Cross validation of experts versus registration methods for target localization in deep brain stimulation.

In the last five years, Deep Brain Stimulation (DBS) has become the most popular and effective surgical technique for the treatent of Parkinson's disease (PD). The Subthalamic Nucleus (STN) is the usual target involved when applying DBS. Unfortunately, the STN is in general not visible in common medical imaging modalities. Therefore, atlas-based segmentation is commonly considered to locate it in the images. In this paper, we propose a scheme that allows both, to perform a comparison between different registration algorithms and to evaluate their ability to locate the STN automatically. Using this scheme we can evaluate the expert variability against the error of the algorithms and we demonstrate that automatic STN location is possible and as accurate as the methods currently used.

Auditory stimulation does not induce implicit memory during anaesthesia

Background and aim of the study: Formation of implicit memory during general anaesthesia is still debated. Perceptual learning is the ability to learn to perceive. In this study, an auditory perceptual learning paradigm, using frequency discrimination, was performed to investigate the implicit memory. It was hypothesized that auditory stimulation would successfully induce perceptual learning. Thus, initial thresholds of the frequency discrimination postoperative task should be lower for the stimulated group (group S) compared to the control group (group C). Material and method: Eighty-seven patients ASA I-III undergoing visceral and orthopaedic surgery during general anaesthesia lasting more than 60 minutes were recruited. The anaesthesia procedure was standardized (BISR monitoring included). Group S received auditory stimulation (2000 pure tones applied for 45 minutes) during the surgery. Twenty-four hours after the operation, both groups performed ten blocks of the frequency discrimination task. Mean of the thresholds for the first three blocks (T1) were compared between groups. Results: Mean age and BIS value of group S and group C are respectively 40 } 11 vs 42 } 11 years (p = 0,49) and 42 } 6 vs 41 } 8 (p = 0.87). T1 is respectively 31 } 33 vs 28 } 34 (p = 0.72) in group S and C. Conclusion: In our study, no implicit memory during general anaesthesia was demonstrated. This may be explained by a modulation of the auditory evoked potentials caused by the anaesthesia, or by an insufficient longer time of repetitive stimulation to induce perceptual learning.

Tissue-specific opposing functions of the inflammasome adaptor ASC in the regulation of epithelial skin carcinogenesis.

A chronic inflammatory microenvironment favors tumor progression through molecular mechanisms that are still incompletely defined. In inflammation-induced skin cancers, IL-1 receptor- or caspase-1-deficient mice, or mice specifically deficient for the inflammasome adaptor protein ASC (apoptosis-associated speck-like protein containing a CARD) in myeloid cells, had reduced tumor incidence, pointing to a role for IL-1 signaling and inflammasome activation in tumor development. However, mice fully deficient for ASC were not protected, and mice specifically deficient for ASC in keratinocytes developed more tumors than controls, suggesting that, in contrast to its proinflammatory role in myeloid cells, ASC acts as a tumor-suppressor in keratinocytes. Accordingly, ASC protein expression was lost in human cutaneous squamous cell carcinoma, but not in psoriatic skin lesions. Stimulation of primary mouse keratinocytes or the human keratinocyte cell line HaCaT with UVB induced an ASC-dependent phosphorylation of p53 and expression of p53 target genes. In HaCaT cells, ASC interacted with p53 at the endogenous level upon UVB irradiation. Thus, ASC in different tissues may influence tumor growth in opposite directions: it has a proinflammatory role in infiltrating cells that favors tumor development, but it also limits keratinocyte proliferation in response to noxious stimuli, possibly through p53 activation, which helps suppressing tumors.

Sensorimotor Plasticity after Music-Supported Therapy in Chronic Stroke Patients Revealed by Transcranial Magnetic Stimulation

BACKGROUND: Several recently developed therapies targeting motor disabilities in stroke sufferers have shown to be more effective than standard neurorehabilitation approaches. In this context, several basic studies demonstrated that music training produces rapid neuroplastic changes in motor-related brain areas. Music-supported therapy has been recently developed as a new motor rehabilitation intervention. METHODS AND RESULTS: In order to explore the plasticity effects of music-supported therapy, this therapeutic intervention was applied to twenty chronic stroke patients. Before and after the music-supported therapy, transcranial magnetic stimulation was applied for the assessment of excitability changes in the motor cortex and a 3D movement analyzer was used for the assessment of motor performance parameters such as velocity, acceleration and smoothness in a set of diadochokinetic movement tasks. Our results suggest that the music-supported therapy produces changes in cortical plasticity leading the improvement of the subjects' motor performance. CONCLUSION: Our findings represent the first evidence of the neurophysiological changes induced by this therapy in chronic stroke patients, and their link with the amelioration of motor performance. Further studies are needed to confirm our observations.

Nouvelles techniques de stimulation cérébrale: perspectives thérapeutiques en psychiatrie [Novel brain stimulation techniques: therapeutic perspectives in psychiatry]

Recent advances have allowed the development of new physical techniques in neurology and psychiatry, such as Transcranial Magnetic Stimulation (TMS), Vagus Nerve Stimulation (VNS), and Deep Brain Stimulation (DBS). These techniques are already recognized as therapeutic approaches in several late stage refractory neurological disorders (Parkinson's disease, tremor, epilepsy), and currently investigated in psychiatric conditions, refractory to medical treatment (obsessive-compulsive disorder, resistant major depression). In Paralell, these new techniques offer a new window to understand the neurobiology of human behavior.

Mechanisms underlying functional recovery after in vivo focal cerebral ischemia : from preconditioning to diffusion MRI

Version abregée L'ischémie cérébrale est la troisième cause de mort dans les pays développés, et la maladie responsable des plus sérieux handicaps neurologiques. La compréhension des bases moléculaires et anatomiques de la récupération fonctionnelle après l'ischémie cérébrale est donc extrêmement importante et représente un domaine d'intérêt crucial pour la recherche fondamentale et clinique. Durant les deux dernières décennies, les chercheurs ont tenté de combattre les effets nocifs de l'ischémie cérébrale à l'aide de substances exogènes qui, bien que testées avec succès dans le domaine expérimental, ont montré un effet contradictoire dans l'application clinique. Une approche différente mais complémentaire est de stimuler des mécanismes intrinsèques de neuroprotection en utilisant le «modèle de préconditionnement» : une brève insulte protège contre des épisodes d'ischémie plus sévères à travers la stimulation de voies de signalisation endogènes qui augmentent la résistance à l'ischémie. Cette approche peut offrir des éléments importants pour clarifier les mécanismes endogènes de neuroprotection et fournir de nouvelles stratégies pour rendre les neurones et la glie plus résistants à l'attaque ischémique cérébrale. Dans un premier temps, nous avons donc étudié les mécanismes de neuroprotection intrinsèques stimulés par la thrombine, un neuroprotecteur «préconditionnant» dont on a montré, à l'aide de modèles expérimentaux in vitro et in vivo, qu'il réduit la mort neuronale. En appliquant une technique de microchirurgie pour induire une ischémie cérébrale transitoire chez la souris, nous avons montré que la thrombine peut stimuler les voies de signalisation intracellulaire médiées par MAPK et JNK par une approche moléculaire et l'analyse in vivo d'un inhibiteur spécifique de JNK (L JNK) .Nous avons également étudié l'impact de la thrombine sur la récupération fonctionnelle après une attaque et avons pu démontrer que ces mécanismes moléculaires peuvent améliorer la récupération motrice. La deuxième partie de cette étude des mécanismes de récupération après ischémie cérébrale est basée sur l'investigation des bases anatomiques de la plasticité des connections cérébrales, soit dans le modèle animal d'ischémie transitoire, soit chez l'homme. Selon des résultats précédemment publiés par divers groupes ,nous savons que des mécanismes de plasticité aboutissant à des degrés divers de récupération fonctionnelle sont mis enjeu après une lésion ischémique. Le résultat de cette réorganisation est une nouvelle architecture fonctionnelle et structurelle, qui varie individuellement selon l'anatomie de la lésion, l'âge du sujet et la chronicité de la lésion. Le succès de toute intervention thérapeutique dépendra donc de son interaction avec la nouvelle architecture anatomique. Pour cette raison, nous avons appliqué deux techniques de diffusion en résonance magnétique qui permettent de détecter les changements de microstructure cérébrale et de connexions anatomiques suite à une attaque : IRM par tenseur de diffusion (DT-IR1V) et IRM par spectre de diffusion (DSIRM). Grâce à la DT-IRM hautement sophistiquée, nous avons pu effectuer une étude de follow-up à long terme chez des souris ayant subi une ischémie cérébrale transitoire, qui a mis en évidence que les changements microstructurels dans l'infarctus ainsi que la modification des voies anatomiques sont corrélés à la récupération fonctionnelle. De plus, nous avons observé une réorganisation axonale dans des aires où l'on détecte une augmentation d'expression d'une protéine de plasticité exprimée dans le cône de croissance des axones (GAP-43). En appliquant la même technique, nous avons également effectué deux études, rétrospective et prospective, qui ont montré comment des paramètres obtenus avec DT-IRM peuvent monitorer la rapidité de récupération et mettre en évidence un changement structurel dans les voies impliquées dans les manifestations cliniques. Dans la dernière partie de ce travail, nous avons décrit la manière dont la DS-IRM peut être appliquée dans le domaine expérimental et clinique pour étudier la plasticité cérébrale après ischémie. Abstract Ischemic stroke is the third leading cause of death in developed countries and the disease responsible for the most serious long-term neurological disability. Understanding molecular and anatomical basis of stroke recovery is, therefore, extremely important and represents a major field of interest for basic and clinical research. Over the past 2 decades, much attention has focused on counteracting noxious effect of the ischemic insult with exogenous substances (oxygen radical scavengers, AMPA and NMDA receptor antagonists, MMP inhibitors etc) which were successfully tested in the experimental field -but which turned out to have controversial effects in clinical trials. A different but complementary approach to address ischemia pathophysiology and treatment options is to stimulate and investigate intrinsic mechanisms of neuroprotection using the "preconditioning effect": applying a brief insult protects against subsequent prolonged and detrimental ischemic episodes, by up-regulating powerful endogenous pathways that increase resistance to injury. We believe that this approach might offer an important insight into the molecular mechanisms responsible for endogenous neuroprotection. In addition, results from preconditioning model experiment may provide new strategies for making brain cells "naturally" more resistant to ischemic injury and accelerate their rate of functional recovery. In the first part of this work, we investigated down-stream mechanisms of neuroprotection induced by thrombin, a well known neuroprotectant which has been demonstrated to reduce stroke-induced cell death in vitro and in vivo experimental models. Using microsurgery to induce transient brain ischemia in mice, we showed that thrombin can stimulate both MAPK and JNK intracellular pathways through a molecular biology approach and an in vivo analysis of a specific kinase inhibitor (L JNK1). We also studied thrombin's impact on functional recovery demonstrating that these molecular mechanisms could enhance post-stroke motor outcome. The second part of this study is based on investigating the anatomical basis underlying connectivity remodeling, leading to functional improvement after stroke. To do this, we used both a mouse model of experimental ischemia and human subjects with stroke. It is known from previous data published in literature, that the brain adapts to damage in a way that attempts to preserve motor function. The result of this reorganization is a new functional and structural architecture, which will vary from patient to patient depending on the anatomy of the damage, the biological age of the patient and the chronicity of the lesion. The success of any given therapeutic intervention will depend on how well it interacts with this new architecture. For this reason, we applied diffusion magnetic resonance techniques able to detect micro-structural and connectivity changes following an ischemic lesion: diffusion tensor MRI (DT-MRI) and diffusion spectrum MRI (DS-MRI). Using DT-MRI, we performed along-term follow up study of stroke mice which showed how diffusion changes in the stroke region and fiber tract remodeling is correlating with stroke recovery. In addition, axonal reorganization is shown in areas of increased plasticity related protein expression (GAP 43, growth axonal cone related protein). Applying the same technique, we then performed a retrospective and a prospective study in humans demonstrating how specific DTI parameters could help to monitor the speed of recovery and show longitudinal changes in damaged tracts involved in clinical symptoms. Finally, in the last part of this study we showed how DS-MRI could be applied both to experimental and human stroke and which perspectives it can open to further investigate post stroke plasticity.

Closed loop electrical muscle stimulation in spinal cord injured rehabilitation

The effect of motor training using closed loop controlled Functional Electrical Stimulation (FES) on motor performance was studied in 5 spinal cord injured (SCI) volunteers. The subjects trained 2 to 3 times a week during 2 months on a newly developed rehabilitation robot (MotionMaker?). The FES induced muscle force could be adequately adjusted throughout the programmed exercises by the way of a closed loop control of the stimulation currents. The software of the MotionMaker? allowed spasms to be detected accurately and managed in a way to prevent any harm to the SCI persons. Subjects with incomplete SCI reported an increased proprioceptive awareness for motion and were able to achieve a better voluntary activation of their leg muscles during controlled FES. At the end of the training, the voluntary force of the 4 incomplete SCI patients was found increased by 388% on their most affected leg and by 193% on the other leg. Active mobilisation with controlled FES seems to be effective in improving motor function in SCI persons by increasing the sensory input to neuronal circuits involved in motor control as well as by increasing muscle strength.

Influence of the implanted pulse generator as reference electrode in finite element model of monopolar deep brain stimulation.

Electrical deep brain stimulation (DBS) is an efficient method to treat movement disorders. Many models of DBS, based mostly on finite elements, have recently been proposed to better understand the interaction between the electrical stimulation and the brain tissues. In monopolar DBS, clinically widely used, the implanted pulse generator (IPG) is used as reference electrode (RE). In this paper, the influence of the RE model of monopolar DBS is investigated. For that purpose, a finite element model of the full electric loop including the head, the neck and the superior chest is used. Head, neck and superior chest are made of simple structures such as parallelepipeds and cylinders. The tissues surrounding the electrode are accurately modelled from data provided by the diffusion tensor magnetic resonance imaging (DT-MRI). Three different configurations of RE are compared with a commonly used model of reduced size. The electrical impedance seen by the DBS system and the potential distribution are computed for each model. Moreover, axons are modelled to compute the area of tissue activated by stimulation. Results show that these indicators are influenced by the surface and position of the RE. The use of a RE model corresponding to the implanted device rather than the usually simplified model leads to an increase of the system impedance (+48%) and a reduction of the area of activated tissue (-15%).

Experimental Results and Evaluation of SmartBox Stimulation Device in a P2P E-learning System

In this paper, we present the experimental results and evaluation of the SmartBox stimulation device in P2P e-learning system which is based on JXTA-Overlay. We also show the design and implementation of the SmartBox environment that is used for stimulating the learners motivation to increase the learning efficiency. The SmartBox is integrated with our P2P system as a useful tool for monitoring and controlling learners¿ activity. We found by experimental results that the SmartBox is an effective way to increase the learner¿s concentration. We also investigated the relation between learner¿s body movement, concentration, and amount of study. From the experimental results, we conclude that the use of SmartBox is an effective way to stimulate the learners in order to continue studying while maintaining the concentration.

Cutting edge: stimulation with the cognate self-antigen induces expression of the Ly49A receptor on self-reactive T cells which modulates their responsiveness.

NK cell self-tolerance is maintained by inhibitory receptors specific for MHC class I molecules. Inhibitory NK receptors are also expressed on memory CD8 T cells but their biological relevance on T cells is unclear. In this study, we describe the expression of the Ly49A receptor on a subset of autoreactive T cells which persist in mice double-transgenic for the lymphocytic choriomeningitis virus-derived peptide gp33 and a TCRalphabeta specific for the gp33. No Ly49A-expressing cells are found in TCRalphabeta single-transgenic mice, indicating that the presence of the autoantigen is required for Ly49A induction. Direct evidence for an Ag-specific initiation of Ly49A expression has been obtained in vitro after stimulation of autoreactive TCRalphabeta T cells with the cognate self-Ag. This expression of Ly49A substantially reduces Ag-specific activation of autoreactive T cells. These findings thus suggest that autoantigen-specific induction of inhibitory NK cell receptors on T cells may contribute to peripheral self-tolerance.

Behavioral changes in brain-injured critical care adults with different levels of consciousness during nociceptive stimulation: an observational study.

PURPOSE: The primary objective of this study was to describe the frequency of behaviors observed during rest, a non-nociceptive procedure, and a nociceptive procedure in brain-injured intensive care unit (ICU) patients with different levels of consciousness (LOC). Second, it examined the inter-rater reliability and discriminant and concurrent validity of the behavioral checklist used. METHODS: The non-nociceptive procedure involved calling the patient and shaking his/her shoulder. The nociceptive procedure involved turning the patient. The frequency of behaviors was recorded using a behavioral checklist. RESULTS: Patients with absence of movement, or stereotyped flexion or extension responses to a nociceptive stimulus displayed more behaviors during turning (median 5.5, range 0-14) than patients with localized responses (median 4, range 0-10) or able to self-report their pain (median 4, range 0-10). Face flushing, clenched teeth, clenched fist, and tremor were more frequent in patients with absence of movement, or stereotyped responses to a nociceptive stimulus. The reliability of the checklist was supported by a high intra-class correlation coefficient (0.77-0.92), and the internal consistency was acceptable in all three groups (KR 20, 0.71-0.85). Discriminant validity was supported as significantly more behaviors were observed during nociceptive stimulation than at rest. Concurrent validity was confirmed as checklist scores were correlated to the patients' self-reports of pain (r s = 0.53; 95 % CI 0.21-0.75). CONCLUSION: Brain-injured patients reacted significantly more during a nociceptive stimulus and the number of observed behaviors was higher in patients with a stereotyped response.

Measuring the effects through time of the influence of visuomotor and visuotactile synchronous stimulation on a virtual body ownership illusion

Previous studies have examined the experience of owning a virtual surrogate body or body part through specific combinations of cross-modal multisensory stimulation. Both visuomotor (VM) and visuotactile (VT) synchronous stimulation have been shown to be important for inducing a body ownership illusion, each tested separately or both in combination. In this study we compared the relative importance of these two cross-modal correlations, when both are provided in the same immersive virtual reality setup and the same experiment. We systematically manipulated VT and VM contingencies in order to assess their relative role and mutual interaction. Moreover, we present a new method for measuring the induced body ownership illusion through time, by recording reports of breaks in the illusion of ownership ("breaks") throughout the experimental phase. The balance of the evidence, from both questionnaires and analysis of the breaks, suggests that while VM synchronous stimulation contributes the greatest to the attainment of the illusion, a disruption of either (through asynchronous stimulation) contributes equally to the probability of a break in the illusion.

Traitement de la douleur chronique: rôle de la stimulation transcrânienne du cortex moteur [Treatment of chronic pain: transcranial stimulation of the motor cortex?].

Chronic pain refractory to medical therapy poses a therapeutic challenge. The repetitive Transcranial Magnetic Stimulation (rTMS) and transcranial Direct Current Stimulation (tDCS) modulate brain activity offering a new approach. Current evidence suggests a potential therapeutic efficacy of motor cortex stimulation for the treatment of pain, but does not (yet) support their recommendation for clinical practice. These methods allow to deepen our knowledge in the pathophysiology of chronic pain while providing new therapeutic approaches.

Long duration response to levodopa in advanced Parkinson's disease patients treated with subthalamic deep brain stimulation

Résumé La levodopa (LD) est le traitement antiparkinsonien le plus efficace et le plus répandu. Son effet est composé d'une réponse de courte (quelques heures) et de longue durée (jours à semaines). La persistance de cette dernière dans les phases avancées de la maladie de Parkinson est controversée, et sa mesure directe n'a jamais été faite en raison des risques liés à un sevrage complet de LD. La stimulation du noyau sous-thalamique est un nouveau traitement neurochirurgical de la maladie de Parkinson, indiqué dans les formes avancées, qui permet l'arrêt complet du traitement médicamenteux chez certains patients. Nous avons étudié 30 patients qui ont bénéficié d'une telle stimulation, et les avons évalués avant l'intervention sans médicaments, et à 6 mois postopératoires, sans médicaments et sans stimulation. Chez 19 patients, la médication a pu être complètement arrêtée, alors qu'elle a dû être réintroduite chez les 11 patients restants. Au cours des 6 mois qui ont suivi l'intervention, le parkinsonisme s'est aggravé de façon significative dans le groupe sans LD, et non dans le groupe avec LD. Cette différence d'évolution s'explique par la perte de l'effet à long terme de la LD dans le groupe chez qui ce médicament a pu être arrêté. En comparant cette aggravation à la magnitude de l'effet à court terme, la réponse de longue durée correspond environ à 80 pourcent de la réponse de courte durée, et elle lui est inversement corrélée. Parmi les signes cardinaux de la maladie, la réponse de longue durée affecte surtout la bradycinésie et la rigidité, mais pas le tremblement ni la composante axiale. La comparaison du parkinsonisme avec traitement (stimulation et LD si applicable) ne montre aucune différence d'évolution entre les 2 groupes, suggérant que la stimulation compense tant la réponse de courte que de longue durée. Notre travail montre que la réponse de longue durée à la LD demeure significative chez les patients parkinsoniens après plus de 15 ans d'évolution, et suggère que la stimulation du noyau sous-thalamique compense les réponses de courte et de longue durée. Abstract Background: Long duration response to levodopa is supposed to decrease with Parkinson's disease (PD) progression, but direct observation of this response in advanced PD has never been performed. Objective: To study the long duration response to levodopa in advanced PD patients treated with subthalamic deep-brain stimulation. Design and settings: We studied 30 consecutive PD patients who underwent subthalamic deep-brain stimulation. One group had no antiparkinsonian treatment since surgery (no levodopa), while medical treatment had to be reinitiated in the other group (levodopa). Main outcome measures: motor Unified Parkinson's Disease Rating Scale (UPDRS). Results: In comparison with preoperative assessment, evaluation six months postoperatively with stimulation turned off for three hours found a worsening of the motor part of UPDRS in the no-levodopa group. This worsening being absent in the levodopa group, it most probably reflected the loss of the long duration response to levodopa in the no-levodopa group. Stimulation turned on, postoperative motor UPDRS in both groups were similar to preoperative on medication scores, suggesting that subthalamic deep-brain stimulation compensated for both the short and long duration responses to levodopa. Conclusions: Our results suggest that the long duration response to levodopa remains significant even in advanced PD, and that subthalamic deep-brain stimulation compensates for both the short and the long duration resposes to levodopa.