No description available.

No description available.

No description available.

Chronic refractory gastrointestinal (GI) motility disorders are a significant burden on the healthcare system, acting as a large public health issue with significant impact on the quality of life in both the pediatric and adult population. Control systems of gastrointestinal motility are complex and involve coordination of smooth muscle contraction and relaxation, which the autonomic nervous system is largely responsible for. Gaps in the diagnosis process, such as overlooking autonomic function, has left patients with diminished quality of life and limited treatment options. Many patients in the clinic have experienced injury within the spinal cord and we hypothesized that GI symptoms might be related to spinal injury causing disruption of sensory and/or motor nerves of the autonomic nervous system. Our objective became to better understand the specific location and nature of spinal injuries and GI symptoms, as completed through the development of a self-report questionnaire. Main findings suggest symptoms indicative of T3-T9 and T10-L2 spinal pathology. COVID-19 did not allow for in-clinic neuromodulation with autonomic assessments, resulting in experiments remotely assessing at-home neuromodulation treatment for GI symptoms with suspected spinal autonomic dysfunction. At-home neuromodulation was not suitable for many patients, but those who were able to manage it showed highly promising results. After years of suffering, transcutaneous electrical nerve stimulation alleviated symptoms, particularly postprandial abdominal pain, constipation, vomiting and nausea. I discuss what we learned to set us up for successful at-home treatment, and we will use all information to design randomized controlled trials to prove the benefit of TENS. The present work offers significant information on the relationship of thoracolumbar spinal pathology and complex GI symptoms, which is now used in the clinic in the diagnosis process of GI dysmotility. In addition, we have learned how to conduct at-home treatment using TENS, which allows us to execute future studies. / Thesis / Master of Science (MSc) / There are gaps in the diagnosis process of complex gastrointestinal (GI) dysmotility disorders, including lack of testing of autonomic function, leaving patients suffering with diminished quality of life with unsuccessful treatment attempts. As many patients also experience injury or conditions of the spine, I have hypothesized that GI symptoms may be related to spinal injury-induced dysfunction of the autonomic nervous system. Experimental models aim to understand the location and nature of spinal pathology with GI symptoms for future diagnoses, as well as potential treatment options such as neuromodulation. Findings of this thesis suggest symptoms indicative of particular thoracolumbar spinal pathology and promising results of transcutaneous electrical nerve stimulation (TENS) to alleviate GI symptoms, including T3-T9 and T10-L2 spinal pathology-related postprandial abdominal pain, constipation, nausea, and vomiting. This work offers information for the diagnostic process of GI dysmotility and the future design of clinical trials of neuromodulation therapies.

La stimulation du nerf vague (SNV) a reçu l’approbation de Santé Canada en 2001, comme en Europe, pour le traitement de la dépression réfractaire et en 2005 aux États-Unis. Les études européennes et américaines rapportent un taux de réponse de 50% et de rémission de 30% après un an de traitement. La sélection des patients, encadrée par la recherche de marqueurs biologiques et des critères de résistance, pourrait contribuer à améliorer les taux de réponse. Cette étude décrit le suivi des patients ambulatoires souffrant de dépression réfractaire, d’un spectre unipolaire ou bipolaire (n=13) sous SNV. Une révision exhaustive de l’histoire médicale et thérapeutique précède une évaluation clinique intensive. Si un consensus d’équipe est obtenu, une investigation clinique à la recherche des marqueurs biologiques est effectuée. Ceci inclut une tomographie par émission de photons simples (SPECT), une tomographie par émission de positrons (TEP), une formule sanguine complète, un test de suppression à la dexaméthasone (DST), une collecte d’urine 24h (catécholamines et cortisol), une polysomnographie et une évaluation neuropsychologique abrégée. Après 1 an de traitement, 61,5% (8/13) des patients ont atteint le seuil de réponse (diminution de 50% des symptômes), dont 87.5% (7/8) en rémission. Les patients diagnostiqués d’un trouble bipolaire, présentant un DST anormal et/ou avec déficits cognitifs ont répondu au traitement et poursuivent leur rémission après 2 ans. Une sélection minutieuse des patients pour le SNV serait une méthode efficace pour traiter les dépressions réfractaires, notamment pour prévenir les rechutes, amenant un état euthymique durable pour la plupart des patients. / Since 2001, Vagus Nerve Stimulation (VNS) has been used in treatment-resistant depression (TRD) in Europe and Canada, and in 2005 in the USA. European and American studies have shown a 50% response rate and 30% remission rate respectively after one year. Patient selection, driven by biological correlates and resistance criteria, may contribute to improved response and remission rates. This naturalistic study describes the follow-up of outpatients with TRD in individuals with unipolar or bipolar spectrum disorder (type 1 or 2) (n=13) treated with VNS. An exhaustive review of the medical and treatment history precedes an intensive clinical evaluation consisting of an individual evaluation and a subsequent team evaluation. A consensus is pursued, and if reached, an investigation of putative biological correlates of depression follows. This include a single photon emission computed tomography (SPECT) and a positron emission tomography (PET), a brain magnetic resonance imaging (MRI), a complete blood count, a dexamethasone suppression test (DST), a 24h urine collection; a polysomnography, and a limited neuropsychological evaluation. After one year of treatment, 61,5% (8/13) responded to treatment with at least a 50% reduction of their symptoms. Of those who responded 87.5% (7/8) are in remission. All patients with bipolar disorder, and/or abnormal baseline DST and/or baseline memory deficit responded to VNS therapy and continue to be in remission at the 24 months mark. Careful selection of patients for VNS treatment can be a very effective method of treatment of TRD and subsequent prevention of relapse, resulting in a sustained normothymic state in most responders.

La stimulation du nerf vague (SNV) a reçu l’approbation de Santé Canada en 2001, comme en Europe, pour le traitement de la dépression réfractaire et en 2005 aux États-Unis. Les études européennes et américaines rapportent un taux de réponse de 50% et de rémission de 30% après un an de traitement. La sélection des patients, encadrée par la recherche de marqueurs biologiques et des critères de résistance, pourrait contribuer à améliorer les taux de réponse. Cette étude décrit le suivi des patients ambulatoires souffrant de dépression réfractaire, d’un spectre unipolaire ou bipolaire (n=13) sous SNV. Une révision exhaustive de l’histoire médicale et thérapeutique précède une évaluation clinique intensive. Si un consensus d’équipe est obtenu, une investigation clinique à la recherche des marqueurs biologiques est effectuée. Ceci inclut une tomographie par émission de photons simples (SPECT), une tomographie par émission de positrons (TEP), une formule sanguine complète, un test de suppression à la dexaméthasone (DST), une collecte d’urine 24h (catécholamines et cortisol), une polysomnographie et une évaluation neuropsychologique abrégée. Après 1 an de traitement, 61,5% (8/13) des patients ont atteint le seuil de réponse (diminution de 50% des symptômes), dont 87.5% (7/8) en rémission. Les patients diagnostiqués d’un trouble bipolaire, présentant un DST anormal et/ou avec déficits cognitifs ont répondu au traitement et poursuivent leur rémission après 2 ans. Une sélection minutieuse des patients pour le SNV serait une méthode efficace pour traiter les dépressions réfractaires, notamment pour prévenir les rechutes, amenant un état euthymique durable pour la plupart des patients. / Since 2001, Vagus Nerve Stimulation (VNS) has been used in treatment-resistant depression (TRD) in Europe and Canada, and in 2005 in the USA. European and American studies have shown a 50% response rate and 30% remission rate respectively after one year. Patient selection, driven by biological correlates and resistance criteria, may contribute to improved response and remission rates. This naturalistic study describes the follow-up of outpatients with TRD in individuals with unipolar or bipolar spectrum disorder (type 1 or 2) (n=13) treated with VNS. An exhaustive review of the medical and treatment history precedes an intensive clinical evaluation consisting of an individual evaluation and a subsequent team evaluation. A consensus is pursued, and if reached, an investigation of putative biological correlates of depression follows. This include a single photon emission computed tomography (SPECT) and a positron emission tomography (PET), a brain magnetic resonance imaging (MRI), a complete blood count, a dexamethasone suppression test (DST), a 24h urine collection; a polysomnography, and a limited neuropsychological evaluation. After one year of treatment, 61,5% (8/13) responded to treatment with at least a 50% reduction of their symptoms. Of those who responded 87.5% (7/8) are in remission. All patients with bipolar disorder, and/or abnormal baseline DST and/or baseline memory deficit responded to VNS therapy and continue to be in remission at the 24 months mark. Careful selection of patients for VNS treatment can be a very effective method of treatment of TRD and subsequent prevention of relapse, resulting in a sustained normothymic state in most responders.

La douleur neuropathique centrale est une séquelle fréquente après une atteinte du système nerveux centrale. L’impact négatif de ces douleurs sur la qualité de vie des patients ainsi que l’efficacité modérée (40% de répondeurs) des traitements de 1ère intention font de la recherche de thérapies alternatives un enjeu clinique majeur. Depuis plusieurs années, la technique de stimulation magnétique transcrânienne répétée (rTMS) est présentée comme un outil intéressant pour soulager ce type de douleur sans pour autant que son efficacité clinique n’ait été clairement démontrée. Ce travail de thèse s’attache donc à investiguer l’efficacité de la rTMS pour traiter les douleurs neuropathiques centrales. Nous avons dans un premier temps mis en évidence, dans une étude observationnelle, qu’un minimum de 4-5 séances sur deux mois de rTMS à 20HZ sur le cortex moteur primaire (M1) produit un soulagement de la douleur pouvant se maintenir même après une année de stimulation. Afin d’écarter un possible effet placebo, nous avons objectivé l’efficacité antalgique en répliquant ce protocole dans une étude clinique randomisée, contrôlée, en groupes croisés. Les résultats obtenus confirment ceux de l’étude observationnelle puisque que l’effet antalgique de la rTMS active était significativement supérieure à la stimulation placebo pour le critère principal (% de soulagement, +33%) ou l’intensité douloureuse (EVA, -19%), avec 47% de répondeurs. Pour les patients non-répondeurs à la stimulation de M1, nous avons également testé contre placebo, dans une étude randomisée, l’efficacité d’une cible alternative : le cortex somesthésique secondaire (S2). Aucun des patients n’a été soulagé par cette stimulation mais le faible effectif de cette étude ne nous permet pas de conclure définitivement à l’absence d’effet antalgique. Enfin, compte tenu de l’utilisation croissante de nouvelles cibles corticales plus profondes, nous avons à partir de l’enregistrement du champ-magnétique produit par la rTMS dans différents milieux (l’air et modèle ex-vivo), proposé un modèle de distribution de ce champ selon la profondeur de la cible et le type de sonde de stimulation utilisé. Pour conclure, ces travaux objectivent l’effet antalgique de 4 séances de rTMS à 20Hz de M1 sur les douleurs neuropathiques centrales, validant ainsi son utilisation lorsque les traitements de 1ère intention ont échoué. Les résultats obtenus par la stimulation de S2 ainsi que par la modélisation du champ magnétique doivent permettre à de futures études d’explorer de nouvelles cibles corticales pour les patients qui restent encore en échec de traitement. / Central neuropathic pain is a common sequelae after central nervous system injury. Its negative consequences on the quality of life and the moderate efficacy (40% of responders) of first-line treatments make the search for alternative therapies a major clinical challenge. For several years, the technique of repeated transcranial magnetic stimulation (rTMS) is presented as an interesting tool to relieve this sort of pain even though its clinical efficacy has not been clearly demonstrated. The aim of this thesis was to investigate the effectiveness of rTMS to relieve central neuropathic pain.We first demonstrated, in an observational study, that a minimum of 4-5 sessions over two months of rTMS at 20HZ on the primary motor cortex (M1) produces pain relief that can be maintained even after a year of stimulation. In order to rule out a possible placebo effect, we objectified the analgesic efficacy by replicating this protocol in a randomized, controlled, cross-over clinical study. The results obtained confirm those of the observational study since the analgesic effect of the active rTMS was significantly greater than the placebo stimulation for the main criterion (% of pain relief, +33%) or pain intensity (VAS, -19%), with 47% of responders. For patients who did not respond to M1 stimulation, we also tested the efficacy of an alternative target in a randomized study: the secondary somatosensory cortex (S2). None of the patients were relieved by this stimulation, but the small size of this study does not allow us to definitively conclude that there is no analgesic effect. Finally, given the increasing use of new deeper cortical targets in rTMS for pain treatment, we have from the recording of the magnetic field produced by the rTMS in different media (air and ex-vivo model), proposed a magnetic-field distribution model according to the depth of the target and the type of stimulation coils used.To conclude, this work objectify the analgesic effect of 4 rTMS sessions at 20 Hz of M1 to relieve central neuropathic pain, validating its use when first-line treatments have failed. The results obtained by S2 stimulation as well as magnetic field modeling should allow future studies to explore new cortical targets for patients who are still failing treatment

No description available.

Introdução: Após décadas de experimentação em estimulação transcraniana por corrente contínua (ETCC), poucos protocolos alcançaram robusta aceitação científica. Protocolos de ETCC foram sugeridos para influenciar alterações no controle postural de indivíduos saudáveis e pacientes após acidente vascular cerebral. No entanto, a escassa literatura nesta área revela a indispensável investigação do efeito doseresposta das estimulações cerebrais a fim de elaborar protocolos mais eficazes. O presente trabalho teve por objetivo verificar o efeito dependente de polaridade e intensidade após o uso da estimulação transcraniana por corrente contínua de alta definição (HD-ETCC) na junção têmporo-parietal (JTP) do hemisfério cerebral direito na assimetria da postura espontânea. Métodos: Este é um ensaio clínico fatorial cruzado, randomizado, controlado por placebo e duplo cego. Foram incluídos 21 indivíduos saudáveis, com idade média de 24,2±4,1 anos, 61,9% mulheres. A intervenção consistiu na aplicação do HD-ETCC com um eletrodo central e 3 eletrodos periféricos posicionados sobre JTP no hemisfério cerebral direito. A descarga de peso corporal (DPC) na posição ortostática foi realizada utilizando uma plataforma de força sobre cada pé do participante, e avaliada durante 2 minutos na medida basal e 5 minutos após cada estimulação. A fim de melhorar a tolerância dos participantes à HD-ETCC, foi realizado um protocolo de acomodação composto por 3 repetições de estimulação com duração e intervalo de 5 segundos cada, nas intensidades fixas de 1, 2 e 3mA. Após um repouso de 5 minutos, foi aplicado o protocolo de estimulação constituído por 3 tipos de polaridade (anodo central; catodo central; placebo) realizadas randomicamente em 3 dias diferentes com intervalo mínimo de 24 horas. Cada sessão de estimulação incluiu 3 repetições de HD-ETCC com duração de 2 minutos em 3 diferentes intensidades (1, 2 e 3mA) com intervalo de 5 minutos. A ordem das intensidades de HD-ETCC foi randomizada. Escala visual analógica foi utilizada para avaliar o grau de desconforto de cada estimulação e efeitos adversos após cada sessão foram registrados. A aquisição de dados foi realizada no Laboratório de Biomecânica e Controle Motor na Escola de Educação Física e Esportes da Universidade de São Paulo-USP. Resultados: A aplicação do HD-ETCC sobre a JTP resultou em efeitos polaridade dependente, provocando assimetria corporal com descarga de peso para o lado direito quando usado condição catodo central em relação à condição placebo nas intensidades de 2mA (Kruskal Wallis: p=0,037; Tukey Post-hoc: p=0,029) e 3mA (Kruskal Wallis: 0,009; Tukey Post-hoc: p=0,049). A DPC mediana na condição cátodo central foi, respectivamente, medida basal de 1,78%[-1,76;4,67]; após 1mA: 2,12%[-0,63;7,08]; após 2mA: 2,33%[- 1,57;6,25]; após 3mA: 2,40%[-0,53;7,16]. Não foi observado efeito dependente de intensidade. Todos os participantes apresentaram boa tolerância dos protocolos de acomodação e estimulação. Conclusão: O protocolo aplicado revelou ser seguro e apresentar boa tolerância dos participantes. Esta é a primeira evidência de que HDETCC aplicada sobre a JTP pode influenciar no controle postural de forma polarizada, o pequeno efeito observado sugere a utilização de protocolos com maior tempo de estimulação. Os resultados deste trabalho favorecem a elaboração da hipótese de aplicação da HD-ETCC no tratamento de desequilíbrio postural / Introduction: After decades of experimentation in transcranial direct current stimulation (tDCS), few protocols achieved robust scientific acceptance. Stimulation protocols were suggested to influence postural control in healthy subjects and patients after stroke. However, the scarce literature in this area reveals imperative investigation of physiological and clinical effects of transcranial stimulations to elaborate more efficient protocols. The aim of the present study was to verify the polarity and intensity dependent effects of high-definition tDCS (HD-tDCS) over the right temporo-parietal junction (JTP) in the weight-bearing asymmetry (WBA). Methods: This is a randomized, double-blind, factorial, crossover controlled clinical trial. We included 21 healthy subjects, mean age of 24,2±4,1 years, and 61.9% women. The intervention consisted of the application of HD-tDCS over the right temporo-parietal junction (TPJ). The WBA in the upright static position was measured using one force plate under each participant\'s foot, assessed during 2 minutes at baseline and 5 minutes after each stimulation. In order to increase participants\' tolerance of the HD-tDCS, we applied an accommodation protocol consisted of 3 stimulation repetitions with 5 seconds of duration and interval, under fixed stimulation intensities of 1, 2 and 3mA. After 5 minutes of rest, the stimulation protocol consisted of 3 types of polarity (anode center; cathode center; sham) applied randomly in different days with a minimal interval of 24 hours. Each stimulation session comprised of 3 repetitions of 2 minutes HD-tDCS in different intensities (1, 2 and 3 mA). Visual analog scale was used to assess discomfort degree after each stimulation and adverse events after each session were registered. The evaluations were carried out in the Biomechanics and Motor Control Laboratory at the Ribeirão Preto School of Physical Education and Sport-USP. Results: The application of HD-tDCS over TPJ resulted in polarity-dependent effects, causing load bearing to the right leg when using central cathode condition in relation to sham at 2mA (Kruskal Wallis: p=0,037; Tukey Post-hoc: p=0,029) and 3mA Kruskal Wallis: 0,009; Tukey Post-hoc: p=0,049). The median WBA of cathode center condition was, respectively, 1,78% [-1,76;4,67] at baseline, 2,12% [-0,63;7,08] after 1mA; 2,33% [- 1,57;6,25] after 2mA; and 2,40% [-0,53;7,16] after 3mA. No intensity dependent effects were observed. Conclusion: The present protocol was feasible and presented good tolerance of participants. This is the first evidence that HD-TDCS over TPJ can influence postural balance. The small effect observed suggests the usage of longer protocols of HD-tDCS. The results of this study enable to hypothesize the application of HD-tDCS over TPJ to treat postural imbalance.

A transmissão sináptica é essencial para o funcionamento do sistema nervoso. A neuromodulação permite regular esse processo de forma precisa. Um desses mecanismos modulatórios é a regulação da liberação de neurotransmissores. A adenosina é um importante modulador da transmissão sináptica. Além disso, a ativação do subtipo A2a dos receptores para adenosina está envolvida com a facilitação da liberação de neurotransmissores no sistema nervoso central. O presente trabalho teve como objetivo avaliar os efeitos modulatórios da ativação do receptor A2a de adenosina sobre a liberação de neurotransmissores e sua via de sinalização intracelular em modelo in vitro. Além disso, a tese contempla a construção histórica dos conceitos abordados no trabalho permitindo uma visão clara de sua evolução. Esse projeto foi o pioneiro no Brasil a utilizar o sensor biossintético fluorescente de liberação de vesículas sinápticas (supereclipse sinapto-pHluorina), o qual foi gentilmente cedido pelo professor Gero Miensenboeck do Sloan-Kettering Institute for Cancer Research. Nossos resultados demonstraram que o tratamento com o agonista do receptor A A2a de adenosina aumentou a fluorescência do supereclipse sinapto-pHluorina, assim como os níveis de glutamato e noradrenalina. Além disso, foi demonstrado que o inibidor da proteína cinase dependente de AMPc aboliu o aumento nos níveis do glutamato e noradrenalina, tal como a fosforilação da proteína sináptica sinapsina I evocado pelo agonista do receptor A2a de adenosina. Desta forma, nossos dados sugerem que a ativação do receptor A2a de adenosina em cultura de células do bulbo de ratos Wistar modula a liberação de neurotransmissores e a fosforilação da sinapsina I, assim como a proteína cinase dependente do AMPc pode ser o modus operandi desse fenômeno modulatório / Synaptic transmission is a sine qua non process for nervous system physiology. Such precise process is accomplished in part due to modulation of neurotransmitter release. Adenosine is a putative synaptic transmission modulator. Moreover, adenosine A2a receptor facilitates neurotransmitter release in the Central Nervous System. The present study focuses on the modulation of neurotransmission by adenosine A2a receptor and its intracellular signaling pathway in in vitro model. Here, we provided evidence that adenosine A2a receptor agonist increases an optical biosynthetic sensor of synaptic vesicle release (supereclipct synapto-pHluorin), as well as glutamate and noradrenaline. Furthermore, it was demonstrated that cAMP-dependent protein kinase inhibitor abolished glutamate and norepinephrin increase, as well as synapsin I phosphorylation evoked by adenosine A2a receptor agonist. Therefore, our data suggest that adenosine A2a receptor activation modulates neurotransmitter release and synapsin I phosphorylation in cultured cells from medulla oblongata of Wistar rats, as well as cAMP-dependent protein kinase might be the modus operandi of this modulatory phenomenon