Mapping intrinsic neural timescale alterations in major depressive disorder

Major depressive disorder (MDD) has been characterized by widespread functional network alterations. However, previous neuroimaging studies have predominantly focused on inter-regional functional connectivity, overlooking intrinsic temporal hierarchies that reflect fundamental neural processing properties.

We quantified intrinsic neural timescales (INT), a measure of temporal autocorrelation in intrinsic neural activity, across cortical and subcortical structures using resting-state functional MRI in patients with MDD and controls. We also assessed the associations between the INT alterations and depressive symptom and age effects. To elucidate neurobiological substrates of the INT alterations, we examined spatial associations with transcriptomic and neurotransmitters profiles.

Patients with MDD exhibited widespread INT reductions across bilateral cingulate, insular, and frontoparietal cortices and subcortical structures. The association between age and INT differed between groups, with patients showing age-related INT increases in the posterior cingulate cortex. Transcriptomic analyses identified gene signatures enriched for synaptic transmission, glutamatergic pathways, and ion channel regulation, showing significant overlap with astrocyte- and excitatory-neuron-specific markers. Neurotransmitter mapping revealed associations spanning serotonergic, GABAergic, glutamatergic, and cholinergic receptor systems.

These findings reveal widespread INT reductions in MDD and their spatial correspondence with normative transcriptomic and neurotransmitter profiles. The co-localization of INT alterations with normative gene expression enriched for synaptic and glutamatergic pathways provides insights into the molecular context of intrinsic temporal processing abnormalities in MDD.