Effects of theta burst stimulation on the corticocortical pathways of the rat brain, in vivo

Abstract

Synaptic plasticity in the motor cortex involves interactions of multiple intrinsic and extrinsic inputs to enable learning of motor tasks. The crossed corticocortical pathways connect the primary cortices (M1) of the hemispheres together to coordinate descending output, but minimal research has been done on synaptic plasticity of these pathways onto pyramidal neurons, the M1 output neurons. The crossed-corticocortical pathways were identified and their efficacy modulated using variations of theta burst stimulation (TBS), a protocol based on the theta rhythms seen in the brain during exploratory learning tasks. Previous studies investigated TBS use as part of a rehabilitation programme by applying it in intermittent (iTBS) or continuous (cTBS) patterns with repetitive transcranial magnetic stimulation. Although successfully applied to the human M1, minimal research has been done on crossed-cortical pathways using animal models to identify cellular mechanisms engaged by iTBS and cTBS. The aim of this study was to use in vivo intracellular recordings to first identify specific crossedcorticocortical pathways by antidromically stimulating the contralateral striatum and cortex, and second to investigate the effects of iTBS and cTBS applied to either of these areas on the crossed-corticocortical pathway. Application of iTBS to the contralateral striatum decreased postsynaptic potential (PSP) slopes (-20.7 ± 5.7% at 10min post; -11.3 ± 10.5% at 20min post; n=11) whereas cTBS to the same area increased PSP slope (+15.5 ± 8.2% at 10min; +20.4 ± 7.5% at 20min; n = 11). Stimulating the contralateral cortex produced a mixed effect that showed little change after stimulation with iTBS (+9.1 ± 7.6% at 10min) and cTBS (-2.5 ± 5.6% at 10min). These plasticity results suggest striatal stimulation activates a single population of crossed-cortical axons whereas mixed effects are induced in the cortex by recruiting other corticocortical axons. To target specific cortical pathways iTBS was applied at a low intensity and recorded the effects using a protocol based on human interhemispheric inhibition (IHI) experiments. This consisted of a low intensity conditioning stimulus applied to the contralateral cortex 4 to 10ms before a test stimulus applied to the ipsilateral cortex, which decreased the slope of the test PSP (-18% of control, p < 0.05, paired t-test; n = 40). Interhemispheric inhibition was then modulated by applying iTBS to the contralateral cortex. When iTBS was applied at a level sufficient to evoke a PSP in the neuron (suprathreshold), IHI was unchanged (-15% of control, n = 7). When iTBS intensity was below threshold for evoking a PSP (subthreshold), IHI was abolished (+3% of control, n = 7; p < 0.05, unpaired t-test). Since cannabinoids can suppress GABA release the endocannabinoid antagonist AM251 (n = 4) was used to partially block these effects, suggesting GABAergic mechanisms in the cortex are preferentially activated with low intensity stimuli. Overall, it was found crossed-corticocortical pathways could be identified using antidromic activation, and these were targeted with iTBS and cTBS by stimulating the contralateral striatum or using low stimulus intensities. Targeting a specific pathway with tailored electrical stimulus protocols could enhance future rehabilitation after stroke or head injury.