🧠 A poorly "cleaned" brain can lead to schizophrenia

How can we explain the onset of psychotic symptoms characteristic of schizophrenia? Despite their major and often irreversible impact on intellectual abilities and autonomy, the biological mechanisms preceding their emergence remain poorly understood.

A team from the Department of Psychiatry of the Faculty of Medicine and the Synapsy Center for Neuroscience Research in Mental Health at the University of Geneva (UNIGE) provides new insight. An early dysfunction of the glymphatic system, responsible for removing waste from the brain, could constitute a key vulnerability factor. This work is published in Biological Psychiatry: Global Open Science.


Hallucinations and delusions are among the characteristic psychotic symptoms of schizophrenia spectrum disorders, which can also be accompanied by social withdrawal and cognitive decline. These neurodevelopmental disorders most often emerge during adolescence or early adulthood and have an estimated prevalence between 0.5% and 3% in the general population.

The hippocampus, a brain region notably involved in memory and cognition, is known to play a major role in the emergence of these clinical manifestations. A first psychotic episode, which often marks the entry into schizophrenia, can be accompanied by a decline in cognitive functions. Understanding the brain vulnerabilities present before clinical onset is therefore a crucial challenge for preventing, delaying, or reducing their intensity, especially in at-risk individuals.

When it malfunctions, the brain's drainage system could promote inflammation and neuronal toxicity.

Brain cleaning involved?

A UNIGE team investigated 22q11.2 deletion syndrome, a genetic condition associated with a 30% to 40% risk of developing psychotic symptoms. This microdeletion includes genes involved in the integrity of the glymphatic system, which acts as the brain's cleaning network.

This cleaning removes metabolic waste, inflammatory molecules, and excess neurotransmitters through the circulation of cerebrospinal fluid and its exchanges with the interstitial fluid in which brain cells are bathed. When it malfunctions, this true brain drainage system could promote inflammation and neuronal toxicity. These two phenomena are suspected of promoting the onset of psychotic symptoms.

A neurodevelopmental vulnerability

The team analyzed a cohort of individuals with 22q11.2 deletion, followed from childhood to adulthood, and compared them to healthy individuals. Longitudinal imaging data, whose acquisition began more than twenty-five years ago, were reanalyzed using new techniques, optimized and automated by the team. Within the 22q11.2 group, a subgroup developed psychotic symptoms during follow-up, allowing for the identification of distinct neurodevelopmental trajectories.

Using a specific methodology applied to a diffusion magnetic resonance imaging technique—which measures the diffusion of water molecules in the brain—the team was able to indirectly estimate the functioning of the glymphatic system. They observed that the brain's cleaning system was significantly altered in individuals with 22q11.2 deletion, and this from childhood. Furthermore, while the efficiency of the glymphatic system normally increases during development, this progression was not observed in a subgroup of individuals with 22q11.2 deletion who developed psychotic symptoms.

"This atypical trajectory suggests that a vulnerability, resulting from the interaction between biological and environmental factors, is present long before the onset of symptoms," explains Alessandro Pascucci, first author of the study, a PhD student in the Department of Psychiatry of the Faculty of Medicine and the Synapsy Center at UNIGE, as well as a resident physician in child psychiatry at the Pôle Autisme Foundation.

The researchers also measured the balance between excitation and inhibition signals in the hippocampus, by studying two types of neurotransmitters: glutamate, which stimulates neuronal activity, and GABA, which inhibits it. The lower the efficiency of the cleaning system, the more pronounced this imbalance was. "An excess of excitation can become toxic to neurons and contribute to alterations in certain brain regions particularly vulnerable and involved in psychosis, such as the hippocampus. Our results suggest there is a link between glymphatic system dysfunction, neurotoxicity mechanisms, and psychosis," the clinician-researcher believes.

Towards early interventions?

These results suggest that a fragile glymphatic system could make the brain more vulnerable to the onset of psychosis, possibly through inflammation or excess neuronal excitation. The next steps will aim to analyze the links between peripheral inflammation, observable in the blood, and sleep quality known to influence glymphatic function and the onset of psychosis.

"Identifying such modifiable predictive factors could open the way to strategies aimed at delaying, or even preventing, a first psychotic episode," concludes Stephan Eliez, full professor in the Department of Psychiatry of the Faculty of Medicine and the Synapsy Center at UNIGE, director of the Pôle Autisme Foundation.