Depressive-cognitive interactions modulate amygdala and hippocampus functional connectivity in mild cognitive impairment

BackgroundDepressive symptoms frequently co-occur with cognitive impairment in older adults. Although depression and cognition interact in brain activity, the underlying functional connectivity mechanisms in mild cognitive impairment (MCI) remains unclear.ObjectiveTo investigate how depressive symptoms modulate the relationship between cognition and amygdala/hippocampus functional connectivity in MCI.MethodsThis study included 138 participants (45 healthy controls and 93 MCI patients) who underwent resting state functional magnetic resonance imaging (rs-fMRI) and neuropsychological assessment using the Montreal Cognitive Assessment-Basic (MoCA-B) for cognitive function and Hamilton Depression Rating Scale (HAMD) for depressive symptoms. Seed-based functional connectivity analysis was performed using bilateral amygdala and hippocampus as seed regions to quantify the HAMD × MoCA-B non-monotonic interactions on whole-brain connectivity. Simple slopes analyses were conducted to characterize directionality changes across depression severity levels.ResultsWhole-brain analyses revealed significant HAMD × MoCA-B interaction effects (cluster p value < 0.05, voxel p value < 0.01, GRF corrected) demonstrating symptom-dependent reorganization of cognition-FC relationships. Amygdala connectivity decreased to anterior/middle cingulate and precuneus but increased to triangular part of inferior frontal gyrus (IFGtri), medial superior frontal gyrus, and cerebellar lobule IX. Hippocampal connectivity decreased to cuneus, insula, thalamus, and caudate but increased to opercular part of inferior frontal gyrus (IFGop), orbitofrontal cortex, and cerebellar lobule VIII.ConclusionDepressive symptoms alter amygdala and hippocampal FC relationships with cognition in MCI. Depression-dependent hippocampal/amygdala connectivity changes with the frontoparietal network (FPN-A)-particularly IFGop/IFGtri and cerebellum-suggest their role as critical hubs for emotional-cognitive integration, highlighting them as potential neuromodulation targets for cognitive and depressive symptoms in MCI.