Biology subjects

Chen, J. J.

Publications and source records attributed to Chen, J. J..

At least 37 records · Page 2Linked to original sources

bioRxiv2025

Modulating cerebrospinal fluid dynamics using pulsed photobiomodulation: feasibility, parameter and skin-colour dependence

The use of photobiomodulation (PBM) to enhance brain health, specifically glymphatic drainage and thus neurotoxic waste clearance, may make it a promising therapeutic tool against neurodegenerative diseases such as Alzheimers disease. This study investigates whether PBM can modulate cerebrospinal fluid (CSF) flow in 45 healthy young adults. We conducted forehead transcranial PBM (tPBM) and intranasal PBM (iPBM) at the nostril level, and measured CSF dynamics using blood-oxygenation level-dependent (BOLD) functional MRI (fMRI). Our data demonstrates 4 min of PBM-induced increases in CSF flow. Our data shows that (1) even a short PBM of 4 min can induce a change in CSF dynamics, in the form of an immediate increase in intracranial CSF volume and a reduction in CSF inflow; (2) skin melanin had a significant effect on the CSF response in tPBM, with lighter skin associated with higher responses; (3) both iPBM and tPBM displayed a dose-dependent effect on CSF dynamics in terms of a irradiance-wavelength interaction; (4) intranasal PBM (iPBM) can be used to produce a significant change in CSF dynamics that is equivalent to forehead transcranial PBM (tPBM) with a small fraction of the irradiance. The most likely explanation for the observed fMRI signal changes in CSF regions of interest for both tPBM and iPBM is an increased CSF outflow pressure due to PBM-induced vasodilation that transiently increases intracranial CSF volume and reduces net CSF inflow. This study establishes that PBM can modulate CSF flow in the healthy human brain in real time. This study also suggests that iPBM may be more efficient in CSF modulation due to the proximity to the olfactory system and the lack of melanin dependence. The influence of melanin on tPBM, the feasibility of iPBM and the dose dependence of both will require further investigation in healthy and patient populations.

physiology↗

bioRxiv2025

The Link to Oxidative Metabolism Varies across rs-fMRI Metrics: A Whole-Brain Assessment Using Macrovascular Correction

One of the major obstacles to the clinical application of resting-state functional magnetic resonance imaging (rs-fMRI) is the complex nature of its measurements, which limits interpretability. An approach to enhance the interpretability of the rs-fMRI metrics is to link them to more fundamental brain physiology, especially cerebral metabolism. Previous studies have established associations between glucose metabolism (CMRglu) and rs-fMRI measurements. In spite of this, oxidative metabolism (CMRO2) is more closely related to cerebral blood flow (CBF) and thus the BOLD signal, and its relationship with CMRglu is complex. Additionally, most currently published rs-fMRI metrics are uncorrected for macrovascular contribution, which may obscure the neuronal contributions. In this study, we measured resting CMRO2 (along with the oxygen extraction fraction, OEF and cerebral blood flow, CBF) using gas-free calibrated fMRI. We used linear mixed-effects (LME) models to examine associations between CMRO2 and various rs-fMRI metrics before and after macrovascular correction. We found that: 1) significant associations exist between CMRO2 and multiple rs-fMRI metrics, with the strongest association found for the global functional density (gFCD) and the weakest for seed-based functional connectivity (FC); 2) associations with rs-fMRI metrics also varied for OEF and CBF; 3) significant sex differences were observed in the above associations; 4) the use of macrovascular correction substantially strengthened the goodness fit of all LME models examined. This latter improvement further validates the use of macrovascular correction in rs-fMRI. These results provide a framework for linking rs-fMRI metrics to fundamental brain physiology, thus improving interpretability of rs-fMRI measurements. This is the first study to formally link whole-brain MRI-based baseline CMRO2 and rs-fMRI metrics, and helps to push the envelope for rs-fMRI in future clinical applications.

neuroscience↗

bioRxiv2024

Sex-specific effects of intensity and dose of physical activity on BOLD-fMRI cerebrovascular reactivity and cerebral pulsatility

Cerebrovascular reactivity (CVR) and cerebral pulsatility (CP) are important indicators of cerebrovascular health and have been shown to be associated with physical activity (PA). Sex differences have been shown to influence the impact of PA on cerebrovascular health. However, the sex-specific effects of PA on CP and CVR, particularly in relation to intensity and dosage of PA, remains unknown. Thus, this cross-sectional study aimed to evaluate the sex-specific effects of different intensities and doses of PA on CVR and CP. The Human Connectome - Aging dataset was used, including 626 participants (350 females, 276 males) aged 36-85 (mean age: 58.8 {+/-} 14.1 years). Females were stratified into premenopausal and postmenopausal groups to assess the potential influence of menopausal status. Novel tools based solely on resting state fMRI data were used to estimate both CVR and CP. The International Physical Activity Questionnaire was used to quantify weekly self-reported PA as metabolic equivalent of task. Results indicated that both sexes and menopausal subgroups revealed negative linear relationships between relative CVR and PA. Furthermore, females presented a unique non-linear relationship between relative CVR and total PA in the cerebral cortex. In females, there were also relationships with total and walking PA in occipital and cingulate regions. In males, we observed relationships between total or vigorous PA and CVR in parietal and cingulate regions. Sex-specific effects were also observed with CP, whereby females benefited across a greater number of regions and intensities than males, especially in the postmenopause group. Overall, males and females appear to benefit from different amounts and intensities of PA, with menopause status significantly influencing the effect of PA on cerebrovascular outcomes, underscoring the need for sex-specific recommendations in promoting cerebrovascular health.

neuroscience↗

bioRxiv2024

The influence of basal CO2 on neurofluid dynamics measured using resting-state BOLD fMRI

An understanding of neurofluid dynamics has been gaining importance, in part given the link between neurofluid dynamics and glymphatic flow. Recently, CSF pulsations have been attributed to widespread changes in cerebral blood volume (CBV) driven by sleep-state slow-wave electrocortical activity (Fultz et al., 2019), by localized neuronal activity (Williams et al., 2023), by respiration-related autonomic tone (Picchioni et al., 2022) and by vigilance (Z. Yang et al., 2024). It was further suggested that the slow-wave induced CSF pulsations are in fact driven by autonomic (ANS) regulation (Picchioni et al., 2022), and that CSF dynamics are ultimately modulated by ANS mechanisms instead of by sleep per se. To further understand the role of this ANS regulation of vascular tone independently of sleep, and given the established influence of carbon dioxide (CO2) on both ANS tone and vascular tone, we hypothesized that a modulation of basal CO2, producing altered global vascular tone and respiration, may highlight the role of ANS regulation in driving CSF flow, and more broadly, neurofluid flow. In this work, we report on observations of neurofluid dynamics at awake normocapnia as well as mild hyper- and hypocapnia steady states. We use the resting-state BOLD fMRI time courses in neurofluid regions (i.e. blood vessels, CSF compartments) as a surrogate of neurofluid dynamics. We found that 1) the manner biomechanical does not drive the variations in neurfluid dynamics across capnias; 2) besides respiration, cardiac pulsation also independently drives neurofluid flow as an indication of the ANS pathway of control; 3) changed CO2 alters neurofluid dynamics primarily through frequency rather than amplitude of heart-rate and respiratory-volume variability. These findings suggest that hyper- and hypocapnia both represent a disruption of homeostasis that engages ANS regulation, as reflected by the deviations in CRF and RRF from normocapnia. Our work demonstrates in awake humans previously reported ANS regulation observed during sleep. As basal CO2 can modulate this ANS regulation, it represents a new avenue for modulating neurofluid dynamics independently of sleep, attention or neuronal activation. More broadly, individuals with different basal capnic states may manifest differences in CSF dynamics, giving rise to a novel paradigm for modulating neurofluid flow in awake humans.

physiology↗

bioRxiv2024

Simulation-based dosimetry of transcranial and intranasal photobiomodulation of the human brain: the roles of wavelength, power density and skin colour

Photobiomodulation (PBM) is a novel technique that is actively studied for neuromodulation. However, despite the many in vivo studies, the stimulation protocols for PBM vary amongst studies, and the current understanding of neuromodulation via PBM is limited in terms of the extent of light penetration into the brain and its dosage dependence. Moreover, as near-infrared light can be absorbed by melanin in the skin, skin tone is a highly relevant but under-studied variable of interest. In this study, to address these gaps, we use Monte Carlo simulations (with MCX) of a single laser source for transcranial (tPBM) and intranasal (iPBM, nostril position) irradiated on a healthy human brain model. We investigate wavelengths of 670, 810 and 1064 nm in combination with light ("Caucasian"), medium ("Asian") and dark ("African") skin tones. Our simulations show that a maximum of 15% of the incidental energy for tPBM and 1% for iPBM reaches the cortex from the light source at the skin level. The rostral dorsal prefrontal cortex in tPBM and the ventromedial prefrontal cortex for iPBM accumulates the highest highest light energy, respectively for both wavelengths. Specifically, the 810 nm wavelength for tPBM and 1064 nm wavelength for iPBM produced the highest energy accumulation. Optical power density was found to be linearly correlated with energy. Moreover, we show that "Caucasian" skin allows the accumulation of higher light energy than other two skin colours. This study is the first to account for skin colour as a PBM dosing consideration, and provides evidence for hypothesis generation in in vivo studies of PBM.

biophysics↗

bioRxiv2024

Predicting the macrovascular contribution to resting-state fMRI functional connectivity at 3 Tesla: A model-informed approach

Macrovascular biases have been a long-standing challenge for fMRI, limiting its ability to detect spatially specific neural activity. Recent experimental studies, including our own (Huck et al., 2023; Zhong et al., 2023), found substantial resting-state macrovascular BOLD fMRI contributions from large veins and arteries, extending into the perivascular tissue at 3 T and 7 T. The objective of this study is to demonstrate the feasibility of predicting, using a biophysical model, the experimental resting-state BOLD fluctuation amplitude (RSFA) and associated functional connectivity (FC) values at 3 Tesla. We investigated the feasibility of both 2D and 3D infinite-cylinder models as well as macrovascular anatomical networks (mVANs) derived from angiograms. Our results demonstrate that: 1) with the availability of mVANs, it is feasible to model macrovascular BOLD FC using both the mVAN-based model and 3D infinite-cylinder models, though the former performed better; 2) biophysical modelling can accurately predict the BOLD pairwise correlation near to large veins (with R2 ranging from 0.53 to 0.93 across different subjects), but not near to large arteries; 3) compared with FC, biophysical modelling provided less accurate predictions for RSFA; 4) modelling of perivascular BOLD connectivity was feasible at close distances from veins (with R2 ranging from 0.08 to 0.57), but not arteries, with performance deteriorating with increasing distance. While our current study demonstrates the feasibility of simulating macrovascular BOLD in the resting state, our methodology may also apply to understanding task-based BOLD. Furthermore, these results suggest the possibility of correcting for macrovascular bias in resting-state fMRI and other types of fMRI using biophysical modelling based on vascular anatomy.

biophysics↗

bioRxiv2024

BOLDsωimsuite: A new software suite for forward modeling of the BOLD fMRI signal

In trying to elucidate the mechanisms of the blood-oxygenation level-dependent (BOLD) functional MRI (fMRI) techniques and to expand on the potential of the transverse relaxation time (T2*) in quantitative MRI, many methods for the forward modelling of the BOLD effect have been created and analyzed. Simulations of this nature can be difficult to implement without prior experience, and differences made by methodological choices can be unclear, which provides a significant barrier of entry into the field. In this paper, we present BOLDswimsuite, a toolbox for forward modeling of the BOLD effect, which collects many of the principal methods used in the literature into a single coherent package. Implemented as a Python package, simulations are built-in scripts by combining various simulation components, while providing flexibility in methodological choices. The goal of this toolbox is to provide an open-source, reproducible software suite that is adaptable for simulations in different MRI applications, and to which additional features can be added by the user with relative ease. This paper first provides an overview of the methods available in the package and how these methods can be constructed from the toolboxs modular code components. Then, a brief theoretical explanation of each simulation component is given, supported by the relevant contributors. Next, sample simulations and analyses that can be created using the package are presented to display its features. Finally, recommendations regarding computational requirements are included to help users choose the best simulation methods to fit their needs. This package has many use cases and significantly reduces methodological barriers to forward modeling. It can also be a good learning tool for MR physics as well as a powerful tool to promote reproducible science.

biophysics↗

bioRxiv2024

Developmental order, fibre caliber, and vascularization predict tract-wise declines: Testing retrogenesis and physiological predictions in white matter aging

To understand the consistently observed spatial distribution of white-matter (WM) aging, developmentally driven theories termed "retrogenesis" have gained traction, positing that the order of WM tract development predicts the order of declines. Regions that develop first are expected to deteriorate the last, i.e. "last-in-first-out". Alternatively, regions which develop most rapidly may also decline most rapidly in aging, or "gains-predict-loss". The validity of such theories remains uncertain, in part due to lack of clarity on the definition of developmental order. Importantly, our recent findings suggest that WM aging is also associated with physiological parameters such as perfusion, which may be linked to fibre metabolic need, which in turn varies with fibre size. Here we address the extent to which the degree of WM aging is determined by development trajectory (i.e. retrogenesis) and/or by physiological state. We obtained microstructural and perfusion measures using data from the Human Connectome Project in Aging (HCP-A), complemented by a meta-analysis involving maps of fibre calibre and macrovascular volume. Our results suggest that (1) while tracts that appear last or finish myelinating first in development display the slowest aging, the pattern of aging is not fully explained by retrogenesis; in fact, time courses of tract emergence and myelination give rise to opposite associations with WM decline; (2) tracts that appear earlier also have higher mean axon calibre and are also associated with lower degrees of WM microstructural aging; (3) such tracts also tend to exhibit relatively sustained CBF with a higher rate of lengthening of the arterial transit times (ATT), suggestive of collateral blood supply. These findings were also sex dependent in a tract-specific manner. Future work will investigate whether these are ultimately influenced by each tracts metabolic demand and the role of macrovascular collateral flow.

neuroscience↗

bioRxiv2023

The Rtf1/Prf1-dependent histone modification axis and Rpb1 C-terminal domain phosphorylation counteract multi-drug resistance in fission yeast

AbstractRNA polymerase II (RNAPII) transcription elongation directs an intricate pattern of histone modifications. Formation of this pattern involves a highly conserved regulatory axis, key components of which are the elongation factor Rtf1, monoubiquitylation of histone H2B (H2Bub1), and methylation of histone H3 on lysine 4 (H3K4me). Direct contact between Rtf1 and the ubiquitylation complex Rad6-Bre1 stimulates H2Bub1, which in turn promotes H3K4me by stimulating the activity of the Set1C/COMPASS methyltransferase complex. Previous studies have defined the molecular basis for these regulatory relationships, but it remains unclear how they regulate chromatin and transcription in vivo. We found that mutations affecting multiple components of the Rtf1-H2Bub1-H3K4me axis in the model eukaryote Schizosaccharomyces pombe (fission yeast) caused resistance to the ribonucleotide reductase inhibitor hydroxyurea (HU). Resistance correlated with a reduced effect of HU on dNTP pools, bypass of the S-phase checkpoint in the presence of HU, and blunting of the transcriptional response to HU treatment. Mutations in the C-terminal repeat domain (CTD) of the RNAPII large subunit Rpb1 led to a similar spectrum of phenotypes. Moreover, all the HU resistant mutants we identified also exhibited resistance to several azole class antifungal agents. Our results suggest a novel, shared gene regulatory function of the Rtf1-H2Bub1-H3K4me axis and the Rpb1 CTD in controlling fungal drug tolerance.

molecular biology↗

bioRxiv2023

The Dmc1 recombinase physically interacts with and promotes the meiotic crossoverfunctions of the Mlh1-Mlh3 endonuclease

The accurate segregation of homologous chromosomes during the Meiosis I reductional division in most sexually reproducing eukaryotes requires crossing over between homologs. In bakers yeast approximately 80 percent of meiotic crossovers result from Mlh1-Mlh3 and Exo1 acting to resolve double-Holliday junction (dHJ) intermediates in a biased manner. Little is known about how Mlh1-Mlh3 is recruited to recombination intermediates and whether it interacts with other meiotic factors prior to its role in crossover resolution. We performed a haploinsufficiency screen in bakers yeast to identify novel genetic interactors with Mlh1-Mlh3 using sensitized mlh3 alleles that disrupt the stability of the Mlh1-Mlh3 complex and confer defects in mismatch repair but do not disrupt meiotic crossing over. We identified several genetic interactions between MLH3 and DMC1, the recombinase responsible for recombination between homologous chromosomes during meiosis. We then showed that Mlh3 physically interacts with Dmc1 in vitro and at times in meiotic prophase when Dmc1 acts as a recombinase. Interestingly, restricting MLH3 expression to roughly the time of crossover resolution resulted in a mlh3 null-like phenotype for crossing over. Our data are consistent with a model in which Dmc1 nucleates a polymer of Mlh1-Mlh3 to promote crossing over.

genetics↗

bioRxiv2023

Discovery of CMX990: A Potent SARS-CoV-2 3CL Protease Inhibitor Bearing a Novel Covalent Warhead

There remains a need to develop novel SARS-CoV-2 therapeutic options that improve upon existing therapies by increased robustness of response, fewer safety liabilities, and global-ready accessibility. Functionally critical viral main protease (Mpro, 3CLpro) of SARS-CoV-2 is an attractive target due to its homology within the coronaviral family, and lack thereof towards human proteases. In this disclosure, we outline the advent of a novel SARS-CoV-2 3CLpro inhibitor, CMX990, bearing an unprecedented trifluoromethoxymethyl ketone warhead. Compared with the marketed drug nirmatrelvir (combination with ritonavir = PaxlovidTM), CMX990 has distinctly differentiated potency ([~]5x more potent in primary cells) and human in vitro clearance (>4x better microsomal clearance and >10x better hepatocyte clearance), with good in vitro-in vivo correlation. Based on its compelling preclinical profile and projected once or twice a day dosing supporting unboosted oral therapy in humans, CMX990 advanced to a Phase 1 clinical trial as an oral drug candidate for SARS-CoV-2.

microbiology↗

bioRxiv2023

Assessment of the macrovascular contribution to resting-state fMRI functional connectivity at 3 Tesla

In resting-state functional magnetic resonance imaging (rs-fMRI) functional connectivity (FC) mapping, temporal correlation are widely assumed to reflect synchronized neural-related activaty. Although a large number of studies have demonstrated the potential vascular effects on FC, little research has been conducted on FC resulting from macrovascular signal fluctuations. Previously, Tong et al. found (Tong et al., 2019b) a robust anti-correlation between the fMRI signals in the internal carotid artery and the internal jugular vein (and the sagittal sinus). The present study extends the previous study to include all detectable major veins and arteries in the brain in a systematic analysis of the macrovascular contribution to the functional connectivity of the whole-GM. This study demonstrates that: 1) The macrovasculature consistently exhibited strong correlational connectivity among itself, with the sign of the correlations varying between arterial and venous connectivity; 2) GM connectivity was found to have a strong macrovascular contribution, stronger from veins than arteries; 3) functional connectivity originating from the macrovasculature displayed disproportionately high spatial variability compared to across all GM voxels; 4) macrovascular contributions to connectivity were still evident well beyond the confines of the macrovascular space. These findings highlight the extensive contribution to rs-fMRI BOLD and FC predominantly by large veins, but also by large arteries. These findings pave the way for future studies aimed at more comprehensively modeling and thereby removing these macrovascular contributions.

biophysics↗

bioRxiv2023

In search of a unifying theory of white matter aging: tract perfusion-microstructure relationships

One of the most promising interventional targets for brain health is cerebral perfusion, but its link to white matter (WM) aging remains unclear. Motivated by existing literature demonstrating links between declining cortical perfusion and the development of WM hyperintensities, we posit that regional WM hypoperfusion precedes deteriorating WM integrity. Using the Human Connectome Project Aging (HCP-A) data set, we examine tract-wise associations between WM microstructural integrity (i.e. fractional anisotropy, mean diffusivity, axial diffusivity, and radial diffusivity) and perfusion (i.e. cerebral blood flow and arterial transit time) in ten major bilateral WM tracts. Results show that tracts displaying the largest CBF decline in aging do not necessarily display the largest ATT decline, and vice versa. Moreover, significant WM perfusion-microstructure canonical correlations were found in all tracts, but the drivers of these correlations vary by both tract and sex, with female subjects demonstrating more tracts with large microstructural variations contributing to the correlations. Additionally, arterial transit time appears to be the earliest indicator of WM declines, preceding age-related microstructural differences and CBF in several tracts. This study contributes compelling evidence to the vascular hypothesis of WM degeneration, and highlights the utility of blood-flow timing as an early marker of aging.

neuroscience↗

bioRxiv2023

Comparing data-driven physiological denoising approaches for resting-state fMRI: Implications for the study of aging

Physiological nuisance contributions by cardiac and respiratory signals has a significant impact on resting-state fMRI data quality. As these physiological signals are often not recorded, data-driven denoising methods are commonly used to estimate and remove physiological noise from fMRI data. To investigate the efficacy of these denoising methods, one of the first steps is to accurately capture the cardiac and respiratory signals, which requires acquiring fMRI data with high temporal resolution. In this study, we used such high-temporal resolution fMRI data to evaluate the effectiveness of several data-driven denoising methods, including global-signal regression (GSR), white matter and cerebrospinal fluid regression (WM-CSF), anatomical (aCompCor) and temporal CompCor (tCompCor), ICA-AROMA. Our analysis focused on each methods ability to remove cardiac and respiratory signal power, as well as its ability to preserve low-frequency signals and age-related functional connectivity (fcMRI) differences. Our findings revealed that ICA-AROMA and GSR consistently remove more heart-beat and respiratory frequencies, but also the most low-frequency signals. Our results confirm that the ICA-AROMA and GSR removed the most physiological noise at the expense of meaningful age-related fcMRI differences. On the other hand, aCompCor and tCompCor seem to provide a good balance between removing physiological signals and preserving fcMRI information. Lastly, methods differ in performance on young- and older-adult data sets. While this study cautions direct comparisons of fcMRI results based on different denoising methods in the study of aging, it also informs the choice of denoising method for broader fcMRI applications.

neuroscience↗

bioRxiv2023

In search of a unifying theory of white matter aging: tract morphometry-microstructure relationships

While tract-wise differences in volume and microstructure are common targets of investigation in age-related changes in the white matter (WM), there has been relatively little exploration into other attributes of tract morphometry or its relation to microstructure in vivo, and limited understanding on how they jointly inform the interpretation of the WM aging trajectory. This study examines ten WM tracts for tract-wise differences in morphometry (i.e. volume, length, and volume-to-length ratio) and microstructural integrity (i.e. fractional anisotropy, mean diffusivity, axial diffusivity, and radial diffusivity) using diffusion MRI data from the Human Connectome Project in Aging (HCP-A) with the goal of laying the foundation for a unified model of age-related WM microstructure-morphometry trajectories with a special focus on sex differences. Results indicated widely heterogeneous patterns of decline and morphometry-microstructural associations across tracts. Multi-parametric signatures of decline suggest stages or mechanisms of degeneration that differ between sexes. This work highlights the value of integrating microstructural and morphometric measures of WM health instead of observing them separately, suggesting multiple modes of WM degeneration.

neuroscience↗

bioRxiv2022

Histone H1.0 Couples Cellular Mechanical Behaviors to Chromatin Structure

Tuning of genome structure and function is accomplished by chromatin binding proteins, which determine the transcriptome and phenotype of the cell. We sought to investigate how communication between extracellular stress and chromatin structure may regulate cellular mechanical behaviors. We demonstrate that the linker histone H1.0, which compacts nucleosomes into higher order chromatin fibers, controls genome organization and cellular stress response. Histone H1.0 has privileged expression in fibroblasts across tissue types in mice and humans, and modulation of its expression is necessary and sufficient to mount a myofibroblast phenotype in these cells. Depletion of histone H1.0 prevents transforming growth factor beta (TGF-{beta})-induced fibroblast contraction, proliferation and migration in a histone H1 isoform-specific manner via inhibition of a transcriptome comprised of extracellular matrix, cytoskeletal and contractile genes. Histone H1.0 is associated with local regulation of gene expression via mechanisms involving chromatin fiber compaction and reprogramming of histone acetylation, rendering the cell stiffer in response to cytokine stimulation. Knockdown of histone H1.0 prevented locus-specific histone H3 lysine 27 acetylation by TGF-{beta} and decreased levels of both HDAC1 and the chromatin reader BRD4, thereby preventing transcription of a fibrotic gene program. Transient depletion of histone H1.0 in vivo decompacts chromatin and prevents fibrosis in cardiac muscle, thereby linking chromatin structure with fibroblast phenotype in response to extracellular stress. Our work identifies an unexpected role of linker histones to orchestrate cellular mechanical behaviors, directly coupling cellular force generation, nuclear organization and gene transcription. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=166 SRC="FIGDIR/small/518399v1_ufig1.gif" ALT="Figure 1"> View larger version (103K): org.highwire.dtl.DTLVardef@11a38e1org.highwire.dtl.DTLVardef@8c4ab4org.highwire.dtl.DTLVardef@7c822aorg.highwire.dtl.DTLVardef@45d02b_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗

bioRxiv2022

Sensitivity of diffusion-tensor and correlated diffusion imaging to white-matter microstructural abnormalities: application in COVID-19

There has been growing attention on the effect of COVID-19 on white-matter microstructure, especially among those that self-isolated after being infected. There is also immense scientific interest and potential clinical utility to evaluate the sensitivity of single-shell diffusion MRI methods for detecting such effects. In this work, the sensitivities of three single-shell-compatible diffusion MRI modeling methods are compared for detecting the effect of COVID-19, including diffusion-tensor imaging, diffusion-tensor decomposition of orthogonal moments and correlated diffusion imaging. Imaging was performed on self-isolated patients at baseline and 3-month follow-up, along with age- and sex-matched controls. We demonstrate through simulations and experimental data that correlated diffusion imaging is associated with far greater sensitivity, being the only one of the three single-shell methods to demonstrate COVID-19-related brain effects. Results suggest less restricted diffusion in the frontal lobe in COVID-19 patients, but also more restricted diffusion in the cerebellar white matter, in agreement with several existing studies highlighting the vulnerability of the cerebellum to COVID-19 infection. These results, taken together with the simulation results, suggest that a significant proportion of COVID-19 related white-matter microstructural pathology manifests as a change in water diffusivity. Interestingly, different b-values also confer different sensitivities to the effects. No significant difference was observed in patients at the 3-month follow-up, likely due to the limited size of the follow-up cohort. To summarize, correlated diffusion imaging is shown to be a sensitive single-shell diffusion analysis approach that allows us to uncover opposing patterns of diffusion changes in the frontal and cerebellar regions of COVID-19 patients, suggesting the two regions react differently to viral infection.

biophysics↗

bioRxiv2022

Is adiposity associated with white matter microstructural health and intelligence differently in men and women?

The role of vascular risk in age-related brain degeneration has long been the subject of intense study. As a sub-category of vascular risk, obesity has an increasingly recognized role in influencing brain health and health-care strategies, but its association with brain health remains under-studied. Notably, no prior study has addressed sex differences in the association between adiposity and white-matter microstructural integrity, an important early marker of brain degeneration, despite known sex differences in fat storage and usage. This study focuses on the associations between adiposity (abdominal fat ratio: AFR, and liver proton density fat fraction: PDFF) and brain microstructural health (measures of white-matter microstructure using diffusion-tensor imaging, DTI). We found that fluid intelligence and reaction time are indeed associated with body fat differently in men and women. We also found significant differences in the associations of AFR with DTI metrics between sexes. These sex differences are mirrored in the associations of SBP and age with DTI metrics. Moreover, these sex differences in the AFR and SBP associations with DTI metrics persist when controlling for age. Taken together, these findings suggest that there are inherent sex-driven differences in how brain health is associated with vascular risk factors such as obesity.

systems biology↗