Exploring Motor Network Connectivity in State-Dependent Transcranial Magnetic Stimulation: A Proof-of-Concept Study

State-dependent non-invasive brain stimulation (NIBS) informed by electroencephalography (EEG) has contributed to the understanding of NIBS inter-subject and inter-session variability. While these approaches focused on local EEG characteristics, it is acknowledged that the brain exhibits an intrinsic long-range dynamic organization in networks. This proof-of-concept study explores whether EEG connectivity of the primary motor cortex (M1) in the pre-stimulation period aligns with the motor network (MN) and how MN state affects responses to transcranial magnetic stimulation (TMS) of M1. One thousand suprathreshold TMS pulses were delivered to left M1 in 8 subjects at rest, with simultaneous EEG. Motor evoked potentials (MEPs) were measured from the right hand. Source-space functional connectivity of left M1 to the whole-brain was assessed using the imaginary part of the Phase Locking Value at the frequency of the sensorimotor µ-rhythm in a 1-second window before the pulse. Group-level connectivity revealed functional links between left M1, left supplementary motor area, and right M1. Also, pulses delivered at high MN connectivity states result in a greater MEP amplitude compared to low connectivity states. At single-subject level, this relation is more expressed in subjects that feature an overall high cortico-spinal excitability. In conclusion, this study paves the way for MN connectivity based NIBS. Highlights ### Competing Interest Statement The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: R.J.I. has received consulting fees from Nexstim plc and has patents and patent applications on TMS technology. C.Z. reports an interest in a start-up company, sync2brain GmbH, which commercializes the real-time EEG analysis technology. U.Z. received grants from the German Ministry of Education and Research (BMBF), German Research Foundation (DFG), Takeda Pharmaceutical Company Ltd.; and consulting fees from CorTec GmbH, all not related to this work. The other authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.