Targeting brain networks: a review of multi-site TMS techniques and applications

Transcranial magnetic stimulation (TMS) has evolved from a focal brain stimulation method to a network-level neuromodulation tool. This review examines the emerging field of multi-site TMS—approaches that target two or more brain regions to influence inter-regional dynamics and large-scale networks underlying cognition and clinical disorders. Three major forms are described: sequential multi-site TMS, which stimulates different targets in succession and is applied in disorders such as depression and Alzheimer’s disease; dual-site TMS, exemplified by cortico-cortical paired associative stimulation (ccPAS), which employs precisely timed pulses to alter directional connectivity and synaptic plasticity; and multi-locus TMS, a hardware-based method enabling simultaneous, electronically guided stimulation of distributed cortical areas with millisecond precision. While each offers distinct advantages for probing and modulating brain networks, challenges remain, such as parameter variability, individual differences, and technical complexity. Adaptive, personalized protocols guided by neuroimaging are needed to address anatomical and functional variability. In parallel, unified computational models are being developed to optimize protocol design and improve reproducibility. Overall, multi-site TMS represents a promising frontier in neuroscience and neurotherapeutics, bridging local stimulation with global brain dynamics to enable more effective and individualized interventions.