Moving back in the brain to drive the field forward: Targeting neurostimulation to different brain regions in animal models of depression and neurodegeneration

et al. 2022

Sci Rep

Self Cite

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.

Section: Resultsmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

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

Moretti

Terstege

et al. 2022

Sci Rep

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“…Left hemisphere: Simulated e-field in mV/mm induced by the LI-rTMS coil placed above lambda with a current of 1.83 mA/μs [17]. Right hemisphere: Top-down view of brain regions with significantly upregulated (yellow) or downregulated (pink) overall c-Fos density following acute (A) or chronic (B) LI-rTMS compared to sham controls.…”

Section: Resultsmentioning

confidence: 99%

“…However, those studies used a human rTMS coil, which was too large to deliver focal stimulation to the small mouse brain, precluding the study of connectivity changes [16]. To better emulate the spatial characteristics of human rTMS, and provide the opportunity to study activation of networks downstream of defined brain regions, here we delivered stimulation to the mouse brain using a miniaturised coil [17].…”

Section: Introductionmentioning

confidence: 99%

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

Moretti

Terstege

et al. 2022

Preprint

Self Cite

Background: 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. Hypothesis: We investigated whether LI-rTMS modulates neuronal activity and functional connectivity. We also specifically assessed modulation of parvalbumin interneuron activity. Methods: 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 10Hz 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. Results: 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. Conclusion: 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.

“…The extent of reorganisation may also depend on the relative distance of the coil to the different neuronal compartments, which determines the intensity of the induced electric field. Because the effects of rTMS are highest at the surface of the cortex and the SC [ 69 ], the strongest induced electric field is likely received by the dendrites, cell bodies, and terminals of corticotectal projections, but only the axon terminals of the geniculocortical projections. Recent computational models of high-intensity TMS pulses have suggested that the axon terminals are more likely to be modulated than the neuronal cell bodies or dendritic compartments [ 70 ].…”

Section: Discussionmentioning

confidence: 99%

Manipulating the Level of Sensorimotor Stimulation during LI-rTMS Can Improve Visual Circuit Reorganisation in Adult Ephrin-A2A5-/- Mice

Green

Agostinelli

et al. 2022

IJMS

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Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive brain stimulation technique that has the potential to treat a variety of neurologic and psychiatric disorders. The extent of rTMS-induced neuroplasticity may be dependent on a subject’s brain state at the time of stimulation. Chronic low intensity rTMS (LI-rTMS) has previously been shown to induce beneficial structural and functional reorganisation within the abnormal visual circuits of ephrin-A2A5-/- mice in ambient lighting. Here, we administered chronic LI-rTMS in adult ephrin-A2A5-/- mice either in a dark environment or concurrently with voluntary locomotion. One day after the last stimulation session, optokinetic responses were assessed and fluorescent tracers were injected to map corticotectal and geniculocortical projections. We found that LI-rTMS in either treatment condition refined the geniculocortical map. Corticotectal projections were improved in locomotion+LI-rTMS subjects, but not in dark + LI-rTMS and sham groups. Visuomotor behaviour was not improved in any condition. Our results suggest that the beneficial reorganisation of abnormal visual circuits by rTMS can be significantly influenced by simultaneous, ambient visual input and is enhanced by concomitant physical exercise. Furthermore, the observed pathway-specific effects suggest that regional molecular changes and/or the relative proximity of terminals to the induced electric fields influence the outcomes of LI-rTMS on abnormal circuitry.