Introdução: A disfunção da marcha é um dos maiores comprometimentos funcionais do paciente com a doença de Parkinson (DP). A estimulação cerebral profunda do núcleo subtalâmico tem mostrado melhora da marcha e equilíbrio. Esse efeito pode ser mantido e potencializado por programas de reabilitação motora específicos, como o treino em esteira sem e com suporte de peso corporal. No entanto, faltam estudos desses treinos em pacientes com a DP em uso desta estimulação. Objetivo: Comparar parâmetros cinemáticos lineares e angulares da marcha de pacientes com a DP em uso de estimulação cerebral profunda bilateral do núcleo subtalâmico, antes e após dois treinamentos: esteira sem e com suporte de peso corporal, associados à cinesioterapia convencional. Métodos: 12 pacientes (60,9 ± 10,6 anos; 20 ± 7 anos de doença e 20 ± 4 meses de tempo de cirurgia) completaram ambos os treinos em estudo cruzado fixo. Os pacientes passaram por 8 semanas de treino de marcha em esteira sem suporte de peso corporal e programa de cinesioterapia convencional, seguidas por 6 semanas de período sem intervenção. Posteriormente, realizaram 8 semanas de treino de marcha em esteira com suporte de peso corporal e o mesmo programa de cinesioterapia regular. As intervenções tiveram frequência de duas vezes por semana e duração de 90 minutos por sessão. A análise cinemática da marcha envolveu oito câmeras infravermelhas que detectaram 19 marcadores reflexivos nos membros inferiores dos pacientes. A análise estatística utilizou o teste Wilcoxon e foi adotado valor de p <= 0,05 como estatisticamente significante. Resultados: Ambos os treinos não mostraram diferenças significativas nos parâmetros lineares. Após o treino com suporte, observou-se aumento significativo dos seguintes parâmetros angulares: amplitude de movimento da pelve (inclinação, obliquidade e rotação); amplitude de movimento do quadril (abduçãoadução e rotação); % da fase de balanço que corresponde à flexão máxima do joelho e amplitude de movimento da progressão do pé. Conclusão: O treino em esteira com suporte de peso corporal mostrou capacidade de promover mudanças em parâmetros cinemáticos angulares da marcha. As implicações do treino em suspensão podem ter sido somadas aos efeitos neurofisiológicos da estimulação cerebral profunda e então desencadeado a melhora da mobilidade dos membros inferiores durante a marcha / Introduction: Gait disturbance is one of the hallmark features of Parkinson\'s disease (PD). Subthalamic nucleus deep brain stimulation (DBS) has shown improvements in gait and balance, and this effect can be maintained and enhanced by specific motor rehabilitation programs, such treadmill training without and with body weight support. However, at present there is a paucity of research on these combined interventions in PD with of this stimulation. Objective: To compare training-induced changes in gait linear and angular kinematic parameters among patients with PD who have used bilateral subthalamic nucleus DBS, and a combined intervention of conventional physical therapy with either treadmill training with body weight support or without support. Methods: 12 patients (age: 60.9 ± 10.6 years; disease duration: 20 ± 7 years; and time since DBS surgery: 20 ± 4 months) completed both training protocols in a fixed cross-over design. All patients received 8 weeks of treadmill training without body weight support in conjunction with conventional physical therapy, followed by a 6 weeks wash out period of no training. Thereafter, all patients received 8 weeks of body weight support treadmill training, in conjunction with the same conventional physical therapy. Both interventions had a frequency of two times per week, and duration of 90 minutes per session. Gait kinematic analysis involved eight infrared cameras that detected 19 reflective spherical markers attached to the limb lower of patients. Statistical analysis used the Wilcoxon and was adopted the value of p <= 0,05 as statistically significant. Results: Both the training no showed significant differences in linear parameters. After the body weight support training, observed there was a significant increase in following angular parameters: pelvis\' range of motion (tilt, obliquity, rotation); hip\'s range of motion (abduction-adduction and rotation); % Knee maximal flexion on Swing phase and foot progression\' range of motion. Conclusion: Treadmill training with body weight support showed an ability to promote changes in gait angular kinematic parameters. The implications of this training may have been added to the neurophysiological effects of DBS and then triggered the improved of mobility of lower limbs during gait

INTRODUÇÃO: Os episódios depressivos são bastante prevalentes e, potencialmente, incapacitantes ao longo do curso do transtorno bipolar (TB). Todavia, ainda não se dispõe de opções terapêuticas com eficácia e tolerabilidade satisfatórias. A estimulação transcraniana por corrente contínua (ETCC) é uma nova modalidade de estimulação cerebral não-invasiva com poucos eventos adversos, que mostrou resultados promissores na depressão unipolar. OBJETIVO: Avaliar a eficácia e a segurança da ETCC como tratamento aditivo aos psicofármacos na depressão bipolar (DB). MÉTODOS: Foi realizado um ensaio clínico, duplo-cego, randomizado, em ambiente acadêmico. 59 pacientes com transtorno bipolar (TB) tipos I ou II em episódio depressivo maior, em regime farmacológico estável, com escores Hamilton (HDRS-17) superiores a 17. Os dados foram analisados por intenção de tratamento. A ETCC foi aplicada em 2 mA/25cm2, sendo o ânodo e o cátodo posicionados sobre as áreas correspondentes ao córtex dorsolateral pré-frontal esquerdo e direito, respectivamente, por 30 minutos, diários, por dez dias consecutivos, exceto aos finais de semana. Após este período, duas estimulações adicionais foram aplicadas, em semanas alternadas, até o final do estudo (6a semana). A alteração na escala de HDRS -17, na 6a semana, foi o desfecho primário. RESULTADOS: Cinquenta e nove pacientes (40 mulheres), com média de idade de 45,9 anos participaram; 36 (61%) com transtorno bipolar tipo I e 23 (39%) com tipo II foram randomizados e 52 finalizaram o ensaio. Na análise por intenção de tratamento, os pacientes do grupo ETCC ativa apresentaram melhora estatisticamente significativa relação àqueles que receberam ETCC simulada (número necessário para tratar [NNT], 5,8; intervalo de confiança [IC] 95%, 3,3-25,8; p = 0,01). A taxa de resposta cumulativa foi maior no grupo ativo em relação ao simulado (67,6% vs 30,4%, NNT, 2,69; IC 95%, 1,84-4,99; p = 0,01), mas não para taxa de remissão (37,4% vs 19,1%; NNT, 5,46; IC 95%, 3,38-14,2; p = 0,18). Os eventos adversos, incluindo virada maníaca, foram semelhantes entre os grupos; com exceção de vermelhidão na pele, maior no grupo ativo (54% vs 19%; P = 0,01). CONCLUSÃO: Nesse estudo, a ETCC foi uma intervenção eficaz, segura e tolerável para esta pequena amostra de pacientes com depressão bipolar. Todavia, outros estudos são necessários para que se possa examinar a eficácia da ETCC em amostras maiores / INTRODUCTION: More effective, tolerable interventions for bipolar depression treatment are needed. Transcranial direct current stimulation (tDCS) is a novel therapeutic modality virtually devoid of severe adverse effects that showed promising results for unipolar depression. OBJECTVE: To determine the efficacy and safety of tDCS as an add-on treatment for bipolar depression. METHODS: A randomized, sham-controlled, double-blind trial was conducted at an academic setting. Participants included 59 adults with type I or II bipolar disorder in a major depressive episode and receiving a stable pharmacologic regimen with 17-item Hamilton Depression Rating Scale (HDRS-17) scores higher than 17. Data were analyzed in the intention-to-treat sample. Ten daily 30-minute, 2-mA, anodal-left and cathodal-right prefrontal sessions of active or sham tDCS on weekdays and then 1 session every fortnight until week 6. The main outcome was the change in HDRS-17 scores at week 6. RESULTS: 59 patients (40 women), with a mean age of 45.9 years participated; 36 (61%) with bipolar I and 23 (39%) with bipolar II disorder were randomized and 52 finished the trial. In the intention-to-treat analysis, patients in the active tDCS condition showed significantly superior improvement compared with those receiving sham (number needed to treat [NNT], 5.8; 95% confidence interval [CI], 3.3-25.8; p = .01). Cumulative response rates were higher in the active vs sham groups (67.6% vs 30.4%; NNT, 2.69; 95% CI, 1.84-4.99; p = .01), but not remission rates (37.4% vs 19.1%; NNT, 5.46; 95% CI, 3.38-14.2; p = .18). Adverse events, including treatment-emergent affective switches, were similar between groups, except for localized skin redness that was higher in the active group (54% vs 19%; p = .01). CONCLUSION: In this trial, tDCS was an effective, safe, and tolerable add-on intervention for this small bipolar depression sample. Further trials should examine tDCS efficacy in a larger sample

INTRODUÇÃO: Os efeitos da levodopa (LD) e da estimulação cerebral profunda (ECP) de núcleo subtalâmico (STN) sobre o equilíbrio e sintomas axiais são até o momento controversos. OBJETIVOS: Avaliar quantitativamente os efeitos da ECP de STN e da LD sobre o equilíbrio estático em pacientes com DP operados, em comparação com a LD em pacientes não operados. MÉTODOS: Trinta e um pacientes submetidos a ECP de STN entre 3 meses e 1 ano e meio antes da avaliação e 26 controles portadores de DP não operados, estágios Hoehn e Yahr 2 a 4 foram avaliados usando UPDRS para avaliação clínica e plataforma de força para avaliar oscilações posturais. O primeiro grupo foi avaliado com ECP e sem medicação, com ECP e com medicação e sem ECP e sem medicação. O segundo grupo foi avaliado com e sem medicação. Cada paciente foi avaliado com os olhos abertos e fechados. O deslocamento do centro de pressão anteroposterior, laterolateral, a área, velocidade e deslocamento total linear foram medidos pela plataforma de força. Os dados paramétricos foram comparados usando o teste t de Student e os dados não-paramétricos foram comparados pelo teste de Kruskal-Wallis. A avaliação clínica consistiu na parte 3 da escala UPDRS e na escala Hoehn e Yahr. Nível de significância estatística considerada foi p=0,05. RESULTADOS: Os pacientes não operados oscilaram mais quando sob efeito da levodopa do que sem medicação. No grupo operado, a maior oscilação é no grupo com ECP desligada e sem medicação. Tende a reduzir sob efeito da ECP apresenta redução significativa sob efeito simultâneo de ECP e levodopa. CONCLUSÃO: A associação da ECP de NST com medicação tem impacto positivo sobre o controle postural. O efeito da ECP de NST reverte o efeito negativo da levodopa sobre as oscilações observadas em pacientes não operados / INTRODUCTION: The effects of bilateral subthalamic (STN) DBS and medication on balance and on axial symptoms in PD have been so far inconsistent. OBJECTIVE: To assess quantitatively the effects of DBS on static balance in PD. METHODS: Thirty-one patients submitted to STN DBS over 3 months before and 26 non-operated controls with PD on Hoehn & Yahr stage \"on\" 2 to 4 were evaluated using UPDRS and a force plate to measure sway. The first group was evaluated on-DBS/off-medication, on-DBS/on-medication and off-DBS/off-medication. The second group was evaluated on and off medication. Each group was assessed with eyes open and then closed. Antero-posterior, laterolateral postural displacements of the center of pressure (COP), as well as 95% sway area, path length and speed of oscillation were analyzed and compared using t-Student test for parametrical data and Kruskal-Wallis test for non-parametrical data. Level of significance was set to p < 0.05. Clinical assessment consisted of UPDRS part 3 and Hoehn & Yahr scores for each of the conditions. RESULTS: Control patients tended to oscillate more in the on medication condition than off medication. DBS patients tended to oscillate more in the off-DBS/off medication condition, with a tendency to decrease the sway when on DBS/off medication with additional decrease when on DBS/on medication. CONCLUSION: Association of bilateral STN DBS and medication positively influences postural control in PD and surgery reverses the tendency of medication to increase body sway in non-operated patients

La stimulation cérébrale profonde (DBS) du gyrus cingulaire subgénual est actuellement en coursd’évaluation comme nouvelle cible thérapeutique chez les patients souffrant de dépression majeure.Afin de caractériser les mécanismes sous-jacents l’action de la DBS, et plus particulièrement, lapossible implication du système glial, les effets de la stimulation du cortex préfrontal infralimbique surplusieurs marqueurs précliniques de la réponse antidépressive ont été évalués chez le rat. Ce travailde thèse, en utilisant des approches électrophysiologiques, immunohistochimiques etcomportementales, montre que la DBS aigue (130 Hz, 150 μA) induit des comportements pseudoantidépresseurs(évalués dans le test de nage forcée) qui sont associés à une augmentation del’activité des neurones 5-HT du raphé dorsal et de la neurogenèse du gyrus denté. De plus, la DBSaigue est capable de renverser les effets du stress sur la métaplasticité synaptique hippocampique.Par ailleurs, la DBS à plus faible intensité (20 μA, 130 Hz) induit des effets pro-cognitifs, i.e. unefacilitation de la plasticité synaptique au sein de l’hippocampe dorsal et une amélioration desperformances mnésiques des rats dans le test de reconnaissance d’objet. De façon importante, ceseffets neurobiologiques sont prévenus par une lésion pharmacologique gliale avec la gliotoxine Lalpha-aminoadipic acid. Ensemble, nos données in vitro et in vivo soulignent pour la première fois lerôle crucial des astrocytes dans les mécanismes d’action de la DBS. Cette étude propose donc quel’intégrité du système glial au niveau le site de stimulation est un pré-requis majeur afin d’optimiserl’efficacité de la DBS / Deep brain stimulation (DBS) of the cingulated gyrus 25 is currently evaluated as a new therapy inpatients with treatment-resistant major depressive disorder. The effects of infralimbic prefrontal cortexDBS on several pre-clinical markers of the antidepressant-like response were assessed in rats toinvestigate the mechanisms underlying DBS action, and particularly, the putative involvement of glialsystem. The present study, using electrophysiological, immunohistochemical and behavioralapproaches, shows that acute DBS (130 Hz, 150 μA) induced an antidepressant-like behavior(evaluated in the forced-swim test) that was associated with an increase of dorsal raphe 5-HTneuronal activity and of dentate gyrus neurogenesis. Moreover, acute DBS was able to reverse theeffects of stress on hippocampal synaptic metaplasticity. Besides, DBS at lower intensity (20 μA, 130Hz) induced pro-cognitive effects, i.e. facilitated the hippocampal synaptic metaplasticity and improvedlearning performance in the novel object recognition task. Importantly, these neurobiological effects ofDBS were prevented by local pharmacological glial lesions with the L-alpha-aminoadipic acid gliotoxin.Taken together, our in and ex vivo findings highlights for the first time the crucial role of glial cells inthe mechanism of action of DBS. The present study, therefore, proposes that an unaltered glial systemwithin stimulation areas may constitute a major prerequisite to optimize DBS efficacy

Introdução: Após a cirurgia de Estimulação Cerebral Profunda (DBS), pacientes com doença de Parkinson (DP) ainda apresentam alterações posturais e da marcha. Assim, intervenções adicionais são necessárias para reduzir a instabilidade postural e quedas. O treino de marcha em esteira é conhecido por melhorar parâmetros do equilíbrio e marcha de pacientes com DP; no entanto, o que ainda não se sabe é se há diferença entre o treino com e sem suspensão do peso corporal e se esses tipos de treinamento são capazes de potencializar os efeitos da DBS. Objetivo: A proposta deste estudo foi comparar os efeitos do treino em esteira, com e sem supensão do peso corporal, em aspectos do equilíbrio de pacientes com DP após DBS. Métodos: Homens (n=6) e Mulheres (n=5) com DP (60.9± 10.6 anos) em uso de DBS bilateral em Núcleo Subtalâmico foram avaliados quanto o equilíbrio e mobilidade antes e após o tratamento, usando o Time Up and Go test (TUG) em três condições: convencional, cognitiva e motora; assim como, a Escala de Berg e a Posturografia Estática. Na fase 1, todos os sujeitos participaram de um programa de fisioterapia convencional associado à treino em esteira por 8 semanas (16 sessões). Após 6 semanas de período de wash-out, cada participante realizou o mesmo treino durante 8 semanas porém, o treino em esteira foi realizado com suspensão do peso corporal. Resultados: Após a fase 1 de treino em esteira sem suspensão, houve melhoras na performance do TUG cognitivo (pré: 15.7±1,8 s versus pós: 13.7±3.1 s; p=0.01) e um aumento do deslocamento corporal ântero-posterior e médio-lateral com os olhos fechados. Após a fase 2 de treino em esteira com suspensão do peso corporal, houve melhoras do TUG convencional (pré: 12.3±2.0 s versus pós: 10.7±1.7 s; p=0.01) e cognitivo (pré: 14.6±3.5 s versus pós: 12.5±1.6 s; p < 0.05). Não houve mudanças significantes nos escores da Escala de Berg após ambas as fases. Conclusão: O treino de marcha em esteira com ou sem suspensão do peso corporal promove melhora do equilíbrio estático e dinâmico em pacientes com DP após a cirurgia de DBS. Ambos os métodos tem resultados similares; No entanto, o treino de marcha com suspensão do peso corporal parece ser uma opção potencialmente superior, uma vez que pacientes sentem-se mais seguros, e isso pode levar à um tipo de treino mais viável / Background: After deep brain stimulation (DBS) surgery, patients with Parkinson`s disease (PD) typically still present significant gait and postural stability problems, and thus additional interventions are needed to reduce slip and fall accidents and injuries. Treadmill training is known to improve balance and gait parameters in PD; however, what remains to be determined is the comparative effectiveness of treadmill training with support versus without and if they could potentiate DBS effects. Objective: The purpose of this study was to evaluate the comparative effectiveness of treadmill training, with and without body weight support, on balance outcomes among patients with PD after DBS. Methods: Male (n=6) and female (n=5) patients with PD (60.9± 10.6 years old) that were using bilateral subthalamic nucleus DBS were evaluated for balance and mobility prior to and following treatments, using Time Up and Go test (TUG) in three conditions: conventional, cognitive and motor, as well as the Berg Balance Scale and Static Posturography. In phase 1, all subjects participated in 8-weeks (16 sessions) of treadmill training in conjunction with conventional physiotherapy. After a six weeks period of wash-out, each patient then participated in a subsequent 8-weeks of treadmill training with partial body weight support. Results: After the phase 1 unsupported treadmill training, there were improvements on the cognitive TUG performance (pre: 15.7±1,8 sec versus post: 13.7±3.1 sec; p=0. 01) and an increase of anteroposterior and medio-lateral body oscillation with eyes closed. After the phase 2 body weight supported treadmill training, there were improvements in conventional (pre: 12.3±2.0 sec versus post: 10.7±1.7 sec; p=0. 01) and cognitive (pre: 14.6±3.5 sec versus post: 12.5±1.6 sec; p < 0. 05) TUG performances. There were no significant changes in the Berg Balance Scale following either training protocol. Conclusions: Both unsupported and supported treadmill training improved static and dynamic balance in patients with PD after DBS surgery. Both methods had similar results; however, supported treadmill training seemed to be a potentially superior option, as patients tended to feel safer, and thus it may prove to be a more viable means of training

Le but de cette étude était d'évaluer le rôle des boucles des ganglions de la base et des voies dopaminergiques sur les mécanismes « bottom-up » et « « top-down » du contrôle de l'attention visuelle (AV). Nous avons comparé les performances sur 3 tâches informatisés, appropriées à l'étude de la capture attentionnelle (CA), des mécanismes de sélection de la réponse motrice et d'initiation du mouvement, de deux groupes de patients avec maladie de Parkinson (MP) - un groupe étant évalué dans trois différentes conditions de stimulation électrique (sans stimulation, ou stimulation sélective de la partie sensorimotrice, SM, ou de la partie associative, AS, du noyau subthalamique, NST), l'autre groupe étant évalué dans deux différentes conditions de traitement médical (avec ou sans levodopa) - avec celles d'un groupe des sujets contrôles. Nos résultats suggèrent dans la MP un affaiblissement des mécanismes « top-down » de contrôle de l'AV, ce qui pourrait aussi expliquer indirectement l'augmentation de la CA. Le traitement dopaminergique est efficace dans le rétablissement des mécanismes « top-down » de l'AV, suggérant une implication des voies dopaminergiques dans ce domaine cognitif. Ces voies semblent aussi jouer un rôle dans les mécanismes « bottom-up » de l'attention, comme l'a suggéré le renforcement de la CA sous traitement dopaminergique. La stimulation du NST a montré un effet similaire à celui obtenu par un traitement dopaminergique, en favour d'une implication directe des boucles des ganglions de la base dans le contrôle de l'AV. Nos résultats ont mis en évidence une spécialisation fonctionnelle de différents sous-territoires du NST en ce qui concerne les mécanismes de « top-down ». La stimulation SM produit des effets marqués sur les processus d'initiation de mouvement et des effets positifs sur les mécanismes endogènes de l'AV, alors que la stimulation de la partie AS semble être plus particulièrement efficace dans l'amélioration des mécanismes de sélection de cible. / We aimed to investigate the possible role of cortico-basal ganglia loops and dopaminergic pathways in the mechanisms of top-down and bottom-up control of visual attention (VA). We compared the performances on 3 computerized tasks, respectively suitable to study attentional capture (AC), motor response selection and movement initiation, of two groups of patients with Parkinson's disease (PD), one evaluated in different sets of electrical stimulation (without stimulation, or selective stimulation of the sensorimotor, SM, or associative, AS, parts of the subthalamic nucleus, STN), the other in different conditions of medication (with or without levodopa), with those of a group of controls. Our results showed that in PD there is a weakening of the mechanisms underlying the top-down control of VA, which also would account indirectly account for the enhancement of AC. Dopaminergic treatment proved to be effective in restoring the top-down mechanisms of VA, suggesting an involvement of dopaminergic pathways in this cognitive domain. These pathways seem to play a role also in the bottom-up mechanisms of attention, as suggested by the enhancement of AC under dopaminergic treatment. The STN-stimulation showed a similar effect to that obtained by dopaminergic treatment, establishing a direct involvement of the basal ganglia loops in VA control. Our results highlighted a functional specialization of different sub-territories of the STN in relation to the top-down mechanisms. SM stimulation produced marked effects on the movement initiation processes and appreciable positive effects on endogenous VA mechanisms, while AS stimulation seems to be especially effective in improving the mechanisms of target selection.

Les troubles exécutifs de la maladie de Parkinson sont invalidants et sans solution thérapeutique satisfaisante. La raison est liée au fait que les fonctions exécutives sont difficiles à appréhender, tant au niveau de leur modélisation cognitive qu'anatomo-fonctionnelle ou neurochimique. Ici, nous nous appuyons sur des avancées théoriques et méthodologiques récentes pour revisiter ces troubles exécutifs. Nous nous intéressons à une fonction, récemment mise en évidence, destinée à verrouiller par anticipation le déclenchement de toute action en situation d'incertitude : le contrôle proactif de l'inhibition non sélective de l'action. Notre hypothèse directrice est que son dysfonctionnement est susceptible de générer une grande variété de troubles exécutifs. Nous avons : 1) recherché les liens entre marqueurs cliniques et troubles du contrôle proactif ; 2) identifié les dysfonctionnements cérébraux associés au moyen de méthodes électroencéphalographiques innovantes combinées à l'enregistrement des effets de la stimulation du noyau sous-thalamique ; et 3) sondé l'origine neurochimique de cette fonction. Nos résultats suggèrent qu'un dysfonctionnement de l'inhibition proactive n'engendre pas uniquement des troubles impulsifs mais explique également des comportements hypo-productifs comme l'akinésie. Ils indiquent que ces troubles ne sont pas d'origine dopaminergique et qu'ils sont liés au dysfonctionnement de l'activité du cortex frontal médian et du noyau sous-thalamique. Ces travaux ouvrent la voie à de nouvelles perspectives thérapeutiques pour la maladie de Parkinson et à une meilleure appréhension de la clinique d'autres pathologies / Executive impairments in Parkinson’s disease are debilitating and have no satisfying therapeutic option. This is partly due to the fact that executive functions are difficult to investigate from cognitive, neuro-functional and neurochemical standpoints. Here, we build on recent theoretical and methodological improvements to revisit executive impairments. We are interested in a function that consists in locking in advance movement initiation mechanisms in the face of uncertainty: proactive control of non-selective inhibition of action. Our leading hypothesis is that dysfunction of proactive inhibitory control could generate widespread and heterogeneous executive impairments. We thus: 1) tried to relate clinical markers of the disease to behavioral indexes of proactive control impairment; 2) identified the associated cerebral dysfunctions by means of advanced electroencephalographic methods and manipulation of deep brain stimulation of the subthalamic nucleus; and 3) investigated the neurochemical origin of this function. Our results suggest that impulsivity is not the only outcome of inhibitory impairment. Disorder of proactive inhibitory control may also account for hypo-productive behaviors such as akinesia. Results also indicate that this mechanism is of non-dopaminergic origin and relies on medial frontal and subthalamic activity. This work opens the way for new therapeutic approaches for Parkinson’s disease as well as a better understanding of clinical symptoms observed in others diseases

Le vieillissement de la population a vu émerger des maladies liées à l'âge telles que les maladies neurodégénératives. La neuromodulation peut être proposée à certains patients lorsque les médicaments ne sont plus efficaces ou qu'ils entraînent des effets secondaires invalidants. L’objectif de cette thèse est de mieux caractériser les structures cérébrales pour optimiser le ciblage de la neuromodulation et, ainsi augmenter les bénéfices thérapeutiques.Le premier axe de recherche porte sur la région locomotrice mésencéphalique (MLR) qui est une cible en cours d'évaluation pour les patients parkinsoniens souffrant de troubles de la marche et de l'équilibre. Nous avons exploré la connectivité de la MLR et les résultats nous ont amené à considérer que le noyau pédonculopontin (PPN), qui est une région constituante de la MLR, est la cible à privilégier. Or, une perte des neurones cholinergiques du PPN a été montrée chez les patients parkinsoniens. Le second projet a consisté à étudier la topographie de la perte de neurones chez différents groupes pathologiques. Nos résultats montrent que le maximum de densité des neurones cholinergiques se situe à +3 mm du début supérieur du PPN et serait la cible optimale de sa neuromodulation. Enfin, nous avons construit un atlas 3D du tronc cérébral humain afin de guider l’implantation d'électrode dans la MLR.Le second axe de recherche concerne le Vim qui est la cible usuelle pour les tremblements essentiels. Nous avons appliqué différentes méthodes de ciblage et comparé les localisations. Nous avons trouvé des différences de distance entre cibles, pouvant affecter les résultats de la neuromodulation, supérieures à 1.5 mm. / The aging of the population has led to the emergence of many age-related diseases such as neurodegenerative diseases. Neuromodulation techniques can be proposed to some patients when medications are no longer effective or have invalidating side effects. The objective of this PhD is to better characterize brain structures in order to optimize neuromodulation targeting and thus increase the therapeutic benefits for patients.The first area of research concerns the mesencephalic locomotor region (MLR), which is a neuromodulation target being evaluated for Parkinsonian patients who suffer from walking and balance disorders. We explored the anatomical connectivity of the MLR and the results led us to consider the pedonculopontin nucleus (PPN), which is a part of the MLR, as the target of neuromodulation to privilege. However, partial loss of cholinergic neurons in the PPN has been shown in Parkinsonian patients. The second project consisted in studying the topography of this loss in different pathological groups. Our results show that the maximum density of cholinergic neurons in all the subjects is situated at +3 mm from the superior edge of the PPN and is the optimal target for its neuromodulation. Finally, we constructed a 3D atlas of the healthy human brainstem in order to guide the implantation of electrodes in the MLR.The second area of research concerns the ventral intermediate nucleus (Vim) of the thalamus, which is the usual neuromodulation target for essential tremors. We applied various targeting methods of the Vim and compared the locations. We found differences in distance between targets greater than 1.5 mm which may affect the neuromodulation results.

<p>Deep brain stimulation (DBS) electrodes are intended to stimulate specific areas of the brain to treat movement disorders including essential tremor, Parkinson's disease and dystonia. An important goal in the design of next generation DBS electrodes is to minimize the power needed to stimulate specific regions of the brain. A reduction in power consumption will prolong battery life and reduce the size of implanted pulse generator. Electrode geometry is one approach to increase the efficiency of neural stimulation and reduce the power required to produce the level of activation required for clinical efficacy. </p><p>We first characterized the impedance of the presently used clinical DBS electrodes <italic>in vitro</italic> and <italic>in vivo</italic>. Characterization of the electrode-tissue interface impedance is required to quantify the composition of charge transfer to the brain tissue. The composition of charge transfer was dependent on both the current density and the sinusoidal frequency. The assumption of the DBS electrode being ideally polarizable was not valid under clinical stimulating conditions. This implies that irreversible processes that can cause electrode or tissue damage might occur when high charge injection is required for DBS. </p><p>Current density distribution is an important factor in determining patterns of neural excitation, tissue damage and electrode corrosion. We developed a recursive simulation scheme to calculate the current density distribution that incorporates the nonlinear electrode-tissue interface into finite-element based models of electrodes. The current density distributions on the electrode surface were strongly dependent on the sinusoidal frequency. The primary current density distribution without including the electrode-tissue interface can be used to estimate neural excitation, tissue damage and electrode corrosion with rectangular stimulus pulses as most of the signal power is at frequencies where the secondary current density distribution matches closely the primary current density distribution.</p><p>We designed and analyzed novel electrode geometries to decrease stimulation thresholds, thus reducing power consumption of implanted stimulators. Our hypothesis was that high-perimeter electrode geometries that increase the variation of current density on the electrode surface will generate larger activating functions for surrounding neurons and thereby increase stimulation efficiency. We investigated three classes of electrodes: segmented cylindrical electrodes, serpentine-perimeter planar electrodes, and serpentine-perimeter cylindrical electrodes. An approach that combined finite element models of potentials and cable models of axonal excitation was used to quantify the stimulation efficiency of electrodes with various geometries. Increasing the electrode perimeter increased the electrode efficiency by decreasing stimulation threshold. Both segmentation and serpentine edges provided means to increase the efficiency of stimulation. Novel cylindrical electrodes that combined segmentation with serpentine edges decreased power consumption by ~20% for axons parallel to the electrode and by ~35% for axons perpendicular to the electrode. These electrode designs could potentially prolong the average battery life of deep brain stimulator by more than one year.</p> / Dissertation

Gamma oscillations of local field potentials (LFP) in the basal ganglia and thalamus had not been studied during saccades. Eleven patients were studied during deep brain stimulation (DBS); 6 were in the subthalamic nucleus (STN); 3 in the globus pallidus interna (GPi); and 2 in the thalamic ventralis intermedius nucleus (Vim). Patients performed horizontal saccades to visual targets while LFPs from DBS electrodes, scalp electroencephalogram (EEG), and electrooculogram (EOG) were recorded. Wavelet spectrograms were generated and saccade onset and event-related gamma synchronizations (ERS) were compared to baseline without eye motion. ERS were recorded at and after saccade onset in the STN, GPi and Vim, EEGs and EOGs; but were absent during target light illumination without saccades. ERS were symmetric in all DBS contacts and appeared identical in DBS LFPs, frontal EEGs and EOGs. These findings indicate their origin from extraocular muscle spike potentials rather than brain neural activity.