rTMS / TENS unit induces Neural Plasticity

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Source: https://www.science.org/doi/10.1126/sciadv.ado6705


Subthreshold repetitive transcranial magnetic stimulation induces cortical layer–, brain region–, and protocol-dependent neural plasticity

8 Jan 2025

Abstract

Repetitive transcranial magnetic stimulation (rTMS) is commonly used to study the brain or as a treatment for neurological disorders, but the neural circuits and molecular mechanisms it affects remain unclear. To determine the molecular mechanisms of rTMS and the brain regions they occur in, we used spatial transcriptomics to map changes to gene expression across the mouse brain in response to two commonly used rTMS protocols. Our results revealed that rTMS alters the expression of genes related to several cellular processes and neural plasticity mechanisms across the brain, which was both brain region– and rTMS protocol–dependent. In the cortex, the effect of rTMS was dependent not only on the cortical region but also on each cortical layer. These findings uncover the diverse molecular mechanisms induced by rTMS, which will be useful in interpreting its effects on cortical and subcortical circuits.

INTRODUCTION

Repetitive transcranial magnetic stimulation (rTMS) is an extremely attractive tool in both basic and clinical neuroscience as there are very few tools that can noninvasively alter neural activity and neural plasticity in the human brain. However, despite its long-standing use and widespread popularity, it remains unclear how rTMS affects neural circuits across the brain and why rTMS outcomes can vary with different rTMS protocols (e.g., stimulation pattern). As a result, interpreting the effect of rTMS on neural processes and selecting which rTMS protocols to treat specific pathologies is challenging. Therefore, characterizing the effect of rTMS across the brain following different stimulation protocols is needed to make more informed interpretations of rTMS neuromodulation and provide an evidence base to select which rTMS protocol should be used to produce specific effects.

Using rodent models, it is known that rTMS induces both neuronal and glial plasticity mechanisms. For example, in entorhinohippocampal slice cultures, 10-Hz magnetic stimulation induces functional synaptic plasticity (1–3) that requires the release of microglial factors (4). In vivo, rTMS in the form of intermittent theta burst stimulation (iTBS) to the adult mouse sensorimotor cortex induces structural synaptic plasticity (altered dendritic spine density and rate of formation and removal) in layer 2/3 and 5 pyramidal neurons (5) as well as oligodendrocyte plasticity in several cortical regions and the corpus callosum (6, 7).

However, it remains unclear how these plasticity mechanisms vary with the rTMS protocol used, if multiple neural plasticity mechanisms are induced simultaneously, and if regions outside the stimulated region also undergo the same plastic changes. Furthermore, given the heterogeneity in the structural and cellular composition of different brain regions and cortical layers, it is likely that the effect of rTMS is not uniform across the brain. This is at least true of oligodendrocyte plasticity as iTBS has been shown to increase the number of new oligodendrocytes in the cortex but only in very superficial and deep cortical layers (L1, L5, and L6) (6).

With the intensity of the rTMS electric field decreasing in depth exponentially from the cortical surface (, the cortical layer–specific changes cannot simply be explained by rTMS intensity differences and suggest that the cellular and structural features of a brain region can influence the rTMS plasticity induced. However, cortical layer–specific changes for other rTMS-induced plasticity mechanisms have not been investigated.

Electrophysiological and microscopy studies in rodents have substantially improved our understanding of the cellular mechanisms underlying rTMS neuromodulation, but these techniques are often limited to characterizing changes to one neural plasticity mechanism at a time in a specific cell type or brain region. Spatial transcriptomics (9), on the other hand, provides a powerful alternative to investigating the molecular mechanisms of rTMS as it can characterize changes to multiple neural plasticity mechanisms across several cortical and subcortical regions of the mouse brain at high resolution. In addition to resolving differences between brain regions, the high spatial resolution of spatial transcriptomics makes it possible to characterize rTMS neuromodulation of the cortex down to individual cortical layers.

In this study, we leveraged the power of spatial transcriptomics to map the changes to cellular processes and neural plasticity induced across the adult mouse brain following rTMS to the primary motor cortex (M1) and somatosensory cortex (SS). In addition, we aimed to characterize whether rTMS induces different changes to the M1 and SS and how consistent these changes are across the cortical layers. Our study focuses on the theta burst stimulation (TBS) protocols as they are commonly used in both basic and clinical rTMS studies.

We first show that rTMS neuromodulation of the cortex was not uniform as characterization of the gross changes to gene expression in the M1 and SS from all cortical layers with bulk RNA sequencing (RNA-seq) showed little to no changes in gene expression following continuous theta burst stimulation (cTBS) and iTBS, respectively, relative to sham stimulation.

In contrast, the high resolution of spatial transcriptomics revealed that both cTBS and iTBS lead to significant changes in gene expression related to multiple cellular processes and neural plasticity mechanisms in the cortex, white matter tracts, and subcortex, with the exact changes dependent on the stimulation protocol, brain region, and cortical layer. In general, the effects of cTBS were mostly on general cellular and neuronal processes, whereas iTBS had a greater effect on oligodendrocyte plasticity–related genes.

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