Perturbation of resting-state network nodes preferentially propagates to structurally rather than functionally connected regions

Abstract

Combining Transcranial Magnetic Stimulation (TMS) with electroencephalography (EEG) offers the opportunity to study signal propagation dynamics at high temporal resolution in the human brain. TMS pulse induces a local effect which propagates across cortical networks engaging distant cortical and subcortical sites. However, the degree of propagation supported by the structural compared to functional connectome remains unclear. Clarifying this issue would help tailor TMS interventions to maximize target engagement. The goal of this study was to establish the contribution of functional and structural connectivity in predicting TMSinduced signal propagation after perturbation of two distinct brain networks. For this purpose, 24 healthy individuals underwent two identical TMS-EEG visits where neuronavigated TMS pulses were delivered to nodes of the default mode network (DMN) and the dorsal attention network (DAN). The functional and structural connectivity derived from each individual stimulation spot were characterized via functional magnetic resonance imaging (fMRI) and Diffusion Weighted Imaging (DWI), and signal propagation across these two metrics was compared. Direct comparison between the signal extracted from brain regions either functionally or structurally connected to the stimulation sites, shows a stronger activation over cortical areas connected via white matter pathways, with a minor contribution of functional projections. This pattern was not observed when analyzing spontaneous resting state EEG activity. Overall, results suggest that structural links can predict network-level response to perturbation more accurately than functional connectivity. Additionally, DWI-based estimation of propagation patterns can be used to estimate off-target engagement of other networks and possibly guide target selection to maximize specificity.

TMS-Evoked Responses Are Driven by Recurrent Large-Scale Network Dynamics

“…In the case of TMS the direct physical and physiological effects at the primary stimulation site of an extracranially-applied magnetic perturbation are reasonably well-understood: secondary electrical currents initially depolarize the membranes of cells in the superficial neural tissue underneath the coil, causing action potentials and an associated local response in the stimulated brain region 21 . Concurrently, this local electrical activation propagates (as some combination of soma-originating and prodromic axon-originating action potentials) along white matter pathways to reach distant cortical and subcortical sites, resulting in predominantly excitatory effects with magnitudes depending on the strength of the anatomical connections 22 . The final EEG-measurable outcomes of this process appear as early (<100ms) and late (>100ms) responses at both the primary stimulation site and a broad set of interconnected brain regions, usually persisting for ∼300ms, and showing reliable characteristic patterns but also high levels of inter-subject variability 23 .…”

Stimulation mapping and whole-brain modeling reveal gradients of excitability and recurrence in cortical networks

“…There is growing awareness amongst neuroscientists that this hierarchical network structure of brain organization shapes the spatiotemporal propagation of activity evoked by brain stimulation 19,20,30 , and specifically that iES effects depend on the network connectivity profile of the region being stimulated [31][32][33][34][35] .…”

“…There is growing awareness amongst neuroscientists that this hierarchical network structure of brain organization shapes the spatiotemporal propagation of activity evoked by brain stimulation 19,20,30 , and specifically that iES effects depend on the network connectivity profile of the region being stimulated 31–35 . A seminal recent study reported that patients’ self-reported perception of iES stimulation intensity depend on the stimulated region’s position in the cortical hierarchy, with simpler effects in lower-level networks and more complex, heterogeneous effects in higher-order networks 36 .…”

“…A compelling modus operandi to casually study principles of brain organization is the perturbational approach, which couples precisely targeted neurostimulation with concurrent fast (electrophysiological) neural activity recordings 18 . Recent studies employing this approach with concurrent transcranial magnetic stimulation and electroencephalography (TMS-EEG) have reported that stimulation-evoked responses exhibit a distinctive pattern of activity propagation, predominantly spreading to distal regions that are both structurally and functionally connected to the target site [19][20][21] . Importantly, these studies also demonstrate that stimulus-evoked activity preferentially propagates to, and exhibits sustained activity within, distal parts of the same (distributed, discontiguous) RSN that was used for the initial TMS targeting.…”

Reliability of M1-P15 as a cortical marker for transcallosal inhibition: a preregistered TMS-EEG study

“…Pioneering studies have shown that TMS-evoked potentials (TEPs) represent the propagation of cortical responses from the stimulated area to the connected ones [4,5], conveying state-dependent information [6,7]. In recent years, a deeper understanding of the TMS-EEG signal was ensured by the integration with other neuroimaging techniques, such as the magnetic resonance, indicating that TMS signal propagates mainly on structural connections of the stimulated networks [8][9][10].…”