Hippocampal subregions (HIPsub) and their network connectivities are generally aberrant in patients with subjective cognitive decline (SCD). This study aimed to investigate whether repetitive transcranial magnetic stimulation (rTMS) could ameliorate HIPsub network connectivity by modulating one node of HIPsub network in SCD. In the first cohort, the functional connectivity (FC) of three HIPsub (i.e., hippocampal emotional, cognitive, and perceptual regions: HIPe, HIPc, and HIPp) were analyzed so as to identify alterations in HIPsub connectivity associated with SCD. Afterwards, a support vector machine (SVM) approach was applied using the alterations in order to evaluate to what extent we could distinguish SCD from healthy controls (CN). In the second cohort, a 2-week rTMS course of 5-day, once-daily, was used to activate the altered HIPsub network connectivity in a sham-controlled design. SCD subjects exhibited distinct patterns alterations of HIPsub network connectivity compared to CN in the first cohort. SVM classifier indicated that the abnormalities had a high power to discriminate SCD from CN, with 92.9% area under the receiver operating characteristic curve (AUC), 86.0% accuracy, 83.8% sensitivity and 89.1% specificity. In the second cohort, changes of HIPc connectivity with the left parahippocampal gyrus and HIPp connectivity with the left middle temporal gyrus demonstrated an amelioration of episodic memory in SCD after rTMS. In addition, SCD exhibited improved episodic memory after the rTMS course. rTMS therapy could improve the posterior hippocampus connectivity by modulating the precuneus in SCD. Simultaneous correction of the breakdown in HIPc and HIPp could ameliorate episodic memory in SCD. Thus, these findings suggested that rTMS manipulation of precuneus-hippocampal circuit might prevent disease progression by improving memory as the earliest at-risk state of Alzheimer's disease in clinical trials and in practice.

Objective: This study aims to compare the cognitive function and social functioning in male patients with deficit syndrome (DS) and non-DS, and to explore whether cognitive function serves as a mediator in the relationship between the two factors of negative symptoms (motivation and pleasure (MAP) and expressivity (EXP) deficits, and social functioning in schizophrenia patients. Methods: One hundred and fifty-six male patients with schizophrenia and 109 age- and education-matched normal controls were enrolled in the current study. The Chinese version of a Schedule for Deficit Syndrome (SDS) was used for DS and non-DS categorization. The Brief Psychiatric Rating Scale (BPRS) and the Brief Negative Symptoms Scale (BNSS) were used to assess psychotic and negative symptoms in patients. The Social-Adaptive Functioning Evaluation (SAFE) was adopted to evaluate patients’ social functioning, and a battery of classical neurocognitive tests was used to assess cognition, including sustained vigilance/attention, cognitive flexibility, ideation fluency, and visuospatial memory. Results: We found that male patients with DS performed worse in all four cognitive domains and social functioning compared to non-DS patients. Both total negative symptoms and its two factors were significantly associated with all four domains of cognition and social functioning in male patients. Interestingly, our results indicate that only cognitive flexibility mediates the relationship between negative symptoms and social functioning in schizophrenia patients, but there were no differences between EXP and MAP negative factors in this model. Conclusion: Our findings suggest that DS patients may represent a unique clinical subgroup of schizophrenia, and the integrated interventions targeting both negative symptoms and cognition, especially cognitive flexibility, may optimally improve functional outcomes in schizophrenia patients.