Fourier Transforms

The 21st century ushered in a new era of technology that has been reshaping everyday life, simplifying outdated processes, and even giving rise to entirely new business sectors. Today, contemporary users of products and services expect more and more personalized products and services that can meet their unique needs. In that sense, it is necessary to further develop existing methods, adapt them to new applications, or even discover new methods. This book provides a thorough review of some methods that have an increasing impact on humanity today and that can solve different types of problems even in specific industries. Upgrading with Fourier Transformation gives a different meaning to these methods that support the development of new technologies and have a good projected acceleration in the future

Repetitive Transcranial Magnetic Stimulation by Theta Burst

Transcranial magnetic stimulation (TMS) is a non-invasive diagnostic and therapeutic technique used to stimulate the brain in several neurological and psychiatric diseases, even though the main bases underlying its action are not fully understood. Theta Burst Stimulation (TBS), a patterned form of repetitive TMS, has been assuming particular importance due to its faster application. Research of TBS effects on some higher cortical functions such as cognition after stimulation of the prefrontal cortex (PFC), or its possible influence in some less studied cortical regions (as the temporal cortex) has been limited and revealed inconsistent results. One of the problems assessing the cognitive TBS after-effects relates to the use of multiple evaluation methods, with different sensitivities. In this matter, the use of neurophysiology studies such as the auditory P300, a cognitive evoked potential, may be of particular importance. To date, studies addressing the association between auditory P300 and TBS are scarce, and some contradictory results were found. The study of other higher cognitive domains such as creativity is even rarer, but it may be relevant given that part of the neural networks involved in creative processing are associated with the PFC. The effect of TMS over the PFC, studying the modulation of functions mediated by the autonomic nervous system has also been reported, but there is still a significant disagreement between the rare studies performed. So far, the extent of the modulatory effects associated with TBS at the sensory level is still poorly known, and research with TBS over the auditory cortex, despite showing some positive results, remains inconclusive, with some reports of sound hypersensitivity after sessions with higher intensity stimulation. It should also be noted that a significant part of the knowledge about the effects of TBS derives from studies in patients, with dysfunctional neuronal networks or hemispheric lesions, which add challenges to the search for scientific evidence in healthy individuals. Given the uncertainties that remain regarding the extent of the neuromodulatory effects of TBS, the primary objective of this thesis focused on increasing the scientific knowledge related to the use of TBS in the healthy brain. Therefore, we intended to study the neurophysiological responses (such as auditory P300), the functional responses (such as auditory thresholds), and the physiological responses (such as cerebral oximetry and blood pressure) associated with the application of TBS in the prefrontal and temporal cortices. All studies used a target population of healthy young adults, with an average age of approximately 23 years, and similar education. TBS was performed accordingly to the 600-pulse paradigm described by Huang et al. (continuous and intermittent). Sham-controlled, double-blind intervention protocols were used, with random distribution by the respective groups. The main objective of the study in chapter III was to evaluate the effect of TBS on the dorsolateral prefrontal cortex (DLPFC) of both cerebral hemispheres in cognitive processing. The objective was to assess if the auditory P300 would be influenced by the stimulation type. Results revealed that the mean P300 peak latency after TBS decreased only after leftward iTBS. A significant delay in P300 latency was originated from both right and left cTBS. Amplitude response did not change significantly. The results covered in chapter IV derived from the use of TBS on the left DLPFC, studying the possibility of a relationship between the post-TBS auditory P300 and the post-TBS neuropsychological tests: Trail Making Test (TMT) and the Stroop Test of Words and Colours. Results revealed that cTBS led to a delay of the P300, also significantly influencing the expected performance on Stroop C and Stroop Interference when compared to the groups submitted to iTBS and sham stimulation. No significant results were found in the TMT tests for any type of TBS stimulation. In Chapter V, we studied the cerebral oximetry using Near Infra-Red Spectroscopy, blood pressure, and heart rate, after applying TBS to the right and left DLPFC. We found a significant reduction in oximetry in the left frontal region after ipsilateral cTBS and a significant decrease in systolic blood pressure after cTBS to the right DLPFC. Chapter VI covered the evaluation of the effects of TBS over the left temporal cortex, specifically studying the auditory thresholds in the ear closest to the coil. Results showed no major side effects after iTBS, cTBS, or sham stimulation. It was also found that iTBS led to lower hearing thresholds, especially when comparing the iTBS and sham groups at 500Hz and between the iTBS and cTBS groups at 4000Hz. Chapter VII addresses a patent concerning the technique and possible use of iTBS as a method to influence creative processing. After iTBS over the right DLPFC, results of an adapted selection of the Torrance Tests of Creative Thinking suggest that divergent thinking, originality and fluency improved significantly compared to the sham group. An integrative analysis of the results shows that TBS seems to effectively influence the underlying cortical neurons and cortico-subcortical networks. The findings thus support the existence of a trans-synaptic effect advocated initially for the classic repetitive TMS, which after the publication of our research can continue to be extended with greater confidence to TBS protocols. Our results also support the most consensual theory about the modulatory effects of the two main forms of TBS – intermittent (excitatory) and continuous (inhibitory) – particularly on the prefrontal and temporal cortices. The effects of TBS seem to be intrinsically correlated with the hemispheric lateralization and this may be related to the specific functions or dominance of each hemisphere and the specific stimulated cortical regions. The combined results of this investigation also seem to suggest that the inhibition induced by cTBS seems more effective when compared to the excitatory effect of iTBS, which seemed stronger in the left hemisphere. After all our research with TBS in more than one cortical region, we can infer that this is a safe technique, with rare and incipient side effects. The encouraging results after using iTBS in the auditory cortex opens new perspectives regarding future implementations of the technique and should be replicated in patients, particularly with mild sensorineural hearing loss, in order to assess whether this stimulation protocol can be a valid therapeutic technique in these cases. We also conclude that the techniques used to study TBS-related effects, as the P300 or the NIRS, can be very useful in the future, as an attempt to identify the effectiveness of the therapeutic use of TBS protocols, possibly allowing to adapt and modify the idealized interventions, leading to a personalized patient intervention. Our findings provide relevant information, necessary to increase the technical and scientific credibility required for achieving a more comprehensive and reliable clinical use of TBS. This is crucial at a time when transcranial magnetic stimulation use as an off-label therapy for numerous neurological and psychiatric diseases grows unregulated, and the patient best interests must be defended.A estimulação magnética transcraniana (EMT) é uma técnica de diagnóstico e terapêutica não invasiva, que tem vindo a evoluir nos últimos 35 anos. A aplicação terapêutica da forma repetitiva da EMT (EMTr), tem vindo a demonstrar a sua utilidade científica e clínica, com aplicação em várias doenças neurológicas e psiquiátricas como a depressão major, a perturbação obsessivo-compulsiva, dor e reabilitação em doentes com acidentes vasculares cerebrais, ainda que as principais bases subjacentes à sua acção não sejam totalmente compreendidas. A EMT baseia-se no princípio da indução magnética e na sua capacidade de induzir correntes elétricas no tecido cortical. Esses campos magnéticos (pulsos) originados por uma bobina adjacente ao couro cabeludo originam um fluxo iónico intracraniano que irá provocar a despolarização da membrana neuronal, desencadeando assim um potencial de ação. Embora a EMT exerça os seus efeitos predominantemente na área cortical adjacente à bobina, os potenciais de ação induzidos espalham-se trans-sinapticamente, originando a propagação da ativação para regiões corticais e subcorticais vizinhas pertencentes à rede neuronal em questão. Parece ocorrer ainda a aparente capacidade de influenciar a função do hemisfério contralateral à estimulação possivelmente por mediação calossal. Os efeitos da EMTr ao nível da modulação da excitabilidade neuronal estão intrinsecamente dependentes das características da estimulação, nomeadamente ao nível da frequência e padronização dos estímulos. A aplicação de frequências inferiores ou iguais a 1 Hz (EMTr de baixa frequência) são associadas à indução de um efeito inibitório neuronal, enquanto que a aplicação de frequências acima de 1 Hz, normalmente acima dos 5 Hz (EMTr de alta frequência), podem induzir um efeito excitatório. Em 2005 surgiu uma forma padronizada de aplicação dos pulsos magnéticos, denominada Theta Burst Stimulation (TBS), na qual grupos de 3 pulsos com alta frequência (bursts de 50Hz) são enviados a cada 200 milissegundos (5 Hz – frequência teta), implicando normalmente a aplicação de 600 pulsos por cada sessão de estimulação. Este é um protocolo que assume particular importância pela sua rápida aplicação, levando menos de 3 minutos a executar, sendo significativamente mais célere do que os protocolos clássicos de EMTr (que podem exceder 30 minutos). Efeitos neuromodulatórios opostos podem ser igualmente induzidos com TBS, sendo que a aplicação ininterrupta da estimulação durante 40 segundos – TBS contínua (cTBS) – parece originar uma diminuição na excitabilidade cortical com uma duração de até 50 minutos pós-estimulação, enquanto que a aplicação de apenas 2 segundos de TBS intervalada por 8 segundos de pausa – TBS intermitente (iTBS) – durante 190 segundos, terá a capacidade de induzir aumento na excitabilidade cortical até cerca de 60 minutos pós-estimulação. Apesar do volume significativo de investigação acumulada na estimulação com EMTr e TBS, demonstrando a sua capacidade modulatória e a sua aplicabilidade na prática clínica, a investigação dos seus efeitos sobre algumas funções corticais superiores como a cognição ou os efeitos da aplicação em algumas regiões corticais menos estudadas como a região temporal tem sido mais limitada (principalmente com a TBS) e apresentado alguns resultados contraditórios. O córtex pré-frontal assume particular importância associado à aplicação da EMTr/TBS dada a extensa rede de conexões com outras regiões corticais (como o córtex motor, o córtex sensitivo, a amígdala, o tálamo e o hipocampo), importantes em doenças como a depressão (desequilíbrio inter-hemisférico pré-frontal verificado por neuroimagem), e ainda pela sua aparente capacidade de influenciar funções autonómicas e cardiovasculares. Meta-análises como a de Lowe et al. 2018, avaliando os efeitos da TBS sobre o córtex pré-frontal, revelam que parece existir um efeito negativo no desempenho das tarefas de função executiva após estimulação com cTBS e um efeito positivo mas em menor grau após estimulação com iTBS. No entanto, o efeito mais definido da estimulação sobre as várias dimensões cognitivas permanece envolto em alguma dúvida, dado que por um lado têm surgido alguns resultados negativos e por outro lado a maioria dos estudos tem usado populações relativamente pequenas, com infrequente recurso a grupos sham. Um dos principais problemas na avaliação dos possíveis efeitos da estimulação magnética repetitiva prende-se com o uso de diversos métodos de avaliação, com diferentes sensibilidades para o estudo das várias dimensões cognitivas, ou ainda com técnicas com menor resolução temporal (como os estudos de imagem cerebral funcional) comparativamente a técnicas neurofisiológicas. Neste ponto, a utilização de estudos no âmbito da neurofisiologia, como os potenciais de longa latência, pode assumir particular importância. O P300 auditivo, é um potencial evocado cognitivo, dependente da atenção e capacidade de discriminação do sujeito, traduzindo estadios mais superiores ou avançados de processamento associado a uma tarefa. As origens neuronais do P300 são múltiplas e bi-hemisféricas, associando-se a regiões como o hipocampo, o córtex pré-frontal ventrolateral e o córtex cingulado posterior. Até à data, são raros os estudos que abordaram a associação entre o P300 auditivo e a EMTr e ainda mais raros combinando a estimulação com TBS e o P300. A avaliação dos resultados prévios sugere que a estimulação magnética pode ser capaz de influenciar o processamento cognitivo e que as alterações podem ser monitorizadas pelo P300, mas são encontrados alguns resultados contraditórios, existindo significativas discrepâncias na metodologia usada. […

Stimulation Paradigms and Transduction Patterns for Optogenetic Intervention of Astrocytes

Gliosis observed in several neurological disorders is associated with neuroinflammation and enhanced astrocytic Ca2+ levels. The inherent multicellular nature of this neuroinflammation poses challenges in deciphering the exact role of astrocytic Ca2+ signaling and whether it leads to the generation and/or exacerbation of neuroinflammation. These challenges are aggravated by the dearth of systematic characterization of a regulated method for eliciting astrocytic Ca2+ increases. The primary goal of this dissertation is to address the lack of a characterized method by studying optogenetics for eliciting astrocytic Ca2+ increases. As part of this analysis, we aim to identify light stimulation paradigms resulting in consistent astrocytic Ca2+ increases and assess optogenetic construct serotypes yielding maximum target cell transduction. Firstly, a novel protocol was devised to perform simultaneous optogenetics and astrocytic Ca2+ imaging in adult murine brain slices. Neocortical astrocytes exhibited synchronous patterns of Ca2+ activity upon light stimulation, drastically different from resting spontaneous activity, and based on the effect of various light paradigms; we identified ix those conducive for robust astrocytic signaling. Secondly, a theoretical model was constructed to study the effect of short and long-term light stimulation of optogenetically-enabled (ChR2-expressing) astrocytes on their Ca2+ spiking activity and basal level. We further investigated how ChR2 gating dynamics, buffering, and coupling coefficient of Ca2+ influence astrocytic activity in a single cell and a network. The response of select variants of ChR2 to varying light stimulation paradigms and key parameters to design future constructs was explored. A preliminary evaluation revealed model similarities to our in situ experimental data. Finally, to facilitate future translational work and eventual comparison to current disease models, astrocytic transduction of various serotypes of an AAV optogenetic construct was assessed in vivo, and the serotype with maximal transduction efficiency was identified. Overall, we identified light stimulation paradigms that lead to repeated robust activation of astrocytes and AAV serotypes with high astrocytic transduction efficiency, thereby verifying that via an analysis of light stimulation paradigms and serotype transduction patterns, optogenetics can be implemented for inducing astrocytic Ca2+ increases in a controlled and tunable manner

VALIDATION OF A MODEL OF SENSORIMOTOR INTEGRATION WITH CLINICAL BENEFITS

Healthy sensorimotor integration – or how our touch influences our movements – is critical to efficiently interact with our environment. Yet, many aspects of this process are still poorly understood. Importantly, several movement disorders are often considered as originating from purely motor impairments, while a sensory origin could also lead to a similar set of symptoms. To alleviate these issues, we hereby propose a novel biologically-based model of the sensorimotor loop, known as the SMILE model. After describing both the functional, and the corresponding neuroanatomical versions of the SMILE, we tested several aspects of its motor component through functional magnetic resonance imaging (fMRI) and transcranial magnetic stimulation (TMS). Both experimental studies resulted in coherent outcomes with respect to the SMILE predictions, but they also provided novel scientific outcomes about such broad topics as the sub-phases of motor imagery, the neural processing of bodily representations, or the extend of the role of the extrastriate body area. In the final sections of this manuscript, we describe some potential clinical application of the SMILE. The first one presents the identification of plausible neuroanatomical origins for focal hand dystonia, a yet poorly understood sensorimotor disorder. The last chapter then covers possible improvements on brain-machine interfaces, driven by a better understanding of the sensorimotor system. -- La façon dont votre sens du toucher et vos mouvements interagissent est connue sous le nom d’intégration sensorimotrice. Ce procédé est essentiel pour une interaction normale avec tout ce qui nous entoure. Cependant, plusieurs aspects de ce processus sont encore méconnus. Plus important encore, l’origine de certaines déficiences motrices encore trop peu comprises sont parfois considérées comme purement motrice, alors qu’une origine sensorielle pourrait mener à un même ensemble de symptômes. Afin d’améliorer cette situation, nous proposons ici un nouveau modèle d’intégration sensorimotrice, dénommé « SMILE », basé sur les connaissances de neurobiologie actuelles. Dans ce manuscrit, nous commençons par décrire les caractéristiques fonctionnelles et neuroanatomiques du SMILE. Plusieurs expériences sont ensuite effectuées, via l’imagerie par résonance magnétique fonctionnelle (IRMf), et la stimulation magnétique transcranienne (SMT), afin de tester différents aspects de la composante motrice du SMILE. Si les résultats de ces expériences corroborent les prédictions du SMILE, elles ont aussi mis en évidences d’autres résultats scientifiques intéressants et novateurs, dans des domaines aussi divers que les sous-phases de l’imagination motrice, les processus cérébraux liés aux représentations corporelles, ou encore l’extension du rôle de l’extrastriate body area. Dans les dernières parties de ce manuscrit, nous dévoilons quelques applications cliniques potentielles de notre modèle. Nous utilisons le SMILE afin de proposer deux origines cérébrales plausibles de la dystonie focale de la main. Le dernier chapitre présente comment certaines technologies existantes, telles que les interfaces cerveaux-machines, pourraient bénéficier d’une meilleure compréhension du système sensorimoteur

Biomedical Signal Analysis of the Brain and Systemic Physiology

Near-infrared spectroscopy (NIRS) is a non-invasive and easy-to-use diagnostic technique that enables real-time tissue oxygenation measurements applied in various contexts and for different purposes. Continuous monitoring with NIRS of brain oxygenation, for example, in neonatal intensive care units (NICUs), is essential to prevent lifelong disabilities in newborns. Moreover, NIRS can be applied to observe brain activity associated with hemodynamic changes in blood flow due to neurovascular coupling. In the latter case, NIRS contributes to studying cognitive processes allowing to conduct experiments in natural and socially interactive contexts of everyday life. However, it is essential to measure systemic physiology and NIRS signals concurrently. The combination of brain and body signals enables to build sophisticated systems that, for example, reduce the false alarms that occur in NICUs. Furthermore, since fNIRS signals are influenced by systemic physiology, it is essential to understand how the latter impacts brain signals in functional studies. There is an interesting brain body coupling that has rarely been investigated yet. To take full advantage of these brain and body data, the aim of this thesis was to develop novel approaches to analyze these biosignals to extract the information and identify new patterns, to solve different research or clinical questions. For this the development of new methodological approaches and sophisticated data analysis is necessary, because often the identification of these patterns is challenging or not possible with traditional methods. In such cases, automatic machine learning (ML) techniques are beneficial. The first contribution of this work was to assess the known systemic physiology augmented (f)NIRS approach for clinical use and in everyday life. Based on physiological and NIRS signals of preterm infants, an ML-based classification system has been realized, able to reduce the false alarms in NICUs by providing a high sensitivity rate. In addition, the SPA-fNIRS approach was further applied in adults during a breathing task. The second contribution of this work was the advancement of the classical fNIRS hyperscanning method by adding systemic physiology measures. For this, new biosignal analyses in the time-frequency domain have been developed and tested in a simple nonverbal synchrony task between pairs of subjects. Furthermore, based on SPA-fNIRS hyperscanning data, another ML-based system was created, which is able distinguish familiar and unfamiliar pairs with high accuracy. This approach enables to determine the strength of social bonds in a wide range of social interaction contexts. In conclusion, we were the first group to perform a SPA-fNIRS hyperscanning study capturing changes in cerebral oxygenation and hemodynamics as well as systemic physiology in two subjects simultaneously. We applied new biosignals analysis methods enabling new insights into the study of social interactions. This work opens the door to many future inter-subjects fNIRS studies with the benefit of assessing the brain-to-brain, the brain-to-body, and body-to-body coupling between pairs of subjects