Biology subjects

Miller, A.

Publications and source records attributed to Miller, A..

At least 19 recordsLinked to original sources

bioRxiv2026

Alternatively polarized neutrophils metabolically restrain macrophage-driven inflammation

Macrophage-driven inflammation underlies many inflammatory diseases, yet the mechanisms that restrain macrophage activation within inflamed tissues remain poorly understood. Using mouse models of foreign body granuloma formation and macrophage activation syndrome, we show that neutrophils accumulate at sites of inflammation and metabolically restrain macrophage-driven pathology. Neutrophil depletion or genetic impairment exacerbated tissue pathology, whereas induced neutrophilia attenuated inflammatory damage. Tissue-infiltrating neutrophils acquired an alternatively polarized state characterized by high arginase 1 activity that was regulated by an IL4Ra-STAT3-NOX2 signaling axis. Functionally, polarized neutrophils depleted extracellular arginine in an arginase 1-dependent manner, thereby limiting macrophage effector programs. Human neutrophils exhibited conserved regulation of arginase activity, and alternatively polarized neutrophils were detected in patients with sarcoidosis and macrophage activation syndrome. Together, these findings identify an arginine-dependent metabolic mechanism through which alternatively polarized neutrophils restrain macrophage-driven inflammation and reveal a previously unrecognized immune-regulatory role for these cells in chronic inflammatory disease.

immunology↗

bioRxiv2026

Genomics of Educational Attainment Across 80 Years of Social and Political Transformation in Germany

Abrupt social and political transformations in twentieth-century Germany may have shifted how polygenic indices relate to educational outcomes across birth cohorts. Following a prespecified analysis plan, we harmonized genomic, educational, and regional data from four German studies, comprising 13,049 individuals born between 1918 and 1995. Polygenic index associations with educational attainment were robust and strengthened modestly across more recent birth cohorts, with no detectable difference between East and West Germany. Associations with intergenerational educational mobility showed no evidence of such strengthening but were stronger in the East than in the West. Polygenic indices were less predictive of educational attainment and educational mobility for women than for men, with no evidence of regional variation. We discuss the methodological limitations of polygenic indices for examining gene-environment interactions, and emphasize that evaluating whether these differences represent progress towards equal educational opportunity requires a normative framework that social science genetics alone cannot supply.

genomics↗

bioRxiv2026

Complex patterns of biological connectivity highlight risks of local depletion in an Australian fishery

Sustainable management of commercial and recreational fisheries depends on accurately resolving population connectivity, across both ecological and evolutionary timescales. However, dispersal can vary markedly among life stages, making stock connectivity difficult to resolve using single-method approaches that often differ in spatio-temporal resolution. Here, we integrated population genomics, otolith stable isotope chemistry, and mark-recapture analyses to provide a multi-faceted assessment of stock connectivity in mulloway (Argyrosomus japonicus). Mulloway are a commercially, culturally, and recreationally important estuary associated fish distributed throughout the Indo-Pacific region, including south-eastern Australia where this study was conducted. Genome-wide single nucleotide polymorphism (SNP) analyses revealed significant genetic differentiation between regions influenced by different current systems, but limited structure within regions across distances exceeding 900 km. In contrast, otolith {delta}13C and {delta}18O signatures revealed fine-scale spatial structuring among estuaries, consistent with prolonged occupancy of local habitats. Mark-recapture analyses supported this interpretation, with most fish exhibiting strong estuarine fidelity over extended periods despite occasional long-distance coastal movements. Reconstructed age structures from fish otoliths revealed remarkably similar cohort composition among estuaries, with populations dominated by cohorts originating from a major recruitment pulse centred on 2011-2012, likely associated with a broad-scale flood-driven spawning and recruitment event. Together, our findings indicate that mulloway fisheries function as regionally connected networks of partially independent estuarine assemblages, where strong local residency is periodically offset by dispersive individuals and episodic recruitment events that maintain long-term demographic and genetic connectivity. Consequently, local estuarine populations may be vulnerable to localised depletion despite broader regional connectivity, particularly where sustained fishing pressure coincides with reductions in freshwater flows that constrain spawning and recruitment. More broadly, our study demonstrates the value of integrating complementary approaches to identify biological connections and define meaningful management units in species with complex life histories.

evolutionary biology↗

bioRxiv2026

Real-world results from a Machine Learning-guided, phenotypic High-Throughput Screen for novel antibiotics

Antimicrobial resistance is an urgent global health threat, with over 2.8 million multidrug-resistant infections killing over 35,000 annually in the US. Machine Learning (ML) has emerged as a potential solution to improve efficiency of antibiotic high-throughput screens (HTS). We report ML-guided high-throughput screening against E. coli. Large-scale Learning-to-Rank models were trained on public and proprietary datasets to maximize phenotypic inhibition and minimize human cell cytotoxicity. We evaluated several pre-plated compound libraries and a set of "cherry-picked", structurally novel compounds. We screened against a hyperpermeable lptD- mutant, followed by hit confirmation, profiling, cytotoxicity counter-screening, and MOA determination. Results demonstrated a doubled hit rate and 3X fewer toxic hits. Additionally, activity improved against both Wild Type E. coli and the lptD- mutant. ML models showed robust predictive power on structurally dissimilar compounds. The combination of large-scale HTS, ML innovation, and both library-wise selection and cherry-picking strategies distinguishes this study in the antibiotic discovery field.

microbiology↗

bioRxiv2026

Disturbance regime changes leave long-lasting legacies on a microbial community's composition and function

Mortality-inducing disturbances are important, ubiquitous drivers of community composition and function. Importantly, human activities and climate change are increasingly altering disturbance regimes. Most disturbance studies focus on the effects of current disturbance regimes, rarely considering those of historical regimes. However, recent theoretical work predicts that historical regimes can leave persistent legacies, modulating the communitys response to novel disturbances and invasive species. Here, we complement this theoretical approach using a model bacterial system that experienced disturbance regimes for [~]120 generations, followed by novel regimes and invasions for another [~]120 generations. Our results show persistent effects of historical legacies on disturbance-diversity relationships. Furthermore, some combinations of past and novel regimes promote invasion with increasing resident diversity, while others prevent it; legacies may explain conflicting diversity-invasibility relationships. These findings demonstrate the importance of historical legacies in disturbance-prone ecosystems, and underscore the challenges in predicting future community responses to disturbance regime changes.

ecology↗

bioRxiv2026

Preserving Native Cellulose-Xylan Architecture Enables Structure-Property Control in Holocellulose Nanofibrils and High-Performance Sustainable Materials

The hierarchical organization of cellulose microfibrils and their intimate interactions with hemicelluloses such as xylan underpin the exceptional mechanical performance of plant cell walls. However, translating these biological design principles into sustainable nanocellulosic materials remains limited by conventional cellulose nanofibril production routes, which rely on harsh chemical treatments that disrupt the native cellulose-hemicellulose architecture. Here, we present an optimized isolation strategy for holocellulose nanofibrils (hCNFs) that preserves native cellulose structure, xylan substitution and conformation, and cellulose-xylan interactions. Using wild-type Arabidopsis thaliana, a xylan glucuronidation-deficient gux1/2 mutant, and Brassica napus straw as model systems, we systematically elucidate how xylan content and substitution pattern govern nanofibril isolation, interfacial interactions, and macroscopic properties. Two-dimensional 13C magic-angle spinning NMR demonstrates retention of native cellulose glucosyl environments, the presence of two-fold and three-fold helical xylan conformations, and cellulose-associated two-fold helical xylan. Cryogenic transmission electron microscopy reveals fibril widths of [~]3 nm, consistent with elementary cellulose I{beta} microfibrils. We show that xylan glucuronidation regulates colloidal stability, hydration behavior, and interfibrillar cohesion, whereas xylan content controls nanofibrillation efficiency. These multiscale structural features translate directly into moisture sorption, thermal behavior, and mechanical performance. Notably, Brassica napus hCNF films exhibit exceptional strength and extensibility, surpassing many chemically modified CNF systems. This work demonstrates that preserving the native cellulose-hemicellulose architecture enables high-performance, sustainable nanocellulosic materials without chemical reconstruction.

biochemistry↗

bioRxiv2026

Deep Learning-Based Structure Modeling of the Treponema pallidum Proteome: Insights into Pathogenesis and Syphilis Vaccine Development

Treponema pallidum ssp. pallidum, the causative agent of syphilis, has a small proteome and encompasses numerous strains. Knowledge gaps remain in understanding the molecular mechanisms of pathogenesis of this bacterium, as well as the structure and function of the full complement of proteins encoded by T. pallidum. Here, an AI-based structure-to-function modeling workflow was used to investigate the complement of proteins encoded by T. pallidum. High-confidence structure models were generated for 976 T. pallidum proteins, covering 99% of the proteome. Analysis of the generated models using the protein structure comparison server DALI enabled high-confidence, structure-based functional annotation of 877 T. pallidum proteins, including 240 of the 323 proteins of unknown function encoded by this pathogen. Additionally, 63 putative pathogenesis related proteins (PPRPs) and seven treponemal proteins with previously uncharacterized similarity to outer membrane proteins (OMPs) from Gram-negative bacteria were identified. A workflow for B cell epitope (BCE) prediction identified 1133 surface-exposed, host-facing potential epitopes in known and predicted T. pallidum OMPs, of which 92 were prioritized based on bioinformatic analyses, biophysical properties, amino acid sequence conservation, and previous protein expression data. This work provides insight into T. pallidum pathogenesis through structure modeling-based functional annotation, including characterization of proteins of unknown function. This study also informs syphilis vaccine design by identifying new potential T. pallidum OMPs, as well as host-facing regions of T. pallidum OMPs that have conserved amino acid sequences in globally circulating strains. Statement of importance/impactThis study presents the first AI-based global structure modeling-to-function analysis of the proteome of Treponema pallidum, the bacterium that causes syphilis. Structure-based functional predictions of previously uncharacterized proteins, including proteins potentially involved in virulence, provide novel insight into mechanisms of pathogenesis. The work also informs syphilis vaccine development by the identification and structural characterization of new candidate vaccine proteins in globally circulating strains of T. pallidum.

microbiology↗

bioRxiv2026

Rapid GeneXpert surveillance of influenza A virus in seabirds and the environment provides early warning for wildlife health in Aotearoa New Zealand

The global expansion of highly pathogenic avian influenza (HPAI) virus A(H5N1) underscores the need for rapid surveillance at high-risk wildlife interfaces. Taiaroa Head (45.7828{degrees} S, 170.7333{degrees} E) in the South Island of Aotearoa New Zealand hosts a plethora of aquatic wildlife including a large red-billed gull (Chroicocephalus novaehollandiae scopulinus) colony as well as the only mainland breeding colony of northern royal albatross (Diomedea sanfordi). The Royal Albatross Centre is also a major nature tourism destination, attracting tens of thousands of visitors annually, thereby creating a dense ecological and human-wildlife interface vulnerable to viral incursion. We evaluated the GeneXpert II platform using the Xpert(R) Xpress Flu/RSV cartridge as a field-deployable tool for avian influenza virus detection in environmental and wildlife-associated samples. The assay detected synthetic influenza A viral RNA and multiple endemic low pathogenic avian influenza virus subtypes (A(H3N8), A(H1N9), A(H5N2) and A(H7N7)) circulating in New Zealand birds. Influenza A virus was reliably identified in spiked environmental water samples with no consistent PCR inhibition as well as naturally occurring avian influenza virus in duck pond water. Field deployment demonstrated that the system could be operated by non-laboratory personnel with minimal training in a non-clinical setting. This study establishes the feasibility of near-real-time environmental monitoring. Repurposing clinical cartridge-based point-of-care diagnostics offers a practical early warning approach for avian influenza virus surveillance at ecologically and economically significant locations.

microbiology↗

bioRxiv2026

A single point mutation in the σ3 protein encoded by the reovirus S4 gene substantially attenuates the virulence of a highly myocarditic reassortant virus in neonatal mice

Viral myocarditis is a major cause of heart damage, sudden death, and heart failure. Some strains of Mammalian Orthoreoviruses (REOV) cause myocarditis in newborn mice. This study examines the role of the REOV {sigma}3 protein, encoded by the S4 gene, in modulating the virulence and myocarditic potential of a highly virulent T1L/T3DM2 reassortant virus that contains the M2 gene from the Type 3 Dearing (T3D) strain in the Type 1 Lang background. We introduced single-point mutations in the double-stranded RNA-binding region of {sigma}3 in the T1L/T3DM2 background. Our findings show that the K287T mutation in {sigma}3 prevents the myocarditic phenotype and significantly reduces the virulence of T1L/T3DM2. Unlike the parental reassortant virus and a control reassortant mutant S4(R296T), infection of neonatal mice with the T1L-S4(K287T)/T3DM2 virus resulted in 100% survival, lower viral titers, particularly in the heart and spleen, and no gross or severe histological signs of myocarditis. This attenuation, despite similar in vitro growth and in vivo dissemination, indicates a tissue-specific replication deficit and highlights a key role for {sigma}3 in the development of myocardial disease. The K287T mutation, unlike R296T, eliminates {sigma}3s capacity to inhibit protein kinase R (PKR) activation and to suppress NF-{kappa}B-driven transcription, leading to a strong innate immune response that likely controls viral replication and reduces cardiac damage. These results underscore the crucial role of the {sigma}3 protein in modulating host innate immune responses and in influencing the outcome of REOV infection and myocarditis development. IMPORTANCEViral myocarditis is a serious disease with life-threatening consequences, particularly in neonates and young animals. Infection of neonatal mice with certain strains of mammalian reovirus induces myocarditis. A reassortant virus containing the M2 gene from the Type 3 Dearing Strain in an otherwise Type 1 Lang background causes severe myocarditis in 100% of neonatal mice. Here, we show that a single point mutation in the S4 gene, which abolishes the capacity of the encoded {sigma}3 protein to inhibit protein kinase R (PKR) and to suppress transcription of NF-{kappa}B-dependent genes, significantly attenuates the lethality of the T1L/T3DM2 reassortant and significantly reduces the severity of myocarditis. These findings highlight the importance of viral innate immune suppression in the induction of myocarditis.

microbiology↗

bioRxiv2026

Acute Sublethal Heat Stress Impairs Blood Feeding and Trypanosome Infection in the Kissing Bug, Rhodnius prolixus

Kissing bugs are the primary vectors of Trypanosoma cruzi, the causative agent of Chagas disease. Kissing bugs are exposed to thermal variability, including short periods of heat stress, which can induce mortality or exert sublethal effects. This study investigated Rhodnius prolixus following brief periods of high thermal stress with respect to survival, blood feeding, developmental processes, and T. cruzi infection, with a focus on sublethal effects. Our results demonstrated a significant decrease in survival for R. prolixus at 42 {degrees}C for 8 hours. When exposed to sub-lethal thermal stress (40{degrees}C for 8 hours), blood ingestion (amount and proportion) was reduced after 24 hours of recovery from thermal stress. Among the bugs that fed after 24 hours, molting was not impacted by temperature exposure. The infection rate decreased after heat exposure, likely due to reduced blood volume ingested when feeding 24 hours after heat stress. A week of recovery after exposure to higher temperatures improved feeding and increased infection rates to levels comparable to those of kissing bugs not exposed to thermal stress. Our findings offer insights into how extreme temperature events may influence Chagas disease. Specifically, these studies highlight the need to clarify how temperature, particularly at sublethal levels, interacts with vector biology to alter parasite transmission.

physiology↗

bioRxiv2026

Inflammatory Proteins are Highly Variable During a Natural Stressor: A Call for Intensive Longitudinal Blood Microsampling

Much research investigates how inflammation might play a role in stress-mediated diseases such as heart disease and depression. However, standard longitudinal designs often have measurement lags of months or years between assessments. This status quo is at odds with evidence that inflammatory biology and stress are both highly dynamic and would require much shorter time lags to quantify change as it naturally occurs, with minimal risk of confounding or effects diluting over time. Inspired by the use of intensive longitudinal data collection in psychological research, this study collected high frequency (every 3 days) blood microsamples over 22 days as 86 incoming college students transitioned onto campus (total observations = 622 blood samples). Samples were analyzed for CRP, TNF-, IFN-{gamma}, IL-1{beta}, IL-2, IL-4, IL-6, IL-10, IL-12p70, and IL-17A. Results using both bivariate correlation and intra-class correlation coefficients (which can be used for future power analyses for longitudinal research with these proteins) demonstrate low reliability. Notably, hierarchical linear models demonstrated that, even at this frequency of assessment, most proteins were characterized by less than 6% stable between-person differences. These results provide compelling evidence that investment in intensive longitudinal data collection of immune proteins is critical for understanding how inflammatory biology might function in psychosocial models of risk and resilience.

immunology↗

bioRxiv2026

Smartphone image capture system and image analysis pipelines enable accurate and efficient phenotyping of spaced plant mapping populations

Plain Language SummaryThe lack of low-cost, user-friendly and expedient methods for plant phenotyping challenges researchers ability to efficiently collect accurate phenotypic data in large field experiments. Here, we demonstrate the use of a novel, smartphone-based image capture system and two user-friendly image analysis pipelines (utilizing PlantCV or Biodock AI) to increase the throughput of plant phenotyping in two large, spaced plant populations. We showed that the image capture system collected images of adequate quality for downstream analysis using either the PlantCV or Biodock AI pipeline. Both image analysis pipelines produced phenotype values in line with those obtained using manual image annotation. Together, these results provide researchers with a low-cost, user-friendly image-based phenotyping method that can be widely applied to increase phenotyping throughout in field experiments.

plant biology↗

bioRxiv2025

Engineering protein expression dynamics with Tet-ON and dTAG degron systems: from precise control to oscillations

Precise temporal control of protein expression is essential for dissecting protein function and dynamic cellular processes. We present a framework for engineering tunable oscillatory protein expression (repeated pulses in expression) using widely adopted molecular tools, applying them to modulate NGN3 expression. Single-cell time-lapse microscopy reveals that the Tet-On system unexpectedly generates asynchronous oscillations in protein expression under continuous doxycycline administration. These oscillations are dependent on protein instability and are not tunable by doxycycline concentration. In contrast, the dTAG degron system enables precise, reversible, concentration-dependent control of protein degradation and reaccumulation. Coupled with a constitutive promoter, we achieve synchronous oscillatory protein expression (COD: Constituitive promoter driving Oscillations via Degradation). Mathematical modelling identifies optimal dTAG drug addition and removal timings using the COD system to flexibly tune NGN3 oscillation periods while maintaining other oscillatory parameters (mean level and peak-to-trough fold-change). Using microfluidics (COD+CHIPS) we reproduce model-predicted 5 and 10 hours periodicities while maintaining similar mean levels and peak-to-trough fold-changes. This work introduces a generalisable, programmable approach for generating and modulating protein oscillations, allowing investigation into how dynamic protein expression governs cellular function.

developmental biology↗

bioRxiv2025

Domain-specific mechanisms of YAP1 variants in ocular coloboma revealed by in-vitro and organoid studies

The conserved transcriptional co-activator YAP1 is a central regulator of organ development and tissue homeostasis, integrating mechanical and biochemical cues to control cell proliferation and survival. YAP1 variants underlie a spectrum of congenital disorders, including autosomal dominant coloboma that can occur alone or with syndromic features. Despite this clinical significance, the functional role of YAP1 in human eye development, as well as the impact of disease-associated missense variants, remains poorly understood. Here we show YAP1 expression at the optic fissure in human embryos, a key structure involved in coloboma pathogenesis. We also identify a novel YAP1 variant in a proband with syndromic coloboma and investigate five previously reported coloboma-associated YAP1 variants. Using in silico prediction, cell-based assays, and fluorescence cross-correlation spectroscopy (FCCS) to directly quantify YAP1-TEAD binding, we demonstrate that the position of YAP1 missense variants dictates their functional changes. TEAD-binding domain mutations most strongly disrupted transcriptional activity in a luciferase assay, whereas all tested variants impaired induction of endogenous YAP1-TEAD target genes. Furthermore, mimicking reduced YAP1-TEAD binding using verteporfin small molecule in retinal organoids led to reduced progenitor proliferation and survival. These findings establish defective YAP1-dependent transcription as a mechanism driving congenital eye malformations and provide a framework for interpreting the pathogenicity of human YAP1 variants. More broadly, this study highlights the need for functional analyses to connect genetic variation with disease.

developmental biology↗

bioRxiv2025

Indistinct changes in the mammal fauna between 1986-2017 at Judbarra-Gregory National Park, Northern Territory

The mammal fauna in many parts of northern Australia has undergone dramatic changes in the past 20-30 years, though longitudinal data that spans this period are limited and largely from coastal and high rainfall regions. We examined data from Judbarra-Gregory National Park that has been collected in a systematic manner (once in 1986 and then 2005-2017), including two years where camera trapping was included (2015 and 2017). We standardised this data in a simple manner (i.e., species by relative abundance and site frequency) to examine if there were any stark changes over this time span. We also undertook some simple modelling of mammal pattern with respect to fire and fractional green and bare cover metrics. Though we recognise some limitations in our comparisons (i.e., spatial variation in sites and methods), the data indicated that the mammal fauna had generally not changed substantially in composition, relative abundance or frequency across sites. There were meaningful models correlating mammal pattern to fire frequency, time since fire, fraction green and bare parameters. However, some species symptomatic of small mammal decline elsewhere (i.e., Rattus tunneyi) may have become less common, whereas other species were recorded for the first time in more recent years (2010-2017), particularly by camera traps (i.e., Trichosurus vulpecula, Isoodon macrourus, Melomys burtoni). We postulate that change in the mammal fauna on the semi-arid fringe of tropical savannas may have occurred prior to the 1980s, with a long history of cattle grazing a possible contributing factor. The mammal fauna there, is also perhaps naturally sparse and heterogeneous in spatial and temporal distribution.

ecology↗

bioRxiv2025

A Rapid Gene Expression Profiler Classifies AML Tumor Responsiveness to Standard Therapies

The emergence of transcriptional signatures that define cell types and pathways has made it possible to guide cancer therapy selection through gene expression profiling. We developed a rapid qPCR-based platform to profile cell state, stemness, and BCL2 family gene expression as a companion diagnostic test for acute myeloid leukemia (AML). We validated the stability and utility of the signatures across multiple measurement platforms and using patient samples from two centers. Integrating these signatures with clinical features enables an expedient means to predict the likelihood of patient responses to two standard-of-care therapies: intensive chemotherapy and hypomethylating agent plus venetoclax (HMA+Ven). For patients treated with HMA+Ven, expression levels of the promonocyte-like signature and BCL2 add predictive value for response and overall survival in multivariable models that include genetic features. The incorporation of the rapid profiler into the prospective evaluation of newly diagnosed AML patients may enhance treatment stratification and improve outcomes.

cancer biology↗

bioRxiv2025

Dehydrating microhabitats increase mite activity and intensify ectoparasitism of Drosophila

Parasites interact with their host in variable environments that are often subject to water scarcity and dehydration. Drosophila fruit flies and associated ectoparasitic mites interact across a range of microhabitats, typically in decaying organic matter, such as fallen fruit and cactus tissue, that dries out and deteriorates over periods ranging from days to months. Here, we report that mite parasitism of Drosophila increases with exposure to increasingly dry conditions for two fly-mite systems (D. nigrospiracula-Macrocheles and D. melanogaster-Gamasodes). In D. melanogaster, artificial selection for behavioral resistance did not eliminate this effect, as previously selected lines remained relatively more resistant than non-selected controls even under dry conditions. Water balance assays confirmed that mites became dehydrated when held under dry conditions, which was also associated with increased mite activity. Exposure of D. melanogaster to mites dehydrated by exposure to low relative humidity increased parasitism, further supporting that mite infestation intensifies under dry conditions. The results indicate that ectoparasitism in this system is affected by the water content of the mites. The increased motivation of mites to parasitise flies under dry conditions may serve to replenish mite water stores and facilitate dispersal to more favorable microhabitats.

physiology↗

bioRxiv2025

A Coupling Model of Transcranial Magnetic Stimulation Induced Electric Fields to Neural State Variables

Transcranial magnetic stimulation (TMS) is a non-invasive brain stimulation technique used to modulate neural activity, with applications in clinical treatment, diagnostics, and neuroscientific research. TMS targeting the human primary motor cortex (M1) is well studied, aided by experimental readouts from the cerebral cortex, the spinal cord, and activated muscle targets. One key readout is a series of pulses that descend the spinal cord following TMS, called DI-waves. These reflect the output of M1 to the spinal cord and are influenced by TMS parameters such as orientation, strength, and waveform. Previous modeling studies have deployed numerous strategies to explain DI-wave generation, but generally approximate TMS inputs as semi-arbitrary current or synaptic inputs. A consistent missing piece to these models is a biophysically motivated coupling between TMS and the neural states of cells and cell populations. This study aims to leverage cable simulations of realistic neuron morphologies to couple TMS induced electric fields to average state variables of cortical cell populations. This coupling model quantifies the spatial-temporal activation function of directly stimulated axonal fibers and the average input current that downstream cells receive due to synaptic inputs from directly stimulated cells. An example M1 cortical circuit is studied, in which TMS stimulates layer 2/3 excitatory and inhibitory neurons that project synapses onto layer 5 corticospinal neurons. Results indicate that TMS induces unique directionally sensitive distributions of synaptic outputs in time and space for each cell type. Directional and dosage sensitivity carries forward to the dendritic current flowing into layer 5 cells. Ultimately, the coupling model provides a novel architecture to translate electric fields from TMS into activation functions that alter neural states and serve as inputs to cortical circuit modeling. The study of other brain regions is achievable through an alternate choice of cell morphologies, cell locations, and circuit design. Author summaryTranscranial magnetic stimulation is a powerful technique to interfere with the brains function in a non-invasive way. It does so by magnetically inducing an electric field in the brain that influences the state of neurons. It has widespread medical application for diagnostics and treatment of diseases, such as depression. Moreover, it is valuable for fundamental brain research as it allows stimulating the brain and then observing its response. In order to optimize its utility in medicine and drawing more well-founded conclusions from scientific experiments, it is important to precisely describe its working mechanisms. In this work, we introduce a computational technique to simulate a crucial ingredient of these mechanisms, namely the precise way the induced electric field excites populations of interconnected neurons. We exemplify the technique for the case of stimulating the motor areas of the cortex, causing muscle activity. However, it can be generalized to a wide variety of use cases, thus forming an important tool that helps researchers to devise accurate mechanistic links between transcranial magnetic stimulation and its observed effects. In consequence, it supports future research aiming at the development of better diagnostics and treatment of brain diseases, as well as better understanding of brain function.

neuroscience↗