A specialized network responsible for washing away cellular waste in the brain might play a role in the development of schizophrenia and other psychotic disorders. In a recent brain imaging study, researchers found that young people at a high genetic risk for psychosis showed early signs of a malfunctioning brain clearance system, which was linked to a toxic buildup of stimulating chemicals. The research was published in the journal Biological Psychiatry Global Open Science.
Alessandro Pascucci, a doctoral student in the Department of Psychiatry at the University of Geneva and a resident doctor in child psychiatry at the Fondation Pôle Autisme, led the research team. Stephan Eliez, a professor of psychiatry at the University of Geneva, directed the broader clinical project.
Every day, the brain generates metabolic waste as it processes information. To keep the biological environment stable, a network called the glymphatic system flushes out this debris. This system pushes cerebrospinal fluid into the brain tissue, where it mixes with the fluid surrounding the cells. The fluid then washes away extra neurotransmitters, inflammatory proteins, and misfolded proteins.
This fluid movement is driven by star-shaped brain cells called astrocytes. Astrocytes have specialized water channels, called aquaporin-4 channels, that act like tiny valves. When these channels fail to work properly, or when the blood vessels leak, the entire clearance process slows down. Waste products then accumulate in the brain tissue, potentially causing damage.
To understand how this plumbing system might relate to psychiatric illness, the researchers looked at a genetic condition called 22q11.2 deletion syndrome. People with this condition are missing a tiny piece of chromosome 22. This missing genetic material leads to a roughly 30 to 40 percent chance of developing psychotic symptoms later in life.
Psychosis involves a disconnection from reality, often taking the form of hallucinations or delusions. Scientists suspect that the genetic deletion in this syndrome might damage the blood-brain barrier and alter how astrocytes mature. Because it dramatically increases the risk of schizophrenia, this genetic syndrome provides an excellent biological model for studying how psychosis develops over time.
People with 22q11.2 deletion syndrome also often have a weakened immune system. This makes them more susceptible to infections early in life. Recurrent infections can cause widespread inflammation, which puts extra stress on the brain’s waste clearance system. Over time, this chronic stress might overload the perivascular spaces, which are the fluid-filled channels surrounding blood vessels in the brain.
The research team was also interested in the balance of chemical messengers in the brain. Healthy brain function requires an exact equilibrium between glutamate, a chemical that excites neurons, and GABA, a chemical that inhibits them. If glutamate builds up and causes too much excitation, the overstimulation can become toxic and damage brain cells.
This toxic overstimulation is known to happen in the hippocampus, a brain region involved in memory and emotion. The scientists suspected that a faulty brain drainage system might fail to clear away excess glutamate. By tracking these biological changes over time, they hoped to pinpoint exactly when the brain becomes vulnerable to psychosis.
The research team analyzed brain scans from 85 individuals with 22q11.2 deletion syndrome and 83 healthy individuals. They followed these participants from childhood into early adulthood, taking multiple magnetic resonance imaging scans over several years. This long-term approach allowed the scientists to map how the brain’s internal environment changes as people grow.
To estimate the efficiency of the brain’s waste clearance, the scientists used a technique called diffusion tensor imaging. This method tracks how water molecules diffuse along the microscopic spaces surrounding blood vessels in the brain. The team calculated a specific metric, known as the ALPS index, to act as an indirect measure of how well the drainage system was working.
The researchers noticed that the brain’s clearance system was already altered in children with the genetic deletion. Compared to healthy individuals, the group with the genetic condition had lower clearance efficiency. This difference was especially apparent in the right side of the brain.
The most revealing results emerged when the scientists split the genetic group based on who eventually developed clinically diagnosed psychotic symptoms. In healthy individuals and those who never developed psychosis, the brain’s drainage system became more efficient as they grew up. This matches the normal maturation process expected in a healthy brain.
However, the group that developed positive psychotic symptoms followed an entirely different path. Their brain clearance efficiency failed to increase with age. Instead, their developmental trajectory remained flat or even declined slightly over the years.
“This atypical trajectory suggests that a vulnerability resulting from an interaction between biological and environmental factors is present well before the onset of symptoms,” Pascucci said in a press release. The researchers think the early failure of this system might leave the brain unprotected during sensitive periods of development.
The team also conducted a secondary test on a smaller group of 39 individuals with the genetic deletion. They used a specialized magnetic resonance technique that acts like a chemical analysis tool. This allowed them to measure the exact levels of excitatory and inhibitory chemicals in the right hippocampus without needing an invasive procedure.
The scientists discovered a clear link between poor waste clearance and an unhealthy chemical environment. Individuals with a lower ALPS index had a higher ratio of excitatory glutamate compared to calming GABA. This means that as the brain’s plumbing system failed, the chemical environment became increasingly overstimulating.
“Excessive excitation can become toxic to neurons and contribute to alterations in certain brain regions that are particularly vulnerable and involved in psychosis, such as the hippocampus,” Pascucci noted. “Our results suggest a link between glymphatic system dysfunction, mechanisms of neurotoxicity, and psychosis.”
The right hippocampus requires a lot of energy to function and has a dense network of blood vessels. This makes it particularly sensitive to oxidative stress and inflammation. When waste products build up, this specific brain region may be one of the first to suffer from toxic overstimulation.
The researchers noted a few limitations to their work. The chemical analysis was only performed at a single point in time, meaning the scientists cannot definitively prove that poor clearance causes the chemical imbalance. The chemical measurements were also restricted to the right hippocampus, leaving it unclear if the same imbalance happens throughout the rest of the brain.
Additionally, the method used to estimate brain clearance relies on the movement of water molecules near brain cavities. This means it is an indirect measure, and other structural changes in the brain’s white matter could potentially influence the results. The study also only tracked participants into early adulthood, so the long-term effects in older age remain unknown.
Future research will need to track chemical changes over a longer period and across the entire brain. Scientists also hope to investigate how sleep quality and body-wide inflammation affect the brain’s plumbing system. Identifying early warning signs could eventually help doctors intervene before a first psychotic episode occurs.
The study, “Developmental Alterations in the DTI-ALPS Index Suggest Possible Glymphatic-Related Mechanisms Underlying Excitation/Inhibition Imbalance and Psychosis Vulnerability in 22q11.2 Deletion Syndrome,” was authored by Alessandro Pascucci, Silas Forrer, Corrado Sandini, Valentina Mancini, Yasser Alemán-Gómez, Stephan Eliez, and Farnaz Delavari.
