The research team recruited 21 adolescents experiencing a first episode of schizophrenia who had not yet received any antipsychotic medication, together with 21 age-matched healthy controls. This drug-naïve design matters enormously for interpretation. Most imaging studies of schizophrenia are conducted on patients who have been taking antipsychotic drugs for months or years, and because these medications act directly on dopamine and other neurotransmitter receptors, they can themselves reshape brain structure and function. By scanning patients before treatment began, the researchers could be far more confident that the abnormalities they observed were related to the illness process itself rather than to the pharmacological consequences of therapy.

The methodological strategy unfolded in three stages. First, the team used voxel-based morphometry, or VBM, a computational technique that compares the volume of gray matter, the densely packed tissue containing neuronal cell bodies, at every point across the brain. VBM normalizes each participant’s scan to a common template, segments the tissue into gray matter, white matter, and cerebrospinal fluid, and then performs statistical comparisons voxel by voxel to locate regions where tissue volume differs between groups. In this study, VBM revealed that patients with adolescent-onset schizophrenia had significantly increased gray matter volume in two regions: the right supramarginal gyrus and the precuneus.

That finding of increased, rather than reduced, gray matter is itself noteworthy. The dominant narrative in schizophrenia research has long emphasized gray matter loss, particularly in frontal and temporal cortices, reflecting excessive synaptic pruning during adolescence. The supramarginal gyrus, tucked into the parietal lobe, is involved in language processing, spatial attention, and the integration of sensory information, while the precuneus, buried deep in the medial parietal cortex, is one of the brain’s most metabolically active hubs, central to self-referential thinking, episodic memory, and consciousness itself. Both regions have been repeatedly implicated in the hallucinations and disturbances of self-experience that characterize psychosis. Elevated volume in these areas during early adolescence may reflect delayed or disrupted developmental maturation, a possibility the authors suggest fits with neurodevelopmental models of the disorder in which the typical adolescent refinement of cortical circuits goes awry.

Next came the second and arguably most innovative stage: Granger causality analysis, or GCA, applied to resting-state functional MRI data. While conventional functional connectivity analysis measures how correlated the activity of two brain regions is, it cannot say anything about direction. Granger causality analysis addresses this by exploiting the temporal structure of the signals: if the past activity of region A improves the prediction of future activity in region B beyond what region B’s own past activity can achieve, then region A is said to Granger-cause region B. In the context of fMRI, this provides a model of directed influence, an estimate of which brain regions are driving which. The researchers used the regions showing gray matter abnormalities, the right supramarginal gyrus and the right precuneus, as seeds, and computed directed connectivity from these structural abnormality hubs to the rest of the brain.

The results revealed a strikingly asymmetric pattern of disruption. From the enlarged right supramarginal gyrus, patients showed increased Granger causal connectivity to two targets: the right superior occipital gyrus, a visual processing area, and the right precentral gyrus, the site of the primary motor cortex. Heightened causal drive from a parietal association region into visual and motor areas could plausibly relate to some of schizophrenia’s most characteristic symptoms, including visual distortions and the sense that one’s own movements or perceptions are being generated or controlled by external forces. Meanwhile, a different and opposite pattern emerged from the precuneus: patients showed decreased Granger causal connectivity from the right precuneus to the orbital part of the right inferior frontal gyrus, a prefrontal region involved in emotion regulation, decision-making, and inhibitory control. Weakened top-down influence from the precuneus onto this orbital frontal territory may reflect a breakdown in the communication between self-referential processing circuits and the frontal systems that normally regulate emotion and behavior.

The third stage of the study is what elevates it beyond a conventional case-control imaging comparison. The team employed the JuSpace toolbox, a software package designed to correlate spatial maps of brain imaging findings with atlas-based maps of neurotransmitter receptor and transporter distributions. These atlases, derived from positron emission tomography studies, chart where in the brain particular molecular targets are densely expressed. The logic is elegant: if a pattern of connectivity alteration is not randomly distributed across the cortex but instead aligns with the spatial fingerprint of a specific neurotransmitter system, that system becomes a candidate molecular mechanism underlying the observed disruption. In this case, the alterations in Granger causal connectivity anchored to the right precuneus showed significant spatial correspondence with an unusually broad set of neurotransmitter systems: serotonergic markers including the 5-HT1b receptor and the serotonin transporter SERT, dopaminergic markers including the D1 and D2 receptors and the dopamine transporter DAT, the GABAa receptor of the inhibitory GABAergic system, the metabotropic glutamate receptor mGluR5, the kappa opioid receptor, and the vesicular acetylcholine transporter VAChT.

The breadth of this molecular correspondence is scientifically provocative. Dopamine has dominated schizophrenia research for half a century, and all effective antipsychotic drugs block D2 receptors, but the dopamine hypothesis alone has never fully explained the disorder. The finding that precuneus-based connectivity disruptions align with dopaminergic, serotonergic, GABAergic, glutamatergic, opioid, and cholinergic maps simultaneously supports contemporary models in which schizophrenia arises from disturbances distributed across multiple interacting neurotransmitter systems rather than from a single chemical lesion. The glutamatergic and GABAergic findings are particularly interesting because excitatory-inhibitory balance in cortical circuits is thought to be a core mechanism disrupted during adolescent brain development, and the serotonergic and opioid systems have been increasingly implicated in the negative and affective symptoms of psychosis.

The authors are careful to frame these findings as hypothesis-generating rather than definitive. The sample size of 21 patients per group is modest, as is almost inevitable in studies of first-episode, drug-naïve adolescents, and Granger causality analysis applied to fMRI carries well-known interpretive caveats, since hemodynamic signals are an indirect and slow measure of neural activity and causal inferences from them must be made cautiously. Spatial correlations with neurotransmitter maps, moreover, are computed at the group level and cannot establish that any individual patient’s symptoms arise from a particular receptor system. The gray matter increases observed here also diverge from some prior reports of volume loss in psychosis, underscoring that adolescent-onset disease may follow a partially distinct neuroanatomical trajectory from adult-onset schizophrenia.

Even with those caveats, the study makes a genuine contribution by braiding together three levels of analysis that are usually pursued separately: brain structure, directed functional communication, and molecular architecture. For a disorder that typically announces itself in adolescence and exacts a lifelong toll, identifying which circuits are structurally anomalous, how their influence over the rest of the brain is distorted, and which neurotransmitter systems their disruptions track could ultimately sharpen the search for targeted treatments. The authors suggest that their findings point toward potential therapeutic strategies based on neurotransmitter modulation, and the multi-system pattern they uncovered suggests that the pharmacological future of adolescent-onset schizophrenia may be more nuanced than the dopamine blockade that has defined the field’s past. As larger longitudinal cohorts follow drug-naïve patients from their first episode through treatment and recovery, this kind of structure-to-circuit-to-chemistry mapping may become a standard lens for understanding, and eventually intervening in, the earliest stages of psychotic illness.

Subject of Research: Granger causal connectivity abnormalities and neurotransmitter correlates of gray matter alterations in adolescent-onset schizophrenia

Article Title: Granger causal connectivity abnormalities based on altered gray matter volume in adolescent-onset schizophrenia and their spatial correspondence with neurotransmitter maps

Article References: Wang, L., Liao, J., Liu, R., Lu, S., Xiong, X., Zhuo, L., & Li, H. (2026). Granger causal connectivity abnormalities based on altered gray matter volume in adolescent-onset schizophrenia and their spatial correspondence with neurotransmitter maps. BMC Psychiatry. https://doi.org/10.1186/s12888-026-08716-4

Image Credits: AI Generated

DOI: 10.1186/s12888-026-08716-4

Keywords: adolescent-onset schizophrenia, gray matter volume, voxel-based morphometry, Granger causality analysis, resting-state fMRI, precuneus, supramarginal gyrus, neurotransmitter maps, dopamine, serotonin, JuSpace toolbox, neurodevelopment