Repetitive transcranial magnetic stimulation (rTMS) triggers dose-dependent homeostatic rewiring in recurrent neuronal networks

Abstract

Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive brain stimulation technique used to induce neuronal plasticity in healthy individuals and patients. Designing effective and reproducible rTMS protocols poses a major challenge in the field as the underlying biomechanisms remain elusive. Current clinical protocol designs are often based on studies reporting rTMS-induced long-term potentiation or depression of synaptic transmission. Herein, we employed computational modeling to explore the effects of rTMS on long-term structural plasticity and changes in network connectivity. We simulated a recurrent neuronal network with homeostatic structural plasticity between excitatory neurons, and demonstrated that this mechanism was sensitive to specific parameters of the stimulation protocol (i.e., frequency, intensity, and duration of stimulation). The feedback-inhibition initiated by network stimulation influenced the net stimulation outcome and hindered the rTMS-induced homeostatic structural plasticity, highlighting the role of inhibitory networks. These findings suggest a novel mechanism for the lasting effects of rTMS, i.e., rTMS-induced homeostatic structural plasticity, and highlight the importance of network inhibition in careful protocol design, standardization, and optimization of stimulation. Author summaryThe cellular and molecular mechanisms of clinically employed repetitive transcranial magnetic stimulation (rTMS) protocols remain not well understood. However, it is clear that stimulation outcomes depend heavily on protocol designs. Current protocol designs are mainly based on experimental studies that explored functional synaptic plasticity, such as long-term potentiation of excitatory neurotransmission. Using a computational approach, we sought to address the dose-dependent effects of rTMS on the structural remodeling of stimulated and non-stimulated connected networks. Our results suggest a new mechanism of action--activity-dependent homeostatic structural remodeling--through which rTMS may assert its lasting effects on neuronal networks. We showed that the effect of rTMS on structural plasticity critically depends on stimulation intensity, frequency, and duration and that recurrent inhibition can affect the outcome of rTMS-induced homeostatic structural plasticity. These findings emphasize the use of computational approaches for an optimized rTMS protocol design, which may support the development of more effective rTMS-based therapies.