Thalamic, hippocampal, amygdalar and brainstem long-term changes in schizophrenia co-localised with normative neurotransmitter distributions

Background: Schizophrenia Spectrum Disorders (SSD) is associated with spatially heterogeneous structural abnormalities across distributed brain systems, but the longitudinal evolution and neurochemical context of subcortical subregional changes remain poorly understood. We investigated longitudinal volume changes across thalamic, hippocampal, amygdalar, and brainstem subregions and their relationships with clinical characteristics and normative neurotransmitter distribution. Methods: A total of 357 SSD individuals with first-episode and 196 healthy controls were included. Clinical assessments were performed at baseline and at 1, 3, 5, 10, 15, and 20 years of follow-up. Using T1-weighted structural MRI, subregional volumes were quantified across the thalamus, hippocampus, amygdala, and brainstem. We examined baseline group differences, longitudinal volume changes, and associations with clinical variables, including symptom severity. Spatial patterns of regional associations were compared with normative maps of neurotransmitter receptor and transporter distributions. Results: Patients showed heterogeneous structural alterations across the examined subcortical subregions. The hippocampus showed prominent early volume deficits in specific subfields and demonstrated a strong association with antipsychotic medication doses. Amygdalar volumetric reductions were more widespread and were strongly associated with positive symptom severity. Localised structural abnormalities were also observed in the thalamus and brainstem, although these showed weak associations with clinical symptomatology. The spatial co-location of normative neurotransmitter maps with the structural and clinical associations revealed distinct overlapping with dopaminergic, GABAergic, glutamatergic, serotonergic and cholinergic systems. Conclusions: Longitudinal structural alterations in SSD showed marked anatomical heterogeneity across thalamic, limbic, and brainstem systems. Their spatial correspondence with normative neurochemical architecture suggests that regional and subregional structural vulnerability and clinical heterogeneity may be organized along distinct, partially overlapping neurotransmitter profiles.