Modulation of interhemispheric inhibition and its effect on stroke recovery in the rat

Rationale: Residual disability following stroke is a significant challenge for patients and the healthcare system, both in New Zealand and worldwide. Poor recovery from motor cortex (M1) stroke has been associated with an increase in interhemispheric inhibition (IHI) initiated by the unlesioned cortex (Murase, Duque, Mazzocchio, & Cohen, 2004). Previously we showed using intracellular recordings from single neurons that intermittent theta-burst stimulation (iTBS; bursts of three pulses at 50 Hz at 5 Hz) delivered to the contralateral M1 acutely reduced IHI in normal rats (Barry, Boddington, Igelström, et al., 2014). Additionally, this stimulation improved motor recovery sub acutely following stroke (Boddington, Gray, Schulz, & Reynolds, 2020). In the present study we aimed to record IHI changes in the freely moving, stroke affected rat and measure any association with behavioural impairment. We also aimed to determine if iTBS could modify IHI and improve behaviour. Method: A method of measuring IHI in rats using EEG recording techniques was first developed. Second, to study effects of stroke and iTBS, lesions were induced by injecting endothelin-1 into M1 and dorsal sub-cortical regions and electrodes implanted to measure IHI in freely moving animals. Sham stimulation or iTBS was delivered at low intensity to the contralesional cortex for 15 days, followed by three weeks of no stimulation. Behaviour was recorded throughout, using grid walking and pasta handling tasks. Results: Baseline IHI was 19.1% ± 4.4 and was increased to 34.3% ± 5.5 one week following lesion induction (mean difference: 15.2 ± 6.0, p=0.033). In addition, increased IHI was weakly associated with worsened motor performance (R2: 0.11, p<0.005). Comparing iTBS and sham stimulated animals, in the final week of the study, iTBS animals showed a 54% ± 8.7 functional improvement in foot faults from their post stroke grid walking impairment, compared to only 15% ± 11 in the sham group; mixed effects model: p<0.05. The pasta handling task also revealed significantly greater improvement following iTBS (improvement of 56% ± 17) compared to sham (14% ± 7.4): p<0.05. In addition, delivery of iTBS reduced IHI to a greater degree than the spontaneous reduction observed in the sham group (linear mixed model: p