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

Abstract

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.

In vivo low‐intensity magnetic pulses durably alter neocortical neuron excitability and spontaneous activity

“…The influence of brain state on rTMS outcome is well established in both animal (Gersner et al, 2011;Poh et al, 2018Poh et al, , 2022 and human studies (see Bradley et al, 2022;Silvanto & Pascual-Leone, 2008 for reviews). Brain state varies with the level of vigilance, voluntary attention, concurrent behaviour and anaesthesia.…”

Interactions between Guidance Cues and Neuronal Activity: Therapeutic Insights from Mouse Models

“…Consistent with this hypothesis, some effects of LI-rTMS appear to require concurrent sensory-evoked cortical activity. LI-rTMS effects on cortical visual evoked potential (VEP) characteristics and corticocollicular circuitry in ephrin-A2/A5 −/− mice were abolished when stimulation was delivered in the dark [ 83 , 108 ]. However, it is likely that some of these effects are pathway-specific because the reorganization of geniculocortical projections by LI-rTMS was not prevented in a dark environment [ 108 ].…”

“…LI-rTMS effects on cortical visual evoked potential (VEP) characteristics and corticocollicular circuitry in ephrin-A2/A5 −/− mice were abolished when stimulation was delivered in the dark [ 83 , 108 ]. However, it is likely that some of these effects are pathway-specific because the reorganization of geniculocortical projections by LI-rTMS was not prevented in a dark environment [ 108 ]. This suggests that in some circuits, normal vision or rTMS alone is not sufficient to reorganize abnormal topography, but together, they partially rescue the phenotype.…”

“…It isn’t clear whether this is an additive effect: more activity results in better refinement or if the two interventions act via distinct mechanisms. However, additional improvement was observed when rTMS was delivered in the light and concurrently with physical exercise [ 108 ], suggesting that it is possible to manipulate brain activity to increase the strength and impact of activity-dependent plasticity processes, even in the adult brain.…”

Molecular Mechanisms of Neural Plasticity: From Basic Research to Implications for Visual Functional Rescue

“…Among the possible experimental approaches capable of promoting brain plasticity, particularly promising are those based on non-invasive procedures that can enhance the potential for plasticity retained by neural circuitries without being associated with dangerous side effects. Poh et al [ 13 ] used repetitive transcranial magnetic stimulation (rTMS), a non-invasive brain stimulation technique, asking whether the beneficial effects of this treatment may be dependent on the subject’s brain state at the time of stimulation. To monitor the impact of rTMS, the authors employed mice with homozygous null mutations of the ephrin-A2 and -A5 genes, which are known to exhibit aberrant retinotectal, geniculocortical and corticotectal projections, and which have been previously shown to be susceptible to the effects of rTMS [ 14 ].…”