Frequency-Dependent Whole-Brain Reconfiguration Following Left DLPFC rTMS in Older Adults: A 106-Channel fNIRS Study

Objective: The classic excitation/inhibition dichotomy may be insufficient to describe rTMS mechanisms in the aging brain. This study investigated immediate whole-brain resting-state functional connectivity effects of 10 Hz (high-frequency) and 1 Hz (low-frequency) rTMS over the left dorsolateral prefrontal cortex (DLPFC) in healthy older adults. Methods: Thirty healthy older adults (aged 60-75 years) participated in a randomized, single-blind, crossover study, and underwent 20-min 10 Hz and 1 Hz rTMS in separate visits. A 106-channel fNIRS system was used to record resting-state activity before and immediately after each intervention. Functional connectivity was analyzed at the channel, region-of-interest (ROI) and network summary levels, including graph-theoretic metrics and distance-stratified connectivity summaries. Results: At the network summary level, 10 Hz stimulation was associated with relatively more positive changes in global topology and spatially distributed connectivity summaries, whereas 1 Hz stimulation showed the opposite overall trend. In the graph-theoretic analyses, stimulation frequency × time interaction effects were observed for global efficiency, local efficiency, clustering coefficient, and mean node strength. At the edge level, only a small number of effects survived FDR correction, and the broader connection-wise patterns were therefore interpreted as exploratory. Uncorrected analyses suggested widespread enhancement after 10 Hz stimulation and widespread reduction after 1 Hz stimulation, together with localized paradoxical effects, including selective decreases after 10 Hz and selective increases after 1 Hz (e.g., bilateral primary motor cortex connectivity). Conclusions: These findings suggest that 10 Hz and 1 Hz rTMS over the left DLPFC are associated with different patterns of immediate whole-brain network reconfiguration in healthy older adults. The presence of localized paradoxical effects further suggests that rTMS responses in the aging brain may involve more complex forms of reorganization than a simple excitatory/inhibitory dichotomy would predict. Significance: The present study provides preliminary support for a network-level perspective on neuromodulation in older adults and highlights the value of whole-brain fNIRS for characterizing distributed responses to rTMS. Larger, sham-controlled, behavior-linked, and longitudinal studies are needed to determine the robustness and functional significance of these effects.