Towards establishing long-lasting neuroplastic change in the human primary motor cortex.

Abstract

Neuroplasticity is critical for learning, memory, and recovery of lost function following neurological insult. Whilst non-invasive brain stimulation techniques capable of inducing these neuroplastic changes within the human cortex could be therapeutically beneficial for a range of neurological and psychiatric conditions, the short duration, instability, and variability of induced effects limits their therapeutic potential. This thesis has investigated approaches to enhance the duration, stability, and consistency of the neuroplastic response to non-invasive brain stimulation protocols applied to the human primary motor cortex. The neuroplasticity-inducing paradigm employed throughout this thesis was continuous theta burst stimulation (cTBS), a repetitive transcranial magnetic stimulation (rTMS) paradigm shown to suppress human motor cortical excitability. Studies in animals have shown the repeated, spaced application of stimulation protocols to prolong the duration of experimentally-induced synaptic plasticity. Therefore, Chapter 2 examined whether the spaced application of repeated cTBS protocols enhanced the lifetime of induced neuroplastic effects within the human primary motor cortex. Whilst the neuroplastic response to a single cTBS protocol was minimal, paired cTBS protocols spaced 10 min apart induced a strong suppression of motor cortical excitability that lasted for at least 2 h. A further set of experiments were performed to determine the possible contribution of the inhibitory motor networks to this enhanced neuroplastic response (Chapter 3). Although paired cTBS reduced the excitability of GABAA-[A- subscript]mediated inhibitory motor networks, this effect was only modest. Also, paired cTBS had no effect on GABAB-[B-subscript] mediated inhibition. These findings suggest that the enhanced neuroplastic response to paired cTBS was likely the result of greater suppression within excitatory motor networks rather than a facilitation of inhibitory motor networks. In addition to prolonging the duration of experimentally-induced synaptic plasticity, the repeated application of stimulation protocols has also been shown to consolidate these plastic changes in animal models, making them resistant to reversal by subsequent behaviourally-relevant physiological activity. In Chapter 4, I investigated whether the neuroplastic response to paired cTBS was similarly resistant to reversal by behavioural engagement of the stimulated motor regions. Whilst a voluntary activation of the targeted hand muscles reversed the neuroplastic response to a single cTBS protocol, the long-lasting neuroplastic response to paired cTBS was resistant to the same reversal effects. These results suggest that, similar to animal models of synaptic plasticity, the neuroplasticity induced by cTBS may be consolidated when repeated protocols are applied in a spaced manner. Although Chapters 2, 3, and 4 show a long-lasting and robust response to repeated cTBS protocols, the neuroplastic response to a single cTBS was highly variable between subjects. This may have been due, in part, to non-optimal stimulation characteristics. Therefore, the experiments described in Chapter 5 compared the efficacy of the standard cTBS paradigm (cTBSstd [std subscript]) to that of a slightly modified variant (cTBSmod [mod subscript]). Compared to cTBSstd [std subscript], cTBSmod- [mod- subscript]induced neuroplasticity was highly consistent between subjects, suggesting that this may be the more effective neuroplasticity-inducing paradigm. This thesis demonstrates approaches for inducing long-lasting neuroplastic changes within the human primary motor cortex. These findings have important implications for the therapeutic application of rTMS.