Effects of electrical theta burst stimulation on interhemispheric inhibition and functional recovery after stroke.

Abstract

Interhemispheric inhibition is the inhibitory influence exerted from one hemisphere of the brain to the other, and is thought to oppose motor activation in the opposite hemisphere during unimanual movement execution. Stroke, a leading cause of death and disability in the developed world, can enhance this inhibitory signal from the unaffected (contralesional) hemisphere, which is thought to negatively impact recovery by over-inhibiting the stroke-affected (ipsilesional) hemisphere. Restoring normal interhemispheric inhibition using brain stimulation techniques may represent a potential therapeutic strategy to enhance motor recovery following stroke. Our initial work showed that the application of low-intensity electrical theta burst stimulation (TBS) applied to the healthy rat motor cortex reduces interhemispheric inhibition onto the opposite hemisphere, suggesting the use of this same stimulation pattern could normalise interhemispheric inhibition after stroke. Therefore, the aim of the experiments presented in this thesis was to determine whether this same low-intensity electrical stimulation applied to the contralesional hemisphere would provide therapeutic benefit for recovery in a rat model of stroke, and whether this related to lasting changes in interhemispheric inhibition in the brain.

A photothrombotic stroke was induced in the rat motor cortex, and either no stimulation (sham), intermittent TBS (iTBS), or continuous TBS (cTBS) was applied to the contralesional homologous motor cortex. A single protocol of TBS or sham stimulation was applied twice weekly for three weeks commencing either three, ten or thirty-one days after stroke induction, and motor recovery was assessed using a grid-walking test. The early application of this minimal dose of iTBS beginning on day three accelerated and enhanced recovery compared with sham- and cTBS-treatment. Although promising, this early stimulation has limited clinical applicability since human stroke patients would be unlikely to have invasive electrodes implanted early post-stroke. However, the same minimal dose of contralesional iTBS did not enhance recovery when beginning on days ten or thirty-one post-stroke. Applying contralesional iTBS more intensively (five three-minute sessions per day, five days a week) was much more promising and trended towards substantial improvement compared with both sham and cTBS treatment beginning ten days after stroke.

It was hypothesised that these alterations in recovery would be related to the cellular effects of TBS on interhemispheric inhibition. To investigate this, after the completion of all behavioural assessments, in vivo intracellular sharp electrode recordings were made from pyramidal neurons in the animal’s peri-infarct cortex. Contrary to the hypothesis, the chronic application of iTBS of either intensity did not alter interhemispheric inhibition, however recovery was instead strongly correlated with ipsilesional evoked and spontaneous activity. Consistent with a reduction in ipsilesionally-evoked post-synaptic potentials, the minimal dose of cTBS enhanced interhemispheric inhibition, whereas the intensive dose only tended towards reducing interhemispheric inhibition.

These results indicate that iTBS and cTBS modulate interhemispheric inhibition and functional recovery in different ways. However, the relationship between interhemispheric inhibition and functional recovery is complex. The enhancement of functional recovery with contralesional iTBS suggests that invasive electrical stimulation may represent a promising avenue for enhancing stroke rehabilitation, irrespective of its effects on modulation of interhemispheric inhibition.