The primary motor cortex (M1) is a key brain area for the generation and control of motor behaviour. Output from M1 can be driven in part by long-range inputs from a collection of thalamic nuclei termed the motor thalamus (MTh), but how MTh input shapes activity in M1 and forelimb motor behaviour remains largely unresolved. To address this issue, we first defined the 3D anatomical coordinates of mouse forelimb motor thalamus (MThFL) by employing conventional retrograde and virus-based tracing methods targeted to the forelimb region of M1 (M1FL). These complimentary approaches defined MThFL as a ~0.8 mm wide cluster of neurons with anatomical coordinates 1.1 mm caudal, 0.9 mm lateral to bregma and 3.2 mm below the pial surface. Thus, MThFL incorporates defined areas of the ventrolateral, ventral anterior and anteromedial thalamic nuclei. To investigate the importance of M1FL and MThFL during skilled motor behaviour, we developed and optimised a quantitative behavioural paradigm in which head-restrained mice execute forelimb lever pushes in response to an auditory cue to receive a water reward. Forelimb movement trajectories were mapped using high-speed digital imaging and multi-point kinematic analysis. We inactivated both M1FL and MThFL of mice performing this motor behaviour using a pharmacological strategy, which in both cases resulted in a significant reduction in task performance. Inactivating M1FL significantly affected forelimb coordination and dexterity, resulting in erratic motion and posture. In contrast, mice with MThFL inactivated displayed a reduction in total motor output, although correct posture was maintained. We performed extracellular recordings in MThFL of expert-level mice, demonstrating that motor thalamic output during execution of task was dominated by a robust response to the onset of the auditory cue. Cue-evoked responses were also observed in motor thalamic neurons of naive mice. We have developed a novel solution to the stability problem encountered when performing whole-cell patch-clamp recordings from the motor cortex of head-restrained mice performing forelimb motor behaviour, and present preliminary recordings maintained through the execution of forelimb behaviour.

The neural correlates of bilateral upper limb movement are poorly understood. It has been proposed that interhemispheric pathways contribute to the modulation of motor cortical excitability during bimanual movements, possibly via direct connections between primary motor areas (M1), or via a central cortical structure, such as the supplementary motor area (SMA). The ability of one hemisphere to facilitate activation in the other presents a unique opportunity for motor rehabilitation programs using bilateral movements. The focus of this thesis was to investigate the mechanisms underlying bimanual movements in a group of healthy control participants using functional magnetic resonance imaging (fMRI), and subsequently to identify the types of movements that are most likely to maximize M1 activity. It was hypothesized first, that movements involving more proximal muscles, which are known to have a greater number of transcallosal connections, would produce a larger facilitation of M1 activity; and secondly, that the greatest facilitation would occur during those phases of movements where homologous muscles are active simultaneously (i.e. in-phase bilateral movements). The current results demonstrate that the M1 regions and the SMA work together to modulate motor cortical excitability, and that the greatest modulation of activity is seen during movements involving proximal muscles. The findings presented may have clinical relevance to motor rehabilitation programs involving bilateral movements.

The neural correlates of bilateral upper limb movement are poorly understood. It has been proposed that interhemispheric pathways contribute to the modulation of motor cortical excitability during bimanual movements, possibly via direct connections between primary motor areas (M1), or via a central cortical structure, such as the supplementary motor area (SMA). The ability of one hemisphere to facilitate activation in the other presents a unique opportunity for motor rehabilitation programs using bilateral movements. The focus of this thesis was to investigate the mechanisms underlying bimanual movements in a group of healthy control participants using functional magnetic resonance imaging (fMRI), and subsequently to identify the types of movements that are most likely to maximize M1 activity. It was hypothesized first, that movements involving more proximal muscles, which are known to have a greater number of transcallosal connections, would produce a larger facilitation of M1 activity; and secondly, that the greatest facilitation would occur during those phases of movements where homologous muscles are active simultaneously (i.e. in-phase bilateral movements). The current results demonstrate that the M1 regions and the SMA work together to modulate motor cortical excitability, and that the greatest modulation of activity is seen during movements involving proximal muscles. The findings presented may have clinical relevance to motor rehabilitation programs involving bilateral movements.

Neuroplasticity provides the basis for many of our most fundamental processes including learning, memory and the recovery of function following injury. This thesis is concerned with the neurophysiological and functional correlates of sensorimotor neuroplasticity in the healthy and focal dystonic populations. My initial experiments were conducted to determine the functional correlates of neuroplasticity induced in the primary motor (M1) and primary sensory (S1) cortices during a grip lift task. In healthy subjects these experiments further quantified the role of M1 in the anticipatory control of grip force scaling and demonstrated a role for S1 in triggering subsequent phases of the motor plan. My second series of experiments served to extend these findings by examining the functional correlates of neuroplasticity induced in the supplementary motor area (SMA). This study provided evidence for the role of left SMA in the control of grip force scaling and a role for left and right SMA in the synchronization of grip force and load force during the grip-lift synergy. Afferent input is known to be a powerful driver of cortical reorganisation. In particular, the timing and pattern of afferent input is thought to be crucial to the induction of plastic change. In healthy subjects, I examined the neurophysiological effects of applying “associative” (synchronous) and “non-associative” (asynchronous) patterns of afferent input to the motor points or digits of the hand. I observed an increase in the volume and area of the cortical representation of stimulated muscles when associative stimulation was applied over the motor points of two hand muscles. This pattern of stimulation also caused the centres of gravity of the stimulated muscles to move closer together, mimicking the maladaptive changes seen in focal hand dystonia. Non-associative stimulation and stimulation applied to the digits did not produce such an effect. Task-specific focal dystonia is characterised by excessive representational plasticity resulting in cortical representations which are significantly larger, and demonstrate greater overlap, than those seen in healthy individuals. These changes are thought to be driven, in part, by repetitive movement patterns which promote associative patterns of afferent input over an extended time period. On the basis of this knowledge, I applied non-associative stimulation to the hand muscles of dystonic subjects. Following this intervention, I noted a contraction of representational maps and a separation in the centres of gravity of the stimulated muscles. These neurophysiological changes were accompanied by improvements on a cyclic drawing task. This thesis demonstrates the functional correlates of neuroplasticity in M1, S1 and SMA during object manipulation using a precision grasp. These findings further extend our knowledge on the mechanisms underlying effective grasp control and assist us in the development of future rehabilitation protocols for neurological conditions involving grasp dysfunction. In addition, this thesis is the first to demonstrate an improvement in both neurophysiological and functional measures in focal dystonia following a period of non-associative afferent stimulation. These results open up exciting new avenues for the development of effective treatment protocols in those with focal hand dystonia. / Thesis (Ph.D.) -- University of Adelaide, School of Molecular and Biomedical Science, 2010

Neuroplasticity provides the basis for many of our most fundamental processes including learning, memory and the recovery of function following injury. This thesis is concerned with the neurophysiological and functional correlates of sensorimotor neuroplasticity in the healthy and focal dystonic populations. My initial experiments were conducted to determine the functional correlates of neuroplasticity induced in the primary motor (M1) and primary sensory (S1) cortices during a grip lift task. In healthy subjects these experiments further quantified the role of M1 in the anticipatory control of grip force scaling and demonstrated a role for S1 in triggering subsequent phases of the motor plan. My second series of experiments served to extend these findings by examining the functional correlates of neuroplasticity induced in the supplementary motor area (SMA). This study provided evidence for the role of left SMA in the control of grip force scaling and a role for left and right SMA in the synchronization of grip force and load force during the grip-lift synergy. Afferent input is known to be a powerful driver of cortical reorganisation. In particular, the timing and pattern of afferent input is thought to be crucial to the induction of plastic change. In healthy subjects, I examined the neurophysiological effects of applying “associative” (synchronous) and “non-associative” (asynchronous) patterns of afferent input to the motor points or digits of the hand. I observed an increase in the volume and area of the cortical representation of stimulated muscles when associative stimulation was applied over the motor points of two hand muscles. This pattern of stimulation also caused the centres of gravity of the stimulated muscles to move closer together, mimicking the maladaptive changes seen in focal hand dystonia. Non-associative stimulation and stimulation applied to the digits did not produce such an effect. Task-specific focal dystonia is characterised by excessive representational plasticity resulting in cortical representations which are significantly larger, and demonstrate greater overlap, than those seen in healthy individuals. These changes are thought to be driven, in part, by repetitive movement patterns which promote associative patterns of afferent input over an extended time period. On the basis of this knowledge, I applied non-associative stimulation to the hand muscles of dystonic subjects. Following this intervention, I noted a contraction of representational maps and a separation in the centres of gravity of the stimulated muscles. These neurophysiological changes were accompanied by improvements on a cyclic drawing task. This thesis demonstrates the functional correlates of neuroplasticity in M1, S1 and SMA during object manipulation using a precision grasp. These findings further extend our knowledge on the mechanisms underlying effective grasp control and assist us in the development of future rehabilitation protocols for neurological conditions involving grasp dysfunction. In addition, this thesis is the first to demonstrate an improvement in both neurophysiological and functional measures in focal dystonia following a period of non-associative afferent stimulation. These results open up exciting new avenues for the development of effective treatment protocols in those with focal hand dystonia. / Thesis (Ph.D.) -- University of Adelaide, School of Molecular and Biomedical Science, 2010

Neuroplasticity provides the basis for many of our most fundamental processes including learning, memory and the recovery of function following injury. This thesis is concerned with the neurophysiological and functional correlates of sensorimotor neuroplasticity in the healthy and focal dystonic populations. My initial experiments were conducted to determine the functional correlates of neuroplasticity induced in the primary motor (M1) and primary sensory (S1) cortices during a grip lift task. In healthy subjects these experiments further quantified the role of M1 in the anticipatory control of grip force scaling and demonstrated a role for S1 in triggering subsequent phases of the motor plan. My second series of experiments served to extend these findings by examining the functional correlates of neuroplasticity induced in the supplementary motor area (SMA). This study provided evidence for the role of left SMA in the control of grip force scaling and a role for left and right SMA in the synchronization of grip force and load force during the grip-lift synergy. Afferent input is known to be a powerful driver of cortical reorganisation. In particular, the timing and pattern of afferent input is thought to be crucial to the induction of plastic change. In healthy subjects, I examined the neurophysiological effects of applying “associative” (synchronous) and “non-associative” (asynchronous) patterns of afferent input to the motor points or digits of the hand. I observed an increase in the volume and area of the cortical representation of stimulated muscles when associative stimulation was applied over the motor points of two hand muscles. This pattern of stimulation also caused the centres of gravity of the stimulated muscles to move closer together, mimicking the maladaptive changes seen in focal hand dystonia. Non-associative stimulation and stimulation applied to the digits did not produce such an effect. Task-specific focal dystonia is characterised by excessive representational plasticity resulting in cortical representations which are significantly larger, and demonstrate greater overlap, than those seen in healthy individuals. These changes are thought to be driven, in part, by repetitive movement patterns which promote associative patterns of afferent input over an extended time period. On the basis of this knowledge, I applied non-associative stimulation to the hand muscles of dystonic subjects. Following this intervention, I noted a contraction of representational maps and a separation in the centres of gravity of the stimulated muscles. These neurophysiological changes were accompanied by improvements on a cyclic drawing task. This thesis demonstrates the functional correlates of neuroplasticity in M1, S1 and SMA during object manipulation using a precision grasp. These findings further extend our knowledge on the mechanisms underlying effective grasp control and assist us in the development of future rehabilitation protocols for neurological conditions involving grasp dysfunction. In addition, this thesis is the first to demonstrate an improvement in both neurophysiological and functional measures in focal dystonia following a period of non-associative afferent stimulation. These results open up exciting new avenues for the development of effective treatment protocols in those with focal hand dystonia. / Thesis (Ph.D.) -- University of Adelaide, School of Molecular and Biomedical Science, 2010

abstract: The activation of the primary motor cortex (M1) is common in speech perception tasks that involve difficult listening conditions. Although the challenge of recognizing and discriminating non-native speech sounds appears to be an instantiation of listening under difficult circumstances, it is still unknown if M1 recruitment is facilitatory of second language speech perception. The purpose of this study was to investigate the role of M1 associated with speech motor centers in processing acoustic inputs in the native (L1) and second language (L2), using repetitive Transcranial Magnetic Stimulation (rTMS) to selectively alter neural activity in M1. Thirty-six healthy English/Spanish bilingual subjects participated in the experiment. The performance on a listening word-to-picture matching task was measured before and after real- and sham-rTMS to the orbicularis oris (lip muscle) associated M1. Vowel Space Area (VSA) obtained from recordings of participants reading a passage in L2 before and after real-rTMS, was calculated to determine its utility as an rTMS aftereffect measure. There was high variability in the aftereffect of the rTMS protocol to the lip muscle among the participants. Approximately 50% of participants showed an inhibitory effect of rTMS, evidenced by smaller motor evoked potentials (MEPs) area, whereas the other 50% had a facilitatory effect, with larger MEPs. This suggests that rTMS has a complex influence on M1 excitability, and relying on grand-average results can obscure important individual differences in rTMS physiological and functional outcomes. Evidence of motor support to word recognition in the L2 was found. Participants showing an inhibitory aftereffect of rTMS on M1 produced slower and less accurate responses in the L2 task, whereas those showing a facilitatory aftereffect of rTMS on M1 produced more accurate responses in L2. In contrast, no effect of rTMS was found on the L1, where accuracy and speed were very similar after sham- and real-rTMS. The L2 VSA measure was indicative of the aftereffect of rTMS to M1 associated with speech production, supporting its utility as an rTMS aftereffect measure. This result revealed an interesting and novel relation between cerebral motor cortex activation and speech measures. / Dissertation/Thesis / Doctoral Dissertation Speech and Hearing Science 2018

The locus coeruleus (LC) projects ubiquitously to the cortex, and noradrenaline (NA) exerts powerful neuromodulatory control on cortical excitation and inhibition. Previous work has shown that NA plays an important role in motor processes, and further posits that dysregulation in NA function could be one of the culprits of motor-related deficits in many neurodevelopmental disorders, including Autism Spectrum Disorder. In order to characterize the change in NA levels during motor learning in awake and behaving mice, I employed a newly developed optical NA sensor, combined with in vivo two-photon imaging, to visualize spatiotemporal activation patterns of NA in the motor cortex. This experimental approach allows us to track and chronically image the same region of the motor cortex over multiple days, thus permitting the characterization of NA activity throughout the entirety of the motor learning process. I found that NA levels increase significantly during the initial phase of learning, which coincides with the structural and functional plastic changes that have been previously reported in the motor cortex during early stages of motor learning. The NA activity returns to baseline levels as the mice develop their movement strategy; however, the regions of NA release become more spatially clustered during the learning process. The results reported in this thesis provide a novel glimpse into the dynamics of NA activity in the motor cortex during motor learning, and it will provide new direction for the development of therapeutic strategies and diagnostic criteria for motor-related dysfunction in neurodevelopmental diseases.

Myeloarchitecture is a prominent feature that can identify the primary motor and sensory areas in the cerebral cortex and is increasingly imaged in magnetic resonance imaging (MRI) studies of cortical parcellation in humans. However, MRI studies of cortical myeloarchitecture are technically difficult for two reasons: the cortex is only a few millimeters thick, and intracortical contrast due to myelin is much smaller than the overall anatomical contrast between cortical tissue and underlying white matter that is typically utilized in imaging. The research in this thesis thus presents specific MRI protocols to visualize intracortical myelin, image processing protocols to delineate the heavily myelinated cortex from the adjacent typical cortex and the application of these techniques in the precentral motor cortex to study morphology of the highly myelinated dorso-medial part, consisting of Brodmann area (BA) 4 and part of BA 6. Optimization of the MRI protocols involved determining the sequence parameters for a T1-weighted MRI sequence to obtain maximal intracortical contrast at 0.7 mm isotropic resolution in imaging time of 15 min, based on T1 differences between cortex that is myelinated (GMm) or unmyelinated (GM). As part of the optimization, T1 values were measured in the following brain tissues: GM, GMm and white matter (WM). The optimization was carried out by simulating the MRI signal for a 3D, magnetization prepared, gradient echo sequence, using the measured T1 values in the analytical signal equations. It was found that lengthening the time delay at the end of each inner phase encoding loop increased the intracortical contrast. The optimization of MRI protocols also included implementing techniques to reduce radio frequency field (B1) inhomogeneities. It was found that dividing the optimized, T1-weighted MRI with a predominantly proton density weighted image resulted in a ratio image with significantly reduced B1 inhomogeneities. The goal of the image processing protocols developed in this thesis was to visualize the variation of intracortical myelin across the precentral motor cortex and to delineate its well-myelinated dorso-medial part. The myeloarchitectonic feature that was selected to visualize the variation in intracortical myelination was the thickness of GMm in the deeper parts of the cortex relative to the cortical thickness, referred to as the proportional myelinated thickness (p). To measure p, the following processing steps were performed. The ratio image was segmented into four tissues: GM, GMm, WM and cerebrospinal fluid (CSF) using fuzzy C-means clustering technique. Using a level set approach, thickness of the cortex was determined as the distance between the outer boundaries of GM and WM and thickness of GMm or myelinated thickness (m) was determined as the distance between the outer boundaries of GMm and WM. The proportional myelinated thickness p, was calculated as follows: p= m/t. The well-myelinated dorso-medial part of the precentral cortex, referred to as Mm, was distinguishable from the adjacent cortex when the proportional myelinated thickness was projected on the outer cortical surface. The optimized MRI and image processing techniques developed in this thesis were used to investigate cortical plasticity in amputees. Two morphological features of the myeloarchitecture over Mm, the mean proportional myelinated thickness and area, were measured in four lower limb amputees and four matched controls. A comparison of these morphological features showed no statistically significant difference (p < 0.05) between the two groups. / Thesis / Doctor of Philosophy (PhD)

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