Factors influencing the induction of neuroplastic changes in human motor cortex.

Abstract

The human primary motor cortex (M1) undergoes structural and functional change throughout life by a process known as neuroplasticity. Techniques which artificially induce neuroplastic changes are seen as potential adjunct therapies for neurological conditions reliant on neuroplasticity for recovery of function. Unfortunately, the reported improvements in function when these techniques have been used in combination with regular rehabilitation have so far been inconsistent. One reason attributed to this is the large variability in effectiveness of these techniques in inducing neuroplastic change. This thesis has investigated factors influencing the effectiveness and reproducibility of neuroplasticity induction in human M1 using several experimental paradigms. The effectiveness and reproducibility of inducing neuroplasticity in human M1 using two variants of a paired associative stimulation (PAS) protocol was investigated in the first set of experiments (Chapter 2). Both protocols repeatedly paired a peripheral electrical stimulus to the median nerve of the left wrist with single-pulse transcranial magnetic stimulation (TMS) delivered 25 ms later to the contralateral M1. Neuroplastic changes were quantified by comparing the amplitude of the muscle evoked potential (MEP) recorded in abductor pollicis brevis (APB) muscle by suprathreshold TMS prior to and following PAS. With both protocols, neuroplasticity induction was more effective, and the responses across sessions more reproducible, if the experiments were performed in the afternoon compared to the morning. Subsequent experiments confirmed the time of day modulation of PAS-induced neuroplasticity by repeatedly testing twenty-five subjects on two separate occasions, once in the morning (8 am), and once in the evening (8 pm) (Chapter 3). Time of day was also shown to modulate GABAergic inhibition in M1. In a further set of experiments, a double-blind, placebo-controlled study demonstrated that artificially elevated circulating cortisol levels (with a single oral dose of hydrocortisone) inhibits PAS-induced neuroplasticity in the evening (8 pm), indicating that the time of day modulation of neuroplasticity induction with PAS is due, at least in part, to differences in circulating cortisol levels (Chapter 3). The cortical circuits that are modulated by PAS have also been shown to be important in motor learning. Therefore, the final set of experiments, described in Chapter 4, investigated whether motor-training-related changes in motor performance (and cortical excitability) following a ballistic motor training task are also modulated by time of day. Twenty-two subjects repeatedly abducted their left thumb with maximal acceleration for thirty minutes during two experimental sessions (morning (8 am) and evening (8 pm)) on separate occasions. Motor training improved motor performance, and increased cortical excitability, however these changes were independent of time of day. It may be that the motor training task and/or outcome measures used were not sufficiently sensitive to detect a subtle time of day effect of motor training on motor performance. Alternatively, the normally functioning motor system may be able to compensate for changes in cortical excitability to maintain optimal motor performance. These findings have important implications for therapies reliant on neuroplasticity for recovery of function, and indicate that rehabilitation may be most effective when circulating cortisol levels are low.