Biology subjects

MacNicol, E.

Publications and source records attributed to MacNicol, E..

8 recordsLinked to original sources

bioRxiv2026

Longitudinal magnetic resonance imaging and spectroscopy in a mouse model of cuprizone-induced demyelination

The cuprizone (CPZ) lesioned mouse is a widely used model of demyelination and remyelination, but most studies rely on histology at terminal timepoints, limiting understanding of disease dynamics. Here, we present a longitudinal multimodal magnetic resonance imaging and spectroscopy (MRI/MRS) study of CPZ-induced pathology, pooling control arms from three independent experiments (n = 40). Mice were imaged at baseline, then exposed to 0.2% cuprizone for 5 weeks and repeatedly imaged at days 24, 35, 49, 63 and 77 after the start of CPZ. Imaging included multiparametric mapping (MPM), diffusion tensor imaging (DTI), tensor-based morphometry (TBM), and single-voxel MRS in the corpus callosum. Histology (MBP, silver, GFAP, Iba1) was performed at selected timepoints for validation. An additional group of 18 CPZ-lesioned mice were imaged ex vivo using a different higher resolution MRI protocol and compared against 19 non-CPZ controls. MPM-derived MTsat{delta} and R1 reductions indicated robust demyelination in the corpus callosum and deep cerebellar nuclei by day 24, expanding to cortex and hippocampus by day 35. Partial recovery was observed by day 77 but changes persisted, consistent with histological evidence. TBM revealed dynamic volumetric alterations, including hippocampal and cerebellar expansion alongside cortical and subcortical shrinkage, persisting beyond CPZ cessation. DTI demonstrated early (days 24-35) decreases in FA and MD, followed by complex trajectories consistent with microstructural disruption and partial repair. MRS detected early increases in GABA, glutamine, taurine, and glutathione, with corresponding decreases in NAA, while inositol showed a biphasic decrease-increase profile, likely reflecting acute astrocytic dysfunction followed by gliosis - neuroinflammatory processes that were corroborated by immunohistochemistry. Together, these results demonstrate that multimodal MRI/MRS sensitively captures widespread, dynamic, and only partially reversible pathology in CPZ-treated mice. Longitudinal imaging provides a non-invasive, translational approach to characterising demyelination, gliosis, and remyelination, offering a powerful alternative to histology for preclinical studies and longitudinal therapeutic screening.

neuroscience↗

bioRxiv2025

Complement receptor C3ar1 deficiency does not alter brain structure or functional connectivity across early life development

Genetic deletion of the complement C3a anaphylatoxin chemotactic receptor (C3ar1), a key component of the innate immune response, is reported to induce behavioural phenotypes consistent with psychiatric symptomatology in mice, but when and where C3ar1 is needed in the brain is unresolved. These questions are significant because, as a G-protein-coupled receptor, human C3AR1 serves as a potential therapeutic target for disorders associated with complement dysregulation, such as schizophrenia. To provide a brain-wide (where) assessment of developmental C3ar1 activity, we used longitudinal (when) tensor-based morphometry, diffusion-weighted magnetic resonance imaging (MRI) and blood oxygen-level dependent functional MRI in male and female C3ar1-deficient mice and wild-type littermates, with behavioural assessment in adulthood. Unexpectedly, we did not find a robust C3ar1-dependent phenotype in any of these measures. Therefore, our study does not support neurodevelopmental hypotheses for C3ar1, which is encouraging for therapeutic strategies targeting this receptor since interventions are unlikely to disrupt brain development.

neuroscience↗

bioRxiv2024

Quality assessment and control of unprocessed anatomical, functional, and diffusion MRI of the human brain using MRIQC

Quality control of MRI data prior to preprocessing is fundamental, as substandard data are known to increase variability spuriously. Currently, no automated or manual method reliably identifies subpar images, given pre-specified exclusion criteria. In this work, we propose a protocol describing how to carry out the visual assessment of T1-weighted, T2-weighted, functional, and diffusion MRI scans of the human brain with the visual reports generated by MRIQC. The protocol describes how to execute the software on all the images of the input dataset using typical research settings (i.e., a high-performance computing cluster). We then describe how to screen the visual reports generated with MRIQC to identify artifacts and potential quality issues and annotate the latter with the "rating widget" - a utility that enables rapid annotation and minimizes bookkeeping errors. Integrating proper quality control checks on the unprocessed data is fundamental to producing reliable statistical results and crucial to identifying faults in the scanning settings, preempting the acquisition of large datasets with persistent artifacts that should have been addressed as they emerged. RELATED LINKSO_ST_ABSKey reference(s) using this protocolC_ST_ABSEsteban, O. et al. (2017), PLoS ONE 12(9): e0184661. [10.1371/journal.pone.0184661] Esteban, O. et al. (2019), Sci Data 6, 30. [10.1038/s41597-019-0035-4] Esteban, O. et al. (2020), Nat Prot 15, 2186-2202. [10.1038/s41596-020-0327-3] Provins, C. et al. (2023), Front. Neuroinform. 1, 2813-1193. [10.3389/fnimg.2022.1073734] Bissett P. et al. (2024) Sci Data 11: 809. [10.1038/s41597-024-03636-y] Key data used in this protocolAmsterdam Open MRI Collection: Population Imaging of Psychology1 (AOMIC-PIOP1; ds002785 [https://openneuro.org/datasets/ds002785]).

neuroscience↗

bioRxiv2024

Activation mapping in multi-center rat sensory-evoked functional MRI datasets using a unified pipeline.

Functional Magnetic Resonance Imaging (fMRI) in rodents is pivotal for understanding the mechanisms underlying Blood Oxygen Level-Dependent (BOLD) signals and phenotyping animal models of disorders, amongst other applications. Despite its growing use, comparing rodent fMRI results across different research sites remains challenging due to variations in experimental protocols. Here, we aggregated and analyzed 22 sensory-evoked rat fMRI datasets from 12 imaging centers, totaling scans from 220 rats, to assess the consistency of results across diverse protocols. We applied a standardized preprocessing pipeline and evaluated the impact of different hemodynamic response function models on group and individual level activity patterns. Our analysis revealed inter-dataset variability attributed to differences in experimental design, anesthesia protocols, and imaging parameters. We identified robust activation clusters in all (22/22) datasets. The comparison between stock human models implemented in software and rat-specific models showed significant variations in the resulting statistical maps. Our findings emphasize the necessity for standardized protocols and collaborative efforts to improve the reproducibility and reliability of rodent fMRI studies. We provide open access to all datasets and analysis code to foster transparency and further research in the field.

neuroscience↗

bioRxiv2023

EiDA: A lossless approach for the dynamic analysis of connectivity patterns in signals; application to resting state fMRI of a model of ageing

AO_SCPLOWBSTRACTC_SCPLOWDynamic Functional Connectivity (dFC) is the study of the dynamical patterns emerging from brain function. We introduce EiDA (Eigenvector Dynamic Analysis), a method that losslessly reduces the dimension of the instantaneous connectivity patterns of a time series to characterise dynamic Functional Connectivity (dFC). We apply EiDA to investigate the signatures of ageing on brain network dynamics in a longitudinal dataset of resting-state fMRI in ageing rats. Previous dFC approaches have relied on the concept of the instantaneous phase of signals, computing the instantaneous phase-locking matrix (iPL) and its eigenvector decomposition. In this work, we fully characterise the eigenstructure of the iPL analytically, which provides a 1000 fold speed up in dFC computations. The analytical characterization of the iPL matrix allows us to introduce two methods for its dynamic analysis. 1) Discrete EiDA identifies a discrete set of phase locking modes using k-means clustering on the decomposed iPL matrices. 2) Continuous EiDA provides a 2-dimensional "position" and "speed" embedding of the matrix; here, dFC is conceived as a continuous exploration of this 2-D space rather than assuming the existence of discrete brain states. We apply EiDA to a cohort of 48 rats that underwent functional magnetic resonance imaging (fMRI) at four stages during the course of their lifetime. Using Continuous and Discrete EiDA we found that brain phase-locking patterns become less intense and less structured with ageing. Using information theory and metastability measures derived from the properties of the iPL matrix, we see that ageing reduces the available functional repertoire postulated to be responsible for flexible cognitive functions and overt behaviours, and reduces the area explored in the embedding space.

neuroscience↗

bioRxiv2022

The effects of acute Methylene Blue administration on cerebral blood flow and metabolism in humans and rats

Methylene Blue (MB) is a brain-penetrating drug with putative neuroprotective, antioxidant and metabolic enhancing effects. In vitro studies suggest that MB enhances mitochondrial complexes activity. However, no study has directly assessed the haemodynamic and metabolic effects of MB in the human brain. We used in vivo neuroimaging to measure the effect of MB on cerebral blood flow (CBF) and brain metabolism in humans and in rats. Two doses of MB (0.5 and 1 mg/kg in humans; 2 and 4 mg/kg in rats; iv) induced reductions in global cerebral blood flow (CBF) in humans (F(1.74, 12.17)5.82, p=0.02) and rats (F(1,5)26.04, p=0.0038). Human cerebral metabolic rate of oxygen (CMRO2) was also significantly reduced (F(1.26, 8.84)8.01, p=0.016), as was the rat cerebral metabolic rate of glucose (CMRglu) (t=2.6(16) p=0.018). This was contrary to our hypothesis that MB will increase CBF and energy metrics. Nevertheless, our results were reproducible across species and dose dependent. One possible explanation is that the concentrations used, although clinically relevant, reflect MBs hormetic effects, i.e., higher concentrations produce inhibitory rather than augmentation effects on metabolism. Additionally, here we used healthy volunteers and healthy rats with normal cerebral metabolism where MBs ability to enhance cerebral metabolism might be limited.

neuroscience↗

bioRxiv2021

MRI-derived brain age as a biomarker of ageing in rats: validation using a healthy lifestyle intervention

MRI data can be used as input to machine learning models to accurately predict brain age in healthy human subjects. A large difference between predicted and chronological brain age (the so-called BrainAGE score) has been associated with disease and neurodegeneration, indicating the potential utility of neuroimaging-based ageing biomarkers. So far, most brain age prediction studies have been carried out on humans. However, it is important for such a biomarker to be validated on laboratory animals too, in order to better account for specific environmental or genetic factors within a more controlled laboratory framework. In this work, we developed a new algorithm for rat brain age prediction based on the combination of Gaussian process regression and a logistic regression classifier. The algorithm was trained on a cohort of 31 normal rats. High prediction accuracy was achieved using leave-one-out cross-validation (mean absolute error = 4.87 weeks, correlation between predicted and chronological age r = 0.92), supporting the validity and potential of the method. Furthermore, the trained model was tested on two independent groups of 24 rats each: a new normal control group and a "healthy lifestyle" group that underwent long-term environmental enrichment and dietary restriction (EEDR) between 3 and 17 months of age. After fitting a linear mixed-effects model, the BrainAGE values were found to increase more slowly with chronological age in the EEDR group than in the controls (slope = 0.52 vs. 0.61; p = 0.015 for the interaction term). When survival analysis was performed with a Cox regression model, the BrainAGE score at 5 months of age had a significant prediction power (p = 0.03). Our results demonstrate that BrainAGE, as computed by the proposed approach, is significantly modulated by EEDR intervention, hence it is a sensitive marker of biological ageing. These findings also support the potential of lifestyle-related prevention approaches to slow down the brain ageing process. Moreover, the results of the survival analysis further demonstrate that BrainAGE is indeed a predictor of ageing outcome.

neuroscience↗

bioRxiv2021

TemplateFlow: a community archive of imaging templates and atlases for improved consistency in neuroimaging

Reference anatomies of the brain and corresponding atlases play a central role in experimental neuroimaging workflows and are the foundation for reporting standardized results. The choice of such references --i.e., templates-- and atlases is one relevant source of methodological variability across studies, which has recently been brought to attention as an important challenge to reproducibility in neuroscience. TemplateFlow is a publicly available framework for human and nonhuman brain models. The framework combines an open database with software for access, management, and vetting, allowing scientists to distribute their resources under FAIR --findable, accessible, interoperable, reusable-- principles. TemplateFlow supports a multifaceted insight into brains across species, and enables multiverse analyses testing whether results generalize across standard references, scales, and in the long term, species, thereby contributing to increasing the reliability of neuroimaging results.

neuroscience↗