Disrupted white matter function in subthreshold depression correlate with cognitive, neurotransmitter, and genetic profiles

INTRODUCTION: White matter (WM) tract function has only recently been investigated. However, whether WM function is altered in individuals with subthreshold depression (StD) remains largely unknown. OBJECTIVES: To examine WM functional alterations in StD and their associations with cognitive performance, neurotransmitter systems, and gene expression patterns. METHODS: A total of 188 individuals with StD and 136 healthy controls (HCs) were recruited from Jinan University in the study. Participants underwent mood and cognitive assessments, as well as resting-state functional MRI.WM function was evaluated using the amplitude of low-frequency fluctuations (ALFF) in conjunction with the automated fiber quantification (AFQ) method. Correlation and linear regression analyses were performed. Subsequently, spatial associations between postmortem gene expression/neurotransmitters and WM functional alterations were investigated to uncover neural mechanisms underlaying StD from a multidimensional perspective. RESULTS: Individuals with StD showed decreased social cognition and composite cognition compared to HCs. Individuals with StD displayed ALFF decrease in the right anterior thalamic radiation (ATR), inferior fronto-occipital fasciculus, inferior longitudinal fasciculus (ILF), and uncinate fasciculus. Rumination and depressive symptoms were associated with ALFF decrease in the right ATR; anxiety symptom was associated with ALFF decrease in the right ILF. Moreover, the abnormal pattern of WM function in StD was spatially associated with modulation of chemical synaptic transmission, regulation of synaptic plasticity, cation channel activity, and neuron projection, as well as dopaminergic and serotonergic neurotransmission. CONCLUSION: To conclude, these findings reveal WM functional alterations in StD that are associated with mood and cognitive disturbances, and suggest that these alterations may be linked to underlying transcriptomic and neurotransmitter correlates. This study provides new clues to understand the neuro-pathophysiology of StD.