Work

Contrasting Patterns of Cortical Volume Change in First-Episode Schizophrenia-Spectrum Psychosis

Year: 2026

Type: preprint

Abstract: Importance Average gray matter volume (GMV) loss in early psychosis may conceal clinically relevant differences in brain change. Objective To identify longitudinal GMV-change patterns, their cross-site correspondence, and clinical associations. Design, Setting, and Participants Prospective cohort with T1-weighted MRI acquired during 2011–2026 at 2 Czech sites; median follow-up, approximately 13 months. Participants were 222 patients with first-episode schizophrenia-spectrum psychosis and 178 healthy controls frequency-matched by site and baseline age. Exposure First-episode psychosis vs healthy control status. Main Outcomes and Measures Diagnosis-blind clustering by site of image-quality-corrected, subsequently annualized GMV change across 333 cortical parcels; longitudinal voxel-based morphometry (VBM); Global Assessment of Functioning and consensus 5-factor Positive and Negative Syndrome Scale negative-symptom scores. Results Among 400 participants (mean [SD] age, 28.2 [7.5] years), 208 (52.0%) were male. Each site independently yielded 3 clusters: C1 (near-stable GMV), C2 (pronounced decrease), and C3 (increase). Cross-site centroid correlations across 333 parcels were strong for C2 and C3 (Spearman ρ = 0.865 and 0.861); C1 correlation was weak (ρ = 0.138), as expected for near-zero profiles with little regional variation. C2/C3 correspondence supported pooling matched site-specific clusters for post hoc analyses. Pooled clusters contained 77 patients and 125 controls in C1, 66 patients and 16 controls in C2, and 79 patients and 37 controls in C3. Suffixes −P and −HC identify patient and control subgroups. To situate patient changes relative to controls, post hoc VBM revealed an unanticipated gradient of increasingly pronounced GMV reduction across C1-HC → C1-P → C2-P, prominently involving association cortex, and bilateral ventral temporal GMV increase in C3-P (familywise error–corrected P < .05). The opposite contrast along this ordering showed periventricular changes consistent with progressively greater ventricular enlargement. C2-P had the lowest mean follow-up functioning and highest mean negative-symptom severity (adjusted omnibus P = .005 and .02); clinical changes from baseline did not differ significantly among patient groups. Conclusions and Relevance Early GMV change in psychosis was not uniform but comprised two contrasting directions: a clinically relevant, control-anchored pattern of increasingly pronounced GMV loss involving default mode regions and a distinct, directionally opposing ventral temporal increase. Key Points Question What patterns of cortical gray matter volume change emerge over approximately 1 year after first-episode schizophrenia-spectrum psychosis? Findings In this 2-site cohort of 222 patients and 178 controls, nearly two-thirds of patients lay along a gradient from near-stability in controls to widespread volume decrease, whereas one-third showed an opposing ventral temporal increase. Follow-up functioning and negative symptoms differed significantly among patient groups, with the least favorable scores in those showing the greatest decrease. Meaning Directions of within-person brain change may capture clinically relevant heterogeneity obscured by average volume loss.

Source: medRxiv

DOI: 10.64898/2026.10.08.26365057