Replicable subcortical alterations linked to neurological soft signs in schizophrenia spectrum disorders

BACKGROUND: Neurological soft signs (NSS) are frequent in schizophrenia spectrum disorders (SSD) and have been linked to structural alterations in basal ganglia-thalamic (BGT) regions. We hypothesized that SSD patients would show BGT volume differences compared to healthy controls (HC) and that NSS severity would relate to BGT volume and surface morphology in a replicable pattern. METHODS: Structural 3T T1-weighted MRI scans were obtained from 327 SSD patients and 134 matched HC in Mannheim (Germany) and Bern (Switzerland). NSS were assessed using the Heidelberg Scale and the Neurological Evaluation Scale (NES). BGT volumes were segmented using FSL-FIRST and compared across groups using general linear models adjusted for age, sex, intracranial volume, and daily antipsychotic medication. Associations with NSS scores were tested using regression analyses. RESULTS: High-NSS compared to low-NSS SSD patients showed reduced left accumbens volume in both cohorts, with a significant main effect in the Mannheim cohort (β = -43.73, p = .002 uncorrected, p = .019 corrected) and a partial replication in the Bern cohort (β = -53.06, uncorrected p = .03, p > .05, corrected). In contrast, IF-related effects on left accumbens and bilateral thalamic volumes were cohort specific. Daily antipsychotic medication and illness duration did not mediate or moderate these associations. CONCLUSIONS: This bicentric MRI study provides converging evidence that NSS severity in SSD is associated with BGT alterations, particularly reduced left nucleus accumbens volume. However, thalamic and surface-level findings were cohort specific, indicating partial rather than uniform reproducibility. Associations were not explained by daily dosage of antipsychotic medication or illness duration.