Summary: Schizophrenia and related psychotic disorders are often preceded by “silent” brain vulnerabilities long before symptoms like hallucinations emerge. A groundbreaking study has identified a potential culprit: the glymphatic system, the brain’s internal waste-clearance mechanism.
By studying individuals with 22q11.2 deletion syndrome—a high-risk genetic condition—researchers found that a “clogged” drainage system in childhood predicts the onset of psychosis in adulthood. This dysfunction leads to a toxic buildup of neurotransmitters in the hippocampus, potentially triggering the neurodevelopmental shift toward schizophrenia.
Key Facts
- The Glymphatic System: Functioning like a brain “dishwasher,” this system uses cerebrospinal fluid to flush out metabolic waste, inflammatory molecules, and excess neurotransmitters.
- The 22q11.2 Connection: People with this microdeletion have a 30–40% risk of psychosis. The study found their clearance systems are altered as early as childhood.
- Trajectory of Risk: In healthy individuals, glymphatic efficiency increases with age. In those who later develop psychosis, this “maturation” of the drainage system never happens.
- Chemical Imbalance: Poor drainage was directly linked to an imbalance in the hippocampus between glutamate (excitation) and GABA (inhibition). When glutamate isn’t cleared, it becomes toxic to neurons.
- Predictive Power: This study suggests that monitoring the brain’s waste-clearance efficiency could serve as an early warning system for psychiatric disorders.
Source: University of Geneva
Hallucinations and delusions are among the characteristic psychotic symptoms of schizophrenia spectrum disorders, which may also be accompanied by social withdrawal and cognitive decline. These disorders, considered neurodevelopmental conditions, most often emerge during adolescence or early adulthood and have an estimated prevalence of 0.5–3% 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, often marking the onset of schizophrenia, may be accompanied by a decline in cognitive functions.
Understanding the brain vulnerabilities present before clinical onset is therefore crucial for preventing, delaying, or reducing symptom severity, particularly in individuals at risk.
Is the brain’s clearance system involved?
The UNIGE research team focused on 22q11.2 deletion syndrome, a genetic condition associated with a 30-40% risk of developing psychotic symptoms. This microdeletion includes genes involved in the integrity of the glymphatic system, which acts as a brain waste-clearance system.
It eliminates metabolic waste, inflammatory molecules, and excess neurotransmitters through the circulation of cerebrospinal fluid and its exchanges with the interstitial fluid that surrounds brain cells.
This cerebral drainage system may promote inflammation and neuronal toxicity when it is not functioning properly. Both of these phenomena are suspected of promoting the onset of psychotic symptoms.
A neurodevelopmental vulnerability
The team analysed a cohort of individuals with 22q11.2 deletion syndrome who were followed from childhood to adulthood and compared them to healthy individuals. Longitudinal imaging data, that were first collected more than twenty-five years ago, were reanalysed using new techniques that were optimised and automated by the team.
Within the 22q11.2 group, a subgroup developed psychotic symptoms during follow-up, allowing 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 glymphatic system function.
The researchers thus observed that the brain’s clearance system was significantly altered in individuals carrying the 22q11.2 deletion, and already in childhood. Moreover, while glymphatic system efficiency normally increases during development, this progression was not observed in a subgroup of participants with the 22q11.2 deletion who developed psychotic symptoms.
“This atypical trajectory suggests that a vulnerability resulting from an interaction between biological and environmental factors is present well before the onset of symptoms,” explains Alessandro Pascucci, first author of the study, PhD student in the Department of Psychiatry at the Faculty of Medicine and at the Synapsy Center at UNIGE, and resident doctor in child psychiatry at the Fondation Pôle Autisme.
The researchers also measured the balance between excitatory and inhibitory 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 brain’s clearance system, the more pronounced this imbalance was.
“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. Our results suggest a link between glymphatic system dysfunction, mechanisms of neurotoxicity, and psychosis,” says the clinician-researcher.
Towards early intervention?
These results suggest that an impaired glymphatic system could make the brain more vulnerable to the onset of psychosis, possibly through inflammation or excessive neuronal excitation. The next steps will be to analyse the links between peripheral inflammation, observable in the blood, sleep quality, which is known to influence glymphatic function, and the onset of psychosis.
“Identifying such modifiable predictive factors could pave the way for strategies to delay or even prevent a first psychotic episode,” concludes Stephan Eliez, full professor in the Department of Psychiatry at the Faculty of Medicine and at the Synapsy Center at UNIGE, and director of the Pôle Autisme Foundation.
Key Questions Answered:
A: Indirectly, yes. If the brain can’t flush out metabolic waste and excess chemicals (like glutamate), those substances build up and become “neurotoxic.” This toxicity specifically attacks vulnerable areas like the hippocampus, which handles memory and reality-testing. When those circuits are damaged or over-excited, the brain can start generating the “false signals” we call hallucinations or delusions.
A: This is a neurodevelopmental vulnerability. The study shows that the “drainage pipes” are poorly constructed from the start due to genetics. As the brain grows and produces more waste, the system can’t keep up. The damage accumulates slowly until the brain reaches a breaking point—usually in late adolescence—resulting in a first psychotic episode.
A: That is the ultimate goal of this research. While we can’t change genetics yet, we know that things like sleep quality significantly improve glymphatic function. Future treatments might focus on boosting brain drainage through better sleep, anti-inflammatory strategies, or specific medications to prevent the toxic buildup before it causes permanent damage.
Editorial Notes:
- This article was edited by a Neuroscience News editor.
- Journal paper reviewed in full.
- Additional context added by our staff.
About this psychosis and neuroscience research news
Author: Antoine Guenot
Source: University of Geneva
Contact: Antoine Guenot – University of Geneva
Image: The image is credited to Neuroscience News
Original Research: Open access.
“Developmental Alterations in the DTI-ALPS Index Suggest Possible Glymphatic-Related Mechanisms Underlying Excitation/Inhibition Imbalance and Psychosis Vulnerability in 22q11.2 Deletion Syndrome” by Alessandro Pascucci, Silas Forrer, Corrado Sandini, Valentina Mancini, Yasser Alemán-Gómez, Stephan Eliez, and Farnaz Delavari. Biological Psychiatry Global Open Science
DOI:10.1016/j.bpsgos.2026.100713
Abstract
Developmental Alterations in the DTI-ALPS Index Suggest Possible Glymphatic-Related Mechanisms Underlying Excitation/Inhibition Imbalance and Psychosis Vulnerability in 22q11.2 Deletion Syndrome
Background
Impairment of the glymphatic system may contribute to atypical brain development and increased vulnerability to psychiatric conditions such as psychosis. In particular, disrupted glymphatic efficiency may affect neurochemical homeostasis during critical maturational windows, leading to structural and circuit-level alterations. However, its role in early neurodevelopmental trajectories remains largely unexplored.
Methods
We combined longitudinal diffusion tensor imaging (DTI) in 85 individuals with 22q11.2 deletion syndrome (22q11DS), a neurodevelopmental condition associated with elevated psychosis risk (143 scans), with cross-sectional magnetic resonance spectroscopy (MRS) in a subset of 39 individuals with 22q11DS. Glymphatic function was estimated indirectly using the DTI-ALPS index, a diffusion-based proxy derived from manual and automated ROI placement. Excitation/inhibition ratio was assessed in the right hippocampus via CSF-corrected Glx and GABA levels.
Results
ALPS index was significantly reduced in 22q11DS compared to controls (p = 0.017), especially in the right hemisphere. Individuals with positive psychotic symptoms (PPS+) showed a divergent developmental trajectory, failing to exhibit the age-related ALPS increase seen in PPS− (group x age interaction: p = 0.009). In a subset with spectroscopy data (n = 39), lower ALPS predicted higher Glx/GABA ratio in the right hippocampus (p = 0.002).
Conclusions
These findings provide in vivo evidence that glymphatic-related dysfunction, as indexed by the DTI-ALPS proxy, emerges early and follows atypical developmental trajectories in those at risk for psychosis. Impaired ALPS index is also associated with excitatory/inhibitory imbalance. This dysfunction may represent a novel pathway contributing to psychosis vulnerability and a potential target for early intervention.
