Low intensity repetitive transcranial magnetic stimulation modulates brain-wide functional connectivity to promote anti-correlated c-Fos expression

Jessica Moretti; Dylan J. Terstege; Eugenia Z. Poh; Jonathan R. Epp; Jennifer Rodger

doi:10.1038/s41598-022-24934-8

Low intensity repetitive transcranial magnetic stimulation modulates brain-wide functional connectivity to promote anti-correlated c-Fos expression

Jessica Moretti, Dylan J. Terstege, Eugenia Z. Poh, Jonathan R. Epp, Jennifer Rodger

Research output: Contribution to journal › Article › peer-review

15 Citations (Scopus)

Abstract

Repetitive transcranial magnetic stimulation (rTMS) induces action potentials to induce plastic changes in the brain with increasing evidence for the therapeutic importance of brain-wide functional network effects of rTMS; however, the influence of sub-action potential threshold (low-intensity; LI-) rTMS on neuronal activity is largely unknown. We investigated whether LI-rTMS modulates neuronal activity and functional connectivity and also specifically assessed modulation of parvalbumin interneuron activity. We conducted a brain-wide analysis of c-Fos, a marker for neuronal activity, in mice that received LI-rTMS to visual cortex. Mice received single or multiple sessions of excitatory 10 Hz LI-rTMS with custom rodent coils or were sham controls. We assessed changes to c-Fos positive cell densities and c-Fos/parvalbumin co-expression. Peak c-Fos expression corresponded with activity during rTMS. We also assessed functional connectivity changes using brain-wide c-Fos-based network analysis. LI-rTMS modulated c-Fos expression in cortical and subcortical regions. c-Fos density changes were most prevalent with acute stimulation, however chronic stimulation decreased parvalbumin interneuron activity, most prominently in the amygdala and striatum. LI-rTMS also increased anti-correlated functional connectivity, with the most prominent effects also in the amygdala and striatum following chronic stimulation. LI-rTMS induces changes in c-Fos expression that suggest modulation of neuronal activity and functional connectivity throughout the brain. Our results suggest that LI-rTMS promotes anticorrelated functional connectivity, possibly due to decreased parvalbumin interneuron activation induced by chronic stimulation. These changes may underpin therapeutic rTMS effects, therefore modulation of subcortical activity supports rTMS for treatment of disorders involving subcortical dysregulation.

Original language	English
Article number	20571
Journal	Scientific Reports
Volume	12
Issue number	1
DOIs	https://doi.org/10.1038/s41598-022-24934-8
Publication status	Published - Dec 2022

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title = "Low intensity repetitive transcranial magnetic stimulation modulates brain-wide functional connectivity to promote anti-correlated c-Fos expression",

abstract = "Repetitive transcranial magnetic stimulation (rTMS) induces action potentials to induce plastic changes in the brain with increasing evidence for the therapeutic importance of brain-wide functional network effects of rTMS; however, the influence of sub-action potential threshold (low-intensity; LI-) rTMS on neuronal activity is largely unknown. We investigated whether LI-rTMS modulates neuronal activity and functional connectivity and also specifically assessed modulation of parvalbumin interneuron activity. We conducted a brain-wide analysis of c-Fos, a marker for neuronal activity, in mice that received LI-rTMS to visual cortex. Mice received single or multiple sessions of excitatory 10 Hz LI-rTMS with custom rodent coils or were sham controls. We assessed changes to c-Fos positive cell densities and c-Fos/parvalbumin co-expression. Peak c-Fos expression corresponded with activity during rTMS. We also assessed functional connectivity changes using brain-wide c-Fos-based network analysis. LI-rTMS modulated c-Fos expression in cortical and subcortical regions. c-Fos density changes were most prevalent with acute stimulation, however chronic stimulation decreased parvalbumin interneuron activity, most prominently in the amygdala and striatum. LI-rTMS also increased anti-correlated functional connectivity, with the most prominent effects also in the amygdala and striatum following chronic stimulation. LI-rTMS induces changes in c-Fos expression that suggest modulation of neuronal activity and functional connectivity throughout the brain. Our results suggest that LI-rTMS promotes anticorrelated functional connectivity, possibly due to decreased parvalbumin interneuron activation induced by chronic stimulation. These changes may underpin therapeutic rTMS effects, therefore modulation of subcortical activity supports rTMS for treatment of disorders involving subcortical dysregulation.",

author = "Jessica Moretti and Terstege, {Dylan J.} and Poh, {Eugenia Z.} and Epp, {Jonathan R.} and Jennifer Rodger",

note = "Funding Information: Funding for this study was provided in part by an NSERC Discovery Grant (RGPIN-2018-05135) to JRE. JM was supported by an Australian Government Research Training Program (RTP) scholarship, and Byron Kakulas Prestige scholarship. DJT received fellowships from NSERC and the Canadian Open Neuroscience Platform. JR was supported by a fellowship from Multiple Sclerosis Western Australia (MSWA). We acknowledge the Hotchkiss Brain Institute Advanced Microscopy Platform and the Cumming School of Medicine for support and use of the Olympus VS120-L100-W slide scanning microscope. Funding Information: Funding for this study was provided in part by an NSERC Discovery Grant (RGPIN-2018-05135) to JRE. JM was supported by an Australian Government Research Training Program (RTP) scholarship, and Byron Kakulas Prestige scholarship. DJT received fellowships from NSERC and the Canadian Open Neuroscience Platform. JR was supported by a fellowship from Multiple Sclerosis Western Australia (MSWA). We acknowledge the Hotchkiss Brain Institute Advanced Microscopy Platform and the Cumming School of Medicine for support and use of the Olympus VS120-L100-W slide scanning microscope. Publisher Copyright: {\textcopyright} 2022, The Author(s).",

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doi = "10.1038/s41598-022-24934-8",

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AU - Rodger, Jennifer

N1 - Funding Information: Funding for this study was provided in part by an NSERC Discovery Grant (RGPIN-2018-05135) to JRE. JM was supported by an Australian Government Research Training Program (RTP) scholarship, and Byron Kakulas Prestige scholarship. DJT received fellowships from NSERC and the Canadian Open Neuroscience Platform. JR was supported by a fellowship from Multiple Sclerosis Western Australia (MSWA). We acknowledge the Hotchkiss Brain Institute Advanced Microscopy Platform and the Cumming School of Medicine for support and use of the Olympus VS120-L100-W slide scanning microscope. Funding Information: Funding for this study was provided in part by an NSERC Discovery Grant (RGPIN-2018-05135) to JRE. JM was supported by an Australian Government Research Training Program (RTP) scholarship, and Byron Kakulas Prestige scholarship. DJT received fellowships from NSERC and the Canadian Open Neuroscience Platform. JR was supported by a fellowship from Multiple Sclerosis Western Australia (MSWA). We acknowledge the Hotchkiss Brain Institute Advanced Microscopy Platform and the Cumming School of Medicine for support and use of the Olympus VS120-L100-W slide scanning microscope. Publisher Copyright: © 2022, The Author(s).

PY - 2022/12

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Low intensity repetitive transcranial magnetic stimulation modulates brain-wide functional connectivity to promote anti-correlated c-Fos expression

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Multi-model approach shows novel and diverse effects of low-intensity repetitive transcranial magnetic stimulation on brain cells and behaviour

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