Multimodal single-cell sequencing data provide detailed views into the molecular biology of cells. To allow for interactive analyses of such rich data and to readily derive insights from it, new analysis solutions are required. In this work, we present Cellenium, our new scalable visual analytics web application that enables users to semantically integrate and organize all their single-cell RNA-, ATAC-, and CITE-sequencing studies. Users can then find relevant studies and analyze single-cell data within and across studies. An interactive cell annotation feature allows for adding user-defined cell types.https://github.com/Bayer-Group/cellenium). The server backend is implemented in PostgreSQL, Python 3, and GraphQL, the frontend is written in ReactJS, TypeScript, and Mantine css, and plots are generated using plotlyjs, seaborn, vega-lite, and nivo.rocks. The application is dockerized and can be deployed and orchestrated on a standard workstation via docker-compose.Source code and documentation are freely available under an MIT license and are available on GitHub ( The rapidly expanding volume of single-cell omics data in biomedical research not only represents an invaluable resource for unraveling biological mechanisms underlying cellular changes during for instance normal development and disease but also presents an unprecedented challenge for data curation, data storage, and visualization. Several single-cell browsers have been developed with a focus on visualizing transcriptomics data , but oftCellenium consists of a central Postgres database for hosting all expression- and metadata, a Postgraphile-based GraphQL API layer, as well as a reactjs/typescript GUI, all of which are dockerized and orchestrated using docker-compose (for details see Single-cell omics studies to be integrated need to be provided in the AnnData format (h5ad) or a multi-omics variant thereof (h5mu). Cellenium expects metadata attributes of a study to be added to the unstructured annotation field of AnnData files (uns-dictionary). These include title, description as well as species (NCBI taxonomy), disease annotation (NCBI MeSH), or tissue types (NCIT) of the study. Further metadata such as previously annotated cell types can also be provided. In addition, Cellenium uses CellO  to provihttps://seaborn.pydata.org/) and plotlyjs (https://plotly.com/javascript/). In the co-expression view, pairwise gene expression scatter plots can be generated. In addition, correlated genes can be identified transcriptome wide for any given gene of interest. Additionally, the user can explore and store self-defined cell types using an interactive cell-marker definition widget. These cell types can then be interactively visualized on the projection plots. Through this functionality, the user can for instance analyze how user-defined cell types relate to pre-annotated cell types or identify differentially expressed genes for the defined cell types. To allow for a visual comparison of the relationships between different cell type annotations within a study, we developed an interactive Sankey plot implemented using the javascript library nivo.rocks (https://github.com/plouc/nivo).In the single study analysis section (use case 1), users can interactively identify marker genes of predefined cell types. The selection of cell types is possible either on the provided annotations on the side panel of the GUI or on the UMAP-based projection plot by clicking on the corresponding cells directly see . For effThe cross-study analysis section (use case 2) enables the comparison of gene expression levels in the CellO-based predicted standardized cell types across different studies. The expression levels are visualized by vega-lite  using a The third section (use case 3) is designed for conducting marker gene searches across all integrated studies. Here, users can input genes of interest (e.g. insulin) and analyze in what cell types these genes are specifically expressed within their corresponding study (in the case of insulin the users would for example find pancreatic beta-cells). Since differential gene expression is pre-calculated during the data ingestion, results are obtained in real-time without delay. Differential expression is visualized using inline volcano plots for quick inspection.In this publication, we have described Cellenium, a scalable, interactive, and highly performant web application for multimodal single-cell data storage, retrieval, and analysis. Cellenium provides a flexible and intuitive user interface for common integrative analysis and visualization tasks and enables deep analysis of integrated single-cell studies. We believe that the simplicity of the application design might enable also non-bioinformaticians to gain detailed insights from vast single-cell sequencing studies through elaborate analysis techniques.btad349_Supplementary_DataClick here for additional data file.


AusGeochem platform (https://ausgeochem.auscope.org.au) and freely accessible to scientists from around the world. To demonstrate the power of the platform, three regional datasets from Kenya, Australia and the Red Sea are placed in their 4D geological, geochemical, and geographic contexts, revealing insights into the tectono-thermal evolutions of these areas. Beyond facilitating data interpretation, the archival of fission track and (U-Th)/He (meta-)data in relational schemas unlocks future potential for greater integration of thermochronology and numerical geoscience techniques. The power of formatting data to interface with external tools is demonstrated through the integration of GPlates Web Service with AusGeochem, enabling thermochronology data to be readily viewed in their paleogeographic context through deep time from within the platform.Low-temperature thermochronology is a powerful tool for constraining the thermal evolution of rocks and minerals in relation to a breadth of tectonic, geodynamic, landscape evolution, and natural resource formation processes through deep time. However, complexities inherent to these analytical techniques can make interpreting the significance of results challenging, requiring them to be placed in their geological context in 4-dimensions (3D + time). We present a novel tool for the geospatial archival, analysis and dissemination of fission-track and (U-Th)/He data, built as an extension to the open-access  Consequently, low-temperature thermochronology is an important tool for studying surface weathering processes5, paleoclimate8, and climate change10, as well as for constraining the formation and preservation of various natural resources, such as hydrocarbons12, hydrothermal and supergene ore deposits16, and geothermal energy fields18. In certain instances, such analyses can even record thermal events related to localised conductive heat transfer related to igneous activity19, volcanic eruptions21, groundwater advection23, hydrothermal fluid flow24, faulting and shear heating26, wildfires27, or meteorite formation28. These insights into the thermal history of the crust reflect the geodynamic, tectonic, magmatic and surficial processes which govern the evolution of our planet’s asthenosphere, lithosphere, biosphere and atmosphere.Low-temperature thermochronology encompasses a group of temperature-sensitive radiometric dating techniques which provide unique insights into the thermal history of Earth’s upper crust. These observations, in turn, allow scientists to constrain the timing and rate of a breadth of geological processes which can affect the thermal state of the crust over geological time, including the advection of mass and heat due to the growth of mountain belts, extensional basin formation, and long-term denudation238U atoms29, and the subsequent repair of these tracks via thermal annealing30. The (U-Th)/He system is based on the production of alpha particles (4He) in mineral grains during the decay chains of 238U, 235U, and 232Th, and the loss of 4He by thermally activated volume diffusion31. However, unlike some higher-temperature geochronology systems, such as the U–Pb or Lu–Hf systems, whose systems can be considered closed at temperatures near or above those at which the analysed geological material has crystallised or lithified32, the decay products  of low-temperature thermochronometers remain open at relatively low temperatures at which crustal and near-surface geological processes occur . The temperature sensitivities of the fission-track and (U-Th)/He methods are further complicated by their dependence on other variables, such as cooling rate, mineral chemistry, crystal size, and radiation damage accumulation38. As a result, apparent ages (dates) produced by thermochronometers may not correspond to distinct geological events. Rather, these thermochronological data often require integration with additional measurements of kinetic parameters42 and numerical modelling43, often using thermal history modelling software45, to unravel and quantify the thermal histories that they record.The most commonly used low-temperature thermochronometers are the fission-track and (U-Th)/He methodologies. Like all absolute radiometric dating techniques, these systems are based on the radioactive decay of certain unstable isotope(s) to their decay product(s) at a known rate over geological time. The fission-track system, for example, is based on the formation and accumulation of microscopic damage trails  in mineral grain crystal lattices due to the spontaneous fission of Consequently, interpreting the geological significance of thermal histories recorded by complex low-temperature thermochronology data requires placing those results in their three-dimensional geospatial, geological, and geographic context through time. These data must, therefore, be interrogated in the context of previously acquired analyses, other related geochemistry data, local geology, and modern topography. This work generally involves laborious data mining from publications and disparate repositories into private data models, bespoke to an individual analyst or research group. In the current low-temperature thermochronology data ecosystem, all of these laborious data management and synthesis tasks must then be repeated for each new study region and by each subsequent geoscientist wishing to work in that particular area. While the number of samples with low-temperature thermochronology analyses for any given region may be modest, perhaps on the order of a few thousand per continent, the variety and volume of detailed (meta-)data attributes associated with each of these results  and the increasing rate at which these analyses are being produced make these traditional data processing workflows ineffectual. Even in the rare instances that such low-temperature thermochronology data syntheses are published in scientific journals or data repositories, they often remain unintelligible to non-specialists due to the inherent complexities of these methodologies. Thus, new intuitive tools are needed to enable the wider geoscience community to interrogate and understand these powerful datasets.AusGeochem geochemistry data platform, https://ausgeochem.auscope.org.au46, which enables users to upload, disseminate, interrogate, and publicise geosample metadata and secondary ion mass spectrometry U-Pb data in a geospatial context. The structured archival of detailed low-temperature thermochronology analyses in relational schemas, including fine-grained data on the individual crystal-, spot-, and track-scale , facilitates rapid derivation of inter-data relationships, permitting data compilation, analysis, and visualisation of thousands of analyses generated by laboratories across the globe in real-time. As such, this AusGeochem extension presents the low-temperature thermochronology community with an unprecedented instrument for FAIR  fission-track and (U-Th)/He data management and Big Data investigation.Here, we present a novel tool for efficient geospatial examination and dissemination of global fission-track and (U-Th)/He Big Data. This robust relational low-temperature thermochronology database is an extension of the open AusGeochem /He analyses are stored in AusGeochem enables live cross-data analytics to be performed within the platform46. The persistent data structure also allows for potential future developments for performing real-time computing. By making calls to the relational database, computer programs can readily retrieve the necessary data elements needed to perform a range of routines, such as the recalculation of ages based on updated decay constants, bulk thermal history modelling of regional data sets, and placing data in their palinspastic context.The relational low-temperature thermochronology database architecture of hem Fig.  enables AusGeochem provides users with two interfaces to interact with data: My Data, where data can be managed, and Map View, where samples and analyses can be explored geospatially data publicly available. If users wish to upload compilations that include data produced by other authors, which they are welcome and encouraged to do, the original data producers must be appropriately cited by linking the relevant people, papers and reports to those data points via the Data section of the platform.While the aim is for the database to grow organically through the collective upload of data by platform users, a few regional datasets have been cleaned and uploaded by the authors to provide a foundation on which the database can grow. At the time of submission, > 2000 detailed apatite and zircon (U-Th)/He and apatite, zircon and titanite fission-track data from across Australia, New Zealand, Central Asia are publicly available. However, the volume of open-access thermochronology data available in the platform is expected to grow significantly over the coming year.AusGeochem46, where users can upload and edit analyses individually or in bulk via a drag-and-drop tool using .csv or .xlsx data templates downloadable from within the platform. For efficient data uploading, single-grain fission-track count data and length measurements obtained using the digital fission-track analysis software FastTracks51 can be rapidly uploaded into AusGeochem using the ‘AusGeochem Count Data’ and ‘AusGeochem Length Data’ export formats available in FastTracks (version 3.3.5 and above), which can be dropped directly into the bulk upload boxes on the respective My Data tabs.Fission-track and (U-Th)/He data management is performed in the Data section of In addition to uploading analyses of unknowns, AusGeochem users are also highly encouraged to archive associated secondary reference material results, such as age determinations of well-characterised standards in the case of (U-Th)/He data. This is critical as it allows platform users to independently assess data quality based on the reproducibility of well-characterised reference materials of known composition and/or age. For fission-track analysis, this includes reporting analyst-specific zeta-calibration factors, neutron irradiation parameters and dosimeter fission track densities in the case of External Detector Method-generated data, or fission-track age or trace element concentration determinations for reference materials in the case of absolute fission-track dating via LA-ICP-MS or EPMA. Once uploaded, the associated reference material results for a given unknown analysis can then be quickly viewed under the Analytical Data pop-up when that sample is selected in Map View Fig. .Figure 3AusGeochem enables users to mint persistent identifiers, such as International Generic Sample Numbers (ISGNs)53 and Digital Object Identifiers (DOIs), to ensure their samples and analyses are more FAIR . Once finalised and made public, data packages can thus be made citable by minting a DOI. The DOI can then be included in associated publications and reports, providing a direct link to data stored in AusGeochem where they can be interrogated and extracted.Leveraging Lithodat’s DataCite membership, AusGeochem’s Map View user interface enables geological sample and geochemistry data to be explored in their geospatial context. Users can select data types and perform further data filtering in Map View using a combination of lithological, mineralogical, elevation, and method-specific attributes  or spherical projection Fig. . Where aSimple sample and analytical information can be retrieved via a pop-up window by hovering the cursor over a sample point on the map Fig. b, while The bespoke fission-track and (U-Th)/He dashboard provides users with intuitive tools to interrogate select collations of thermochronology data via a range of maps, tables, and interactive plots Fig. c, all ofAusGeochem is equipped with an Open REST Application Programming Interface (API), allowing any developer to build clients that can interact with the platform to, for example, automatically upload or retrieve data from its database, add enhanced data visualisation tools and create direct links to analytical equipment. Potential uses of this powerful tool for the low-temperature thermochronology community could include the development of clients enabling automated data upload using common data formats  and automated data retrieval for bulk thermal history modelling or landscape evolution modelling .AusGeochem.API documentation and user instructions on how to access the API can be found under the Help tab in GPlates Web Service with AusGeochem. The GPlates Web Service is developed by the EarthByte Group at the University of Sydney as a part of the GPlates58 project, which allows users to access GPlates’ plate tectonic reconstruction functionality via HTTP requests over the internet or local networks. The GPlates Web Service places geological samples and their associated geochemistry data, retrieved via the AusGeochem API, in their paleogeographic position according to published plate tectonic reconstruction models .Selected data can be extracted from both Map View and My Data and exported in .csv and .xlsx formats, with a shapefile exporting functionality under development. Users are also encouraged to code their own routines for streamlined fission-track and (U-Th)/He data upload and download directly to and from third-party software, repositories, or databases using 47. Assuming users properly link their data to their associated references upon upload, reference information for each data point in AusGeochem can then be found in their metadata under “Literature” in the Data Section, or in the pop-up window when an individual sample is selected on the Map /He data in their geospatial context is demonstrated using the built-in tools currently available within AusGeochem. While these examples highlight regional fission-track and (U-Th)/He methods applications in intracontinental rifting, continental breakup, and passive margin settings, it is stressed that AusGeochem is designed to geospatially interrogate low-temperature thermochronology data at all scales, across the full breadth of geological environments. The case studies are followed by a discussion of potential future developments and powerful applications of this relational thermochronology data platform.The relational fission-track and (U-Th)/He data models of AusGeochem. These compilations include data produced by the authors, as well as a significant number of detailed data mined from the literature. These compilations are meant to serve as a foundation to the thermochronology database, with the intention and hope that future users will continue to add detailed fission-track and (U-Th)/He datasets, both legacy and new.Readers can interrogate and utilise the detailed regional fission-track and (U-Th)/He datasets discussed below, which are freely available on 60 first reported an apparent relationship between the modern topography of the southeast Australian margin and apatite fission-track data observed along a transect orthogonal to the coast, low-temperature thermochronology has routinely been used to constrain the denudation history of rifted continental margins63, leading to the development of a range of tectonic models for passive margin development65. Specifically, Moore and colleagues60 observed a transition from relatively young apatite fission-track ages and long confined track lengths at the coast, through to moderate ages with short track lengths on the erosional escarpment, and eventually to old ages and long track lengths atop the escarpment, which they collectively attributed to a Late Cretaceous rift-related thermal event that preferentially reset apatite fission-track data along the southeast Australian margin  has long attracted geoscientists looking to employ low-temperature thermochronology to investigate intracontinental rift processes. This has resulted in a dense coverage of low-temperature thermochronology analyses, particularly apatite fission-track data in Kenya Fig. . When vi73 that once may have extended across the Turkana Depression into South Sudan74. Surprisingly, few data yield Neogene cooling ages  within Kenya are found in Archean rocks of the Tanzanian Craton and Neoproterozoic mobile belts of central Kenya. While the geological significance of these dates is poorly understood, in part due to a dearth of confined track data collected using modern techniques , the preservation of these old ages attest to the relative stability of the Tanzanian Craton since the Palaeozoic. The most prominent tectonothermal signature documented in the region, however, is recorded by a profusion of ~ 100–50 Ma ages  and the addition of unknown, but no doubt significant, amounts of igneous material in the sub-surface79. Yet, apatite fission-track data yield very few Neogene ages recording the influence of conductive heating related to the extensive magmatic history of the rift. This is consistent with previous assertions that the conductive thermal effect of magmatism on low-temperature thermochronology is restricted to similar length scales of individual lava flow thicknesses and intrusive body dimensions69. By readily placing Kenyan thermochronology in its geological context using AusGeochem, the utility of regional apatite fission-track assays for constraining the spatio-temporal denudational response to upper crustal extensional strain is demonstrated, even in a magmatic intracontinental rift setting.However, some of the most important insights into what governs the low-temperature thermochronology of the upper crust in intracontinental settings can be found when Kenyan apatite fission-track data are juxtaposed against the regional geology Fig. . Despite65. Such is the case for the conjugate Nubian-Arabian margins, whose transformation from being topographically subdued in the Early Oligocene to displaying their modern steep coastal escarpments is attributed to the development of the Red Sea rift system since the Late Oligocene81.Long-term denudation rates estimated from low-temperature thermochronology can provide important constraints for the geomorphic evolution of rifted margins82, as clearly shown when viewed in AusGeochem. The Nubian margin, whose low-lying deserts are separated from the coast by the narrow Red Sea Hills (500 m mean elevation), contrasts starkly with the broad highlands  of the Arabian margin that attains heights of up to 3,200 m at its southern end. This physiographic asymmetry is reflected in the low-temperature thermochronology data. Whereas the Arabian margin yields Oligo-Miocene apatite fission-track and (U-Th)/He ages and long mean track lengths along much of its rift escarpment, indicative of rapid exhumation during that time period, the Nubian margin exhibits significantly older thermochronological ages along most of its topographically subdued profile. The observed asymmetry in Oligo-Miocene cooling is consistent with predicted differences in the paleotopographic expression of the margins at that time /He databases heralds the beginning of a new era of structured Big Data in the field of low-temperature thermochronology. By methodically archiving detailed fission-track and (U-Th)/He (meta-)data in structured schemas, intractably large datasets comprising 1000 s of analyses produced by numerous laboratories from around the globe can be readily interrogated in new and powerful ways. The collective use of a single community-designed data reporting schema will also aid the low-temperature thermochronology community to converge on more consistent data reporting practices, better connecting data producers and users. The ability to geospatially search available fission-track and (U-Th)/He data and immediately access all of the associated detailed analyses would significantly streamline future data mining, while also providing a means to rapidly identify data gaps for future research.AusGeochem’s open API could be leveraged to automate data extraction to interface with other existing numerical geoscience tools, such as thermal history or numerical landscape evolution modelling codes and applications. The power of the API is demonstrated through the integration of GPlates Web Service with AusGeochem, enabling fission-track and (U-Th)/He analyses to be readily interrogated in plate tectonic and paleotopographic frameworks through deep time in a way never before possible. An additional platform extension currently under development which will allow thermal history modelling results to be stored in AusGeochem alongside raw data will only further expand the utility of this dynamic thermochronology data tool.Yet, the ability to rapidly visualise and synthesise fission-track and (U-Th)/He analyses in a geospatial context is but a hint at the true potential of archiving low-temperature thermochronology data in a structured database architecture. With detailed thermochronology data stored in relational schemas, the step to developing scripts capable of re-calculating and re-modelling analyses using user-defined constants and kinetic algorithms is relatively straightforward. Such a future advancement would enable analyses determined using different parameters and constants to be equated and compared across regional- to global scales. Similarly, all global thermochronology data, old and new, must be made discoverable and publicly available in structured, machine-readable formats via relational platforms like AusGeochem. This will inevitably involve the significant task of aggregating the plethora of global legacy thermochronology data. Fortunately, the volume of legacy data is finite, and data compilation need only be performed once if done thoroughly and made publicly available. The advent of “web scraping” tools88 could also help to automate legacy data mining already stored in online repositories, though these still require a degree of manual cleaning. It is equally important that prospective data are made open-access and reported in full detail following community-guided best practices31. While AusGeochem provides tools for more efficient data ingestion through its drag-n-drop uploader and API, an unavoidable degree of manual data wrangling will nevertheless be required for the foreseeable future. Data producers and compilers must therefore be incentivised to proactively contribute their datasets to open access platforms, like AusGeochem, through proper data source attribution. Thus, a concerted data-culture transformation must take place in our community if we wish to truly usher in a new era of thermochronology Big Data.However, to take full advantage of the wealth of invaluable thermochronology data and maximise their use for numerical modelling techniques, AusGeochem at https://ausgeochem.auscope.org.au.Readers may freely register and explore AusGeochem platform (https://ausgeochem.auscope.org.au46) was developed to simultaneously serve as a geosample registry, a geochemical data repository, and a data interrogation tool. In collaboration with method-specific advisory groups of geochemistry experts and adopting established international data reporting practices, community-agreed upon data schemas have been developed for rock and mineral geosample metadata, secondary ion mass spectrometry U–Pb analysis, fission-track and (U-Th)/He analysis. These will be accompanied progressively by additional data models for laser ablation inductively coupled mass spectrometry (LA-ICP-MS) U–Pb and Lu–Hf, oxide and major, minor and trace element geochemistry, and Ar–Ar, all currently under development, with the intention of additional method-specific geochemistry data models to follow.In 2019, a consortium of Australian university research laboratories named the AuScope Geochemistry Network set out to build a collaborative platform for the express purpose of collating, preserving, and disseminating geochemistry and geochronology data. In partnership with geoscience-data-solutions company Lithodat Pty Ltd, the open, cloud-based AusGeochem fission-track data model (Tables S1-S5) and (U-Th)/He data model (Tables S6-S8) were designed with the aim of accommodating retrospective and prospective datasets alike. Such flexibility requires that the data schema can archive analyses produced across mineral systems and via the breadth of historical fission-track and (U-Th)/He techniques. For the fission-track system, this includes results generated from the outdated population method89, conventional external detector method , and state-of-the-art in-situ fission track analysis using laser ablation inductively coupled plasma mass spectrometry  or electron probe microanalysis (EPMA), in the case of analysis of relatively U-rich mineral assemblages like zircon92. For the (U-Th)/He system, the current version of the (U-Th)/He relational data model is built to accommodate whole-grain and in-situ age determinations. While the current AusGeochem (U-Th)/He relational data model cannot accommodate results generated via the emerging 4He/3He or Continuous Ramped Heating methods31, its flexible architecture would allow for straightforward integration of bespoke data tables for these analysis types, should they be designed in the future , or legacy binned confined track data reported simply as length histograms without the corresponding detailed length parameters (Table S5). While the fission-track model is strictly designed to accommodate fission-track analyses sensu stricto, associated in-situ geochemical analyses obtained via EPMA or LA-ICP-MS trace element analysis can be archived and related to fission-track results on a per-sample, per-grain, and per-spot basis in the linked Major, Minor and Trace Element Geochemistry Data Model data reporting granularity found across the gamut of published thermochronology studies. So, in addition to archiving whole-rock fission-track results Table S1), the model can accommodate both detailed single-grain fission-track count (Table S3) and age data (Table S2), when available. Similarly, users are able to upload both comprehensive confined fission-track length data (Table S4) generated using digital microscopy software  was designed after the recommended data reporting practices currently being prepared for submission to Geological Society of America Bulletin special edition on “Reporting and Interpretation of Fission-Track Chronology Data”, with which co-authors of this article  are involved.The (meta-)data fields and corresponding units of the fission-track and (U-Th)/He data tables were designed after global community-agreed reporting recommendations. The (U-Th)/He data model and corresponding tables (Tables S6-S8) were designed following the data reporting best-practices of Flowers et al.AusGeochem46 relational database architecture /He data models presented herein were designed as an extension to the ure Fig. . The AusAusGeochem will also be able to accommodate the archival of double- and triple-dating results involving combined fission-track, U–Pb, and (U-Th)/He determinations94.Geological mineral and rock samples, along with their associated information, are stored in the Core Model. From here, samples can be linked to Method-Specific analyses, such as those stored in the fission-track or (U-Th)/He data models. Each sample can have multiple related method-specific Data Points, each of which represents a particular analysis performed on that geosample. In other words, an individual sample can be linked to multiple analyses, such that the reanalysis of a given sample would simply be uploaded as a new method-specific Data Point . This 1-n relationship between the Core Model and the Method-Specific Models also allows geochemical data of different kinds to be related on a per-sample or per-aliquot basis. This is particularly relevant for fission-track analyses which are often accompanied by other complementary geochemical measurements. For example, fission track results can be linked to corresponding electron probe microanalysis, LA-ICP-MS trace element, and U–Pb data stored in other Method-Specific Data Models via their shared Sample, Mount, Grain, and in some cases, Spot IDs ’ derived for each Data Point, such as age, chemistry, isotopic ratio, or time–temperature history, are stored90.The fourth component of the Supplementary Information 1.Supplementary Information 2.Supplementary Information 3.


Fifty-one percent of individuals with multiple sclerosis (MS) develop cognitive impairment (CI) in information processing speed (IPS). Although IPS scores are associated with health and well-being, neural changes that underlie IPS impairments in MS are not understood. Resting state fMRI can provide insight into brain function changes underlying impairment in persons with MS.We aimed to assess functional connectivity (FC) differences in (i) persons with MS compared to healthy controls (HC), (ii) persons with both MS and CI (MS-CI) compared to HC, (iii) persons with MS that are cognitively preserved (MS-CP) compared to HC, (iv) MS-CI compared to MS-CP, and (v) in relation to cognition within the MS group.z-score cut-off of z-score of ≥0. Control groups (HCMS-CI and HCMS-CP) were based on the nearest age-matched HC participants. A whole-brain ROI-to-ROI analysis was performed followed by specific contrasts and a regression analysis.We included 107 participants with MS , and 94 controls . Each participant was administered the Symbol Digit Modalities Test (SDMT) and underwent a resting state fMRI scan. The MS-CI group was created by applying a MS-CI that involved the cerebellum, visual and language-associated areas, thalamus, and caudate. SDMT scores were correlated with FC between the cerebellum and lateral occipital cortex in MS. No differences were observed between the MS-CP and HCMS-CP or MS-CI and MS-CP groups.Individuals with MS showed FC differences compared to HC that involved the cerebellum, visual and language-associated brain regions, and the thalamus, hippocampus, and basal ganglia. The MS-CI showed FC differences compared to HCOur findings emphasize FC changes of cerebellar, visual, and language-associated areas in persons with MS. These differences were apparent for (i) all MS participants compared to HC, (ii) MS-CI subgroup and their matched controls, and (iii) the association between FC and SDMT scores within the MS group. Our findings strongly suggest that future work that examines the associations between FC and IPS impairments in MS should focus on the involvement of these regions. Multiple Sclerosis (MS) is an inflammatory and neurodegenerative disease that can cause multiple symptoms including cognitive impairment. Many individuals with MS develop impaired cognitive function, and the domain of information processing speed is affected most often in up to 51% of individuals . The neuResting state functional magnetic resonance imaging (rs-fMRI) measures brain activity data while the participant is not performing a task. Analyses of the temporal correlations between activity in different brain regions provide measures of functional connectivity (FC) , 4. WherAltered FC of the thalamus, hippocampus, and temporal cortex, as well as regions associated with frontoparietal (FP), dorsal attention (DA), and DMN networks, has been linked to global cognitive impairment in MS . HoweverMS-CI). Since previous work that examined IPS using the SDMT has reported inconsistent results, we formed preliminary hypotheses based on previously reported FC changes in individuals with MS with global CI—we hypothesized that the MS-CI group would show altered FC in thalamus, hippocampus, temporal cortex, and regions associated with the FP, DA, and DMN. Second, to identify MS-related differences in FC that exist in the absence of cognitive impairment, we compared FC between cognitively preserved participants with MS (MS-CP) and approximately age-matched HC (HCMS-CP). Finally, to assess how FC relates to cognitive impairment exclusively within MS, we contrasted the MS-CI and MS-CP groups. Given that prior research has not restricted comparisons of FC specifically between cognitively preserved MS participants to cognitively preserved HC, or IPS impairment within MS, these last two contrasts were exploratory in nature.To that end, we aimed to examine whether changes in FC could be observed using a whole-brain region-of-interest approach, comparing participants with MS and HC. In line with previous literature, we compared FC more broadly by contrasting all patients with MS to all HC, with both groups exhibiting an unrestricted range of cognitive capabilities. We hypothesized that, relative to HC, MS participants would show altered (either higher or lower) FC involving thalamus, hippocampus, basal ganglia, amygdala, and medial temporal lobes, as well as altered FC involving brain regions commonly associated with VIS, SMN, and DMN functional networks. Next, we performed three different comparisons to characterise the association between FC and IPS impairment in MS. First, we compared participants with MS and CI (MS-CI) to approximately age-matched controls  of the HC reference group. The MS-CI group included individuals with SDMT z-scores <−1.5SD below the HC mean .Cognitive testing included the Weschler Test of Adult Reading (WTAR)  and the  HC mean . The nea1-weighted images were acquired using the MPRAGE sequence. T2-weighted FLAIR scans were acquired for subsequent lesion detection. Resting state fMRI was acquired using the Human Connectome Project “cmrr_mbep2d_bold” sequence with an acquisition time of 7:12 min. Lesion segmentation was completed with the Lesion Segmentation Tool in SPM12, and lesion masking and filling were accomplished in FSL. Lesion-filled MS structural raw data and HC structural raw data were entered into the processing pipeline. Functional data for MS and HC were processed identically. In brief, rs-fMRI data were spatially preprocessed using SPM12 which included removal of the first 10 brain volumes, realignment, distortion correction, coregistration to MNI space, and smoothing with a 4.0 mm full-width half-maximum 3D Gaussian kernel. The images were then imported to the CONN toolbox (version 18b)  was used to isolate only low frequency fluctuations   for subsion 18b)  (ART) wituations .t-tests, and Mann–Whitney U tests as appropriate.We summarized participant characteristics using descriptive statistics, and compared groups using chi-square tests, Student’s MS-CI (−1)]. Third, we performed the contrast comparing cognitively preserved MS patients and HC, controlling for sex [MS-CP (1) HCMS-CP (−1)]. Finally, we contrasted the cognitively impaired MS participants with cognitively preserved MS participants [MS-CI (1) MS-CP (−1)]. Significant ROI-to-ROI connections were thresholded by intensity at p < 0.05 corrected for multiple comparisons using the false discovery rate . The ROI-to-ROI connection threshold was set to ery rate .We included 107 participants with MS and 94 controls after excluding 4 participants with MS and 6 HC participants due to insufficient MRI data quality. The MS group was older and had a higher proportion of women relative to the HC group. As expected, the MS group had lower SDMT scores than the HC group, but the two groups did not differ with respect to premorbid IQ based on the WTAR .For the contrast of MS vs. HC, we found 37 pairwise differences (ROI-to-ROI pairings) that distinguished the FC of the MS group from HC .Twenty-six of these pairwise differences involved lower FC in the MS group relative to controls, shown in Eleven of the pairwise differences involved higher FC in the MS group relative to controls, shown in Overall, in terms of associated function, 20 of the ROI-to-ROI pairings included at least one ROI associated with visual processing, and 8 included at least one ROI associated with language. Eleven pairings included at least one ROI in the cerebellar vermis, a region associated with affective processing .z-score, we retained 43 people in the MS-CI group and 23 in the MS-CP group. Both MS-CI and MS-CP groups had a higher proportion of women than their nearest age-matched counterparts. The MS-CI group performed worse and the MS-CP group performed better on the SDMT than age-matched controls .We did not find any differences in FC between the MS-CP group and matched controls .One pairwise connection was significantly correlated with the SDMT scores in the MS group. FC between the left cerebellum 9 and the left inferior division of the lateral occipital cortex ROIs was observed  showed higher FC with the temporooccipital part of the middle temporal gyrus (toMTG) bilaterally, a region that is implicated in language comprehension and syntactic processing . While VAs hypothesized based on prior findings , we obseWe found widespread altered FC in brain regions associated with the VIS network that are consistent with previous work, though the direction of FC differences varies . These iBased on previous studies, we did not expect to see changes in FC at regions other than those that are associated with the VIS, DMN, or SMN. However, we found increased FC in the MS group between the left planum temporale, a region involved in complex auditory and speech processing , 48 and In the group of MS-CI individuals with impaired IPS, we showed altered FC in the cerebellum, thalamus, and basal ganglia, as well as areas associated with VIS and LAN networks. Current literature on associations between FC and IPS is contradictory, with conflicting findings on the correlation between SDMT scores and FC measures , 14, 15.There were FC changes in common at 2 ROI pairs between the analysis of all MS and HC, and the analysis of our MS-CI group compared to nearest age-matched controls. Both the MS group and the MS-CI group had lower FC between left occipital pole and right SCC and lower FC between left thalamus and cerebellar vermis 9. These results are consistent with previous systematic reviews which indicate altered FC involving thalamic and visual areas in MS , 6. TheyMS-CI  may represent the FC changes that are common to individuals with MS. A larger sample size of cognitively preserved individuals with MS may then detect changes in these same common regions. The additional regions present only in the MS-CI vs. HCMS-CI contrast  may represent a signature of additional IPS impairment. FC of cerebellar lobule 9 was implicated in impaired cognition in MS, based on the results of our linear regression of SDMT scores in the MS group. These posterior cerebellar lobules should be used as seeds in follow-up analyses that examine the relationship between FC and IPS in individuals with MS. While we observed ROI pairings that significantly differed between cognitively impaired participants with MS and age-matched healthy controls, these results were less robust than those observed in the overall MS vs. HC contrast. We speculate that this may be due to a combination of the fact that (1) the contrast between cognitively impaired participants with MS and healthy controls provides a narrower reflection of differences between MS and healthy state, relative to the FC underlying information processing speed impairment and (2) the contrast between cognitively impaired MS participants and their matched healthy controls included a smaller sample size for the contrast groups, compared to the overall MS vs. HC contrast. Thus, this contrast had less power to detect group differences than the overall MS vs. HC contrast. With a larger sample size of cognitively impaired participants with MS and controls, it may be possible to detect additional differences. In addition, larger sample sizes of cognitively impaired MS participants would support analyses focused on individual variability and associations between MS, FC, and cognitive impairment. Future work should attempt to replicate these findings in larger, more diverse samples, and should investigate the network properties of these regions. We expect that this will bring further insight into the FC changes that underlie MS-related declines in IPS.We propose that regions of FC change in common between MS versus HC and MS-CI versus HCThe contrast between HC and participants with MS and CI cannot distinguish FC differences related exclusively to CI from those related to MS, given that the groups varied both in their cognitive status as well as by MS status. This was the rationale for including the contrast of the cognitively preserved MS participants and their matched healthy controls, and the contrast of the cognitively intact vs. cognitively preserved participants within the MS group. Our results did not isolate FC differences specific to MS without cognitive impairment in our comparison of cognitively preserved MS patients to HC. Neither did we isolate FC differences specific to cognition impairment in MS in our comparison of cognitively impaired vs. cognitively preserved individuals with MS. The small sample size of the MS-CP group, which was common to both contrasts, may account for this. Future work using a larger sample size of cognitively preserved participants with MS will determine if this is a false negative due to low power.We made attempts to follow the standardization and study quality recommendations from Jandric and coauthors when designing this study, which include the study of phenotype-specific influences, controlling for age, using well-established measures, defining ROIs consistently with previous research, and conducting model-led research . We contUsing a whole-brain ROI-to-ROI approach, we found significant differences for FC among those with MS compared to healthy controls, with ROI-pairings involving the affective and cognitive regions of the cerebellum, as well as visual and language-associated regions. Our results were generally concordant with recent findings demonstrating altered FC in subcortical and visual structures in persons with MS, but the precise direction of FC changes was not always consistent. In contrast with previous work, we did not show altered FC at regions associated with the DMN or SMN. We report that individuals with MS and impaired IPS have altered FC of the cerebellum, visual-related, and language-related areas. The regions we identified on the posterior lobe of the cerebellum have not been linked to impairments in IPS in MS previously. We suggest that further work examines the associations between IPS and FC of these regions in persons with MS.rmarrie@hsc.mb.ca.The datasets presented in this article are not readily available because some participants did not agree to data sharing. Components of the datasets may be made accessible to qualified investigators with the appropriate ethical approvals and data use agreements upon request. Requests to access the datasets should be directed to RM, The studies involving humans were approved by University of Manitoba Bannatyne Research Ethics Board. The studies were conducted in accordance with the local legislation and institutional requirements. The participants provided their written informed consent to participate in this study.SC, JK, RM, JF, and RP contributed to the study design. SC, RP, JF, CF, RM, EM, MU, KW, LG, JB, JM, CB, and JK participated in data acquisition, processing, revised the manuscript, and approved the final version. SC and JK conducted the analyses and drafted the manuscript. All authors contributed to the article and approved the submitted version.Ruth Ann Marrie, Charles N. Bernstein, Jennifer Kornelsen, John D. Fisk, Ronak Patel, Chase R. Figley, Md Nasir Uddin, Sean L. Carter, Kaihim Wong, Teresa D. Figley, Carl A. Helmick, Erin L. Mazerolle, Christopher B. O’Grady, Salina Pirzada, Marco R. Essig, Lesley A. Graff, James M. Bolton, and James J. Marriott.


This study aimed to determine the test-retest reliability and concurrent validity of the International Physical Activity Questionnaire Short Form (IPAQ-SF) in Chilean adults.A cross-sectional validation study was carried out on 161 adults aged between 35 and 65, selected from a population-based study in Temuco, Chile. IPAQ-SF was completed twice, seven days apart, to analyze the test-retest reliability with the intraclass correlation coefficient (ICC). Objective PA was assessed by accelerometry (ActiGraph GT3X+) for seven consecutive days. Intraclass correlation coefficients were used to determine the reliability. Spearman correlation coefficients (rho) and Bland-Altman plots were calculated to assess validity.144 subjects  answered the IPAQ-SF on both occasions and had valid accelerometry data. The IPAQ-SF showed moderate reliability for sitting time (ICC = 0.62), while it was poor for walking (ICC = 0.40), moderate PA (ICC = 0.41), vigorous PA (ICC = 0.48), and total PA (ICC = 0.33). There were weak correlations between IPAQ-SF and accelerometry for sedentary behavior , walking , moderate PA , vigorous PA , and total PA .The results suggest that the IPAQ-SF test and retest would provide an acceptable measure of total SB and MVPA, and a weak correlation between IPAQ-SF and accelerometer. Strong scientific evidence shows that physical activity (PA) is one of the major factors in the prevention, control, and treatment of chronic non-communicable diseases, like cardiovascular diseases (CVD), diabetes, and some specific cancers –4. For tThus, this study aimed to determine the test-retest reliability and concurrent validity of the International Physical Activity Questionnaire Short Form (IPAQ-SF) in Chilean adults.Participants of the present cross-sectional validation study were selected from a population-based study (CESCAS), a prospective cohort with a multistage probabilistic sampling of participants aged 35–74 years from four mid-sized cities representing the Southern Cone of Latin America were included. A detailed description of the study population and design has been presented elsewhere . The crohttps://sites.google.com/view/ipaq/download). IPAQ-SF includes seven questions compared with the 27 of the IPAQ-long version.Self-reported PA data were collected using the Spanish (USA) version of IPAQ-SF  and another (IPAQ2). The IPAQ-SF asks participants to report PA performed for at least 10 minutes during the last seven days. Respondents were asked to report time spent in PA three intensities: walking, moderate, and vigorous in all daily life domains. Examples of activities that represent each intensity were provided. We use the Compendium of physical activities to specify activities by MET intensity .The IPAQ also asks daily sitting time to indicate sedentary behavior (SB). Total weekly PA was estimated using IPAQ scoring protocol. The total time for each intensity and activity type was calculated. Total energy expenditure per week (MET min week) was derived from the time spent in each activity intensity multiplied by its estimated metabolic equivalent of task (MET). The IPAQ scoring protocol assigns the following MET values for walking, moderate-intensity, and vigorous-intensity activities: 3.3 METs, 4.0 METs, and 8.0 METs, respectively .Objective PA was assessed by accelerometry using ActiGraph GT3X+ , an electronic device validated and widely used in biomedical research . All parWe obtained information on sociodemographic and anthropometric variables. Specifically, study participants reported their sex, age, marital status, and educational level. Marital status was categorized into two categories: being married and being unmarried, which also included being single, separated, divorced, and widowed. Educational level was classified into primary, secondary, and university studies. Weight and height were measured under standardized conditions . Body maCharacteristics of the study population were described in the total sample and by sex. The sociodemographic characteristics of subjects were described with frequency distribution, while anthropometric features were described using means and standard deviations (SD). As physical activity data were not normally distributed, we used nonparametric tests, and data are shown as medians and interquartile ranges. Intraclass correlation coefficients (ICC) were used to assess the test-retest reliability of the IPAQ between one interview (IPAQ1) and another (IPAQ2). The ICC is a recommended estimator to evaluate the magnitude of the relationship between multiple assessments of the same variable . SpearmaThe characteristics of the study population are shown in vs. 9.3 h/day). Moreover, physical activity was significantly lower when measured with the IPAQ-SF compared with the accelerometry for the total sample, and it was similar in both sexes.The descriptive data for the IPAQ-SF and accelerometric PA assessment are shown in Finally, accelerometry detected differences between men and women in vigorous PA  and steps per day , which IPAQ did not .The test-retest reliability between IPAQ1 and IPAQ2 and their different domains determined by the intraclass correlation coefficient (ICC) fluctuated between 0.40 and 0.62 . ModeratThe validity of the IPAQ-SF was tested by Spearman correlation coefficients (Rho) for PA intensities assessed by IPAQ-SF and accelerometry . There wBland-Altman plots for the agreement of data assessed by IPAQ-SF and accelerometry for sedentary behavior (SB) and total moderate to vigorous PA (MVPA) are shown in panel A). The data suggest that adjusting the self-report might decrease the measurement bias.The IPAQ-SF underestimates time compared with accelerometers for measurement of time spent performing SB. Most values of the difference between SB measurements are negative and grouped in a band, indicating a constant distance between the self-report and the accelerometer measurement panel A.panel B). Therefore, the higher the PA, the greater the difference between the measurements in the self-report.Regarding MVPA in IPAQ-SF, this is underestimated in subjects with a low level of PA but overestimated in subjects with a high level of PA. Moreover, a non-zero slope was observed, which suggests PA level-dependent differences between the self-report and accelerometry panel B.The results of the current study suggest that IPAQ-SF test and retest reliability would provide an acceptable measure of total SB and MVPA in Chilean adults. Concerning validity between IPAQ-SF and accelerometry, our results revealed a weak correlation for SB and MVPA. Additionally, it was found that IPAQ-SF underestimates MVPA in subjects with a low level of PA and overestimates MVPA in adults with high levels of PA. The IPAQ-SF systematically underestimates the sitting time for measurement of time spent performing SB.et al. performed a systematic review of twenty-three validation studies, which reported a weak correlation between total physical activity level measures by IPAQ-SF and objective measurement in most studies. This systematic review reported a correlation from 0.09 to 0.39 [et al. found modest reliability and poor validity in a convenience sample of Mexican adults [et al., reported acceptable validity for IPAQ-SF in Asian adults, and they found that the instrument can classify responders as achieving or not achieving the recommended PA levels [Our results are consistent with other studies made in different populations and countries. Evidence shows that PA questionnaires have moderate reproducibility and low validity compared with objective methods . Lee et  to 0.39 . Moreoven adults . Likewisn adults . In addiA levels . A revieA levels . ConsideA levels , no simpA levels .Related to sedentary behavior, in concordance with a systematic review carried out in adults in the European Union, our results revealed a reliable measure and weak validity for the single-item sedentary behavior question of IPAQ-SF . HoweverIn order to recommend an instrument to measure physical activity and sedentary behavior in the population, evidence suggests that the intraclass correlation coefficient (ICC) or the weighted Kappa must be greater than or equal to 0.5 compared with objective methods for physical activity measurement . Our stuet al., [Finally, a review carried out by Helmerhorst et al.,  that comThe main strength of the study is the methodology used to allow comparability with similar studies, following the same protocol as other validity IPAQ- SF studies , 14, 37.Based on these results, the IPAQ-SF test and retest would provide an acceptable measure of total SB and MVPA but weak correlation between IPAQ-SF and accelerometry. In this sense, the IPAQ-SF did not provide acceptable levels of validity compared with the gold-standard measure (accelerometry) and did not meet the minimum acceptable standard of 0.5 for objective activity measuring devices. However, the reliability of the IPAQ-SF assessed by test and retest was acceptable and the strength of the relationship according to correlation coefficients was fair to moderate. These results imply that the relationship between multiple assessments of physical activity by IPAQ-SF was reasonable, and the questionnaire could be a valuable instrument to measure changes in physical activity when the objective is to compare this behavior with a baseline measurement assessed by IPAQ-SF. A significant result is that the IPAQ performs differently when this is applied to sedentary and active subjects. Regarding MVPA, the IPAQ-SF, underestimated physical activity in subjects with a low level of PA but overestimated it in subjects with a high level of PA.


Mental health issues, including panic disorder (PD), are prevalent and often co-occur with anxiety and bipolar disorders. While panic disorder is characterized by unexpected panic attacks, and its treatment often involves antidepressants, there is a 20–40% risk of inducing mania (antidepressant-induced mania) during treatment, making it crucial to understand mania risk factors. However, research on clinical and neurological characteristics of patients with anxiety disorders who develop mania is limited.p < 0.05, with the cluster-forming threshold at the voxel level of uncorrected p < 0.001.In this single case study, we conducted a larger prospective study on panic disorder, comparing baseline data between one patient who developed mania (PD-manic) and others who did not (PD-NM group). We enrolled 27 patients with panic disorder and 30 healthy controls (HCs) and examined alterations in amygdala-based brain connectivity using a seed-based whole-brain approach. We also performed exploratory comparisons with healthy controls using ROI-to-ROI analyses and conducted statistical inferences at a threshold of cluster-level family-wise error-corrected The patient with PD-mania showed lower connectivity in brain regions related to the default mode network  and frontoparietal network , and higher in brain regions associated with visual processing network  in the patient with PD-mania compared to the PD-NM group. One significantly identified cluster, the left medial temporal gyrus , presented higher resting-state functional connectivity with the right amygdala. Additionally, ROI-to-ROI analysis revealed that significant clusters between PD-manic and PD-NM groups differed from HCs in the PD-manic group but not in the PD-NM group.Here, we demonstrate altered amygdala-DMN and amygdala-FPN connectivity in the PD-manic patient, as reported in bipolar disorder (hypo) manic episodes. Our study suggests that amygdala-based resting-state functional connectivity could serve as a potential biomarker for antidepressant-induced mania in panic disorder patients. Our findings provide an advance in understanding the neurological basis of antidepressant-induced mania, but further research with larger cohorts and more cases is necessary for a broader perspective on this issue. Panic disorder (PD) is a common mental disorder often encountered by primary care physicians . The halThe comorbidity of anxiety and bipolar disorder (BD) is prevalent . In clinTo our knowledge, research on the clinical and neurological characteristics of patients with anxiety disorders who develop mania after therapy is lacking. Significant advancements in understanding the pathogenesis, making accurate diagnoses, and investigating novel therapeutics for neuropsychiatric disorders can be achieved through the combined efforts of clinical, experimental, and computational medicine , 14. TheEfforts have been made to identify biomarkers for BD prediction using neuroimaging . Among tAlterations in amygdala-based connectivity have been consistently reported in the remission state (euthymic mood) of patients with BD compared with healthy controls (HCs) . HoweverThis report discusses the case of a young man diagnosed with PD with no history of BD who developed mania after treatment with antidepressants. This patient participated in a prospective study related to PD; therefore, we obtained rs-fMRI images before mania onset. In addition, rs-fMRI images of patients with PD who had not developed mania at a follow-up of more than 4 months and of HCs in that study were also acquired. Therefore, this report discusses the differences in the clinical features and amygdala-based resting-state functional connectivity (rsFC) in patients who experience mania during treatment. We believe that this study will support healthcare providers in considering neuroimaging for predicting mania in patients with PD.The current study is a single case study of antidepressant-induced mania in the longitudinal follow-up of a prospective study aimed to develop a predictive model of treatment response and prognosis in patients with PD using brain images combined with virtual reality-based anxiety behavior evaluation systems . In thisPatients with PD were recruited through outpatient clinics and public advertisements. A psychiatrist interviewed all patients using the Mini-International Neuropsychiatric Interview to screen for psychiatric illnesses and substance use . The eliTwenty-seven PD and 30 HCs met the eligibility criteria and participated in the study. During the study, one patient progressed to a manic episode (PD-manic patient), and the remaining 26 patients with PD did not progress to mania (PD-NM group) after at least 4 months of follow-up. All patients with PD, including PD-manic patient in the study, used serotonin-norepinephrine reuptake and selective serotonin reuptake inhibitors at baseline, according to treatment guidelines.A 22-year-old man patient visited our psychiatric clinic in April 2022, reporting recurrent panic attacks and anticipatory anxiety since February 2022. The patient, a university student with no psychiatric history, first sought psychiatric care in February 2022 after experiencing a panic attack that manifested as palpitations, shortness of breath, chest pain, dizziness, and a sense of impending doom. He reported impairment in social functioning due to anticipatory anxiety, experienced 1–2 or more panic attacks daily, and feared being alone. After a limited therapeutic response with persistent panic attacks and anxiety for 2 months at the primary clinic, he was referred to our clinic for further evaluation.The patients did not report any family history of any psychiatric disorder, including PD, mood disorders, or suicide attempts, was not discovered. He denied any history of BD and alcohol or benzodiazepine abuse. For the first 2 months, the patient was prescribed medications, including an adequate dose of escitalopram (20 mg/day), desvenlafaxine (100 mg/day), and aripiprazole (5 mg/day), as augmentation treatment. Alprazolam (0.25 mg) and propranolol (10 mg) were prescribed up to three times daily for symptomatic relief of panic attacks and anxiety. After 8 weeks of treatment (June 2022), the patient's frequency of panic attacks decreased to 1–2 times per week, with moderate improvement in the associated anticipatory anxiety, avoidance behaviors, and related social behavior problems. However, he was rated as moderately ill, with a panic disorder severity scale score of 14.For the patient's symptoms associated with PD, desvenlafaxine was increased from the previous dose to 200 mg/day in June 2022, and aripiprazole was increased to 7 mg/day 4 weeks later. In July 2022, the treatment effect was unsatisfactory, with no further improvement in panic attacks and anxiety  and worsening depression with neurovegetative symptoms. In August 2022, increased impulsivity, overspending, and polydipsia were reported, and a manic episode was considered, with a score of 18 on the Young Mania Rating Scale (YMRS). Escitalopram and desvenlafaxine were tapered off and escalated to lithium (900 mg/day) and quetiapine XR (600 mg/day) for 5 weekweeks. The patient returned to a euthymic state with YMRS scores of 12 and 6 in September 2022 and October 2022, respectively. During the 2 months, the patient did not report any panic attacks.The patient participated in a prospective study conducted in our psychiatric clinic in June 2021; therefore, we obtained fMRI images produced when he was diagnosed with and treated for PD before his manic episode.The same assessments as those in the VRABES feasibility study were performed at baseline before the fMRI. PDSS was used as an interview measure of PD severity , and the*-weighted (BOLD) image was obtained . Images were acquired in the transverse orientation. The participants were advised to relax, stay awake, keep their eyes open, and focus on the cross symbol displayed on the screen throughout the scanning process.A 3 T Philips Ingenia scanner  was used to collect the images. Coronal anatomical images were acquired using a 3D T1-weighted (T1w) fast gradient echo sequence (repetition time (TR) = 4.6 ms, echo time (TE) = 9.9 ms, 220 slices, slice thickness = 1 mm, and field of view (FOV) = 224 × 224 × 224). For the functional images, a T2The results included in this manuscript are from the preprocessing performed using fMRIPrep 21.0.2 , which iICBM 152 Non-linear Asymmetrical template version 2009c , followed by flirt (FSL 6.0.5.1:57b01774) (preprocessed BOLD: framewise displacement (FD), differential variation in signals (DVARS), and three region-wise global signals. The FD was computed using two formulations: power (absolute sum of relative motions) (Nipype (CompCor) (preprocessed BOLD time series (using a discrete cosine filter with a 128 s cut-off) for the two CompCor variants: temporal (tCompCor) and anatomical (aCompCor). The tCompCor components were calculated from the top 2% of the variable voxels within the brain mask. For aCompCor, three probabilistic masks  were generated in anatomical space. The implementation differs from that of Behzadi et al.; instead of eroding the masks by two pixels in the BOLD space, the aCompCor masks were subtracted from a mask of pixels that likely contained a volume fraction of the gray matter. This mask was obtained by thresholding the corresponding partial volume map at 0.05, which ensured that the components were not extracted from the voxels containing a minimal fraction of gray matter. Finally, these masks were resampled into the BOLD space and binarized by thresholding at 0.99 . The components of the WM and CSF masks were calculated separately. For each CompCor decomposition, the k components with the largest singular values were retained, such that the time series of the retained components was sufficient to explain 50% of the variance across the nuisance mask . The remaining components were excluded from the analysis. The head motion estimates calculated in the correction step were also placed in the corresponding confounding file. The confounded time series derived from the head motion estimates and global signals was expanded by including temporal derivatives and quadratic terms . Gridded (volumetric) resampling was performed using antsApplyTransforms (ANTs), configured with Lanczos interpolation to minimize the smoothing effects of other kernels . First, a reference volume and its skull-stripped version were generated using the custom fMRIPrep methodology. Head-motion parameters with respect to the BOLD reference (transformation matrices and six corresponding rotation and translation parameters) were estimated before spatiotemporal filtering using mcflirt (FSL 6.0.5.1:57b01774) . The BOL7b01774)  with the7b01774)  cost funmotions)  and Jenkmotions) . The FD  (Nipype . Three gic terms . Frames  kernels . Non-grip (pFWE) < 0.05, with the cluster-forming threshold at the voxel level of uncorrected p < 0.001.In line with our hypothesis that alterations in amygdala-based brain connectivity would appear between the PD-manic patient and PD-NM group prior to a manic episode, we conducted a seed-based, whole-brain analysis using two regions of interest (ROIs): the right and left amygdala. The automated anatomical labeling (AAL2) atlas was employed to define these ROIs . Anatomip < 0.05 andROI-level false-discovery rate corrected (pFDR).The main hypothesis focuses on differences between the anxiety disorder group, who did not develop mania, and patients who did; however, exploratory comparisons between HCs and the non-manic anxiety group in seed-based functional connectivity were also performed. To evaluate the degree to which observed differences between the PD-NM and PD-manic groups reflect aberrant brain functioning, ROI-to-ROI analyses were performed using both amygdalae (AAL41 & 42) and identified brain regions in the seed-based analysis as seed ROIs. Fisher's z-transformed correlations were calculated to indicate the connectivity strength between each pair of ROIs. Between-group differences (PD-NM vs. HC) were studied using analysis of covariance, controlling for age, sex, and years of education. ROI-to-ROI results were reported as significant if t-test for continuous data and a chi-square test for categorical data. p < 0.05 was considered statistically significant.Statistical analyses of the demographic and psychological characteristics between the PD-NM and HC groups were conducted using a software package . Demographics and psychological evaluations of the PD-NM and HC groups were compared using an independent The demographic features and assessment scores of the PD-NM, HC, and PD-manic groups are presented in After adjusting for the potential effects of age, sex, and years of education, seven clusters with the left amygdala and one with the right amygdala in which the PD-NM group and PD-manic patient differed were identified . Comparet51 = −3.36, pFDR = 0.001; t51 = −3.88, pFDR < 0.001), right FOC , and left PrC  and higher rsFC in the right LOC , right MTG , right LG , and left MTG  compared to the HC group.The relative HC and PD-NM groups revealed no suprathreshold differences in ROI-to-ROI analysis, considering both the amygdala (AAL41 & 42) and identified brain regions in the seed-based analysis as seed ROIs. However, PD-manic patients revealed lower rsFC from the left amygdala in the ROI of the two ROI in left SMG  group to the PD-manic patient, and not when comparing the HC group to the PD-NM group.We investigated the differences in amygdala-based rsFC between the patient with PD who developed mania during treatment and those who did not. Our findings indicate that, in the case of antidepressant-induced mania, left amygdala-based rsFC was lower in the left PrC, right MFG, and left SMG, and higher in the right LOC, right LG, and right MTG when compared to PD patients without mania. Additionally, right amygdala-based rsFC exhibited a stronger association with the left MTG in the PD-manic patient than in the PD-NM group. Furthermore, connectivity associated with significant clusters between the PD-manic patient and PD-NM groups differed from that of the HCs only in the patient with the PD-manic patient and not in the PD-NM group. The implications of these results are discussed below.We identified reduced L. amygdala–L. PrC connectivity in the PD-manic group compared with the PD-NM group. The PrC is an important region associated with the DMN . ChangesIn a euthymic state or depressive episode, there is increased functional connectivity between the amygdala and the DMN , 32. AddReduced functional connectivity between the L. amygdala, R. MFG, and L. SMG was observed in the PD-manic group compared with the PD-NM group. In contrast, the functional connectivity between the R. amygdala-L. MFG was increased in the PD-manic group compared to the PD-NM group. Additionally, this trend of results was consistent in the exploratory comparison between the HC group and the PD-manic patient, while no significant difference was found between the PD-NM group and the HC group. The SMG and MFG are crucial nodes of the FPN . AlteratAs decreased connectivity between the amygdala and the FPN has been reported in both BD and PD compared to HC, our finding of a significant difference in the PD-manic patient needs to be viewed in the context of clinical presentation. Decreased amygdala-FPN connectivity has been linked to response inhibition , which mTo our knowledge, there have been no reports on the asymmetric nature of the left and right amygdala-based rsFC in patients with BD. A previous study investigating the asymmetry of the left and right amygdala-based rsFC in healthy individuals reported distinct connectivity patterns and a more prominent right amygdala-based rsFC . FurtherThe PD-manic patient revealed stronger rsFC between the L. amygdala–R. LG, R, MTG, R.LOC and R. amygdala–L. MTG than the PD-NM group. The LG, MTG, and LOC are known to be involved in visual processing , 85. PreOur study had several limitations that constrain its interpretations. First, this study characterized one unexpected case in a longitudinal study; therefore, the altered amygdala-based functional connectivity discovered in this study cannot be generalized to patients with PD concerning antidepressant induced mania. However, we conducted an exploratory comparison with the HC group to support the specificity of our results and obtained results consistent with our hypotheses. Second, we did not control for the type and dose of medication. As different classes of antidepressants vary in the risk associated with antidepressant induced mania, this may be a confounding factor; thus, our results should be interpreted with caution . HoweverAccording to our findings, altered rsFC between the amygdala-DMN and amygdala-FPN, which has been reported in (hypo)manic episodes of BD, was observed both in patients with PD and HCs without mania. Additionally, differences in rsFC related to the visual processing network were identified, which have not been reported in previous studies. This study provides preliminary evidence and considerations for the future use of amygdala-based rsFC as a biomarker of antidepressant-induced mania in treating patients with PD. Further studies with larger cohorts and different cases are required to verify clinical relevance of our findings. However, given the possible practical benefits of our discovery, we believe that this study will excite both professionals and scholars.The boilerplate text of “2.5 Preprocessing” was automatically generated by fMRIPrep with the express intention that users should copy and paste this text into their manuscripts unchanged. It was released under the CC0 license.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by the local Ethics Committee of Korea University Guro Hospital. The patients/participants provided their written informed consent to participate in this study.Conceptualization, formal analysis, and writing—original draft preparation: B-HK and JK. Participant evaluation and data acquisition: S-HK, CH, H-GJ, and M-SL. Writing—review and editing and supervision: JK. All authors contributed to the article and approved the submitted manuscript.


Non-coding ribonucleic acids  are involved in epigenetic regulations and could mediate pre- or post-transcriptional gene silencing. These molecules are opening new avenues for therapeutic purposes with putative consequences for immunity. Similarly, emerging studies have demonstrated that extracellular vesicles (EVs) are involved in many immune response dysregulations and diseases. EVs, such as apoptotic bodies, exosomes, and microvesicles, are membrane-bound vesicles ranging in size from 30 to 1,000 nm in diameter. During pathological conditions, the number, size, and content of EVs are found to be altered and have been shown to play crucial roles in disease progression. Likewise, bacteria or a host can produce EVs containing ncRNAs that can mediate intercellular communication with epithelial and immune cells, potentially regulating the expression of genes involved in resistance to pathologies.This Research Topic brought together various articles, including primary research articles, reviews, methods, and systematic reviews, that focus on elucidating the role of ncRNAs and EVs in molecular immunotherapy and cross talk with genetic or epigenetic mechanisms in controlling cellular function in disease biology as potential therapeutic tools.Nie et al. discussed the lack of early diagnosis of hepatocellular carcinoma (HCC), which results in poor prognosis for patients. The authors mentioned that early HCC diagnosis currently depends on the level of serum alpha-fetoprotein (AFP) and imaging technologies which are not optimal. Through meta-analysis, Nie et al. identified key circular RNAs in exosomes for screening and diagnosing HCC. According to the authors, HCC is rated the fourth highest cause of death worldwide but lacks accurate biomarkers for early detection. The authors emphasized the role of the unique expression of circular RNAs in HCC including circ_0000798, circSATD3, hsa_circ_0007750, and cMTO1 in suppressing HCC progression with their possible use in diagnosis or treatment.Yousuf et al. used a panel of three miRNAs  to detect HCC in the early stage. The authors reported a correlation between the expression of the three miRNAs and AFP in the serum and tissues, indicating promises for early diagnosis of HCC. Therefore, they proposed the use of these miRNAs in combination with AFP as biomarkers for early diagnosis of HCC and on a large cohort of HCC patients. Lu et al.’s study is similar to that of Yousuf et al. because it identified the use of miRNAs for the diagnosis and prognosis of HCC. However, the fundamental difference was that Lu et al.’s study was based on a meta-analysis. The authors cataloged different studies from PubMed, Embase, and Wan Fang databases and identified the miR-17–92 cluster in context of diagnosis and prognosis of HCC. Lu et al. determined the sensitivity, specificity, and diagnostic odds ratio (DOR) on the miR-17–92 cluster for disease diagnosis. They found that the sensitivity of the diagnosis of HCC using the miR-17–92 cluster was 0.75 [at 95% confidence interval (CI)], with a specificity of 0.73 at 95% CI and a DOR of 7.87. Based on their results, Lu et al. finally suggested that the miR-17–92 cluster could be used as a diagnostic and prognostic biomarker for HCC.Ruiz-Manriquez et al. discussed miRNA-mediated regulation in key signaling pathways during hepatocellular carcinoma development. The authors emphasized that microRNAs are directly or indirectly involved in cellular signaling, and manipulating those miRNAs can potentially affect key signaling pathways resulting in carcinogenesis. In addition, Ruiz-Manriquez et al. suggested that miRNA-media/ted PI3K/Akt/mTOR, Hippo-YAP/TAZ, and Wnt/β-catenin signaling pathways could lead to HCC development. This perspective could help for a better understanding of diagnosis and management of HCC.A mini-review by Hong-Bin et al. used RNA sequencing analysis and clinical information to decipher an iron metabolic-related lncRNA signature that could be used to determine osteosarcoma (OS) survival and the immune landscape. The authors identified a total of 302 iron metabolism-related lncRNAs including lncRNA GAS5, UNC5B-AS1, PARD6G-AS1, and LINC01060 that are capable of regulating cell proliferation, migration, and invasion during osteosarcoma. The authors concluded that iron metabolism-related lncRNA signatures had good performance in predicting survival outcomes and the immune landscape for OS patients.Knowing that long non-coding RNAs (lncRNAs) could act as epigenetic regulators in diverse cellular processes including ferroptosis and iron metabolism, Zhao et al. showed the importance of 11 autophagy-related lncRNAs for esophageal squamous cell carcinoma (ESCC). They analyzed the immune function and tumor mutational burden between two groups with varying sensitivity to chemotherapy and immunotherapy. Overall, Zhao et al. reported the signature expression of some lncRNAs, including AL078604.2, BDNF-AS, HAND2-AS1, and ZEB1-AS1, among others, to be co-expressed with autophagy genes. Importantly, the authors provided an lncRNA risk model that could be used as a tool for the prognosis and treatment of patients with ESCC.Peeples et al., neonatal hypoxic–ischemic brain injury (HIBI) is reported to present varying phenotypes, posing difficult diagnosis and increased morbidity and mortality despite available therapy. This calls for an alternative novel therapy to safeguard the life of infants. Peeples et al. elucidated the role of miRNAs in gene regulation during HIBI as a promising therapeutic target for miRNA-based therapy. Overall, they found 61 unique miRNAs being differentially expressed in various regions of the brain including miR-410-5p, -1264-3p, 1298-5p, -5,126, and -34b-3p. These miRNAs targeted pathways associated with inflammation, metabolism, and cell death.As described by Zhang et al. highlighted the importance of miRNAs in coronary artery disease (CAD) from microarray datasets using various bioinformatics tools. The authors defined CAD as a cardiovascular disease associated with low-density lipoprotein cholesterol and categorized it as a major source of death worldwide. They also observed a correlation between miRNA expression pattern and CAD, although the role of many of the miRNAs in CAD is still unclear. Zhang et al. reported that miR-22-3p interacted with eight transcription factors in the cardiovascular system and suggested it as a better predictor for CAD, making it a potential biomarker for disease diagnosis.Morenikeji et al. identified important miRNAs that could target RNA-dependent RNA polymerase (RdRp), an enzyme necessary for coronavirus replication inside the host. Due to frequent mutations in coronavirus, several disease control measures, such as vaccines and antiviral drugs, are less effective in completely controlling viral replication. Since the RdRp is conserved among coronavirus variants, the authors found it to be an important target for miRNAs in controlling virus replication. Ultimately, the authors reported the ability of hsa-miR-1283, hsa-miR-579-3p, and hsa-miR-664b-3p to block virus replication through binding to their RdRp target and noted their potential use as a broad-spectrum antiviral.It is noteworthy that host ncRNAs also play a significant role in modulating viral replication during host–pathogen interactomes. Li et al. shed light on the role of melatonin and its interactions with ncRNAs in regulating osteoarthritis (OA). OA is a slowly progressive and irreversible disease of joints and lacks early treatments. Therefore, the authors gathered substantial knowledge about the melatonin-mediated modulation of ncRNAs in the early stage of OA. In addition, the authors proposed that the interaction between ncRNAs and target genes constitutes a complex network of OA regulation. In conclusion, they suggested that a combination of ncRNAs or their regulators with melatonin may be a new approach for the treatment of OA in the future.Liu et al. examined the role of circRNA E3 ubiquitin–protein ligase (circRNA ITCH) in clinical applications during tumor and non-tumor diseases. circRNA is a closed-loop RNA capable of up- or down-regulating gene expression at different levels. They have been implicated in cellular processes, including inhibiting cell proliferation, migration, and invasion and promoting apoptosis. Due to their molecular function and other involvement in biological processes, circ-ITCH could be used as a marker to monitor disease progression.A review by Hitit et al. highlighted the role of miRNAs during embryo implantation. They also provided an understanding of circulating miRNA in maternal plasma as a biomarker for early detection of pregnancy in sheep. They found that 22 miRNA expression patterns were associated with the estrous cycle and early pregnancy, of which two were oar-miR-218a- and oar-miR-1185-3p-targeted genes related to embryonic morphogenesis and developmental process. The authors concluded that circulating miRNAs from plasma hold a promise for early detection of pregnancy in sheep.The uterine environment is important for a successful pregnancy, especially during the peri-implantation stage. Alotabi described the use of exomiRs as biomarkers for cancer diagnosis, treatment response, metastasis, and promotion of T cell anti-tumor immunity via activation of immune checkpoint molecules. The author pinpointed how exomiRs could better regulate the expression of immune checkpoint molecules, leading to activation of T cell anti-tumor immunity. Alotabi reviewed multiple literature records to underscore the importance of sEVs, especially in patients with immune rejection.Body fluids carrying small extracellular vesicles (sEVs) have been isolated from blood, pleural fluids, saliva, and urine as biomarkers. These sEVs could be carrying cargoes with exosomal miRNAs (exomiRs), which have been found responsible for cancer pathogenesis. Some exomiR expressions could indicate cancer progression, cancer growth, and drug response/resistance. Furthermore, Luo et al. also discussed the role of sEVs carrying ncRNA cargoes and summarized their impact on kidney diseases. The authors found that sEVs could be produced by all cell types in the kidney, including neighboring cells like renal tubular epithelial cells, podocytes, collecting duct cells, and leap cells. These sEVs could then be loaded with aberrant ncRNAs that could be responsible for many kidney diseases. Luo et al. concluded that the sEV-ncRNAs could play a fundamental role in the early detection and prognosis of kidney diseases.The article by Singh et al. identified estrus biomarkers through biofluid, such as saliva, using proteomic profiling of buffaloes in different stages of the estrus cycle. They used both label-free quantitation (LFQ) and labeled (TMT) quantitation and mass spectrometry analysis. The authors reported an over-expression of proteins such as SERPINB1, HSPA1A, VMO1, SDF4, LCN1, OBP, and ENO3 in buffalo saliva estrus, depicting a novel method for estrus detection. The markers were functionally classified to be over-represented in several ontologies, including glycolysis, pyruvate metabolism, endopeptidase inhibitor activity, salivary secretion, innate immune response, calcium–ion binding, oocyte meiosis, and estrogen signaling. Singh et al. concluded by generating an array panel of candidate proteins that may be considered buffalo estrus biomarkers, applied in the development of a diagnostic kit for estrus detection in buffaloes.Finally, our editorial summarizes various articles on the role of non-coding ribonucleic acids and extracellular vesicles to understand epigenetic mechanisms that control cellular functions in different diseases. We believe that various findings in this research topic would be of much help in expanding the basic knowledge in disease studies and as potential therapeutic tools. We appreciate all contributors to this research article, including the authors, reviewers, and the editorial team, Frontiers in Genetics.


Research on cross-task EEG signals analysis methods has become a fast-growing research hotspot. In recent years, more and more researchers applied the features, which were widely used in EEG signal analysis to cross-task EEG signal analysis studies, including power spectral density (PSD) features  sets in spectral properties using sequential forward floating selection (SFFS)  Research based on feature fusion. Kakkos et al. improved the performance of cross-task classification by combining PSD with functional connectivity (FC) features  Research based on brain network features. Guan et al. proposed a dynamic brain network analysis method based on EEG microstates  Research based on fuzzy entropy features. Xing et al. used fuzzy entropy features for cross-task EEG signal analysis  Neural network method. Kamrud et al. studied the commonality of three different models in terms of cross-task: MLPNN, temporal convolutional network (TCN), TCN auto encoder (TCN-AE)  Domain adaptive method. Zhou et al. explored four domain adaptation methods to bridge differences between tasks  Support vector machine. Boring et al. compared the cross-task classification performance of SVM, linear discriminant analysis (LDA), and k-nearest neighbors (KNN) under sliding window  CNN. Mota et al. proposed a cross-task classification method based on CNN and compressed excitation blocks  RNN. Gupta et al. proposed a deep RNN model  Multi-classifier combination. Zhou et al. proposed a cross-task method for classification using raw data  Metric-based method. Jia et al. proposed a metric-based Spatial Filtering Transformer (MSFT) model, which used the angle margin loss function  Cross-subject methods are innovatively applied to cross-task research. In 2012, Khalighi et al. proposed a cross-subject method for unsupervised domain adaptation  Cross-task methods are innovatively applied to cross-subject research. In 2016, Touryan et al. studied the PSD features of cross-task EEG signals  Increasing the sample size. In the future, more EEG data can be collected or data augmentation techniques can be used to increase the sample size in order to improve the generalization performance of cross-task methods.(2) Research from the perspectives of both feature extraction and feature classification. At present, most cross-task researches were carried out independently from the perspective of feature extraction or feature classification, and it is a valuable practice to find common ground from these two perspectives simultaneously in the future, such as multi-source domain adaptation  Task subdivision. In the future, it is necessary to subdivide different tasks to improve the practicability of cross-task research, such as the corresponding EEG signal datasets can be analyzed on tasks with the same cognitive domain but different cognitive training content, or tasks with different cognitive domains and different cognitive training content.(4) The research of cross-task regression models can be explored in depth. The study results of Ke et al. suggested that regression models rather than classifiers should be used for obtaining optimal results in some cross-task studies (Ke et al., In conclusion, this paper introduced some research trends in the future. If cross-task research can continue to advance in these areas, it will take this type of research to a higher level.DW, ZP, and YZ contributed to conception and design of the study. ZP searched the database. DW, ZP, and JL performed the analysis of literatures. DW and ZP wrote the first draft of the manuscript. XW and JL wrote sections of the manuscript. YZ and XD revised this paper. All authors contributed to manuscript revision, read, and approved the submitted version.