Biology subjects

McCann, S.

Publications and source records attributed to McCann, S..

10 recordsLinked to original sources

bioRxiv2025

Characterising longitudinal dynamics of infant neurodevelopment using functional change point detection

SignificanceHabituation is an early-developing cognitive process linked to learning, typically reflected in functional near-infrared spectroscopy (fNIRS) studies as a reduction in evoked hemodynamic response amplitude. Conventional fNIRS analyses rely on linear time-invariance assumptions, potentially limiting insight into how responses evolve across repeated stimulus presentations. AimTo determine whether functional change point (FCPt) detection can characterize trial-specific changes in the infant hemodynamic response and reveal developmental differences in habituation timing. ApproachFunctional data analysis (FDA) treats entire response curves as statistical objects. Within this framework, FCPt detection identifies statistically significant structural shifts in the mean response across trials. FCPt detection with wild binary segmentation was applied to infant fNIRS data (n = 204) collected from infants living in rural Gambia at 5-, 8-, and 12-months of age during a habituation and novelty detection paradigm. ResultsSignificant changes were identified within auditory cortical regions. A high proportion of detected change points corresponded to decreases in response magnitude at 8- and 12-months. Ordinal regression revealed an age-related shift toward earlier occurrence of decreasing change points, indicating that older infants completed habituation sooner within the trial sequence. ConclusionFCPt detection provides temporal information on the infant hemodynamic response unavailable to conventional analysis. This additional information has revealed a previously overlooked developmental change in the habituation response during the first year of infancy.

neuroscience↗

bioRxiv2025

Neuronal extracellular vesicles regulate axon development in primary cortical neurons via local miR-99a targeting of HS3ST2

Fully functional neural competence and integrity requires a complex array of communication means among neurons, with extracellular vesicles (EVs) emerging as a relevant mechanism for cell-cell interaction in the CNS. Despite the growing number of studies demonstrating the presence of microRNAs (miRNAs) in axon and EVs, the molecular mechanisms of those miRNAs present in EVs and their functional role in nervous system development has not been fully explored. In this study, we investigated whether neuronal EVs can have a role in neuron-to-neuron communication during the development of neuron connectivity in mouse primary cortical neuron cultures. Our results demonstrate how miR-99a can regulate axonal growth via its EV-mediated delivery and through the targeting of HS3ST2, a heparan sulphate glucosamine 3-O-sulphotransferase, which is predominantly expressed in the brain and generates rare 3-O-sulphated domains in heparan sulphate proteoglycans, with growing importance in development and neurodegenerative mechanisms. Importantly, we show how in compartmentalised microfluidic cultures, where axons are isolated from neuronal somas, the growth-promoting effects of neuron-derived EVs are local to the axon. These findings establish that neuronal EVs can deliver miRNAs to discrete subcellular domains to acutely modulate local gene expression, thereby driving axonal growth and shaping neurodevelopment.

neuroscience↗

bioRxiv2025

Investigating the effect of channel pruning on functional near-infrared spectroscopy data collected from children aged 5-24 months

SignificanceInfant functional near-infrared spectroscopy (fNIRS) data are particularly vulnerable to noise; participant behaviour can result in motion artefacts and reduced set-up times can cause poor optode coupling. Accurate channel pruning is therefore essential but approaches vary and often use adult-derived thresholds, risking unnecessary data loss. AimThis work systematically compared pruning approaches and parameter choices to evaluate their effects on data quality and retention in infant fNIRS. ApproachData from 5-24 month-old infants were collected across two cohorts, using two paradigms. Channel pruning was performed using the coefficient of variation (CV) and the Quality Testing of Near Infrared Scans (QT-NIRS) tool, varying key thresholds. Multilevel models assessed effects of pruning method, parameter choice, age, motion, and testing site on signal-to-noise ratio (SNR) and channels retained. ResultsQT-NIRS produced significantly higher SNR than CV pruning across nearly all age, task, and cohort combinations, when matched for data retention. Higher QT-NIRS thresholds improved quality but reduced retention. Motion prevalence strongly reduced both SNR and retention; testing site and age had smaller but notable effects. ConclusionsQT-NIRS offers a better balance of data quality and retention than CV pruning. Lower QT-NIRS thresholds than adult defaults are recommended for infant data. These findings provide practical guidance for preprocessing pipelines in developmental fNIRS research.

neuroscience↗

bioRxiv2025

Examining Cross-Paradigm fNIRS Brain Activity in Neonates across The Gambia and UK

SignificanceNeonates undergo rapid development, yet the examination of emerging brain markers across paradigms, cognitive domains and diverse global populations remains limited. AimThis study investigated whether brain responses at one-month-of-age could be interrogated across paradigms to offer deeper context-specific insights into neurodevelopment. ApproachFunctional near-infrared spectroscopy (fNIRS) was used to assess frontal and temporal brain responses during natural sleep in 181 Gambian (GM) and 58 UK infants during three auditory paradigms: Social Selectivity, Habituation and Novelty Detection (HaND) and Functional Connectivity (FC). Paradigm-level brain responses were analysed using threshold-free cluster enhancement and cross-paradigm comparisons of individual responses. ResultsAt the group level, both GM and UK infants showed habituation but not novelty responses, higher inter-versus intra-hemispheric connectivity, stronger inter-hemispheric connectivity in temporal regions relative to frontal regions, stronger inter-regional connectivity between right temporal and left frontal regions, and UK infants also showed non-vocal > vocal selectivity. ConclusionsCross-cohort differences in the cross-paradigm analyses suggest context-specific developmental markers are evident within the first month of life and show high individual variability. Cross-paradigm analyses revealed that greater vocal selectivity (UK) was associated with higher inter-hemispheric connectivity, potentially allowing us to identify biomarkers of more mature neurodevelopment within the first weeks of postnatal life.

neuroscience↗

bioRxiv2025

Functional specialisation across the first five years of life: a longitudinal characterisation of social perception with fNIRS

Research in typically developing infants has shown robust and consistent brain activation to social versus non-social visual and auditory stimuli in a network of brain regions, including the inferior frontal, anterior temporal and posterior superior temporal cortex. However, large-scale, longitudinal neuroimaging studies across early childhood, particularly in low- and middle-income countries are rare, yet important, given that they offer a powerful means of capturing within-person changes in neurodevelopment and identifying targets for intervention and support. Here we investigated brain responses to social perception longitudinally across the first five years of life of participants in The Gambia with functional near-infrared spectroscopy (fNIRS) within the Brain Imaging for Global Health (BRIGHT) Project. We found that social visual stimuli elicited a selective right posterior temporal response across all six age points studied here (5, 8, 12, 18, 24 months and 3-5 years of age), with concurrent selective left responses at four of the six time points (5, 8, 18 months and 3-5 years of age). Inferior frontal regions showed brain activation at multiple ages, with the youngest (5 months) and oldest (24 months to 3-5 years) time points evidencing more widespread frontal social visual responses. Conversely, auditory social stimuli elicited a significantly stronger and more prolonged response than auditory non-social stimuli across all six age points from 5 months to 3-5 years across a range of frontal and temporal areas. Finally, from individual infant trajectories of brain activation, we identified different profiles of age-dependent specialisation to auditory social stimuli, with some specialising earlier than others. Future work could take advantage of such profiles to investigate the effects of adversity and resilience factors on neurodevelopment.

neuroscience↗

bioRxiv2025

Longitudinal Habituation and Novelty Detection neural responses from infancy to early childhood in The Gambia and UK

As infants and young children learn from and respond to their environment, their development is driven by their ability to filter out irrelevant stimuli and respond to salient stimuli. While sources and types of stimuli vary across cultural contexts, research to understand the neural mechanisms of these behaviors have largely focused on relatively homogeneous populations in high income settings. To address this lack of diverse representation the Brain Imaging for Global health project (BRIGHT) collected longitudinal data in The Gambia (N=204) and the UK (N=61). Here we present results of the Habituation and Novelty Detection (HaND) fNIRS neuroimaging task. Gambian infants showed persistent response suppression (Habituation) at all visits (from 5mo to 60mo) while Novelty Detection was only observed once infants reached 18 and 24mo. In the UK, infants only showed persistent habituation from 5-12mo, while the response was not evident at 18 and 24mo. Furthermore, in contrast to The Gambia, alongside the habituation patterns observed Uk infants showed novelty detection from 5-12mo. This is the first longitudinal description of the HaND response in individuals from different contextual backgrounds across such a broad age range and number of time points, revealing different patterns of specialization in The Gambia and UK. HighlightsO_LIThis is the first characterization of Habituation and Novelty Detection (HaND) responses in infants and young children from contrasting settings across low and high-income countries. C_LIO_LIIn the Gambian cohort, Habituation was typically observed from 5 to 60months; only weak patterns of Novelty Detection were observed at 18 and 24months. C_LIO_LIIn the UK cohort, HaND responses were observed up to 12months of age; but were not evident at 18 and 24months. C_LIO_LIDevelopmental trajectories of HaND responses follow different patterns of specialization from birth to five years of age in individuals living in different contexts. C_LI

neuroscience↗

bioRxiv2025

Different mechanisms link gain and loss of kinesin functions to axonal degeneration

Axons are the slender, often meter-long projections of neurons that form the biological cables wiring our bodies. Most of these delicate structures must survive for an organisms lifetime, meaning up to a century in humans. Long-term maintenance and sustained functionality of axons requires motor protein-driven transport distributing life-sustaining materials and organelles to places of need. It seems therefore plausible that loss of motor function would cause axon degeneration; however, also gain-of-function conditions were linked to disorders including motor neuron disease or spastic paraplegia. To understand this phenomenon, we studied [~]40 genetic manipulations of motor proteins, cargo linkers and regulators of reactive oxygen species in one standardised Drosophila primary neuron system. Using axonal microtubule bundle organisation as a relevant readout reflecting the state of axon integrity, we found that losses of Dynein heavy chain, KIF1A/Unc-104 and KIF5/Kinesin heavy chain (Khc) all cause bundle disintegration in the form of chaotically curled microtubules. Detailed functional studies of Khc and its adaptor proteins revealed that losses of mitochondrial or lysosomal transport cause ROS dyshomeostasis, which is a microtubule-curl-inducing condition in fly and mouse neurons alike. We find that hyper-activated Khc induces the same microtubule curling phenotype, not through ROS but likely more directly through enhanced mechanical forces. Studies with loss of Unc-104 or KIFBP and expression of an ALS-linked mutant form of the human Khc orthologue KIF5A suggest that loss or hyperactivation of different types of transport motors cause MT curling as a shared feature. We discuss a model which can explain our findings and their relevance for understanding motor-linked neurodegeneration.

neuroscience↗

bioRxiv2024

Early life microbial succession in the gut follows common patterns in humans across the globe

Characterizing the dynamics of microbial community succession in the infant gut microbiome is crucial for understanding child health and development, but no normative model currently exists. Here, we estimate child age using gut microbial taxonomic relative abundances from metagenomes, with high temporal resolution ({+/-}3 months) for the first 1.5 years of life. Using 3,154 samples from 1,827 infants across 12 countries, we trained a random forest model, achieving a root mean square error of 2.61 months. We identified key taxonomic predictors of age, including declines in Bifidobacterium spp. and increases in Faecalibacterium prausnitzii and Lachnospiraceae. Microbial succession patterns are conserved across infants from diverse human populations, suggesting universal developmental trajectories. Functional analysis confirmed trends in key microbial genes involved in feeding transitions and dietary exposures. This model provides a normative benchmark of "microbiome age" for assessing early gut maturation that can be used alongside other measures of child development.

microbiology↗

bioRxiv2024

A randomized, controlled, two-center preclinical trial assessing the efficacy of a new benzodiazepine-dihydropyridine hybrid molecule (JM-20) in rodent models of ischemic stroke

JM-20 is a novel multifunctional benzodiazepine molecule with potent neuroprotective effects in rat focal cerebral ischemia. To confirm previous results obtained in single laboratories with small sample sizes, and to provide a robust preclinical evidence base for potential clinical development in stroke, we have performed a two-center preclinical trial with sufficiently large group sizes to detect relevant effects, minimizing biases in experimental design as much as possible (randomization, blinding, predefined in- and exclusion criteria) and increasing external and construct validities by performing experimental focal cerebral ischemia by different surgeons in two different laboratories on two continents, including two species (480 mice and 55 rats), different suppliers, young, young adult, and mature adult animals (range 2 -16 months) as well as comorbid animals (diabetes). While JM-20 improved functional outcomes after middle cerebral artery occlusion in young adult mice at day 7 and appeared to reduce mortality (not statistically significant), it had no effect in mature adult or comorbid (STZ-induced diabetes) mice. Effect sizes, where statistically significant, were modest, and much lower than those reported in the previous studies. Meta-analysis of all individual mouse data did not reveal statistically significant different functional outcomes or mortalities between vehicle- and JM-20-treated animals, although neuroscores and survival were slightly better in JM-20-treated animals. In the less severe model of permanent cortical focal cerebral ischemia in rats, JM-20 significantly reduced brain infarction. We conclude that we were able to confirm the neuroprotective potential of JM-20. However, effect sizes were substantially lower as previously described in small, monocentric trials. Further study is needed to determine whether JM-20 could be effective in less severe cases of focal cerebral ischemia or when used in combination with thrombolysis.

pharmacology and toxicology↗

bioRxiv2024

Growth in early infancy drives optimal brain functional connectivity which predicts cognitive flexibility in later childhood

Functional brain network organization, measured by functional connectivity (FC), reflects key neurodevelopmental processes for healthy development. Early exposure to adversity, e.g. undernutrition, affects neurodevelopment, observable via disrupted FC, and leads to poorer outcomes from preschool age onward. We assessed longitudinally the impact of early growth trajectories on developmental FC in a rural Gambian population from age 5 to 24 months. To investigate how these early trajectories relate to later childhood outcomes, we assessed cognitive flexibility at 3-5 years. We observed that early physical growth before the fifth month of life drove optimal developmental trajectories of FC that in turn predicted cognitive flexibility at pre-school age. In contrast to previously studied developmental populations, this Gambian sample exhibited long-range interhemispheric FC that decreased with age. Our results highlight the measurable effects that poor growth in early infancy has on brain development and the possible subsequent impact on pre-school age cognitive development, underscoring the need for early life interventions throughout global settings of adversity.

neuroscience↗