Il existe plusieurs théories du contrôle moteur, chacune présumant qu’une différente variable du mouvement est réglée par le cortex moteur. On trouve parmi elles la théorie du modèle interne qui a émis l’hypothèse que le cortex moteur programme la trajectoire du mouvement et l’activité électromyographique (EMG) d’une action motrice. Une autre, appelée l’hypothèse du point d’équilibre, suggère que le cortex moteur établisse et rétablisse des seuils spatiaux; les positions des segments du corps auxquelles les muscles et les réflexes commencent à s’activer. Selon ce dernier, les paramètres du mouvement sont dérivés sans pré-programmation, en fonction de la différence entre la position actuelle et la position seuil des segments du corps. Pour examiner de plus près ces deux théories, nous avons examiné l’effet d’un changement volontaire de l’angle du coude sur les influences cortico-spinales chez des sujets sains en employant la stimulation magnétique transcrânienne (TMS) par-dessus le site du cortex moteur projetant aux motoneurones des muscles du coude. L’état de cette aire du cerveau a été évalué à un angle de flexion du coude activement établi par les sujets, ainsi qu’à un angle d’extension, représentant un déplacement dans le plan horizontal de 100°. L’EMG de deux fléchisseurs du coude (le biceps et le muscle brachio-radial) et de deux extenseurs (les chefs médial et latéral du triceps) a été enregistrée. L’état d’excitabilité des motoneurones peut influer sur les amplitudes des potentiels évoqués moteurs (MEPs) élicitées par la TMS. Deux techniques ont été entreprises dans le but de réduire l’effet de cette variable. La première était une perturbation mécanique qui raccourcissait les muscles à l'étude, produisant ainsi une période de silence EMG. La TMS a été envoyée avec un retard après la perturbation qui entraînait la production du MEP pendant la période de silence. La deuxième technique avait également le but d’équilibrer l’EMG des muscles aux deux angles du coude. Des forces assistantes ont été appliquées au bras par un moteur externe afin de compenser les forces produites par les muscles lorsqu’ils étaient actifs comme agonistes d’un mouvement. Les résultats des deux séries étaient analogues. Un muscle était facilité quand il prenait le rôle d’agoniste d’un mouvement, de manière à ce que les MEPs observés dans le biceps fussent de plus grandes amplitudes quand le coude était à la position de flexion, et ceux obtenus des deux extenseurs étaient plus grands à l’angle d’extension. Les MEPs examinés dans le muscle brachio-radial n'étaient pas significativement différents aux deux emplacements de l’articulation. Ces résultats démontrent que les influences cortico-spinales et l’activité EMG peuvent être dissociées, ce qui permet de conclure que la voie cortico-spinale ne programme pas l’EMG à être générée par les muscles. Ils suggèrent aussi que le système cortico-spinal établit les seuils spatiaux d’activation des muscles lorsqu’un segment se déplace d’une position à une autre. Cette idée suggère que des déficiences dans le contrôle des seuils spatiaux soient à la base de certains troubles moteurs d’origines neurologiques tels que l’hypotonie et la spasticité. / According to a dominant theory, the motor cortex is directly involved in pre-programming motor outcome in terms of movement trajectories and electromyographic (EMG) patterns. In contrast, the equilibrium point theory suggests that the motor cortex sets and resets the spatial thresholds, i.e., the positions of body segments at which muscles and reflexes begin to act. Movement parameters thereby emerge without pre-programming, depending on the difference between the actual and the threshold position of the body segments. To choose between these two theories of motor control, we investigated corticospinal influences associated with voluntary changes in elbow joint angle in healthy individuals using transcranial magnetic stimulation (TMS) of the brain site projecting to motoneurons of the elbow muscles. In order to minimize the influence of motoneuronal excitability on the evaluation of corticospinal influences, motor evoked potentials (MEPs) elicited by TMS were obtained during the EMG silent period produced by a brief muscle shortening prior to the TMS pulse. MEPs were obtained at a flexion and an extension elbow angle actively established by subjects. MEPs were recorded from 2 elbow flexors (biceps and brachioradialis) and 2 extensors (medial and lateral heads of triceps). Flexor MEP amplitude was bigger at the elbow flexion position in the case of the biceps and extensor MEPs were bigger at the extension position in both extensors studied (reciprocal pattern). MEPs observed in the brachioradialis did not differ at the two elbow orientations. A similar difference in corticospinal influences at the two elbow positions was often preserved when the tonic activity of elbow muscles was equalized by compensating the passive muscle forces at the two positions with a torque motor. Thus, corticospinal influences and EMG activity were de-correlated and it can be concluded that the corticospinal system is not involved in pre-determining the magnitude of motor commands to muscles. Results suggest that the corticospinal system resets the spatial thresholds for muscle activation when segments move from one position to another. This implies that deficits in spatial threshold control may underlie different neurological motor problems (e.g., hypotonia and spasticity).

No description available.

Introdução: Apesar do grande impacto da ressonância magnética funcional em neurociências, a sua aplicabilidade clínica ainda é pequena. Um dos principais motivos é a falta de dados populacionais para dar suporte à decisão clínica. Esta tese teve por objetivo formar um banco de dados normais, representativo de pacientes do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (HCFMUSP). Métodos: Foram estudados 64 acompanhantes normais dos pacientes do HCFMUSP. Cada indivíduo realizou tarefas quem envolviam função de linguagem, somatossensorial, motor, audiovisual e de memória em aparelho de 1,5 T. Foram colhidos dados demográficos, de desempenho e neuropsicológicos dos sujeitos e de controle de qualidade do magneto de RM. As imagens funcionais foram analisadas através do software XBAM para cada indivíduo, para os grupos e para análise de correlação comportamental. Resultados: A amostra teve uma distribução demográfica variada. Os resultados das análises de grupo mostraram padrões de acordo com a literatura. O paradigma motor mostrou efeito BOLD positivo nos giros pré e pós-centrais estendendo-se para regiões pré-motoras e parietais, área motora suplementar, áreas somatosensoriais secundárias, núcleos da base e tálamo contralaterais à mão avaliada e hemisférios cerebelares ipsilaterais. O paradigma somatossensorial das mãos demonstrou efeito BOLD positivo nos giros pré e pós-centrais, núcleos da base e tálamos contralaterais à mão estimulada, cerebelo ipsilateral à mão estimulada e o córtex somatossensorial secundário bilateralmente e o da face mostrou os giros pré e pós-centrais, o córtex parietal, regiões pré-motoras, regiões temporais posteriores e inferiores e área somatosensorial secundária bilateralmente. A análise de grupo dos paradigmas de linguagem mostrou efeito BOLD positivo no giro frontal inferior e ínsula bilateralmente, maiores à esquerda, giro frontal médio esquerdo, cíngulo anterior, área motora suplementar, cerebelo à direita e vermis cerebelar, núcleos da base e tálamos à esquerda e em particular na fluência verbal falada com apresentação de letras diferentes, lobo parietal esquerdo. No paradigma audiovisual a condição visual mostrou efeito BOLD positivo no córtex occipital, parietal e cerebelo bilateralmente e a condição auditiva, nos lobos temporais bilaterais, com extensão fronto-parietal à esquerda. A análise de grupo do paradigma memória mostrou áreas no cerebelo, córtex occipital, giro frontal médio, região frontal mesial anterior e lobo parietal, com predomínio à direita. Nos mapas individuais foram detectadas muitas regiões em cada paradigma e houve grande variabilidade, sendo as regiões cerebrais que apresentaram efeito BOLD positivo com maior frequência ( 85%): giro pré-central esquerdo (95%) e cerebelo superior direito (87%) no movimento da mão direita; giro pré-central direito (88%) no movimento da mão esquerda; giro pós-central esquerdo (88%) no estímulo somatosensorial da mão direita; giro pós-central direito (89%) no estímulo somatosensorial da mão esquerda; giro lingual direito (90%) e esquerdo (88%) no estímulo visual; e giro temporal médio direito (93%) e esquerdo (91%) na condição auditiva. As tarefas de memória e fluência verbal não tiveram nenhuma região com frequência acima de 80%. Conclusões: Os padrões de ativação cerebral obtidos nas imagens de RMf do grupo de participantes são semelhantes à literatura. A freqüência das regiões com efeito BOLD positivo foi maior nos córtices primários sensoriais e motores. As informações colhidas no trabalho constituem uma base de dados que pode ser utilizada para suporte à decisão clínica. / Introduction: Functional magnetic resonance imaging has had a great impact on neuroscience, but its clinical applicability is still small. One of the main reasons is the lack of populational databases to support clinical decision. The aim of this work was to constitute a local normal database, representative of the patients from the Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (HC-FMUSP). Methods: The sample included 64 normal subjects who, at some point, accompanied patients from the HCFMUSP. They all performed motor, somatosensory, language, audiovisual and memory paradigms in a 1,5 T magnet. Demographic, neuropsychological and behavioral data were collected. Scanner quality control was also verified. Data was analyzed through XBAM software on individual and group basis, and for behavioral correlation. Results: The sample had a variable demographic distribution. Group analysis showed results in agreement with the literature. The motor paradigm elicited positive BOLD effect in the pre and postcentral gyri, extending to premotor and parietal regions, supplementary motor area, secondary somatosensory areas, basal ganglia and thalamus contralateral to the hand in question, and ipsilateral cerebellum. Group analysis of the hand somatosensory paradigm showed pre and postcentral gyri, basal ganglia and thalamus contralateral to the stimulated hand, ipsilateral cerebellum and bilateral secondary somatosensory areas. The group analysis of the somatosensory paradigm of the face showed pre and postcentral gyri, parietal cortex, premotor areas, inferior-posterior temporal cortex and secondary somatosensory areas bilaterally. Language paradigms showed positive BOLD effect in the inferior frontal gyrus and insula bilaterally, bigger on the left, left middle frontal gyrus, anterior cingulate, supplementary motor area, right cerebellum, cerebellar vermis, left basal ganglia and thalamus, and in particular, overt verbal fluency with presentation of different letters also showed the left parietal lobe. The audiovisual paradigm group analysis showed positive BOLD effect in the occipital and parietal cortex and cerebellum bilaterally during the visual condition, and bilateral temporal with left frontal and parietal extension during the auditory condition. Finally, working memory task showed activation in the occipital cortex, cerebellum, middle frontal gyri, parietal association cortex and mesial frontal region bilaterally, with right predominance. On individual basis we detected a multitude of brain areas in each paradigm with great variability, and those with the higher frequency ( 85%) were: left precentral gyrus (95%) and superior right cerebellum (87%) during the right hand movement; right precentral gyrus (88%) during the left hand movement; left postcentral gyrus (88%) for the somatosensory stimulus of the right hand; right postcentral gyrus (89%) for the somatosensory stimulus of the left hand; right (90%) and left (88%) lingual gyri during the visual stimulus; and right (93%) and left (91%) middle temporal gyrus for the auditory stimulus. Working memory and verbal fluency had no region with a frequency above 80%. Conclusions: The patterns of cerebral activations obtained in group analysis are in agreement with the literature. Individual analysis showed a higher frequency of positive BOLD effect in the primary and sensory cortices. The data collected during this work constitute a database that can be used to support clinical decision.

Made available in DSpace on 2016-03-15T19:39:55Z (GMT). No. of bitstreams: 1 Olivia Morgan Lapenta.pdf: 1151745 bytes, checksum: 91e51a2bad20664489c6aae6c59924b6 (MD5) Previous issue date: 2012-08-17 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / The Mental Simulation theory suggests activation of the motor network during imagery and execution of movements, similarly to the activation during observation and execution of actions, which is mediated by the Mirror Neuron System. This activation can be measured using eletroencefalography register of Mu rhythm suppression. It is propose that motor network activation and therefore increase of cortical excitability at primary motor cortex and Mu dessynchronization are due to premotor Miror-Neuron System inputs. Transcranial direct current stimulation is a neuromodulation technique that induce facilitation and inhibition of neural firing leading to enhance or decrease in cortical excitability, respectively. Thus, we propose to evaluate the polarity dependent effects of this technique in the Mu rhythm during biological and non-biological movements observation and imagery tasks. Therefore we applied anodal, cathodal and sham stimulation in 21 male subjects (mean age 23.8+3,06), over left primary motor cortex (2mA for 20min) and immediately after we registered the electroencephalography considering the electrodes C3, C4 and surrounding C3 and C4 and Cz. Analyses of C3 and C4 showed significant effects according to Movement (p=0.005), and also for the interactions between type of stimulation and hemisphere (p=0.04) and type of stimulation, movement and hemisphere (p=0.02). Surrounding electrodes analyses revealed significant effect for the interaction between stimulation type, task condition and movement type (p=0.03). Thus, the main findings of this study were i. Mu suppression for biological movement (in both imagery and observation) of the hand region in the contralateral hemisphere after sham stimulation, ii. reverse effect for the surrounding electrodes during imagery condition and iii. polarity-dependent neuromodulation of the Mu rhythm. The results are discussed considering focal ERD/ surrounding ERS according to the type of task. We concluded that there are contralateral focal Mu dessynchronization during observation and imagery of biological movements together with syncronizarion of the motor areas not involved in the task only for the imagery condition and that transcranial direct current stimulation has a significant effect under the entire electrode and according to the applied polarity. The use of transcranial direct current stimulation followed by observation and imagery tasks might be an interesting intervention strategy for disturbances involving motor ability impairment as well as deficits related to imitation and comprehension of other s actions. / A teoria de simulação mental sugere ativação da rede neural motora durante mentalização e execução de movimentos, de maneira análoga à ativação em observação e execução de ações, o que é mediado pelo Sistema de Neurônios-Espelho. Esta ativação pode ser mensurada por supressão do ritmo Mu registrado por eletroencefalografia. É proposto que a ativação de áreas motoras e, portanto, o aumento de excitabilidade cortical em cortex motor primário e a dessincronização do ritmo Mu ocorram em consequência de insumo proveniente do Sistema Neurônios-Espelho pré-motor. A estimulação transcraniana por corrente contínua consiste numa técnica de neuromodulação por facilitação e inibição de disparo neuronal levando a aumento e redução de excitabilidade cortical, respectivamente. Assim, foi proposto avaliar os efeitos polaridade dependentes desta técnica sobre ritmo Mu durante tarefas de observação e mentalização de movimentos biológicos e não biológicos. Para tal, aplicamos estimulação anódica, catódica e placebo em 21 homens destros (idade média de 23.8+3,06), sobre córtex motor primário esquerdo (2mA por 20min) e, em seguida foi feito o registro eletroencefalográfico considerando os eletrodos C3, C4 e entorno de C3 e C4 e Cz. A análise de C3 e C4 apresentou efeitos significativos quanto ao tipo de Movimento (p=0.005) e ainda quanto as interações entre tipo de estimulação e hemisfério (p=0.04) e tipo de estimulação, de movimento e hemisfério (p=0.02). A análise dos eletrodos do entorno revelou efeito significativo para a interação entre tipo de estimulação, condição da tarefa e tipo de movimento (p=0.03). Assim, os principais achados do estudo foram i. supressão de Mu para movimento biológico (em mentalização e observação) da região da mão em hemisfério contralateral após estimulação placebo, ii. efeitos inversos para eletrodos de entorno em condição de mentalização e iii. neuromodulação polaridade dependente de ritmo Mu. Os resultados de oscilação de Mu são discutidos considerando ERD focal/ ERS entorno de acordo com o tipo de tarefa. Concluímos que há dessincronização contralateral focal de Mu durante observação e mentalização de movimentos biológicos, acompanhada por sincronização de áreas motoras não envolvidas na tarefa apenas na condição de mentalização e que a estimulação transcraniana por corrente contínua tem efeito sob toda a superfície do eletrodo e difere de acordo com a polaridade aplicada. O uso da estimulação transcraniana por corrente contínua combinada com tarefas de observação e mentalização pode conferir uma estratégia interessante de intervenção em distúrbios envolvendo comprometimento das habilidades motoras bem como comprometimento de habilidades de imitação e compreensão das ações do outro.

Introdução: Ativação exacerbada de processos excitatórios mediados por NMDA e excesso de inibição mediada por GABA são descritos, respectivamente, nas fases agudas e subagudas após o traumatismo cranioencefálico (TCE). No entanto, existem poucos estudos a respeito do funcionamento desses circuitos na fase crônica do TCE. Objetivo: Avaliar a excitabilidade cortical (EC) de pacientes em fase crônica que sofreram TCE, especificamente diagnosticados com lesão axonial difusa (LAD). Métodos: Todos os 31 pacientes adultos foram avaliados após 1 ano, pelo menos, do TCE moderado ou grave. Inicialmente, os pacientes foram submetidos à avaliação de funções executivas - atenção, memória, fluência verbal e velocidade de processamento de informação - por meio de bateria neuropsicológica. Em seguida, a avaliação da EC foi realizada utilizando-se uma bobina circular para aplicar pulsos simples e pareados de estimulação magnética transcraniana na região cortical representativa do abdutor curto do polegar (pollicis brevis) na área M1 de ambos hemisférios. Os parâmetros de EC medidos foram: Limiar Motor de Repouso (LMR), Potenciais Evocados Motores (PEM), Inibição Intracortical de Intervalo Curto (IICIC) e Facilitação Intracortical (FIC). Todos os dados foram comparados aos dados normativos de EC já descritos na literatura e também aos de um grupo controle de pessoas saudáveis. Resultados: Não houve diferença significativa entre os hemisférios direto e esquerdo. Desta forma, os dados foram analisados de forma agrupada (\"pooled data\"). Os valores de LMR e FIC dos pacientes com LAD estavam dentro dos valores de normalidade. No entanto, os valores de PEMs a 120% do LMR, a 140% do LMR e IICIC estavam aumentados (respectivamente p=0,013; p=0,012; p < 0,001): PEM-120% LAD 524,95 [365,42 ; 616,66] versus Controles 303,50 [241,49 ; 399,19]; PEM-140% LAD 1150,00 [960,56 ; 1700,00] vs Controles 670,5 [575,43 ; 1122,78] e IICIC LAD 1,09 [0,82 ; 1,35] vs Controles 0,34 [0,28 ; 0,51]; pp02-Rel LAD 0,85 [0,64 ; 1,36] vs Controles 0,28 [0,20 ; 0,37]; pp04-Rel LAD 1,03 [0,88 ; 1,34] vs Controles 0,38 [0,29 ; 0,62] - sugerindo um possível desarranjo no sistema inibitório (p < 0.001). Os achados neuropsicológicos mostraram alterações na memória, atenção e velocidade de processamento de informação, mas possuíam correlação fraca com os dados de EC. Conclusão: Como os processos inibitórios envolvem circuitos mediados por GABA, além de outros, existe a possível inferência de que a própria fisiopatologia do LAD (rompimento de axônios) possa depletar GABA contribuindo com a desinibição do sistema neural na fase crônica do LAD / Background: Overactivation of NMDA-mediated excitatory processes and excess of GABA-mediated inhibition are described after a brain injury on the acute and subacute phases, respectively. Nevertheless, there are few studies regarding the circuitry on the chronic phase of brain injury. Objective: To evaluate the cortical excitability (CE) on the chronic phase of Traumatic Brain Injury (TBI) victims, specifically diagnosed with Diffuse Axonal Injury (DAI). Method: All 31 adult patients were evaluated after one year, at least, from the moderate and severe TBI. First, all patients underwent a broad neuropsychological assessment to evaluate executive functions - attention, memory, verbal fluency and information processing speed. Then, subsequently, the CE assessment was performed with a circular coil applying single-pulse and paired-pulse transcranial magnetic stimulation over the cortical representation of the abductor pollicis brevis muscle on M1 of both hemispheres. The CE parameters measured were: Resting Motor Threshold (RMT), Motor-Evoked Potentials (MEP), Short Interval Intracortical Inhibition (SIICI), and Intracortical Facilitation (ICF). All data were compared to normative data previously described on literature and to a control group that consisted of healthy subjects. Results: No significant difference between Left and Right hemispheres were found on these DAI patients. Therefore, parameters were analyzed as pooled data. Values of RMT and ICF from DAI patients were found within the normality. However, MEPs and SIICI values were higher on DAI patients (respectively p=0,013; p=0,012; p < 0,001): MEP-120% DAI 524,95 [365,42 ; 616,66] versus Control 303,50 [241,49 ; 399,19]; MEP-140% DAI 1150,00 [960,56 ; 1700,00] vs Control 670,5 [575,43 ; 1122,78] and SIICI DAI 1,09 [0,82 ; 1,35] vs Control 0,34 [0,28 ; 0,51]; pp02-Rel DAI 0,85 [0,64 ; 1,36] vs Control 0,28 [0,20 ; 0,37]; pp04-Rel DAI 1,03 [0,88 ; 1,34] vs Control 0,38 [0,29 ; 0,62] - suggesting a disarranged inhibitory system (p < 0.001). The neuropsychological findings had weak correlation with CE data. Conclusion: As inhibition processes also involve GABA-mediated circuitry, it is likely to infer that DAI pathophysiology itself (disruption of axons) may deplete GABA contributing to a disinhibition of the neural system on the chronic phase of DAI

Les sensations en provenance de notre corps se combinent pour donner lieu à des perceptions extrêmement variées, pouvant aller de la brûlure douloureuse au toucher agréable. Ces deux types d'informations dites nociceptives et non nociceptive sont traitées au sein du système nerveux somatosensoriel. Dans ce travail de thèse, nous avons modélisé et caractérisé l'activité électrique du cortex operculo-insulaire au sein des réseaux somatosensoriels non-douloureux et nociceptif, grâce à des enregistrements non-invasifs chez l'Homme. La validité du modèle en réponse à un stimulus nociceptif a été évaluée par comparaison avec des enregistrements intra-corticaux réalisés chez des patients épileptiques. Nous avons ensuite utilisé ce modèle pour déterminer si la stimulation corticale non invasive classiquement utilisée pour soulager les douleurs neuropathiques (stimulation magnétique du cortex moteur) permettait de modifier les réponses nociceptives chez des participants sains. Nous avons montré que cette intervention n'est pas plus efficace qu'une stimulation factice (placebo) sur le plan du blocage nociceptif. Finalement, nous avons tenté de stimuler directement le cortex operculo-insulaire, par trois méthodes différentes : par stimulation électrique locale, intracrânienne et par stimulations non-invasives magnétique (rTMS) et électrique (tDCS). Dans l'ensemble, les travaux présentés ici montrent comment une approche non-invasive chez l'Homme permet de caractériser et de moduler l'activité du cortex operculo-insulaire, qui pourrait être une cible intéressante pour le traitement des douleurs réfractaires / The somatosensory system participates in both non-nociceptive and nociceptive information Processing. In this thesis work, we model and characterize the electrical activity of the operculo-insular cortex within non-painful and nociceptive networks, using non-invasive electrophysiological recordings in humans. Validity of the modeled response to a nociceptive stimulus was evaluated by comparing it to intra-cranial recordings in epileptic patients, revealing excellent concordance. We went on to use this model to determine whether a technique of non-invasive cortical stimulation currently used to relieve neuropathic pain (motor cortex magnetic stimulation) was able to modulate acute nociceptive processing in healthy participants. We show that this intervention is not more efficacious than placebo stimulation in blocking nociception. This raises questions regarding the mechanisms of action of this technique in patients, which might implicate a modulation of pain perception at a higher level of processing. Finally, we attempted to stimulate the operculo-insular cortex directly, using three different methods. Low-frequency intra-cortical stimulation in epileptic, transcranial magnetic stimulation (TMS) of the same region in healthy participants and multipolar transcranial electrical stimulation (tDCS).Altogether, the studies presented here show how a non-invasive approach in humans allows characterising and modulating the activity of the operculo-insular cortex. While this region might be an interesting target for future treatment of drug-resistant pain, its stimulation in patients would require further investigation of parameters and procedures

No description available.

A full-sine (biphasic) pulse waveform is most commonly used for repetitive transcranial magnetic stimulation (TMS), but little is known about how variations in duration or amplitude of distinct pulse segments influence the effectiveness of a single TMS pulse to elicit a corticomotor response. Using a novel TMS device, we systematically varied the configuration of full-sine pulses to assess the impact of configuration changes on resting motor threshold (RMT) as measure of stimulation effectiveness with single-pulse TMS of the non-dominant motor hand area (M1). In young healthy volunteers, we (i) compared monophasic, half-sine, and full-sine pulses, (ii) applied two-segment pulses consisting of two identical half-sines, and (iii) manipulated amplitude, duration, and current direction of the first or second full-sine pulse half-segments. RMT was significantly higher using half-sine or monophasic pulses compared with full-sine. Pulses combining two half-sines of identical polarity and duration were also characterized by higher RMT than fullsine stimuli resulting. For full-sine stimuli, decreasing the amplitude of the halfsegment inducing posterior-anterior oriented current in M1 resulted in considerably higher RMT, whereas varying the amplitude of the half-segment inducing anterior-posterior current had a smaller effect. These findings provide direct experimental evidence that the pulse segment inducing a posterior anterior directed current in M1 contributes most to corticospinal pathway excitation. Preferential excitation of neuronal target cells in the posterior-anterior segment or targeting of different neuronal structures by the two half-segments can explain this result. Thus, our findings help understanding the mechanisms of neural stimulation by full-sine TMS.

La stimulation magnétique transcrânienne (SMT) et la spectroscopie par résonance magnétique (SRM) sont des techniques non-invasives permettant de quantifier l’activité GABAergique et glutamatergique du cerveau. La SMT et la SRM ont plusieurs applications en clinique et en recherche. En effet, ces outils peuvent être utilisés afin de déterminer l’efficacité d’un traitement ou la progression d’un processus pathologique. Cependant, malgré leur utilisation croissante dans le domaine médical, une certaine incertitude demeure quant aux substrats neurochimiques de ces techniques et à la stabilité à long terme des données acquises par SMT et SRM. Donc, dans un premier temps, la stabilité à long terme de plusieurs mesures prises par SMT et par SRM a été étudiée. En second lieu, afin de mieux comprendre quelles composantes du système GABAergique sont ciblées par ces deux techniques, des mesures de SRM et de SMT ont été obtenues après l’administration d’une benzodiazépine, le lorazépam, selon un devis expérimental randomisé, croisé, à double-aveugle et contrôlé par placébo. Deux articles composent cette thèse. Le premier article fait état d’une étude longitudinale, auprès d’adultes en santé, ayant pour but de déterminer la stabilité à long terme des concentrations de GABA et de Glx (glutamate + glutamine) obtenues par SRM ainsi que la stabilité des mesures d’inhibition et de facilitation corticale obtenues par SMT (rMT : seuil moteur au repos, %MSO : pourcentage d’intensité maximale du stimulateur, SICI : inhibition intra-corticale courte, LICI : inhibition intra-corticale longue, ICF : facilitation intra-corticale). Il a été démontré que les niveaux de GABA et de Glx sont stables au cours d’une période de trois mois. Alors que les mesures SMT de seuil moteur au repos, d’excitabilité corticale et de période corticale silencieuse sont stables à travers le temps, l’inhibition corticale à court intervalle et à long intervalle ainsi que la facilitation corticale sont beaucoup plus variables. Le deuxième article vise à comprendre la dissociation dans la sensibilité des mesures de SMT et SRM à refléter différentes facettes de l’activité GABAergique du cortex moteur. L’article porte sur une étude dans laquelle du lorazépam a été administré à des participants adultes en santé selon un devis randomisé, croisé, à double-aveugle et contrôlé par placébo. Des données SRM (GABA et Glx; cortex sensorimoteur et occipital) ainsi que des mesures SMT (cortex moteur) ont été obtenues suivant l’administration de lorazépam (ou de placébo). Il a été démontré que la prise de lorazépam réduisait les niveaux de GABA occipitaux, augmentait l’inhibition corticale et réduisait l’excitabilité du cortex moteur. La prise de médicament n’avait pas d’effet sur les autres mesures obtenues. De plus, il a été trouvé que l’effet du traitement sur l’inhibition corticale dépendait des concentrations endogènes de GABA dans le cortex sensorimoteur; une plus grande concentration de GABA étant prédictive d’une plus grande inhibition corticale suivant la prise de lorazépam. Dans leur ensemble, les résultats provenant des deux articles présentés dans cette thèse permettent de conclure que les mesures SRM des divers neurométabolites sont stables à long terme dans le cortex moteur et pourraient potentiellement servir de marqueurs dans l’évaluation de l’efficacité d’un traitement ou de l’évolution de processus pathologiques. Par contre, bien que certaines mesures SMT soient stables à long terme (rMT, %MSO, CSP), d’autres sont beaucoup plus variables (SICI, LICI, ICF); ainsi, la prudence est conseillée dans l’interprétation de ces mesures lors d’études cliniques. De plus, les effets différents que produit la prise de lorazépam sur les mesures SRM et SMT supportent la théorie selon laquelle les deux techniques n’ont pas les mêmes substrats neurochimiques. En effet, alors que les mesures TMS d’inhibition corticale refléteraient l’activité phasique des récepteurs GABAA, le signal SRM de GABA serait majoritairement intracellulaire et ne représenterait pas la neurotransmission GABAergique. / Transcranial magnetic stimulation (TMS) and magnetic resonance spectroscopy (MRS) are non-invasive techniques that allow the measurement of GABAergic and glutamatergic activity in the brain. TMS and MRS can be used to assess inhibitory and excitatory mechanisms, treatment response or disease presence and progression in vivo. However, despite their growing use in research and medical settings, ambiguity remains regarding their neurochemical substrates and long-term reproducibility. The goal of the present thesis is twofold. First, the long-term stability and reliability of various MRS and TMS measurements, obtained in the motor cortex, was investigated. Second, to better understand which aspects of the GABAergic network are targeted by the two techniques, TMS and MRS measures reflecting cortical inhibition and excitation were obtained following lorazepam administration using a placebo-controlled, double-blind, randomized, crossover design. Two articles comprise this thesis. The first article is a longitudinal assessment of the stability and reliability of MRS-GABA and Glx (glutamate + glutamine) and TMS measures of cortical inhibition and facilitation in the sensorimotor (SMC) cortex of healthy adults. It was determined that MRS-GABA and MRS-Glx are stable over a three-month interval. TMS measures of resting motor threshold (rMT), cortical excitability (% maximum stimulator output; MSO) and cortical silent period (CSP) were also found to be stable and reliable. However, paired-pulse TMS measures such as short-interval cortical inhibition (SICI), long-interval cortical inhibition (LICI) and intracortical facilitation (ICF) had greater variability. The second article aims to understand the differential sensitivity of TMS and MRS with respect to GABAergic activity in the primary motor cortex. It is based on the results and conclusions of a placebo-controlled, double-blind, randomized, crossover study, where benzodiazepine lorazepam was given to healthy adult volunteers. Magnetic resonance spectroscopy (GABA and Glx) was performed in the sensorimotor cortex and occipital cortex (OC). TMS measurements were acquired in the motor cortex only. MRS and TMS measures of cortical inhibition and excitability (rMT, input/output (I/O) curve, SICI, LICI, ICF, CSP) were obtained following lorazepam or placebo administration. Lorazepam was found to decrease occipital GABA concentration, increase motor cortical inhibition and decrease cortical excitability. Lorazepam administration had no effect on other neurometabolites or TMS measurements. The effect of Lorazepam on short-interval cortical inhibition was found to depend on endogenous GABA levels in the SMC; higher GABA concentrations predicted a greater increase in SICI following drug intake. Taken together, the studies presented in this thesis indicate that MRS neurometabolite levels are stable over time and may thus potentially serve as markers for the monitoring of disease progression and treatment response. However, while some TMS measures have good long-term stability (rMT, %MSO, CSP), others are not as reliable nor stable (SICI, LICI, ICF); care must be taken in clinical settings. Furthermore, the differential effects of lorazepam on MRS and TMS measures support the idea that the two techniques probe different aspects of the GABAergic system. Whereas TMS measures of cortical inhibition reflect phasic GABAA receptor activity, MRS-GABA primarily reflects intracellular, non-neurotransmitter metabolic GABA.

86.000 canadiens souffrent de lésions de la moelle épinière, représentant l’une des causes majeures de paralysie. 70% de ces lésions sont partielles, signifiant qu’une partie des voies de communication entre le cortex, important dans la planification, le contrôle et l’exécution de mouvements volontaires, et la moelle épinière, qui les génèrent, reste préservée. Bien que plusieurs études supportent la grande valeur des stratégies ciblant le contrôle supra-spinal en tant qu’approche pour rétablir la marche, la majorité des interventions de réhabilitation n’engagent pas directement le cortex moteur. Afin de pallier ce manque, nous avons développé une neuroprothèse permettant de stimuler électriquement les deux cortex moteur de façon cohérente lors de la marche. Nous avons utilisé un modèle de chat de contusion thoracique (T10) induisant une paralysie transitoire des membres postérieurs et des déficits locomoteurs à long terme, tel que le traînement du pied. Chez n=3 chats, avant et après contusion spinale, nous avons augmenté la réponse motrice évoquée en optimisant l’amplitude, la synchronisation, la durée et le site de la stimulation. Avant et après la contusion spinale, la neuroprothèse corticale a permis de moduler la trajectoire des membres postérieurs durant la locomotion, tel que démontrée par une augmentation significative de la hauteur du pas et de la vitesse de flexion corrélée avec l’augmentation de l’amplitude de stimulation. Après contusion, notre neuroprothèse bi-corticale a permis une réduction de 40% du traînement en comparaison à la locomotion spontanée. Ces données fournissent une preuve de concept que des protocoles de stimulation corticale peuvent être déployés afin d’améliorer la locomotion et pourraient promouvoir la récupération après une lésion médullaire. / 86.000 Canadians suffer from traumatic spinal cord injury (SCI), which is one of the leading causes of paralysis. Most SCIs are “incomplete”, meaning that some connections between the cortex -which is essential for planning, controlling and executing voluntary movements- and the spinal circuits, which generate them, are spared. Despite several studies supporting the concept that targeting supraspinal centers is a valuable approach to restore walking, most rehabilitation interventions do not directly engage the motor cortex. To address this need, we developed a neuroprosthesis that allows timely delivery of stimulation to the motor cortices during locomotion. We used a cat model of thoracic spinal cord contusion (T10) which induces a transient paralysis of both hindlimbs and long-term locomotor impairments, such as foot drag. In n=3 cats, we bilaterally implanted chronic intracortical electrode arrays within the leg representation of the primary motor cortex. Before and after spinal contusion, we enhanced the evoked motor response by optimizing the amplitude, timing, duration and site of stimulation. Both before and after SCI, we modulated the hindlimb trajectory during gait, which was shown by a significant increase in step height and velocity of flexion that correlated with the increase of stimulation amplitude. After SCI, the use of our bi-cortical neuroprosthesis led to a reduction of 40% in foot drag compared to spontaneous locomotion. These data provide a proof of concept that cortical stimulation protocols can be deployed to improve locomotion acutely after SCI and could be used for movement assistance therapies to promote recovery.