Planet Neuroscience

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The brain in Spain: The legacy of Santiago Ramón y Cajal

The Neuroscientist, Ahead of Print.
The legacy of Santiago Ramón y Cajal, Spain’s first Nobel laureate neuroscientist recognized as the founding father of modern neuroscience, is to be preserved in a new museum in Madrid: the National Museum of Natural Sciences (MNCN), one of the most important scientific research institutes in the country sciences in the scope of natural sciences of the Spanish National Research Council. For a boy who dreamed of being an artist but started his career apprenticed to first a barber and then a cobbler, Santiago Ramón y Cajal made a distinguished mark in science. One of Cajal’s most important contributions to our understanding of the brain was his discovery of the direction of the information flow within neurons and in neural circuits, which he called the “dynamic polarization law,” without a doubt the founding principle of neurosciences. The exposition planned by the MNCN is a perfect occasion to show the academy and, it is hoped, the general public at large the beautiful organization of the nervous system as first acknowledged by modern science. With the highly motivated organizers of this well-planned initiative, neuroscientists at the Cajal Institute are confident that this sample of the Cajal legacy will also be taken as an esthetic experience for those who approach it for the first time. It might be that science and art often go together.

in The Neuroscientist on 2025-01-20 07:33:25 UTC.

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Cortical Acetylcholine Response to Deep Brain Stimulation of the Basal Forebrain in Mice

Journal of Neurophysiology, Ahead of Print.

in Journal of Neurophysiology on 2025-01-20 07:11:27 UTC.

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Changes in thoracic erector spinae regional activation during postural adjustments and functional reaching tasks after spinal cord injury

Journal of Neurophysiology, Ahead of Print.

in Journal of Neurophysiology on 2025-01-20 05:21:20 UTC.

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Multiplex Nodal Modularity: A novel network metric for the regional analysis of amnestic mild cognitive impairment during a working memory binding task

arXiv:2501.09805v1 Announce Type: new Abstract: Modularity is a well-established concept for assessing community structures in various single and multi-layer networks, including those in biological and social domains. Biological networks, such as the brain, are known to exhibit group structure at a variety of scales -- local, meso, and global scale. Modularity, while useful in describing mesoscale brain organization, is limited as a metric to a global scale describing the overall strength of community structure. This approach, while valuable, overlooks important localized variations in community structure at the node level. To address this limitation, we extended modularity to individual nodes. This novel measure of nodal modularity ($nQ$) captures both meso and local scale changes in modularity. We hypothesized that $nQ$ illuminates granular changes in the brain due to diseases such as Alzheimer's disease (AD), which are known to disrupt the brain's modular structure. We explored $nQ$ in multiplex networks of a visual short-term memory binding task in fMRI and DTI data in the early stages of AD. Observed changes in $nQ$ in fMRI and DTI networks aligned with known trajectories of AD and were linked to common biomarkers of the disease, including amyloid-$\beta$ and tau. Additionally, $nQ$ clearly differentiated MCI from MCI converters showing indications that $nQ$ may be a useful diagnostic tool for characterizing disease stages. Our findings demonstrate the utility of $nQ$ as a measure of localized group structure, providing novel insights into temporal and disease related variability at the node level. Given the widespread application of modularity as a global measure, $nQ$ represents a significant advancement, providing a granular measure of network organization applicable to a wide range of disciplines.

in arXiv: Quantitative Biology: Neurons and Cognition on 2025-01-20 05:00:00 UTC.

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Evaluation and Efficiency Comparison of Evolutionary Algorithms for Service Placement Optimization in Fog Architectures

arXiv:2501.09958v1 Announce Type: new Abstract: This study compares three evolutionary algorithms for the problem of fog service placement: weighted sum genetic algorithm (WSGA), non-dominated sorting genetic algorithm II (NSGA-II), and multiobjective evolutionary algorithm based on decomposition (MOEA/D). A model for the problem domain (fog architecture and fog applications) and for the optimization (objective functions and solutions) is presented. Our main concerns are related to optimize the network latency, the service spread and the use of the resources. The algorithms are evaluated with a random Barabasi-Albert network topology with 100 devices and with two experiment sizes of 100 and 200 application services. The results showed that NSGA-II obtained the highest optimizations of the objectives and the highest diversity of the solution space. On the contrary, MOEA/D was better to reduce the execution times. The WSGA algorithm did not show any benefit with regard to the other two algorithms.

in arXiv: Computer Science: Neural and Evolutionary Computing on 2025-01-20 05:00:00 UTC.

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Dendritic Localized Learning: Toward Biologically Plausible Algorithm

arXiv:2501.09976v1 Announce Type: new Abstract: Backpropagation is the foundational algorithm for training neural networks and a key driver of deep learning's success. However, its biological plausibility has been challenged due to three primary limitations: weight symmetry, reliance on global error signals, and the dual-phase nature of training, as highlighted by the existing literature. Although various alternative learning approaches have been proposed to address these issues, most either fail to satisfy all three criteria simultaneously or yield suboptimal results. Inspired by the dynamics and plasticity of pyramidal neurons, we propose Dendritic Localized Learning (DLL), a novel learning algorithm designed to overcome these challenges. Extensive empirical experiments demonstrate that DLL satisfies all three criteria of biological plausibility while achieving state-of-the-art performance among algorithms that meet these requirements. Furthermore, DLL exhibits strong generalization across a range of architectures, including MLPs, CNNs, and RNNs. These results, benchmarked against existing biologically plausible learning algorithms, offer valuable empirical insights for future research. We hope this study can inspire the development of new biologically plausible algorithms for training multilayer networks and advancing progress in both neuroscience and machine learning.

in arXiv: Computer Science: Neural and Evolutionary Computing on 2025-01-20 05:00:00 UTC.

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Fast energy-aware OLSR routing in VANETs by means of a parallel evolutionary algorithm

arXiv:2501.09996v1 Announce Type: new Abstract: This work tackles the problem of reducing the power consumption of the OLSR routing protocol in vehicular networks. Nowadays, energy-aware and green communication protocols are important research topics, specially when deploying wireless mobile networks. This article introduces a fast automatic methodology to search for energy-efficient OLSR configurations by using a parallel evolutionary algorithm. The experimental analysis demonstrates that significant improvements over the standard configuration can be attained in terms of power consumption, with no noteworthy loss in the QoS.

in arXiv: Computer Science: Neural and Evolutionary Computing on 2025-01-20 05:00:00 UTC.

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A swarm algorithm for collaborative traffic in vehicular networks

arXiv:2501.10007v1 Announce Type: new Abstract: Vehicular ad hoc networks (VANETs) allow vehicles to exchange warning messages with each other. These specific kinds of networks help reduce hazardous traffic situations and improve safety, which are two of the main objectives in developing Intelligent Transportation Systems (ITS). For this, the performance of VANETs should guarantee the delivery of messages in a required time. An obstacle to this is that the data traffic generated may cause network congestion. Data congestion control is used to enhance network capabilities, increasing the reliability of the VANET by decreasing packet losses and communication delays. In this study, we propose a swarm intelligence based distributed congestion control strategy to maintain the channel usage level under the threshold of network malfunction, while keeping the quality-of-service of the VANET high. An exhaustive experimentation shows that the proposed strategy improves the throughput of the network, the channel usage, and the stability of the communications in comparison with other competing congestion control strategies.

in arXiv: Computer Science: Neural and Evolutionary Computing on 2025-01-20 05:00:00 UTC.

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Infrastructure Deployment in Vehicular Communication Networks Using a Parallel Multiobjective Evolutionary Algorithm

arXiv:2501.10016v1 Announce Type: new Abstract: This article describes the application of a multiobjective evolutionary algorithm for locating roadside infrastructure for vehicular communication networks over realistic urban areas. A multiobjective formulation of the problem is introduced, considering quality-of-service and cost objectives. The experimental analysis is performed over a real map of M\'alaga, using real traffic information and antennas, and scenarios that model different combinations of traffic patterns and applications (text/audio/video) in the communications. The proposed multiobjective evolutionary algorithm computes accurate trade-off solutions, significantly improving over state-of-the-art algorithms previously applied to the problem.

in arXiv: Computer Science: Neural and Evolutionary Computing on 2025-01-20 05:00:00 UTC.

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Random-Key Algorithms for Optimizing Integrated Operating Room Scheduling

arXiv:2501.10243v1 Announce Type: new Abstract: Efficient surgery room scheduling is essential for hospital efficiency, patient satisfaction, and resource utilization. This study addresses this challenge by introducing a novel concept of Random-Key Optimizer (RKO), rigorously tested on literature and new, real-world inspired instances. Our combinatorial optimization problem incorporates multi-room scheduling, equipment scheduling, and complex availability constraints for rooms, patients, and surgeons, facilitating rescheduling and enhancing operational flexibility. The RKO approach represents solutions as points in a continuous space, which are then mapped in the problem solution space via a deterministic function known as a decoder. The core idea is to operate metaheuristics and heuristics in the random-key space, unaware of the original solution space. We design the Biased Random-Key Genetic Algorithm with $Q$-Learning, Simulated Annealing, and Iterated Local Search for use within an RKO framework, employing a single decoder function. The proposed metaheuristics are complemented by lower-bound formulations, providing optimal gaps for evaluating the effectiveness of the heuristic results. Our results demonstrate significant lower and upper bounds improvements for the literature instances, notably proving one optimal result. Furthermore, the best-proposed metaheuristic efficiently generates schedules for the newly introduced instances, even in highly constrained scenarios. This research offers valuable insights and practical solutions for improving surgery scheduling processes, offering tangible benefits to hospitals by optimising resource allocation, reducing patient wait times, and enhancing overall operational efficiency.

in arXiv: Computer Science: Neural and Evolutionary Computing on 2025-01-20 05:00:00 UTC.

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Optimal Restart Strategies for Parameter-dependent Optimization Algorithms

arXiv:2501.10173v1 Announce Type: cross Abstract: This paper examines restart strategies for algorithms whose successful termination depends on an unknown parameter $\lambda$. After each restart, $\lambda$ is increased, until the algorithm terminates successfully. It is assumed that there is a unique, unknown, optimal value for $\lambda$. For the algorithm to run successfully, this value must be reached or surpassed. The key question is whether there exists an optimal strategy for selecting $\lambda$ after each restart taking into account that the computational costs (runtime) increases with $\lambda$. In this work, potential restart strategies are classified into parameter-dependent strategy types. A loss function is introduced to quantify the wasted computational cost relative to the optimal strategy. A crucial requirement for any efficient restart strategy is that its loss, relative to the optimal $\lambda$, remains bounded. To this end, upper and lower bounds of the loss are derived. Using these bounds it will be shown that not all strategy types are bounded. However, for a particular strategy type, where $\lambda$ is increased multiplicatively by a constant factor $\lambda$, the relative loss function is bounded. Furthermore, it will be demonstrated that within this strategy type, there exists an optimal value for $\lambda$ that minimizes the maximum relative loss. In the asymptotic limit, this optimal choice of $\lambda$ does not depend on the unknown optimal $\lambda$.

in arXiv: Computer Science: Neural and Evolutionary Computing on 2025-01-20 05:00:00 UTC.

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Octopus Inspired Optimization Algorithm: Multi-Level Structures and Parallel Computing Strategies

arXiv:2410.07968v2 Announce Type: replace Abstract: This paper introduces a novel bionic intelligent optimisation algorithm, Octopus Inspired Optimization (OIO) algorithm, which is inspired by the neural structure of octopus, especially its hierarchical and decentralised interaction properties. By simulating the sensory, decision-making, and executive abilities of octopuses, the OIO algorithm adopts a multi-level hierarchical strategy, including tentacles, suckers, individuals and groups, to achieve an effective combination of global and local search. This hierarchical design not only enhances the flexibility and efficiency of the algorithm, but also significantly improves its search efficiency and adaptability. In performance evaluations, including comparisons with existing mainstream intelligent optimisation algorithms, OIO shows faster convergence and higher accuracy, especially when dealing with multimodal functions and high-dimensional optimisation problems. This advantage is even more pronounced as the required minimum accuracy is higher, with the OIO algorithm showing an average speedup of 2.27 times that of conventional particle swarm optimisation (PSO) and 9.63 times that of differential evolution (DE) on multimodal functions. In particular, when dealing with high-dimensional optimisation problems, OIO achieves an average speed of 10.39 times that of DE, demonstrating its superior computational efficiency. In addition, the OIO algorithm also shows a reduction of about 5\% in CPU usage efficiency compared to PSO, which is reflected in the efficiency of CPU resource usage also shows its efficiency. These features make the OIO algorithm show great potential in complex optimisation problems, and it is especially suitable for application scenarios that require fast, efficient and robust optimisation methods, such as robot path planning, supply chain management optimisation, and energy system management.

in arXiv: Computer Science: Neural and Evolutionary Computing on 2025-01-20 05:00:00 UTC.

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Evidence for a co-regulation of decision-making and movement generation

Journal of Neurophysiology, Ahead of Print.

in Journal of Neurophysiology on 2025-01-20 04:31:12 UTC.

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Targeted Antisense Oligonucleotide Treatment Rescues Developmental Alterations in Spinal Muscular Atrophy Organoids

Spinal muscular atrophy (SMA) is a severe neurological disease caused by mutations in the SMN1 gene, characterized by early onset and degeneration of lower motor neurons. Understanding early neurodevelopmental defects in SMA is crucial for optimizing therapeutic interventions. Using spinal cord and cerebral organoids generated from multiple SMA type I donors, we revealed widespread disease mechanisms beyond motor neuron degeneration. Single-cell transcriptomics uncovered pervasive alterations across neural populations, from progenitors to neurons, demonstrating SMN-dependent dysregulation of neuronal differentiation programs. Multi-electrode array analysis identified consistent hyperexcitability in both spinal and brain organoids, establishing altered electrical properties as a central nervous system-wide feature of pathogenesis. Early administration of an optimized antisense oligonucleotide (ASO) that restored SMN levels rescued morphological and functional deficits in spinal cord organoids across different genetic backgrounds. Importantly, this early intervention precisely corrected aberrant splicing in newly identified SMN1 targets enriched at critical nodes of neuronal differentiation. Our findings demonstrate that early developmental defects are core features of SMA pathogenesis that can be prevented by timely therapeutic intervention, providing new insights for optimizing treatment strategies.

in bioRxiv: Neuroscience on 2025-01-19 00:00:00 UTC.

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7-ketocholesterol contributes to microglia-driven increases in astrocyte reactive oxygen species in Alzheimer's disease

Oxidative stress is a prominent feature of Alzheimer's disease. Within this context, cholesterol undergoes oxidation, producing the pro-inflammatory product 7-ketocholesterol (7-KC). In this study, we observe elevated levels of 7-KC in the brains of the 3xTg mouse model of AD. To further understand the contribution of 7-KC on the oxidative environment, we developed a method to express a genetically encoded fluorescent hydrogen peroxide (H2O2) sensor in astrocytes, the primary source of cholesterol in the brain. With this sensor, we discovered that 7-KC increases H2O2 levels in astrocytes in vivo, but not when directly applied to astrocytes in vitro. Interestingly, when 7-KC was applied to a microglia cell line alone or mixed astrocyte and microglia cultures, it resulted in microglia activation and increased oxidative stress in astrocytes. Depletion of microglia from 3xTg mice resulted in reduced 7-KC in the brains of these mice. Taken together, these findings suggest that 7-KC, acting through microglia, contributes to increased astrocyte oxidative stress in AD. This study sheds light on the complex interplay between cholesterol oxidation, microglia activation, and astrocyte oxidative stress in the pathogenesis of AD.

in bioRxiv: Neuroscience on 2025-01-19 00:00:00 UTC.

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NAc-DBS selectively enhances memory updating without effect on retrieval

Deep brain stimulation (DBS) has emerged as a widely used therapeutic option when pharmacological treatments prove ineffective or refractory for psychiatric patients. The nucleus accumbens (NAc) represents a frequently targeted site in DBS interventions due to its demonstrated safety profile and therapeutic efficacy in obsessive-compulsive disorder, major depression, and anorexia nervosa. However, limited mechanistic understanding hampers its broader clinical applicability. This study sought to delineate the distinct behavioural dimensions modulated by NAc-DBS, its impact on distinct facets of memory, and to elucidate the underlying brain-network mechanism of action. We developed a novel spatial navigation task for rats and employed a high-dimensional behavioural analysis complemented by fMRI to dissect the cognitive, behavioural and neurobiological effects of NAc-DBS. Active NAc-DBS produced a selective enhancement of long-term memory encoding without affecting memory recall or working memory. We found no effect of NAc-DBS on motor, appetitive or stress-related behaviours. Sustained neuronal activation in the NAc, septum, entorhinal and insular cortex demonstrated no desensitization to chronic NAc-DBS, which triggered a functional reorganization among dopaminergic-related structures. These findings suggest that NAc-DBS induces a functional reorganization in the mesocorticolimbic system, potentially mimicking a dopaminergic novelty signal to enhance memory updating. This provides a mechanistic basis for the therapeutic use of NAc-DBS, particularly in improving cognitive flexibility in psychiatric disorders.

in bioRxiv: Neuroscience on 2025-01-19 00:00:00 UTC.

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Reciprocal interaction between cortical SST and PV interneurons in regulating top-down retinothalamic refinement

Refinement of thalamic circuits is crucial for the proper maturation of sensory circuits. In the visual system, this process is regulated by corticothalamic feedback during the experience-dependent phase of development. Yet the cortical circuits modulating this feedback remain elusive. Here, we demonstrate opposing roles for cortical somatostatin (SST) and parvalbumin (PV) interneurons in shaping retinogeniculate connectivity during the thalamic sensitive period (P20-30). Early in the refinement process, SST interneurons promote the strengthening and pruning of retinal inputs in the thalamus, as evidenced by disrupted synaptic refinement following their ablation. In contrast, PV interneurons, which mature later, act as a brake on this refinement, with their ablation leading to enhanced pruning of retinogeniculate connections. Notably, manipulating the relative balance between these inhibitory circuits can regulate sensory deprivation-induced retinogeniculate remodeling. Taken together, our findings show that cortical SST and PV interneuron circuits drive reciprocal antagonism that gate experience-dependent feedforward thalamic refinement.

in bioRxiv: Neuroscience on 2025-01-19 00:00:00 UTC.

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Decreased KCC2 expression in the human spinal dorsal horn associated with chronic pain and long-term opioid use

Loss of GABAergic and glycinergic inhibitory efficacy in the spinal dorsal horn is associated with neuropathic pain and opioid-induced hyperalgesia in rodent models. Downregulation of the KCC2 chloride extrusion transporter is a key mechanism underlying this decreased inhibitory efficacy, but to-date there is no evidence supporting or opposing this hypothesis in humans. Here we demonstrate that KCC2 expression is decreased in superficial dorsal horn neurons of organ donors who died with a documented history of pain, or of long-term opioid use. We show profoundly decreased KCC2 dorsal horn membrane expression in a primary cohort associated with either chronic pain or opioid use, and in a replication cohort of mixed chronic pain and opioid use history. These results show that decreased dorsal horn inhibitory efficacy likely promotes chronic pain in humans and support the development of therapeutics augmenting KCC2 function as a treatment for chronic pain and opioid use disorders.

in bioRxiv: Neuroscience on 2025-01-19 00:00:00 UTC.

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Persistent interferon signaling that causes sensory neuron plasticity and pain in arthritis

While the inflammatory processes in rheumatoid arthritis have been described, mechanisms driving pain are poorly defined. Here, we used a multitude of approaches to uncover the neural basis, mediators, intracellular signaling pathway and the mechanism of inflammatory pain. In cartilage autoantibody-induced arthritis mice, an early immune-activation and a cytokine storm were mainly driven by vascular cells and monocyte/macrophages in the dorsal root ganglion. However, persistently elevated interferons and receptor-activation of the MNK1/2-eIF4E signaling pathway at all disease phases caused sensory-motor dysfunction and pain by inducing hyperexcitability and sensitization of Gfra3+ sensory neurons. Like mice, human sensory neurons expressed interferon receptors and interferons were elevated only in individuals with painful rheumatoid arthritis. Signaling pathway inhibition in vivo reversed pain and restored limb function. The finding that joint pain before and during arthritis is caused by a defined cytokine and signaling pathway holds promise for targeted therapies for pain relief in arthritis.

in bioRxiv: Neuroscience on 2025-01-19 00:00:00 UTC.

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Integrative Gene Co-expression Network Analysis Reveals Protein-Coding and lncRNA Genes Associated with Alzheimer's Disease Pathology

Introduction: Alzheimer's disease (AD) is a complex neurodegenerative disorder involving widespread molecular disruptions, many of which remain poorly understood. While AD pathology progresses through distinct brain regions, it is unclear whether these regions are similarly affected. Long non-coding RNAs (lncRNAs) have emerged as key regulators in cellular processes, but their roles in AD remain largely unexplored. A comprehensive analysis of the complex molecular interactions underlying AD, particularly the roles of lncRNAs in their interactions with protein-coding genes and the comparison of networks across brain regions, could offer valuable insights into the disease's progression and underlying mechanisms. Method: To address this, we applied consensus weighted gene co-expression network analysis using a meta-analytic approach to 396 postmortem brain RNA-seq samples to explore AD pathophysiology mechanisms. Results: Our study revealed significant network rewiring in AD, with pronounced alterations in the temporal cortex compared to the frontal cortex. While the temporal cortex showed adaptive changes in gene interactions, the frontal cortex exhibited a loss of healthy correlations, potentially reflecting different levels of disease progression. We identified key players in the temporal cortex AD network, including 46 protein-coding genes and 27 lncRNAs. Using the established functions of protein-coding genes as anchors, we provided functional annotations for over 100 lncRNAs across two brain regions, identifying potential lncRNAs involved in AD pathology and highlighting their roles in both healthy and diseased states. Conclusion: We provided novel insights into the molecular interactions underlying AD and introduced new candidate protein-coding and lncRNA genes for further experimental validation and therapeutic exploration.

in bioRxiv: Neuroscience on 2025-01-19 00:00:00 UTC.

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Takens' theorem to assess EEG traces: regional variations in brain dynamics

Takens' theorem (TT) proves that the behaviour of a dynamical system can be effectively reconstructed within a multidimensional phase space. This offers a comprehensive framework for examining temporal dependencies, dimensional complexity and predictability of time series data. We applied TT to investigate the physiological regional differences in EEG brain dynamics of healthy subjects, focusing on three key channels: FP1 (frontal region), C3 (sensorimotor region), and O1 (occipital region). We provided a detailed reconstruction of phase spaces for each EEG channel using time-delay embedding. The reconstructed trajectories were quantified through measures of trajectory spread and average distance, offering insights into the temporal structure of brain activity that traditional linear methods struggle to capture. Variability and complexity were found to differ across the three regions, revealing notable regional variations. FP1 trajectories exhibited broader spreads, reflecting the dynamic complexity of frontal brain activity associated with higher cognitive functions. C3, involved in sensorimotor integration, displayed moderate variability, reflecting its functional role in coordinating sensory inputs and motor outputs. O1, responsible for visual processing, showed constrained and stable trajectories, consistent with repetitive and structured visual dynamics. These findings align with the functional specialization of different cortical areas, suggesting that the frontal, sensorimotor and occipital regions operate with autonomous temporal structures and nonlinear properties. This distinction may have significant implications for advancing our understanding of normal brain function and enhancing the development of brain-computer interfaces. In sum, we demonstrated the utility of TT in revealing regional variations in EEG traces, underscoring the value of nonlinear dynamics.

in bioRxiv: Neuroscience on 2025-01-19 00:00:00 UTC.

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Elaborating the connections of a closed-loop forebrain circuit in the rat: Circumscribed evidence for novel topography within a cortico-striato-pallidal triple descending projection, with thalamic feedback, to the anterior lateral hypothalamic area

Motivated behaviors are regulated by distributed forebrain networks. Traditional approaches have often focused on individual brain regions and connections that do not capture the topographic organization of forebrain connectivity. We performed co-injections of anterograde and retrograde tract tracers in rats to provide novel high-spatial resolution evidence of topographic connections that elaborate a previously identified closed-loop forebrain circuit implicated in affective and motivational processes. The nodes of this circuit include select regions of the medial prefrontal cortex (defined here more specifically as the cingulate region, CNG), a dorsomedial portion of the nucleus accumbens (ACBdm), a portion of the medial substantia innominata (SIm), and the anterior lateral hypothalamic area (LHAa). The circuit also reportedly receives a feedback loop from the anterior region of the paraventricular thalamic nucleus (PVTa). In this draft report, we provide detailed circumscribed evidence supporting these regions as interconnected nodes, and provide several novel findings concerning the topographic organization of their projections. First, we identified the ACBdm based on its unique connectivity. Anterograde labeling from anterior paraventricular thalamic nucleus (PVTa) and retrograde labeling from medial substantia innominata (SIm) and lateral hypothalamic area (LHA) were restricted to the dorsomedial ACB (ACBdm). Strikingly, this labeling formed a longitudinal column extending along virtually the entire anteroposterior axis of ACBdm. Subsequent analysis revealed a convergence of ACBdm axon terminals and retrogradely labeled neurons from LHA within the anterior SIm. Furthermore, we identified cortical CNG regions related to this circuit. These regions contained retrograde labeling from both ACBdm and LHA, and anterograde labeling from PVTa. These cortical subdomains included regions previously implicated in the circuit but for which detailed organization has been unknown: (1) a region between the posterior prelimbic and infralimbic areas; (2) posterior part of basolateral and basomedial amygdalar nuclei, and (3) anterior pole of ventral subiculum. Our circumscribed findings, which await additional samples and analysis, support the existence of a topographically organized closed-loop circuit and identify two additional novel features: (1) direct evidence for an elaborate core rostrocaudal topography for a cortico-striato-pallidal motif comprising a triple descending projection to the LHA via direct, indirect, and hyperdirect pathways, and (2) a thalamic feedback system with specific projections to each cortical and striatal node of the circuit. We discuss the implications of this newly elaborated circuit for understanding the neural basis of motivational processes.

in bioRxiv: Neuroscience on 2025-01-19 00:00:00 UTC.

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Transcriptional and synaptic regulation of NMDA glutamate receptor-mediated hippocampal plasticity and memory

Synapse-to-nucleus signaling regulates activity-dependent synaptic plasticity underlying memory by linking N-methyl-D-aspartate (NMDA) glutamate receptors (GluN) to gene transcription mediated by the transcription factor cAMP-response element binding protein (CREB), but the underlying gene programs mediating potentiation at excitatory synapses are unknown. Here, we analyzed genome-wide chromatin immunoprecipitation sequencing (ChIP-seq) datasets of mouse and human CREB and the synaptonuclear factor CREB-regulated transcription coactivator1 (CRTC1) to identify relevant target genes and biological pathways coupling neuronal activity to synaptic function/plasticity. Our analyses indicate that CRTC1 specifically couples neuronal activity with synaptic plasticity by binding to conserved promoters of CREB target genes comprising inducible transcription factors (including c-fos, Crem, Npas4 and Nr4a1-3), and neuronal excitability and plasticity genes, including Ntrk2, Homer1, Dlg4 (PSD-95) and the NMDA receptor subunit Grin1 (GluN1). CRTC1/CREB target genes were highly enriched in gene ontology (GO) nuclear terms, including several members of the CREB family, and transcriptional modulators and repressors. Interestingly, GO enrichment and protein-protein interaction (PPI) network analyses revealed that genes mediating synapse-to-nucleus signaling (including most known synaptonuclear factors and direct interacting modulators) are collectively regulated by CREB/CRTC1, and that protein kinase C (PKC) is a key interactor of the CRTC1/14-3-3 complex at synapses. In agreement with these in silico analyses, we show that CRTC1 regulates synaptic activity-dependent phosphorylation and synaptic recruitment of GluN1 mediated by PKC in hippocampal neurons, and that PKC activation reverses NMDA receptor-mediated currents and long-term potentiation (LTP) deficits caused by CRTC1 silencing in the hippocampus. Consistent with genomics and functional data, morphological and behavioral analyses show crucial roles of CRTC1 on dendritic spine structure, plasticity, and hippocampal-dependent associative memory. Our results support a model in which neuronal activity and synaptic inputs are integrated in the nucleus through conserved CREB/CRTC1-regulated transcriptional programs sustaining global synapse-to-nucleus signaling pathways impacting on synaptic plasticity and memory.

in bioRxiv: Neuroscience on 2025-01-19 00:00:00 UTC.

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Shared and individual tuning curves for social vision

A stimulus with light is clearly visual; a stimulus with sound is clearly auditory. But what makes a stimulus "social", and how do judgments of socialness differ across people? Here, we characterize both group-level and individual thresholds for perceiving the presence and nature of a social interaction. We take advantage of the fact that humans are primed to see social interactions-e.g., chasing, playing, fighting-even in very un-lifelike stimuli such as animations of geometric shapes. Unlike prior work using these stimuli, we exploit their most advantageous property, which is that their visual features are fully parameterizable. We use this property to construct psychophysics-inspired "social tuning curves" for individual subjects. Social tuning curves are stable within individuals, unique across individuals, and show some relationship to socio-affective traits. Results support the view that social information processing begins early in the perceptual hierarchy. Further, our approach lays the foundation for a generative account of social perception in single subjects.

in bioRxiv: Neuroscience on 2025-01-19 00:00:00 UTC.

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A Causal and Dissociable Role for the Right Inferior Prefrontal Cortex in Empathy for Physical and Social Pain

The right inferior frontal gyrus (rIFG) and dorsomedial prefrontal cortex (dmPFC) are key nodes in the social brain, implicated in empathy for physical and social pain. However, their causal and dissociable contributions remain unclear. In this study, 52 young adults underwent focal transcranial direct current stimulation (f-tDCS) targeting the rIFG or dmPFC in a sham-controlled, double-blind, crossover design. Participants rated the intensity of pain in images depicting social or physical pain during stimulation. Anodal stimulation to the rIFG increased ratings of physical pain and decreased ratings of social pain, suggesting dissociable roles in processing empathy for these two pain types. In contrast, dmPFC stimulation did not modulate ratings, potentially reflecting its role in higher-order social cognitive processes rather than affective empathy. The effects of rIFG stimulation on social pain were significantly stronger in the initial trials, suggesting potential habituation within the rIFG or stimulation-specific effects. These results provide causal, dissociable evidence for the rIFG's involvement in empathy, with its effects differing based on the type of pain. This supports the proposal that distinct neural processes underlie empathy for social versus physical pain.

in bioRxiv: Neuroscience on 2025-01-19 00:00:00 UTC.

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Brain Sciences, Vol. 15, Pages 93: The Neural Development of Chinese Lexical Tone Perception: A Mismatch Negativity Study Across Childhood, Adolescence, and Adulthood

Brain Sciences, Vol. 15, Pages 93: The Neural Development of Chinese Lexical Tone Perception: A Mismatch Negativity Study Across Childhood, Adolescence, and Adulthood

Brain Sciences doi: 10.3390/brainsci15010093

Authors: Han Wu Yixiao Zhang Yiru Liu Shijun Zhang Linjun Zhang Hua Shu Yang Zhang

Background/Objectives: In a tonal language like Chinese, phonologically contrasting tones signify word meanings at the syllable level. Although the development of lexical tone perception ability has been examined in many behavioral studies, its developmental trajectory from childhood to adulthood at the neural level remains unclear. This cross-sectional study aimed to examine the issue by measuring the mismatch negativity (MMN) response to a Chinese lexical tonal contrast in three groups. Methods: The MMN response to a flat-falling tonal contrast (Tone1 versus Tone4) were recorded from children (25 participants aged 6&ndash;8), adolescents (26 participants aged 12&ndash;14), and young adults (20 participants aged 18&ndash;24). Nonsense speech stimuli were also used by superimposing Tone1 and Tone4 on an English syllable. Results: All three groups demonstrated typical early MMN responses in both the meaningful and nonsense syllable conditions. However, the MMN amplitudes varied significantly across groups, with the child group showing smaller responses compared to the adolescent and adult groups, while the latter two groups had similar MMN amplitudes. Conclusions: Neural sensitivity to tonal contrasts is not fully mature in children and reaches a more adult-like level during adolescence, with no significant difference in sensitivity to meaningful versus nonsense syllables. These results provide new insights into the neural development of lexical tone perception in a tonal language, highlighting its maturation during adolescence in this process.

in Brain Sciences on 2025-01-19 00:00:00 UTC.

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Brain Sciences, Vol. 15, Pages 92: Gustatory-Visual Interaction in Human Brain Cortex: fNIRS Study

Brain Sciences, Vol. 15, Pages 92: Gustatory-Visual Interaction in Human Brain Cortex: fNIRS Study

Brain Sciences doi: 10.3390/brainsci15010092

Authors: Karolina Jezierska Aneta Cymbaluk-Płoska Justyna Zaleska Wojciech Podraza

Background: Many studies, for example, on taste-visual dissonance, have shown that the influence of the visual cortex on taste sensation is enormous. The presented work aims to investigate, using fNIRS, whether a taste stimulus, in this case, the taste of bitter, also causes stimulation of the visual cortex in the fNIRS study. Methods: fNIRS was used to examine 51 participants (204 examinations, 9996 records), collecting signals from the left hemisphere. Differences between the maximum and minimum changes in oxyHb concentrations (&Delta;oxyHb) for the areas of the brain cortex considered responsible for recording visual and gustatory signals were analyzed. Protocols I, II, III, and IV&mdash;activation with distillate water, coffee with lower concentration, reference (no stimulation), and coffee with higher concentration, respectively, were used. Results: We recorded high signals for teste activation on channels covering the gustatory cortex, which confirms the correctness of the choice of research method. As expected, a significant statistical difference was observed between protocols I, II, and IV and reference III (without stimulation). What seems important is the fact that we also received high signals for the channels 45&ndash;49, which cover the visual cortex. The statistical analysis shows no differences between protocols I, II, and IV (different taste activation&mdash;water, coffee A, and coffee B) for specific channels for analyzing regions of interest. As a result of the analysis of the correlation between the subjective bitterness assessment solutions and the signal &Delta;oxyHb height, it was observed that a statistically significant correlation, although weak, occurs only for 14 and gustatory channels, only for coffee with a higher concentration. Additionally, the only statistically significant difference between women and men was observed in Protocol I (water), where the &Delta;oxyHb signal was twice as high in women compared to men. Conclusions: In conclusion, we can clearly state that the senses of sight and taste work closely together. Moreover, this cooperation is not one-sided: while visual activation influences taste perception, interestingly, a taste stimulus can also generate a hemodynamic response, activating the visual cortex.

in Brain Sciences on 2025-01-19 00:00:00 UTC.

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Brain Sciences, Vol. 15, Pages 91: Exploring the Dimensions of Perfectionism in Adolescence: A Multi-Method Study on Mental Health and CBT-Based Psychoeducation

Brain Sciences, Vol. 15, Pages 91: Exploring the Dimensions of Perfectionism in Adolescence: A Multi-Method Study on Mental Health and CBT-Based Psychoeducation

Brain Sciences doi: 10.3390/brainsci15010091

Authors: Magdalena Chęć Krystian Konieczny Sylwia Michałowska Karolina Rachubińska

Background: Perfectionism in adolescents can have both adaptive and maladaptive forms, with implications for mental health and school performance. This study aimed to investigate the relationships among perfectionism, mental health factors, and emotional regulation in adolescents and to evaluate the efficacy of psychoeducational interventions. Methods: Two studies were conducted: (1) A cross-sectional study (n = 261) examined the correlations among perfectionism, mental health factors, and emotional regulation. (2) An experimental study (n = 115) evaluated the effects of psychoeducation on perfectionism and healthy habits compared with a control group. The measures included questionnaires on perfectionism, depression, anxiety, stress, and emotional regulation. Results: Study 1 found that maladaptive perfectionism was positively correlated with depression (r = 0.52, p &lt; 0.001), anxiety (r = 0.48, p &lt; 0.001), stress (r = 0.45, p &lt; 0.001), and difficulties in emotional regulation (r = 0.39, p &lt; 0.001). Adaptive perfectionism was negatively correlated with deficits in emotional understanding (r = &minus;0.31, p &lt; 0.05). Study 2 showed that psychoeducational interventions reduced maladaptive perfectionism (mean difference = &minus;5.7, p &lt; 0.05, Cohen&rsquo;s d = 0.62) and depression levels (mean difference = &minus;3.2, p &lt; 0.05, Cohen&rsquo;s d = 0.38) but increased stress in the experimental groups. No significant changes were observed in adaptive perfectionism or the anxiety level. Conclusions: These findings highlight the complex relationships among perfectionism, mental health, and emotional regulation in adolescents. Targeted interventions can reduce maladaptive perfectionism and its associated negative effects. Further research is needed on the long-term outcomes and refinement of interventional strategies.

in Brain Sciences on 2025-01-19 00:00:00 UTC.

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Subventricular Zone Microstructure in Pediatric‐Onset Multiple Sclerosis

Objective

The aim of this study was to explore the microstructural dynamics of the subventricular zone (SVZ) with aging and their associations with clinical disability and brain structural damage in pediatric-onset multiple sclerosis (MS) patients.

Methods

One-hundred and forty-one pediatric-onset MS patients (67 pediatric and 74 adults with pediatric-onset) and 233 healthy controls (HC) underwent neurological and 3.0 T MRI assessment. Fractional anisotropy (FA) and mean diffusivity (MD) were extracted from the SVZ and the thalamus (as control region).

Results

In HC, SVZ FA was higher until age 40 then declined, whereas MD was lower until age 35 before rising (false discovery rate p value [pFDR] ≤ 0.008). Thalamic FA was higher until age 30 and then declined, whereas MD was higher until age 50 (pFDR ≤ 0.007). Pediatric MS patients showed significantly higher SVZ FA than pediatric HC (pFDR < 0.001), while adult patients showed no differences compared to adult HC (pFDR ≤ 0.724). Adult patients had lower thalamic FA and higher MD (pFDR < 0.001). Adults had lower SVZ FA and MD, but higher thalamic MD compared to pediatric patients (pFDR < 0.001). In pediatric MS, higher SVZ FA and MD were associated with higher white matter (WM) lesion volume (LV) and choroid plexus volume and lower brain and thalamic volumes (pFDR ≤ 0.047). In adult patients, higher SVZ MD associated with higher WM LV, lower brain volumes, and lower z-SDMT (pFDR≤0.019). Thalamic microstructural abnormalities were associated with more severe disability and brain damage in both groups (pFDR ≤ 0.018).

Interpretation

Our findings suggest that microstructural changes in the SVZ occur early in pediatric MS and are associated with brain structural damage but not with clinical impairment. ANN NEUROL 2025

in Annals of Neurology on 2025-01-18 12:00:08 UTC.

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Quantitative Pupillometry Predicts Neurologic Deterioration in Patients with Large Middle Cerebral Artery Stroke

Objective

This study assesses whether longitudinal quantitative pupillometry predicts neurological deterioration after large middle cerebral artery (MCA) stroke and determines how early changes are detectable.

Methods

This prospective, single-center observational cohort study included patients with large MCA stroke admitted to Boston Medical Center's intensive care unit (2019–2024). Associations between time-to-neurologic deterioration and quantitative pupillometry, including Neurological Pupil Index (NPi), were assessed using Cox proportional hazards models with time-dependent covariates adjusted for age, sex, and Alberta Stroke Program Early CT Score. Models using dilation velocity were compared with partial likelihood ratio tests. Pupillometric changes over 2-h intervals in the 12 h preceding deterioration were analyzed with linear mixed-effects modeling and Tukey's test. Matched referents (age, sex, stroke side, follow-up duration) were used for comparison. Optimal thresholds were identified using the Youden Index.

Results

Among 71 patients (mean age 66.5 years; 59.2% women), 32 (45.1%) experienced deterioration. A 1-unit decrease in NPi was associated with a higher hazard of deterioration (hazard ratio 2.46; 95% confidence interval 1.68–3.61). Dilation velocity improved model performance compared to NPi alone. NPi was significantly lower at 0–2 h (3.81 vs. 4.38, p = 0.001) and 2–4 h (3.71 vs. 4.38, p < 0.001) before deterioration compared to 10–12 h prior. Optimal thresholds were 4.01 for NPi, 0.49 mm/s for dilation velocity, and −0.15 change in NPi over 12 h.

Interpretation

Quantitative pupillometry predicts neurological deterioration in MCA stroke, with declines detectable up to 12 h prior. Dilation velocity shows promise as a novel biomarker. ANN NEUROL 2025

in Annals of Neurology on 2025-01-18 11:57:49 UTC.

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Immunotherapy‐Resistant Neuropathic Pain and Fatigue Predict Quality‐of‐Life in Contactin‐Associated Protein‐Like 2 Antibody Disease

The long-term clinical outcomes and associated prognostic factors in contactin-associated protein-like 2 (CASPR2)-antibody diseases are unknown. A total of 75 participants with CASPR2 antibodies were longitudinally assessed for disability, quality-of-life, and chronic pain. Although most symptoms improved within 6 months of treatment, neuropathic pain and fatigue were the most immunotherapy refractory, and persisted for up to 6 years. Furthermore, these two factors—but not CASPR2 antibody levels or subclasses—independently predicted worse disability and quality-of-life at 24 months. Quality-of-life varied widely for any given modified Rankin Scale score, indicating a divergence between patient and clinician assessed outcomes. Further work should study the relative importance of these measures, and the immunopathogenesis underlying intractable symptoms. ANN NEUROL 2025

in Annals of Neurology on 2025-01-18 11:46:43 UTC.

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Localization of Cholecystokinin/Sulfakinin Neuropeptides in Biomphalaria glabrata, an Intermediate Host for Schistosomiasis

Neuropeptides belonging to the cholecystokinin/sulfakinin (CCK/SK) family mediate satiety signals across phylogeny. In this study, a potential anatomical substrate for such satiety signals was described in the snail Biomphalaria glabrata. We propose that CCK/SK signals directly modulate gustatory sensory neurons that project from the lips to the brain.

ABSTRACT

Snails belonging to the genus Biomphalaria serve as obligatory intermediate hosts for the trematode Schistosoma mansoni, the causative agent for the most widespread form of schistosomiasis. The simpler nervous systems of gastropod molluscs, such as Biomphalaria, provide advantageous models for investigating neural responses to infection at the cellular and network levels. The present study examined neuropeptides related to cholecystokinin (CCK), a major multifunctional regulator of central nervous system (CNS) function in mammals. A neural transcriptome generated from the CNS of Biomphalaria alexandrina included a transcript encoding two CCK-related peptides, designated Balex-CCK1 (pEGEWSYDY_(SO ₃ _H)GLGGGRF-NH₂) and Balex-CCK2 (NYGDY_(SO ₃ _H)GIGGGRF-NH₂). Peptide expression was examined in Biomphalaria glabrata at the mRNA level using the hybridization chain reaction (HCR) protocol and at the protein level using an antibody against Balex-CCK1. Expression was detected in 60–70 neurons distributed throughout the CNS, as well as in profuse fiber systems connecting the ganglia and projecting to the periphery. CCK-like immunoreactive (CCK_li) fibers were also observed on organs associated with the cardiorespiratory (nephridium, mantle, gill) and male reproductive systems. A comparison of mRNA and peptide localization suggested that CCK expression could be regulated at the level of translation. A potential role of these peptides in mediating responses to infection by larval schistosomes is discussed.

in Journal of Comparative Neurology on 2025-01-18 10:42:42 UTC.

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NFE2-driven neutrophil polarization promotes pancreatic cancer liver metastasis progression

Xu et al. investigated the single-cell characteristics of pancreatic cancer liver metastasis and found that the pro-metastatic neutrophil cluster is enriched at the metastatic border. NFE2-driven neutrophil phenotypic polarization represents a critical pro-metastatic mechanism. TGF-β/SMAD3 activates NFE2, further promoting NET release at the invasive front by transcriptional regulation of PADI4.

in Cell Reports: Current Issue on 2025-01-18 00:00:00 UTC.

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TWEAK-Fn14 signaling protects mice from pulmonary fibrosis by inhibiting fibroblast activation and recruiting pro-regenerative macrophages

Liu et al. demonstrated a protective role of TWEAK-Fn14 signaling in lung fibrosis. Fn14 deficiency promotes fibroblast activation thus increasing ECM production, impairs macrophage infiltration in the lung and diminishes pro-regenerative IntermM and AM subpopulations, leading to impaired alveolar regeneration and exacerbated lung fibrosis.

in Cell Reports: Current Issue on 2025-01-18 00:00:00 UTC.

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Chronic intermittent fasting impairs β cell maturation and function in adolescent mice

Intermittent fasting (IF) is generally associated with improved metabolism, but whether there are age-dependent limitations of IF needs to be explored. Matta et al. now demonstrate that while IF improved β cell function in old and middle-aged mice, long-term IF impaired β cell maturation and function in adolescent mice.

in Cell Reports: Current Issue on 2025-01-18 00:00:00 UTC.

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The adult table: Chronic intermittent fasting improves β cell health only in adults

Intermittent fasting (IF) improves metabolic health in some individuals but increases health risks in others. Matta et al. now show that IF oppositely affects β cells depending on age: beneficial at old but deleterious at young age.

in Cell Reports: Current Issue on 2025-01-18 00:00:00 UTC.

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Biased replay of aversive and uncertain outcomes underlies irrational decision making

Humans often make irrational decisions when facing uncertain or aversive future events despite careful deliberation. How we make choices, including irrational ones, has been the object of extensive study both behaviourally and neurally and is the focus of influential behavioural economic theories. Yet, little is known about how these (irrational) decisions are carved out in the brain. Here, using magnetoencephalography (MEG), we show that the construction and outcome evaluation of irrational decisions involves rapid, sequential state reactivation, or "replay.". During deliberation, we show that forward replay is biased towards choice options with more negative and uncertain outcomes, with this bias further amplified immediately preceding irrational choice. Likewise, post-decision evaluation relates to replay in a choice-dependent manner. Following irrational choices, relief-like signals were evident as stronger backward replay of worse counterfactual options, while after rational decisions, regret-like signals appeared as stronger backward replay of better counterfactual options. Together, these findings suggest that neural replay shapes both the formation and reflection of irrational decisions, and poise replay as a candidate mechanism underlying pervasive decision biases in humans.

in bioRxiv: Neuroscience on 2025-01-18 00:00:00 UTC.

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Lipid-protecting disulfide bridges are the missing molecular link between ApoE4 and sporadic Alzheimers disease in humans

As the principal lipid transporter in the human brain, apolipoprotein E (ApoE) is tasked with the transport and protection of highly vulnerable lipids required to support and remodel neuronal membranes, in a process that is dependent on ApoE receptors. Human APOE allele variants that encode proteins differing only in the number of cysteine (Cys)-to-arginine (Arg) exchanges (ApoE2 [2 Cys], ApoE3 [1 Cys], ApoE4 [0 Cys]) comprise the strongest genetic risk factor for sporadic Alzheimers disease (AD); however, the specific molecular feature(s) and resultant mechanisms that underlie these isoform-dependent effects are unknown. One signature feature of Cys is the capacity to form disulfide (Cys-Cys) bridges, which are required to form disulfide bridge-linked dimers and multimers. Here we propose the overarching hypothesis that the super-ability (for ApoE2), intermediate ability (for ApoE3) or inability (for ApoE4) to form lipid-protecting intermolecular disulfide bridges, is the central molecular determinant accounting for the disparate effects of APOE alleles on AD risk and amyloid-{beta} and Tau pathologies in humans. We posit that presence and abundance of Cys in human ApoE3 and ApoE2 respectively, conceal and protect vulnerable lipids transported by ApoE from peroxidation by enabling formation of ApoE homo-dimers/multimers and heteromeric ApoE complexes such as ApoE-ApoJ and ApoE-ApoD. We thus propose that the inability to form intermolecular disulfide bridges makes ApoE4-containing lipoproteins uniquely vulnerable to peroxidation and its downstream consequences. Consistent with our model, we found that brain-enriched polyunsaturated fatty acid-containing phospholipids induce disulfide-dependent dimerization and multimerization of ApoE3 and ApoE2 (but not ApoE4). By contrast, incubation with the artificial peroxidation-resistant lipid DMPC or cholesterol alone had minimal effects on dimerization. These novel concepts and findings are integrated into our unifying model implicating peroxidation of ApoE-containing lipoproteins, with consequent ApoE receptor-ligand disruption, as the initiating molecular events that ultimately lead to AD in humans.

in bioRxiv: Neuroscience on 2025-01-18 00:00:00 UTC.

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Lecanemab binds to transgenic mouse model-derived amyloid-β fibril structures resembling Alzheimer 's disease type-I, type-II and Arctic folds

Lecanemab, an Alzheimer's disease US Food and Drug Administration approved monoclonal antibody was previously reported to have a high affinity against intermediately sized amyloid-{beta} aggregates. Subsequently, it was observed by immunogold labelling that lecanemab can also bind to human type-I amyloid-{beta} fibrils. Therefore, to determine whether lecanemab binds to amyloid-{beta} fibril structures other than type-I, we performed immunogold labelling on extracted amyloid-{beta} fibril preparations from six different Alzheimer's disease mouse models whose structures were previously solved by cryo-EM. Our results show that lecanemab exhibits high binding affinity to amyloid-{beta} fibril structures that have a flexible N-terminus in common, as it is the case for type-I, type-II and murine type-III amyloid-{beta} fibril polymorphs which resemble or are identical to human structures observed in sporadic and familial cases of Alzheimer's disease, including a case with the Arctic (E22G) mutation. In contrast, only weak, if any, lecanemab binding was observed for amyloid-{beta} fibril folds with a fixed and ordered N-terminus.

in bioRxiv: Neuroscience on 2025-01-18 00:00:00 UTC.

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Rescue of hippocampal synaptic plasticity and memory performance by Fingolimod (FTY720) in APP/PS1 model of Alzheimer's disease is accompanied by correction in metabolism of sphingolipids, polyamines, and phospholipid saturation composition

Previously, our metabolomic, transcriptomic, and genomic studies characterized the ceramide/sphingomyelin pathway as a therapeutic target in Alzheimer's disease, and we demonstrated that FTY720, a sphingosine-1-phospahate receptor modulator approved for treatment of multiple sclerosis, recovers synaptic plasticity and memory in APP/PS1 mice. To further investigate how FTY720 rescues the pathology, we performed metabolomic analysis in brain, plasma, and liver of trained APP/PS1 and wild-type mice. APP/PS1 mice showed area-specific brain disturbances in polyamines, phospholipids, and sphingolipids. Most changes were completely or partially normalized in FTY720-treated subjects, indicating rebalancing the "sphingolipid rheostat", reactivating phosphatidylethanolamine synthesis via mitochondrial phosphatidylserine decarboxylase pathway, and normalizing polyamine levels that support mitochondrial activity. Synaptic plasticity and memory were rescued, with spermidine synthesis in temporal cortex best corresponding to hippocampal CA3-CA1 plasticity normalization. FTY720 effects, also reflected in other pathways, are consistent with promotion of mitochondrial function, synaptic plasticity, and anti-inflammatory environment, while reducing pro-apoptotic and pro-inflammatory signals.

in bioRxiv: Neuroscience on 2025-01-18 00:00:00 UTC.

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Microglial SIRT2 deficiency aggravates cognitive decline and amyloid pathology in Alzheimer's disease

Sirtuin 2 (SIRT2), a NAD+-dependent deacetylase, has been implicated in aging and neurodegenerative diseases such as Alzheimer's disease (AD). While global SIRT2 inhibition has shown promise in reducing amyloid-beta pathology and cognitive deficits in different mouse models of AD, peripheral SIRT2 inhibition has been associated with adverse effects, such as increased inflammation. This suggests that targeted inhibition of specific cellular populations within the brain may represent a more precise and effective approach for the treatment of AD. To explore this hypothesis, we generated a conditional microglial SIRT2 knockout mouse model in the context of AD. Our results reveal that microglial SIRT2 reduction does not confer protective effects in the APP/PS1 model; rather, it aggravates cognitive decline, accelerates amyloid plaque deposition, and increases levels of pro-inflammatory cytokines at early stages of AD pathology. Transcriptomic analysis further indicates that SIRT2-deficient microglia exhibit altered expression of genes associated with aging and synaptic dysfunction. This phenotype was accompanied by increased phagocytosis of synaptic elements and impaired long-term potentiation. These findings suggest that while SIRT2 inhibition in some contexts may be beneficial, targeted inhibition within microglia could accelerate AD progression, underscoring the need for cell-specific approaches when considering SIRT2 as a therapeutic target.

in bioRxiv: Neuroscience on 2025-01-18 00:00:00 UTC.

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Impact of meningioma and glioma on whole-brain dynamics

Brain tumors, particularly meningiomas and gliomas, can profoundly affect neural function, yet their impact on brain dynamics remains incompletely understood. This study investigates alterations in normal brain function among meningioma and glioma patients by assessing dynamical complexity through the Intrinsic Ignition Framework. We analyzed resting-state fMRI data from 34 participants to quantify brain dynamics using intrinsic ignition and metastability metrics. Our results revealed distinct patterns of disruption: glioma patients showed significant reductions in both metrics compared to controls, indicating widespread network disturbances. In contrast, meningioma patients exhibited significant changes predominantly in regions with substantial tumor involvement. Resting-state network analysis demonstrated strong metastability and metastability/ignition correlations between regions in controls, which were slightly weakened in meningioma patients and severely disrupted in glioma patients. These findings highlight the differential impacts of gliomas and meningiomas on brain function, offering insights into their distinct pathophysiological mechanisms. Furthermore, these results show that brain dynamics metrics can be effective biomarkers for identifying disruptions in brain information transmission caused by tumors.

in bioRxiv: Neuroscience on 2025-01-18 00:00:00 UTC.

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Efficacy of functional connectome fingerprinting using tangent-space brain networks

Functional connectomes (FCs) are estimations of brain region interaction derived from brain activity, often obtained from functional Magnetic Resonance Imaging recordings. Quantifying the distance between FCs is important for understanding the relation between behaviour, disorders, disease, and changes in connectivity. Recently, tangent space projections, which account for the curvature of the mathematical space of FCs, have been proposed for calculating FC distances. We compare the efficacy of this approach relative to the traditional method in the context of subject identification using the Midnight Scan Club dataset, in order to study resting-state and task-based subject discriminability. The tangent space method is found to universally out-perform the traditional method. We also focus on the subject identification efficacy of subnetworks. Certain subnetworks are found to outperform others, a dichotomy which largely follows the `control' and `processing' categorization of resting state networks, and relates subnetwork flexibility with subject discriminability. Identification efficacy is also modulated by tasks, though certain subnetworks appear task independent. The uniquely long recordings of the dataset also allow for explorations of resource requirements for effective subject identification. The tangent space method is found to universally require less data, making it well suited when only short recordings are available.

in bioRxiv: Neuroscience on 2025-01-18 00:00:00 UTC.

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Post-movement beta rebound reflects strategic re-aiming during motor adaptation, but not re-aiming accuracy

Motor adaptation results from several interacting learning mechanisms, including learning via cognitive strategies and implicit adaptation. While strategy-based and implicit learning can be dissociated at a behavioural level, their underlying systems-level physiology is poorly understood. A neural signal that undergoes pronounced changes during motor adaptation is the post-movement beta-rebound (PMBR). However, it is unclear how these changes relate to the specific learning mechanisms that contribute to motor adaptation. We measured electroencephalography (EEG) while healthy participants (N=27) performed reaching movements towards a target. In most trials, a cursor showed the veridical position of the unseen hand, however, for some reaches, the direction of the cursor was rotated relative to the position of the hand. Participants were informed that, once a rotation occurred, it could persist for a single trial (1x condition), or for two consecutive trial (2x condition). In the 2x condition, participants could therefore redirect the rotated cursor through the target in the second rotated trial by re-aiming, while they had to continue aiming at the target in the 1x condition. We observed a stronger decrease of PMBR following the first rotated reach in the 2x condition, compared to the 1x condition, despite similar kinematics. This corroborates our previous results that PMBR reflects strategic re-aiming (Korka et al., 2023). However, when we collapsed data from the two studies (total N=53), we found that the degree to which the PMBR decreases does not predict re-aiming accuracy. We discuss the role of PMBR in motor adaptation, including implications for clinical disorders.

in bioRxiv: Neuroscience on 2025-01-18 00:00:00 UTC.

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Cholinergic Modulation of Chandelier Cells via Heteromeric Nicotinic Receptors in Prefrontal Cortex

Chandelier cells (ChCs) are a distinct subtype of GABAergic interneurons that form vertical arrays of presynaptic boutons targeting the axon initial segment (AIS) of pyramidal neurons (PNs). They are particularly abundant in prefrontal cortex, where cholinergic inputs modulate cognitive functions and shape ChC axonal development. However, the effects of the cholinergic system on ChC activity in the adult brain remain largely unexplored. Here, using a genetic intersectional strategy (VipR2-Pvalb-Ai65) in adult mice, we selectively labeled ChCs in the secondary motor cortex (M2). Immunohistochemistry and electrophysiology confirmed morphological and functional properties distinguishing them from basket cells. We found that these ChCs exhibit an inward current in response to nicotinic acetylcholine receptor (nAChR) agonists. Pharmacological blockade and fluorescent in situ hybridization revealed that this effect is primarily mediated by heteromeric nAChRs containing {beta}2 subunits, with a smaller contribution from 3 subunits. Optogenetic stimulation of basal forebrain (BF) cholinergic axons evoked inward currents in ChCs, confirming a functional cholinergic drive. Furthermore, in vivo two-photon calcium imaging revealed a strong correlation between ChC activity and behavioral markers of arousal, including locomotion and pupil dilation. Importantly, the application of nicotinic receptor antagonists significantly diminished ChC activity during movement. Together, these results indicate that ChCs are modulated by cholinergic input via heteromeric nAChRs, emphasizing their importance in facilitating state-dependent cortical dynamics.

in bioRxiv: Neuroscience on 2025-01-18 00:00:00 UTC.

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Hypoxia-inducible factor 1 protects neurons from Sarm1-mediated neurodegeneration

The Sarm1 NAD+ hydrolase drives neurodegeneration in many contexts, but how Sarm1 activity is regulated remains poorly defined. Using CRISPR/Cas9 screening, we found loss of VHL suppressed Sarm1-mediated cellular degeneration. VHL normally promotes O2-dependent constitutive ubiquitination and degradation of hypoxia-inducible factor 1 (HIF-1), but during hypoxia, HIF-1 is stabilized and regulates gene expression. We observed neuroprotection after depletion of VHL or other factors required for HIF-1 degradation, and expression of a non-ubiquitinated HIF-1 variant led to even stronger blockade of axon degeneration in mammals and Drosophila. Neuroprotection required HIF-1 DNA binding, prolonged expression, and resulted in broad gene expression changes. Unexpectedly, stabilized HIF-1 prevented the precipitous NAD+ loss driven by Sarm1 activation in neurons, despite NAD+ hydrolase activity being intrinsic to the Sarm1 TIR domain. Our work argues hypoxia inhibits Sarm1 activity through HIF-1 driven transcriptional changes, rendering neurons less sensitive to Sarm1-mediated neurodegeneration when in a hypoxic state.

in bioRxiv: Neuroscience on 2025-01-18 00:00:00 UTC.

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Fentanyl blockade of K+ channels contribute to Wooden Chest Syndrome

Fentanyl is a potent synthetic opioid widely used perioperatively and illicitly as a drug of abuse. It is well established that fentanyl acts as a -opioid receptor agonist, signaling through Gi/o intracellular pathways to inhibit electrical excitability, resulting in analgesia and respiratory depression. However, fentanyl uniquely also triggers muscle rigidity, including respiratory muscles, hindering the ability to execute central respiratory commands or to receive external resuscitation. This potentially lethal condition is termed Wooden Chest Syndrome (WCS), the mechanisms of which are poorly understood. Here we show that fentanyl directly blocks a subset of EAG-class potassium channels. Our results also demonstrate that these channels are widely expressed in cervical spinal motoneurons, including those innervating the diaphragm. A significant fraction of these motoneurons is excited by fentanyl, concomitant with blockade of voltage-dependent non-inactivating K+ currents. In vivo electromyography revealed a persistent tonic component of diaphragmatic muscle activity elicited by fentanyl, but not morphine. Taken together our results identify a novel off-target mechanism for fentanyl action, independent of -opioid receptor activation, with a paradoxical excitatory effect that may underlie WCS. We anticipate these findings may inform the design of safer analgesics and generalize to other neuronal circuits implicated in fentanyl-related maladaptive behaviors.

in bioRxiv: Neuroscience on 2025-01-18 00:00:00 UTC.

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Conditioning electrical stimulation enhances functional rewiring in a mouse model of nerve transfer to treat chronic spinal cord injury

Nerve transfer surgery is a state-of-the-art surgical approach to restore hand and arm function in individuals living with tetraplegia, significantly impacting daily life. While nearly a third of all individuals with chronic SCI may benefit from this intervention, variability in outcomes can limit the functional impact. A bedside-to-bench approach was taken to address the variable response of tetraplegic individuals to nerve transfer surgery. We used a hierarchical multiple factor analysis to evaluate the effects of conditioning electrical stimulation (CES) on outcomes in a mouse model of nerve transfer to treat chronic cervical spinal cord injury. We found that CES of donor nerves one week prior to nerve transfer surgery enhanced anatomical and functional measures of innervation of targeted muscles. Furthermore, CES increased the rate of recovery of naturalistic behavior. While the model has some limitations due to the small size of the rodent, our results support the use of CES as an effective approach to improve outcomes in clinical nerve repair settings.

in bioRxiv: Neuroscience on 2025-01-18 00:00:00 UTC.

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circAβ-a RNA encoded Aβ175--the hidden driver of β-amyloid plaque formation and deposition in sporadic Alzheimer's disease.

Mechanisms that trigger A{beta} production in sporadic Alzheimer's disease are still obscure. We recently reported the expression of a human circular RNA (circA{beta}-a) encoded A{beta} peptide precursor variant (A{beta}175). Presently, we demonstrated that AAV9 virus-expressed circA{beta}-a gave rise to extensive extracellular A{beta} plaque depositions and microglial activation in mouse brain; this recapitulates critical pathogenic hallmarks within a sporadic AD mouse model. Specifically developed antibodies detected robust endogenous A{beta}175 expression in HEK293 cells and hNSC-derived human neurons, underscoring the potential of A{beta}175 as a salient A{beta} precursor. Furthermore, we detected high levels of A{beta}175 oligomers in young-adult human brains. In intermediate and old-age human brain samples, accumulation of soluble A{beta}175 pentamers was reduced and A{beta}175 oligomers were components of most insoluble A{beta} plaques in older human brain. We propose a causal relationship between human circA{beta}-a RNA expression, dysregulation of A{beta}175 oligomer processing/aggregation and A{beta} plaque accumulation in sporadic AD.

in bioRxiv: Neuroscience on 2025-01-18 00:00:00 UTC.

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Partial Wwox Loss of Function Increases Severity of Murine Sepsis and Neuroinflammation

Rationale: WW domain-containing oxidoreductase (WWOX) is a gene associated implicated in both neurologic and inflammatory diseases and is susceptible to environmental stressors. We hypothesize partial loss of Wwox function will result in increased sepsis severity and neuroinflammation. Methods: Wwox WT/P47T mice, generated by CRISPR/Cas9, and Wwox WT/WT mice were treated with intraperitoneal PBS vs LPS (10mg/kg) and euthanized 12 hours post-injection. Open Field Testing (OFT) and Murine Sepsis Severity Scores (MSS) were utilized to measure sickness behavior and sepsis severity, respectively. Brain tissue was analyzed using immunohistochemistry and PCR to measure neuroinflammation and apoptosis. Results: Wwox WT/P47T LPS mice demonstrated a more significant response to sepsis with an increase in sickness behavior, sepsis severity, gliosis, and apoptosis compared to Wwow WT/WT LPS littermates. Conclusions: Partial loss of Wwox function increases risk for severe sepsis and neuroinflammation. Given the susceptibility of WWOX to environmental stressors, this may be a target for future therapeutic interventions.

in bioRxiv: Neuroscience on 2025-01-18 00:00:00 UTC.

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Simultaneous EEG-PET-MRI identifies temporally coupled, spatially structured hemodynamic and metabolic dynamics across wakefulness and NREM sleep

Sleep entails significant changes in cerebral hemodynamics and metabolism. Yet, the way these processes evolve throughout wakefulness and sleep and their spatiotemporal dependence remain largely unknown. Here, by integrating a novel functional PET technique with simultaneous EEG-fMRI, we reveal a tightly coupled temporal progression of global hemodynamics and metabolism during the descent into NREM sleep, with large hemodynamic fluctuations emerging as global glucose metabolism declines, both of which track EEG arousal dynamics. Furthermore, we identify two distinct network patterns that emerge during NREM sleep: an oscillating, high-metabolism sensorimotor network remains active and dynamic, whereas hemodynamic and metabolic activity in the default-mode network is suppressed. These results elucidate how sleep diminishes awareness while preserving sensory responses, and uncover a complex, alternating balance of neuronal, hemodynamic, and metabolic dynamics in the sleeping brain. This work also demonstrates the potential of EEG-PET-MRI to explore neuro-hemo-metabolic dynamics underlying cognition and arousal in humans.

in bioRxiv: Neuroscience on 2025-01-18 00:00:00 UTC.

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Functional organization of the neonatal thalamus across development depicted by functional MRI

The thalamus is a central component of the brain that is involved in a variety of functions, from sensory processing to high-order cognition. Its structure and function in the first weeks of extrauterine life, including its connections to different cortical and subcortical areas, have not yet been widely explored. Here, we used resting state functional magnetic resonance imaging data of 730 newborns from the developing Human Connectome Project to study the functional organization of the thalamus from 37 to 44 post-conceptual weeks. We introduce KNIT: K-means for Nuclei in Infant Thalamus. The framework employs a highly granular vector space of 40 features, each corresponding to functional connectivity to a brain region, using k-means clustering and uncertainty quantification through bootstrapping to delineate thalamic units. Although the different clusters showed common patterns of increased connectivity to the superior temporal gyrus, the parietal, and the frontal cortex, implying an expected decrease in specialization at that age, they also show some specificity. That is, a pulvinar unit was identified, similar to the adult thalamus. Ventrolateral motor and medial salience units were also highlighted. The latter appeared around 41 weeks of age, while the former showed at least from 37 weeks, but had a decrease in volume through age, replaced mostly by a dominant dorsal thalamic unit. We also observed an increase in clustering robustness and in hemispheric bilateral symmetry with age, suggesting more specialized functional units. We also found a burst in global thalamic connectivity around 41 weeks. Finally, we demonstrate the benefits of this method in terms of granularity compared to the more conventional winner-takes-all approach.

in bioRxiv: Neuroscience on 2025-01-18 00:00:00 UTC.

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Postnatal reduction of eIF4E overexpression in D1-SPNs ameliorates KCNQ dysfunction, hyperexcitability and ASD-like behaviours.

An imbalance between the direct and indirect pathways of the striatum has been implicated in the pathophysiology of ASD, which corresponds with an increase in repetitive behaviours and hyperactivity. The ASD risk gene EIF4E promotes translation, and its overexpression in mice increases repetitive behaviours and hyperactivity. We used the eIF4E-transgenic mouse model of ASD to study cell-type specific disruptions in the direct and indirect pathways using fibre photometry, electrophysiology, conditional gene silencing, and behavioural analysis. We found that direct pathway SPNs activity increased during exploratory behaviour and identified D1-SPN hyperexcitability and reduced KCNQ channel function in striatal slices. Reduction of eIF4E specifically in the D1-SPNs of adult mice normalised KCNQ function, D1-SPN hyperexcitability and ameliorated repetitive and hyperactive behaviours. Our results highlight the critical role of eIF4E in ASD-associated motor behaviours, elucidate cell-specific mechanisms driving hyperactivity and provide new insight into potential therapeutic targets for ASD and other neurodevelopmental disorders. Overall, this study underscores the translational potential of modulating protein synthesis pathways to address core motor symptoms in ASD.

in bioRxiv: Neuroscience on 2025-01-18 00:00:00 UTC.

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Differential regulation of brain-specific molecular pathways is the reason for curcumin adult life-phase specific DAergic neuroprotection: Insights from ALSS Drosophila model of Parkinson disease

Curcumin (CU), a bioactive compound of turmeric, has been put forward as a golden molecule due to its anti-inflammatory, antioxidant, hepatoprotective, neuroprotective, and anti-cancer ability, as proven by research conducted over the decade and more. Our laboratory, developed an adult life stage specific (ALSS) Drosophila model of sporadic Parkinson disease (PD), and for first time demonstrated that dopaminergic (DAergic) neuroprotective efficacy of curcumin is limited to health phase viz. adult-young life stage and is absent during transition phase viz. adult senior life stages when PD set in. This observation suggests the limitation of curcumin as a therapeutic agent for late-onset disorders like PD. Further, our laboratory also demonstrated that despite curcumin ability to sequester oxidative stress during both the adult life stages, neuroprotection and brain dopamine replenishment is granted only in health stages but not in a vulnerable transition stage, which prompted to put forward the hypothesis that the molecular target(s) of CU, may be absent or inadequate in the transition stage of aging brain. With this insight, the current study was implemented to analyse the life stage-specific differential regulation of multiple molecular players of neuro-integral pathways in brain of ALSS Drosophila model of PD with curcumin intervention. It is discovered that curcumin-mediated health phase-specific neuroprotection underlies the correction of an altered expression of 1. dFOXO, GADD45, Puc of Bsk-dFOXO stress response pathway, 2. Mfn2 of Mitochondrial dynamics 3. CncC, GCLC, Prx 2540 -1,2, Jafrac1, Prx3 of Phase II antioxidant defense system pathway. Further, it is discovered that significant aging-associated naturally altered expression of certain molecular targets exists, that may contribute to the limitation of curcumin DAergic neuroprotective efficacy during the adult-transition stage. This knowledge will help in developing altered therapeutic strategies for PD as molecular targets of curcumin are conserved among fly, mice and human.

in bioRxiv: Neuroscience on 2025-01-18 00:00:00 UTC.

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Brain Sciences, Vol. 15, Pages 90: Differential Impact of Risk Factors for Cognitive Decline in Heterosexual and Sexual Minority Older Adults in England

Brain Sciences, Vol. 15, Pages 90: Differential Impact of Risk Factors for Cognitive Decline in Heterosexual and Sexual Minority Older Adults in England

Brain Sciences doi: 10.3390/brainsci15010090

Authors: Riccardo Manca Jason D. Flatt Annalena Venneri

Background/Objectives: Sexual minority older adults (SMOAs) report greater subjective cognitive decline (SCD) than heterosexual older adults (HOAs). This study aimed to compare the impact of multiple psycho-social risk factors on objective and subjective cognitive decline in HOAs and SMOAs. Methods: Two samples of self-identified HOAs and SMOAs were selected from the English Longitudinal Study of Ageing. Reliable change indices for episodic and semantic memory were created to assess cognitive decline. SCD was self-reported for memory and general cognition. Depressive symptoms, loneliness, marital status and socio-economic status were investigated as risk factors. Results: No between-group differences were found in cognitive decline. Higher depression was associated with greater SCD risk and worse semantic memory decline. The latter effect was stronger in SMOAs. The findings were largely replicated in the sensitivity analysis. Conclusions: Poor mental health may represent the strongest driver of cognitive decline in SMOAs and to a greater extent than in HOAs.

in Brain Sciences on 2025-01-18 00:00:00 UTC.

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Brain Sciences, Vol. 15, Pages 89: Impact of Exercise on Tramadol-Conditioned Place Preference

Brain Sciences, Vol. 15, Pages 89: Impact of Exercise on Tramadol-Conditioned Place Preference

Brain Sciences doi: 10.3390/brainsci15010089

Authors: Haneen Amawi Alaa M. Hammad Aseel Abdullah Ibrahim Nosyba Alsbih Frank Scott Hall Fawaz Alasmari Bahaa Al-Trad

Background: Tramadol (TRA) is an opioid that is used to manage moderate to severe pain. Long-term use of TRA can lead to the development of opioid use disorder. Objectives: This study investigates the role of forced exercise in reducing TRA-seeking behavior. Methods: Adult male rats (240&ndash;260 g) were divided into five groups; the control group received vehicle injections, the TRA group received TRA (75 mg/kg, i.p) every other day for 8 days, and three TRA&ndash;exercise groups were forced to run on a treadmill (60 min/day, 5 days/week) for 2, 4, or 6 weeks prior to conditioning with TRA. A tramadol-conditioned place preference (CPP) procedure assessed TRA reinforcement, after which all rats were euthanized, tissue extracted, and mRNA expression for brain-derived neurotrophic factor (Bdnf) and interleukin 1 beta (Il-1&beta;) determined in hippocampus (Hipp), prefrontal cortex (PFC), and nucleus accumbens (NAc). Results: TRA-seeking behavior was seen in the TRA group and the 6 weeks forced exercise group. By contrast, forced exercise for 2 or 4 weeks attenuated TRA-seeking behavior. This attenuation was associated with a significant increase in Bdnf mRNA expression in the Hipp and NAc, but not the PFC. Additionally, the TRA-induced elevations in Il-1&beta; mRNA expression were reversed by all durations of exercise in Hipp. However, only 2 and 4 weeks, but not 6 weeks, of exercise reduced elevations in PFC and NAc Il-1&beta; expression. Conclusion: Forced exercise for 2 and 4 weeks attenuates TRA-seeking behavior partially through the regulation of Bdnf and Il-1&beta; mRNA expression.

in Brain Sciences on 2025-01-18 00:00:00 UTC.

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Eye Movements during Measurements of Visual Vertical in the Poststroke Subacute Phase

The subjective visual vertical (VV), the visually estimated direction of gravity, is essential for assessing vestibular function and visuospatial cognition. In this study, we aimed to investigate the mechanisms underlying altered VV perception in stroke participants with unilateral spatial neglect (USN), specifically by examining their eye movement patterns during VV judgment tasks. Participants with USN demonstrated limited eye movement scanning along a rotating bar, often fixating on prominent ends, such as the top or bottom. This suggests a reflexive response to visually salient areas, potentially interfering with accurate VV perception. In contrast, participants without USN showed broader scanning around the center of the bar. Notably, participants with USN without frontal lobe lesions occasionally exhibited extended scanning that included the bar’s center, which was associated with accurate VV judgments. These findings suggest that (1) a tendency to fixate on peripheral, prominent areas and (2) frontal lobe involvement in disengaging and redirecting spatial attention may influence VV perception in USN. Based on these results, targeted rehabilitation strategies that encourage individuals with USN to extend their visual scanning beyond prominent endpoints and include central areas could improve VV accuracy. This study highlights the specific eye movement behaviors contributing to VV misperception, emphasizing the importance of training that broadens scanning to improve VV perception effectively.

in eNeuro on 2025-01-17 17:30:24 UTC.

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Exploring Relevant Features for EEG-Based Investigation of Sound Perception in Naturalistic Soundscapes

A comprehensive analysis of everyday sound perception can be achieved using electroencephalography (EEG) with the concurrent acquisition of information about the environment. While extensive research has been dedicated to speech perception, the complexities of auditory perception within everyday environments, specifically the types of information and the key features to extract, remain less explored. Our study aims to systematically investigate the relevance of different feature categories: discrete sound-identity markers, general cognitive state information, and acoustic representations, including discrete sound onset, the envelope, and mel-spectrogram. Using continuous data analysis, we contrast different features in terms of their predictive power for unseen data and thus their distinct contributions to explaining neural data. For this, we analyze data from a complex audio-visual motor task using a naturalistic soundscape. The results demonstrated that the feature sets that explain the most neural variability were a combination of highly detailed acoustic features with a comprehensive description of specific sound onsets. Furthermore, it showed that established features can be applied to complex soundscapes. Crucially, the outcome hinged on excluding periods devoid of sound onsets in the analysis in the case of the discrete features. Our study highlights the importance to comprehensively describe the soundscape, using acoustic and non-acoustic aspects, to fully understand the dynamics of sound perception in complex situations. This approach can serve as a foundation for future studies aiming to investigate sound perception in natural settings.

in eNeuro on 2025-01-17 17:30:24 UTC.

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Alterations of White Matter Microstructure in Migraine Patients Vary in the Peri-ictal Phases

Alterations in white matter (WM) microstructure are commonly found in migraine patients. Here, we employ a longitudinal study of episodic migraine without aura using diffusion magnetic resonance imaging (dMRI) to investigate whether such WM microstructure alterations vary through the different phases of the pain cycle. Fourteen patients with episodic migraine without aura related with menstruation were scanned through four phases of their (spontaneous) migraine cycle (interictal, preictal, ictal, and postictal). Fifteen healthy controls were studied in the corresponding phases of the menstrual cycle. Multishell dMRI data were acquired and preprocessed to obtain maps of diffusion parameters reflecting WM microstructure. After a whole-brain analysis comparing patients with controls, a region-of-interest analysis was performed to determine whether the patients’ microstructural changes varied across the migraine cycle in specific WM tracts. Compared with controls, patients showed reduced axial diffusivity (AD) in several WM tracts across the whole brain in the interictal phase and increased fractional anisotropy (FA) in commissural fibers in the ictal phase. Interestingly, AD returned to baseline levels during peri-ictal phases in specific projection and association fibers. In contrast, FA values decreased in the ictal phase away from normal values in a few commissural and projection tracts. Widespread WM fiber tracts suffer structural variations across the migraine cycle, suggesting microstructural changes potentially associated with limbic and salience functional networks and highlighting the importance of the cycle phase in imaging studies of migraine.

in eNeuro on 2025-01-17 17:30:24 UTC.

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Loss of PV Interneurons in the BLA May Contribute to Altered Network and Behavioral States in Chronically Epileptic Mice

Psychiatric disorders, including anxiety and depression, are highly comorbid in people with epilepsy. However, the mechanisms mediating the shared pathophysiology are currently unknown. There is considerable evidence implicating the basolateral amygdala (BLA) in the network communication of anxiety and fear, a process demonstrated to involve parvalbumin-positive (PV) interneurons. The loss of PV interneurons has been well described in the hippocampus of chronically epileptic mice and in postmortem human tissue of patients with temporal lobe epilepsy (TLE). We hypothesize that a loss of PV interneurons in the BLA may contribute to comorbid mood disorders in epilepsy. To test this hypothesis, we employed a ventral intrahippocampal kainic acid model of TLE in mice, which exhibits profound behavioral deficits associated with chronic epilepsy. We demonstrate a loss of PV interneurons and dysfunction of the remaining PV interneurons in the BLA of chronically epileptic mice. Furthermore, we demonstrate altered principal neuron function and impaired coordination of BLA network and behavioral states in chronically epileptic mice. To determine whether the loss of PV interneurons contributes to these altered network and behavioral states, we partially ablated PV interneurons in the BLA by stereotaxically injecting AAV-Flex-DTA into the BLA of PV-Cre mice. Loss of PV interneurons in the BLA is sufficient to alter behavioral states, such as increasing avoidance behaviors and impairing fear learning. These data suggest that compromised inhibition in the BLA in chronically epileptic mice may contribute to behavioral deficits, suggesting a novel mechanism contributing to comorbid anxiety and epilepsy.

in eNeuro on 2025-01-17 17:30:24 UTC.

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The Epilepsy-Aphasia Syndrome Gene, Cnksr2, Plays a Critical Role in the Anterior Cingulate Cortex Mediating Vocal Communication

Epilepsy–aphasia syndrome (EAS) is a spectrum of childhood disorders that exhibit complex comorbidities that include epilepsy and the emergence of cognitive and language disorders. CNKSR2 is an X-linked gene in which mutations are linked to EAS. We previously demonstrated Cnksr2 knock-out (KO) mice model key phenotypes of EAS analogous to those present in clinical patients with mutations in the gene. Cnksr2 KO mice have increased seizures, impaired learning and memory, increased levels of anxiety, and loss of ultrasonic vocalizations (USVs). The intricate interplay between these diverse phenotypes at the brain regional and cell-type level remains unknown. Here, we leverage conditional deletion of the X-linked Cnksr2 in a neuronal cell-type manner in male mice to demonstrate that anxiety and impaired USVs track with its loss from excitatory neurons. Finally, we further narrow the essential role of Cnksr2 loss in USV deficits to excitatory neurons of the ACC, a region in mice recently implicated in USV production associated with specific emotional states or social contexts, such as mating calls, distress calls, or social bonding signals. Together, our results reveal Cnksr2-based mechanisms that underlie USV impairments that suggest communication impairments can be dissociated from seizures or anxiety. Furthermore, we highlight the cortical circuitry important for initiating USVs.

in eNeuro on 2025-01-17 17:30:24 UTC.

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Influencing factors of health-related quality-of-life perceived by both children/adolescents patients with type-1 diabetes mellitus and their parents: A North-African study [version 2; peer review: 2 approved]

Aim To determine the influencing factors of health-related quality-of-life (HRQoL) perceived by North-African children/adolescents with type-1 diabetes-mellitus (T1DM) and their parents. Methods It was a cross sectional study conducted in Tunisia. A total of 116 patients ( ie ; 43 children and 73 adolescents) and their parents were included. The Arabic validated version of the Pediatric Generic Core Quality-of-Life Inventory 4.0-Scale (PedsQL4.0) was used to evaluate the HRQoL of children/adolescents as perceived by patients and parents. The dependent data were the patients’ self-report and the parents’ proxy-report of the PedsQL4.0 total scores, and the independent data were the patients and parents characteristics. Results Patients’ PedsQL4.0 total score was influenced significantly by siblings in the family > 2; lipodystrophy, and glycosylated hemoglobin (HbA1C). The combination of these factors explained 34.84% of the PedsQL4.0 total score variability. Parents’ PedsQL4.0 total score was influenced significantly by lipodystrophy, siblings; body mass index (BMI), hypoglycemia episodes, and HbA1C. The combination of these factors explained 56.92% of the PedsQL4.0 total score variability. Conclusion T1DM patients self-reported HRQoL was influenced by siblings in the family > 2; lipodystrophy, and HbA1C. The parents’ proxy-report HRQoL was influenced by lipodystrophy, siblings, BMI, hypoglycemia episodes, and HbA1C.

in F1000Research on 2025-01-17 17:13:36 UTC.

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Klebsiella pneumoniae with capsule type K64 is overrepresented among invasive disease in Vietnam [version 2; peer review: 2 approved with reservations]

Introduction Recent reports indicate the emergence of community-acquired pneumonia associated with K64- Klebsiella pneumoniae (K. pneumoniae). Here, we identify the capsular types and sequence type of invasive and commensal K. pneumoniae isolates from Vietnam. Methods We included 93 K. pneumoniae isolates from patients hospitalized at the National Hospital for Tropical Diseases, Hanoi between 2007 and 2011; and 110 commensal isolates from throat swabs from healthy volunteers living in rural and urban Hanoi in 2012. We determined sequence types (STs) by multi-locus sequence typing (MLST) and capsule typing for seven K types by PCR. Antibiotic susceptibility testing was performed using disk diffusion. Results The most common detected capsule types were K1 (39/203, 19.2%, mainly ST23) and K2 (31/203, 15.3%, multiple STs: ST65, ST86, ST380). We found significantly more K2 isolates among invasive in comparison to commensal isolates (22.6% vs 9%, p = 0.01) but no significant difference was observed between invasive and commensal K1 isolates (14.5% vs 24.7%, p = 0.075). K64 with varying sequence types were predominantly seen among invasive K. pneumoniae (8 vs. 3) and were isolated from sepsis and meningitis patients. Among K64 isolates, one was carbapenem-resistant with ST799. Conclusion Our study confirms that capsule type K64 K. pneumoniae is associated with community-acquired invasive infections in Vietnam. Research is needed to unravel the mechanisms of virulence of capsule type K64 in both community and hospital settings.

in F1000Research on 2025-01-17 17:10:23 UTC.

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AIH-PBC Overlap Syndrome Unmasked by Tuberculosis Treatment: Report of Two Cases and Literature Review [version 2; peer review: 1 not approved]

This article presents two patients who were diagnosed with genuine autoimmune liver disease (autoimmune hepatitis and primary biliary cholangitis overlap syndrome) during anti-tuberculosis therapy, which is a rarely reported occurrence. It highlights the challenges in distinguishing drug-induced liver injury from authentic autoimmune liver disease. It also points out the importance of considering autoimmune liver disease as a potential diagnosis revealed by the setting of drug-induced liver injury.

in F1000Research on 2025-01-17 17:07:27 UTC.

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Factors associated with the use of rehabilitation services among people with disabilities in Chile: A population-based study [version 2; peer review: 2 approved with reservations]

Background Rehabilitation services are necessary for many people with disabilities to improve their functioning and be included in society. This study aimed to determine the factors associated with the use of rehabilitation services among people with disabilities in Chile in 2015. Methods This cross-sectional analysis of secondary data from Chile’s 2015 Second National Disability Study (ENDISC II) included people with disabilities aged ≥18 years. The dependent variable was the use of rehabilitation services in the previous year, and the exposure variables were sociodemographic and confounders. Poisson regression was used to determine associated factors, and prevalence ratios (PR) with their 95% confidence intervals (95% CI) were estimated. All results were weighted according to the ENDISC II complex sampling. Results A total of 2610 people with disabilities were included, and 19.1% used some rehabilitation services in the previous year. Educational level (PR 0.43; 95% CI 0.25–0.75), having a mental illness (PR 1.77; 95% CI 1.44–2.18), and caregiver assistance (PR 1.57; 95% CI 1.25–1.97) were factors associated with the use of rehabilitation services. Conclusions In 2015, one-fifth of people with disabilities in Chile used some rehabilitation services in the previous year. People with disabilities with lower educational levels were less likely to access these services. By contrast, people with mental illness and caregiver assistance were more likely to use rehabilitation services.

in F1000Research on 2025-01-17 17:03:24 UTC.

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Diversity, Distribution, and Phenotypic Characterization of Cultivable Wild Yeasts Isolated from Natural Forest [version 1; peer review: awaiting peer review]

Background Yeasts are unicellular fungi that inhabit a variety of environments including plant surfaces, water, soil, and animal hosts. However, limited research has been conducted on soil and plant associated yeasts in Africa, with most studies originating from developed regions. Methods This study explored the diversity, distribution, and phenotypic characterization of cultivable wild yeast in samples from rhizosphere soil, leaves, litter, and tree bark collected from South West Ethiopia. Yeast isolates were characterized using morphological, physiological and biochemical methods, Stress-tolerant yeast species were identified using Matrix-Assisted Laser Desorption Ionization-Time of Flight (MALDI-TOF). Results Based on morphological, physiological, and biochemical analyses, a total of 15 yeast genera were identified from 23 plant species. Predominant yeast species included Candida spp., Saccharomyces spp., Meyerozyma spp., Pichia spp., Geotrichum spp., and Hanseniaspora spp. Plant species with the highest yeast diversity were Ficus vasta, Ficus exasperata, Ficus sycomorus, Cordia africana, and Ritchiea albersii. Bark samples yielded more yeast isolates than rhizosphere soil, litter, and leaves. Stress-tolerant species such as Saccharomyces cerevisiae, Candida pelliculosa, Meyerozyma guilliermondii, Pichia kluyveri, and Trichosporon asahii were identified using MALDI-TOF. Correlation analysis revealed no significant relationship between yeast populations in bark and leaf samples or between rhizosphere soil and leaves, though a weak positive correlation was found between rhizosphere soil and bark or litter. Seasonal analysis showed a strong positive correlation between yeast abundance in spring and summer, but no association between autumn and spring. Conclusion Ethiopian forests are home for various yeast species including the stress-tolerant wild yeasts. This study highlights the significant yeast diversity in Ethiopian forests, with potential applications in improving industrial fermentation processes that operate under stressful conditions.

in F1000Research on 2025-01-17 16:32:03 UTC.

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Argentometric determination of chloride content in tap water at Gimba city administration, South wollo, Ethiopia [version 1; peer review: awaiting peer review]

Background This study investigates chloride concentrations in tap water samples from Gimba city administration, using the argentometric method to assess water quality. Chloride levels are a key indicator of water treatment effectiveness, particularly the adequacy of chlorination, which is critical for preventing waterborne diseases. Methods Chloride concentrations in tap water samples from various locations in Gimba city administration, were determined using the argentometric titration method. Silver nitrate (AgNO₃) was employed as the titrant to precisely quantify chloride ions. The water samples were collected from different sites in Gimba, and chloride levels were measured to evaluate the adequacy of water treatment processes. Results The chloride concentrations across all samples ranged from 52.8 mg/L to 71.9 mg/L, well below the World Health Organization’s recommended limit for drinking water. Significant variation in chloride levels was observed, with Dembesh exhibiting the highest concentration and Medera the lowest. Conclusion The low chloride concentrations suggest insufficient chlorination at the sampling sites, which may compromise the effectiveness of water disinfection and contribute to the prevalence of waterborne diseases in the region. The study underscores the need for enhanced water treatment and disinfection practices in Gimba city to ensure safe drinking water and reduce health risks.

in F1000Research on 2025-01-17 16:29:06 UTC.

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Development and validation of the HEALTH scoring system = A novel and non-invasive laboratory panel to differentiate intestinal tuberculosis from other gastrointestinal diseases [version 1; peer review: awaiting peer review]

Backgrounds Tuberculosis (TB) remains a significant health issue in Indonesia, ranking second globally in TB incidence in 2021. Diagnosing intestinal tuberculosis (ITB) is challenging due to its symptoms, which mimic other diseases, limited laboratory tests, and the need for invasive procedures like colonoscopy. This study aimed to develop a non-invasive laboratory panel for ITB using various biomarkers. Methods A cross-sectional study from November 2020 to December 2022 was carried out at Dr. Cipto Mangunkusumo National Central General Hospital. Laboratory parameters from 143 subjects were identified by Chi-square test and multiple regression analysis. The scoring system was developed based on the identified independent diagnostic parameters scored by regression coefficient β value and standard errors, with the cut-off value determined by the ROC curve. The sensitivity and specificity of the scoring system were determined using the ROC curve. Results Among 143 subjects, 22 were diagnosed with ITB and 121 Non-ITB (prevalence of 15.38%). This study was dominated by females (65.03%), with a ratio of 1.86: 1. The median age in this study was 41 years. The scoring system to differentiate ITB and Non-ITB consisted of 6 diagnostic parameters (referred to as the HEALTH scoring system) as follows: stool HBD-2 (1 and 0 points), ESR (1 and 0 points), blood ADA activity (1 and 0 points), Lymphocyte (0 and 1 point), stool TB PCR (2 and 0 points), and NLR (1 and 0 points). Subjects with scores ≥ 4 could be diagnosed as ITB. The sensitivity and specificity of the HEALTH scoring system were 68.18% and 95.04%, respectively. Conclusion This study developed and validated a laboratory panel called the HEALTH scoring system based on clinical biomarkers of stool HBD-2 level, ESR, blood ADA activity, lymphocytes, stool TB PCR, and NLR, which could be used to differentiate ITB from other gastrointestinal diseases.

in F1000Research on 2025-01-17 16:27:39 UTC.

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“Analyzing the determinants of rural household welfare in Ethiopia: Does agricultural technology adoption matters”: Using seemingly unrelated multi-variate probit model” [version 1; peer review: awaiting peer review]

Background This study analyzed the nexus between rural household welfare and agricultural technology adoption in Ethiopia using secondary data from the Ethiopian Socioeconomic Survey (ESS). The agricultural sector plays a pivotal role in Ethiopia’s economy, contributing significantly to income, consumption, and employment. This research aims to analyze how adopting agricultural technologies such as improved seeds, fertilizers, and irrigation affects poverty and food insecurity among rural households. The research examined poverty and food insecurity levels in Ethiopia and investigates the impact of adopting agricultural technologies on rural household welfare. Methods We used both Descriptive and econometric methods, in which descriptive analysis has been used to assess poverty and food insecurity levels, and a seemingly unrelated bivariate and multivariate probit model applied to analyze the effect of agricultural technology adoption. Result From descriptive summary, it is noted that out of a total sample of the study, 47.61% (2322 out of 4877) are adopting agricultural technologies in many forms more than 70% of female-headed households are food secured and non-poor and 68% of male-headed households are food secured and nun poor. The findings from regression model indicate that access to irrigation, improved seeds, and fertilizers significantly reduces the likelihood of poverty and food insecurity among rural households. Conclusion Based on these results, policy recommendations include promoting agricultural technologies, enhancing access to credit, investing in agricultural extension services, diversifying livelihoods, improving education, and implementing targeted poverty alleviation programs. Further research is encouraged to explore the reasons behind insignificant variables and to identify additional factors affecting rural household welfare in Ethiopia.

in F1000Research on 2025-01-17 16:25:33 UTC.

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Measuring life satisfaction of self-help groups: Role of perceived social support and social empowerment [version 1; peer review: awaiting peer review]

Background This study was designed to investigate the mediation effects of social empowerment (SE) in the relationship between perceived social support (PSS) and life satisfaction (LS) in women self-help group members. Also, this research attempted to understand the moderating effect of decision making (DM) and external communication (EC) on the relationship between the constructs. Methods To achieve the above objective, the primary data were collected from the self-help group women members by using an existing scale. In this survey, 333 participants who are members of self-help group completed the questionnaire and considered for the study. The study is non-experimental and survey-based, with no interventions or manipulations involved. In line with ethical guidelines, we obtained informed consent directly from each respondent before their participation. Conclusion The path coefficient values, t-statistics and P-Values confirmed the positive relationship between PSS->LS; PSS->SE & SE->LS in women self-group members. PLS structural equation modelling estimated by the bootstrap method revealed that SE partially mediates the relationship between PSS & LS. With regard to the interaction effect, the slope analysis and f2 effect size confirmed the moderating effect of EC in the relationship between PSS -> LS & SE -> LS.

in F1000Research on 2025-01-17 16:22:51 UTC.

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Flexible modular dwelling for rural environments; specific case: Cebadas – Ecuador [version 2; peer review: 1 approved, 1 approved with reservations]

Background Sustainable modular dwelling design for rural areas should focus on creating healthy and economically accessible spaces, sensitive to local needs and integrating environmental, functional, sociological and technological aspects. Flexibility is essential to reduce the initial investment and allow future transformations, optimizing the recovery and reuse of materials. These houses must be adaptable, safe and have basic services, satisfying the needs and stages of families’ development. In Ecuador, poverty and energy inefficiency worsen the quality of life in rural areas. This project in the Cebadas parish proposes modular dwelling that applies bioclimatic and sustainable criteria, using local materials to improve habitability and promote the social and economic development of the community. Method The research approach is qualitative-quantitative. Qualitative, since it is necessary to identify the qualities of the sector, bibliographic exploration of guidelines and sustainable strategies. Quantitative, to evaluate the degree of affectation through a diagnosis of the study site and to provide efficient solutions that respond to the context and social reality. Results The spaces presented in the proposal respond to the spatial need for growth and expansion of the users of the sector, through 6 basic guidelines that this type of dwelling should have: Environment, Visual, Form, Function, Bioclimatic and Materials. Conclusions The flexible modular dwelling project for rural environments addresses complex housing needs, highlighting the flexibility and adaptability of an expandable module. It includes income generation with a duplex apartment, fosters communal and cultural life with public and commercial spaces, promotes tourism and rural development with landscape design and crops. In addition, it ensures sustainability through bioclimatic strategies and responsible use of resources.

in F1000Research on 2025-01-17 16:20:19 UTC.

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Sentiment analysis of internet posts on vaccination using ChatGPT and comparison with actual vaccination rates in South Korea [version 3; peer review: 1 approved, 1 approved with reservations]

Background This study used ChatGPT for sentiment analysis to investigate the possible links between online sentiments and COVID-19 vaccination rates. It also examines Internet posts to understand the attitudes and reasons associated with vaccine-related opinions. Methods We collected 500,558 posts over 60 weeks from the Blind platform, mainly used by working individuals, and 854 relevant posts were analyzed. After excluding duplicates and irrelevant content, attitudes toward and reasons for vaccine opinions were studied through sentiment analysis. The study further correlated these categorized attitudes with the actual vaccination data. Results The proportions of posts expressing positive, negative, and neutral attitudes toward COVID-19 vaccines were 5%, 83%, and 12%, respectively. The total post count showed a positive correlation with the vaccination rate, indicating a high correlation between the number of negative posts about the vaccine and the vaccination rate. Negative attitudes were predominantly associated with societal distrust and perceived oppression. Conclusions This study demonstrates the interplay between public perceptions of COVID-19 vaccines as expressed through social media and vaccination behavior. These correlations can serve as useful clues for devising effective vaccination strategies.

in F1000Research on 2025-01-17 16:16:00 UTC.

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Optimizing machine learning performance for medical imaging analyses in low-resource environments: The prospects of CNN-based Feature Extractors [version 1; peer review: awaiting peer review]

Background Machine learning (ML) algorithms have generally enhanced the speed and accuracy of image-based diagnosis, and treatment strategy planning, compared to the traditional approach of interpreting medical images by experienced radiologists. Convolutional neural networks (CNNs) have been particularly useful in this regard. However, training CNNs come with significant time and computational cost necessitating the development of efficient solutions for deploying CNNs in low-resource environments. This study investigates the use of pre-trained CNNs as feature extractors in medical imaging analyses and highlights the key considerations to be taken into account when implementing these extractors. Methods Eight medical imaging datasets covering several diseases (e.g. breast cancer, brain tumor and malaria) were used. Five ML algorithms (k-nearest neighbours, logistic regression, naïve Bayes, random forests and light gradient boosting machine) were implemented with three pre-trained CNN models (VGG-16, EfficientNet-B0, and ResNet-50). These pre-trained models were deployed as feature extractors fed into the classifiers for image classification tasks. The performance of these classifiers was assessed using a ten-fold cross validation scheme with metrics such as accuracy, F1 score, specificity, sensitivity, AUC-ROC, Matthews’ correlation coefficient (MCC), precision, time and space complexities. Results From our experiments, we found a general improvement in ML models’ performance after feature extraction (FE). Of the three FE models tested,EfficientNet-B0 performed best in terms of predicitve performance i.e. accuracy, specificity, sensitivity, AUC-ROC, MCC, F1 score, and precision. However, VGG-16 had the best performance in terms of time and memory efficiency. Our results identify two conditions necessary for the optimal performance of the FE models; (i) balanced datasets - a set where classes or categories are represented in approximately equal proportions, (ii) big data sets - adequate number of objects for training and testing. Interestingly, the performance of the ML models did not correlate with the number of class labels i.e. the type of classification task whether binary or multi-class had no influence in the models’ performance. Of the five algorithms investigated, logistic regression benefitted the most from the adoption of the feature extractors. Conclusion Our results confirm that the use of CNNs as feature extractors offer an effective balance between high performance and computational efficiency, making them well-suited for use in low-resource environments.

in F1000Research on 2025-01-17 16:01:23 UTC.

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Genotoxic effects in island populations of Cartagena de Indias, Colombia due to environmental exposure to mercury and cadmium [version 3; peer review: 1 approved, 1 approved with reservations]

Background Contamination of Cartagena Bay, Colombia with heavy metals such as mercury (Hg) and cadmium (Cd) presents a major environmental and public health concern, particularly for human communities residing on nearby islands and coastal areas. These populations face enhanced exposure risks owing to their traditional fishing practices and continuous interactions with polluted marine environments. This study aimed to evaluate the genotoxic effects of environmental exposure to Hg and Cd in populations from the island zone of the Cartagena district, Bolívar. Methods Ninety-four individuals from the four island communities (study group) and 30 individuals from the urban area of Cartagena (control group) participated in this study. The blood samples were collected to measure total mercury (T-Hg) and Cd concentrations, and a Buccal Micronucleus Cytome (BMCyt) assay was used to evaluate exposure effects. Results Cadmiun levels in the blood of the study group were within the normal range and comparable to those of the control group (p > 0.05). However, the study group exhibited significantly higher T-Hg levels (7.34 μg/L) compared to the control group (2.01 μg/L), surpassing the accepted limit. Moreover, the study group showed a higher incidence of DNA damage and cell death biomarkers (p < 0.05). Additionally, significant correlations were observed between total blood Hg levels and the frequencies of micronuclei, karyorrhexis, and karyolysis. Conclusion These results suggest that island populations of Cartagena are exposed to high levels of Hg and exhibit genotoxic damage, indicating a problem that must be addressed.

in F1000Research on 2025-01-17 15:54:54 UTC.

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Adaptation optimizes sensory encoding for future stimuli

by Jiang Mao, Constantin A Rothkopf, Alan A Stocker

Sensory neurons continually adapt their response characteristics according to recent stimulus history. However, it is unclear how such a reactive process can benefit the organism. Here, we test the hypothesis that adaptation actually acts proactively in the sense that it optimally adjusts sensory encoding for future stimuli. We first quantified human subjects’ ability to discriminate visual orientation under different adaptation conditions. Using an information theoretic analysis, we found that adaptation leads to a reallocation of coding resources such that encoding accuracy peaks at the mean orientation of the adaptor while total coding capacity remains constant. We then asked whether this characteristic change in encoding accuracy is predicted by the temporal statistics of natural visual input. Analyzing the retinal input of freely behaving human subjects showed that the distribution of local visual orientations in the retinal input stream indeed peaks at the mean orientation of the preceding input history (i.e., the adaptor). We further tested our hypothesis by analyzing the internal sensory representations of a recurrent neural network trained to predict the next frame of natural scene videos (PredNet). Simulating our human adaptation experiment with PredNet, we found that the network exhibited the same change in encoding accuracy as observed in human subjects. Taken together, our results suggest that adaptation-induced changes in encoding accuracy prepare the visual system for future stimuli.

in PLoS Computational Biology on 2025-01-17 14:00:00 UTC.

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BuDDI: Bulk Deconvolution with Domain Invariance to predict cell-type-specific perturbations from bulk

by Natalie R. Davidson, Fan Zhang, Casey S. Greene

While single-cell experiments provide deep cellular resolution within a single sample, some single-cell experiments are inherently more challenging than bulk experiments due to dissociation difficulties, cost, or limited tissue availability. This creates a situation where we have deep cellular profiles of one sample or condition, and bulk profiles across multiple samples and conditions. To bridge this gap, we propose BuDDI (BUlk Deconvolution with Domain Invariance). BuDDI utilizes domain adaptation techniques to effectively integrate available corpora of case-control bulk and reference scRNA-seq observations to infer cell-type-specific perturbation effects. BuDDI achieves this by learning independent latent spaces within a single variational autoencoder (VAE) encompassing at least four sources of variability: 1) cell type proportion, 2) perturbation effect, 3) structured experimental variability, and 4) remaining variability. Since each latent space is encouraged to be independent, we simulate perturbation responses by independently composing each latent space to simulate cell-type-specific perturbation responses. We evaluated BuDDI’s performance on simulated and real data with experimental designs of increasing complexity. We first validated that BuDDI could learn domain invariant latent spaces on data with matched samples across each source of variability. Then we validated that BuDDI could accurately predict cell-type-specific perturbation response when no single-cell perturbed profiles were used during training; instead, only bulk samples had both perturbed and non-perturbed observations. Finally, we validated BuDDI on predicting sex-specific differences, an experimental design where it is not possible to have matched samples. In each experiment, BuDDI outperformed all other comparative methods and baselines. As more reference atlases are completed, BuDDI provides a path to combine these resources with bulk-profiled treatment or disease signatures to study perturbations, sex differences, or other factors at single-cell resolution.

in PLoS Computational Biology on 2025-01-17 14:00:00 UTC.

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Differentiating the contributions of Na+/K+ pump current and persistent Na+ current in simulated voltage-clamp experiments

Journal of Neurophysiology, Ahead of Print.

in Journal of Neurophysiology on 2025-01-17 12:30:32 UTC.

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NORSE, FIRES, and a Polygenic Trickle of Autoimmunity

in Annals of Neurology on 2025-01-17 11:58:16 UTC.

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Annals of Neurology: Volume 97, Number 2, February 2025

in Annals of Neurology on 2025-01-17 11:58:16 UTC.

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Issue Information

in Annals of Neurology on 2025-01-17 11:58:16 UTC.

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Balamuthia Mandrillaris Encephalitis Post‐Raw Beef Ingestion

in Annals of Neurology on 2025-01-17 11:58:16 UTC.

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Bilaterally Symmetrical Globus Pallidus Infarction

in Annals of Neurology on 2025-01-17 11:58:16 UTC.

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Multiple Aneurysms and Cerebral Infarction in a Patient with Sneddon Syndrome

in Annals of Neurology on 2025-01-17 11:58:16 UTC.

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Recessive Variants in PIGG Cause a Motor Neuropathy with Variable Conduction Block, Childhood Tremor, and Febrile Seizures: Expanding the Phenotype

Biallelic variants in phosphatidylinositol glycan anchor biosynthesis, class G (PIGG) cause hypotonia, intellectual disability, seizures, and cerebellar features. We present 8 patients from 6 families with a childhood-onset motor neuropathy and neurophysiology demonstrating variable motor conduction block and temporal dispersion. All individuals had a childhood onset tremor, 5 of 8 had cerebellar involvement, and 6 of 8 had childhood febrile seizures. All individuals have biallelic PIGG variants, including the previously reported pathogenic variant Trp505*, plus 6 novel variants. Null enzyme activity is demonstrated via PIGO/PIGG double knockout system for Val339Gly and Gly19Glu, and residual activity for Trp505* due to read-through. Emm negative blood group status was confirmed in 1 family. PIGG should be considered in unsolved motor neuropathy. ANN NEUROL 2025;97:388–396

in Annals of Neurology on 2025-01-17 11:58:16 UTC.

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Evaluation of Soluble Colony Stimulating Factor 1 Receptor (CSF1R) in Peripheral Blood as a Diagnostic Marker of CSF1R‐Related Disorder (CSF1R‐RD) in a Murine Model and CSF1R‐RD Patients

Mutations in colony stimulating factor 1 receptor (CSF1R) result in CSF1R-related disorder (CSF1R-RD). Our previous study demonstrated a proteolytic generation of a soluble CSF1R (sCSF1R) that could potentially serve as a diagnostic biomarker of CSF1R-RD. Herein, we observed that sCSF1R is released into peripheral serum as a highly glycosylated monomer in Csf1r ^+/− mice that mimic the clinical symptoms of CSF1R-RD patients. Notably, we found that serum sCSF1R could distinguish CSF1R-RD cohorts from controls with high accuracy as evaluated by receiver operating characteristic (ROC) curves. This study demonstrates that reduced sCSF1R in serum may serve as a diagnostic biomarker for CSF1R-RD. ANN NEUROL 2025;97:397–403

in Annals of Neurology on 2025-01-17 11:58:16 UTC.

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RNA Binding Protein Dysfunction Links Smoldering/Slowly Expanding Lesions to Neurodegeneration in Multiple Sclerosis

Objective

Despite the advances in treatments for multiple sclerosis (MS), unremitting neurodegeneration continues to drive disability and disease progression. Smoldering/slowly expanding lesions (SELs) and dysfunction of the RNA binding protein (RBP) heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1) are pathologic hallmarks of MS cortex and intricately tied to disability and neurodegeneration, respectively. We hypothesized that neuronal hnRNP A1 dysfunction contributes to neurodegeneration and is exacerbated by smoldering/SELs in progressive MS.

Methods

Neuronal hnRNP A1 pathology (nucleocytoplasmic mislocalization of hnRNP A1) was examined in healthy control and MS brains using immunohistochemistry. MS cases were stratified by severity of hnRNP A1 pathology to examine the link between RBP dysfunction, demyelination, and neurodegeneration.

Results

We found that smoldering/SELs were only present within a subset of MS tissues characterized by elevated neuronal hnRNP A1 pathology (MS-A1^high) in adjacent cortical gray matter. In contrast to healthy controls and MS with low hnRNP A1 pathology (MS-A1^low), MS-A1^high showed elevated markers of neurodegeneration, including neuronal loss and injury, brain atrophy, axonal loss, and axon degeneration. Additionally, we discovered a subpopulation of morphologically intact neurons lacking expression of NeuN, a neuron-specific RBP, in cortical projection neurons in MS-A1^high cases.

Interpretation

hnRNP A1 dysfunction contributes to neurodegeneration and may be exacerbated by smoldering/SELs in progressive MS. The discovery of NeuN-negative neurons suggests that some cortical neurons may only be injured and not lost. By characterizing RBP pathology in MS cortex, this study has important implications for understanding the pathogenic mechanisms driving neurodegeneration, the substrate of disability and disease progression. ANN NEUROL 2025;97:313–328

in Annals of Neurology on 2025-01-17 11:58:16 UTC.

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A Prospective Multicenter Analysis of Mobile Stroke Unit Cost‐Effectiveness

Objective

Given the high disease and cost burden of ischemic stroke, evaluating the clinical efficacy and cost-effectiveness of new approaches to prevent and treat ischemic stroke is critical. Effective ischemic stroke management depends on timely administration of thrombolytics after stroke onset. This study evaluates the cost-effectiveness associated with the use of mobile stroke units (MSUs) to expedite tissue plasminogen activator (tPA) administration, as compared with standard management through emergency medical services (EMS).

Methods

This study is a prospective, multicenter, alternating-week, cluster-controlled trial of MSU versus EMS. One-year and life-time cost-effectiveness analyses, using the incremental cost-effectiveness ratio (ICER) method, were performed from the perspective of CMS's Medicare. Quality-adjusted life years (QALYs) estimated using patient-reported EQ-5D-5L data were used as the effectiveness measure. Health care utilizations were converted to costs using average national Medicare reimbursements. ICERs excluding patients with pre-existing disability, and limited to stroke-related costs were also calculated.

Results

The first-year ICER for all tPA-eligible patients using total cost differences between MSU and EMS groups was $238,873/QALY; for patients without pre-existing disability was $61,199/QALY. The lifetime ICERs for all tPA-eligible patients and for those without pre-existing disability were $94,710 and $31,259/QALY, respectively. All ICERs were lower when restricted to stroke-related costs and were highly dependent on the number of patients treated per year in an MSU.

Interpretation

MSUs' cost-effectiveness is borderline if we consider total first-year costs and outcomes in all tPA-eligible patients. MSUs are cost-effective to highly cost-effective when calculations are based on patients without pre-existing disability, patients' lifetime horizon, stroke-related costs, and more patients treated per year in an MSU. ANN NEUROL 2025;97:209–221

in Annals of Neurology on 2025-01-17 11:58:16 UTC.

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Association Between Early‐Life and Premorbid Measurements of Body Composition and Risk of Motor Neuron Disease: A Prospective Cohort Study in the UK Biobank

Objective

The objective of this study was to investigate the association between developmental and premorbid body composition measurements and the risk of motor neuron disease (MND).

Methods

We performed a cohort study in the UK Biobank to assess the association of developmental body metrics and premorbid body composition measures (using 28 measurements and 7 patterns of body composition) with the risk of MND. Among participants with longitudinal measures, we compared the changes in body composition over time between individuals who later developed MND and those who remained free of MND.

Results

Among the 412,691 individuals included in this study, 549 people received an MND diagnosis during the follow-up visit. Higher birth weight was associated with an increased risk of MND among individuals born over 4 kg (hazard ratio [HR] per kg increase = 2.21, 95% confidence interval [CI] = 1.38–3.55), and taller adult height was associated with an increased risk of MND (HR per 5 cm increase = 1.10, 95% CI = 1.03–1.17). We observed that measures of elevated fat mass were associated with a lower risk of MND more than 5 years before diagnosis. A higher “leg-dominant fat distribution” pattern was associated with an increased risk whereas higher “muscle strength” was associated with a reduced risk of MND 5 years before diagnosis. Longitudinal analyses indicated a faster decline in measures of fat mass and muscle strength, as well as a shift in fat distribution from arm to leg dominant, among individuals who later developed MND, compared with others.

Interpretation

Body composition at early and middle age may be indicative of the risk of MND development. ANN NEUROL 2025;97:259–269

in Annals of Neurology on 2025-01-17 11:58:16 UTC.

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Fighting Amyotrophic Lateral Sclerosis by Protecting the Liver? A Prospective Cohort Study

[Color figure can be viewed at www.annalsofneurology.org]

Background

Previous studies have observed liver abnormalities in amyotrophic lateral sclerosis (ALS) patients. This study aimed to investigate whether early signs of liver disease, measured by magnetic resonance imaging-derived iron-corrected T1-mapping (cT1), are risk factors for developing ALS.

Methods

cT1 and proton density fat fraction were measured and automatically analyzed using LiverMultiScan® software. The Fibrosis-4 index was calculated using an established formula based on age and blood markers. Cox proportional hazard models were used to examine the relationship between liver disease, liver biomarkers, and incident ALS.

Results

In a cohort of 533,707 individuals from UK Biobank, 24 ALS cases were identified among 28,328 participants with liver disease during the follow-up period. Among a total of 33,959 individuals with complete liver imaging data, 15 incident ALS cases were observed during a median follow-up period of 5.6 years. Individuals with liver disease had a higher risk of developing ALS, with an adjusted hazard ratio of 7.35 (95% CI 4.47–12.09; p < 0.001). An increase in cT1 was also associated with a higher risk of ALS. After adjusting for age, sex, Townsend deprivation index, smoking status, alcohol intake frequency, body mass index, proton density fat fraction, Fibrosis-4, and metabolic syndrome, an increase in cT1 remained significantly associated with a higher risk of ALS, with an adjusted hazard ratio of 3.15 (95% CI 1.79–5.55) per 1-SD increase. Sensitivity analyses confirmed these robust results.

Interpretation

Liver disease activity, indicated by cT1, increases the risk of developing ALS, independent of metabolic syndrome, liver fat, or fibrosis. ANN NEUROL 2025;97:270–280

in Annals of Neurology on 2025-01-17 11:58:16 UTC.

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Longitudinal Magnetic Resonance Imaging in Asymptomatic C9orf72 Mutation Carriers Distinguishes Phenoconverters to Amyotrophic Lateral Sclerosis or Amyotrophic Lateral Sclerosis With Frontotemporal Dementia

Objective

We prospectively studied asymptomatic C9orf72 mutation carriers, identifying those developing amyotrophic lateral sclerosis (ALS) or frontotemporal dementia (FTD).

Methods

We enrolled 56 asymptomatic family members (AFM) with a C9orf72 mutation (AFM C9+), 132 non-carriers (AFM C9−), and 359 population-based controls. Using 3 T magnetic resonance imaging, we measured cortical thickness, gyrification, and subcortical volumes longitudinally. Linear mixed-effects models on non-converting AFM C9+ scans (n = 107) created a reference for these measurements, establishing individual atrophy patterns. Atrophy patterns from presymptomatic phenoconverters (n = 10 scans) served as a template for group comparisons and similarity assessments. Similarity with phenoconverters was quantified using Dice similarity coefficient (DSC) for cortical and Kullback–Leibler similarity (KLS) for subcortical measures. Using longitudinal similarity assessments, we predicted when participants would reach the average similarity level of phenoconverters at their first post-onset scan.

Results

Five AFM C9+ converted to ALS or ALS-FTD. Up to 6 years before symptoms, these phenoconverters exhibited significant atrophy in frontal, temporal, parietal, and cingulate cortex, along with smaller thalamus, hippocampus, and amygdala compared to other AFM C9+. Some non-converted AFM C9+ had high DSC and KLS, approaching values of phenoconverters, whereas others, along with AFM C9− and controls, had lower values. At age 80, we predicted 27.9% (95% confidence interval, 13.2–40.1%) of AFM C9+ and no AFM C9− would reach the same DSC as phenoconverters.

Interpretation

Distinctive atrophy patterns are visible years before symptom onset on presymptomatic scans of phenoconverters. Combining baseline and follow-up similarity measures may serve as a promising imaging biomarker for identifying those at risk of ALS or ALS-FTD. ANN NEUROL 2025;97:281–295

in Annals of Neurology on 2025-01-17 11:58:16 UTC.

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A Novel Mouse Model for Cerebral Inflammatory Demyelination in X‐Linked Adrenoleukodystrophy: Insights into Pathogenesis and Potential Therapeutic Targets

[Color figure can be viewed at www.annalsofneurology.org]

Objective

X-linked adrenoleukodystrophy (ALD) is caused by mutations in ABCD1, a peroxisomal gene. More than half of males with an ABCD1 mutation develop inflammatory cerebral demyelination (cALD), but underlying mechanisms remain unknown and therapies are limited. We sought to develop and characterize a mouse model of cALD to facilitate study of disease mechanisms and therapy development.

Methods

We used immunoassays and immunohistochemistry to assess novel (interleukin 18 [IL-18]) and established molecular markers in cerebrospinal fluid (CSF) and postmortem brain tissue from cALD patients. We generated a cALD phenotype in Abcd1-knockout mice using a 2-hit method that combines cuprizone and experimental autoimmune encephalomyelitis models. We then used magnetic resonance imaging (MRI) and immunohistochemistry to assess the fidelity of cALD molecular markers in the mice.

Results

Human and mouse cALD lesions shared histologic features of myelin phagocytosis, myelin loss, abundant microglial activation, T and B-cell infiltration, and astrogliosis. Compared to wild-type controls, Abcd1-knockout mice displayed more cerebral demyelination, blood–brain barrier disruption, and perivascular immune cell infiltration. This enhanced inflammatory response was associated with higher levels of fibrin deposition, oxidative stress, demyelination, and axonal injury. IL-18 immunoreactivity co-localized with perivascular monocytes/macrophages in both human and mouse brain tissue. In cALD patients, CSF IL-18 levels correlated with MRI lesion severity.

Interpretation

Our results suggest loss of Abcd1 function in mice predisposes to more severe blood–brain barrier disruption, cerebral inflammation driven by the infiltration of peripheral immune cells, demyelination, and axonal damage, replicating human cALD features. This novel mouse model could shed light on cALD mechanisms and accelerate cALD therapy development. ANN NEUROL 2025;97:296–312

in Annals of Neurology on 2025-01-17 11:58:16 UTC.

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Cost‐Effectiveness of Endovascular Thrombectomy in Patients with Large Ischemic Stroke

Objectives

Whereas highly cost-effective and cost-saving for patients with small infarcts, whether endovascular thrombectomy (EVT) remains cost-effective in patients with extensive ischemic injury is uncertain.

Methods

We conducted a model-based cost-effectiveness analysis from the United States, Australian, and Spanish societal perspectives, using a 7-state Markov model, with each state defined by the modified Rankin Scale (mRS) score. Initial probabilities at 3 months were derived from the SELECT2 trial. All other model inputs, including transition probabilities, health care and non-health care costs, and utility weights, were sourced from published literature and government websites. Our analysis included extensive sensitivity and subgroup analyses.

Results

EVT in patients with large ischemic stroke improved health outcomes and was associated with lower costs from a societal viewpoint. EVT was cost-effective with a mean between-group difference of 1.24 quality-adjusted life years (QALYs), and a cost-saving of $23,409 in the United States, $10,691 in Australia, and $30,036 in Spain, in addition to uncosted benefits in productivity for patients and carers. Subgroup analyses were directionally consistent with the overall population, notably with preserved cost-effectiveness in older patients (≥ 70 years) and those with more severe strokes (National Institutes of Health Stroke Scale [NIHSS] ≥ 20). Sensitivity analyses were largely consistent with the base-case results.

Interpretation

EVT demonstrated cost-effectiveness in patients with large core across different settings in the United States, Australia, and Spain, including older patients and those with more severe strokes. These results further support adaptation of systems of care to accommodate the expansion of thrombectomy eligibility to patients with large cores and maximize EVT benefits. ANN NEUROL 2025;97:222–231

in Annals of Neurology on 2025-01-17 11:58:16 UTC.

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Efficacy and Safety of Sodium Oxybate in Isolated Focal Laryngeal Dystonia: A Phase IIb Double‐Blind Placebo‐Controlled Cross‐Over Randomized Clinical Trial

Objective

To examine the efficacy and safety of sodium oxybate versus placebo in a phase IIb randomized double-blind placebo-controlled 2-period cross-over clinical trial in patients with isolated laryngeal dystonia (LD).

Methods

The study was conducted from January 2018 to December 2021, pausing during the COVID-19 pandemic, at Massachusetts Eye and Ear in 106 patients with alcohol-responsive (EtOH+) and alcohol-non-responsive (EtOH−) LD (53 to receive 1.5g of sodium oxybate first, 53 to receive matching placebo first). The primary outcome was a change from baseline in LD symptom severity 40 minutes after drug intake. Safety was based on vital signs, cognitive function, suicidality, daytime sleepiness, and adverse events. Patients, investigators, and outcome assessors were masked to study procedures.

Results

Compared to baseline, EtOH+ but not EtOH− patients had a statistically significant improvement in LD symptoms following sodium oxybate versus placebo (EtOH+: 98.75% confidence interval [CI] = 0.6–26.9; p = 0.008; EtOH−: 98.75% CI = −6.2 to 18.7; p = 0.42). Statistically significant minimum drug efficacy in EtOH+ patients was found at ≥16% symptom improvement (OR = 2.09; 98.75% CI = 0.75–5.80; p = 0.036), with an average of 40.81% benefits (98.75% CI = 34.7–48.6). Drug efficacy waned by 300 minutes after intake without a rebound. No changes were found in cognitive function, suicidality, or vital signs. Common adverse events included mild dizziness, nausea, and daytime sleepiness.

Interpretation

Sodium oxybate showed clinically meaningful improvement of symptoms in EtOH+ LD patients, with acceptable tolerability. Sodium oxybate offers the first pathophysiologically relevant oral treatment for laryngeal dystonia. ANN NEUROL 2025;97:329–343

in Annals of Neurology on 2025-01-17 11:58:16 UTC.

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Sex Modifies the Severity and Outcome of Spontaneous Intracerebral Hemorrhage

Objective

The limited existing evidence on sex differences in the clinical characteristics of patients with spontaneous, non-traumatic intracerebral hemorrhage (ICH) comes from small, single-center studies. Here, we performed an individual patient data meta-analysis of 3 randomized clinical trials and 1 multi-ethnic observational study of ICH to investigate the impact of sex on ICH severity and outcome.

Methods

Inclusion criteria in our study were a neuroimaging-confirmed ICH. We evaluated whether sex was associated with ICH severity (hematoma volume and expansion) and poor functional outcomes (modified Rankin Scale >3) 3 or 6 months after the ICH.

Results

A total of 4,812 ICH patients were evaluated (mean age 62, 40% female). Males with ICH were younger, more likely to be smokers and have diabetes, and less likely to be on anticoagulants (all p < 0.05). In multivariable analyses, male sex was associated with non-lobar location (odds ratio [OR]: 1.63; 95% confidence interval [CI]: [1.39–1.92]; p < 0.001), larger hemorrhages (beta: 0.16 [0.08–0.23]; p < 0.001) and a higher risk of hematoma expansion (OR: 1.43 [1.20–1.71]; p < 0.001). Despite the larger hemorrhage volume and higher risk of expansion, male sex was associated with a 24% lower risk of poor outcomes (OR: 0.76 [0.64–0.90]; p = 0.002).

Interpretation

Compared to females, males with ICH have larger bleeds and higher risk of hematoma expansion. Despite the larger bleeds and higher risk of hematoma expansion, males with ICH have lower risk of poor outcomes. Our results suggest that the biology and clinical trajectory are different in females and males with ICH, supporting sex-specific research in this condition. ANN NEUROL 2025;97:232–241

in Annals of Neurology on 2025-01-17 11:58:16 UTC.

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Enhancement of Glutamate Uptake as Novel Antiseizure Approach: Preclinical Proof of Concept

Allosteric activation of glutamate uptake as novel antiseizure approach. [Color figure can be viewed at www.annalsofneurology.org]

Objective

Excitotoxicity is a common hallmark of epilepsy and other neurological diseases associated with elevated extracellular glutamate levels. Thus, here, we studied the protective effects of (R)-AS-1, a positive allosteric modulator (PAM) of glutamate uptake in epilepsy models.

Methods

(R)-AS-1 was evaluated in a range of acute and chronic seizure models, while its adverse effect profile was assessed in a panel of standard tests in rodents. The effect of (R)-AS-1 on glutamate uptake was assessed in COS-7 cells expressing the transporter. WAY 213613, a selective competitive EAAT2 inhibitor, was used to probe the reversal of the enhanced glutamate uptake in the same transporter expression system. Confocal microscopy and Western blotting analyses were used to study a potential influence of (R)-AS-1 on GLT-1 expression in mice.

Results

(R)-AS-1 showed robust protection in a panel of animal models of seizures and epilepsy, including the maximal electroshock- and 6 Hz-induced seizures, corneal kindling, mesial temporal lobe epilepsy, lamotrigine-resistant amygdala kindling, as well as seizures induced by pilocarpine or Theiler's murine encephalomyelitis virus. Importantly, (R)-AS-1 displayed a favorable adverse effect profile in the rotarod, the minimal motor impairment, and the Irwin tests. (R)-AS-1 enhanced glutamate uptake in vitro and this effect was abolished by WAY 213613, while no influence on GLT-1 expression in vivo was observed after repeated treatment.

Interpretation

Collectively, our results show that (R)-AS-1 has favorable tolerability and provides robust preclinical efficacy against seizures. Thus, allosteric enhancement of EAAT2 function could offer a novel therapeutic strategy for treatment of epilepsy and potentially other neurological disorders associated with glutamate excitotoxicity. ANN NEUROL 2025;97:344–357

in Annals of Neurology on 2025-01-17 11:58:16 UTC.

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Distinct Constructs Underlie Patient‐Reported and Performance‐Rated Outcomes after Stroke

Objective

Patient-reported outcome measures (PROMs), which capture patients' perspectives on the consequences of health and disease, are widely used in neurological care and research. However, it is unclear how PROMs relate to performance-rated impairments. Sociodemographic factors are known to affect PROMs. Direct damage to brain regions critical for self-awareness (i.e., parietal regions and the salience/ventral-attention network) may also impair self-report outcomes. This study examined the relationship between PROMs and performance-based measures in stroke survivors with arm motor impairments. We hypothesized that PROMs would be distinct from performance-based outcomes, influenced by sociodemographic factors, and linked to damage in brain circuits involved in self-perception.

Methods

We longitudinally assessed 54 stroke survivors using patient-reported and performance-rated measures at 4 timepoints. We used factor analysis to reveal the outcome battery's factorial structure. Linear regression examined the association between classes of measures and sociodemographics. Voxel-lesion-symptom-mapping, region-of-interest-based analysis, and voxel-lesion-network-mapping investigated the relationship between classes of outcomes and stroke-related injury.

Results

Performance-based and patient-reported measures formed distinct factors, consistent across recovery phases. Higher education (β1 = 0.36, p = 0.02) and income adequacy (β2 = 0.48, p = 0.05) were associated with patient-reported, but not performance-rated outcomes. Greater parietal lobe injury, irrespective of hemisphere, was associated with worse patient-reported outcomes; greater corticospinal tract injury related to worse performance-rated outcomes. Lesions with greater functional connectivity to the salience/ventral-attention network were associated with worse patient-reported outcomes (r = −0.35, p = 0.009).

Interpretation

Our findings reveal important differences between performance-rated and patient-reported outcomes, each with specific associated factors and anatomy post-stroke. Incorporating sociodemographic and neuroanatomic characteristics into neurorehabilitation strategies may inform and optimize patient outcomes. ANN NEUROL 2025;97:242–253

in Annals of Neurology on 2025-01-17 11:58:16 UTC.

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Association of Seizure Control with Mortality, Cognition, and Function in People With Dementia

Objectives

The effects of seizure control on outcomes in persons with dementia (PWD) remain unclear. Our study aimed to investigate the impact of seizure control on mortality, function, cognition, and mood among PWD.

Methods

This longitudinal, multicenter study is based on 39 Alzheimer's disease centers (ADCs) in the United States from September 2005 to December 2021. PWD were grouped by seizure status into recurrent (seizures in the past year), remote (prior seizures but none in the past year), and no seizures (controls). The primary outcome was all-cause mortality among seizure groups. We used Weibull survival analysis to assess the mortality risks by seizure status after adjusting for age, sex, education, race, ethnicity, hypertension, diabetes, hyperlipidemia, degree of cognitive impairment, dominant Alzheimer's disease (AD) mutation, brain trauma, stroke, Parkinson's disease, alcohol abuse, and depression. Cognition (Clinical Dementia Rating), function (physical dependence and nursing home residence), day-to-day activities (Functional Assessment Scores), and mood (Geriatric Depression Scale) were compared among seizure groups after adjusting for dementia duration and age.

Results

Among 26,501 participants, 374 (1.4%) had recurrent seizures and 510 (1.9%) had remote seizures. In multivariable survival analysis, recurrent seizures were associated with a higher mortality risk than remote and no seizures (adjusted hazard ratio [aHR], 95% confidence interval [95% CI]; recurrent aHR = 1.79, 95% CI = 1.51 to 2.12; remote aHR = 1.17, 95% CI = 0.98 to 1.38). Median time-to-death for recurrent, remote, and no seizures was 2.4, 4.0, and 4.7 years, respectively. People with recurrent seizures had worse cognition, day-to-day function, and physical dependence than those with remote seizures and controls.

Interpretation

PWD with poorly controlled recurrent seizures have worse mortality, functional, and cognitive outcomes than PWD with remote and no seizures. These findings underscore the need for timely identification and management of ongoing seizures in PWD. ANN NEUROL 2025;97:358–368

in Annals of Neurology on 2025-01-17 11:58:16 UTC.

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Neurologic Manifestations of Long COVID Disproportionately Affect Young and Middle‐Age Adults

Objective

To investigate neurologic manifestations of post-acute sequelae of SARS-CoV-2 infection (Neuro-PASC) in post-hospitalization Neuro-PASC (PNP) and non-hospitalized Neuro-PASC (NNP) patients across the adult lifespan.

Methods

Cross-sectional study of the first consecutive 200 PNP and 1,100 NNP patients evaluated at a Neuro-coronavirus disease 2019 (COVID-19) clinic between May 2020 and March 2023. Patients were divided into younger (18–44 years), middle-age (45–64 years), and older (65+ years) age groups.

Results

Younger and middle-age individuals accounted for 142 of 200 (71%) of PNP and 995 of 1100 (90.5%) of NNP patients. Significant age-related differences in the frequencies of comorbidities and abnormal neurologic findings demonstrated higher prevalence in older patients. Conversely, 10 months from COVID-19 onset, we found significant age-related differences in Neuro-PASC symptoms indicating lower prevalence, and therefore, symptom burden, in older individuals. Moreover, there were significant age-related differences in subjective impression of fatigue (median [interquartile range (IQR)] patient-reported outcomes measurement information system [PROMIS] score: younger 64 [57–69], middle-age 63 [57–68], older 60.5 [50.8–68.3]; p = 0.04) and sleep disturbance (median [IQR] PROMIS score: younger 57 [51–63], middle-age 56 [53–63], older 54 [46.8–58]; p = 0.002) in the NNP group, commensurate with higher impairment in quality of life (QoL) among younger patients. Finally, there were significant age-related differences in objective executive function (median [IQR] National Institutes of Health [NIH] toolbox score: younger 48 [35–63], middle-age 49 [38–63], older 54.5 [45–66.3]; p = 0.01), and working memory (median [IQR] NIH toolbox score: younger 47 [40–53], middle-age 50 [44–57], older 48 [43–58]; p = 0.0002) in NNP patients, with the worst performance coming from the younger group.

Interpretation

Younger and middle-age individuals are disproportionally affected by Neuro-PASC regardless of acute COVID-19 severity. Although older people more frequently have abnormal neurologic findings and comorbidities, younger and middle-age patients suffer from a higher burden of Neuro-PASC symptoms and cognitive dysfunction contributing to decreased QoL. Neuro-PASC principally affects adults in their prime, contributing to profound public health and socioeconomic impacts warranting dedicated resources for prevention, diagnosis and interventions. ANN NEUROL 2025;97:369–383

in Annals of Neurology on 2025-01-17 11:58:16 UTC.

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Examining the effects of anxiety and education level on mental health: The role of spiritual intelligence as an intervening variable in post COVID-19 patients in Indonesia [version 3; peer review: 2 approved with reservations]

Background The COVID-19 pandemic has profoundly affected global health systems and daily life, exacerbating vulnerabilities, particularly in Indonesia. This study investigates the impact of anxiety and education level on mental health, with spiritual intelligence as an intervening variable among post-COVID-19 patients in Indonesia. Methods Utilizing a cross-sectional design, data were collected from 390 post-COVID-19 patients in Indonesia. Structured questionnaires assessed anxiety, education level, spiritual intelligence, and mental health. Structural Equation Modeling (SEM) was used to analyze the relationships among these variables. Results The findings indicate that anxiety significantly affects both spiritual intelligence and mental health, with spiritual intelligence acting as a mediating factor. Additionally, higher educational attainment is positively associated with enhanced spiritual intelligence and improved mental health outcomes. Conclusions The study underscores the importance of incorporating spiritual development practices into mental health interventions and educational programs to boost resilience and overall well-being in the post-pandemic era. While these findings are promising, the cross-sectional design limits causal inferences, and future research should consider longitudinal studies to examine these relationships over time. These practices can help mitigate the adverse effects of anxiety and educational disparities on mental health.

in F1000Research on 2025-01-17 10:21:27 UTC.

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Impact of public health expenditure on malnutrition among Peruvians during the period 2010-2020: A panel data analysis [version 3; peer review: 1 approved, 1 not approved]

Background The study analyzes the impact of public health spending on malnutrition among Peruvians, using data from the National Household Survey, the Central Reserve Bank of Peru, the National Institute of Statistics and Informatics and the Ministry of Economy and Finance from 2010. -2020. Previous studies have revealed the existing relationship of health spending with the reduction of malnutrition. Methods A quantitative approach is considered, with an explanatory type of research using panel data methodology considering the bidimensionality of the data, which allows quantifying this effect for the Peruvian case using the National Household Survey, data from the Central Reserve Bank of Peru, as well as information from the National Institute of Statistics and Informatics and the Transparency Portal of the Ministry of Economy and Finance in the period 2010-2020. Results The results show that public expenditure on health has a negative relationship with malnutrition; the rural sector has a positive relationship with malnutrition given the limitations present for access to adequate food. Similarly, the unemployment rate shows a positive relationship with malnutrition, given that being unemployed leads to a higher cause of malnutrition in the population, and the gross domestic product has a negative relationship with malnutrition, given that greater economic growth produces an impact on reducing malnutrition, with the greatest impact being on the rural population and the gross domestic product. Conclusions In the analysis period 2010-2020 in Peru, based on the panel data analysis, the impact of public health expenditure on reducing malnutrition is observed in 10 departments, achieving a reduction in malnutrition; while in 14 departments, this indicator has not been reduced.

in F1000Research on 2025-01-17 10:18:42 UTC.

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Predicting determinants of modern contraceptive use among reproductive-age women in Ethiopia using machine learning algorithm: Evidence from the Performance Monitoring and Accountability (PMA) Survey 2019 dataset [version 1; peer review: awaiting peer rev

Introduction Globally, around 40% of women report unintended pregnancies, with approximately 214 million women in developing countries wanting to avoid pregnancy but not using any contraception. Modern contraceptives (MCs) are effective tools for preventing unintended pregnancies, controlling rapid population growth, and reducing fertility and maternal mortality rates, particularly in developing countries. Low use of contraceptives is responsible for the high fertility and maternal mortality rates in sub-Saharan African nations like Ethiopia. Thus, this study aimed to identify the determinants of modern contraceptive use among Ethiopian women of reproductive age using machine learning (ML) algorithms. Methodology The study utilized secondary data from the 2019 Performance Monitoring and Accountability (PMA) Ethiopia survey, analyzing 8,837 samples. Preprocessing steps included data cleaning, feature engineering, dimensionality reduction, and splitting the data, with 80% used for training and 20% for testing the algorithms. Six supervised ML algorithms were employed and assessed using confusion matrices, with information gain applied to identify critical attributes for predicting MC use. Results Only 24% of participants used modern contraceptives {95% CI (23.1%, 24.9%). Extreme gradient boosting (XGB) demonstrated the highest predictive accuracy (81.97%, 95% CI {79.06%, 82.7%}) and area under the ROC curve (76.63%), followed by logistic regression (80.52%) and support vector machines (80.41%). Key determinants of MC use included starting family planning at age 20 or older, being single, having partner approval, being the wife of the household head, age between 36–49 years, advice from healthcare providers, concerns about side effects, and having a household size of five or more. Conclusion and Recommendations The use of modern contraceptives among Ethiopian women remains low. Extreme gradient boosting proved most effective in predicting determinants of MC use. Improved counseling during ANC/PNC visits, promoting partner discussions on family planning, and addressing concerns about family size and contraceptive use are recommended strategies to enhance MC uptake.

in F1000Research on 2025-01-17 10:13:06 UTC.

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Clinical Relevance of ‘Cap’ and ‘Track’ Development after Recent Small Subcortical Infarct

Objective

After a recent small subcortical infarct (RSSI), some patients develop perilesional or remote hyperintensities (‘caps/tracks’) to the index infarct on T2/FLAIR MRI. However, their clinical relevance remains unclear. We investigated the clinicoradiological correlates of ‘caps/tracks’, and their impact on long-term outcomes following RSSI.

Methods

We identified participants with lacunar stroke and MRI-confirmed RSSI from 3 prospective studies. At baseline, we collected risk factors, RSSI characteristics, small vessel disease (SVD) features, and microstructural integrity on diffusion imaging. Over 1-year, we repeated MRI and recorded ‘caps/tracks’ blinded to other data. We evaluated predictors of ‘caps/tracks’, and their association with 1-year functional (modified Rankin Scale score ≥2), mobility (Timed Up-and-Go), cognitive outcomes (Montreal Cognitive Assessment [MoCA] score <26), and recurrent cerebrovascular events (stroke/transient ischemic attack/incident infarct) using multivariable regression.

Results

Among 185 participants, 93 (50.3%) developed ‘caps/tracks’ first detected at median 198 days after stroke. ‘Caps/tracks’ were independently predicted by baseline factors: larger RSSI, RSSI located in white matter, higher SVD score, and higher mean diffusivity in normal-appearing white matter (odds ratio [OR] [95% confidence interval {CI}], 1.15 [1.07–1.25], 6.01 [2.80–13.57], 1.77 [1.31–2.44], 1.42 [1.01–2.03]). At 1 year, ‘cap/track’ formation was associated with worse functional outcome (OR: 3.17, 95% CI: 1.28–8.22), slower gait speed (β: 0.13, 95% CI: 0.01–0.25), and recurrent cerebrovascular events (hazard ratio [HR]: 2.05, 95% CI: 1.05–4.02), but not with cognitive impairment.

Interpretation

‘Caps/tracks’ after RSSI are associated with worse clinical outcomes, and may reflect vulnerability to progressive SVD-related injury. Reducing ‘caps/tracks’ may offer early efficacy markers in trials aiming to improve outcome after lacunar stroke. ANN NEUROL 2025

in Annals of Neurology on 2025-01-17 09:06:11 UTC.

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Distinct myeloid-derived suppressor cell populations in human glioblastoma

Science, Volume 387, Issue 6731, January 2025.

in Science on 2025-01-17 08:00:00 UTC.

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Neuronal-ILC2 interactions regulate pancreatic glucagon and glucose homeostasis

Science, Volume 387, Issue 6731, January 2025.

in Science on 2025-01-17 08:00:00 UTC.

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A panoramic view of cell population dynamics in mammalian aging

Science, Volume 387, Issue 6731, January 2025.

in Science on 2025-01-17 08:00:00 UTC.

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Evolution of interorganismal strigolactone biosynthesis in seed plants

Science, Volume 387, Issue 6731, January 2025.

in Science on 2025-01-17 08:00:00 UTC.

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