Treatment-associated structural connectome reorganization following high-frequency rTMS in major depressive disorder:...

High-frequency repetitive transcranial magnetic stimulation (rTMS) of the left dorsolateral prefrontal cortex (DLPFC) is an established treatment for major depressive disorder (MDD), but associated changes in structural-connectome topology remains unclear. Specifically, higher-order structural connectivity (HOSC), defined by similarities between regional structural connectivity profiles, may provide information beyond direct low-order structural connectivity (LOSC).

Diffusion tensor imaging (DTI) data were acquired from 23 patients with MDD before and after 10-Hz rTMS and from 30 matched healthy controls (HCs). LOSC networks were constructed based on deterministic tractography, whereas HOSC networks were derived from similarities between regional LOSC profiles. Graph-theoretical analysis and network-based statistics were employed to characterize topological and subnetwork differences.

Depressive symptoms decreased significantly after treatment. Global LOSC topology remained stable, whereas HOSC showed case-control differences in network segregation and post-treatment differences in small-world organization relative to HCs. Network-based analysis revealed focal strengthening of a left insula-hippocampal-inferior temporal component in LOSC and distributed HOSC variation involving cortico-striato-thalamo-cortical circuitry, particularly the thalamus and caudate. Nodal analyses further identified treatment-associated centrality changes involving the thalamus and hippocampus.

High-frequency rTMS treatment was associated with coordinated structural-connectome variation across low- and high-order network organization in MDD. These findings should be interpreted as treatment-associated changes rather than effects attributable specifically to rTMS and suggest that HOSC may provide a complementary representation of network variation accompanying clinical improvement.