Longitudinal Changes in Hippocampal-Default Mode Network Connectivity and Cognition During Electroacupuncture Intervention in Type 2 Diabetes-Associated Cognitive Decline: A Pilot Resting-State fMRI Study

Background: Type 2 diabetes mellitus-associated cognitive dysfunction (T2DACD) is strongly linked to disruption of cognition-supporting brain networks. Electroacupuncture (EA) has increasingly been examined as a nonpharmacological intervention targeting cognitive impairment; however, the longitudinal neurobiological patterns accompanying EA in T2DACD have not been fully characterized. In this exploratory pilot study, we evaluated alterations in resting-state functional connectivity (RSFC) across hippocampal subregions and default mode network (DMN) nodes in individuals with T2DACD. Methods: For this exploratory, open-label, non-randomized, uncontrolled pilot investigation, we enrolled 20 individuals with T2DACD and 26 healthy controls (HCs). Longitudinal analyses included 15 participants who had usable post-treatment data. T2DACD was defined according to clinical type 2 diabetes mellitus criteria, and a Montreal Cognitive Assessment (MoCA) score <26. Patients underwent an 8-week Adjust Zang-fu and Arouse Spirit electroacupuncture (AZASE) intervention. Cognitive, emotional, metabolic, and seed-based resting-state functional magnetic resonance imaging (rs-fMRI) outcomes were evaluated. Clinical longitudinal analyses were carried out according to protocol, whereas imaging analyses were limited to participants with usable scans after treatment. Results: At baseline, individuals with T2DACD showed lower MoCA scores than HCs and had poorer executive and working-memory outcomes. Among the 15 participants with complete longitudinal neuroimaging data, MoCA scores increased from 23.27 ± 1.71 to 26.07 ± 1.53 over the intervention period. Within-group alterations were observed for Flanker-conflict reaction time and accuracy, Stroop-conflict reaction time, 1-back reaction time, Self-Rating Anxiety Scale score, and Hamilton Depression Rating Scale score. Omnibus group analyses detected significant effects for the left anterior hippocampus-left angular gyrus connection and the left posterior hippocampus-right middle occipital gyrus connection. Post-treatment scans demonstrated reduced RSFC in several hippocampal-DMN and intra-DMN connections. The association between change in left anterior hippocampus-left angular gyrus RSFC and change in Stroop-conflict performance was no longer statistically significant after Bonferroni correction. For neuroimaging outcomes, cluster-level family-wise error (FWE) correction (p < 0.05) was applied to control for multiple comparisons; clinical outcomes are reported descriptively as hypothesis-generating findings. Conclusions: In this exploratory pilot study, we identified preliminary alterations in cognitive outcomes and hippocampal-DMN connections over an 8-week EA intervention in individuals with T2DACD. In view of the small sample size and the open-label, non-randomized, uncontrolled design, the findings should be interpreted as hypothesis-generating observations rather than definitive evidence of a specific causal treatment effect. Larger controlled studies will be needed to determine whether the observed neural and behavioral alterations are reproducible and clinically meaningful in practice. Clinical Trial Registration: No: ChiCTR2000040268, https://www.chictr.org.cn/hvshowproject.html?id=76145&v=1.3.