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Edwards, T.

Publications and source records attributed to Edwards, T..

At least 19 recordsLinked to original sources
bioRxiv2026

Intelligence and the Big Five personality traits share a genetic and biological basis

Intelligence is often considered to be fundamentally different from other personality traits. Twin studies show that intelligence and the Big Five personality traits are partly influenced by the same genetic factors, but it remains unclear to what degree shared genes, SNPs, and biological pathways influence them. To address these questions, we analyzed the genetic associations of all six traits. First, we calculated their genetic correlations using LD score regression. We then quantified polygenic overlap using a bivariate causal mixture model, finding that approximately 90% of the genetic variants influencing the Big Five personality traits also impact intelligence. Finally, we performed gene prioritization and gene set enrichment analysis on each trait, once again finding substantial overlap. At each level, intelligence was as similar to the Big Five traits as they were to one another. Genetically and biologically, intelligence fits in with the rest of personality.

genomics↗
bioRxiv2026

Integrated pangenome and population genomics reveal selection on standing genetic variation driving fiber flax-linseed divergence

Flax (Linum usitatissimum L.) has been domesticated for dual end uses as linseed and fiber flax, yet the genomic basis of morphotype divergence remains unclear. Here, we constructed a morphotype-resolved pangenome by integrating three newly generated near telomere-to-telomere genome assemblies with 14 previously published ones. Despite substantial variation in assembly size, driven primarily by DNA transposons, gene content was highly conserved, with little evidence for significant morphotype-specific gene presence-absence variation. Population genomic analyses of 407 accessions revealed that fiber flax had reduced nucleotide diversity, extended linkage disequilibrium, and a more compact population structure relative to linseed, consistent with stronger selection and a narrower genetic base. Genome-wide differentiation was heterogeneous and concentrated in discrete regions. Integration of FST, nucleotide diversity ratios, Tajimas D, and genome-wide association signals identified morphotype-enriched genomic blocks distributed across the genome. Many candidate regions are primarily supported by directional shifts in nucleotide diversity rather than extreme differentiation, indicating selection on standing genetic variation. Genome-wide association analyses identified 1,712 unique quantitative trait nucleotides (QTNs), with predominantly small effect sizes and strong enrichment in gene-proximal regions, consistent with a polygenic architecture. Overall, fiber flax traits tend to be controlled by fewer loci with moderate-to-large effects, whereas linseed traits exhibit a more diffuse genetic architecture. Patterns of Tajimas D further support non-classical selection dynamics, with predominantly positive values in linseed and localized negative values in fiber flax, consistent with selection on standing genetic variation. Together, our results suggest that flax morphotype divergence is driven primarily by selection on pre-existing allelic variation within a conserved gene repertoire. This study provides a comprehensive framework linking genome structure, population genomics, and trait architecture, and highlights the importance of standing genetic variation as a key resource for flax breeding and improvement.

genomics↗
bioRxiv2026

Evolutionary dynamics of Aegilops revealed through comparative genome assembly of all 25 species

Aegilops species are the closest wild relatives of wheat and an important reservoir of genetic diversity for its improvement. Despite their potential, many Aegilops genomes remain poorly characterized. Here we present high-quality assemblies of 18 diploid, tetraploid, and hexaploid Aegilops genomes, which, along with the previously published genomes, complete the production of reference assemblies for all 25 genomes in this genus. Assembly sizes ranged from 5.24 Gb in diploids to 12.65 Gb in hexaploids, with scaffold N50 values up to 749.2 Mb. Gene annotation identified 53,035-156,779 protein-coding genes, of which 21,865-60,490 were classified as high-confidence. Orthogroup-based pangenome analysis across the 25 Aegilops genomes identified 80,521 orthogroups, including 15,809 core, 61,735 dispensable, and 2,977 species-specific orthogroups, highlighting substantial gene content variation among genomes. Phylogenetic analysis of 63 Triticum and Aegilops genomes/subgenomes based on near single-copy orthologs defines the phylogenetic relationships within the Triticum/Aegilops complex and confirms diploid progenitors of polyploid lineages. Ae. mutica (T) and Ae. speltoides (S) belong to the B lineage while the remaining Sitopsis grouped within the D lineage. Structural variation analyses using diploid progenitors as references revealed extensive large-scale rearrangements following polyploidization, emphasizing the dynamics of their evolution. Transposable element (TE) annotation further highlighted subgenome-specific TE expansions and contractions, providing insights into the mechanisms shaping genome structure after polyploidization. Collectively, these genomic resources provide a comprehensive framework for exploring Aegilops diversity, understanding polyploid evolution, and accelerating wheat improvement.

genomics↗
bioRxiv2026

Near telomere-to-telomere Linum genomes reveal a lineage-specific DNA transposon associated with chromosome architecture remodeling

Chromosome number variation and structural reorganization are key drivers of plant evolution, yet their genomic basis remains unclear due to incomplete representation of repetitive regions in existing assemblies. The Linum genus exhibits exceptional karyotypic diversity (n = 7-43), providing a powerful system to investigate chromosome evolution. Here, we generated near telomere-to-telomere (T2T) genome assemblies for four species, including cultivated flax (L. usitatissimum cv. CDC Bethune; n = 15), its wild progenitor (L. bienne; n = 15), and two related species (L. decumbens and L. grandiflorum; n = 8). Together with published genomes of L. lewisii (n = 9) and L. tenue (n = 10), these enabled reconstruction of chromosome evolution across six lineages. Phylogenomic analyses revealed a shared ancestral whole-genome duplication (WGD) associated with the n = 9 karyotype, followed by lineage-specific WGDs and divergent diploidization. The transition from n = 8 to the derived n = 15 flax lineage not only occurred without chromosome length expansion, but also with genome size reduction, indicating extensive internal restructuring. Comparative analyses showed that this restructuring was associated with lineage-specific expansion of a single DNA transposon family (TE_00003234; hAT), which is highly enriched in expansive pericentromeric regions that are characterized by low gene density and nucleotide diversity, suppressed recombination, segregation distortion, and extensive synteny disruption, unlike the LTR retrotransposon-rich pericentromeres typical of most plant genomes. These findings support a model in which lineage-specific DNA transposon expansion is associated with remodeling of pericentromeric architecture and large-scale chromosome restructuring following polyploidization.

genomics↗
bioRxiv2026

Optimization of AAV tools to target M&uumlller glial cells for retinal gene therapy

Reprogramming of Muller glial (MG) cells into retinal neurons has the potential to treat vision loss by regenerating the retina. Development of efficient gene delivery systems to target the MG cells is critical. Adeno-associated virus (AAV) serotypes and promoter specificity are important factors that influence AAV transduction profile in the retina. However, studies that optimize these parameters to specifically target MG cells are limited, in particular in rats which are commonly used for eye research. Here we tested 4 AAV serotypes and 14 promoters to optimize gene delivery to human MG cells in vitro and/or rat MG cells in vivo. We showed that the combinatorial use of MG-specific serotypes and promoters achieved high specificity for MG cell targeting, with ShH10Y serotype and the GFAP (gfaABC1D) promoter as the best performing tool to target rat MG cells in vivo. We developed new AAV vectors using known and novel MG-specific promoters and engineered short promoter variants to improve the cargo capacity of AAV delivery. Our results highlighted a number of promoters that can target MG cells in vitro or in vivo. This study further expands the AAV toolbox to target MG cells, which has important implications for retinal gene therapy development.

bioengineering↗
bioRxiv2026

A novel antiviral strategy targeting human metapneumovirus through pH modulation in human airway epithelial cells

Human metapneumovirus (hMPV) is a major cause of respiratory infections, particularly among infants, older adults, and immunocompromised individuals, yet no approved vaccines or targeted antiviral therapies are currently available. pH-regulated processes, including airway epithelial physiology, endosomal acidification, and viral fusion mediated by the fusion (F) protein, are critical for hMPV infection. This study evaluates PHOH-001, an inhaled alkaline buffer, as a potential therapeutic strategy to modulate airway epithelial pH and inhibit hMPV infection. Using a recombinant hMPV expressing green fluorescent protein (rhMPV-GFP), viral replication was assessed in primary human airway epithelial cells (HAECs). PHOH-001 significantly reduced GFP expression at 72 hours post-infection in both submerged and air-liquid interface (ALI) cultures, with effects comparable to those of the endosomal acidification inhibitor bafilomycin A1. In Vero E6 cells, used as a mechanistic in vitro model, PHOH-001 increased extracellular and intracellular pH in a concentration-dependent manner and correspondingly reduced hMPV infection. In HAECs, PHOH-001 reduced viral replication, as measured by TCID50 assays of infectious virus, and inhibited syncytium formation, a key step in viral spread. Furthermore, PHOH-001 altered F protein localization and was associated with changes in actin organization, consistent with impaired viral spread. Collectively, these findings demonstrate that PHOH-001 alters multiple pH-dependent steps in hMPV infection in vitro and support airway pH modulation as a potential antiviral strategy against hMPV.

molecular biology↗
bioRxiv2026

Comparison of multiple cefiderocol susceptibility testing methods against genomic determinants of resistance in blaNDM carbapenemase producing Enterobacterales

BackgroundCefiderocol is a siderophore-conjugated cephalosporin antibiotic used to treat multi drug resistant Gram negative infections, including metallo-beta-lactamase producing Enterobacterales. Antimicrobial useage is guided by antimicrobial susceptibility testing (AST) which is hampered by differences between EUCAST and CLSI breakpoints, methodological challenges of AST, and lack of information on clinical outcome related to AST. ObjectivesThis study assessed the agreement between AST methods under EUCAST and CLSI breakpoints in a collection of 57 blaNDM producing Enterobacterales isolated from a UK hospital network. MethodsAll isolates, including Klebsiella pneumoniae, Enterobacter hormaechei, Escherichia coli and Citrobacter freundii, were whole-genome sequenced and tested with disk diffusion and MIC gradient test strip, and broth microdilution MICs were determined for a subset. Categorical agreement between methods was calculated using both EUCAST and CLSI breakpoints. Mutations and acquired resistance genes associated with cefiderocol resistance were identified and compared with AST results. ResultsThe disk diffusion method, based on EUCAST interpretation, classified 94.7% of isolates as cefiderocol resistant and 5.3% as susceptible, with 22.8% within the Area of Technical Uncertainty. The CLSI breakpoint classified one isolate as resistant (1.8%) and 5.26% intermediate. Category agreement of broth microdilution and disk diffusion for E. coli using EUCAST guidelines was 38.5%. Mutations associated with cefiderocol resistance were highly prevalent and varied between species. ConclusionsThe discordant EUCAST and CLSI breakpoint values provided have large impacts on the classification of isolates susceptibility to cefiderocol, which will impact global cefiderocol usage and surveillance of resistance, further complicated by poor agreement between AST methods.

microbiology↗
bioRxiv2026

Structural Basis of Glycolytic Control in Trypanosoma cruzi: Insights from Enolase and PGI

Trypanosoma cruzi, the etiological agent of Chagas disease, depends on glycolysis for ATP production, rendering its glycolytic enzymes attractive targets for therapeutic development. Here, we report the high-resolution crystal structures of two essential glycolytic enzymes, glucose-6-phosphate isomerase (Tc PGI, 1.8 [A]) and enolase (Tc enolase, 2.4 [A]) and provide structural and computational analyses to support structure-based drug design. Tc PGI adopts a dimeric {beta} sandwich fold and features a parasite-specific 53-residue N-terminal extension and a unique C-terminal hook region which both distinguish it from its human ortholog. Tc enolase exhibits the conserved (/{beta}) 8 TIM barrel fold but harbors minor distinct structural deviations, including an extended 17 helix and a structured 1 region, which differentiate it from human isoforms. Both enzymes exhibited high thermal stability, consistent with adaptation to the parasites complex life cycle. Structure-based virtual screening using a scaffold with known multi-target potential identified distinct high-affinity inhibitors for each enzyme. Molecular dynamics simulations further confirmed stable enzyme-inhibitor interactions and favorable binding energetics. Collectively, these findings reveal structural signatures unique to T. cruzi glycolytic enzymes and lay the groundwork for the development of selective antiparasitic therapeutics.

biochemistry↗
bioRxiv2025

Optimization of AAV tools to target Muller glial cells for retinal gene therapy

Reprogramming of Muller glial (MG) cells into retinal neurons has the potential to treat vision loss by regenerating the retina. Development of efficient gene delivery systems to target the MG cells is critical. Adeno-associated virus (AAV) serotypes and promoter specificity are important factors that influence AAV transduction profile in the retina. However, studies that optimize these parameters to specifically target MG cells are limited, in particular in rats which are commonly used for eye research. Here we tested 4 AAV serotypes and 14 promoters to optimize gene delivery to human MG cells in vitro and/or rat MG cells in vivo. We showed that the combinatorial use of MG-specific serotypes and promoters achieved high specificity for MG cell targeting, with ShH10Y serotype and the GFAP (gfaABC1D) promoter as the best performing tool to target rat MG cells in vivo. We developed new AAV vectors using known and novel MG-specific promoters and engineered short promoter variants to improve the cargo capacity of AAV delivery. Our results highlighted a number of promoters that can target MG cells in vitro or in vivo. This study further expands the AAV toolbox to target MG cells, which has important implications for retinal gene therapy development.

molecular biology↗
bioRxiv2025

Dynamic Culture Improves the Predictive Power of Bronchial and Alveolar Airway Models of SARS-CoV-2 Infection

Human in vitro lung models represent advanced tools for studying respiratory infections, particularly those caused by emerging respiratory pathogens. Despite scientific advances, vaccine and therapeutics pre-clinical development has yet to fully adopt human-relevant testing platforms due in part to a lack of validation. In this study, we characterised how static and dynamic flow culture conditions influence microphysiological systems (MPS) generated using primary bronchial and alveolar epithelial cells. We assessed epithelial structure, functional differentiation, and infection dynamics. This study represents the first direct comparison of how dynamic flow and endothelial co-culture influence viral tropism, replication kinetics, and host responses across anatomically distinct regions of the respiratory tract in vitro. Dynamic flow promoted formation of more physiologically relevant tissue architecture, pseudostratified bronchial epithelium and alveolar sac-like structures, with enhanced epithelial differentiation and retention of region-specific cell phenotypes at the transcriptomic level. Both static and dynamic flow models demonstrated responsiveness to inflammatory stimuli (poly(I:C), LPS), producing distinct, tissue-specific cytokine profiles and supporting infection with multiple SARS-CoV- 2 variants. Differences in infection efficiency, viral replication, and host gene expression were observed between variants, with dynamic flow models offering enhanced sensitivity and resolution. In alveolar tissues, dynamic flow increased infection efficiency and reduced variability, enabling more robust and consistent transcriptional responses. This facilitated the identification of interferon signalling pathways as key targets of the host response. Among the variants tested, Delta induced the most extensive tissue damage and strongest transcriptional response, whereas Omicron BA.5 exhibited greater infectivity in alveolar models compared to earlier variants. Our findings demonstrate that dynamic flow MPS more closely replicate human lung tissue architecture and cellular diversity, while also enhancing the predictive power and clinical relevance of airway models for ex vivo studies of SARS-CoV-2 infection. These improvements strengthen the reliability of data generated for the study of host-pathogen interaction studies and support the use of dynamic systems for evaluating novel anti-infectives, immunomodulators, and functional characterisation of immune sera generated by next-generation vaccines. Collectively, our results highlight the value of integrating dynamic in vitro models into preclinical pipelines for emerging respiratory pathogens.

microbiology↗
bioRxiv2025

Multiple long-range cis interactions generate CTCF insulator-dependent viral chromatin domains in quiescent HSV-1 genomes

In cellular genomes, CTCF insulators impact transcription over small distances in a one-dimensional manner and over much longer distances in a three-dimensional manner by maintaining chromatin loops. We have previously shown that the latent HSV-1 genome contains CTCF insulators that function to regulate lytic transcription of adjacent genes in a one-dimensional manner. Here, we test the hypothesis that HSV-1 CTCF insulators nucleate chromatin loops to regulate the expression of distance separated gene regions through three-dimensional organization of viral genomes. We used 4C-seq methods to identify multiple long-range cis interactions in HSV-1 genomes that generate viral chromatin domains, including those nucleated by the viral CTCF insulator CTRL2. Deletion of the CTRL2 insulator disrupted these viral chromatin domains. Loop-nucleating interactions were quantitated with a novel approach (UMI-4C-seq) that utilizes unique molecular identifiers to label and count chromatin interactions associated with specific viewpoint primers. Cis-interaction peaks across four different viewpoints were quantified. Viral genomes lacking CTRL2 displayed more cis-interaction peaks and wider ranges of interaction lengths compared to wt virus, suggesting altered chromatin organization. Furthermore, differential looping analysis showed viral genomes lacking CTRL2 displayed a more transcriptionally permissive chromatin environment. Thus, the CTRL2 insulator functions as a critical regulator of long-range chromatin interactions and its deletion reshapes the viral chromatin landscape, leading to a more accessible and dynamic regulatory environment that may influence HSV-1 transcriptional programs and latency-associated chromatin states.

microbiology↗
bioRxiv2025

Influence of solvent, sex, and age on pharmacokinetic and acute behavioral effects of vaporized cannabis extract in mice

The legalization of cannabis in several states across the US has increased the need to better understand its effects on the body, brain, and behavior, particularly in different populations. Rodent models are particularly valuable in this respect because they provide precise control over external variables. Previous rodent studies have found age and sex differences in response to injected {Delta}9-tetrahydrocannabinol (THC), the major psychoactive component of cannabis. However, this route of administration does not mimic the most common way humans consume cannabis, i.e. through inhalation. Here, we sought to address this gap by investigating age and sex differences in pharmacokinetics and the acute behavioral effects of vaporized cannabis extract in mice. Adolescent (postnatal day [P] 35-50) and adult ([≥] P70) mice of both sexes received noncontingent exposure to 0 mg/ml, 150 mg/ml, or 300 mg/ml vaporized cannabis extract diluted in either 80% propylene glycol/20% vegetable glycerol (PG/VG) or 100% polyethylene glycol 400 (PEG). Immediately after exposure, body temperature, hot plate withdrawal latency, and locomotion were assessed. Blood was collected at 0, 30, and 60 min after vapor exposure, and plasma THC and its metabolites were analyzed. Measured THC levels were higher in both the plasma of vapor-exposed mice and the cannabis extract solutions themselves when PEG was the solvent compared to PG/VG. Vaporized cannabis (dissolved in PEG) at the highest dose tested induced hypothermic, antinociceptive, and locomotor-suppressing effects in all groups of mice. We found a dose-dependent age difference in locomotion, indicating that adolescents were less sensitive to the locomotor-suppressing effects of vaporized cannabis, which may be related to the plasma THC levels achieved. Although we found no significant sex differences in the acute behavioral effects of vaporized cannabis, there were significant sex differences in plasma THC metabolites indicating that female mice may metabolize vaporized cannabis more slowly than male mice. Taken together, the current findings add to a growing number of studies implementing vaporized cannabinoid delivery approaches by revealing PEG as the superior solvent for studies involving cannabis extract.

animal behavior and cognition↗
bioRxiv2024

A mycobacterial DNA extraction protocol designed for resource limited settings generates high quality whole genome sequencing

Mycobacteria are major global human pathogens and include Mycobacterium tuberculosis, the causative agent of tuberculosis, and M. abscessus, an emerging multidrug resistant pathogen. M. abscessus affects people with structural lung disease and those who are immunocompromised, most commonly causing pulmonary disease but also disseminated infections in the central nervous system and skin. High quality whole genome sequencing is essential to research mycobacterial epidemiology, pathogenesis and antimicrobial resistance. However, current DNA extraction protocols are time consuming, use toxic chemicals, require cold chain storage for certain reagents and can often result in poor quality, degraded DNA that directly impacts whole genome sequencing outputs. This is a particular challenge in low-income settings. Here, we report a novel optimised DNA extraction workflow for M. tuberculosis and M. abscessus that invariably generates high quality Illumina short read sequencing data. We evaluated input culture CFU and physical cell disruption times. DNA quantity was determined using a Qubit fluorometer system with DNA integrity assessed using the Agilent TapeStation platform. We showed that this protocol facilitated complete genome assemblies of M. abscessus and M. tuberculosis reference strains. There is no requirement for cold chain transport or storage of reagents, solvent extractions, or boiling to heat inactivate cultures, and the method does not require surfactant chemicals such as cetyltrimethylammonium bromide (CTAB).

microbiology↗
bioRxiv2024

Using RNA-targeting CRISPR-Cas13 and engineered U1 systems to reduce ABCA4 splice variants in Stargardt disease

Dysregulation of the alternative splicing process results in aberrant mRNA transcripts, leading to dysfunctional proteins or nonsense-mediated decay that cause a wide range of mis-splicing diseases. Development of therapeutic strategies to target the alternative splicing process could potentially shift the mRNA splicing from disease isoforms to a normal isoform and restore functional protein. As a proof of concept, we focus on Stargardt disease (STGD1), an autosomal recessive inherited retinal disease caused by biallelic genetic variants in the ABCA4 gene. The splicing variants c.5461-10T>C and c.4773+3A>G in ABCA4 cause the skipping of exon 39-40 and exon 33-34 respectively. In this study, we compared the efficacy of different RNA-targeting systems to modulate these ABCA4 splicing defects, including four CRISPR-Cas13 systems (CASFx-1, CASFx-3, RBFOX1N-dCas13e-C and RBFOX1N-dPspCas13b-C) as well as an engineered U1 system (ExSpeU1). Using a minigene system containing ABCA4 variants in the human retinal pigment epithelium ARPE19, our results show that RBFOX1N-dPspCas13b-C is the best performing CRISPR-Cas system, which enabled up to 80% reduction of the mis-spliced ABCA4 c.5461-10T>C variants and up to 78% reduction of the ABCA4 c.4773+3A>G variants. In comparison, delivery of a single ExSpeU1 was able to effectively reduce the mis-spliced ABCA4 c.4773+3A>G variants by up to 84%. We observed that the effectiveness of CRISPR-based and U1 splicing regulation is strongly dependent on the sgRNA/snRNA targeting sequences, highlighting that optimal sgRNA/snRNA designing is crucial for efficient targeting of mis-spliced transcripts. Overall, our study demonstrated the potential of using RNA-targeting CRISPR-Cas technology and engineered U1 to reduce mis-spliced transcripts for ABCA4, providing an important step to advance the development of gene therapy to treat STGD1.

molecular biology↗
bioRxiv2023

Molecular mechanisms of re-emerging chloramphenicol susceptibility in extended-spectrum beta-lactamase producing Enterobacterales

Infections with Enterobacterales (E) are increasingly difficult to treat due to antimicrobial resistance. After ceftriaxone replaced chloramphenicol (CHL) as empiric therapy for suspected sepsis in Malawi in 2004, ESBL-E rapidly emerged. Concurrently, resistance to CHL in Escherichia coli and Klebsiella spp. decreased, raising the possibility of CHL re-introduction. However, many phenotypically susceptible isolates still carry CHL acetyltransferase (CAT) genes. We used a combination of genomics, phenotypic susceptibility assays, experimental evolution and functional assays for CAT activity to understand the molecular mechanisms and stability of this re-emerging CHL susceptibility. Of 840 Malawian isolates, 31% had discordant CHL susceptibility genotype-phenotype, and we selected 42 isolates for in-depth analysis. Stable degradation of cat genes by insertion sequences led to re-emergence of CHL susceptibility. Our study suggests CHL could be reintroduced as reserve agent for critically ill patients with ESBL-E infections in Malawi and similar settings and highlights the ongoing challenges in inferring antimicrobial resistance from sequence data.

microbiology↗
bioRxiv2023

Online Bayesian Optimization of Nerve Stimulation

ObjectiveIn bioelectronic medicine, neuromodulation therapies induce neural signals to the brain or organs modifying their function. Stimulation devices, capable of triggering exogenous neural signals using electrical wave forms, require a complex and multi-dimensional parameter space in order to control such wave forms. Determining the best combination of parameters (wave form optimization, or dosing) for treating a particular patients illness is therefore challenging. Comprehensive parameter searching for an optimal stimulation effect is often infeasible in a clinical setting, due to the size of the parameter space. Restricting this space, however, may lead to sub-optimal therapeutic results, reduced responder rates, and adverse effects. ApproachAs an alternative to a full parameter search, we present a flexible machine learning, data acquisition and processing framework for optimizing neural stimulation parameters requiring as few steps as possible using Bayesian optimization. Such optimization builds a model of the neural and physiological responses to stimulations enabling it to optimize stimulation parameters and to provide estimates of the accuracy of the response model. The vagus nerve innervates, among other thoracic and visceral organs, the heart, thus controlling heart rate and is therefore ideal for demonstrating the effectiveness of our approach. Main results. The efficacy of our optimization approach was first evaluated on simulated neural responses, then applied to vagus nerve stimulation intraoperatively in porcine subjects. Optimization converged quickly on parameters achieving target heart rates and optimizing neural B-fibre activations despite high intersubject variability. SignificanceAn optimized stimulation waveform was achieved in real time with far fewer stimulations than required by alternative optimization strategies, thus minimizing exposure to side effects. Uncertainty estimates helped avoiding stimulations outside a safe range. Our approach shows that a complex set of neural stimulation parameters can be optimized in real-time for a patient to achieve a personalized precision dosing.

neuroscience↗
bioRxiv2023

Using neural biomarkers to personalize dosing of vagus nerve stimulation

BackgroundVagus nerve stimulation (VNS) is an established therapy for treating a variety of chronic diseases, such as epilepsy, depression, obesity, and for stroke rehabilitation. However, lack of precision and side-effects have hindered its efficacy and extension to new conditions. ObjectiveTo achieve a better understanding of the relationship between VNS parameters and neural and physiological responses to enable the design of personalized dosing procedures to improve precision and efficacy of VNS therapies. MethodsWe used biomarkers from recorded evoked neural activity and short-term physiological responses (throat muscle, cardiac and respiratory activity) to understand the response to a wide range of VNS parameters in anaesthetised pigs. Using signal processing, Gaussian processes (GP) and parametric regression models we analyse the relationship between VNS parameters and neural and physiological responses. ResultsFirstly, we observe inter-subject variability for both neural and physiological responses. Secondly, we illustrate how considering multiple stimulation parameters in VNS dosing can improve the efficacy and precision of VNS therapies. Thirdly, we describe the relationship between different VNS parameters and the evoked neural activity and show how spatially selective electrodes can be used to improve fibre recruitment. Fourthly, we provide a detailed exploration of the relationship between the activations of neural fibre types and different physiological effects, and show that recordings of evoked neural activity are powerful biomarkers for predicting the short-term physiological effects of VNS. Finally, based on these results, we discuss how recordings of evoked neural activity can help design VNS dosing procedures that optimize short-term physiological effects safely and efficiently. ConclusionUnderstanding of evoked neural activity during VNS provide powerful biomarkers that could improve the precision, safety and efficacy of VNS therapies.

neuroscience↗