Keywords: Neurofluids, Brain

Motivation: Quantitative analysis of blood and CSF flow dynamics is vital to understand the intracranial pulsating fluid movement environment and its role in brain homeostasis.

Goal(s): To characterize the correlation between blood (arterial/venous) and CSF flow within one cardiac cycle.

Approach: Flow dynamic measurements in neck arteries and veins, cervical CSF (CSFc) and CSF in the aqueduct of Sylvius (CSFAq) were obtained using cine phase-contrast MRI from 18 healthy volunteers. 

Results: Net blood and CSFc flow wave curves depict a compensatory mechanism resulting in balance of total fluid inflow and outflow. CSFAq flow patterns mimic CSFc ones with some temporal delay.

Impact: Understanding how blood and CSF flow influence each other in healthy subjects provides a reference frame to investigate alterations caused by neurological disease. We showed a dynamic interplay between neck blood and CSF flow at the cervical and aqueduct level.

Keywords: Neurofluids, Neurofluids

Motivation: A driver of macroscopic CSF flux across ventricles and basal cisternae is hypothesized to be global cerebral blood volume, possibly induced by changes in brain-wide neuronal activity.

Goal(s): We intended to test this hypothesis experimentally in healthy human subjects.

Approach: We performed two experiments: (1) electro-encephalography and functional MRI (fMRI) during burst-suppression anesthesia, and (2) arterial spin labeling and fMRI during transient hypercapnic challenges in wakefulness.

Results: Changes in brain blood volume, induced by neuronal activity switches during burst-suppression or brain blood flow during hyper-normocapnia transitions, cause fMRI signal changes in the basal cisternae which represent CSF flux from or into the brain.

Impact: Two distinct experiments revealed a consistent and direct coupling between macroscopic CSF flux and brain blood volume, which can be induced by changes in global neuronal activity. This may contribute to perivascular CSF flow and facilitate brain waste clearance.

Keywords: Neurofluids, Neurofluids

Motivation: The absorption of CSF into the superior-sagittal-sinus (SSS) is an important CSF drainage pathway and has been implicated in brain disorders like Alzheimer’s disease and idiopathic-intracranial-hypertension. However, we still lack non-invasive and non-contrast techniques to evaluate this CSF-venous drainage system.

Goal(s): To develop a novel non-contrast MRI technique to assess the CSF drainage into the SSS.

Approach: We propose to magnetically label the CSF spins and use a control-label subtraction to isolate signals from the CSF spins that have been absorbed into SSS.

Results: In all subjects, we observed considerable signals from absorbed CSF spins in frontal SSS. Test-retest experiments demonstrated good reproducibility.

Impact: We have proposed a novel non-contrast MRI technique to assess the drainage of CSF into the superior-sagittal-sinus, which may address an important technical gap in evaluating the circulation of CSF.

Keywords: Neurofluids, Diffusion/other diffusion imaging techniques, IVIM, diffusion, choroid plexus

Motivation: Measuring vascular perfusion in the Choroid Plexus (ChP) is challenging due to its smaller size and the pronounced partial volume effects from CSF.

Goal(s): To improve blood perfusion assessment of ChP utilizing Inversion recovery (IR) prepared IVIM imaging.

Approach: Higher in-plane resolution (1.5x1.5mm²) IVIM diffusion MRI data with and without the IR preparation were acquired. The signal was analyzed using inverse Laplace transform (ILT) to estimate diffusion compartments within ChP for IVIM-derived perfusion fraction analysis.

Results: ILT analysis of IR-prepared IVIM revealed three diffusion compartments within the ChP and reported higher perfusion fraction observed in IR-prepared IVIM versus IVIM without IR-preparation.

Impact: This study provides a novel approach to investigate the microvascular perfusion in Choroid Plexus (ChP) with CSF signal removed. IR preparation does not completely remove the free-diffusion compartment but increases the microvascular perfusion fraction estimation in ChP.

Keywords: Neurofluids, Neurofluids, Glymphatic system

Motivation: There is still lack non-invasive methods to quantitative measure the paravascular cerebrospinal fluid (pCSF) flow speed and directions pulsations of arterial vessel .

Goal(s): To explore whether dynamic DTI_low-b could capture the artery-pulsation dependence of pCSF flow in human and how DTI_low-b metrics are modulated by artery pulsation. 

Approach: Six-direction dynamic DTI_low-b was acquired simultaneously with finger pulse oximeter recording on eight subjects.

Results: Both the axial and radial diffusivity of pCSF and whole-brain white matter is increased by artery dilation. DTI_low-b signal of pCSF at b = 0 mm²/s also shows artery-pulsation dependence but lags from diffusivity changes.

Impact: The proposed dynamic DTI_low-b with ultra-long TE could potentially capture the volume and flow dynamics of MRI-visible and -invisible pCSF in artery pulsation.

Keywords: Neurofluids, Neurofluids

Motivation: Vasomotion has been hypothesized as a mechanism for brain paravascular clearance, which could be impaired in multiple neurodegenerative conditions. 

Goal(s): To measure vasomotion in vivo in human brains using MRI. 

Approach: A single-shot T1-weighted Cine-FLASH sequence was optimized to provide high temporal resolution in two adults, as well as during a visual stimulation paradigm in one. We performed a Fourier decomposition of the signal in brain vascular structures.

Results: An ultra-low-frequency signal was observed consistent with vasomotion in posterior cerebral arteries while no such signal could be identified in the parenchyma. A substantial amplification of this signal could be observed during visual stimulation. 

Impact: This method could help studying brain waste clearance and its dysfunction in humans in vivo. 

Keywords: Alzheimer's Disease, Alzheimer's Disease, Glymphatic system, CSF

Motivation: The glymphatic system plays a crucial role in brain waste clearance, and dysfunction has been linked to neurodegenerative diseases like Alzheimer's Disease. Understanding this system is essential for advancing our knowledge of brain health.

Goal(s): We aim to develop a non-invasive method to assess glymphatic activity in the human brain.

Approach: We utilize a quantitative CSF measurement technique with a three-pool model and multi-echo spin-echo images.

Results: Significant variations in glymphatic activity were observed across different brain regions and found to be influenced by sleep. 

Impact: Our method can potentially reveal sleep-influenced glymphatic activity variations, enabling early Alzheimer's Disease diagnosis. 

Keywords: Neurofluids, Aging, Sodium MRI, EEG

Motivation: Alzheimer's disease is associated with neurotoxic amyloid-beta(Aβ) plaques. Studies in mice demonstrate that impaired cerebrospinal fluid(CSF) clearance reduces Aβ clearance by 70%. Sleep enhances CSF clearance by expanding extracellular space.

Goal(s): However, the impact of sleep on extracellular volume change remains unclear in human brains due to a lack of non-invasive technology.

Approach: To address this gap, we use sodium(²³Na) MRI to measure the extracellular volume fraction in 16 healthy human brains. We monitor the sleep stage with MRI-compatible Electroencephalography(EEG). 

Results: On average, a decrease in extracellular volume fraction was observed in the gray matter significantly, but not significant in the white matter.

Impact: Our research may shed light on how sleep may facilitate Aβ clearance in humans, bridging the gap between animal and human studies.

Keywords: Neurofluids, Neurofluids, Brain Clearance

Motivation: Perivascular spaces (PVS) are mediating brain clearance, i.e. cerebrospinal fluid (CSF) - interstitial fluid exchange, and dilated PVS are a hallmark of cerebral amyloid angiopathy (CAA). However, until now, brain clearance function could not be assessed in humans in vivo.

Goal(s): Goal of this study was to assess perivascular cerebrospinal fluid (CSF) mobility in CAA patients.

Approach: A CSF mobility-specific 7-Tesla MRI sequence was applied for the first time in patients with CAA and healthy control (HC) subjects.

Results: The study revealed perturbed CSF mobility in enlarged perivascular spaces in CAA compared to HC subjects, suggesting impaired perivascular clearance in CAA.

Impact: With the finding of a perturbed CSF mobility in enlarged PVS in CAA patients, the study provides proof-of-principal for in vivo measurements of perivascular CSF mobility as a crucial component of the brain clearance pathway in health and disease.

Keywords: Neurofluids, Neurofluids

Motivation: The rose of cerebrospinal fluid (CSF) in neural health is recognized, yet its outflow and egress within the optic nerve, especially amidst new findings about the glymphatic system, remains less explored.

Goal(s): Investigate CSF interactions within the optic nerve using advanced MRI techniques, highlighting implications for conditions like glaucoma.

Approach: Utilized advanced Time-Slip sequences on a 3-T MR imager, targeting specific brain regions to study CSF outflow and egress.

Results: Clear CSF egress pathways through the optic nerve were found, with distinct outflow influenced by participants’ optical attributes.
 

Impact: Enhances understanding of CSF outflow and egress, providing pivotal insights for addressing neuro-ophthalmological disorders like glaucoma.

Keywords: Neurofluids, High-Field MRI, Tissue Characterization, Diffusion Acquisition, fMRI Analysis, Multi-Contrast

Motivation: Understanding the spatiotemporal relationships between blood volume changes, tissue displacement, and CSF flow is important for elucidating brain waste clearance mechanisms, and measuring these compartments concurrently would enable effective analysis.

Goal(s): To demonstrate the feasibility of leveraging both magnitude-valued and phase-valued data to measure BOLD fMRI and tissue motion simultaneously.

Approach: We apply a combination of computer simulations and in vivo imaging with visual stimulation using the Displacement Encoding with Stimulated Echoes (DENSE) pulse sequence.

Results: DENSE magnitude-valued data show significant response to visual stimulation in the visual cortex, while the phase-valued data show typical cardiac-gated motion in both cortex and brainstem.

Impact: BOLD fMRI can be acquired simultaneously with brain tissue displacement quantification using the DENSE pulse sequence, enabling future spatiotemporal analyses of concurrent blood volume changes, tissue displacement, and CSF flow for understanding waste clearance mechanisms.

Keywords: Neurofluids, fMRI (task based), CSF flow, brain clearance

Motivation: Glymphatic clearance is impaired in neurodegenerative disease. Vasomotion has been suggested to drive CSF flow and influence clearance. Furthermore, low frequency sensory stimulation can enhance vasomotion. Whether low frequency visual stimulation can drive CSF flow in humans is still unclear.

Goal(s): To study the effect of different visual stimulation frequencies on BOLD signal and CSF flow.

Approach: 7T BOLD-fMRI scans were acquired in healthy volunteers watching a checkerboard flashing at 0.025, 0.05, or 0.1 Hz.

Results: Visual cortex BOLD responses clearly oscillated at the stimulation frequencies, with increased power at lower frequencies. CSF flow responses observed in the fourth ventricle, however, were modest.

Impact: This preliminary study confirms that BOLD responses can be evoked locally in the brain with low frequency visual stimulation, but that there is only modest effect on ventricular CSF flow.

Keywords: Neurofluids, Neurofluids

Motivation: Glaucoma is an age-related neurodegenerative disease of the visual system. Recent studies suggested that glaucoma may lead to changes in cerebrospinal fluid (CSF) dynamics, which can be influenced by neural activity. However, it remains unclear how the CSF dynamics is altered in glaucoma.

Goal(s): To test whether the impact of visual stimulation on CSF inflow is impaired in glaucoma.

Approach: We used visually-evoked BOLD fMRI responses to compare the coupling between BOLD activity and CSF inflow across healthy individuals and glaucoma patients.

Results: Our findings indicate that the influence of visual stimulation on CSF inflow decreases with glaucoma severity.

Impact: Our findings suggest that CSF inflow is altered in glaucoma. Future studies should investigate whether this reduced impact of visual stimulation on CSF inflow is due to impaired neural activity or impaired interaction between cerebrovascular activity and CSF dynamics.

Keywords: Neurofluids, High-Field MRI, Cerebrospinal fluid efflux

Motivation: The astroglia-mediated circulation of metabolites and waste between cerebrospinal fluid (CSF) and blood or lymph, recently termed the glymphatic system, is implicated in processes from autoimmunity to neurodegeneration. 

Goal(s): Many details of CSF dynamics, particularly efflux routes from brain to periphery including nasal pathways as we examine here, remain to be clarified. 

Approach: Here we investigate CSF efflux in living mice using 9.4-T in vivo dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). 

Results: We show that gadolinium-based contrast agent injected into the cisterna magna (CM) of live mice dose-rate-dependently effluxes into the nasal mucosa in a manner affected by olfactory neuronal integrity. 

Impact: Controversy surrounds the current model of CSF efflux from brain ventricles to periphery. We show with high-field DCE-MRI in live mice that nasal efflux of CSF from cisterna magna adapts to both a flow rate challenge and olfactory neuronal damage. 

Keywords: Neurofluids, Neurofluids, CSF, dura mater

Motivation: The GBCA enhancement detected in the parasagittal dura (PSD) is hypothesized to originate from the dura mater blood vessels lacking a blood-brain-barrier. The dura mater consists of two layers: periosteal and meningeal dura mater. No prior study has examined the pattern of GBCA enhancement within these layers.

Goal(s):  To visualize GBCA enhancement in the periosteal and meningeal layers of dura mater in the human brain.

Approach: High-resolution black-blood and FLAIR MRI were performed at 7T.

Results: The two layers and their GBCA-enhancement could be visualized. T1 and T2* values in each layer were measured.

Impact: This work allows us investigate the relationship between GBCA-enhancement in the dura mater and GBCA-induced-signal-changes in the PSD and meningeal-lymphatic-vessels. This is of importance given that GBCA-enhanced MRI has been a gold-standard technique for investigating human brain clearance.

Keywords: Neurofluids, Neurofluids

Motivation: Water exchange between tissue and CSF may contribute to CSF production and glymphatic clearance. The large difference in T2 between tissue and fluid suggests T2 saturation transfer can be used to image this exchange.

Goal(s): We aimed to develop a method for water exchange imaging using T2 saturation.

Approach: A novel strategy to control for systematic errors from direct effects of T2 saturation on fluid is proposed and evaluated in healthy volunteers.

Results: Three dimensional images at longer TE show exchange signal surrounding the choroid plexus, but also more modest exchange near the cerebellar vermis and the cerebellar and cerebral cortices.

Impact: A new strategy for T2 selective water exchange imaging can enable in vivo studies of CSF exchange that may reflect changes in glymphatic clearance or CSF production with aging, Alzheimer’s disease, intracranial hypertension and other disorders.

Keywords: Neurofluids, Neurofluids, Cerebrospinal Fluid Flow, CSF, phase contrast, velocity

Motivation: The flow of cerebrospinal fluid (CSF) is essential for maintenance of brain function.

Goal(s): We aimed to understand the effects of respiration on CSF flow dynamics by quantitatively testing the change in CSF flow across varying paced breathing frequencies.

Approach: Using flow-sensitive fMRI, phase contrast imaging, and physiological recordings, we measured changes in CSF flow and velocity during a visually guided paced breathing task.

Results: We examined CSF flow across breath frequencies ranging from 0.1 Hz to 0.25 Hz, and found that slower frequencies of breathing increase CSF flow, independent of breath depth. 

Impact: Our results demonstrate that key features of human respiration, its timing and its depth, induce separate effects on CSF flow. Our identification of respiratory frequency as a modulator of CSF flow provides an accessible mechanism to modulate CSF flow.

Keywords: Neurofluids, Reproductive, gBOLD-CSF coupling, Glymphatics, Sleep deprivation

Motivation: The coupling strength of global blood-oxygen-level-dependent (gBOLD) signals and cerebrospinal fluid (CSF) inflow have been suggested to be an indicator of glymphatic system function. However, few studies have validated its test-retest reproducibility. 

Goal(s): To assess the reproducibility of gBOLD-CSF coupling.

Approach: Thirteen adults of the sleep deprivation (SD) group and 14 adults of the control group underwent three fMRI. The reliability of gBOLD-CSF coupling was evaluated by the intraclass correlation coefficient (ICC). 

Results: A higher ICC (0.525, P = 0.001) was observed in the control group compared with the SD group (0.137, P = 0.086).

Impact: The gBOLD-CSF coupling shows good reproducibility, but care should be taken when interpreting longitudinal changes of the gBOLD-CSF coupling that may be influenced by participants’ drowsiness. Sleep should be considered an important factor in future studies exploring the glymphatic system. 

Keywords: Neurofluids, Perfusion

Motivation: Aggressive gliomas are known to migrate in the direction of interstitial fluid flow (IFF), though it is difficult to measure interstitial fluid flow using MRI.

Goal(s): Our goal is to develop a computational method for measuring IFF using DCE-MRI.

Approach: We developed localized convolutional function regression (LCFR), validated in silico, in porous hydrogel, and apply it to in vivo tumors.

Results: LCFR accurately measures fluid flow and perfusion to less than 10% error in silico, and measures IFF in a mouse model of glioma to be 1.63E-3 mm/s. In a case study, the method tentatively predicts invasion across the corpus collosum.
 

Impact: This method will allow physicians and researchers to investigate how highly aggressive gliomas invade healthy tissue, and can be further used to predict how therapeutic agents or cells will disperse throughout the tumor, predicting disease progression and response.

Keywords: Neurofluids, Neurofluids, CSF, MT, magnetization transfer

Motivation: While challenging in humans, measuring fluid exchange between the brain parenchyma tissue and CSF compartments is essential for understanding the role of CSF-mediated metabolic waste clearance in neurodegeneration.

Goal(s): We demonstrate the feasibility of detecting such fluid exchange in human brains, unaffected by CSF-flow and partial-volume artifacts.

Approach: Free-water spins inside parenchyma were selectively saturated and labeled by magnetization transfer, and subsequent partial saturations were quantified within CSF compartments.

Results: We found 3.6% saturation in subarachnoid space (SAS), significant saturation difference between SAS and lateral ventricles (1.3%), and higher saturations in slow-flowing, narrow compartments (e.g. SAS and longitudinal fissure) than larger ventricle spaces.

Impact: We demonstrated feasibility of detecting fluid exchange between brain parenchyma and CSF compartments in human brains through selective parenchyma saturation and CSF saturation quantification. Measuring such exchange is important for understanding the role of CSF-mediated metabolic waste clearance in neurodegeneration.