Brain 'Suffocates' in Its Own Fluid After a Stroke

Cerebral edema, swelling that occurs in the brain, is a severe and potentially fatal complication of stroke.

New research, which was conducted in mice and appears in the journal Science, shows for the first time that the glymphatic system - normally associated with the beneficial task of waste removal - goes awry during a stroke and floods the brain, promoting edema and suffocating brain cells.

"These findings show that the glymphatic systems plays an important role in driving the acute tissue swelling in the brain after a stroke. Understanding this dynamic - which is propelled by storms of electrical activity in the brain - could point the way to potential new strategies that could improve stroke outcomes," said Maiken Nedergaard, professor at the University of Copenhagen and University of Rochester Medical Center (URMC) and lead author of the article.

Trapped in the skull

The glymphatic system, first discovered by Nedergaard's lab in 2012, consists of a network that piggybacks on the brain's blood circulation network. The system consists of layers of plumbing, with the inner blood vessel encased by an outer 'tube' transporting cerebral spinal fluid (CSF). The system pumps CSF through brain tissue, primarily while we sleep, washing away toxic proteins and other waste.

While edema is a well-known consequence of stroke, there are limited treatment options and the severity of swelling in the brain depends upon the extent and location of the stroke. Because the brain is trapped in the skull, it has little room to expand. If the swelling is severe, it can push in on important structures such as the brainstem, which regulates the cardiovascular and respiratory systems, resulting in death. After several hours and if unabated, the swelling can eventually result in a breakdown of the blood-brain barrier, at which point the edema becomes irreversible and potentially fatal. As a last resort, surgeons will often remove a part of the skull to relieve the pressure on the brain.

Prior to the findings of the new study, it has been assumed that the source of swelling was the result of fluids from the blood and inflammation.

An electrical wave, then the flood

Ischemic stroke, the most common form of stroke, occurs when a vessel in the brain is blocked. Because this denies cells the nutrients and oxygen they need to function, they quickly become compromised and expand, a phenomenon known as cytotoxic edema. In an effort to survive, neurons depolarize and discharge stored energy reserves. As the cells fire, they trigger neighboring nerve cells, creating a domino effect that results in an electrical wave that expands outward from the site of the stroke, called spreading depolarization.

During spreading depolarization, vast amounts of potassium are released by neurons into the brain. The potassium binds with the smooth muscles cells that form the walls of blood vessels -which are already contracting due to low blood flow from the stroke - causing them to seize up and shrink. These processes are experimentally observed and are included in a mathematical model developed by Associate professor Poul G. Hjorth, Associate Professor Erik A. Martens, and masterstudent Peter A. R. Bork from DTU Compute.

CSF flows into the ensuing vacuum, inundating brain tissue and causing the area to expand further. The already vulnerable brain cells in the path of the flood essentially drown in CSF. The experimental observations can be mechanistically by the mathematical model. These depolarization waves can continue in the brain for days and even weeks after the stroke, compounding the damage.

Single largest disruption of brain function

At the University of Copenhagen, the researchers have measured these waves with the advanced equipment in the Panum NMR Core Facility. Here, it is possible to use technological machines to scan the brain in mice and produce images of the brain processes. This work was led by Yuki Mori, who is a Professor at the University of Copenhagen.

"When you force every single neuron, which is essentially a battery, to release its potential it represents the single largest disruption of brain function you can achieve - you basically discharge the entire brain in one fell swoop," said Humberto Mestre Payne, M.D., a Ph.D. student in the Nedergaard lab and co-author of the study. "The double whammy of the ensuing spike in potassium and ischemia makes the blood vessels cramp, resulting in a level of constriction that is completely abnormal and creating conditions for CSF to rapidly flow into the brain."

The findings point to potential new treatment strategies that could be used in combination with existing therapies focused on restoring blood flow to the brain after a stroke. It could also have implications for brain swelling observed in other conditions such as subarachnoid and intracerebral hemorrhages and traumatic brain injury.

Approaches that block specific receptors on nerve cells could inhibit or slow the cycle of spreading depolarization. Additionally, the flow of CSF into the brain is regulated by waterchannels or aquaporins on astrocytes - an important support cell. When the team conducted the stroke experiments in mice genetically modified to lack aquaporins, CSF flow into the brain slowed significantly. Aquaporin inhibitors currently under development as a potential treatment for cardiac arrest and other diseases could eventually be candidates to treat stroke.

The research was supported by The Novo Nordisk Foundation, The Lundbeck Foundation and E.U. Horizon 2020. Along with funding from the National Institute of Neurological Disorders and Stroke, the National Institute of Aging, the U.S. Army Research Office, Fondation Leducq Transatlantic Networks of Excellence Program.

See the entire study: "Cerebrospinal fluid influx drives acute ischemic tissue swelling"