Transcranial magnetic stimulation (TMS) is a non-invasive technique that can be used to assess the integrity neuronal circuits in the motor cortex, both at the intrahemispheric and interhemispheric level. In the present study, TMS was used to examine age-related modulation of corticospinal function. Participants underwent hand function testing to examine possible links between TMS measures and manual ability. Participants consisted of healthy young (n=13) and senior (n=17) right-handed individuals. Hand function testing consisted of a battery of tests administered bilaterally to assess each participant’s dexterity, strength, movement speed and reaction time. The following TMS measures were assessed bilaterally: resting motor threshold, recruitment curve and silent periods of the contralateral and ipsilateral hand. Both young and senior subjects showed significant intermanual differences in most behavioral measures, favoring their dominant right hand. There was an age-related difference in TMS measures indicating a decline in intrahemispheric excitability and interhemispheric inhibition. A general trend linking specific TMS measures in the active state with age-related changes in hand function on the dominant hand was found. Our results suggest that TMS markers of corticospinal excitability can be used to predict declining hand function with age and thus could provide an early diagnosis of pathological aging.

Chronic neck pain, including subclinical neck pain (SCNP), is a significant problem that places a burden on the healthcare system. Chiropractic manipulation has shown not only to be effective in treating symptoms of neck pain, but also in providing a neuromodulatory effect on the central nervous system. The motor cortex and cerebellum are thought to be important neural structures involved in motor learning and sensorimotor integration (SMI), and are therefore key structures to investigate how SMI is changed in a SCNP group following chiropractic care. Motor sequence learning (MSL) has also been shown to provide alterations in cerebellar projections to the motor cortex. Therefore, the studies in this thesis set out to determine if it was possible to induce both cortical and cerebellar learning, and if chiropractic care could alter motor output via transcranial magnetic stimulation measures to facilitate this learning. The study‟s results suggest that in a healthy group of subjects there is alteration in the intracortical inhibition of the motor cortex and no significant change in the cerebellum, following MSL. However, the results also suggest that in a SCNP group, there is a modulation of the cerebellar connections to the motor cortex but no effect specific to the motor cortex following both MSL and chiropractic manipulation. Therefore, these findings suggest that people with intermittent neck pain have concomitant changes in SMI and could manifest as clinical symptomology. / UOIT

This thesis consists of four chapters. In this thesis we explored associative plasticity of human motor cortex with the use of noninvasive transcranial magnetic stimulation (TMS). Paired Associative Stimulation (PAS) has grown in popularity because of its potential clinical applications. We used TMS techniques in combination with electromyographic (EMG) measurements to study cortical excitability and kinematic features of arm movement. This work has focused in a cohesive approach to answer certain fundamental questions about a) the rules of cortical plasticity and mechanism of PAS, b) the interaction between the state of neuronal excitability at the targeted cortical network and the effects of PAS, and c) translation of these effects into obvious measurable kinematic changes starting from network level changes and ending up with the behavioral modulation of arm movement. First we explored the role of GABAergic intracortical networks and intracortical facilitation on modulation of cortical excitability by showing for the first time that PAS can be conditioned by these inhibitory and facilitatory intracortical networks. Next, using standard indirect approaches utilizing peripheral EMG measures, we showed a graded excitability response for the PAS technique and showed that interactions of PAS with motor learning depends on the degree as well as the state of cortical excitability. Rules governing the interactions of brain stimulation techniques and motor learning are important because brain stimulation techniques can be used to modify, improve or disrupt motor adaptation and skill learning with great potential for clinical applications such as facilitation of recovery after stroke. TMS provide us with a unique opportunity to study the rules of plasticity at a systems level, which is a combination of synaptic and nonsynaptic (metaplastic) changes. These changes can occur either in the direction to limit the physiological range of neuronal functioning (homeostatic) or against the direction established state of neurons.

Transcranial magnetic stimulation (TMS) is a non-invasive technique that can be used to assess the integrity neuronal circuits in the motor cortex, both at the intrahemispheric and interhemispheric level. In the present study, TMS was used to examine age-related modulation of corticospinal function. Participants underwent hand function testing to examine possible links between TMS measures and manual ability. Participants consisted of healthy young (n=13) and senior (n=17) right-handed individuals. Hand function testing consisted of a battery of tests administered bilaterally to assess each participant’s dexterity, strength, movement speed and reaction time. The following TMS measures were assessed bilaterally: resting motor threshold, recruitment curve and silent periods of the contralateral and ipsilateral hand. Both young and senior subjects showed significant intermanual differences in most behavioral measures, favoring their dominant right hand. There was an age-related difference in TMS measures indicating a decline in intrahemispheric excitability and interhemispheric inhibition. A general trend linking specific TMS measures in the active state with age-related changes in hand function on the dominant hand was found. Our results suggest that TMS markers of corticospinal excitability can be used to predict declining hand function with age and thus could provide an early diagnosis of pathological aging.

Humans possess the ability to generate an incredible degree of complex, highly skilled, and coordinated movements. Although much is known about the anatomical and physiological components of upper limb movement, the exact means by which these different areas coordinate is still far from understood. The ability to perform symmetrical, bimanual tasks with ease suggest a default coupling between mirror motor regions – a default coupling that is perceptible in unilateral movements. During intended unimanual movement in the upper limbs, bilateral changes to motor cortex output occur. The purpose of this study was to investigate the neural underpinnings of these bilateral changes and investigate the involvement of intracortical inhibitory circuits. Previous studies have shown that transcallosal connections between cortical representations of the intrinsic muscles of the hands are relatively sparser than the more proximal muscles of the upper limbs. It was hypothesized that differential responses in overall motor output or intracortical inhibition to ipsilateral muscle activation between the FDI and ECR could infer the involvement of transcallosal pathways; although interhemispheric transfer was not directly investigated in this thesis. Two studies used focal transcranial magnetic stimulation (TMS), specifically paired-pulse protocols, to investigate changes in short-interval intracortical inhibition (SICI) and long-interval intracortical inhibition (LICI) in response to contraction of contralateral homologous muscle groups to the inactive test muscle. Also, the response to activation of a non-homologous, but spatially close, muscle was investigated. Lastly, two muscle groups were investigated, a distal, intrinsic muscle of the hand (first dorsal interosseous) and a relatively more proximal muscle of the upper limb (extensor carpi radialis). These studies revealed that at low levels of force generation, unilateral isometric contractions facilitate ipsilateral mirror motor representations and reduce local GABA¬A receptor mediated inhibition. Notably, while similar facilitation occurred in both the distal and proximal effectors, decreases in SICI were much more robust in the ECR. Findings from this thesis provides insight into the neural mechanisms governing bilateral changes with unilateral movement and is important in the guiding the focus of future research.

Humans possess the ability to generate an incredible degree of complex, highly skilled, and coordinated movements. Although much is known about the anatomical and physiological components of upper limb movement, the exact means by which these different areas coordinate is still far from understood. The ability to perform symmetrical, bimanual tasks with ease suggest a default coupling between mirror motor regions – a default coupling that is perceptible in unilateral movements. During intended unimanual movement in the upper limbs, bilateral changes to motor cortex output occur. The purpose of this study was to investigate the neural underpinnings of these bilateral changes and investigate the involvement of intracortical inhibitory circuits. Previous studies have shown that transcallosal connections between cortical representations of the intrinsic muscles of the hands are relatively sparser than the more proximal muscles of the upper limbs. It was hypothesized that differential responses in overall motor output or intracortical inhibition to ipsilateral muscle activation between the FDI and ECR could infer the involvement of transcallosal pathways; although interhemispheric transfer was not directly investigated in this thesis. Two studies used focal transcranial magnetic stimulation (TMS), specifically paired-pulse protocols, to investigate changes in short-interval intracortical inhibition (SICI) and long-interval intracortical inhibition (LICI) in response to contraction of contralateral homologous muscle groups to the inactive test muscle. Also, the response to activation of a non-homologous, but spatially close, muscle was investigated. Lastly, two muscle groups were investigated, a distal, intrinsic muscle of the hand (first dorsal interosseous) and a relatively more proximal muscle of the upper limb (extensor carpi radialis). These studies revealed that at low levels of force generation, unilateral isometric contractions facilitate ipsilateral mirror motor representations and reduce local GABA¬A receptor mediated inhibition. Notably, while similar facilitation occurred in both the distal and proximal effectors, decreases in SICI were much more robust in the ECR. Findings from this thesis provides insight into the neural mechanisms governing bilateral changes with unilateral movement and is important in the guiding the focus of future research.

<p>Phase correction has the potential to increase the image quality of real-time 3D (RT3D) ultrasound, especially for transcranial ultrasound. Such improvement would increase the diagnostic utility of transcranial ultrasound, leading to improvements in stroke diagnosis, treatment, and monitoring. This work describes the implementation of the multi-lag least-squares cross-correlation and partial array speckle brightness methods for static and moving targets and the investigation of contrast-enhanced (CE) RT3D transcranial ultrasound.</p><p>The feasibility of using phase aberration correction with 2D arrays and RT3D ultrasound was investigated. Using the multi-lag cross-correlation method on electronic and physical aberrators, we showed the ability of 3D phase aberration correction to increase anechoic cyst identification, image brightness, contrast-to-noise ratio (CNR), and, in 3D color Doppler experiments, the ability to visualize flow. With a physical aberrator, CNR increased by 13%, while the number of detectable cysts increased from 4.3 to 7.7.</p><p>We performed an institutional review board (IRB) approved clinical trial to assess the ability of a novel ultrasound technique, namely RT3D CE transcranial ultrasound. Using micro-bubble contrast agent, we scanned 17 healthy volunteers via a single temporal window and 9 via the sub-occipital window and report our detection rates for the major cerebral vessels. In 82% of subjects, we identified the ipsilateral circle of Willis from the temporal window, and in 65% we imaged the entire circle of Willis. From the sub-occipital window, we detected the entire vertebrobasilar circulation in 22% of subjects, and in 50% the basilar artery. </p><p>We then compared the performance of the multi-lag cross-correlation method with partial array reference on static and moving targets for an electronic aberrator. After showing that the multi-lag method performs better, we evaluated its performance with a physical aberrator. Using static targets, the correction resulted in an average contrast increase of 22.2%, compared to 13.2% using moving targets. The CNR increased by 20.5% and 12.8%, respectively. Doppler signal strength and number of Doppler voxels increased, by 5.6% and 14.4%, respectively, for the static method, and 9.3% and 4.9% for moving targets. </p><p>We performed two successful in vivo aberration corrections. We used this data and measure the isoplanatic patch size to be an average of 10.1°. The number of Doppler voxels increased by 38.6% and 19.2% for the two corrections. In both volunteers, correction enabled the visualization of a vessel not present in the uncorrected volume. These results are promising, and could potentially have a significant impact on public health.</p><p>Lastly, we show preliminary work testing the feasibility of a unique portable dedicated transcranial ultrasound system capable of simultaneous scanning from all three acoustic windows. Such a system would ideally be used in a preclinical setting, such as an ambulance.</p> / Dissertation

Transcranial magnetic stimulation (TMS) is a non-invasive technique that can be used to assess the integrity neuronal circuits in the motor cortex, both at the intrahemispheric and interhemispheric level. In the present study, TMS was used to examine age-related modulation of corticospinal function. Participants underwent hand function testing to examine possible links between TMS measures and manual ability. Participants consisted of healthy young (n=13) and senior (n=17) right-handed individuals. Hand function testing consisted of a battery of tests administered bilaterally to assess each participant’s dexterity, strength, movement speed and reaction time. The following TMS measures were assessed bilaterally: resting motor threshold, recruitment curve and silent periods of the contralateral and ipsilateral hand. Both young and senior subjects showed significant intermanual differences in most behavioral measures, favoring their dominant right hand. There was an age-related difference in TMS measures indicating a decline in intrahemispheric excitability and interhemispheric inhibition. A general trend linking specific TMS measures in the active state with age-related changes in hand function on the dominant hand was found. Our results suggest that TMS markers of corticospinal excitability can be used to predict declining hand function with age and thus could provide an early diagnosis of pathological aging.

This thesis consists of four chapters. In this thesis we explored associative plasticity of human motor cortex with the use of noninvasive transcranial magnetic stimulation (TMS). Paired Associative Stimulation (PAS) has grown in popularity because of its potential clinical applications. We used TMS techniques in combination with electromyographic (EMG) measurements to study cortical excitability and kinematic features of arm movement. This work has focused in a cohesive approach to answer certain fundamental questions about a) the rules of cortical plasticity and mechanism of PAS, b) the interaction between the state of neuronal excitability at the targeted cortical network and the effects of PAS, and c) translation of these effects into obvious measurable kinematic changes starting from network level changes and ending up with the behavioral modulation of arm movement. First we explored the role of GABAergic intracortical networks and intracortical facilitation on modulation of cortical excitability by showing for the first time that PAS can be conditioned by these inhibitory and facilitatory intracortical networks. Next, using standard indirect approaches utilizing peripheral EMG measures, we showed a graded excitability response for the PAS technique and showed that interactions of PAS with motor learning depends on the degree as well as the state of cortical excitability. Rules governing the interactions of brain stimulation techniques and motor learning are important because brain stimulation techniques can be used to modify, improve or disrupt motor adaptation and skill learning with great potential for clinical applications such as facilitation of recovery after stroke. TMS provide us with a unique opportunity to study the rules of plasticity at a systems level, which is a combination of synaptic and nonsynaptic (metaplastic) changes. These changes can occur either in the direction to limit the physiological range of neuronal functioning (homeostatic) or against the direction established state of neurons.

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. / Thesis (Ph.D.) - University of Adelaide, School of Molecular and Biomedical Science, 2009