Le rôle respectif des ganglions de la base (GB) et de la région locomotrice dans le contrôle locomoteur et postural n'est pas établi chez l'homme. Au sein de ces circuits, le noyau sous-thalamique (NST) et le noyau pédunculopontin (NPP) semblent impliqués dans le pattern locomoteur et le maintien de l'équilibre. En effet, chez les patients avec maladie de Parkinson (MP), caractérisée par une perte des neurones dopaminergiques et représentant un modèle de dysfonctionnement des GB, des dysfonctionnements de l'activité du NST seraient à l'origine d'un freinage du mouvement, jusqu'au blocage moteur (freezing de la marche-FOG). Dans le NPP, des lésions cholinergiques sont retrouvées chez les patients MP avec des chutes. Dans ce travail de recherche nous avons étudié le rôle du NST et les effets de la modulation de l'activité du NPP sur les étapes de l'initiation de la marche (GI) chez les patients avec MP. Nous avons retrouvé une synchronisation dans la bande de fréquence alpha précédant l'exécution du pas, en cohérence avec le NPP. La stimulation à basse fréquence du NPP améliore le contrôle postural. Ces données suggèrent que le NST est impliqué dans la préparation de la GI, et que le NPP a un rôle dans le contrôle postural chez l'homme. Dans une seconde partie, nous avons examiné le rôle des lésions du circuit cortex-GB-NPP dans la survenue du FOG et des chutes chez des sujets âgés non-parkinsoniens et démontré une lésion sélective de ce circuit chez ces sujets. Finalement, l'ensemble de ces données confortent les hypothèses physiopathologiques à l'origine des troubles de la marche et de l'équilibre chez les patients MP avec lésion/dysfonction du circuit cortex-GB-NPP. / The respective roles of basal ganglia (BG) and the mesencephalic locomotor region (MLR) in the postural control and locomotion are not clearly established in humans. In these circuits, the subthalamic nucleus (STN) and the pedunculopuntine nucleus (PPN), two interconnected structures, appear to be involved in the locomotor pattern control and postural maintenance. Indeed, in patients with Parkinson’s disease (PD), characterized by a progressive loss of dopaminergic neurons and representing a model of dysfunction of the BG, there are dysfunctions of STN activity that could cause braking of movement underlying motor block (freezing of gait-FOG). In the PPN, greater loss of cholinergic neurons is observed in PD patients with falls. In this research, we studied STN activity and the effects of modulating the PPN activity during the stages of gait initiation (GI) in patients with PD. We found a modulation of activity of the STN with synchronization in the alpha frequency band before the postural adjustments and the execution of step, with PPN coherence. Low frequency stimulation of the PPN improved postural control with no significant effect on the locomotion. These data suggest that the STN is involved in the preparation of GI and the PPN has a leading role in postural control in humans. In a second part, we examined the role of the cortex-basal ganglia-PPN circuit in FOG and falls in a non-parkinsonian elderly population and demonstrated a selective lesion of this circuit in these subjects. Taken together, these data support the pathophysiological hypothesis for the origin of abnormal gait and balance in patients with PD, with lesion and/or dysfunction of the cortex-BG-PPN.

Background: The posterior subthalamic area (PSA) is essentially composed of the caudal Zona incerta and the prelemniscal radiation. Subthalamotomy in the PSA was renowned for its effectiveness in alleviating movement disorders and particularly tremor. The modern literature on DBS of this area is limited, but promising results have been presented for Parkinson’s disease (PD), essential tremor (ET) and other movement disorders.   Aim: To evaluate the safety of PSA DBS with emphasis on the panorama of side effects, the distribution of stimulation-induced side effects and the effects of PSA DBS on verbal fluency. To evaluate the therapeutic effect of PSA DBS on less common forms of tremor, tremor-dominant PD, and concerning the long-term results in ET. Method: 40 patients were evaluated regarding side effects of the procedure. 28 patients with ET were analyzed for stimulation-induced side effects in a standardized manner. The locations of the contacts that caused stimulation-induced side effects were plotted on atlas slides. A 3-D model of the area was created based on these slides. Verbal fluency was analyzed in 17 patients with ET before surgery, after 3 days and finally after 1 year. Five patients with less common forms of tremor and 18 with ET were evaluated according to the ETRS at baseline and one year or 3-5 years after surgery, respectively. 14 patients with mainly unilateral tremor-dominant PD were evaluated a mean of 18 months after surgery according to the motor part of UPDRS. Results: PSA DBS was associated with few serious side-effects, but a transient and mild postoperative dysphasia was found in 22.5% of the patients. There was a slight transient decline in the performance on verbal fluency tests immediately after surgery. Visualization of the contacts causing stimulation-induced side effects showed that identical responses can be elicited from various points in the PSA and its vicinity. The effect on the less common forms of tremor was excellent except for neuropathic tremor where the effect was moderate. A pronounced and sustained microlesional effect was seen for some of the patients. After a mean of 4 years with unilateral PSA DBS the total ETRS score was improved by 52.4%, tremor by 91.8% and hand function by 78.0% in the patients with ET. There was no increase in the stimulation strength over time. In PD, the scores improved 47.7% for contralateral UPDRS III. Contralateral tremor, rigidity, and bradykinesia improved by 82.2%, 34.3%, and 26.7%, respectively. Conclusions: PSA DBS generally seem to be a safe procedure, but it may be associated with transient declines of verbal fluency. There was no clear somatotopic pattern with regard to stimulation-induced side effects in the PSA. PSA DBS can alleviate tremor regardless of the etiology. The long-term effects in ET were favorable when compared to our previous results of Vim DBS. The effect on Parkinsonian tremor was satisfying, however, the reductions of rigidity and bradykinesia were less compared to previous studies of PSA DBS for PD.

Quantification of blood fraction (fblood), blood oxygenation (S<img src="http://onlinelibrary.wiley.com/store/10.1002/jbio.201200055/asset/equation/tex2gif-inf-2.gif?v=1&amp;t=h70man4a&amp;s=4a6d004ec608a2a6ec8e8597f73bdb6be30286e8" />), melanin, lipofuscin and oxidised and reduced Cytochrome aa 3 and c was done from diffuse reflectance spectra captured in cortex, white matter, globus pallidus internus (GPi) and subthalamus during stereotactic implantations of 29 deep brain stimulation (DBS) electrodes with the aim of investigating whether the chromophores can give physiological information about the targets for DBS. Double-sided Mann-Whitney U -tests showed more lipofuscin in GPi compared to white matter and subthalamus (p &lt; 0.05). Compared to the other structures, fbloodwas significantly higher in cortex (p &lt; 0.05) and S<img src="http://onlinelibrary.wiley.com/store/10.1002/jbio.201200055/asset/equation/tex2gif-inf-4.gif?v=1&amp;t=h70man4c&amp;s=855c70105e88a292de25618487573dfc7d30e08a" /> lower in GPi (p &lt; 0.05). Median values and range for fblood were 1.0 [0.2–6.0]% in the cortex, 0.3 [0.1–8.2]% in white matter, 0.2 [0.1–0.8]% in the GPi and 0.2 [0.1–11.7]% in the subthalamus. Corresponding values for S<img src="http://onlinelibrary.wiley.com/store/10.1002/jbio.201200055/asset/equation/tex2gif-inf-6.gif?v=1&amp;t=h70man4e&amp;s=151ec25bee7270bcfc2292e70d6f4aea18348dbc" /> was 20 [0–81]% in the cortex, 29 [0–78]% in white matter, 0 [0–0]% in the GPi and 0 [0–92]% in the subthalamus. In conclusion, the measurements indicate very low oxygenation and blood volume for DBS patients, especially in the GPi. It would be of great interest to investigate whether this is due to the disease, the normal situation or an artefact of doing invasive measurements.

Objective: In patients with Parkinson’s disease (PD), deep brainstimulation of the subthalamic nucleus (STN DBS) is well recognizedin improving limb function, but the outcome on swallowing functionhas rarely been studied. The aim of this work was to evaluate theeffect of STN DBS on pharyngeal swallowing function in patientswith PD using self-estimation and fiberoptic endoscopic evaluation ofswallowing. Methods: Eleven patients (aged 41–72, median 61 years)were evaluated preoperatively and at 6 and 12 months after STN DBSsurgery. All patients were evaluated with self-estimation on a visualanalogue scale, and eight of them with a fiberoptic endoscopicexamination with a predefined swallowing protocol includingRosenbek’s Penetration-Aspiration Scale, Secretion Severity Scale,preswallow spillage, pharyngeal residue, and pharyngeal clearance. Results: The self-assessments of swallowing function revealed asubjective improvement with STN DBS stimulation, whereas the datafrom the swallowing protocol did not show any significant effect ofthe STN DBS treatment itself. The prevalence of aspiration was notaffected by the surgery. Conclusions: The results show thatswallowing function was not negatively affected by STN DBS and therisk of aspiration did not increase. Self-estimation of swallowingfunction showed a subjective improvement due to stimulation / Speech, voice and swallowing outcomes after deep brain stimulation (DBS)

Background: Essential tremor (ET) is the most common movement disorder. In cases resistant to pharmacological treatment, functional stereotactic neurosurgery can be an alternative. Lesional surgery has largely been replaced by deep brain stimulation (DBS). The current target of choice is the ventrolateral thalamus (Vim). Vim DBS has generally shown good results, but in some cases it is associated with a suboptimal effect as well as side effects. DBS in the posterior subthalamic area/caudal zona incerta (PSA/cZi) has recently shown promising effects. Recently the role of lesional therapy in selected cases has been discussed. Aim: The aim is to evaluate stereotactic functional procedures in the treatment of ET, with special emphasis on PSA DBS. Further the effects of DBS in the PSA are evaluated. The optimal target is also assessed by evaluating the effect of Vim and PSA DBS in relation to the position of the electrode. An attempt to identify patient-specific factors of prognostic importance for the outcome after DBS will be made. The quality of life (QoL) of patients treated with PSA DBS for ET will be assessed. Finally, the aim is also to analyze retrospectively the long-term outcome of lesional procedures (thalamotomies). Method: The thesis consists of five studies. The optimal electrode location is evaluated in a study analyzing the location of the electrode contact yielding the best effect in Vim DBS and PSA DBS groups. The efficacy of PSA DBS in 21 patients is evaluated in a prospective study. The correlation between outcome, age, tremor grade and gender is established in a prospective study consisting of 68 patients. Finally, the degree of improvement in QoL is determined in 16 patients operated on in the PSA. The very long-term effect of lesional surgery has been investigated in a retrospective study of nine patients who have undergone thalamotomy. Results: In the study of PSA DBS the total score on the Essential Tremor Rating Scale (ETRS) was reduced by 60% compared to the baseline value. Tremor of the arm was improved by 95%. The study evaluating the optimal contact location showed that the best effect was in the PSA in 54% and in the Vim in 12%. The efficacy of DBS was not related to age, gender, or the severity of tremor with regard to the percentage reduction of tremor on stimulation. In patients with a more severe tremor at baseline, a higher degree of residual tremor on stimulation was seen. With regard to QoL, the activities of daily living (ADL) according to the ETRS score were significantly improved, as well as according to the ADL and psychosocial subscores on the Questionnaire for Essential Tremor (QUEST) scale. No significant changes were found on the generic Short Form (SF-36) QoL scale. Thalamotomy had some positive effects, but also a significant amount of side effects that might be attributed to the surgery. Conclusions: The effect of PSA DBS was very satisfying and compares well with the results from Vim DBS. When both Vim and PSA DBS are considered, the optimal target seems to be located in the PSA. PSA DBS shows good results in improving ADL, but the results have been difficult to demonstrate on QoL scales. The efficacy of DBS could not be shown to be associated with gender or age. Nor was it associated with the severity of tremor regarding the percentage of tremor reduction on stimulation. The preoperative severity of tremor was the most important factor regarding outcome following DBS. With regard to thalamotomies, some possible remaining benefit of the surgery could be seen along with some severe side effects.

Il a été montré que la lésion du noyau subthalamique (NST) était impliqué dans la motivation en augmentant cette dernière pour la nourriture et la réduisant pour la cocaïne. On sait aussi que le NST est impliqué dans des processus émotionnels. La notion de motivation est difficilement dissociable de celle de plaisir. Le premier objectif de ce travail de thèse a donc été de séparer la motivation du plaisir pour mieux comprendre le role du NST sur les processus hédoniques grâce à des expériences de choix entre une récompense hédonique (saccharine) et une récompense calorique (glucose) puis des expériences de choix entre nourriture et cocaïne. Dans un second temps nous avons étudié le rôle du NST dans l’influence du contexte social sur la prise de cocaïne. Il parait assez évident de penser que l’addiction aux drogues se développe la plupart du temps dans un contexte social. Cependant, bien que le contexte social global ait beaucoup été étudié, c’est seulement récemment que les modèles animaux d’addiction en neurosciences ont intégré le rôle des facteurs sociaux proximaux (FSP, ceux présents au moment de l’exposition aux drogues), sans pour autant en étudier les bases neurobiologiques. On sait que la présence d’un congénère mais aussi son comportement influence le comportement d’auto-administration de drogue d’un individu. Cependant, les études menées dans ce cadre ne se sont pas intéressées au substrat neurobiologique de ces modulations comportementales. Ainsi, la suite de ce travail de thèse s’est attaché à étudier le rôle du noyau subthalamique sur l’influence des FSP dans la prise de cocaïne. / It has been shown that subthalamic nucleus (STN) is involved in motivation, increasing it for food, while decreasing it for cocaine. It has also been shown that STN is involved in emotional processes. The idea of motivation is hardly dissociable from the notion of pleasure. We currently know the role of STN in motivation, but not so much has been done regarding its implication in hedonic processes. The first aim of my work was to separate motivation from pleasure to better understand the role of STN in hedonic processes, using choice procedures between hedonic (saccharine) and caloric reward (glucose), and between food or cocaine. We wanted thus to understand better the role of STN in the modulation exerted by the context, especially the social context, on cocaine intake. We know that drug addiction often develops in a social context. However, even if global social context has been studied a lot, it is only since recently that animal studies have taken into account the role of proximal social factors (PSF, those that are immediately present at the time of drug exposure). However, these studies do not provide any information regarding neurobiological basis. Here, we examine how PSF interact with the STN, in the context of cocaine intake. Altogether, these results contribute to a better understanding of the STN involvement in the control of pleasure. Moreover, they provide evidence of the influence of proximal social factors on drug consumption and its neurobiological basis among which the STN seems to play a critical role.

Introdução: A estimulação cerebral profunda (DBS) tem sido utilizada para controle das alterações motoras nos pacientes com Doença de Parkinson (DP). O núcleo subtalâmico (NST) é o alvo preferencialmente escolhido na cirurgia. Entretanto, a técnica tem sido associada com declínio cognitivo, principalmente na fluência verbal, alterações de humor e de comportamento. Objetivo: Verificar a ocorrência de alterações na cognição, humor e atividades funcionais por meio de avaliação neuropsicológica. Métodos: Vinte e um pacientes submetidos à cirurgia no período de Maio de 2008 a Março de 2013 foram examinados por meio da avaliação neuropsicológica incluindo testes de memória, funções executivas, funções atencionais, linguagem, praxia, escala hospitalar de depressão e ansiedade (HADS) e atividades funcionais (Pfeffer), nas fases pré e pós-operatória. Os dados foram analisados utilizando SPSS versão 17.0 e os resultados foram comparados através do teste pareado t-Student ou chi-quadrado. Foi adotado um nível de significância igual ou menor que 5% (p < 0,05) para todas as análises. Resultados: Não foram encontradas diferenças significativas nas funções cognitivas, no humor e nas atividades funcionais avaliadas. Resultado marginal foi observado na memória episódica imediata verbal (p=0,051). Conclusão: DBS-NST parece não ter impacto negativo nas funções cognitivas e humor. Apesar da amostra ser relativamente pequena, a técnica parece ser segura do ponto de visto cognitivo em pacientes adequadamente selecionados / Introdution: Deep brain stimulation (DBS) has been used for control of motor disorders in patients with Parkinson\'s disease (PD). The subthalamic nucleus (STN) is the main target used in surgery. However, the technique has been associated with cognitive decline, mainly in verbal fluency, mood and behavior. Objective: To investigate the occurrence of changes in cognition, mood, and activities of daily living through neuropsychological assessment. Methods: Twenty one patients operated between May, 2008 and March, 2013 were submitted to pre- and post-operative neuropsychological testing including memory, executive functions, attentional functions, language and praxis assessment, and to hospital anxiety and depression scale (HADS) and activities of daily living (Pfeffer) scale rating as well. Data were analyzed using SPSS version 17.0 and the results were compared using the paired Student t-test or chi-square. A significance level equal or lower than 5% (p < 0.05) was adopted. Results: No significant differences were found in cognitive functions, mood and activities of daily living. Marginal results were observed in immediate verbal episodic memory (p=0.051). Conclusion: DBS - STN did not show a negative impact on cognitive function, mood and daily activities. Despite the relatively small sample, the technique appears to be safe from the cognitive point of view in appropriately selected patients

Abstract Deep brain stimulation (DBS) of the subthalamic nucleus (STN) has been gaining importance in the treatment of advanced Parkinson's disease. This study was undertaken to evaluate the beneficial effects of bilateral STN stimulation on patient's clinical symptoms and quality of life related to the potential risks and side effects of the treatment. A consecutive series of 42 patients operated on for Parkinson's disease with STN DBS in Oulu University Hospital were included. A subgroup of these patients was evaluated using the Unified Parkinson's Disease Rating Scale (UPDRS), neuropsychological tests, and Health Related Quality of Life (HRQoL) instruments i.e. the Parkinson's Disease Questionnaire (PDQ-39) and the Finnish version of the Nottingham Health Profile (NHP). The costs of the treatment were calculated from the perspective of the health care provider. The possible effects of bilateral STN-operation on cardiovascular autonomic function were analyzed by measuring various time- and frequency domain indexes as well as non-linear indexes of heart rate variability (HRV) from 24-hour EKG recording before and 12 months after the operation. This study showed that STN DBS significantly improves the clinical symptoms and HRQoL of parkinsonian patients. The dyskinesia and clinical fluctuation scores were reduced very significantly in the UPDRS IV subscale. The clinical fluctuations were reduced by 53 %. After DBS best motor response (UPDRS III) scores also improved significantly. The HRQoL measured with both instruments improved significantly. Improvement was seen in the PDQ-39 summary index and the subscales of activities of daily living, emotional well-being, stigma and bodily discomfort. Only communication became worse during the follow-up. There was a statistically significant improvement in the score of the subscales of NHP measuring problems with energy, sleep, emotional reactions and social isolation. One patient died from pulmonary embolism and another contracted a late postoperative intracerebral hemorrhage leading to a permanent deterioration of her neurological condition to the bedridden stage. Other complications were much milder. Clinical improvement and improvement in HRQoL were positively correlated. STN DBS does not influence tonic autonomic cardiovascular regulation. The incremental costs of performing bilateral STN DBS in Finland compared to preoperative medical treatment amounted to an average of 25 591 EUR per patient during the first postoperative year. The majority of parkinsonian patients experienced significant and long lasting relief in their motor symptoms and an improvement in HRQoL following STN stimulation.

Les noyaux gris centraux (ganglions de la base en anglais) sont un réseau de structures sous-corticales dont la persistance dans l'ensemble des vertébrés plaide en faveur d'une fonction clef au cours de l'évolution. Comme ce fut remarqué dès le 18ème siècle, ils ont l'unique particularité de concentrer des afférences de l'entièreté de la surface corticale. Cette position centrale et l'analyse de l'anatomie du réseau leur ont valu le rôle d'arbitre central du cerveau, réglant les conflits entre processus neuronaux concomitants bien qu'incompatibles. Au sein du réseau, le noyau subthalamique jouit d'une notoriété particulière. Ce noyau, sur la base de ses afférences corticales, et en vertu de ses projections sur le soma des neurones pallidaux, aurait pour fonction de filtrer les programmes comportementaux codés par le striatum et concourant pour leur expression. Rapporté aux théories de la prise de décision, le noyau subthalamique fixerait le seuil décisionnel, ou la quantité d'information à accumuler en faveur d'une option comportementale afin qu'elle soit exprimée. Mais si ce petit noyau est devenu si célèbre, c'est surtout qu'il est la cible d'une procédure chirurgicale spectaculaire: la stimulation cérébrale profonde. Cette opération du cerveau est le dernier recours pour les patients souffrant d'une maladie de Parkinson ou d'un trouble obsessionnel compulsif sévère. Elle parvient même parfois à faire disparaître leurs symptômes. Malgré cette efficacité remarquable, les mécanismes de la stimulation cérébrale profonde restent inconnus. Il faut, entre autres, blâmer l'obscurité qui règne encore sur le noyau subthalamique, car les fonctions mentionnées ci-dessus restent des conjectures théoriques en manque de validation expérimentale. La première étape de ce travail a été d'en valider les bases anatomiques. En effet, l'existence d'une voie fronto-subthalamique - nécessaire au modèle - n'était connue que sur la base d'études menées chez le rat. Nous avons démontré, par des méthodes de traçage axonal, l'existence de cette connexion chez le primate. En sus, cette connexion aura permis de redéfinir les frontières médiales du noyau subthalamique avec les conséquences cliniques qui peuvent en être tirées. Le deuxième objectif global de cette thèse était de tester la validité fonctionnelle du modèle, la stimulation cérébrale profonde offrant un accès rare aux activités du noyau subthalamique. Cependant, il était d'abord nécessaire de caractériser la population étudiée, à savoir des patients souffrants d'un trouble obsessionnel compulsif. Grâce à l'imagerie de diffusion nous démontrons une diminution ainsi qu'une désorganisation des connexions cortico-sous corticales, se traduisant probablement par un défaut de contrôle conscient sur le processus de sélection. Une étude de magnétoencéphalographie est en cours pour approfondir les changements d'activité corticale. Pour tester le rôle du noyau subthalamique dans l'établissement du seuil décisionnel nous avons enregistré son activité électrophysiologique pendant que les patients effectuaient une tâche de prise de décision perceptuelle. Nous démontrons que les neurones du noyau subthalamique ont une réponse multimodale, concordant en cela avec nos données anatomiques qui montrent une convergence d'informations au niveau du noyau subthalamique. De plus, une augmentation de l'activité est retrouvée dans les conditions attendues... / The basal ganglia are a network of subcortical structures of which the invariant architecture throughout vertebrate evolution suggests a key function in evolution. As was noted as early as the 18th century, they have the unique characteristic of concentrating afferences from the entire cortical surgace. Given this central position and the internal architecture of the network, they could provide a centralised selection mechanism in the brain, arbitrating between any two conflicting processes. Among the basal ganglia, the subthalamic nucleus has become of particular interest as it is the target of deep brain stimulation, a neurosurgical procedure used to treat severe Parkinson’s disease and obsessive-compulsive disorder. It would have for function to integrate contextual information from its cortical inputs to filter behavioural programs encoded by the striatum. Within the framework of decision-making models, this filtering function is akin to setting the decision threshold, or the amount of evidence required before selecting a program. However, this considerations remain hypothetical as they are lacking experimental support. The first objective of this work was to validate the anatomical basis of these assumptions. Indeed, the existence of a prefrontal-subthalamic pathway, necessary to expand the decision models to every type of decision, had only been demonstrated in rodents. We demonstrated its existence in the primate using anterograde axonal tracing. In addition, this projection will have allowed us to redefine the medial border of the subthalamic nucleus with the clinical consequences that that may have. The second objective of this thesis was to test the functional validity of the models, and specifically the role of the subthalamic nucleus in setting decision thresholds. Deep brain stimulation offers a rare access to the electrophysiology of this structure; however, it is a patient population, here obsessive-compulsive disorder patients. A first step was, therefore, to characterise this population, anatomically and behaviourally, to understand how it might be of use as a model of decision-making in the basal ganglia. We demonstrated a reduction in the strength of cortico-subcortical anatomical connections. We suggest that this prevents accurate conscious control over decision mechanisms. Behaviourally, patients displayed a pathologically low confidence levels in their decisions and we hypothesised that this would lead to an increase of the decision threshold and matching subthalamic activity. To test this, we recorded the activity of the subthalamic nucleus during a decision-making task. We demonstrate that subthalamic neurons have a multimodal activity, consistent with our demonstration of convergent cortical inputs. However, we were unable to demonstrate a link between subthalamic activity and decision threshold, although this may be due to technical considerations…

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