Aberrant prefrontal-hippocampal connectivity of cross-modal associative memory impairment in schizophrenia

Objective: Associative memory (AM) impairment is considered as a core cognitive dysfunction and indicative of poor function in schizophrenia. Despite the robust findings of abnormalities in prefrontal-hippocampal network, yet the specific regions and definitive patterns have remained elusive. We adopted an innovative AM paradigm to disentangle the contributions of prefrontal-hippocampal network. Methods: In this cross-sectional study, 30 schizophrenia patients and 30 matched healthy controls (HCs) were recruited, scheduled for an MRI session on a 3.0T Siemens, and completed clinical evaluations. We performed seed-based functional connectivity (FC) analyses using the bilateral hippocampus (Hipp) as seeds and conducted Pearson's correlation analyses between FC and the AM performance. Results: Compared to HCs, patients exhibited poorer AM functions in both same- and cross-domain conditions. Left Hipp exhibited decreased FC with clusters from medial and orbital superior frontal gyrus (SFG) bilaterally (p-FDR < 0.001), while enhanced FC with clusters from bilateral inferior frontal gyrus (IFG), pars opercularis and triangularis (p-FDR < 0.01) in the schizophrenia relative to HCs. Notably, decreased left Hipp-related FC was moderately positively correlated with cross-modal AM performance in HCs but not in the schizophrenia group. Conversely, a significant positive correlation was found between left Hipp-bilateral IFG FC values and cross-modal AM capacities in schizophrenia. Conclusions: The current study demonstrated the disparities in AM deficits and substantiate correlative evidence for prefrontal-hippocampal network involvement in AM. These findings provide evidence for neuropathological mechanisms in schizophrenia, which potentially guiding relevant interventions and treatments.