Age related changes in corticomotor and intracortical excitability in men.
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Date
2012
Authors
Smith, Ashleigh Elizabeth
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Pitcher, Julia Blanche
Ridding, Michael Charles
Ridding, Michael Charles
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Thesis
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Abstract
Age-related motor deficits manifest in many ways including slowing of movement, increased unwanted movements and difficulties learning new motor tasks. Despite this decline in “motor” brain function, the physiological mechanisms underlying these changes are largely unknown. One brain region innately involved in the control of voluntary movement is the human primary motor cortex. The mono-synaptic corticospinal output cells projecting from the primary motor cortex to the periphery, as well as the intra-cortical excitatory and inhibitory interneurons that synapse onto the corticospinal output neurons are important for facilitating voluntary movement. Whether or not the efficacy of these neuronal pathways is altered with advancing age has not previously been investigated in depth. Therefore, the overall aim of the studies described in this thesis was to characterise the changes in corticomotor and intracortical inhibitory network excitability that occur with ageing in otherwise neurologically healthy human males. Previous studies have provided some limited evidence of age-related changes in corticomotor excitability in humans. However interpretation of these data is complicated by the fact that all the studies were performed on both men and women; there is increasing evidence that post-menopausal loss of neuroactive estrogen in women alters cortical excitability and may have confounded the findings of previous studies where sex-specific changes have not been considered. Therefore in chapter 2 I investigated whether corticomotor excitability differed when a group of ageing men was compared with a group of young adult men. I found that corticomotor excitability was not influenced by age in either hemisphere, suggesting that in men aged less than 75 years, the efficacy of the corticomotor projection is preserved when examined in the absence of voluntary activation. The excitability of the corticospinal output neurons is highly influenced by the net balance of excitatory and inhibitory inputs onto them by cortical interneurons. In the absence of voluntary activation, the excitability of the intracortical inhibitory networks is high. This so-called intracortical inhibition is principally mediated by the neurotransmitter gamma-aminobutyric acid (GABA) acting at different classes of GABA receptors, probably on different neuronal populations. The two main GABA receptor types mediating motor intracortical inhibition are GABA receptor type A (GABAA[A in subscript]) and GABA receptor type B (GABAB[B in subscript]). Studies using paired pulse transcranial magnetic stimulation (TMS) techniques to examine these different types of inhibition in the motor cortex have shown that inhibition mediated by GABAA[A in subscript] receptors tends to occur at short interstimulus intervals (1 – 5 ms) and is therefore commonly termed short-interval intracortical inhibition (SICI). Conversely, motor cortex inhibition mediated by GABAB[B in subscript] receptors tends to occur at longer interstimulus intervals (100 – 200 ms) and is therefore commonly termed long-interval intracortical inhibition (LICI). There have been few investigations of the possible influence of ageing on SICI and the results have been equivocal with no consensus on whether SICI is increased, decreased or unchanged by ageing. Only one previous study has examined the effects of ageing on LICI in males and females, and reported it to be increased. Therefore, I investigated the influence of ageing on GABAA[A in subscript] (Chapter 3) and GABAB[B in subscript] (Chapter 4) mediated motor cortex inhibition when ageing and young adult men were compared. In chapter 3, I show that SICI is unchanged by ageing in men. I also present evidence of how the findings of previous studies are likely to have been confounded by several methodological aspects, particularly the TMS parameters used to study SICI, specifically the intensity of the conditioning stimulus. In chapter 4, I present evidence that suggests that LICI is increased in ageing men when compared with young adult men. While statistically significant, the magnitude of this increase in GABAB[B in subscript] mediated inhibition was very small and required a relatively large sample size to elucidate. However, the functional influence of this increase in LICI with age was not investigated, and whether or not this change is of sufficient magnitude to be behaviourally relevant is yet to be confirmed. On balance, the studies described in Chapters 2-4 inclusive provide little evidence of major changes in either corticomotor excitability or intracortical inhibitory network efficacy with age. However, these three studies were all performed in the absence of voluntary activation of the motor cortex or corticospinal tract, i.e. “at rest”. It may be that ageing alters the ability to modulate the excitability of these networks (e.g. by afferent input from the periphery) rather than their absolute level of excitability. Indeed, afferent input has been shown to be a powerful modulator of intracortical inhibition, particularly SICI, and this interaction appears to be important for motor control during an ongoing movement or preparation for movement. Therefore, in chapter 5 I describe a study where SICI was compared in young and ageing men under two conditions; firstly in the absence of voluntary activation and, secondly, in the presence of cutaneous afferent stimulation of the skin overlying a finger controlled by a muscle in whose cortical representation SICI was being examined. In several previous studies of young adults by others, this afferent input has been shown to reduce the amount of motor cortex inhibition subsequently evoked. Confirming the findings reported in Chapter 3, when assessed in the absence of voluntary activation or afferent input, SICI did not differ when young and old men were compared. However, with appropriately timed afferent input the subsequent degree of inhibition evoked was only reduced in the young men, but not in the old men. Using a process of elimination, I concluded that this reduced modulation of inhibition in the old men was most likely due to altered cortical sensorimotor integration of afferent input with age, as the peripheral afferent volley to the cortex appeared preserved and the level of SICI in the absence of afferent input was not different between the two age groups. It is probably not possible to confirm the exact cortical site and mechanism underlying this alteration in vivo in humans. However, my findings suggest that it is likely to involve neural projections (originating either within the motor cortex, or from elsewhere) that probably synapse with motor cortex inhibitory interneurons and are responsible for the modulation of their activity via afferent input from the periphery. In summary, the studies described in this thesis contribute two main general findings. Firstly, when investigated without voluntary activation and/or significant afferent input, the efficacy of the corticospinal tract and the main inhibitory interneurons acting upon corticospinal output cells, is not altered by ageing in otherwise neurologically healthy men. However, the “at rest” condition may mask ageing-related changes in the neural mechanisms that modulate corticomotor excitability and GABAergic intracortical inhibition. Therefore, future studies probing the neural mechanisms underlying ageing-related changes in human motor cortex function should not only be sex-specific, but also need to be undertaken under conditions that include input to the motor cortex from the periphery (i.e. afferent input) or other brain regions involved in voluntary motor system activation.
School/Discipline
School of Paediatrics and Reproductive Health
Dissertation Note
Thesis (Ph.D.) -- University of Adelaide, School of Paediatrics and Reproductive Health, 2012
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