Resting-state brain age is associated with cognitive and sensorimotor abnormalities in schizophrenia spectrum disorders: a validation & longitudinal study.
Resting-state functional connectivity brain-age models revealed higher brain-age gap in schizophrenia spectrum disorders versus controls, but within SSD, more negative (younger-appearing) BAG was associated with poorer cognitive performance, longer duration of illness, and higher neurological soft signs, suggesting FC-based BAG captures clinically relevant heterogeneity rather than uniform acceleration.
Key Findings
Results
Patients with schizophrenia spectrum disorders showed higher functional connectivity-based brain-age gap compared to healthy controls across independent cohorts and two brain atlases.
The brain-age gap (BAG) is defined as predicted brain age minus chronological age
The effect size was modest: β ≈ 0.4–0.6 across independent cohorts
Results were consistent across two brain atlases
Four independent SSD case-control cohorts were evaluated
The rs-FC brain-age models were trained on aggregated lifespan data from healthy controls (n ≈ 2200)
Results
Within SSD, more negative (younger-appearing) BAG was associated with poorer cognitive performance.
This is a within-SSD finding, distinct from the case-control direction of effect
The association indicates that patients whose functional brain age appeared younger relative to their chronological age performed worse cognitively
This finding was replicated across independent cohorts
The direction of association (younger-appearing = worse outcomes) contrasts with the simple 'acceleration' framing
Results
Within SSD, more negative (younger-appearing) BAG was associated with longer duration of illness.
Longer duration of illness correlated with more negative FC-based BAG within the SSD group
This suggests that the functional brain-age profile does not simply track chronological aging in SSD
This association was observed across independent cohorts
The finding supports the interpretation that younger-appearing functional profiles may index greater neurodevelopmental burden
Results
Within SSD, more negative (younger-appearing) BAG was associated with higher neurological soft signs (NSS).
Neurological soft signs (NSS) are subtle neurological abnormalities associated with sensorimotor dysfunction
Higher NSS scores correlated with more negative FC-based BAG within SSD
This within-group association was consistent across independent cohorts
NSS are considered markers of neurodevelopmental abnormalities in schizophrenia
Results
Over 12–24 weeks of longitudinal follow-up, increases in BAG were associated with reductions in NSS motor coordination and hard signs.
The longitudinal component spanned 12–24 weeks
Increases in FC-based BAG (i.e., brain age becoming more 'mature' relative to chronological age) were linked to improvement in motor symptoms
Specific domains included NSS motor coordination and hard signs
This longitudinal finding suggests FC-based BAG may be sensitive to treatment-related or time-related neuroplastic changes
Methods
The rs-FC brain-age model was trained on aggregated lifespan data from approximately 2200 healthy controls and evaluated in four independent SSD case-control cohorts.
Training sample: n ≈ 2200 healthy controls spanning the lifespan
Evaluation was conducted in four independent cohorts to assess generalizability
Two brain atlases were used to assess robustness of findings
This design constitutes both a validation and longitudinal study as described in the title
Discussion
The authors conclude that FC-based BAG may reflect heterogeneity in network-level development and reorganization, with younger-appearing functional profiles potentially indexing greater neurodevelopmental burden.
The findings challenge a uniform 'acceleration' model of brain aging in SSD
The authors frame the younger-appearing BAG as potentially reflecting neurodevelopmental rather than neurodegenerative processes
FC-based brain age captures 'both a small case-control shift and a clinically relevant dimension within SSD'
The clinical relevance is linked to cognitive performance, illness duration, and sensorimotor abnormalities
What This Means
This research suggests that the brain's functional connectivity patterns—how different brain regions communicate with each other at rest—can be used to estimate a 'brain age' that differs from a person's actual age in people with schizophrenia spectrum disorders (SSD). The study trained a computer model on brain scans from about 2,200 healthy people across the lifespan to learn what typical brain connectivity looks like at different ages. When this model was applied to patients with SSD across four separate patient groups, it found that on average, patients' brains appeared slightly older than expected based on their actual age—but the effect was modest.
More importantly, the study found that within the SSD patient group, patients whose brains appeared functionally *younger* than expected actually had worse outcomes: poorer thinking and memory abilities, longer time spent with the illness, and more subtle movement and neurological problems (called neurological soft signs). This seems counterintuitive, but it suggests that a 'younger-appearing' functional brain profile in these patients may reflect incomplete or disrupted brain development rather than preserved youth. Over a follow-up period of 12–24 weeks, patients whose brain age estimates increased (became more 'mature') also showed improvement in motor coordination problems, suggesting the measure may track real clinical changes over time.
This research suggests that functional brain age in schizophrenia is not simply a matter of the brain 'aging faster,' but rather reflects meaningful differences in how individual patients' brains are organized at a network level—with some patients showing patterns that look developmentally younger, which appears to be a marker of greater illness burden. This could eventually help researchers identify subgroups of patients and track responses to treatment, though more work is needed before this could be used clinically.
Volkmer S, Fritze S, Altinok D, Brandt G, Kocak E, Wiegert J, et al.. (2026). Resting-state brain age is associated with cognitive and sensorimotor abnormalities in schizophrenia spectrum disorders: a validation & longitudinal study.. Translational psychiatry. https://doi.org/10.1038/s41398-026-04426-3