A specialized network responsible for flushing out cellular waste in the brain may play a role in the development of schizophrenia and other mental disorders. In a recent brain imaging study, researchers found that young people at high genetic risk for psychosis show early signs of malfunctioning brain clearance systems, which are associated with toxic accumulation of irritating chemicals. The study 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 in child psychiatry at the Paul Autism Foundation, led the research team. Stéphane Elise, professor of psychiatry at the University of Geneva, led the broader clinical project.
Every day, the brain produces metabolic waste products as it processes information. A network called the glymphatic system flushes out this debris to keep the biological environment stable. This system forces cerebrospinal fluid into the brain tissue, where it mixes with the fluid surrounding the cells. This fluid then washes away excess 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 stop working properly or the blood vessels leak, the entire clearance process slows down. Waste products can then accumulate in brain tissue and cause damage.
To understand how this plumbing system is linked to mental illness, researchers turned to a genetic disorder called 22q11.2 deletion syndrome. People with this disease are missing a small portion of chromosome 22. This lack of genetic material leads to an approximately 30-40% chance of developing psychotic symptoms later in life.
Psychosis involves a disconnection from reality and often takes the form of hallucinations and delusions. Scientists suspect that the genetic deletion in this syndrome damages the blood-brain barrier and changes the way astrocytes mature. This genetic syndrome dramatically increases the risk of schizophrenia and therefore provides an excellent biological model to study 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. Recurring infections can cause widespread inflammation, putting extra stress on the brain’s waste removal system. Over time, this chronic stress can overload the perivascular space, the fluid-filled channels that surround blood vessels in the brain.
The research team was also interested in the balance of chemical messengers in the brain. Healthy brain function requires a precise balance between glutamate, a chemical that excites neurons, and GABA, a chemical that inhibits neurons. When glutamate builds up and causes overstimulation, the overstimulation becomes toxic and can damage brain cells.
This toxic overstimulation is known to occur in the hippocampus, a brain region involved in memory and emotion. Scientists suspected that a defect in the brain’s excretion system could result in an inability to remove excess glutamate. By tracking these biological changes over time, the researchers hoped to pinpoint when the brain becomes susceptible to psychosis.
The research team analyzed brain scans of 85 people with 22q11.2 deletion syndrome and 83 healthy people. They followed these participants from childhood to early adulthood, performing multiple magnetic resonance imaging scans over several years. This long-term approach allowed scientists to map how the brain’s internal environment changes as humans grow.
To estimate the efficiency of waste removal in the brain, scientists used a technique called diffusion tensor imaging. The method tracks how water molecules diffuse along the microscopic spaces surrounding blood vessels in the brain. The team calculated a specific index known as the ALPS index to indirectly measure how well the drainage system is working.
Researchers noticed that children with the gene deletion already have altered brain clearance systems. Compared with healthy individuals, the group with genetic diseases had lower clearance efficiency. This difference was particularly pronounced in the right hemisphere.
The clearest results emerged when scientists divided genetic groups based on who ultimately developed clinically diagnosed psychotic symptoms. In healthy people and those who did not develop psychosis, the brain’s drainage system became more efficient as they grew older. This is consistent with the normal maturation process expected in a healthy brain.
However, the group that developed positive psychotic symptoms followed a very different path. Their brain clearance efficiency did not increase with age. Rather, their developmental trajectories remained flat or even declined slightly over the years.
“This unusual course suggests that vulnerability resulting from interactions between biological and environmental factors exists long before symptoms appear,” Pascucci said in a press release. Researchers believe that early dysfunction of this system may leave the brain unprotected during sensitive periods of development.
The research team also conducted secondary testing on a smaller group of 39 people with the gene deletion. They used a special magnetic resonance technique that works like a chemical analysis tool. This allowed us to measure precise levels of excitatory and inhibitory chemicals within the right hippocampus without the need for invasive procedures.
Scientists have found a clear link between poor waste disposal and an unhealthy chemical environment. Those with a low ALPS index had a higher proportion of excitatory glutamate compared to sedative GABA. This means that the brain’s plumbing system has broken down and the chemical environment has become increasingly overstimulated.
“Excessive arousal can be toxic to neurons and contribute to changes in certain brain regions, such as the hippocampus, which is particularly vulnerable and implicated in psychosis,” Dr. 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 them particularly sensitive to oxidative stress and inflammation. As waste products build up, this particular brain area can be one of the first to experience toxic overstimulation.
The researchers noted that their study had several limitations. Because the chemical analysis was only performed at a single time point, the scientists cannot definitively prove that poor clearance is the cause of the chemical imbalance. Chemical measurements were also limited to the right hippocampus, and it is unclear whether the same imbalance occurs in other parts of the brain.
Additionally, the methods used to estimate brain clearance rely on the movement of water molecules near the brain cavities. This means that this is an indirect measurement and other structural changes in the brain’s white matter may influence the results. Additionally, the study only followed participants into early adulthood, so long-term effects in older adults remain unclear.
Future studies will need to track chemical changes throughout the brain over longer periods of time. Scientists also want to investigate how sleep quality and inflammation throughout the body affect the brain’s plumbing system. Identifying early warning signs could ultimately allow doctors to intervene before the first psychotic episode occurs.
The authors of the study, “Developmental changes in the DTI-ALPS index suggest a possible glymphatic-related mechanism underlying excitation/inhibition imbalance and psychosis vulnerability in 22q11.2 deletion syndrome” are Alessandro Pascucci, Silas Forrer, Corrado Sandini, Valentina Mancini, Yasser Alemán-Gómez, Stephan Elise and Farnas Delavalli.
