Posterior-lateral basal forebrain cholinergic nuclei hypoconnectivity in the inferior frontal cortex is associated with verbal fluency deficits in schizophrenia

Abstract Cognitive impairment is a core feature of schizophrenia and remains insufficiently addressed by current treatments. Increasing evidence implicates the cholinergic system, particularly the basal forebrain cholinergic nuclei (BFCN), in cognitive dysfunction. While structural alterations of the BFCN have been reported, alterations in their intrinsic functional connectivity (iFC) remain unclear. The present study examined the iFC of anterior and posterior BFCN subdivisions (aBFCN, pBFCN) in schizophrenia and tested associations with cognitive performance. Resting-state functional magnetic resonance imaging data from the COBRE dataset were analyzed, including 73 healthy controls (HC) and 51 patients with schizophrenia (SCZ). Seed-based connectivity analyses were performed for aBFCN and pBFCN. Group differences were assessed voxel-wise, and group-dependent associations with phonemic verbal fluency (FAS) and processing speed (BACS-SC) were tested using hierarchical regression controlling for age, sex, IQ, and smoking status; verbal learning and memory (HVLT) was examined as a specificity analysis. Exploratory molecular mapping used normative PET-derived neurotransmitter maps, supplemented by spatial-autocorrelation-preserving null models. Distinct connectivity patterns of aBFCN and pBFCN were observed, consistent with previous reports in HC. Compared with HC, SCZ showed reduced pBFCN connectivity with a cluster in the right inferior frontal gyrus (pars opercularis; BA44; p = 0.018, FWE-corrected), whereas no significant differences were observed for aBFCN. The Group × pBFCN–IFG connectivity interaction was significant for FAS ( p = 0.014) but not BACS-SC ( p = 0.762) or HVLT ( p = 0.514). In SCZ, higher pBFCN–IFG connectivity was associated with better FAS performance. Descriptive molecular mapping showed above-average representation of M1 and α4β2 receptor maps as well as several non-cholinergic targets; however, no molecular target showed significant spatial correspondence after spatial-autocorrelation-aware testing and FDR correction. These findings provide evidence for selective pBFCN hypoconnectivity with the right inferior frontal gyrus in schizophrenia. Its association with verbal fluency suggests that disrupted pBFCN connectivity with the inferior frontal cortex may contribute to altered executive control processes involved in verbal fluency in schizophrenia. Together, these findings extend previous evidence of BFCN abnormalities in schizophrenia by demonstrating a systems-level functional alteration of pBFCN–cortical connectivity and its relationship with cognitive performance.