Personalized functional topography-based multisite brain age prediction modeling reveals divergent neurodevelopment in major depression.

A harmonized multicenter brain age prediction model based on individualized functional topography identified two MDD subgroups: one with accelerated brain aging (BAG+) and one with delayed brain development (BAG-).

• The dataset comprised 1,105 MDD patients and 1,065 healthy controls from multiple sites using resting-state functional MRI.
• The model was based on individualized functional topography to capture personalized brain network organization.
• Harmonization procedures were applied to account for multisite data variability.
• The two subgroups were distinguished by the sign of their brain age gap (BAG), representing the difference between predicted and chronological brain age.

In BAG+ patients, expansion of the salience network (SAL) into dorsolateral prefrontal and ventrolateral prefrontal cortices, along with contraction of sensorimotor and dorsal attention networks, contributed to accelerated brain aging.

• The salience network showed topographic shifts specifically into the dorsolateral prefrontal cortex (dlPFC) and ventrolateral prefrontal cortex (vlPFC) in BAG+ patients.
• Sensorimotor network (SMN) and dorsal attention network (DAN) exhibited contraction in the BAG+ subgroup.
• These topographic alterations were linked to the positive brain age gap observed in this subgroup.
• BAG+ patients showed stronger associations between higher-order network topography and mood symptoms clinically.

In BAG- patients, SAL expansion into the orbitofrontal cortex and contraction of visual and sensorimotor networks were linked to delayed brain development.

• The salience network expanded specifically into the orbitofrontal cortex (OFC) in BAG- patients, a distinct pattern from the BAG+ group.
• Visual network and sensorimotor network (SMN) showed contraction in the BAG- subgroup.
• These network topography changes were associated with the negative brain age gap in this group.
• BAG- patients exhibited clinical links between visual/default mode network topography and insomnia symptoms.

The two MDD subgroups exhibited distinct neurodevelopmental trajectories.

• BAG+ and BAG- subgroups showed divergent developmental trajectories beyond just the sign of the brain age gap.
• The divergent trajectories were characterized across the lifespan using the multisite dataset.
• The distinct trajectories suggest fundamentally different neurodevelopmental pathways underlying the two forms of MDD.

At the molecular level, both BAG+ and BAG- groups showed enrichment of genes related to synaptic signaling but displayed distinct expression patterns and divergent expression trajectories in key neurodevelopmental gene sets.

• Both subgroups shared enrichment of synaptic signaling-related genes, representing a common molecular feature.
• Despite this shared enrichment, the two groups showed distinct gene expression patterns.
• Divergent expression trajectories were found specifically in key neurodevelopmental gene sets between the two subgroups.
• These molecular differences align with and help explain the distinct neurodevelopmental profiles observed at the brain network level.

Antidepressant treatment modulated the brain in ways that were specific to each MDD subgroup.

• The treatment-related brain changes differed between the BAG+ and BAG- subgroups.
• This subgroup-specific treatment response suggests that the two neurodevelopmental profiles have implications for personalized treatment approaches.
• The finding offers insights into personalized precision medicine for MDD.

BAG+ patients showed stronger associations between higher-order network topography and mood symptoms, whereas BAG- patients exhibited links between visual/default mode network topography and insomnia.

• In BAG+ patients, the clinically relevant network alterations involved higher-order networks and were associated with mood symptom severity.
• In BAG- patients, visual network and default mode network topography were specifically linked to insomnia symptoms.
• These distinct clinical correlates reflect the divergent symptom profiles associated with the two neurodevelopmental subtypes of MDD.

MDD is associated with widespread alterations in functional brain networks, but heterogeneity in atypical brain development among patients remains largely uncharacterized prior to this study.

• The study addresses the gap in characterizing heterogeneity in atypical brain development in MDD.
• Previous approaches had not fully captured individual differences in functional topography across the lifespan in MDD.
• The authors used individualized (personalized) functional topography rather than group-level parcellations to better capture heterogeneity.