Biology subjects

Richardson, H.

Publications and source records attributed to Richardson, H..

11 recordsLinked to original sources

bioRxiv2026

Diagnostic Labels and Measurement Timing Drive Systematic Inconsistency in ADNI Neuroimaging Data

The Alzheimer's Disease Neuroimaging Initiative (ADNI) is widely used to train machine learning models for Alzheimer's disease, yet whether it provides consistent ground truth for predictive modeling has not been systematically tested. In this paper, we showed that ADNI contains three interacting sources of bias with direct implications for machine learning: (a) diagnostic label inconsistency, (b) technical measurement drift, and (c) longitudinal survivor bias. A substantial proportion of cases, particularly within intermediate stages, fall outside ADNI's own diagnostic thresholds. MRI field strength and evolving processing pipelines introduce significant technical variability in hippocampal volume, while cohort survivor bias arising from differential retention of participants across phases further distorts longitudinal estimates of disease progression. These findings indicated that ADNI does not provide the stable, internally consistent labels often required in machine learning applications. We proposed a practical framework for diagnostic validation, feature harmonization, and cohort accounting, offering guidance for building more robust and biologically meaningful predictive models from large-scale neuroimaging cohorts.

neuroscience↗

bioRxiv2026

The language network does not support music perception across a range of music experience

Music and language share many similarities, yet music does not elicit a response in the language brain areas in adults with typical amounts of music experience, and patients with aphasia show preserved music ability. However, this dissociation might not generalize across development or expertise: it may not yet be present in children, who have limited experience with language and music, or it may be diminished in musicians with extensive music training. To evaluate these possibilities, we here used a precision fMRI approach to examine the responses in the language areas of children (aged 4-16 years, n=80) and adult musicians (n=10) to music. We found that the results obtained previously for non-musician adults replicate in two new control samples and, critically, generalize to both of the newly tested populations: the language areas are already selective for language relative to music in young children, showing no age-related change from early to late childhood, and remain selective despite extensive music training in highly experienced musicians. Thus, it appears that the amount of music exposure and practice have little effect on how the language brain areas respond to music.

neuroscience↗

bioRxiv2026

Adolescent drinking causes a loss of aspartoacylase-expressing oligodendrocytes and hypomyelination of anterior cingulate and corpus callosum axons in male mice, but not females.

Adolescent binge drinking is a strong predictor of alcohol use disorder and related mental health outcomes in adulthood, which may be due to disruptions in myelination during this dynamic period of brain development. White matter expansion in frontal regions during adolescence is essential for mature decision-making and stress regulation, yet the cellular mechanisms by which alcohol disrupts this process remain poorly understood. We used multi-label immunofluorescence and confocal microscopy to visualize proteins in oligodendrocyte lineage cells and myelin ensheathment of axons in the anterior cingulate cortex (Cg1) and corpus callosum (CC) following four weeks of episodic voluntary binge drinking using the Drinking-in-the-Dark model in adolescent male and female C57BL/6NJ mice beginning on postnatal day 28. Contrary to our initial hypothesis that alcohol targets early-stage oligodendrocyte precursor cells (OPCs), binge drinking selectively depleted mature oligodendrocytes expressing aspartoacylase (ASPA) in the Cg1 and CC of male mice, but not females. This enzyme is essential for lipid biosynthesis and myelin production, and this cell-specific loss was accompanied by significant hypomyelination of axons only in males. These findings identify a later maturational stage of oligodendroglial development as a sex-dependent target of alcohol, advancing our mechanistic understanding of prefrontal myelin deficits in adolescent drinking. Furthermore, ASPA emerges as a potential therapeutic target for alcohol use disorder and demyelinating diseases, with differential vulnerability across sex carrying important implications for adult neurodevelopmental outcomes.

neuroscience↗

bioRxiv2026

Fusiform face area development correlates with development in higher-order social brain regions

3.The fusiform face area (FFA) preferentially responds to faces within the first months of life. One hypothesis is that higher-order social responses in middle medial prefrontal cortex (MMPFC) or face responses in superior temporal sulcus (STS) drive the development of face-selective responses in FFA, with right-hemisphere dominance in FFA eventually arising from lateralised connections to these regions. Another hypothesis proposes an innate face template in the amygdala guides attention to face-like shapes. This study opportunistically examined the development of the FFA, MMPFC, STS, and amygdala in childhood using an open cross-sectional movie-viewing fMRI dataset with 3-12-year-olds (N=117, M=6.77 years) and adults (N=33, M=24.77 years). We tested for correlations between FFA development and development in MMPFC, STS, and amygdala on the premise that associations between these regions may be observable even in children, and such associations could constrain hypotheses and analytic approaches in future studies with infants. First, we measured functional maturity-how similar each childs response to the movie was to an adult average response timecourse. In all regions, older childrens responses were more adult-like. Next, we tested whether FFA maturity correlated with functional connectivity with, or functional maturity of, MMPFC, STS, or amygdala. Children with more mature right FFA responses showed stronger right FFA-right MMPFC connectivity. Children with more mature FFA responses also had more mature STS responses, bilaterally. This study provides preliminary evidence that FFA co-develops with higher-order social brain regions and specific metrics to take forward in future research with infants. HighlightsO_LIWhat drives face selective responses in FFA is the subject of recent debate. C_LIO_LI117 children aged 3 to 12 years watched a short movie while undergoing fMRI. C_LIO_LIRight FFA development correlated with functional connectivity to right MMPFC C_LIO_LIFFA development correlated with STS development, bilaterally. C_LIO_LIFFA codevelops with higher-order social brain regions (controlling for age). C_LI

neuroscience↗

bioRxiv2025

Absence of MBP 3' UTR in Mice Disrupts mRNA Transport, Myelination, and Motor Learning

Myelin sheath maturation requires compaction, a cellular phenomenon mediated by local translation of myelin basic protein (MBP), which acts as a molecular zipper to join adjacent membranes and extrude the cytoplasm. Contrary to decades-old microinjection experiments indicating that Mbp mRNA transport is restricted to microtubules, we now show using smFISH that endogenous Mbp mRNA granules indeed localize along actin. To validate the in vivo necessity of Mbp mRNA transport and its dependence on the 3 UTR (untranslated region), we replaced the endogenous Mbp 3 UTR with polyA tail sequences. Though these mice have decreased Mbp mRNA levels, this alone could not account for their striking phenotypes - hypomyelination, baseline tremors, and motor learning defects. Thus, we cultured oligodendrocytes from these mice and found defects in both Mbp mRNA localization and local translation. These results demonstrate that the 3 UTR of a locally translated structural protein is critical for both developmental and activity-induced myelination.

cell biology↗

bioRxiv2024

Precision fMRI reveals that the language network exhibits adult-like left-hemispheric lateralization by 4 years of age

In adults, left hemisphere (LH) damage often leads to aphasia, but many cases of early damage leave linguistic processing intact, with a functional language system developing in the right hemisphere. To explain this early apparent equipotentiality of the two hemispheres for language, some have proposed that the language system is more bilateral during early development and becomes increasingly left-lateralized with age. We examined language lateralization using fMRI in two large developmental cohorts (total n=273 children aged 4-16 years; n=107 adults). Strong, adult-like LH lateralization (in response magnitude and activation volume) was evident by age 4, although other features of the LH language network showed protracted development, including the magnitude of language response and the strength of functional connectivity. Thus, although the RH can take over language function in some cases of early brain damage, this plasticity occurs in spite of adult-level LH bias present by age 4 years.

neuroscience↗

bioRxiv2022

Feature similarity gradients detect alterations in the neonatal cortex associated with preterm birth

The early life environment programmes cortical architecture and cognition across the life course. A measure of cortical organisation that integrates information from multi-modal MRI and is unbound by arbitrary parcellations has proven elusive, which hampers efforts to uncover the perinatal origins of cortical health. Here, we use the Vogt-Bailey index to provide a fine-grained description of regional homogeneities and sharp variations in cortical microstructure based on feature gradients, and we investigate the impact of being born preterm on cortical development. Preterm infants have a homogeneous microstructure in temporal and occipital lobes, and the medial parietal, cingulate, and frontal cortices, compared with term infants. These observations replicated across two independent datasets and were robust to differences that remain in the data after matching samples and alignment of processing and quality control strategies. We conclude that cortical microstructural architecture is altered in preterm infants in a spatially distributed rather than localised fashion.

neuroscience↗

bioRxiv2021

Using child-friendly movie stimuli to study the development of face, place, and object regions from age 3 to 12 years

Scanning young children while watching short, engaging, commercially-produced movies has emerged as a promising approach for increasing data retention and quality. Movie stimuli also evoke a richer variety of cognitive processes than traditional experiments - allowing the study of multiple aspects of brain development simultaneously. However, because these stimuli are uncontrolled, it is unclear how effectively distinct profiles of brain activity can be distinguished from the resulting data. Here we develop an approach for identifying multiple distinct subject-specific Regions of Interest (ssROIs) using fMRI data collected during movie-viewing. We focused on the test case of higher-level visual regions selective for faces, scenes, and objects. Adults (N=13) were scanned while viewing a 5.5 minute child-friendly movie, as well as a traditional experiment with isolated faces, scenes, and objects. We found that just 2.7 minutes of movie data could identify subject-specific face, scene, and object regions. While successful, the movie approach was still less effective than a traditional localizer. Having validated our approach in adults, we then used the same methods on movie data collected from 3-12-year-old children (N=122). Movie response timecourses in 3-year-old childrens face, scene, and object regions were already significantly and specifically predicted by timecourses from the corresponding regions in adults. We also found evidence of continued developmental change, particularly in the face-selective posterior superior temporal sulcus. Taken together, our results reveal both early maturity and functional change in face, scene, and object regions, and more broadly highlight the promise of short, child-friendly movies for developmental cognitive neuroscience.

neuroscience↗

bioRxiv2020

Capturing and Recreating Diverse Antibody Repertoires as Multivalent Recombinant Polyclonal Antibody Drugs

Plasma-derived polyclonal antibodies are polyvalent drugs used for many important clinical indications that require modulation of multiple drug targets simultaneously, including emerging infectious disease and transplantation. However, plasma-derived drugs suffer many problems, including low potency, impurities, constraints on supply, and batch-to-batch variation. In this study, we demonstrated proofs-of-concept for a technology that uses microfluidics and molecular genomics to capture diverse mammalian antibody repertoires as multivalent recombinant drugs. These "recombinant hyperimmune" drugs comprised thousands to tens of thousands of antibodies and were derived from convalescent human donors, or vaccinated human donors or immunized mice. Here we used our technology to build a highly potent recombinant hyperimmune for Severe Acute Respiratory Syndrome Coronavirus-2 (SARS CoV-2) in less than three months. We also validated a recombinant hyperimmune for Zika virus disease that abrogates antibody-dependent enhancement (ADE) through Fc engineering. For patients with primary immune deficiency (PID), we built high potency polyvalent recombinant hyperimmunes against pathogens that commonly cause serious lung infections. Finally, to address the limitations of rabbit-derived anti-thymocyte globulin (ATG), we generated a recombinant human version and demonstrated in vivo function against graft-versus-host disease (GVHD). Recombinant hyperimmunes are a novel class of drugs that could be used to target a wide variety of other clinical applications, including cancer and autoimmunity.

immunology↗

bioRxiv2018

Rapid Diagnosis of Lower Respiratory Infection using Nanopore-based Clinical Metagenomics

Lower respiratory infections (LRIs) accounted for three million deaths worldwide in 2016, the leading infectious cause of mortality. The \"gold standard\" for investigation of bacterial LRIs is culture, which has poor sensitivity and is too slow to guide early antibiotic therapy. Metagenomic sequencing potentially could replace culture, providing rapid, sensitive and comprehensive results. We developed a metagenomics pipeline for the investigation of bacterial LRIs using saponin-based host DNA depletion combined with rapid nanopore sequencing. The first iteration of the pipeline was tested on respiratory samples from 40 patients. It was then refined to reduce turnaround and increase sensitivity, before testing a further 41 samples. The refined method was 96.6% concordant with culture for detection of pathogens and could accurately detect resistance genes with a turnaround time of six hours. This study demonstrates that nanopore metagenomics can rapidly and accurately characterise bacterial LRIs when combined with efficient human DNA depletion.

microbiology↗

bioRxiv2017

Nanopore sequencing and assembly of a human genome with ultra-long reads

Nanopore sequencing is a promising technique for genome sequencing due to its portability, ability to sequence long reads from single molecules, and to simultaneously assay DNA methylation. However until recently nanopore sequencing has been mainly applied to small genomes, due to the limited output attainable. We present nanopore sequencing and assembly of the GM12878 Utah/Ceph human reference genome generated using the Oxford Nanopore MinION and R9.4 version chemistry. We generated 91.2 Gb of sequence data ([~]30x theoretical coverage) from 39 flowcells. De novo assembly yielded a highly complete and contiguous assembly (NG50 [~]3Mb). We observed considerable variability in homopolymeric tract resolution between different basecallers. The data permitted sensitive detection of both large structural variants and epigenetic modifications. Further we developed a new approach exploiting the long-read capability of this system and found that adding an additional 5x-coverage of ultra-long reads (read N50 of 99.7kb) more than doubled the assembly contiguity. Modelling the repeat structure of the human genome predicts extraordinarily contiguous assemblies may be possible using nanopore reads alone. Portable de novo sequencing of human genomes may be important for rapid point-of-care diagnosis of rare genetic diseases and cancer, and monitoring of cancer progression. The complete dataset including raw signal is available as an Amazon Web Services Open Dataset at: https://github.com/nanopore-wgs-consortium/NA12878.

genomics↗