Optimizing Brain Waste Clearance: Enhancing Glymphatic Flow Through Non-Invasive Sensory Stimulation

Prof. Laura Lewis, PhD

Associate Professor, IMES and EECS, MIT

Laura Lewis is the Athinoula A. Martinos Associate Professor in IMES and EECS at MIT, and an Associate Faculty Member at the Martinos Center for Biomedical Imaging at MGH. She completed her Ph.D. in Neuroscience, and conducted postdoctoral work in neuroimaging, in the Society of Fellows at Harvard University. Her research develops multimodal approaches for imaging the human brain, and applies them to study the neural circuitry that controls sleep, and the consequences of sleep for brain function. Her work has shown that fast fMRI can measure subsecond neural dynamics, and discovered waves of cerebrospinal fluid flow that appear in the sleeping human brain. Her research has been recognized by awards such as the Peter and Patricia Gruber International Research Award, the Sloan Fellowship, the McKnight Scholar Award, and the Pew Scholar Award.

Abstract

The brain’s health depends on an intricate waste removal system known as the glymphatic system, which utilizes cerebrospinal fluid (CSF) to "wash" away metabolic byproducts, such as amyloid-beta and tau proteins. This cleansing process is most active during deep sleep, but it significantly declines with age and sleep deprivation. This project, led by Prof. Laura Lewis at MIT, explores a pioneering, non-invasive method to boost this brain-cleaning cycle using precisely timed sensory stimulation, potentially offering a new frontier for promoting resilience in the brain and reducing the risk of neurodegenerative diseases such as Alzheimer's.

Background

As we age, waste products can build up in the brain. One mechanism for this may be a decrease in the efficiency of sleep-dependent CSF flow, leading to a buildup of toxic proteins associated with cognitive decline. Currently, there are no commercially available neurotechnology solutions to maintain or enhance this fluid flow. Traditional methods to measure brain fluid dynamics have been too slow or invasive for broad clinical or consumer use, leading to a gap in our ability to monitor and maintain the brain environment.

Project Goals

Characterize CSF Flow: Understand how CSF flow varies across different ages and sleep stages.

Establish Proof-of-Concept: Demonstrate that non-invasive sensory stimulation can causally increase CSF flow in the human brain.

Future Translation: Lay the groundwork for future non-invasive tools that can maintain brain health and optimize cognitive function throughout life.

Approach

This research leverages a closed-loop approach that combines high-speed imaging with personalized stimulation:

Closed-Loop Sensory Stimulation: Using sensory stimuli synchronized to an individual’s sleep slow waves to induce rhythmic waves of CSF flow.

Simultaneous EEG-fMRI: The platform allows the team to monitor neural activity and CSF flow during sleep, making it possible to see whether stimulation directly changes brain fluid dynamics.

Predictive Algorithms: Developing algorithms to optimize the effect of stimulation on fluid flow.

Methodology

Closed-loop stimulation during sleep

Earlier work from the Lewis lab showed that intense visual stimulation can drive cerebrospinal fluid flow in the awake human brain. However, the induced flow was still smaller than the flow naturally observed during sleep. This project builds on that finding by moving stimulation into sleep itself, when CSF flow is already enhanced.

The study uses a closed-loop EEG-fMRI platform to deliver sensory stimulation during sleep and directly measure its effects on CSF flow. EEG is used to identify slow waves in real time, while fast fMRI measures fluid flow in the brain. This makes it possible to time stimulation to specific phases of sleep slow waves and assess whether those stimuli increase CSF flow.

Optimizing stimulation for the aging brain

Because slow-wave activity changes with age, stimulation protocols developed in young adults may not work as effectively in older adults. The project will first enroll a pilot group of older adults to refine the stimulation parameters, including stimulus timing, intensity, and modality.

The optimized protocol will then be tested in younger and older adults using a within-subject sham-controlled design. This will allow the team to determine whether precisely timed sensory stimulation can enhance slow-wave activity and increase CSF flow, and whether individualized algorithms can further improve the effect in older participants.

Next steps

Next, the team will use the optimized protocol to assess whether closed-loop stimulation can enhance slow-wave activity and CSF flow in both younger and older adults, and whether individualized algorithms can further improve the effect in older participants.

Image: Still from MRI video by Prof. Laura Lewis showing waves of blood oxygenation (red) followed by pulsing cerebrospinal fluid (blue) during deep sleep.