Schizophrenia is a chronic mental health disorder characterized by hallucinations, delusions, disorganized thinking and atypical movement or speech patterns. This psychiatric condition can be highly debilitating, and diagnosed individuals can report markedly different experiences.
Understanding the neurobiological basis of schizophrenia could be highly valuable, as it could inform the development of new interventions to reduce the risk of its emergence or treat its symptoms. The results of many neuroimaging studies carried out so far, however, were inconsistent or inconclusive, failing to clearly delineate the processes and brain regions implicated in its clinical expression.
In a recent paper published in Nature Mental Health, researchers at Taipei Medical University analyzed meta-analyses summarizing the most consistent findings of schizophrenia-related neuroimaging studies. Drawing on the results of this analysis, they developed a new theoretical model that delineates characteristic brain alterations linked to the psychiatric disorder.
“The reality is that, as with any major psychiatric disorder, the causes and mechanisms underlying schizophrenia remain unknown,” Matteo Martino and Paola Magioncalda, co–first authors of the paper, told Medical Xpress.
“A critical first step toward progress is to identify the brain changes that reliably accompany the condition, specifically where they occur and how they evolve over time. Although enormous amounts of data exist, findings are often inconsistent or even contradictory, partly due to challenges in clinical definitions, research methods, and subtype or individual variations. Researchers can easily get lost in this sea of heterogeneous results.”
To paint a clearer picture of the disorder’s neurobiological underpinnings, the researchers conducted an umbrella review of existing neuroimaging meta-analyses on schizophrenia. Their large-scale analysis allowed them to identify the findings that were most consistent across thousands of studies and combine them into a coherent model.
The umbrella review was aimed at uncovering the structural and functional brain alterations that are most linked to schizophrenia. In addition, the team set out to map the spatial distribution of these alterations and how they evolved over time, ultimately enabling the creation of a more precise biological model of schizophrenia.
“We collected all existing meta-analyses of neuroimaging studies in schizophrenia that used unbiased, data-driven voxelwise approaches, meaning they did not assume in advance which brain regions would be affected,” explained Martino and Magioncalda.
“We included studies comparing patients and healthy controls across the prodromal, early, and chronic stages of the illness, as well as studies linking brain changes to schizophrenia symptoms. We then mapped the reported brain coordinates onto a common template to reveal key spatial and temporal patterns of alterations, which we believe may reflect the underlying biology of schizophrenia.”
The recent work by Martino, Magioncalda and their colleague Abhishek Yadav is a further step towards a better understanding of schizophrenia and its neurobiology. The researchers were able to map out various brain alterations linked to the disorder, while also delineating how they typically evolve over time as the disorder progresses.
“Building on these data, we developed a novel conceptual framework that links the spatiotemporal pattern of brain alterations to the underlying pathophysiology and symptomatology of schizophrenia,” said Martino and Magioncalda.
“In the prodromal stage, changes are confined to the midline regions such as the medial prefrontal cortex, whose developmental role suggests early neurodevelopmental vulnerability. In the early psychotic stage, damage extends to gray matter in opercular regions (including the insula and superior temporal gyrus) and to white matter areas near the ventricles, along with dysfunction of the default-mode network. The proximity of the structural damage to cerebrospinal fluid pockets raises the possibility of additional pathological factors, such as immune-related processes, spreading through the cerebrospinal fluid.”
The results of the team’s analyses outlined further patterns of brain alterations that are linked to the experience of psychosis, a state that is experienced by people diagnosed with schizophrenia characterized by a severely disturbed perception of reality. These included structural damage to a brain region called the operculum, particularly a section of it known as the superior temporal gyrus.
Damage in this region, which includes the auditory cortex, was found to be associated with the experience of auditory hallucinations. In contrast, dysfunction in a large-scale brain network, the so-called default-mode network, was found to be linked to delusions (i.e., fixed distorted or false beliefs).
The umbrella review showed that these alterations tend to become more pronounced and widespread at the chronic stage of the disorder, consistently affecting the thalamus and prefrontal cortex. These are important brain regions that support many cognitive functions. Thus, their significant alteration could explain the deterioration of mental abilities observed in patients at advanced stages of schizophrenia.
“We hope that our biological model of schizophrenia, grounded in the most consistent evidence to date, will help move the field toward a mechanistic understanding of the condition—the necessary basis for developing more effective therapies,” said Martino and Magioncalda.
“Theoretically, we are now exploring the overlap and boundaries between schizophrenia, major depressive disorder, and bipolar disorder, aiming to disentangle their shared features and disorder-specific alterations in order to build an integrated framework for understanding severe mental illness.”
In the future, the biological model of schizophrenia introduced by Martino, Magioncalda and their colleagues could be improved further or updated in light of new empirical findings. Meanwhile, the researchers plan to conduct some experiments aimed at testing various hypotheses that emerged from their framework.
“For example, one key hypothesis is that immune-related mechanisms may spread through cerebrospinal fluid and damage nearby brain regions,” added Martino and Magioncalda.
“Another hypothesis focuses on how structural deficits in sensory cortices could give rise to modality-specific hallucinations, as part of the working model of psychosis we outlined in the paper. Our ultimate goal is to achieve a mechanistic understanding of major psychiatric disorders—knowledge that we believe is essential for developing scientifically grounded and truly targeted therapies.”
Written for you by our author Ingrid Fadelli, edited by Gaby Clark, —this article is the result of careful human work. We rely on readers like you to keep independent science journalism alive.
If this reporting matters to you,
please consider a donation (especially monthly).
You’ll get an ad-free account as a thank-you.
More information:
Paola Magioncalda et al, An umbrella review of neuroimaging studies and conceptual framework linking pathophysiology and psychopathology in schizophrenia, Nature Mental Health (2025). DOI: 10.1038/s44220-025-00493-5.
The content is provided for information purposes only.