Biology subjects

Wang, D. J.

Publications and source records attributed to Wang, D. J..

11 recordsLinked to original sources

bioRxiv2026

Distinct spatial organization of human hippocampal perfusion and microvascular pulsatility across age

Arterial pulsation can modulate neuronal activity through mechanosensitive pathways in mice, but whether vascular pulsatility is similarly related to neural organization in humans remains unclear. Here, using 7T MRI in 35 young and older adults, we mapped cerebral perfusion and microvascular volumetric pulsatility index (mvPI) across the unfolded hippocampus and integrated these measures with histological, electrophysiological, and transcriptomic reference maps. Perfusion and mvPI exhibited distinct spatial organization and age-related differences. In young adults, perfusion preferentially corresponded to parvalbumin-interneuron density and beta/gamma distribution, whereas mvPI was associated with theta-band distribution. A number of associations detected in young adults were not detected in the older adults maps. Spectral simulations showed qualitative similarity to heartbeat-related phase resetting as one possible explanation for the mvPI-theta relationship, while spatial transcriptomics revealed perivascular enrichment of PIEZO2, a candidate mediator of vascular mechanotransduction. Together, these findings establish perfusion and tissue-level pulsatility as distinct dimensions of human hippocampal vascular organization and provide a framework for investigating their relationships with neural dynamics across aging.

neuroscience↗

bioRxiv2025

Assessing molecular, cellular and transcriptomic bases of laminar perfusion and cytoarchitecture coupling in the human cortex

Understanding how cellular architecture organizes cortical function requires mesoscopic approaches that resolve structure-function coupling in vivo. Here we introduce cerebral blood flow (CBF) and cell-body staining intensity (CSI) similarity index (CCSI), a localized similarity index between the CBF estimates from ultra-high-field 7T arterial spin labeling images and CSI from the BigBrain histology images to serve as a quantitative marker of laminar perfusion-cytoarchitecture coupling. CCSI revealed a reproducible, region- specific alignment between laminar vascular and cellular profiles across the cortex. Going beyond CBF, CCSI selectively tracked mitochondrial respiratory capacity and colocalized with capillary endothelial and mature non-myelination oligodendrocyte populations forming neurovascular interfaces. Transcriptomic enrichment highlighted pathways related to vascular remodeling, oxidative metabolism, and lipid-myelin homeostasis, indicating that CCSI reflects integrated metabolic-structural specialization. At the systems level, CCSI strengthened structure-function gradient correspondence in transmodal cortices, such as the default mode network. Together, these findings establish CCSI as a physiologically grounded, non-invasive marker of perfusion-cytoarchitecture alignment, providing a cross-scale framework linking cortical microstructure, metabolism, and functional organization.

neuroscience↗

bioRxiv2025

Alteration of Water Exchange Rates Following Focused Ultrasound-Mediated BBB Opening in the Dorsal Striatum of Non-Human Primates: A Diffusion-Prepared pCASL Study

This study applied diffusion-prepared pseudo-continuous arterial spin labeling (DP-pCASL) to quantify cerebral blood flow (CBF), arterial transit time (ATT), and blood-brain barrier (BBB) water exchange rate (Kw) before and after focused ultrasound (FUS)-mediated blood-brain barrier opening (BBBO) in the dorsal striatum of four non-human primates. Six baseline and seven BBBO sessions were performed. DP-pCASL was acquired approximately 45 minutes after FUS sonication combined with intravenous microbubbles, and contrast-enhanced T1-weighted imaging was subsequently used to confirm the BBBO region. Whole-brain analyses revealed no significant changes in CBF or ATT following BBBO (permutation p > 0.05). Region-of-interest analysis within the sonicated caudate demonstrated a significant localized decrease in Kw, with median (IQR) values of 45.0 (40.6 - 55.6) min-1 at the BBBO site versus 61.6 (58.3 - 70.4) min-1 in the contralateral control region (p < 0.05), confirming spatially specific suppression of transendothelial water flux. In contrast, whole-brain Kw increased significantly following BBBO, with median (IQR) values of 49.8 (46.3 - 55.9) min-1 in non-BBBO sessions versus 59.4 (56.6 - 66.3) min-1 in BBBO sessions (p < 0.01), indicating a diffuse enhancement of water exchange across the brain. These findings establish DP-pCASL-derived Kw as a sensitive, non-contrast biomarker for both local and global BBB permeability changes induced by focused ultrasound, supporting its potential for longitudinal monitoring in preclinical and clinical neurotherapeutic applications.

neuroscience↗

bioRxiv2025

Lifespan Trajectories of the Brains Functional Complexity Characterized by Multiscale Sample Entropy

Resting state functional magnetic resonance imaging (rs-fMRI) is a widely used imaging modality that can capture spontaneous neural activity of the brain. The human brain is a complex system, and emerging evidence suggests that the complexity of neural activity may serve as an index of the brains capacity of information processing. In this study we used multiscale sample entropy (MSE) to analyze the complexity of rs-fMRI timeseries of 504 healthy subjects between the age of 6 to 85 years. We constructed the global and regional trajectories of brains functional complexity over the lifespan and analyzed its correlation with executive function. We observed a nonlinear trajectory of fMRI-complexity over the lifespan with a peak age occurring at 23 (95% CI 21.27, 26.38 years) years of age. Males reach the peak age of complexity at 26 years (95% CI 19.95, 33.14 years) whereas females at 23 (95% CI 20.16, 29.18 years). We found significant correlations between complexity and Number-Letter Switching of Trail Making Test in parietal and medial temporal lobes while Inhibition and Inhibition/Switching of Color Word Interference Test also revealed a significant negative correlation with rs-fMRI complexity in lateral and medial frontal cortex. These results help to understand behavior of fMRI-complexity with aging and reveals association with executive function of the brain. As a non-invasive biomarker, fMRI-complexity could provide novel approach to understand information processing capacity in the brain and deficits thereof in illness.

neuroscience↗

bioRxiv2024

Relationships between measures of neurovascular integrity and fluid transport in aging: a multi-modal neuroimaging study

Fluid transport in the neurovascular unit (NVU) is essential for maintaining brain health through nutrient delivery and waste clearance. NVU integrity and fluid regulation can be assessed through MRI measures, including water exchange rate through the NVU (BBB kw), enlarged perivascular spaces (ePVS), cerebral blood flow (CBF), free water (FW), and white matter hyperintensities (WMH). This study investigated relationships between these MRI measures using Bayesian mixed models, and their variation with chronological age or biological brain age (brainageR) using linear regression in 132 non-clinical older adults (mean age=67 years; 68% female). BBB kw positively associated with CBF ({beta}^=0.08, 95% credible interval (CI)=[0.02,0.15]). FW positively associated with both ePVS ({beta}^=0.44, CI=[0.30,0.63]) and WMH ({beta}^=0.13, CI=[0.04,0.21]). BBB kw, CBF and ePVS decreased with age, while FW and WMH increased (all p<.05). There were no associations with brain age (all p>.05). Relationships between FW, ePVS and WMH likely reflect interconnectivity of fluid regulation within different compartments, while the relationship between BBB kw and CBF indicates a link between NVU fluid flow and vessel function. While individual metrics of NVU integrity are associated with age, their inter-relationships appear stable, providing a baseline for future research in fluid transport and vascular health in neurodegenerative disease. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=190 SRC="FIGDIR/small/622194v1_ufig1.gif" ALT="Figure 1"> View larger version (58K): org.highwire.dtl.DTLVardef@df1273org.highwire.dtl.DTLVardef@1343e84org.highwire.dtl.DTLVardef@f475c2org.highwire.dtl.DTLVardef@15f32d1_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical Abstract:C_FLOATNO Neurovascular function and the fluid transport system. The brains fluid transport system comprises the neurovascular unit, interstitial fluid exchange in the parenchyma and venous outflow. a. The flow of water molecules from the vessel to the perivascular space through the blood-brain barrier, and subsequently into the brain (facilitated by aquaporin-4 (AQP4) channels) in quantified by BBB kw. b. Greater cerebral blood flow rate (CBF) is associated with greater BBB kw, possibly due to vessel pulsations increasing osmotic pressure. c. Enlarged perivascular spaces (ePVS) may indicate reduced fluid flow within the NVU and are associated with (d.) increased extracellular free water (FW) in the parenchyma, suggesting a link between fluid regulation within the vasculature and the surrounding brain tissue. Greater white matter hyperintensity (WMH) volume also occurs alongside increase FW, in line with WMH reflecting more severe fluid flow stagnation occurring in concert with neuroinflammation and/or neuronal demyelination. C_FIG

neuroscience↗

bioRxiv2024

Age-Related Decline in BBB Function is More Pronounced in Males than Females

The blood-brain barrier (BBB) plays a pivotal role in protecting the central nervous system (CNS), shielding it from potential harmful entities. A natural decline of BBB function with aging has been reported in both animal and human studies, which may contribute to cognitive decline and neurodegenerative disorders. Limited data also suggest that being female may be associated with protective effects on BBB function. Here we investigated age and sex-dependent trajectories of perfusion and BBB water exchange rate (kw) across the lifespan in 186 cognitively normal participants spanning the ages of 8 to 92 years old, using a non-invasive diffusion prepared pseudo-continuous arterial spin labeling (DP-pCASL) MRI technique. We found that the pattern of BBB kw decline with aging varies across brain regions. Moreover, results from our DP-pCASL technique revealed a remarkable decline in BBB kw beginning in the early 60s, which was more pronounced in males. In addition, we observed sex differences in parietal and temporal regions. Our findings provide in vivo results demonstrating sex differences in the decline of BBB function with aging, which may serve as a foundation for future investigations into perfusion and BBB function in neurodegenerative and other brain disorders. Significance statementThe blood-brain barrier (BBB) serves as a critical protection mechanism for the CNS. A natural decline of BBB function with aging has been reported in both animal and human studies, with possible differences in BBB function by sex. Using our MRI technique, DP-pCASL that measures water exchange rate (kw) without contrast in 186 participants from diverse race and age groups, we identified age and sex-specific patterns in BBB kw especially in parietal and temporal regions. We observed of a decline in kw beginning in the early 60s, especially in males. Our study unveils the dynamic spatiotemporal pattern of kw differences with age and sex, which serve as a foundation for understanding aberrations of BBB function in neurodegenerative and other brain disorders.

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bioRxiv2023

Vessel Density Mapping of Cerebral Small Vessels on 3D High Resolution Black Blood MRI

Cerebral small vessels are largely inaccessible to existing clinical in vivo imaging technologies. This study aims to present a novel analysis pipeline for vessel density mapping of cerebral small vessels from high-resolution 3D black-blood MRI at 3T. Twenty-eight subjects (10 under 35 years old, 18 over 60 years old) were imaged with the T1-weighted turbo spin-echo with variable flip angles (T1w TSE-VFA) sequence optimized for black-blood small vessel imaging with iso-0.5mm spatial resolution at 3T. Hessian-based vessel segmentation methods (Jerman, Frangi and Sato filter) were evaluated by vessel landmarks and manual annotation of lenticulostriate arteries (LSAs). Using optimized vessel segmentation, large vessel pruning and non-linear registration, a semiautomatic pipeline was proposed for quantification of small vessel density across brain regions and further for localized detection of small vessel changes across populations. Voxel-level statistics was performed to compare vessel density between two age groups. Additionally, local vessel density of aged subjects was correlated with their corresponding gross cognitive and executive function (EF) scores using Montreal Cognitive Assessment (MoCA) and EF composite scores compiled with Item Response Theory (IRT). Jerman filter showed better performance for vessel segmentation than Frangi and Sato filter which was employed in our pipeline. Cerebral small vessels on the order of a few hundred microns can be delineated using the proposed analysis pipeline on 3D black-blood MRI at 3T. The mean vessel density across brain regions was significantly higher in young subjects compared to aged subjects. In the aged subjects, localized vessel density was positively correlated with MoCA and IRT EF scores. The proposed pipeline is able to segment, quantify, and detect localized differences in vessel density of cerebral small vessels based on 3D high-resolution black-blood MRI. This framework may serve as a tool for localized detection of small vessel density changes in normal aging and cerebral small vessel disease.

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bioRxiv2022

FMRI complexity correlates with tau-PET in Late-Onset and Autosomal Dominant Alzheimer's Disease

Neurofibrillary tangle pathology detected with tau-PET correlates closely with neuronal injury and cognitive symptoms in Alzheimers disease (AD). Complexity of rs-fMRI time-series, measured by entropy values, have recently been reported to decrease with aging, APOE {varepsilon}4 genotype and cognitive decline in AD. Here we hypothesize that the complexity of BOLD signals provides an index for tau-related neuronal injury and cognitive decline in the AD process. Data were obtained from the Alzheimers Disease Neuroimaging Initiative phase 3 (ADNI3) and the Estudio de la Enfermedad de Alzheimer en Jalisciences (EEAJ) study, including cognitively normal elderly controls, persons with late onset AD (LOAD) and early onset autosomal dominant AD (ADAD) patients and their relatives. Our cohort consisted of a sample of 147 subjects from ADNI3 and 41 subjects from EEAJ with T1 structural, tau-PET (tracer: 18F-AV1451) and fMRI scans. Correlations between SUVR tau-PET and multi-scale entropy (MSE) were calculated voxelwise as well as for standard automated anatomical labeling (AAL) atlas regions while accounting for age, gender, and regional gray matter volume. Potential pathways relating MSE to cognitive function mediated through tau-PET were assessed by path analysis. We found significant negative correlations between low frequency MSE and tau-PET measures in medial temporal lobe, in both ADNI3 and EEAJ cohorts. Furthermore, low frequency MSE showed significant associations with the Clinical Dementia Rating (CDR) scale and the Mini-Mental State Status Exam (MMSE) scores in both ADNI3 and EEAJ cohorts, which were largely mediated through the tau-PET signal. Correlations of MSE with tau-PET in temporal lobes support our hypothesis that the complexity of rs-fMRI is associated with regional tau protein accumulation. Furthermore, the association of MSE with CDR and MMSE, mediated by tau-PET, in disease relevant areas suggests that a reduction in MSE is indicative of decreased information processing capacity and cognitive decline in AD processes.

neuroscience↗

bioRxiv2021

Laminar perfusion imaging with zoomed arterial spin labeling at 7 Tesla

Laminar fMRI based on BOLD and CBV contrast at ultrahigh magnetic fields has been applied for studying the dynamics of mesoscopic brain networks. However, the quantitative interpretations of BOLD/CBV fMRI results are confounded by different baseline physiology across cortical layers. Here we introduce a novel 3D zoomed pseudo-continuous arterial spin labeling technique at 7T that offers the unique capability for quantitative measurements of laminar cerebral blood flow (CBF) both at rest and during task activation with high spatial specificity and sensitivity. We found arterial transit time in superficial layers is [~]100 msec shorter than in middle/deep layers revealing the dynamics of labeled blood flowing from pial arteries to downstream microvasculature. Resting state CBF peaked in the middle layers which is highly consistent with microvascular density measured from human cortex specimens. Finger tapping induced a robust two-peak laminar profile of CBF increases in the superficial (somatosensory and premotor input) and deep (spinal output) layers of M1, while finger brushing task induced a weaker CBF increase in superficial layers (somatosensory input). We further demonstrated that top-down attention induced a predominant CBF increase in deep layers and a smaller CBF increase on top of the lower baseline CBF in superficial layers of V1 (feedback cortical input), while bottom-up stimulus driven activity peaked in the middle layers (feedforward thalamic input). These quantitative laminar profiles of perfusion activity suggest an important role of M1 superficial layers for the computation of finger movements, and that visual attention may amplify deep layer output to the subcortex. Significance StatementCBF or microvascular perfusion measured by arterial spin labeling (ASL) is a key parameter for in vivo assessment of neurovascular function. Compared to BOLD or VASO fMRI, ASL perfusion contrast offers the unique capability for quantitative CBF measurements both at baseline and during task activation, which is critical for quantitative estimation of metabolic activities tightly related to neuronal activation. We proposed a zoomed 3D ASL technique at 7T for laminar perfusion imaging with high spatial specificity and sensitivity. This technique is able to differentiate and quantify the input/output and feedforward/feedback activities of human motor and visual cortex, thereby providing an important tool for quantitative assessment of neurovascular function and metabolic activities of neural circuits across cortical layers.

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bioRxiv2020

Layer-dependent multiplicative effects of spatial attention on contrast responses in human early visual cortex

Attention mechanisms at different cortical layers of human visual cortex remain poorly understood. Using submillimeter-resolution fMRI at 7T, we investigated the effects of top-down spatial attention on the contrast responses across different cortical depths in human early visual cortex. Gradient echo (GE) T2* weighted BOLD signal showed an additive effect of attention on contrast responses across cortical depths. Compared to the middle cortical depth, attention modulation was stronger in the superficial and deep depths of V1, and also stronger in the superficial depth of V2 and V3. Using ultra-high resolution (0.3mm in-plane) balanced steady-state free precession (bSSFP) fMRI, a multiplicative scaling effect of attention was found in the superficial and deep layers, but not in the middle layer of V1. Attention modulation of low contrast response was strongest in the middle cortical depths, indicating baseline enhancement or contrast gain of attention modulation on feedforward input. Finally, the additive effect of attention on T2* BOLD can be explained by strong nonlinearity of BOLD signals from large blood vessels, suggesting multiplicative effect of attention on neural activity. These findings support that top-down spatial attention mainly operates through feedback connections from higher order cortical areas, and a distinct mechanism of attention may also be associated with feedforward input through subcortical pathway. HighlightsO_LIResponse or activity gain of spatial attention in superficial and deep layers C_LIO_LIContrast gain or baseline shift of attention in V1 middle layer C_LIO_LINonlinearity of large blood vessel causes additive effect of attention on T2* BOLD C_LI

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bioRxiv2018

High-definition transcranial direct current stimulation over the dorsal premotor cortex reliably modulates motor network excitability

The effectiveness of transcranial direct current stimulation (tDCS) placed over the motor hotspot (thought to represent the primary motor cortex (M1)) to modulate motor network excitability is highly variable. The premotor cortex--particularly the dorsal premotor cortex (PMd)--may be a promising alternative target to more effectively modulate motor excitability, as it influences motor control across multiple pathways, one independent of M1 and one with direct, modulating connections to M1. This double-blind, placebo-controlled study aimed to differentially excite motor and premotor regions using high-definition tDCS (HD-tDCS) with concurrent functional magnetic resonance imaging (fMRI). HD-tDCS applied over either the motor hotspot or the premotor cortex demonstrated high inter-individual variability in changes on cortical motor excitability. However, HD-tDCS over the premotor cortex led to a higher number of responders and greater changes in local fMRI-based complexity than HD-tDCS over the motor hotspot. Furthermore, an analysis of individual motor hotspot anatomical locations revealed that, in more than half of the participants, the motor hotspot is not located over anatomical M1 boundaries, despite using a canonical definition of the motor hotspot. This heterogeneity in stimulation site may contribute to the variability of tDCS results. Altogether, these findings provide new considerations to enhance tDCS reliability.

neuroscience↗