Post-concussion syndrome (PCS) is a poorly understood sequela of mild traumatic brain injury (mTBI), more commonly referred to as concussion. While PCS is known to affect a subset of individuals following injury, it remains unclear how and why specific individuals incur chronic symptoms. Concussions disrupt normal neurophysiologic function within the brain, however the neurophysiologic underpinnings of PCS are unclear. Using transcranial magnetic stimulation (TMS), it is possible to non-invasively investigate neurotransmission in clinical populations such as those with PCS by stimulating the primary motor cortex (M1) and recording motor outputs in a contralateral hand muscle. A study was conducted using TMS to measure corticospinal excitability, intracortical facilitation and inhibition, and transcallosal inhibition in M1 of a group with PCS and a non-injured, healthy control group. Greater corticospinal excitability, and specific reductions in intracortical and transcallosal inhibition were observed in the PCS group, providing evidence of impaired neurotransmitter receptor activity. Importantly, these findings differed from previous observations in recovered concussion groups using similar stimulation techniques. Furthermore, it was observed that these neurophysiological differences may relate specifically to the presence of depression symptoms rather than general concussion symptoms. The physiologic and clinical implications of the findings of this thesis are discussed, and novel research avenues warranting investigation are identified. / Thesis / Master of Science in Kinesiology

A Neuronavegação é uma técnica de visualização computacional da localização de instrumentos em relação às estruturas neuronais. A estimulação magnética transcraniana (EMT) é uma ferramenta para estimulação cerebral não-invasiva, que tem sido utilizada em aplicações clínicas, para o tratamento de algumas patologias, e também em pesquisas. Entretanto, a EMT é uma técnica altamente dependente de parâmetros como o posicionamento e orientação da bobina de estimulação em relação às estruturas neuronais. Para auxiliar no posicionamento da bobina, uma combinação entre neuronavegação e EMT é utilizada, chamada de EMTnavegada (EMTn). Essa técnica permite o monitoramento em tempo real da bobina de EMT em relação às neuroimagens. Porém, a utilização da EMTn ainda é pouco explorada, tanto na pesquisa quanto no ambiente clínico, devido ao alto custo, exigência da imagem de ressonância magnética, complexidade e baixa portabilidade dos sistemas de EMTn comerciais. O neuronavegador de código aberto e livre, InVesalius Navigator, vem sendo desenvolvido para ajudar a suprir essa necessidade. Assim, o objetivo desta dissertação foi desenvolver ferramentas para o sistema de neuronavegação InVesalius Navigator. As funcionalidades adicionadas foram: i) suporte para três tipos de rastreadores espaciais; ii) sincronização da EMT com o neuronavegador; iii) guia para o reposicionamento da bobina. Além disso, com intuito de contornar a necessidade de utilizar a imagem de ressonância magnética foram realizados estudos para a substituição por uma imagem padrão. Na parte de desenvolvimento, experimentos de caracterização foram realizados para validação das ferramentas. O sistema de neuronavegação apresentou-se intuitivo e de fácil portabilidade. Além disso, a precisão obtida foi semelhante à de sistemas comerciais. Os erros de localização foram inferiores a 3 mm, considerados aceitáveis para aplicações clínicas. Na segunda parte, procedimentos que não exigem extrema precisão, como a localização e digitalização do hotspot, a variabilidade foi considerada aceitável. Portanto, a utilização da imagem média mostrou-se uma possível alternativa para as imagens de ressonância magnética. / Neuronavigation is a computer image-guided technique to locate surgical instruments related to brain structures. The transcranial magnetic stimulation (TMS) is a non-invasive brain stimulation method, it has been used for clinical purposes, treating neurological disorders, and also for research purpose, studying cortical brain function. However, the use of TMS is highly dependent on coil position and orientation related to brain structures. The navigated TMS (nTMS) is a combined technique of neuronavigation system and TMS, this technique allows tracking TMS coil by image guidance. Yet, nTMS is not widely used, either in research and in the clinical environment, due to the high cost, magnetic resonance imaging requirement, complexity, and low portability of commercial TMS systems. Thus, the aim of this dissertation was to develop tools for the neuronavigator system InVesalius Navigator, such as: i) support for three types of spatial trackers; ii) synchronization of the TMS with the neuronavigator; iii) guide for coil repositioning. In addition, in order to overcome the magnetic resonance imaging requirement, studies were made to replace it with a standard brain image. In the development part, characterization experiments were done to validate the new functionalities. Therefore, the accuracy obtained was similar to commercial systems. Localization errors were less than 3 mm considered acceptable for clinical applications. In the second part, for procedures that do not require extreme accuracy, such as the location and scanning of the hotspot, the variability was considered acceptable. Therefore, the use of the standard brain image was a possible alternative for magnetic resonance imaging.

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.

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.