Le rôle clé du noyau pédonculopontin (PPN) dans le contrôle de l’éveil a été démontré chez les petits mammifères mais reste à valider chez le primate. Ainsi, cette étude avait pour but de confirmer le rôle du PPN dans le contrôle de l’éveil chez les primates non humains sains. Un équipement télémétrique a été implanté chez un primate non humain afin de recueillir les données polysomnographiques permettant de déterminer les différents stades de vigilance. Une électrode reliée à un stimulateur a été implantée dans la région du PPN. La somnolence diurne a été évaluée par un test itératif de latence d’endormissement réalisé 10 fois en condition contrôle et 10 fois lors de la stimulation du PPN, 5 à basse fréquence (SBF) puis 5 à haute fréquence (SHF). Les latences moyennes d’endormissement (min) et le temps moyen passé dans les différents stades de veille/sommeil ont été évalués et comparés à l’aide d’une Anova non paramétrique. Les siestes analysées étaient exclusivement composées de sommeil lent léger. Lors de la SBF du PPN, la survenue de ces siestes s’effectuait avec un temps de latence supérieur à celui obtenu lors des tests contrôles (13,5 ± 0,9 min en contrôle vs 18,5 ± 0,5 min en SBF) pour une durée de sommeil plus faible (5,1 ± 0,7 min en contrôle vs 1,1 ± 0,4 min en SBF). La SHF du PPN n’a pas produit de variation significative des paramètres de sommeil par rapport à la situation contrôle. Ces résultats montrent que la SBF du PPN induit une augmentation de l’éveil diurne chez le primate sain.

Le primate non humain rendu parkinsonien par des injections de MPTP présente précocement, comme le patient, une désorganisation du sommeil, avec la survenue d’une somnolence diurne, qui n’a jamais été clairement quantifiée. Cette étude a consisté à caractériser la somnolence diurne précoce du primate non humain rendu parkinsonien. Un équipement télémétrique polysomnographique a été implanté chez un primate non humain afin de déterminer les différents stades de vigilance. La somnolence diurne a été évaluée par un test itératif de latence d’endormissement réalisé 10 fois en condition contrôle et 23 fois en phase prémotrice du syndrome parkinsonien induite par intoxication progressive au MPTP. Les latences moyennes d’endormissement et le temps moyen passé dans les différents stades de vigilance ont été évalués et comparés à l’aide d’une Anova non paramétrique. Au cours de l’intoxication au MPTP, la latence d’endormissement a diminué (13,5 ± 0,9 min en contrôle vs 6,6 ± 0,5 min), la durée du sommeil lent léger a augmenté (5,1 ± 0,7 min vs 7,4 ± 0,3 min) et de petites époques de sommeil lent profond et de sommeil paradoxal sont apparues (0 vs 0,8 ± 0,3 min ; 0 vs 1,7 ± 0,2 min). Globalement, en phase d’installation d’un syndrome parkinsonien, la durée de sommeil a augmenté de manière significative (5,2 ± 0,8 min en contrôle vs 10,0 ± 0,4 min). Ces résultats confirment que la somnolence diurne peut être considérée comme un marqueur prédictif de l’émergence d’une maladie de Parkinson.

We present a novel closed-loop subthalamic nucleus (STN) deep brain stimulation (DBS) scheme for Parkinson's disease (PD) and obsessive-compulsive disorder (OCD). The algorithm is designed to effectuate real-time, adaptive stimulation employing the outcome of the 0-1 test for chaos as a state-specific biomarker. In case of a null outcome, the system identifies optimal patterns of stimulation desynchronizing pathologic neuronal activity with minimal energy consumption, on grounds of a stochastic dynamical model and an appropriately formulated cost function. Simulations are performed utilizing microelectrode recordings (MERs) acquired during 8 and 2 DBS surgical interventions for PD and OCD, respectively.

BACKGROUND:Drug-resistant motor epilepsies are particularly incapacitating for the patients. In a primate model of focal motor seizures induced by intracortical injection of penicillin, we recently showed that seizures propagated from the motor cortex towards the basal ganglia.OBJECTIVE:Using the same animal model here, we hypothesized that disruption of subthalamic nucleus (STN) activity by chronic high frequency stimulation (HFS) could modify pathological excessive cortical synchronisation occurring during focal motor seizures, and therefore could reduce seizure activity.METHODS:Two monkeys were chronically implanted with one electrode positioned into the STN. In each experiment, seizures were induced during 6 hours by injecting penicillin into the motor cortex. During stimulation sessions, HFS-STN was applied at the beginning of penicillin injection.RESULTS:Our results indicate that HFS-STN improved focal motor seizures by delaying the occurrence of the first seizure, by decreasing the number of seizures by 47% and therefore the total time spent seizing by 53% compared to control. These results argue for a therapeutic use of HFS-STN in motor seizures because they were obtained in a very severe primate model of motor status similar to that seen in human. Furthermore, HFS-STN was much more efficient than direct cortical HFS of the epileptic focus, which we already tested in the same primate model.CONCLUSIONS:The present study suggests that HFS-STN could be used as an experimental therapy when other therapeutic strategies are not possible or have failed in humans suffering from motor epilepsy but the present study still warrants controlled studies in humans.

The subthalamic nucleus (STN) has been shown to be implicated in the control of voluntary action, especially during tasks involving conflicting choice alternatives or rapid response suppression. However, the precise role of the STN during nonmotor functions remains controversial. First, we tested whether functionally distinct neuronal populations support different executive control functions (such as inhibitory control or error monitoring) even within a single subterritory of the STN. We used microelectrode recordings during deep brain stimulation surgery to study extracellular activity of the putative associative-limbic part of the STN while patients with severe obsessive-compulsive disorder performed a stop-signal task. Second, 2–4 days after the surgery, local field potential recordings of STN were used to test the hypothesis that STN oscillations may also reflect executive control signals. Extracellular recordings revealed three functionally distinct neuronal populations: the first one fired selectively before and during motor responses, the second one selectively increased their firing rate during successful inhibitory control, and the last one fired selectively during error monitoring. Furthermore, we found that beta band activity (15–35 Hz) rapidly increased during correct and incorrect behavioral stopping. Taken together, our results provide critical electrophysiological support for the hypothesized role of the STN in the integration of motor and cognitive-executive control functions.

The authors proposed an intraventricular ‘floating’ electrode inserted in the third ventricle (V3) adjacent to the ventromedian hypothalamus (VMH) in a freely moving Macaca fascicularis to modulate food intake (FI), body fat (BF), body weight (BW) and body mass index (BMI), as a potential treatment of obesity. Five adult Macaca fascicularis monkeys were implanted stereotactically in the V3 contiguous to the VMH with one deep brain stimulation (DBS) electrode. The study was divided in two phases: (a) acute 24 h-fasting trials: different electrical stimulation parameters were applied to a fasting primate to determine the best combination in reducing FI; and (b) chronic 8-week stimulation trials: three cycles of intraventricular-VMH DBS lasting 8–10 weeks were performed at 130 Hz, 80 Hz (most effective frequency reducing FI) and 30 Hz, respectively. BMI, BW, BF content, skinfolds and hormones were measured during baseline and at the end of each session of stimulation. Acute 24 h-fasting trials: there was a decrease in FI in all subjects at 80 Hz, (11–19%, mean 15%). Chronic 8-week stimulation trials: a significant decrease in BW and BMI was observed in three out of four monkeys at 80 Hz (mean 8±4.4%). Subcutaneous skinfolds were reduced in all four subjects at 80 Hz and slightly increased at 130 Hz. The sham monkey remained stable. No significant adverse effects were recorded. The stimulation of the VMH region through an intraventricular approach might acutely modulate FI and induce a sustained decrease in BW and fat mass in normal non-human primate.

Gigantic neural networks write with remarkable fluency. Can scaling them up lead us to artificial general intelligence, asks Mordechai Rorvig

Functional and connectivity changes in corticostriatal systems have been reported in the brains of patients with obsessive–compulsive disorder (OCD); however, the relationship between basal ganglia activity and OCD severity has never been adequately established. We recently showed that deep brain stimulation of the subthalamic nucleus (STN), a central basal ganglia nucleus, improves OCD. Here, single-unit subthalamic neuronal activity was analysed in 12 OCD patients, in relation to the severity of obsessions and compulsions and response to STN stimulation, and compared with that obtained in 12 patients with Parkinson's disease (PD). STN neurons in OCD patients had lower discharge frequency than those in PD patients, with a similar proportion of burst-type activity (69 vs 67%). Oscillatory activity was present in 46 and 68% of neurons in OCD and PD patients, respectively, predominantly in the low-frequency band (1–8 Hz). In OCD patients, the bursty and oscillatory subthalamic neuronal activity was mainly located in the associative–limbic part. Both OCD severity and clinical improvement following STN stimulation were related to the STN neuronal activity. In patients with the most severe OCD, STN neurons exhibited bursts with shorter duration and interburst interval, but higher intraburst frequency, and more oscillations in the low-frequency bands. In patients with best clinical outcome with STN stimulation, STN neurons displayed higher mean discharge, burst and intraburst frequencies, and lower interburst interval. These findings are consistent with the hypothesis of a dysfunction in the associative–limbic subdivision of the basal ganglia circuitry in OCD's pathophysiology.

In advanced Parkinson's disease, several therapeutical option including not only lesional surgery (VIM, GPi) and deep brain stimulation (STN, GPi, VIM) but also continuous subcutaneous apomorphine infusion therapy can be proposed to the patient. The choice depends on the hope of the patient, patient's general health condition and the experience and choice of the neurosurgical and neurologist team. Here we report our experience based on 400 STN-DBS cases and we discuss, on the basis of our experience and on the literature, the advantage and disadvantage of DBS strategy as compared with non-surgical option such as continuous subcutaneous apomorphine infusion therapy.

For decades, several animal models of locomotion have allowed a better understanding of the basic physiological mechanisms of gait. However, unlike most of the mammals, the Order Primates is characterized by fundamental changes in locomotor behaviour. In particular, some primates use a specific pattern of locomotion and are able to naturally walk bipedally due possibly to a specific supra-spinal control of locomotion. These features must be taken into account when one considers to study the intrinsic properties of human gait. Thus, an experimental model of bipedal locomotion allowing precise and reproducible analysis of gait in non-human primate is still lacking. This study describes a non-human primate model of bipedal locomotion under restrained condition. We undertook a kinematic and biomechanic study in three Macaca fascicularis trained to walk bipedally on a treadmill. One of the primate was evaluated in complete head fixation. Gait visual analysis and electromyographic recordings provided pertinent description of the gait pattern. Step frequencies, step lengths, cycle and stance phase durations were correlated with Froude number (dimensionless velocity), whereas swing phase durations remained non-correlated. Gait patterns observed in our model were similar to those obtained in freely bipedal Macaca fuscata and to a lesser extend to Humans. Gait pattern was not modified by head fixation thereby allowing us to perform precise and repetitive micro electrode recordings of deep cerebral structures. Thus, the present model could provide a pertinent pre-clinical tool to study gait parameters and their neuronal control but also could be helpful to validate new therapeutics interventions.

In order to assess the signal to noise ratio and spatial selectivity of nanostructured microelectrodes, our consortium built an original assembly of surface macroelectrodes and deep microelectrode arrays. Acute and chronic assessments were achieved based on rodent and non human primate model. Eventually, we used this device to monitor by association of the surface and deep microelectrodes nominal behavior of the animals and induced epileptic seizure.

Gait disturbances are frequent and disabling in advanced Parkinson's disease. These symptoms respond poorly to usual medical and surgical treatments but were reported to be improved by stimulation of the pedunculopontine nucleus. We studied the effects of stimulating the pedunculopontine nucleus area in six patients with severe freezing of gait, unresponsive to levodopa and subthalamic nucleus stimulation. Electrodes were implanted bilaterally in the pedunculopontine nucleus area. Electrode placement was checked by postoperative magnetic resonance imaging. The primary outcome measures were a composite gait score, freezing of gait questionnaire score and duration of freezing episodes occurring during a walking protocol at baseline and one-year follow-up. A double-blind cross-over study was carried out from months 4 to 6 after surgery with or without pedunculopontine nucleus area stimulation. At one-year follow-up, the duration of freezing episodes under off-drug condition improved, as well as falls related to freezing. The other primary outcome measures did not significantly change, nor did the results during the double-blind evaluation. Individual results showed major improvement of all gait measures in one patient, moderate improvement of some tests in four patients and global worsening in one patient. Stimulation frequency ranged between 15 and 25 Hz. Oscillopsia and limb myoclonus could hinder voltage increase. No serious adverse events occurred. Although freezing of gait can be improved by low-frequency electrical stimulation of the pedunculopontine nucleus area in some patients with Parkinson's disease our overall results are disappointing compared to the high levels of expectation raised by previous open label studies. Further controlled studies are needed to determine whether optimization of patient selection, targeting and setting of stimulation parameters might improve the outcome to a point that could transform this experimental approach to a treatment with a reasonable risk-benefit ratio.

In animals, the pedunculopontine (PPN) and the sub-cuneiform (SCU) nuclei located in the upper brainstem are involved during the processing of gait. Similar functional nuclei are suspected in humans but their role in gait is unclear. Here we show that, using extra-cellular recordings of the PPN/SCU region obtained in two parkinsonian patients, the SCU neurons increased their firing rate without modifying their firing pattern during mimicked steps. We conclude that SCU neurons are activated during gait processes.

Neurofibromatosis type 2 (NF2) is a complex disease characterized by the development of multiple schwannomas, especially vestibular schwannomas, as well as other types of benign tumours including meningioma and spinal ependymoma. Due to its multisystem nature, the management of NF2 requires a multidisciplinary approach. In England, the delivery of care for NF2 patients has been centralized to four-“hub” centres in Manchester, Cambridge, Oxford and London each having associated “spoke” centres. Each centre has a core multidisciplinary team consisting of genetics, otolaryngology, neurosurgery, paediatrics, neurology, audiology, radiology, psychology, physiotherapy, specialist nurses and administrative staff. In addition, the core team has access to plastic surgery, ophthalmology, peripheral nerve surgery and adult and paediatric oncology. There are weekly multidisciplinary clinics each with six to eight patients. Each patient is discussed during a team meeting and the management decisions that are made are then discussed with the patients. All patients are reviewed at least annually and have annual head magnetic resonance imaging (MRI) and three yearly spinal MRI. Annual audiological assessment is performed. Cochlear implantation and auditory brainstem implantation are offered if indicated. Surgery, stereotactic radiosurgery and bevacizumab therapy are available for the management of intracranial and spinal tumours. The integration of the service in England has provided significant benefits to patient care and, in the long term, will provide robust patient outcome data that will provide an evidence base to assist in optimizing management of patients with NF2.La neurofibromatose de type 2 (NF2) est une maladie complexe caractérisée par le développement de multiples schwannomes, en particulier vestibulaires et d’autres types tumoraux bénins incluant les méningiomes et les épendymomes médullaires. À cause de l’atteinte diffuse, la prise en charge des patients NF2 nécessite une approche multidisciplinaire. En Angleterre, les soins pour les patients NF2 sont regroupés sur 4 centres (Manchester, Cambridge, Oxford et Londres), chacun ayant des centres relais. Chaque centre a une équipe multidisciplinaire compétente en génétique, oto-rhinologie, neurochirurgie, pédiatrie, neurologie, audiologie, radiologie, psychologie, rééducation avec des infirmières spécialisées et un staff administratif. De plus, ces équipes peuvent faire appel à la chirurgie plastique, l’ophtalmologie, la chirurgie des nerfs périphériques et de l’oncologie pédiatrique. Il y a des réunions multidisciplinaires hebdomadaires pour 5 à 6 patients. Le cas de chaque patient est ensuite discuté en équipe et les décisions prises conjointement et expliquées au patient. Tous les patients sont vus au moins une fois par an et ont, en plus du bilan audiologique, une imagerie par résonance magnétique (IRM) cérébrale annuelle et une IRM du rachis tous les 3 ans. L’implant cochléaire et l’implant auditif du tronc cérébral sont disponibles. La chirurgie, la radiochirurgie et le traitement par bévacizumab sont utilisés pour le traitement des lésions intracrâniennes et intrarachidiennes. Ce type d’organisation en Angleterre a montré une amélioration de la prise en charge et à long terme permettra d’avoir suffisamment de données pour optimiser les soins.

The surgical treatment of intractable epilepsies involving eloquent areas of the cortex is still challenging. Deep-brain stimulation could be an alternative to resective surgery because it can modulate the remote control systems of epilepsy, such as the thalamus and basal ganglia. The surgical experience acquired in the field of movement disorder surgery and the low morbidity of this technic could allow one to apply DBS to intractable epilepsies, such as generalized, motor and bitemporal epilepsies. Here we discuss the main experimental and clinical data reported so far in the literature and taken from our own experience.

HFS has become a widely used method in functional neurosurgery. However, its mechanism is not well understood, and its cellular and molecular effects have not yet been investigated. The aim of the study was to understand which cellular events, unrelated to the network organization of cells or neurons, participate in the mechanism of action of HFS.In vitro cellular effects of high (HFS) and low (LFS) frequency electrical stimulation on prolactin secretion in GH3 cell lines (prolactinoma), as well as the catecholaminergic secretion on PC12 cells (pheochromocytoma) were investigated. Cells were cultured in dishes with integrated electrodes to deliver stimulation at the same parameters as those used in clinical conditions to treat advanced forms of Parkinson's disease. Prolactin production was measured in GH3 using a Radio-Immuno-Assay. Dopamine, epinephrine and norepinephrine were measured in PC12 using Enzymo-immuno-assays.HFS for 24 hours reduced prolactin secretion by 40.3%, dopamine by 32.7%, epinephrine by 18.1% (non significant) and norepinephrine by 27.0%. LFS did not induce significant changes. These results suggest that HFS has an inhibitory impact on the cellular machinery responsible for hormone and neurotransmitter production.In this model of isolated cultured cells, network interactions and particularly presynaptic actions are discarded. HFS has inhibitory effects on cellular mechanisms responsible for the production and release of molecules participating in intercellular communication. This HFS-induced inhibition might participate in the lesion-like effect of therapeutic HFS in the basal ganglia during various movement disorders.