bluuebunny/crossref_metadata_2025_split huggingface dataset:
Action-outcome based flexible behavior requires medial prefrontal cortex lead and its enhanced functional connectivity with dorsomedial striatum
Authors: Kőszeghy Áron , Xu Wei , Liu Mingshan , Lu Peiheng , Wan Long , Series Peggy , Gan Jian 
Published: December 2023

AbstractCognitive flexibility plays a key role in ensuring an individual’s survival, and its deficit is a key symptom in many mental conditions and neurodegenerative diseases. The prefrontal cortex and striatum are both essential to cognitive flexibility. However, how the prefrontal cortex and striatum communicate with each other to enable flexible decision-making is not well understood. Competing theories are raised, debating on which structure among these two leads the role in detecting and representing the new circumstances for a change, giving largely opposing predictions on neural activities in the prefrontal cortex and striatum during flexible behavior.To address this question, we trained head-restrained mice to perform an action-outcome based dynamic foraging task and simultaneously recorded single-neuron activities in the medial prefrontal cortex (mPFC) and dorsomedial striatum (DMS). In this task, the animal chooses one of two actions to obtain reward. The animal is guided only by previous reward outcomes. We report that mPFC but not DMS activity stores information about prior reward history. A large fraction of both mPFC and DMS neurons’ activity represents the difference in reward probability between two alternative options, namely the perceived reward probability difference (PRPD), a key decision variable that prescribes which subsequent choice to make. We find that mPFC neural activities track the change of PRPD earlier and faster than those in the DMS, and functional connectivity between mPFC and DMS increases with reducing overall reward proportion.
A software tool for at-home measurement of sensorimotor adaptation
Authors: Jang Jihoon , Shadmehr Reza , Albert Scott T. 
Published: December 2023

AbstractSensorimotor adaptation is traditionally studied in well-controlled laboratory settings with specialized equipment. However, recent public health concerns such as the COVID-19 pandemic, as well as a desire to recruit a more diverse study population, have led the motor control community to consider at-home study designs. At-home motor control experiments are still rare because of the requirement to write software that can be easily used by anyone on any platform. To this end, we developed software that runs locally on a personal computer. The software provides audiovisual instructions and measures the ability of the subject to control the cursor in the context of visuomotor perturbations. We tested the software on a group of at-home participants and asked whether the adaptation principles inferred from in-lab measurements were reproducible in the at-home setting. For example, we manipulated the perturbations to test whether there were changes in adaptation rates (savings and interference), whether adaptation was associated with multiple timescales of memory (spontaneous recovery), and whether we could selectively suppress subconscious learning (delayed feedback, perturbation variability) or explicit strategies (limited reaction time). We found remarkable similarity between in-lab and at-home behaviors across these experimental conditions. Thus, we developed a software tool that can be used by research teams with little or no programming experience to study mechanisms of adaptation in an at-home setting.SignificanceSensorimotor learning is traditionally studied in the laboratory, but recent public health emergencies have caused the community to consider at-home data collection. To accelerate this effort, we implemented a software tool that remotely tracks motor learning. Compared with previous remote data collection strategies, our software (1) generates experiments of arbitrary length that (2) run locally on a participant’s laptop which (3) can be modified without any programming expertise in the research laboratory. Here we show a close correspondence between behaviors captured by our tool and those observed in laboratory environments including savings, interference, spontaneous recovery, and variations in implicit and explicit learning due to changes in perturbation variance, reaction time constraints, and feedback delay. Our software and its corresponding manuals are available here:https://osf.io/e8b63/.
Psilocybin prevents activity-based anorexia in female rats by enhancing cognitive flexibility: contributions from 5-HT1A and 5-HT2A receptor mechanisms
Authors: Conn K , Milton LK , Huang K , Munguba H , Ruuska J , Lemus MB , Greaves E , Homman-Ludiye J , Oldfield BJ , Foldi CJ 
Published: December 2023

AbstractPsilocybin has shown promise for alleviating symptoms of depression and is currently in clinical trials for the treatment of anorexia nervosa (AN), a condition that is characterised by persistent cognitive inflexibility. Considering that enhanced cognitive flexibility after psilocybin treatment is reported to occur in individuals with depression, it is plausible that psilocybin could improve symptoms of AN by breaking down cognitive inflexibility. A mechanistic understanding of the actions of psilocybin is required to tailor the clinical application of psilocybin to individuals most likely to respond with positive outcomes. This can only be achieved using incisive neurobiological approaches in animal models. Here, we use the activity-based anorexia (ABA) rat model and comprehensively assess aspects of reinforcement learning to show that psilocybin (post-acutely) improves body weight maintenance in female rats and facilitates cognitive flexibility, specifically via improved adaptation to the initial reversal of reward contingencies. Further, we reveal the involvement of signalling through the serotonin (5-HT) 1A and 5-HT2A receptor subtypes in specific aspects of learning, demonstrating that 5-HT1A antagonism negates the cognitive enhancing effects of psilocybin. Moreover, we show that psilocybin elicits a transient increase and decrease in cortical transcription of these receptors (Htr2aandHtr1a, respectively), and a further reduction in the abundance ofHtr2atranscripts in rats exposed to the ABA model. Together, these findings support the hypothesis that psilocybin could ameliorate cognitive inflexibility in the context of AN and highlight a need to better understand the therapeutic mechanisms independent of 5-HT2A receptor binding.
Evaluation of resampling-based inference for topological features of neuroimages
Authors: Vandekar Simon N. , Kang Kaidi , Woodward Neil D. , Huang Anna , McHugo Maureen , Garbett Shawn , Stephens Jeremy , Shinohara Russell T. , Schwartzman Armin , Blume Jeffrey 
Published: December 2023

AbstractMany recent studies have demonstrated the inflated type 1 error rate of the original Gaussian random field (GRF) methods for inference of neuroimages and identified resampling (permutation and bootstrapping) methods that have better performance. There has been no evaluation of resampling procedures when using robust (sandwich) statistical images with different topological features (TF) used for neuroimaging inference. Here, we consider estimation of distributions TFs of a statistical image and evaluate resampling procedures that can be used when exchangeability is violated. We compare the methods using realistic simulations and study sex differences in life-span age-related changes in gray matter volume in the Nathan Kline Institute Rockland sample. We find that our proposed wild bootstrap and the commonly used permutation procedure perform well in sample sizes above 50 under realistic simulations with heteroskedasticity. The Rademacher wild bootstrap has fewer assumptions than the permutation and performs similarly in samples of 100 or more, so is valid in a broader range of conditions. We also evaluate the GRF-based pTFCE method and show that it has inflated error rates in samples less than 200. OurRpackage,pbj, is available on Github and allows the user to reproducibly implement various resampling-based group level neuroimage analyses.
Development of endothelial-targeted CD39 as a therapy for ischaemic stroke
Authors: Lee Natasha Ting , Savvidou Ioanna , Selan Carly , Calvello Ilaria , Wright David K , Brkljaca Robert , Willcox Abbey , Chia Joanne SJ , Wang Xiaowei , Peter Karlheinz , Robson Simon C. , Medcalf Robert L , Nandurkar Harshal H , Sashindranath Maithili 
Published: December 2023

AbstractBackgroundIschaemic stroke is characterized by a necrotic lesion in the brain surrounded by an area of dying cells termed the penumbra. Salvaging the penumbra either with thrombolysis or mechanical retrieval is the cornerstone of stroke management. At-risk neuronal cells release extracellular adenosine triphosphate (eATP) triggering microglial activation and causing a thromboinflammatory response culminating in endothelial activation and vascular disruption. This is further aggravated by ischaemia-reperfusion (I/R) injury that follows all reperfusion therapies. The ecto-enzyme CD39 regulates eATP by hydrolysing to adenosine which has anti-thrombotic and anti-inflammatory properties and reverses I/R injury.MethodsWe developedanti-VCAM-CD39that targets the antithrombotic and anti-inflammatory properties of recombinant CD39 to the activated endothelium of the penumbra by binding to vascular cell adhesion molecule (VCAM)-1. Mice were subjected to 30 minutes of middle cerebral artery occlusion (MCAo) and analysed at 24h.Anti-VCAM-CD39or control agents (saline, non-targeted CD39, or anti-VCAM-inactive CD39) were given at 3h post-MCAo.ResultsAnti-VCAM-CD39 treatment reduced neurological deficit; MRI confirmed significantly smaller infarcts together with an increase in cerebrovascular perfusion. Anti-VCAM-CD39 also restored blood brain barrier (BBB) integrity and reduced microglial activation. Coadministration ofanti-VCAM-CD39with thrombolytics (tPA) further reduced infarct volumes and attenuated BBB permeability with no associated increase in intracranial haemorrhage.ConclusionAnti-VCAM-CD39, uniquely targeted to endothelial cells, could be a new stroke therapy even when administered 3 h post ischaemia and may further synergise with thrombolytic therapy to improve stroke outcomes.
Resources to Aid Ethical Review of Clinical Studies: An Exploratory Scoping Review Identifying Gaps and Opportunities
Authors: Pittelkow Merle-Marie , Strech Daniel 
Published: December 2023

AbstractBackgroundResearch Ethics Committees (RECs) review the ethical, legal, and methodological standard of clinical research. However, complying with all requirements and professional expectations while maintaining the necessary scientific and ethical standards can be challenging for applicants and members of the REC alike. There is a need for accessible guidelines and resources to help medical researchers and REC members navigate the legal and ethical requirements and the process of their review.MethodsWe employed an explorative search for resources on the websites of a purposively selected sample of relevant stakeholders including 12 national umbrella organizations (six German-language and six English-language), three English-language international umbrella organizations, and 16 national REC’s of major university hospitals (eight German- and eight English-language). We qualitatively mapped the identified resources onto the guiding principles of ethical clinical research and 35 related checkpoints. To describe the content of the resources we conducted a thematic analysis.ResultsWe extracted a total of 233 resources, including templates (n= 134, 58.5%), guidelines/recommendations (n= 62, 26.6%), checklists (n= 23, 9.9%), tools (n= 5, 2.2%), flowcharts (n= 5, 2.2%), glossaries (n= 3, 1.3%), and one (0.4%) software program. We extracted 101 German and 132 English resources created between 2004 and 2023. The majority (n =204; 87.6%) could be assigned to one checkpoint. The remaining 29 (12.5%) resources were considered unspecific (e.g., a checklist which documents to be submitted for a German drug trial). The specific resources are discussed per checkpoint.ConclusionWhile much support is available for some aspects such as participant information and informed consent forms, it is lacking in other areas such as study design, analysis, and biometrics. More support should be provided in these areas to ensure that research projects are methodologically sound. A more detailed analysis of the quality of available resources could help identify other areas of need.
Scoping review of knowledge graph applications in biomedical and healthcare sciences
Authors: Budhdeo Sanjay , Zhang Joe , Abdulle Yusuf , Agapow Paul M , McKechnie Douglas GJ , Archer Matt , Shah Viraj , Forte Eugenia , Noori Ayush , Zitnik Marinka , Ashrafian Hutan , Sharma Nikhil 
Published: December 2023

AbstractIntroductionThere is increasing use of knowledge graphs within medicine and healthcare, but a comprehensive survey of their applications in biomedical and healthcare sciences is lacking. Our primary aim is to systematically describe knowledge graph use cases, data characteristics, and research attributes in the academic literature. Our secondary objective is to assess the extent of real-world validation of findings from knowledge graph analysis.MethodsWe conducted this review in accordance with the PRISMA extension for Scoping Reviews to characterize biomedical and healthcare uses of knowledge graphs. Using keyword-based searches, relevant publications and preprints were identified from MEDLINE, EMBASE, medRxiv, arXiv, and bioRxiv databases. A final set of 255 articles were included in the analysis.ResultsAlthough medical science insights and drug repurposing are the most common uses, there is a broad range of knowledge graph use cases. General graphs are more common than graphs specific to disease areas. Knowledge graphs are heterogenous in size with median node numbers 46 983 (IQR 6 415-460 948) and median edge numbers 906 737 (IQR 66 272-9 894 909). DrugBank is the most frequently used data source, cited in 46 manuscripts. Analysing node and edge classes within the graphs suggests delineation into two broad groups: biomedical and clinical. Querying is the most common analytic technique in the literature; however, more advanced machine learning techniques are often used.DiscussionThe variation in use case and disease area focus identifies areas of opportunity for knowledge graphs. There is diversity of graph construction and validation methods. Translation of knowledge graphs into clinical practice remains a challenge. Critically assessing the success of deploying insights derived from graphs will help determine the best practice in this area.
Excess mortality and years of life lost from 2020 to 2023 in France: a cohort study of the overall impact of the COVID-19 pandemic on mortality
Authors: Moulaire Paul , Hejblum Gilles , Lapidus Nathanaël 
Published: December 2023

AbstractIntroductionExcess mortality has been frequently used worldwide for summarizing the COVID-19 pandemic-related burden. Estimates for France for the years 2020 to 2022 vary substantially from one report to another, and the year 2023 is poorly documented. The present study assessed the level of excess mortality that occurred in France between 2020 and 2023 together with the corresponding years of life lost (YLL), in order to provide a reliable, detailed, and comprehensive description of the overall impact of the pandemic.MethodThis open cohort study of the whole French population analyzed the 8,451,372 death occurrences reported for years 2010 to 2023. A Poisson regression model was trained with years 2010 to 2019 for determining the age-and sex-specific evolution trends of mortality before the pandemic period. These trends were then used for estimating the excess mortality during the pandemic period (years 2020 to 2023). The life expectancies of the persons in excess deaths were used for estimating the corresponding years of life lost (YLL).ResultsFrom 2020 to 2023, the number of excess deaths (mean [95% CI] (percentage of change versus expected mortality)) was respectively 49,541 [48,467; 50,616] (+8,0%), 42,667 [41,410; 43,909] (+6.9%), 53,129 [51,696; 54,551] (+8.5%), and 17,355 [15,760; 18,917] (+2.8%). Corresponding YLL were 512,753 [496,029; 529,633], 583,580 [564,137; 602,747], 663,588 [641,863; 685,723], and 312,133 [288,051; 335,929]. Individuals younger than 60 years old accounted for 17% of the YLL in 2020, 26% in 2021, 32% in 2022 and 50% in 2023. Males were more affected than females by both excess mortality and YLL.ConclusionThis study highlights the long-lasting impact of the pandemic on mortality in France, with four consecutive years of excess mortality and a growing impact on people under 60, particularly males, suggesting lasting and profound disruption to the healthcare system.Key MessagesWhat is already known on this topicDifferent trends and magnitudes of excess mortality were reported in France for years 2020 to 2022, and estimations of years of life lost, which characterize the remaining life expectancy of people suffering excess mortality, are only available for 2020 and 2021. There is no exhaustive toll covering all years of the COVID-19 pandemic period (2020– 2023).What this study addsExcess mortality peaked in 2022 and remained substantial in 2023 for the fourth year in a row while corresponding years of life lost rose steadily from 2020 to 2022 and remained at a worrying level in 2023.How this study might affect research, practice or policyThis study raises concerns about a potential indirect and long-lasting impact of the COVID-19 pandemic on mortality in France, particularly in males under 60 years old.
Task-Modulated Neural Responses in Scene-Selective Regions of the Human Brain
Authors: Koc Aysu Nur , Urgen Burcu A. , Afacan Yasemin 
Published: December 2023

AbstractThe study of scene perception is crucial to the understanding of how one interprets and interacts with their environment, and how the environment impacts various cognitive functions. The literature so far has mainly focused on the impact of low-level and categorical properties of scenes and how they are represented in the scene-selective regions in the brain, PPA, RSC, and OPA. However, higher-level scene perception and the impact of behavioral goals has not been explored in depth. Moreover, the selection of the stimuli has not been systematic and mainly focused on outdoor environments. In this fMRI experiment, we adopted multiple behavioral tasks, selected real-life indoor stimuli with a systematic categorization approach, and used various multivariate analysis techniques to explain the neural modulation of scene perception in the scene-selective regions of the human brain. Participants (N=21) performed categorization and approach-avoidance tasks during fMRI scans while they were viewing scenes from built environment categories based on different affordances ((i)access and (ii)circulation elements, (iii)restrooms and (iv)eating/seating areas). Searchlight-based classification analysis revealed that the OPA was significantly successful in decoding scene category regardless of the task, and that the task condition affected category decoding performances of all the scene-selective regions. Model-based representational similarity analysis (RSA) revealed that the activity patterns in scene-selective regions are best explained by task. These results contribute to the literature by extending the task and stimulus content of scene perception research, and uncovering the impact of behavioral goals on the scene-selective regions of the brain.
AAGGG repeat expansions trigger RFC1-independent synaptic dysregulation in human CANVAS Neurons
Authors: Maltby Connor J. , Krans Amy , Grudzien Samantha J. , Palacios Yomira , Muiños Jessica , Suárez Andrea , Asher Melissa , Khurana Vikram , Barmada Sami J. , Dijkstra Anke A. , Todd Peter K. 
Published: December 2023

AbstractCerebellar ataxia with neuropathy and vestibular areflexia syndrome (CANVAS) is a late onset, recessively inherited neurodegenerative disorder caused by biallelic, non-reference pentameric AAGGG(CCCTT) repeat expansions within the second intron of replication factor complex subunit 1 (RFC1). To investigate how these repeats cause disease, we generated CANVAS patient induced pluripotent stem cell (iPSC) derived neurons (iNeurons) and utilized calcium imaging and transcriptomic analysis to define repeat-elicited gain-of-function and loss-of-function contributions to neuronal toxicity. AAGGG repeat expansions do not alter neuronal RFC1 splicing, expression, or DNA repair pathway functions. In reporter assays, AAGGG repeats are translated into pentapeptide repeat proteins that selectively accumulate in CANVAS patient brains. However, neither these proteins nor repeat RNA foci were detected in iNeurons, and overexpression of these repeats in isolation did not induce neuronal toxicity. CANVAS iNeurons exhibit defects in neuronal development and diminished synaptic connectivity that is rescued by CRISPR deletion of a single expanded allele. These phenotypic deficits were not replicated by knockdown of RFC1 in control neurons and were not rescued by ectopic expression of RFC1. These findings support a repeat-dependent but RFC1-independent cause of neuronal dysfunction in CANVAS, with important implications for therapeutic development in this currently untreatable condition.SummaryHuman CANVAS neurons exhibit transcriptional and functional synaptic defects that are corrected by heterozygous repeat deletion but are independent of the gene within which they reside—RFC1.
Locus coeruleus modulation of single-cell representation and population dynamics in the mouse prefrontal cortex during attentional switching
Authors: Nigro Marco , Tortorelli Lucas Silva , Garad Machhindra , Zlebnik Natalie E. , Yang Hongdian 
Published: December 2023

AbstractBehavioral flexibility, the ability to adjust behavioral strategies in response to changing environmental contingencies and internal demands, is fundamental to cognitive functions. Despite a large body of pharmacology and lesion studies, the precise neurophysiological mechanisms that underlie behavioral flexibility are still under active investigations. This work is aimed to determine the role of a brainstem-to-prefrontal cortex circuit in flexible rule switching. We trained mice to perform a set-shifting task, in which they learned to switch attention to distinguish complex sensory cues. Using chemogenetic inhibition, we selectively targeted genetically-defined locus coeruleus (LC) neurons or their input to the medial prefrontal cortex (mPFC). We revealed that suppressing either the LC or its mPFC projections severely impaired switching behavior, establishing the critical role of the LC-mPFC circuit in supporting attentional switching. To uncover the neurophysiological substrates of the behavioral deficits, we paired endoscopic calcium imaging of the mPFC with chemogenetic inhibition of the LC in task-performing mice. We found that mPFC prominently responded to attentional switching and that LC inhibition not only enhanced the engagement of mPFC neurons but also broadened single-neuron tuning in the task. At the population level, LC inhibition disrupted mPFC dynamic changes and impaired the encoding capacity for switching. Our results highlight the profound impact of the ascending LC input on modulating prefrontal dynamics and provide new insights into the cellular and circuit-level mechanisms that support behavioral flexibility.