Transcranial magnetic stimulation modulates the brain's intrinsic activity in a frequency-dependent manner

Abstract

Intrinsic activity in the brain is organized into networks. Although constrained by their anatomical connections, functional correlations between nodes of these networks reorganize dynamically. Dynamic organization implies that couplings between network nodes can be reconfigured to support processing demands. To explore such reconfigurations, we combined repetitive transcranial magnetic stimulation (rTMS) and functional connectivity MRI (fcMRI) to modulate cortical activity in one node of the default network, and assessed the effect of this upon functional correlations throughout the network. Two different frequencies of rTMS to the same default network node (the left posterior inferior parietal lobule, lpIPL) induced two topographically distinct changes in functional connectivity. High-frequency rTMS to lpIPL decreased functional correlations between cortical default network nodes, but not between these nodes and the hippocampal formation. In contrast, low frequency rTMS to lpIPL did not alter connectivity between cortical default network nodes, but increased functional correlations between lpIPL and the hippocampal formation. These results suggest that the default network is composed of (at least) two subsystems. More broadly, the finding that two rTMS stimulation regimens to the same default network node have distinct effects reveals that this node is embedded within a network that possesses multiple, functionally distinct relationships among its distributed partners.

Conflict of interest statement

Conflict of interest statement: A.P.-L. serves on the scientific advisory board for Nexstim, Neuronix, Starlab, and Neosync, and is an inventor of several issued and applied patents for the combination of transcranial magnetic stimulation with EEG and neuroimaging.

Figures

Fig. 1.

Experimental design. Each participant first underwent a baseline resting-state fcMRI scanning session to allow for the creation of individualized functional connectivity maps localizing the lpIPL node of their default network. This node served as the future target for two subsequent rTMS stimulation sessions (on separate days): one in which they received 1-Hz rTMS to lpIPL, and another in which they received 20-Hz rTMS to lpIPL. Consistent targeting of lpIPL across sessions was achieved by using a frameless stereotactic neuronavigation system. During each of the two stimulation sessions, subjects completed two fcMRI scans: one immediately before, and another immediately following rTMS.

Fig. 2.

Changes in functional connectivity in the default network as a result of the two frequencies of rTMS. Changes in functional connectivity are shown between the site of rTMS stimulation (lpIPL) and the five other a priori determined default network regions following 20-Hz (solid line) and 1-Hz (dashed line) stimulation across all participants. The y axis represents changes in z-transformed region-to-region correlation strength as a result of rTMS to lpIPL. The regions of interest used for the functional connectivity analysis are shown on the x axis. Error bars represent one SEM. Twenty-hertz and 1-Hz rTMS induced opposing effects upon default network functional connectivity, and did so in a topographically distinct pattern.

Fig. 3.

Functional connectivity maps derived from an lpIPL seed region before and after rTMS. Maps are displayed before (A), after (B), and as the change between before and after (C) 20-Hz rTMS stimulation, and before (D), after (E), and as the change between before and after (F) 1-Hz rTMS stimulation to the lpIPL across all participants. The maps represent uncorrected P values at each location for a voxel-wise one-sample t test for z-transformed correlation coefficients greater than 0 (A, B, D, and E). For difference measures, the maps represent uncorrected P values for a voxel-wise repeated-measures t test comparing z-transformed correlation coefficients before stimulation to after stimulation (C and F). Following 20-Hz stimulation, decreases in functional connectivity with respect to lpIPL were observed in pCC and in mPFC, highlighted with black dotted ovals. Following 1-Hz stimulation, increases in functional connectivity were observed between the lpIPL seed and the bilateral hippocampal formation (left and right HF), indicated with black dotted ovals.

Fig. 4.

Schematic representation of functional connectivity changes across multiple regions within the default network. The thickness of the lines connecting default network regions is proportional to the connectivity strength between these regions. Connectivity is displayed before 1-Hz (A) and 20-Hz (C) rTMS (Left). (Right) Changes in functional connectivity between default network regions as a result of 1-Hz (B) and 20-Hz (D) rTMS. Scaling of line thickness to changes in correlation strength is different between Right and Left. Decreases in functional connectivity are depicted with blue lines, and increases are depicted in red. Large dashed lines signify significant changes (corrected for multiple comparisons). Small dashed lines signify significant correlation changes not surviving multiple comparisons corrections. These results suggest coupling between regions in the default network is dynamic.

Fig. 5.

Changes in functional connectivity with and without intervening rTMS. Plots indicate relative changes (normalized to zero values for pre-rTMS connectivity) for each participant between the stimulation site (lpIPL) and mPFC. The majority of participants showed a decrease in functional connectivity between lpIPL and mPFC following 20-Hz (Center), but no change and significant intersubject variability occurred following 1 Hz (Left) and across their pre–1-Hz and pre–20-Hz rTMS sessions (Right).