Shared amygdalar and thalamic substrates linking depressive symptoms and cognitive function in cerebral small vessel...

Depressive symptoms are common in cerebral small vessel disease (CSVD) and frequently coexist with cognitive impairment, yet the subcortical substrates linking microvascular injury to affective disturbance remain insufficiently defined.

A total of 360 individuals were included, comprising 255 CSVD patients (54 with depressive symptoms, 201 without) and 105 healthy controls. High-resolution structural and resting-state functional MRI quantified subregional morphology and functional connectivity of the hippocampus, amygdala, thalamus, and hypothalamus. Serum cortisol levels were assessed, and sex-stratified analyses evaluated differential susceptibility.

CSVD with depressive symptoms showed atrophy across hippocampal (tail, CA1, CA4, molecular layer, GC_ML_DG), amygdalar (lateral, accessory basal, central, cortical), and non-anterior thalamic subregions, together with reduced hippocampal and amygdala connectivity within default mode and frontotemporal networks, compared with CSVD without depressive symptoms. Serum cortisol modestly associated with anxiety scores and showed minimal relationships with subcortical structure. Females showed greater structural vulnerability, whereas males demonstrated stronger functional disconnection, alongside a sex-by-depression interaction in cortical amygdala nuclei volume. Lateral thalamic volume and right lateral amygdala-angular gyrus connectivity emerged as shared neural correlates of depressive, anxiety, and cognitive symptoms in CSVD. Mediation analyses further indicated that white matter hyperintensity burden was related to depressive severity partly through central amygdala atrophy, which in turn partially accounted for cognitive performance.

This study identifies subregion-specific and sex-dependent alterations within distributed affective-cognitive networks in CSVD. Shared thalamic and amygdalar subregions alterations provide a potential neural basis for the co-occurrence of mood and cognitive symptoms and may help guide interventions targeting both domains.