Background and Objective:As optical coherence tomography (OCT) has enabled the identification of an expanding set of age-related macular degeneration (AMD) risk biomarkers and become central to routine clinical practice, there remains a need for a simplified grading scheme that allows physicians to communicate and synchronize AMD grading directly from standard OCT imaging rather than relying on traditional color fundus imaging. This study aims to establish a standardized OCT-based AMD classification that balances diagnostic accuracy with practicality for use across clinical and research settings. Patients and Methods:Spectral-domain optical coherence tomography scans were independently graded by two retinal specialists following the newly proposed Stanford OCT-Based AMD Classification (SOAC). Discrepancies were adjudicated by a third independent retinal specialist. Intergrader agreement was assessed using weighted kappa coefficients. Results:Among the 109 eyes from 108 patients (mean age 79.61 ± 7.57 years; 41.7% male, 58.3% female), AMD staging based on SOAC was distributed as follows: normal aging in 9 patients (8.3%), early AMD in 16 (14.7%), intermediate AMD in 32 (29.4%), neovascular AMD (nAMD) in 18 (16.5%), geographic atrophy (GA) in 20 (18.3%), and combined nAMD and GA in 14 (12.8%). The overall intergrader agreement demonstrated robust consistency, with a weighted kappa value of 0.95 (95% CI: 0.92-0.98), signifying excellent intergrader reliability and reinforcing the validity of SOAC. Conclusion:SOAC provides a standardized, OCT-based framework for AMD grading that demonstrates high intergrader agreement. By enabling consistent classification from commonly acquired OCT scans, SOAC supports reliable disease staging and facilitates integration across clinical studies and translational research. As imaging and molecular data continue to expand, SOAC can serve as a common OCT-based reference for phenotype refinement and longitudinal AMD studies.

BACKGROUND AND OBJECTIVE:This study assessed risk of mental health disorders in patients with age-related macular degeneration (AMD). PATIENTS AND METHODS:Data were obtained from an aggregated electronic health records database. Patients who were diagnosed with AMD with cataract were propensity score-matched with cataract controls. Diagnoses were identified using International Classification of Diseases, 10th Revision (ICD-10) codes. Subgroup analyses evaluated relative risk (RR) of new diagnoses of mental health disorders among patients with dry AMD, neovascular AMD (nAMD), vision impairment, and receipt of intravitreal therapy. RESULTS:After matching, 126,799 cases comprising 53.1% female patients with a mean age of 74.6 ± 8.9 years were included. Patients with AMD and cataract had elevated risk of receiving diagnoses of depression (RR = 1.27; 95% CI 1.24-1.29) and anxiety (RR = 1.19; 1.17-1.22). These patients were also at increased risk for self-harm (RR = 1.16), substance use (RR = 1.10), dysthymia (RR = 1.41), and psychosis (RR = 1.22) (all P < .05). The presence of visual impairment amplified these risks, particularly for depression (RR = 1.97) and anxiety (RR = 1.62). Patients with dry AMD had an increased risk of depression and anxiety compared to those with nAMD. Treatment with intravitreal injections in nAMD patients was associated with decreased risk of depression (RR = 0.88) and anxiety (RR = 0.82). CONCLUSIONS:AMD is associated with increased risk of mental health disorders, including anxiety, depression, and self-harm, particularly in the first year following diagnosis. Risk varies by disease subtype, visual function, and treatment status.

The rich diversity of synapses facilitates the capacity of neural circuits to transmit, process and store information. We used multiplex super-resolution proteometric imaging through array tomography to define features of single synapses in mouse neocortex. We find that glutamatergic synapses cluster into subclasses that parallel the distinct biochemical and functional categories of receptor subunits: GluA1/4, GluA2/3 and GluN1/GluN2B. Two of these subclasses align with physiological expectations based on synaptic plasticity: large AMPAR-rich synapses may represent potentiated synapses, whereas small NMDAR-rich synapses suggest "silent" synapses. The NMDA receptor content of large synapses correlates with spine neck diameter, and thus the potential for coupling to the parent dendrite. Overall, ultrastructural features predict receptor content of synapses better than parent neuron identity does, suggesting synapse subclasses act as fundamental elements of neuronal circuits. No barriers prevent future generalization of this approach to other species, or to study of human disorders and therapeutics.

Purpose: This case report highlights the importance of monitoring ocular health for patients starting on siponimod treatment, a sphingosine-1-phosphate receptor modulator, for relapsing-remitting multiple sclerosis. By showing how medication adverse events present in patients, we can revisit the current guidelines on ophthalmic evaluation recommendations. Observations: We report a 60-year-old patient who presented with unilateral blurry vision upon initiating siponimod therapy for the treatment of relapsing-remitting multiple sclerosis. Her exam findings did not show visual field defects but were significant for cystoid macular edema distorting the foveal contour. Upon stopping siponimod therapy, the patient's macular edema and symptoms resolved significantly within 7 days and completely resolved 1 month later. Conclusions and importance: This case showcases siponimod-associated cystoid macular edema in a patient without known risk factors, such as diabetes mellitus and uveitis. The patient also had the earliest reported symptom onset to date following the initiation of siponimod therapy. Current recommendations from the American Academy of Ophthalmology and FDA stress the importance of ophthalmic evaluation three to four months after treatment initiation for patients with a history of risk factors. Given our current case and its comparison with four previously reported cases, we recommend that physicians inform patients of possible ocular adverse events with siponimod therapy regardless of their past medical history and duration of treatment.

We present a complicated case of mixed mechanism glaucoma in the setting of failed corneal transplant and aphakia. The patient was a 54-year old male with HLA B27 uveitis and prior open globe injury. He was left aphakic after cataract extraction and had a subsequent corneal transplant for bullous keratopathy. Due to elevated intraocular pressure in the setting of a failed corneal graft, the decision was made to insert a pars plana tube shunt and perform repeat penetrating keratoplasty as a combined case with the glaucoma, cornea, and retina services. We illustrate the surgical steps and decision making and in this complex case.

Antibody (Ab)-based imaging techniques rely on reagents whose performance may be application specific. Because commercial antibodies are validated for only a few purposes, users interested in other applications may have to perform extensive in-house antibody testing. Here, we present a novel application-specific proxy screening step to efficiently identify candidate antibodies for array tomography (AT), a serial section volume microscopy technique for high-dimensional quantitative analysis of the cellular proteome. To identify antibodies suitable for AT-based analysis of synapses in mammalian brain, we introduce a heterologous cell-based assay that simulates characteristic features of AT, such as chemical fixation and resin embedding that are likely to influence antibody binding. The assay was included into an initial screening strategy to generate monoclonal antibodies that can be used for AT. This approach simplifies the screening of candidate antibodies and has high predictive value for identifying antibodies suitable for AT analyses. In addition, we have created a comprehensive database of AT-validated antibodies with a neuroscience focus and show that these antibodies have a high likelihood of success for postembedding applications in general, including immunogold electron microscopy. The generation of a large and growing toolbox of AT-compatible antibodies will further enhance the value of this imaging technique.

Adaptive neuronal circuit function requires a continual adjustment of synaptic network parameters known as “neuromodulation.” This process is now understood to be based primarily on the binding of myriad secreted “modulatory” ligands such as dopamine, serotonin and the neuropeptides to G protein-coupled receptors (GPCRs) that, in turn, regulate the function of the ion channels that establish synaptic weights and membrane excitability. Many of the basic molecular mechanisms of neuromodulation are now known, but the organization of neuromodulation at a network level is still an enigma. New single-cell RNA sequencing data and transcriptomic neurotaxonomies now offer bright new lights to shine on this critical “dark matter” of neuroscience. Here we leverage these advances to explore the cell-type-specific expression of genes encoding GPCRs, modulatory ligands, ion channels and intervening signal transduction molecules in mouse hippocampus area CA1, with the goal of revealing broad outlines of this well-studied brain structure’s neuromodulatory network architecture.

The spectacular successes of recurrent neural network models where key parameters are adjusted via backpropagation-based gradient descent have inspired much thought as to how biological neuronal networks might solve the corresponding synaptic credit assignment problem. There is so far little agreement, however, as to how biological networks could implement the necessary backpropagation through time, given widely recognized constraints of biological synaptic network signaling architectures. Here, we propose that extra-synaptic diffusion of local neuromodulators such as neuropeptides may afford an effective mode of backpropagation lying within the bounds of biological plausibility. Going beyond existing temporal truncation-based gradient approximations, our approximate gradient-based update rule, ModProp, propagates credit information through arbitrary time steps. ModProp suggests that modulatory signals can act on receiving cells by convolving their eligibility traces via causal, time-invariant and synapse-type-specific filter taps. Our mathematical analysis of ModProp learning, together with simulation results on benchmark temporal tasks, demonstrate the advantage of ModProp over existing biologically-plausible temporal credit assignment rules. These results suggest a potential neuronal mechanism for signaling credit information related to recurrent interactions over a longer time horizon. Finally, we derive an in-silico implementation of ModProp that could serve as a low-complexity and causal alternative to backpropagation through time.

Journal Article Using Computational Methods and 3D Volume EM Reconstructions to Examine Interactions Between Microglia and Oligodendrocyte Precursor Cells in Mouse Cortex Get access JoAnn Buchanan, JoAnn Buchanan Allen Institute for Brain Science, Neural Coding, Seattle, WA, USA Corresponding author: joannb@alleninstititue.org Search for other works by this author on: Oxford Academic Google Scholar Jenna Schardt, Jenna Schardt Allen Institute for Brain Science, Neural Coding, Seattle, WA, USA Search for other works by this author on: Oxford Academic Google Scholar Forrest Collman, Forrest Collman Allen Institute for Brain Science, Neural Coding, Seattle, WA, USA Search for other works by this author on: Oxford Academic Google Scholar Stephen J Smith, Stephen J Smith Allen Institute for Brain Science, Neural Coding, Seattle, WA, USA Search for other works by this author on: Oxford Academic Google Scholar Dwight E Bergles, Dwight E Bergles Solomon Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA Search for other works by this author on: Oxford Academic Google Scholar Jenna Glatzer, Jenna Glatzer Solomon Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA Search for other works by this author on: Oxford Academic Google Scholar H Sebastian Seung, H Sebastian Seung Princeton Neuroscience Institute, Princeton University, Princeton, NJ, USA Search for other works by this author on: Oxford Academic Google Scholar R Clay Reid, R Clay Reid Allen Institute for Brain Science, Neural Coding, Seattle, WA, USA Search for other works by this author on: Oxford Academic Google Scholar Nuno da Costa Nuno da Costa Allen Institute for Brain Science, Neural Coding, Seattle, WA, USA Search for other works by this author on: Oxford Academic Google Scholar Microscopy and Microanalysis, Volume 28, Issue S1, 1 August 2022, Pages 1394–1395, https://doi.org/10.1017/S1431927622005682 Published: 01 August 2022

The primary function common to every neuron is communication with other neurons. Such cell-cell signaling can take numerous forms, including fast synaptic transmission and slower neuromodulation via secreted messengers, such as neuropeptides, dopamine, and many other diffusible small molecules. Individual neurons are quite diverse, however, in all particulars of both synaptic and neuromodulatory communication. Neuron classification schemes have therefore proven very useful in exploring the emergence of network function, behavior, and cognition from the communication functions of individual neurons. Recently published single-cell mRNA sequencing data and corresponding transcriptomic neuron classifications from turtle, songbird, mouse, and human provide evidence for a long evolutionary history and adaptive significance of localized peptidergic signaling. Across all four species, sets of at least twenty orthologous cognate pairs of neuropeptide precursor protein and receptor genes are expressed in individually sparse but heavily overlapping patterns suggesting that all forebrain neuron types are densely interconnected by local peptidergic signals.

Brains learn tasks via experience-driven differential adjustment of their myriad individual synaptic connections, but the mechanisms that target appropriate adjustment to particular connections remain deeply enigmatic. While Hebbian synaptic plasticity, synaptic eligibility traces, and top-down feedback signals surely contribute to solving this synaptic credit-assignment problem, alone, they appear to be insufficient. Inspired by new genetic perspectives on neuronal signaling architectures, here, we present a normative theory for synaptic learning, where we predict that neurons communicate their contribution to the learning outcome to nearby neurons via cell-type-specific local neuromodulation. Computational tests suggest that neuron-type diversity and neuron-type-specific local neuromodulation may be critical pieces of the biological credit-assignment puzzle. They also suggest algorithms for improved artificial neural network learning efficiency.

Purpose Animal models have demonstrated the role of dopamine in regulating axial elongation, the critical feature of myopia. Because frequent delivery of dopaminergic agents via peribulbar, intravitreal, or intraperitoneal injections is not clinically viable, we sought to evaluate ocular penetration and safety of the topically applied dopaminergic prodrug etilevodopa. Methods The ocular penetration of dopamine and dopaminergic prodrugs (levodopa and etilevodopa) were quantified using an enzyme-linked immunosorbent assay in enucleated porcine eyes after a single topical administration. The pharmacokinetic profile of the etilevodopa was then assessed in rats. A four-week once-daily application of etilevodopa as a topical eye drop was conducted to establish its safety profile. Results At 24 hours, the studied prodrugs showed increased dopaminergic derivatives in the vitreous of porcine eyes. Dopamine 0.5% (P = 0.0123) and etilevodopa 10% (p = 0.370) achieved significant vitreous concentrations. Etilevodopa 10% was able to enter the posterior segment of the eye after topical administration in rats with an intravitreal half-life of eight hours after single topical administration. Monthly application of topical etilevodopa showed no alterations in retinal ocular coherence tomography, electroretinography, caspase staining, or TUNEL staining. Conclusions At similar concentrations, no difference in ocular penetration of levodopa and etilevodopa was observed. However, etilevodopa was highly soluble and able to be applied at higher topical concentrations. Dopamine exhibited both high solubility and enhanced penetration into the vitreous as compared to other dopaminergic prodrugs. Translational Relevance These findings indicate the potential of topical etilevodopa and dopamine for further study as a therapeutic treatment for myopia.

Animals learn and form memories by jointly adjusting the efficacy of their synapses. How they efficiently solve the underlying temporal credit assignment problem remains elusive. Here, we re-analyze the mathematical basis of gradient descent learning in recurrent spiking neural networks (RSNNs) in light of the recent single-cell transcriptomic evidence for cell-type-specific local neuropeptide signaling in the cortex. Our normative theory posits an important role for the notion of neuronal cell types and local diffusive communication by enabling biologically plausible and efficient weight update. While obeying fundamental biological constraints, including separating excitatory vs inhibitory cell types and observing connection sparsity, we trained RSNNs for temporal credit assignment tasks spanning seconds and observed that the inclusion of local modulatory signaling improved learning efficiency. Our learning rule puts forth a novel form of interaction between modulatory signals and synaptic transmission. Moreover, it suggests a computationally efficient learning method for bio-inspired artificial intelligence.

Purpose: To evaluate the performance of a deep learning algorithm in the detection of referral-warranted diabetic retinopathy (RDR) on low-resolution fundus images acquired with a smartphone and indirect ophthalmoscope lens adapter. Methods: An automated deep learning algorithm trained on 92,364 traditional fundus camera images was tested on a dataset of smartphone fundus images from 103 eyes acquired from two previously published studies. Images were extracted from live video screenshots from fundus examinations using a commercially available lens adapter and exported as a screenshot from live video clips filmed at 1080p resolution. Each image was graded twice by a board-certified ophthalmologist and compared to the output of the algorithm, which classified each image as having RDR (moderate nonproliferative DR or worse) or no RDR. Results: In spite of the presence of multiple artifacts (lens glare, lens particulates/smudging, user hands over the objective lens) and low-resolution images achieved by users of various levels of medical training, the algorithm achieved a 0.89 (95% confidence interval [CI] 0.83-0.95) area under the curve with an 89% sensitivity (95% CI 81%-100%) and 83% specificity (95% CI 77%-89%) for detecting RDR on mobile phone acquired fundus photos. Conclusions: The fully data-driven artificial intelligence-based grading algorithm herein can be used to screen fundus photos taken from mobile devices and identify with high reliability which cases should be referred to an ophthalmologist for further evaluation and treatment. Translational Relevance: The implementation of this algorithm on a global basis could drastically reduce the rate of vision loss attributed to DR.

Purpose: To describe clinical findings, laboratory values, and treatment response of patients with monoclonal gammopathy of undetermined significance (MGUS) demonstrating neurosensory macular detachment. Design: Retrospective case series. Participants: Seven eyes of 4 patients (3 men and 1 woman; age range, 60-81 years) with neurosensory macular detachment, treatment-resistant submacular fluid, and vitelliform material. Methods: We retrospectively reviewed the medical and ocular histories, ocular examination findings, retinal imaging, ocular disease course, and laboratory findings in 4 patients with submacular fluid associated with MGUS. Main Outcome Measures: Description of the macular findings and treatment courses of 4 patients diagnosed with MGUS maculopathy. Results: Seven eyes of 4 patients demonstrated neurosensory macular detachment with treatment-resistant submacular fluid and vitelliform material. No eyes demonstrated signs of significant hyperviscosity retinopathy. Fluorescein angiography showed no definite leakage in any involved eye. Laboratory evaluation revealed immunoglobulin G MGUS in all 4 patients. All 4 patients were resistant to treatments aimed at resolving the subretinal fluid, including some combination of anti-vascular endothelial growth factor injections, photodynamic therapy, topical dorzolamide, oral dosing of eplerenone or acetazolamide, or some combination thereof. In 3 patients, MGUS underwent malignant transformation 24 to 144 months after diagnosis, in 1 patient to lymphoplasmacytic lymphoma and in 2 patients to multiple myeloma. The fourth patient showed no evidence of malignancy 8 years after diagnosis. Conclusions: Submacular fluid without fluorescein leakage and unresponsive to conventional treatment may suggest an underlying immunoproliferative disorder that we have termed monoclonal gammopathy of macular significance. Given the propensity for monoclonal gammopathy of macular significance to transform into malignant disease in our series, serum protein analysis should be considered in patients with neurosensory macular detachment not attributable to known causes. (C) 2019 by the American Academy of Ophthalmology

Purpose: To test the safety and preliminary efficacy of rapid, nonpharmacologic anesthesia via cooling for intravitreal injections. Design: Single-center, randomized phase 1 dose-ranging safety study (ClinicalTrials.gov identifier, NCT02872012). Participants: Adults 18 years of age or older with a diagnosis of exudative macular degeneration or diabetic macular edema requiring bilateral anti-vascular endothelial growth factor therapy were included. Methods: A handheld device was developed to provide anesthesia via cooling to a focal area on the surface of the eye before intravitreal treatment (IVT). In 22 patients undergoing bilateral IVT, 1 eye was randomized to receive standard of care (SOC) lidocaine-based anesthesia and the other eye received cooling-anesthesia at 1 of 5 different temperatures and cooling times. Subjective pain was assessed via the visual analog scale (VAS; range, 1-10) at 2 time points: (1) immediately after IVT and (2) 4 hours after IVT. Treated eyes were assessed for ocular safety 24 hours after IVT. Main Outcome Measures: We determined the occurrence of adverse events in eyes treated with cooling anesthesia. Mean VAS pain scores immediately after IVT and 4 hours after IVT in eyes receiving cooling anesthesia were compared with eyes receiving SOC. Results: A total of 44 eyes were treated, 22 with cooling anesthesia and 22 with SOC. No dose-related toxicity was found with cooling anesthesia. Mild, transient adverse events were recorded in 32% of patients treated with cooling anesthesia versus 44% of patients receiving SOC. The mean +/- standard error of the mean (SEM) VAS pain scores immediately after intravitreal injection were 2.3 +/- 0.4 for patients receiving SOC and 2.2 +/- 0.6 in patients receiving -10 degrees.C cooling anesthesia (P = 0.8). Mean +/- SEM pain scores 4 hours after injection were 1.6 +/- 0.4 for SOC and 1.2 +/- 0.5 in the combined -10 degrees C arms (P = 0.56). Total mean +/- SEM procedure time was 124 +/- 5 seconds for patients treated with cooling anesthesia versus 395 +/- 40 seconds for SOC (P < 0.0001). Conclusions: Ultra-rapid cooling of the eye for anesthesia was well tolerated, with -10 degrees C treatment resulting in comparable levels of anesthesia to SOC with a reduction in procedure time. (C) 2020 by the American Academy of Ophthalmology

Neuropeptides, members of a large and evolutionarily ancient family of proteinaceous cell-cell signaling molecules, are widely recognized as extremely potent regulators of brain function and behavior. At the cellular level, neuropeptides are known to act mainly via modulation of ion channel and synapse function, but functional impacts emerging at the level of complex cortical synaptic networks have resisted mechanistic analysis. New findings from single-cell RNA-seq transcriptomics now illuminate intricate patterns of cortical neuropeptide signaling gene expression and new tools now offer powerful molecular access to cortical neuropeptide signaling. Here we highlight some of these new findings and tools, focusing especially on prospects for experimental and theoretical exploration of peptidergic and synaptic networks interactions underlying cortical function and plasticity.

Purpose: Intravitreal injection therapy (IVT) is the most performed procedure in ophthalmology. This study was conducted to determine current trends in IVT delivery. Methods: An online, 31-question, multiple-choice survey was sent to 1677 retina specialists. The survey consisted of 3 sections: general questions, procedure technique, and postprocedure technique. Results: A total of 264 (16%) retina specialists completed the survey. The use of povidone-iodine (100%) and small-gauge needles (97%) was common, whereas ocular anesthesia was split among lidocaine gel (31%), lidocaine drops (25%), subconjunctival lidocaine (28%), and lidocaine-soaked pledgets (15%). More than 85% indicated povidone-iodine contributes to post-IVT corneal toxicity, and 12% reported that a needlestick injury to physician or staff occurred during IVT. Conclusions: Key areas for IVT improvement include optimized ocular anesthesia, development of a guarded needle for ocular drug delivery, and formulation of a less toxic ocular antiseptic.

A molecular imaging survey reveals the evolution of mouse brain synapse populations from birth through old age