Timing dependent mechanisms of cortical plasticity

[Truncated abstract] Transcranial magnetic brain stimulation (TMS) is being explored as a means of modulating cortical plasticity and improving function in a range of neurological and psychiatric disorders. Advances have been guided by cellular plasticity induction mechanisms that lead to long-term potentiation and depression (LTP/D) of synaptic transmission. Originally employing rate-dependent repetitive TMS (rTMS) protocols that could increase or decrease corticospinal excitability, there are now a number of newer patterned approaches that encompass both rate-dependent and time-dependent plasticity mechanisms. One such timing dependent intervention has recently been described and is designed to target trans-synaptic networks which activate (indirectly) principle cells (pyramidal tract neurons) in human motor cortex, generating a series of indirect (I-)waves with a periodicity of 1.5ms. The intervention, referred to as iTMS, involves the repeated delivery of paired stimuli at I-wave frequency (i.e. 1.5ms) for at least 15 minutes. Its novelty is that it targets the dynamics of synaptic transmission which is central to synaptic plasticity. However, there is much that is still not known about the underlying physiological mechanisms of this intervention, for example how critical the timing is or how the intervention might be developed further. The aim of this thesis was to investigate the mechanisms of the effect of this intervention and explore mechanisms that could extend its design and applicability. Delivering a paired-pulse at an inter-stimulus interval (ISI) of 1.5ms increases MEP amplitude and is known as I-wave facilitation...