TMS over the pre-SMA enhances semantic cognition via remote network effects on task-based activity and connectivity

Background: The continuous decline of executive abilities with age is mirrored by increased neural activity of domain-general networks during task processing. So far, it remains unclear how much domain-general networks contribute to domain-specific processes such as language when cognitive demands increase. The current neuroimaging study explored the potential of intermittent theta-burst stimulation (iTBS) over a domain-general hub to enhance executive and semantic processing in healthy middle-aged to older adults. Methods: We implemented a cross-over within-subject study design with three task-based neuroimaging sessions per participant. Using an individualized stimulation approach, each participant received once effective and once sham iTBS over the pre-supplementary motor area (pre-SMA), a region of domain-general control. Subsequently, task-specific stimulation effects were assessed in functional MRI using a semantic and a non-verbal executive task with varying cognitive demand. Results: Effective stimulation increased activity only during semantic processing in visual and dorsal attention networks. Further, iTBS induced increased seed-based connectivity in task-specific networks for semantic and executive conditions with high cognitive load but overall reduced whole-brain coupling between domain-general networks. Notably, stimulation-induced changes in activity and connectivity related differently to behavior: While stronger activity of the parietal dorsal attention network was linked to poorer semantic performance, its enhanced coupling with the pre-SMA was associated with more efficient semantic processing. Conclusions: iTBS modulates networks in a task-dependent manner and generates effects at regions remote to the stimulation site. These neural changes are linked to more efficient semantic processing, which underlines the general potential of network stimulation approaches in cognitive aging.