however, is that findings are often interpreted through binary distinctions between sets of stimuli (e.g. related/unrelated words, same/different semantic category). This approach ignores the analysis of individual words, which mirrors every-day language use and is crucial for understanding semantic cognition. In this work, we used semantic similarity, as measured by a language model, to investigate how Transcranial Magnetic Stimulation (TMS) effects on semantic cognition unfold at the level of individual words. We re-analyzed 5 publicly available TMS datasets, covering multiple stimulation sites and lexical semantics tasks. We propose a simple methodology that can straightforwardly be applied to any TMS experiment on semantic cognition, and showcase its potential to generate new insights. We modelled trial-level response times using the language model and computed the correlation between the two. We also repeated the analyses for two lower-level variables (word frequency and length). Importantly, for each dataset, we compared correlations for effective and control (sham or vertex) stimulation conditions. We found that, for the language model, correlation was almost always significantly different depending on the type of stimulation (effective or control). Our results provide evidence that the stimulation effect interacts with the meaning of individual words. However, a similar pattern emerged in some cases for word frequency and length, suggesting that the effects of TMS on cognition can be widespread, well beyond their intended functional target. Collectively, our results demonstrate that language models provide new insight into the impact of neurostimulation on semantic processing, complementing standard measures.

Revisiting atypical language lateralization in dyslexia
Hemispheric lateralization has been central to developmental dyslexia research for over a century, yet its role in the etiology of reading and language deficits remains elusive. While altered asymmetries have long been implicated, evidence is inconsistent, with limited consideration given to individual variability in lateralization patterns. This study investigated hemispheric lateralization in 35 adults with dyslexia and 35 matched controls using functional MRI across three language tasks: word generation, rhyming decision, and lexical decision. Laterality indices (LIs) were calculated to comprehensively assess the strength, direction, and consistency of activation across global and regional task-specific brain areas. No significant group differences were found in the absolute strength of lateralization for either global or regional measures. Directional asymmetry was similar across the two groups, except in the fusiform gyrus during the reading task, where dyslexic individuals showed a higher prevalence of right-hemisphere lateralization compared to controls. Importantly, we found that dyslexic participants demonstrated greater inconsistency in regional lateralization during the reading and rhyming tasks. Among individuals with dyslexia, those with inconsistent lateralization in the reading task had lower reading performance and weaker fusiform lateralization, although fusiform LI strength itself did not predict reading outcomes. Our findings suggest that dyslexia is characterized by inconsistent, rather than universally weaker, lateralization patterns. Inconsistencies in task-related and regional lateralization may disrupt the efficiency of language networks, contributing to observed reading deficits. Our results emphasize the need to move beyond traditional group-averaged analyses, highlighting the importance of considering individual variability when investigating language disorders.

Cellular and Regional Vulnerability Shapes the Molecular Landscape of Psychosis in Alzheimers Disease
Approximately 40% of Alzheimers disease (AD) patients develop psychosis, yet the molecular and cellular processes that govern the manifestation of psychotic symptoms in dementia remain poorly understood. To define the neurobiological correlates that distinguish AD patients with psychosis (AD+P) from AD patients that never exhibited psychotic symptoms (AD-P), we performed single-nucleus transcriptome and epigenome profiling from prefrontal cortex and hippocampus of 48 postmortem brains from AD subjects segmented by psychiatric diagnosis. Our snRNA-seq profiling uncovered differentially expressed genes (DEGs) across multiple cell types, including transcriptional signatures of enhanced synaptic transmission in upper-layer pyramidal neurons of the AD+P cortex. Cell fraction analysis and histology both indicate greater loss of upper-layer pyramidal neurons in AD+P in comparison to AD-P cortex. Integrating our snRNA-seq data with functional screens in stem-cell derived brain organoids, we defined how genetic perturbations modify input-output network connectivity in vitro in a model of cortico-cortical communication. We find that differential vulnerability of pyramidal neurons in AD+P is associated with CDK5/p35-associated neurotoxicity and IL6-mediated glial inflammatory expression changes. This neuronal response is associated with microglial exhaustion and astrocytic inflammation signatures triggered by layer-specific neuropathological changes in the brains of AD+P patients. Lastly, we elucidate common and distinct transcriptional signatures between psychosis in AD and several other psychiatric conditions, and found significant enrichment of schizophrenia genetics with AD+P that is most convergent in upper-layer pyramidal neurons. Our work provides novel insight into the pathophysiological role of hyperexcitable circuits in the etiology of neuropsychiatric symptoms of AD.

Distinct evolutionary trajectories of two integration centres, the central complex and mushroom bodies, across Heliconiini butterflies
Neural circuits have evolved to produce cognitive processes that facilitate a species variable behavioural repertoire. Underlying this variation are evolutionary forces, such as selection, that operate on changes to circuitry against a background of constraints. The interplay between selection and potentially limiting constraints determine how circuits evolve. Understanding how this process operates requires an evolutionary framework that facilitates comparative analysis of neural traits, within a clear behavioural and functional context. We leverage a large radiation of Heliconiini butterflies to examine how selection shapes the evolution of the central complex and the mushroom bodies, two integration centres in the insect brain involved in spatial navigation. Within the Heliconiini, one genus, Heliconius, performs systematic spatial foraging and navigation to exploit specific plants as a source of pollen, a novel dietary resource. Closely related genera within Heliconiini lack this dietary adaptation, and are more vagrant foragers. The evolution of increased spatial fidelity in Heliconius has led to changes in brain morphology, and in specific learning and memory profiles, over a relatively short evolutionary time scale. Here, using a dataset of 41 species, we show that in contrast to a massive expansion of the mushroom bodies, the central complex and associated visual processing areas are strongly conserved in size and general architecture. We corroborate this by characterising patterns of fine anatomical conservation, including conserved patterns in dopamine and serotonin expression. However, we also identify a divergence in the expression of a neuropeptide, Allatostatin A, in the noduli, and in the numbers of GABA-ergic ellipsoid body ring neurons and their branching in the fan-shaped body, which are essential members of the anterior compass pathway. These differences match expectations of where evolutionary adaptability might occur inside the central complex network and provide rare examples of divergence of these circuits in a shallow phylogenetic context. We conclude that due to the contrasting volumetric conservation of the central complex and the massive volumetric differences in the mushroom bodies, their circuit logics must determine distinct responses to selection associated with divergent foraging behaviours.

Acute Administration of Oxytocin in the Functional Recovery of Neurocognitive and Social Deficits Following Juvenile Frontal Traumatic Brain Injury
Introduction: Juvenile traumatic brain injury (jTBI) is one of the leading causes of death and disability in children. The prefrontal cortex (PFC) is most susceptible to injury which leads to deficits in executive function, social behaviors, and cognitive flexibility. Prior research has shown a significant role of the oxytocin (OXT) system in the modulation of social behaviors, and that intranasal OXT (IN-OXT) is potentially neuroprotective. Therefore, we believe IN-OXT could improve behavioral deficits caused by a PFC injury. Methods: Animals received a single midline cortical contusion bilaterally damaging the medial PFC (mPFC) and immediately given a single dose of IN-OXT, placebo, or no treatment. Animals were assessed using behavioral and histological measures. Results: The results indicated that IN-OXT in jTBI animals mildly improved spatial learning but did not improve spatial memory. Additionally, TBI increased social dominance behavior, but IN-OXT did not mitigate those behaviors. IN-OXT did not alleviate neuroinflammation but did elevate OXT receptors and OXT peptide levels. Furthermore, TBI decreased OXT in the SON of the hypothalamus, and IN-OXT returned OXT levels in this region to normal. Discussion: These results show that IN-OXT increases OXT levels in the brain via pathways originating in the SON and improved spatial learning.

PW-GAN: Pseudo-Warping Field Guided GAN for Unsupervised Denoising of Fetal Brain MRI Images
Fetal brain magnetic resonance imaging is of great importance for prenatal neural disorder diagnosis. To improve signal-to-noise ratio and coverage, fetal brain MRI often uses thick-slice scanning to reduce motion artifacts and ensure image quality for single slices. Reconstructing 3D MR volumes from multiple motion-corrupted stacks of 2D slices has shown promise in imaging of moving subjects like fetal MRI. However, raw scans acquired with varying slice thicknesses present substantial disparities in quality when retrospectively reconstructed into isotropic high-resolution volumes (e.g. 0.8 mm slice thickness). In particular, thick-slice acquisitions (e.g. 5-6 mm) tend to yield suboptimal reconstruction results compared to thin-slice scans (e.g. 2-3 mm), often exhibiting residual noise, interpolation-induced artifacts, and inter-slice structural discontinuities. This challenge has highlighted the need to further reduce noise caused by reconstruction errors when the reconstructed volumes are used for downstream tasks. With the success of neural networks in computer vision, deep learning methods based on architectures such as convolutional neural networks (CNNs) and generative adversarial networks (GANs) have achieved outstanding performance in single-image denoising. Nevertheless, CNN-based methods still heavily rely on large-scale datasets comprising noisy-clean image pairs. Although unsupervised GAN variants such as CycleGAN have been developed to mitigate this dependency, the inherent variability of GAN-generated outputs often results in tiny anatomical distortions, significantly limiting the applicability of GAN-based methods. While several approaches have introduced regularizations to address this issue, they largely focus on denoising individual slices, overlooking inter-slice structural inconsistencies that arise from treating slices independently. In this work, we propose Pseudo-Warping Field Guided Unsupervised Generative Adversarial Network (PW-GAN), which formulates post-reconstruction optimization as an unpaired style transfer problem between low-quality and high-quality MRI domains. Moreover, by incorporating a pseudo-deformation field module based on optical flow estimation, our method significantly enhances inter-slice continuity in the reconstructed volumes while effectively suppressing residual noise and interpolation artifacts introduced during the reconstruction process. Evaluations on both simulated and in vivo data demonstrate that our method outperforms existing unsupervised models and achieves performance on par with several state-of-the-art supervised methods.

Caspase cleavage of APP contributes to amyloid beta-protein induced synaptic injury
BACKGROUND: Increasing evidence suggests that amyloid beta (Abeta) lies at the center of Alzheimer Disease (AD) pathology and that synapses are the initial site of damage by Abeta. Recent studies have also indicated a role for caspases in AD-related synaptic dysfunction and memory loss, but the mechanism(s) through which the caspases act remains elusive. Previous studies in cell culture indicate that cleavage of a caspase site on the intracellular domain of the amyloid precursor protein (APP) protein contributes to Abeta-induced cell death. However, the role of this cleavage event in synaptic dysfunction has not been established. METHODS: Through a combination of intracellular and extracellular electrophysiological methods and confocal microscopy of dendritic spines, we examined the involvement of caspase-3 and amyloid-precursor protein in Abeta-mediated synaptic dysfunction. RESULTS: Here, we provide evidence that caspase activity at the intracellular domain of APP is required for acute Abeta-induced depression of glutamatergic synapses. We find that local elevation of Abeta levels through over-expression of the C-terminal fragment of APP (C99) failed to depress synapses if caspases were inhibited pharmacologically or in tissue lacking caspase-3. To demonstrate a link between these findings to APP, we found that Abeta-failed to depress synaptic transmission or inhibit synaptic plasticity in neurons lacking APP. To specifically test the role of caspase cleavage of the intracellular domain of APP, we introduced a mutation that inhibits caspase cleavage at site 664 to the C99 construct; this construct produced Abeta but failed to elicit Abeta-induced synaptic depression or spine loss, and reduced caspase-3 activity. CONCLUSION: Taken together, these results suggest an APP-dependent pathway in which caspases contribute to Abeta-induced synaptic depression and spine loss via cleavage of APP.

Decoding of frequency modulated sweeps by core and belt neurons in the alert macaque auditory cortex.
Acoustic stimuli where the spectrum is time-varying are ubiquitous in natural sounds, including animal vocalizations, human speech, and music. Early studies of such stimuli involving frequency-modulated sweeps revealed that neurons in the primary auditory cortex of a variety of mammals show differences in firing rates depending on either the direction of the sweep and/or the sweep velocity. Psychophysical studies have also shown that the perception of such time-varying stimulus parameters is quite acute, underscoring the importance of such signals in normal acoustic perception. Surprisingly, the responses of auditory neurons in alert primates has been little studied, and we have limited information relating neural activity to the perception of these signals. In this study, we investigated the neural discriminability of sweep direction and velocity for frequency-modulated sweeps presented to alert rhesus macaque monkeys in both core and belt auditory cortical areas. We quantified how well these information-bearing parameters were encoded using spike train pattern discriminators, and compared decoder performance when neural responses were restricted to temporal patterns or firing rates. Decoding accuracy for firing rate alone exceeded chance, and rate-normalized, spike-timing information was essentially equivalent to the complete firing pattern. Although most belt areas showed small decreases in decoding accuracy relative to the primary field, all fields encoded and represented sweeps similarly. Thus, there was little evidence of hierarchical processing between core and belt fields for these stimuli, indicating that frequency modulation sweep direction and velocity are not specifically extracted in the early auditory cortical hierarchy.

Amorphous silicon resistors enable smaller pixels in photovoltaic retinal prosthesis
Objective. Clinical trials of the photovoltaic subretinal prosthesis PRIMA demonstrated feasibility of prosthetic central vision with resolution matching its 100 m pixel size. To improve prosthetic acuity further, pixel size should be decreased. However, there are multiple challenges, one of which is related to accommodating a compact shunt resistor within each pixel that discharges the electrodes between stimulation pulses and helps increase the contrast of the electric field pattern. Unfortunately, standard materials used in integrated circuit resistors do not match the resistivity required for small photovoltaic pixels. Therefore, we used a novel material - doped amorphous silicon (a-Si) and integrated it into photovoltaic arrays with pixel sizes down to 20 m. Approach. To fit within a few m2 area of the pixels and provide resistance in the M{Omega} range, the material should have sheet resistance of a few hundred k{Omega}/sq, which translates to resistivity of a few {Omega}*cm. The a-Si layer was deposited by low-pressure chemical vapor deposition (LPCVD) and its resistivity was adjusted by PH3 doping before encapsulating the resistors between SiO2 and SiC for stability in-vivo. Main Results. High-resolution retinal implants with integrated shunt resistors were fabricated with values ranging from 0.75 to 4 M{Omega} on top of the photovoltaic pixels of 55, 40, 30 and 20 m in size. Photoresponsivity with all pixel sizes was approximately 0.53 A/W, as high as in the arrays with no shunt resistor. The shunts shortened electrodes discharge time, with the average electric potential in electrolyte decreasing by only 21-31% when repetition rate increased from 2 to 30 Hz, as opposed to a 54-55% decrease without a shunt. Similarly, contrast of a Landolt C pattern increased from 16-22% with no shunt to 22-34% with a shunt. Further improvement in contrast is expected with pillar electrodes and local returns within each pixel. Significance. Miniature shunt resistors in a MOhm range can be fabricated from doped a-Si in a process compatible with manufacturing of photovoltaic arrays. The shunt resistors improved current injection and spatial contrast at video frame rates, without compromising the photoresponsivity. These advances are critical for scaling pixel sizes below 100 m to improve visual acuity of prosthetic vision.

Large Reaching Datasets Quantify the Impact of Age, Sex/Gender, and Experience on Motor Control
As we age, our movements become slower and less precise - but the extent of this decline remains unclear. To address this, we harmonized data from 2,185 participants across four published studies using a standard center-out reaching task. We found that older age was associated with a steady decline in reaction time (-1.2 ms/year), movement time (-2.3 ms/year), and movement precision (-0.02{degrees}/year). Although the rate of decline did not differ by sex/gender, females consistently reacted more slowly (-8 ms), moved more slowly (-37 ms), and exhibited greater precision (+0.5{degrees}) across the adult lifespan. Notably, sex/gender differences attenuated after accounting for experiential factors such as video game use and the amount of sleep per day, whereas age remained a robust and consistent predictor of motor decline. Together, these findings provide a large-scale quantification of age, sex/gender, and experiential effects on motor control, offering a normative benchmark to inform future clinical interventions aimed at preserving motor function across the lifespan.