Summary: Schizophrenia and related psychotic disorders are frequently preceded by silent brain vulnerabilities that appear long before overt symptoms such as hallucinations or delusions. A major new study points to the glymphatic system—the brain’s internal waste-clearance pathway—as a possible contributor to that early vulnerability.
Researchers studying people with 22q11.2 deletion syndrome, a genetic condition that carries a high risk of psychosis, found that impaired glymphatic drainage in childhood predicts later development of psychotic symptoms. This impaired clearance allows neurotransmitters and metabolic byproducts to accumulate in the hippocampus, which may trigger the neurodevelopmental cascade that leads to schizophrenia spectrum disorders.
Key Facts
- The glymphatic system: This brain-wide clearance network uses cerebrospinal fluid to remove metabolic waste, inflammatory molecules, and excess neurotransmitters, helping maintain neurochemical balance.
- 22q11.2 deletion syndrome link: Individuals with this microdeletion face a 30–40% lifetime risk of psychosis. The study shows altered glymphatic function in these individuals from childhood onward.
- Developmental trajectory: In typically developing people, glymphatic efficiency tends to increase with age. In those who later develop psychosis, that maturation of clearance function does not occur.
- Excitation/inhibition imbalance: Poor glymphatic clearance was associated with a higher ratio of glutamate (excitatory) to GABA (inhibitory) in the hippocampus. Excess extracellular glutamate can be neurotoxic and disrupt circuits involved in cognition and reality monitoring.
- Predictive potential: Measuring glymphatic efficiency may offer an early biomarker to identify individuals at higher risk of psychiatric disorders and could guide preventive strategies.
Source: University of Geneva
Psychotic symptoms such as hallucinations and delusions often emerge alongside social withdrawal and cognitive decline in schizophrenia spectrum disorders. These conditions are considered neurodevelopmental and typically appear in adolescence or early adulthood, with an estimated prevalence between 0.5% and 3% in the general population.
The hippocampus—a brain region central to memory, learning, and the evaluation of experience—has been strongly implicated in the development of psychotic symptoms. A first psychotic episode commonly coincides with declines in cognitive functioning, making it critical to identify the brain changes that exist before clinical onset so we can delay or prevent progression.
Is the brain’s clearance system involved?
A research team at the University of Geneva (UNIGE) investigated the potential role of the glymphatic system in psychosis vulnerability by focusing on individuals with 22q11.2 deletion syndrome. This microdeletion affects genes that contribute to glymphatic integrity and is associated with markedly elevated risk for psychotic disorders.
The glymphatic system removes metabolic waste, inflammatory molecules, and surplus neurotransmitters via cerebrospinal fluid flow and exchanges with the brain’s interstitial fluid. When this system is compromised, waste and inflammatory mediators can accumulate and promote neuronal toxicity—processes suspected to increase the likelihood of psychotic symptoms.
A neurodevelopmental vulnerability
The team reanalyzed longitudinal brain imaging data from people with 22q11.2 deletion syndrome who had been followed from childhood into adulthood, comparing them with healthy controls. The imaging data, collected over more than 25 years, were reassessed using improved, automated methods developed by the researchers.
Within the 22q11.2 group, a subset went on to develop psychotic symptoms, revealing divergent developmental pathways. Using diffusion tensor imaging (DTI) and a specific diffusion-based metric (DTI-ALPS index), the researchers estimated glymphatic function indirectly by measuring water diffusion patterns that reflect perivascular clearance.
They found that glymphatic function was already reduced in childhood among people with the 22q11.2 deletion. Furthermore, whereas glymphatic efficiency typically increases with age in healthy development, participants who later developed psychosis failed to show this age-related improvement—indicating an early and persistent drainage deficit.
The researchers also used magnetic resonance spectroscopy (MRS) to assess the balance between excitatory and inhibitory neurotransmission in the hippocampus, specifically measuring glutamate (Glx) and GABA levels. Lower glymphatic efficiency predicted a higher glutamate-to-GABA ratio, a pattern associated with neuronal overexcitation and potential neurotoxicity in regions vulnerable to psychosis.
“Excessive excitation can damage neurons and alter circuits in brain areas like the hippocampus that are critical for memory and reality testing,” explains Alessandro Pascucci, the study’s first author and a clinician-researcher in child psychiatry. “Our findings link glymphatic dysfunction to neurotoxic mechanisms that may promote psychosis vulnerability.”
Toward early intervention?
These results support the idea that compromised glymphatic clearance increases brain vulnerability to psychosis, potentially through inflammation and excessive neuronal excitation. Next research steps include examining how peripheral inflammation measurable in blood, sleep quality (a known regulator of glymphatic function), and other modifiable factors relate to glymphatic efficiency and psychosis onset.
“If modifiable factors that influence glymphatic function can be identified and validated, they could become targets for interventions aimed at delaying or preventing a first psychotic episode,” says Stephan Eliez, professor in the Department of Psychiatry at UNIGE.
Key Questions Answered:
A: Indirectly, yes. When the brain’s clearance system fails to remove metabolic waste and excess neurotransmitters such as glutamate, these substances can accumulate and become neurotoxic. Vulnerable structures like the hippocampus, which help distinguish internal thoughts from external reality, are especially susceptible. Disruption of these circuits can contribute to the false perceptions and beliefs we label hallucinations and delusions.
A: This reflects a neurodevelopmental vulnerability. Genetic factors can cause the brain’s drainage architecture to be impaired early in life. As the brain matures and metabolic demands increase, an insufficient clearance system cannot keep pace, allowing damage to accumulate gradually until clinical symptoms emerge in adolescence or early adulthood.
A: That is a core objective of this line of research. While we cannot change genetic risk today, improving factors known to enhance glymphatic clearance—most notably sleep quality—may reduce harmful accumulations. Future preventive strategies might include optimizing sleep, reducing inflammation, and developing targeted therapies to support brain clearance before irreversible damage occurs.
Editorial Notes:
- This article was edited by a Neuroscience News editor.
- The full journal paper was reviewed for accuracy.
- Additional context was provided by editorial 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.
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
Impaired glymphatic clearance may contribute to atypical brain maturation and raise vulnerability to psychiatric conditions such as psychosis. Disrupted glymphatic efficiency during critical developmental windows could disturb neurochemical balance and lead to structural or circuit-level changes. Yet the role of glymphatic function in early neurodevelopmental trajectories has remained underexplored.
Methods
The study combined longitudinal diffusion tensor imaging (DTI) in 85 individuals with 22q11.2 deletion syndrome (143 scans) with cross-sectional magnetic resonance spectroscopy (MRS) in a subset of 39 participants. Glymphatic function was estimated indirectly using the DTI-ALPS index, derived from manual and automated region-of-interest placement. Excitation/inhibition balance in the right hippocampus was assessed using cerebrospinal-fluid-corrected Glx and GABA measurements.
Results
The ALPS index was significantly lower in individuals with 22q11.2 deletion syndrome compared to controls (p = 0.017), particularly in the right hemisphere. Participants who developed psychotic symptoms displayed a distinct developmental trajectory, failing to show the age-related ALPS increase seen in those without symptoms (group × age interaction: p = 0.009). In the spectroscopy subset (n = 39), lower ALPS values predicted a higher Glx/GABA ratio in the right hippocampus (p = 0.002).
Conclusions
These in vivo results indicate that glymphatic-related dysfunction appears early and follows an atypical developmental course in individuals at risk for psychosis. Reduced ALPS index is associated with an excitatory/inhibitory imbalance, suggesting a potential pathway by which impaired clearance contributes to psychosis vulnerability and identifying a possible target for early preventive interventions.