Abstract
The pathophysiology and pharmacology of depression are hypothesized to be related to the imbalance of excitation–inhibition that gives rise to hierarchical dynamics (or intrinsic timescale gradient), further supporting a hierarchy of cortical functions. On this assumption, intrinsic timescale gradient is theoretically altered in depression. However, it remains unknown. We investigated altered intrinsic timescale gradient recently developed to measure hierarchical brain dynamics gradient and its underlying molecular architecture and brain-wide gene expression in depression. We first presented replicable intrinsic timescale gradient in two independent Chinese Han datasets and then investigated altered intrinsic timescale gradient and its possible underlying molecular and transcriptional bases in patients with depression. As a result, patients with depression showed stage-specifically shorter timescales compared with healthy controls according to illness duration. The shorter timescales were spatially correlated with monoamine receptor/transporter densities, suggesting the underlying molecular basis of timescale aberrance and providing clues to treatment. In addition, we identified that timescale aberrance-related genes ontologically enriched for synapse-related and neurotransmitter (receptor) terms, elaborating the underlying transcriptional basis of timescale aberrance. These findings revealed atypical timescale gradient in depression and built a link between neuroimaging, transcriptome, and neurotransmitter information, facilitating an integrative understanding of depression.
Highlights
As one of the leading disabling diseases worldwide (Murray et al, 2012), depression affects approximately 350 million people each year (Schmaal et al, 2017)
Imbalance of the E/I is implicated in the pathophysiology and pharmacology of the depression (Covington et al, 2010; Voineskos et al, 2019) and the mechanism of fast-acting antidepressant is related to E/I rebalance (Li, 2020)
Because only two right hemisphere data were included in the Allen Human Brain Atlas (AHBA), we only considered the left hemisphere in our analysis (Arnatkeviciute et al, 2019)
Summary
As one of the leading disabling diseases worldwide (Murray et al, 2012), depression affects approximately 350 million people each year (Schmaal et al, 2017). Imbalance of E/I ratio hypothetically results in the aberrance of hierarchically organized intrinsic neural timescales (Kiebel et al, 2008) that support synchronizing largescale brain networks usually measured with resting-state functional connectivity (rsFC; Buzsáki and Draguhn, 2004). Regions with longer “temporal receptive windows” are subsequently found to exhibit more slowly changing activity and vice versa (Hasson et al, 2015) Regions such as prefrontal areas and parietal areas, densely interconnected central regions, have longer timescales compared to peripheral sensory areas (Chaudhuri et al, 2015) for the reason that prolonged neural timescale is needed to enable these high-order brain regions to integrate various information for robust sensory perception (Hasson et al, 2008), stable memory processing (Bernacchia et al, 2011), and decision-making (Cavanagh et al, 2016). The intrinsic timescale gradient should be altered in depression theoretically, it remains unknown yet
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