Author:

Keywords:

neuroplasticity, TMS, tDCS, behavioral test, animal test

Abstract:

Neuroplasticity refers to the ability of the brain to change as a result of one's experience, indicating that the brain is plastic and malleable. Synaptic plasticity is the ability of synapses to strengthen or weaken over time, in response to increases or decreases of activity. In the clinical context it determines how patients with a brain injury can recover, e. g. after stroke, in order to regain independence and to perform daily life activities (e.g. dressing, eating, self-care and personal hygiene). Previous studies have demonstrated that plasticity can be enhanced by different mechanisms. In this PhD project we tested the effectiveness of non-invasive brain stimulation techniques to influence neuro-plasticity. First, we tested reward related interventions which previously have been proved to boost neuroplasticity. For example monetary reward has been shown to improve the acquisition and particularly long-term retention of a newly acquired motor skill in humans. The physiological substrate mediating this effect is most likely dopamine (DA), a neuromodulator influencing cognitive, emotional, motivational and motor processes. Secondly, we tested the effect of transcranial Direct Current Stimulation (tDCS), known to promote neuroplasticity, in healthy young volunteers. Previous research suggests that anodal tDCS over the primary motor cortex (M1) modulates NMDA receptor dependent processes that mediate synaptic plasticity. We tested this proposal by applying anodal versus sham tDCS while the subjects practiced to flex their thumb as fast as possible. The repetitive practice of this task has been shown to result in performance improvements that reflect use-dependent plasticity resulting from NMDA receptor mediated, long-term potentiation (LTP)-like processes. While, tDCS has received much attention because it can be easily applied in a clinical context, its underlying mechanisms are not clear yet. In order to explore its mechanisms of action we decided to develop an animal model. In the third experiment, we developed an animal model of stroke rehabilitation that better mimics tDCS applications in humans. Here we aimed to develop an animal model where the effect of anodal tDCS over ipsilesional M1 is tested while animals perform goal-directed limb training. Accordingly, rats were trained on the pasta matrix reaching task, which allows the manipulation of limb use in order to mimic human clinical phenomena. We induced photothrombotic stroke in the M1 contralateral to the preferred limb. The photothrombotic stroke animal model aims to induce ischemic damage within a cortical area through photo-activation of a light-sensitive dye previously injected in the blood system. We concluded that behavioural markers of use-dependent plasticity are surprisingly insensitive to monetary reward or punishment which might result from the nature of the task. Our data suggest that anodal tDCS facilitates long-term memory formation reflecting use-dependent plasticity, supporting the idea that anodal tDCS facilitates synaptic plasticity mediated by an LTP-like mechanism. Our data also showed that the application of anodal tDCS during post-stroke training on a reaching and grasping task in rats is feasible. tDCS is beneficial to upper limb recovery, only when the animals performed the grasp training. The availability of an animal model that can be used to closely mimic recovery training in stroke patients opens new avenues for gaining more mechanistic understanding of the underlying principles. Our results suggest that tDCS is a promising adjuvant therapy to facilitate motor recovery following stroke.