Research

In the last decade, there has been a greatly increased appreciation for the vital role that cerebrospinal fluid (CSF) plays in maintaining brain health. This is especially inspired by recent breakthroughs in experimental measurement techniques which have enabled in vivo measurement of CSF flowing into the brain (see figure at right). A growing body of research demonstrates that CSF flow through the brain provides an important mechanism for metabolic waste removal and that disruption to this system is directly involved in the cognitive decline associated with many neurological disorders, including Alzheimer’s disease, stroke, traumatic brain injury, and more. 

This clearance pathway in the brain, dubbed the "glymphatic system" in 2012, includes CSF flow through perivascular spaces (PVSs)—annular channels around blood vessels—in the brain. Interestingly, this flow is largely inhibited during wakefulness but becomes most active during sleep, perhaps providing a reason for the necessity and restorative effect of sleep. There are currently a tremendous number of open questions that engineers are uniquely well-suited to answer, many of which the Tithof lab and collaborators are actively pursuing:

• What drives the flow under physiological conditions? Direct experimental observation suggests the flow is driven by arterial pulsations, but multiple prior, highly idealized simulations have cast doubt on this hypothesis. Relevant publications: Mestre, Tithof, et al 2018
• What is the precise pathway CSF flow follows? Technical limitations currently prevent high-resolution, in vivo measurements throughout the entire brain. Numerical modeling provides a promising approach for predicting brain-wide transport, bridging observations in different experiments, and developing experimentally-testable hypotheses. Relevant publications: Tithof et al 2019, Troyetsky et al 2021, Tithof et al 2022, Boster et al 2022
• Is transport of different solutes dominated by advection or diffusion at different levels of the glymphatic pathway? Understanding modalities of transport is important for identifying optimal approaches to manipulating solute transport in the brain. Such insights will help prevent and treat neurodegenerative diseases (e.g., Alzheimer's) by identifying novel strategies for enhancing clearance of amyloid-β and tau. Relevant publications:  Troyetsky et al 2021, Tithof et al 2022, Boster et al 2022, Mukherjee & Tithof 2022, Watkins et al 2024, Quirk et al 2024, Yousofvand & Tithof 2024 (under review)
• How does this system go awry during acute neurological conditions (e.g., stroke, traumatic brain injury)? Our recent studies implicate glymphatic dysfunction as an important early contributor to brain edema. In particular, many such conditions initiate waves of spreading depolarization (irregular heightened then inhibited neuronal activity) which have recently been demonstrated to disrupt the glymphatic system. Relevant publications: Mestre et al 2020, Du et al 2021, Mukherjee et al 2023, Hussain et al 2023
• What propels CSF drainage from the skull, and how might this drainage become impaired due to aging, injury, or neurological disorders? Recent studies demonstrate that CSF drains from the skull through multiple parallel outflow pathways; this redundancy likely helps ensure adequate CSF drainage. We employ a combination of in vivo experiments in mice and numerical modeling based on experimental parameterization and validation to predict transport mechanisms that may become disrupted due to injury, aging, or various neurological disorders, with the goal of identifying therapeutic strategies that can restore adequate outflow. Relevant publications: Hussain et al 2023, Kim & Tithof 2024
• Can this pathway be utilized as a novel route for drug delivery? The brain is unique from the rest of the body in that it strictly regulates what is able to pass back and forth between the blood and brain tissue (via the blood brain barrier). It may be possible to deliver drugs (e.g., cancer treatments) to the brain more effectively via CSF flow, but it is essential to understand details of brain solute transport. Relevant publications: Plog et al 2018, Quirk et al 2024, Yousofvand & Tithof 2024 (under review)

The Tithof lab is interested in:

• In vivo experiments. We perform direct measurements of CSF flow at the surface of the brain by injecting fluorescent tracers and imaging: (i) at high spatial and temporal resolution using two-photon microscopy, or (ii) at brain-wide length scales use transcranial macroscopic imaging. We collaborate with Professor Kodandaramaiah's research group to leverage cutting-edge technologies enabling novel approaches for probing the glymphatic system.
• Numerical simulations and modeling. We develop in-house codes to model transport through perivascular spaces and meningeal/cervical lymphatic vessels, with the goal of understanding mechanisms of fluid transport and solute exchange. We are especially interested in understanding how arterial pulsations (due to the cadiac cycle, neurovascular coupling, and slow vasomotion) affect transport over large segments of the brain.