The emerging research field of Brain Computer Interfaces (BCIs) has created an invasive type of BCI, the Cortical Motor Prosthetic (CMP) or invasive BCI (iBCI). The goal is to restore lost motor function via prosthetic control signals to individuals who have long-term paralysis. The development of the CMP consists of two major entities: the implantable, chronic microelectrode array (MEA) and the data acquisition hardware (DAQ) specifically the decoder. The iBCI's function is to record primary motor cortex (M1) neural signals via chronic MEA and translate into a motor command via decoder extraction algorithms that can control a prosthetic to perform the intended movement. The ultimate goal is to use the iBCI as a clinical tool for individuals with long-term paralysis to regain lost motor functioning. Thus, the iBCI is a beacon of hope that could enable individuals to independently perform daily activities and interact once again with their environment. This review seeks to accomplish two major goals. First, elaborate upon the development of the iBCI and focus on the advancements and efforts to create a viable system. Second, illustrate the exciting improvements in the iBCI's use for reaching and grasping actions and in human clinical trials. The ultimate goal is to use the iBCI as a clinical tool for individuals with long-term paralysis to regain movement control. Despite the promise in the iBCI, many challenges, which are described in this review, persist and must be overcome before the iBCI can be a viable tool for individuals with long-term. iBCI future endeavors aim to overcome the challenges and develop an efficient system enhancing the lives of many living with paralysis. Standard terms: Intracortical Brain Computer Interface (iBCI), Intracortical Brain Machine Interface (iBMI), Cortical Motor Prosthetic (CMP), Neuromotor Prostheses (NMP), Intracortical Neural Prosthetics, Invasive Neural Prosthetic all terms used interchangeably

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Transcranial magnetic stimulation (TMS) is commonly used to measure corticospinal and intracortical excitability in basic and clinical neuroscience. However, the effect of glucose on TMS-based measures is not well defined, despite a potentially impactful influence on precision and reliability. Here, a double-blinded placebo-controlled study was used to test the effects of glucose on two commonly used TMS measures: short-interval intracortical inhibition (SICI), and the area under the motor evoked potential recruitment curves (AURC). SICI and AURC are thought to reflect inhibitory (GABAergic) and excitatory (glutamatergic) neurotransmission respectively. Healthy males (N=18) each participated in four sessions. Session 1 involved TMS familiarization and acquisition of an individualized blood glucose response curve. During sessions 2, 3 and 4, dependent measures were taken before (T0) and twice after (T1 & T2) drinking 300 mL of solution containing glucose (75 g), sucralose-sweetened placebo (control for sweetness) or plain water (control for time). The T1 and T2 measurements were started 5 minutes prior to the blood glucose peak observed during Session 1. Blood glucose and mean arterial pressure (MAP) were also monitored. Sucralose, but not water or glucose increased AURC and none of the treatments altered SICI. There was no association between blood glucose level and TMS measures, but in all three conditions MAP rose after consumption of the drink. There was a positive correlation between the rise in blood pressure and the relative increase in AURC at the higher stimulus intensities. Eleven participants returned for a fifth session to quantify the smallest detectible change in the AURC measurements and it was confirmed that significant changes were real while non-significant differences in measurement means fell within the range of expected measurement error. This study also suggests a relationship between corticospinal excitability and autonomic tone. Additional investigation is required to understand the mediating factors of this association. / Thesis / Master of Science (MSc)

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Les mouvements sont le résultat de contractions musculaires dont l’organisation spatio-temporelle est régie par des structures cérébrales et médullaires. Etudier les circuits qui les sous-tendent est une étape indispensable pour renforcer nos connaissances des mécanismes à l’origine de la commande des mouvements volontaires et pour mieux comprendre la pathophysiologie des mouvements anormaux. Les muscles squelettiques sont innervés par les motoneurones alpha de la moelle épinière qui à leur out sont influencés par des neurones des aires corticales motrices. Cette voie descendante constitue la voie corticomotoneuronale (CM) et est responsable de l’exécution des mouvements volontaires. Le cortex moteur primaire est considéré comme une structure clé, au cœur du système, permettant l’intégration complexe de nombreuses influences multi-régions pour conduire aux comportements moteurs adéquats. Les interactions qui existent entre les différents groupes de neurones au sein de M1 influent en dernier lieu sur la sortie motrice. De la balance complexe entre ces influences inhibitrices et excitatrices, locales ou à distance va dépendre l’état d’excitabilité des cellules CM contrôlant les différents muscles. L'objectif de ce travail de thèse était d'étudier comment évoluent certains de ces mécanismes excitateurs ou inhibiteurs du cortex moteur primaire lorsque la commande motrice volontaire d’un muscle de l’index est modifiée. Nous avons étudié le rôle de ces mécanismes dans les changements d’excitabilité de la voie CM qui accompagnent la contraction tonique volontaire du muscle premier interosseus dorsalis (FDI) en comparant une tâche simple mais peu naturelle : l’abduction de l'index, une tâche naturelle plus complexe: la pince pouce-index et la condition de repos musculaire. Nous avons également étudié l’effet de la commande motrice sur l’interaction entre deux de ces mécanismes inhibiteurs l’un à longue latence, la LICI, l’autre à courte latence, la SICI. Enfin nous avons souhaité évaluer le décours temporel de ces mécanismes dans un cadre pathologique tâche-dépendant: la crampe de l’écrivain. Pour cela, nous avons utilisé la technique d’electromyographie de surface pour enregistrer les potentiels moteurs évoqués par la Stimulation Magnétique Transcrânienne. Nous avons mis en évidence une modulation tâche-dépendante de la LICI. Par rapport à la tâche d’abduction simple, la LICI s’estompait plus tôt lors de la tâche de pince pouce-index, traduisant une désinhibition plus précoce lors d’un mouvement plus complexe. Nous avons observé, et ce pour la première fois dans la littérature, une phase de facilitation nette qui suivait cette désinhibition, et qui était absente lorsque le muscle était au repos. Ces résultats sont également visibles dans un muscle voisin du FDI, non engagé dans la tâche; cela suggère que les mécanismes à l’origine de la facilitation sont impliqués dans l’activité volontaire sans spécificité topographique. L’interaction entre la LICI et la SICI n’a pas été modifiée par la tâche effectuée, laissant penser qu’elle n’est pas impliquée dans les changements d’excitabilité tâche-dépendants. Enfin, il apparaît que la désinhibition est retardée chez les sujets dystoniques quand le muscle est engagé dans un mouvement complexe de pince pouce-index mais pas dans une tâche simple d’abduction de l’index en comparaison à des sujets contrôles. Ces résultats illustrent le fait que lors d’un mouvement plus complexe, l’efficacité des circuits inhibiteurs du cortex moteur primaire est modifiée, ce qui permet de réguler l’activité des cellules CM, afin d’adapter la commande motrice au mouvement souhaité. Le fait que cette désinhibition soit retardée dans une tâche complexe (proche de la tâche affectée) mais pas dans une tâche simple chez les patients atteints d’une crampe de l’écrivain suggère que les mécanismes à l’origine de la désinhibition pourraient participer aux troubles moteurs qui caractérisent la maladie. / Movements are evoked by muscles contractions whose spatial organization is mediated by both spinal and cortical components. It is important to investigate the underlying circuitry of movements to extend our knowledge on how voluntary movement are controlled and to better understand the pathophysiology of movements disorders. The spinal alpha motoneurons innervating distal muscles are controlled at least in parts by corticomotoneuronal neurons located in the motor cortical areas. Among them, the primary motor cortex is considered as a key structure, performing a complex integration of multi-regional influences leading to appropriate motor behaviors. Axons from corticomotoneuronal (CM) cells of the primary motor cortex reach the spinal cord via descending motor pathway. CM neurons are influenced by local or distant, inhibitory and excitatory components which determine the balance of excitability. The aim of this thesis was to explore changes of some of the excitatory and inhibitory mechanisms of motor cortex as a function of the task being performed. We assessed the time course of Long-interval Intracortical Inhibition (LICI), Late Cortical Disinhibition (LCD) and Long interval Intracortical Facilitation (LICF), which are mechanisms that potentially act to modulate the output of CM controlling the first dorsal interosseus (FDI) muscle. We compared three conditions : index finger abduction (a simple but not natural task), precision grip between index and thumb ( amore natural and complex task), and rest. We also evaluated the effect of task on interaction between LICI and Short Interval Intracortical Inhibition (SICI). Finally, we assessed the time course of LICI in patients suffering from writer’s cramp. For this purpose, we used surface electromyography to record motor potentials evoked by Transcranial Magnetic Stimulation.We showed a task-dependent change in late inhibitory and disinhibitory components. Compared with abduction task, the LICI induced during precision grip was shorter, suggesting an early disinhibition in more complex task. The disinhibition was followed by a period of facilitation only during the active tasks, i.e. facilitation was not observed when all muscles were at restat rest. However, long interval intracortical facilitation can be observed in a muscle at rest not engaged in an active task if a neighboring muscle is activated. It is therefore likely that mechanisms underlying facilitation are associated with voluntary contraction albeit with lack of topographic specificity. Interaction between LICI and SICI was not modified between tasks, suggesting that it was not involved in task-dependent changes of cortical excitability. Lastly, disinhibition was shown to be delayed in dystonic patients when the FDI was actively engaged in a precision grip but not in index abduction, compared with control subjects. An explanation might be that mechanisms underlying disinhibition are impaired in thumb-index precision grip (a task similar to that inducing unwanted contractions in writer’s cramp). Task-specidic disruption of LICI and late cortical disinhibition may therefore be at least in part responsible for pathophysiology of dystonia. It is likely that during complex task, the efficacy of LICI, and more generally of motor cortex inhibitory mechanisms, is modified to allow adaptation of CM neurons activity to the functional requirements of the motor task being performed.

Cortical representations are plastic and are allocated based on the proportional use or disuse of a pathway. A steady stream of sensory input maintains the integrity of cortical networks; while in contrast, alterations in afferent activation promote sensorimotor reorganization. After an incomplete spinal cord injury (SCI), damage to the ascending and/or descending pathways induces widespread modifications to the sensorimotor system. Strengthening these spared sensorimotor pathways may be therapeutic by promoting functional recovery after injury. Using a technique called transcranial magnetic stimulation (TMS), we show that the leg motor cortex is facilitated by peripheral sensory inputs via disinhibition and potentiation of excitatory intracortical circuits. Hence, in addition to its crucial role in sensory perception, excitation from peripheral sensory afferents can reinforce muscle activity by engaging, and possibly shaping, the activity of the human motor cortex. After SCI, the amount of excitation produced by afferent stimulation reaching the motor cortex is expectantly reduced and delayed. This reduction of sensory inflow to the motor cortex may contribute to our findings that cortical inhibition is down-regulated after SCI, and this compensation may aid in the recruitment of excitatory networks in the motor cortex as a result of the damage to its output neurons. By repeatedly pairing sensory inputs from a peripheral nerve in the leg with direct cortical activation by TMS, in an intervention called paired associative stimulation, we show that the motor system can be potentiated in both uninjured individuals and after SCI. In the uninjured subjects, we show that in order to produce associative facilitation, the time window required for coincident activation of the motor cortex by TMS and peripheral sensory inputs is not as narrow as previously thought (~100 vs. ~20 ms), likely due to the persistent activation of cortical neurons following activation by TMS. The potential to condition the nervous system with convergent afferent and cortical inputs suggests that paired associative stimulation may serve as a priming tool for motor plasticity and rehabilitation following SCI.

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Postmenopausal osteoporosis is a disease characterized by bone loss and increased risk of fracture, and represents a significant burden on the Canadian health care system. Current treatments lack the ability to simultaneously address the therapeutic needs for promoting bone formation and inhibiting resorption. Our approach employs a novel conjugate drug in which an anabolic agent (EP4 receptor agonist) is reversibly joined with an anti-resorptive agent (alendronate) through a linker. This allows the bone-targeting ability of alendronate to deliver the EP4 agonist to bone sites, thereby mitigating the side effects associated with systemic administration of the EP4 agonist. This study investigated the in vivo efficacy of this drug in a curative experiment to treat postmenopausal osteoporosis using an ovariectomized rat model. Results showed that conjugate treatment dose-dependently stimulated bone formation and restored ovariectomy-induced bone loss, and conjugation between alendronate and the EP4 agonist was crucial to the drug’s anabolic effect.

Postmenopausal osteoporosis is a disease characterized by bone loss and increased risk of fracture, and represents a significant burden on the Canadian health care system. Current treatments lack the ability to simultaneously address the therapeutic needs for promoting bone formation and inhibiting resorption. Our approach employs a novel conjugate drug in which an anabolic agent (EP4 receptor agonist) is reversibly joined with an anti-resorptive agent (alendronate) through a linker. This allows the bone-targeting ability of alendronate to deliver the EP4 agonist to bone sites, thereby mitigating the side effects associated with systemic administration of the EP4 agonist. This study investigated the in vivo efficacy of this drug in a curative experiment to treat postmenopausal osteoporosis using an ovariectomized rat model. Results showed that conjugate treatment dose-dependently stimulated bone formation and restored ovariectomy-induced bone loss, and conjugation between alendronate and the EP4 agonist was crucial to the drug’s anabolic effect.

Transcranial magnetic stimulation (TMS) is a widely-used investigative technique in motor cortical evaluation. TMS is now being used in the investigation of fatigue to help partition the effects of central fatigue. Few studies have utilized this technique to evaluate the effects of locomotor exercise and none in conditions of extreme exercise. Therefore, the purpose of this thesis was twofold; first, to answer methodological questions pertaining to the use of TMS in fatigue evaluation, particularly of the quadriceps, and second, to investigate the effects of extreme exercise conditions on the development of central and supraspinal fatigue and corticospinal excitability and inhibition. In Studies 1 and 2, the effect of approaching a target force in different ways before the delivery a TMS pulse and the difference between commonly-employed methods of determining TMS intensity on the selection of optimal TMS intensity were investigated. In Study 3, the effect of one night sleep deprivation on cognitive and exercise performance and central parameters was investigated. The effect of a 110-km ultra-trail on the supraspinal component of central fatigue was evaluated in Study 4. The principal findings from this thesis are that during TMS evaluation during brief voluntary contractions, it is essential to deliver the TMS pulse once the force has stabilized at the target and that a stimulus-response curve at 20% MVC is appropriate for determining optimal TMS intensity in exercise and fatigue studies. Furthermore, while sleep deprivation negatively-impacted cognitive and exercise performance, it did not influence neuromuscular parameters nor result in greater central fatigue. Supraspinal fatigue develops and corticospinal excitability increases during endurance/ultra-endurance running and cycling, while the effects on inhibitory corticospinal mechanisms are equivocal and probably depend on exercise characteristics and TMS intensity