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Schizophrenia and related psychotic disorders, long understood as complex neurodevelopmental conditions, are often preceded by subtle, "silent" brain vulnerabilities that emerge years before overt symptoms like hallucinations and delusions manifest. A significant new study from the University of Geneva has identified a compelling potential mechanism underlying this predisposition: the glymphatic system, the brain’s intrinsic waste-clearance network. Researchers, by meticulously studying individuals with 22q11.2 deletion syndrome – a high-risk genetic condition – have discovered that impaired glymphatic drainage in childhood strongly predicts the subsequent onset of psychosis in adulthood. This dysfunction is posited to lead to a toxic accumulation of neurotransmitters within critical brain regions, particularly the hippocampus, potentially triggering the neurodevelopmental trajectory towards schizophrenia. This finding not only offers unprecedented insight into the early origins of psychosis but also opens promising new avenues for preventative interventions.
The Silent Precursors to Psychosis: Understanding Neurodevelopmental Vulnerability
Psychotic disorders, including schizophrenia, are characterized by a spectrum of debilitating symptoms, most notably hallucinations and delusions, but also encompassing social withdrawal, disorganized thought, and cognitive decline. These conditions typically emerge during the critical developmental windows of adolescence or early adulthood, affecting an estimated 0.5% to 3% of the general population worldwide. The concept of schizophrenia as a "neurodevelopmental" disorder suggests that its roots lie in atypical brain development, long before clinical symptoms become apparent. Identifying these early, often silent, vulnerabilities is paramount for developing effective strategies to prevent, delay, or mitigate the severity of symptoms, especially in individuals known to be at elevated risk. The hippocampus, a deep brain structure crucial for memory formation, learning, and emotional regulation, has been consistently implicated in the pathophysiology of psychotic disorders. Its dysfunction is thought to contribute significantly to the cognitive impairments and altered reality perception observed in patients. A first psychotic episode often coincides with a noticeable decline in cognitive functions, highlighting the progressive nature of the disorder and the urgent need for early detection and intervention.
Unveiling the Glymphatic System’s Critical Role
Central to this groundbreaking research is the glymphatic system, a sophisticated, recently characterized network responsible for waste clearance within the central nervous system. Discovered in 2012, this system acts as the brain’s lymphatic equivalent, facilitating the rapid removal of metabolic byproducts, inflammatory molecules, and excess neurotransmitters from the brain’s interstitial fluid. This vital cleansing process is primarily driven by the circulation of cerebrospinal fluid (CSF) through specialized peri-arterial spaces, which then exchanges with the interstitial fluid surrounding brain cells, ultimately draining into the peripheral lymphatic system.
The efficiency of the glymphatic system is profoundly influenced by sleep, during which the interstitial space expands, allowing for enhanced waste removal. When this intricate drainage system falters, waste products can accumulate, leading to chronic inflammation and neuronal toxicity. Both inflammation and neurotoxicity are increasingly recognized as significant contributors to various neurodegenerative and neuropsychiatric conditions, including those suspected of promoting the onset of psychotic symptoms. The University of Geneva team hypothesized that disruptions in this fundamental clearance mechanism could be a key "silent" vulnerability preceding psychosis.
The 22q11.2 Deletion Syndrome: A Genetic Window into Psychosis
To investigate the glymphatic system’s role, the research team focused on individuals with 22q11.2 deletion syndrome (22q11DS), also known as DiGeorge syndrome or velocardiofacial syndrome. This genetic condition results from a microdeletion on chromosome 22 and is one of the strongest known genetic risk factors for developing psychotic disorders, with an estimated 30% to 40% of affected individuals progressing to schizophrenia or other psychoses by adulthood. Beyond the elevated risk for psychiatric conditions, 22q11DS presents a wide array of physical and developmental challenges, including congenital heart defects, immune deficiencies, characteristic facial features, learning disabilities, and developmental delays. Its prevalence is estimated to be between 1 in 3,000 to 1 in 6,000 live births.
Crucially for this study, the 22q11.2 microdeletion encompasses genes that are known to be involved in maintaining the integrity and function of the glymphatic system. This genetic predisposition offered the researchers a unique "natural experiment" to explore the link between impaired glymphatic function and psychosis vulnerability in a well-defined at-risk population. By tracking these individuals over many years, the team could observe developmental trajectories and identify early markers of risk.
Methodology: A Longitudinal Look at Brain Dynamics
The robustness of the University of Geneva study stems from its longitudinal design, a critical aspect that allowed researchers to observe changes over time. The team re-analyzed a cohort of individuals with 22q11DS who had been followed from childhood into adulthood, with initial imaging data collected more than twenty-five years ago. This extensive dataset was revisited using cutting-edge, newly optimized, and automated analytical techniques, enabling a deeper dive into brain physiology than was previously possible. A control group of healthy individuals was also studied for comparison.
To indirectly estimate glymphatic system function, the researchers employed a specific methodology applied to diffusion magnetic resonance imaging (DTI). DTI is an advanced MRI technique that measures the diffusion of water molecules in the brain, providing insights into the microstructural organization of brain tissue. The DTI-ALPS (Diffusion Tensor Imaging-based Analysis of Lymphatic Drainage Pathways) index, a diffusion-based proxy, was used to quantify glymphatic efficiency. This innovative approach allowed the team to assess the brain’s "cleanliness" non-invasively.
Furthermore, in a subset of the cohort, magnetic resonance spectroscopy (MRS) was utilized to measure the balance between excitatory and inhibitory neurotransmitters in the right hippocampus. Specifically, MRS quantified levels of glutamate (Glx, a measure of glutamate and glutamine), which stimulates neuronal activity, and gamma-aminobutyric acid (GABA), which inhibits it. An imbalance in this delicate excitation/inhibition (E/I) ratio is a known hallmark of various neurological and psychiatric disorders.
Key Findings: A Clogged System from Childhood Predicts Psychosis
The study yielded several compelling and interconnected findings. Firstly, the DTI-ALPS index, indicating glymphatic system efficiency, was found to be significantly reduced in individuals carrying the 22q11.2 deletion compared to healthy controls, and this impairment was evident as early as childhood. This suggests a fundamental, genetically linked vulnerability in the brain’s waste clearance mechanism from an early age.
Secondly, and perhaps most critically, the researchers observed a divergent developmental trajectory within the 22q11DS group. While glymphatic system efficiency typically improves with age and brain maturation in healthy individuals, this normal progression was absent in the subgroup of participants with the 22q11.2 deletion who subsequently developed psychotic symptoms during the follow-up period. As Alessandro Pascucci, first author of the study and a PhD student in the Department of Psychiatry at the Faculty of Medicine and at the Synapsy Center at UNIGE, explained, "This atypical trajectory suggests that a vulnerability resulting from an interaction between biological and environmental factors is present well before the onset of symptoms." This highlights a persistent, uncorrected glymphatic dysfunction that accumulates over years, increasing the risk for psychosis.
Adding another layer of evidence, the study revealed a direct correlation between impaired glymphatic efficiency and neurotransmitter imbalance. Specifically, the lower the efficiency of the brain’s clearance system, the more pronounced was the excitation/inhibition imbalance in the hippocampus, characterized by a higher Glx/GABA ratio. This indicates an excess of excitatory signaling relative to inhibitory control. "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 Hippocampus: A Vulnerable Hub for Neurotoxicity
The focus on the hippocampus is particularly significant. This seahorse-shaped structure deep within the temporal lobe is a cornerstone of learning and memory. Its vulnerability to stress, inflammation, and neurotoxicity makes it a prime candidate for involvement in disorders like schizophrenia. In psychosis, the hippocampus is often observed to be smaller or show abnormal activity. The study’s finding that glymphatic dysfunction leads to an excitatory overload in the hippocampus provides a concrete mechanism by which early brain vulnerabilities can translate into later symptomatic expression. The accumulation of excess glutamate, for instance, can overstimulate neurons to the point of damage or death, a process known as excitotoxicity. Over time, this chronic neurotoxic environment could progressively compromise hippocampal function, contributing to the distorted reality perception and cognitive deficits characteristic of psychosis.
Implications for Early Intervention and Future Research
These findings represent a significant leap forward in understanding the etiology of psychotic disorders. By identifying a modifiable biological pathway – the glymphatic system – that is compromised years before symptom onset, the research opens exciting new avenues for early intervention. If a "clogged" brain drainage system is a key vulnerability, then strategies aimed at improving glymphatic function could potentially delay or even prevent the first psychotic episode in at-risk individuals.
The next steps for the research team will involve exploring the intricate links between peripheral inflammation (observable in blood markers), sleep quality, and the onset of psychosis. Sleep is a well-established factor in glymphatic efficiency, with deeper, restorative sleep significantly enhancing the system’s waste-clearing capabilities. Therefore, interventions targeting sleep hygiene or pharmaceutical approaches to improve sleep architecture could be promising avenues for future clinical trials. Similarly, anti-inflammatory strategies could mitigate the neurotoxic effects of impaired glymphatic function.
As 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, concluded, "Identifying such modifiable predictive factors could pave the way for strategies to delay or even prevent a first psychotic episode." This sentiment resonates across the scientific community, as the potential to intervene pre-symptomatically in such a devastating illness is a long-held goal.
Broader Impact and Expert Perspectives
This study’s implications extend beyond 22q11.2 deletion syndrome, offering a potential generalizable mechanism for psychosis vulnerability. While the genetic condition provides a clear model, similar glymphatic impairments could arise from other genetic predispositions, environmental factors, or a combination thereof, contributing to psychosis risk in the broader population. The ability to indirectly assess glymphatic function using non-invasive imaging techniques like DTI also suggests the potential for developing early diagnostic biomarkers that could identify at-risk individuals even before the appearance of subtle behavioral changes.
The research also underscores the increasing recognition of the brain’s immune and waste-clearance systems in neuropsychiatric disorders. For decades, the focus was primarily on neurotransmitter imbalances; now, the interplay of genetics, neurodevelopment, neuroinflammation, and waste clearance is coming into sharper focus. This holistic view is crucial for developing multi-faceted treatment approaches that address the underlying biological vulnerabilities rather than merely managing symptoms. The findings are expected to stimulate further research into the glymphatic system’s role in other neurodevelopmental and neurodegenerative disorders, potentially unlocking common mechanisms of disease.
In conclusion, the University of Geneva’s pioneering work highlights that the seeds of psychosis can be sown in childhood, long before symptoms emerge, through a fundamental breakdown in the brain’s ability to cleanse itself. By linking genetic vulnerability, impaired glymphatic function, neurotoxic accumulation, and eventually, the onset of psychosis, this study provides a crucial piece of the puzzle in understanding and ultimately combating these complex and challenging conditions. The prospect of leveraging these insights for early intervention offers a beacon of hope for individuals and families affected by schizophrenia spectrum disorders.
Source: University of Geneva
Author: Antoine Guenot
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.
