Processing large cohorts of data is very important to increase statistical power in neuroscience and neuroimaging. The Brain Imaging Data Structure (BIDS) standard has been developed to facilitate this task, but researchers are still facing the challenge of reusing scripts to analyse data coming from different projects or different centres. Here, our goal was to develop a tool, BIDS Manager-Pipeline, to process automated analyses using open-source research software solutions on several subjects at the same time. BIDS Manager-Pipeline builds upon BIDS Manager, a software recently developed in our lab to collect, organise, and manage multimodal multicentre datasets. When processing data, BIDS Manager-Pipeline coordinates the use of several modules originating from different software environments and executable programs and can thus be considered as a bridge between BIDS datasets and software solutions. Through a graphical user interface, users can filter the subjects of interest in the dataset by ID or by other subject criteria and common input analysis parameters. BIDS Manager-Pipeline first controls whether the selected values can be applied to the selected subset, provided the inputs and the outputs, and then run the process on all selected data. The results of analyses are stored using specifications for BIDS derivatives. In addition, BIDS Manager-Pipeline creates a table gathering the different metrics resulting from the analyses across subjects, for later statistical analyses. In short, BIDS Manager-Pipeline allows processing data from large cohorts, either in basic neuroscience or in clinical research. This framework can take advantage of tools developed by the neuroscience community, by centralizing and facilitating their use.

Introduction: The modular organization of the cortex suggests that discrete cortical regions are associated with specific dynamical properties. These properties, as characterized by input-output functions may provide more accurate brain excitability markers. Here, we combined robotized TMS with EEG to unravel region-specific input-output patterns and derive new cortical excitability indexes from single trial regression of early components of TMS-evoked potentials (TEPs).

OBJECTIVE:As electrodes are required to interact with sub-millimeter neural structures, innovative microfabrication processes are required to enable fabrication of microdevices involved in such stimulation and/or recording. This requires the development of highly integrated and miniaturized systems, comprising die-integration-compatible technology and flexible microelectrodes. To elicit selective stimulation and recordings of sub-neural structures, such microfabrication process flow can beneficiate from the integration of titanium nitride (TiN) microelectrodes onto a polyimide substrate. Finally, assembling onto cuffs is required, as well as electrode characterization. APPROACH:Flexible TiN microelectrode array integration and miniaturization was achieved through microfabrication technology based on microelectromechanical systems (MEMS) and complementary metal-oxide semiconductor processing techniques and materials. They are highly reproducible processes, granting extreme control over the feature size and shape, as well as enabling the integration of on-chip electronics. This design is intended to enhance the integration of future electronic modules, with high gains on device miniaturization. MAIN RESULTS:(a) Fabrication of two electrode designs, (1) 2 mm long array with 14 TiN square-shaped microelectrodes (80  ×  80 µm2), and (2) an electrode array with 2 mm  ×  80 µm contacts. The average impedances at 1 kHz were 59 and 5.5 kΩ, respectively, for the smaller and larger contacts. Both designs were patterned on a flexible substrate and directly interconnected with a silicon chip. (b) Integration of flexible microelectrode array onto a cuff electrode designed for acute stimulation of the sub-millimeter nerves. (c) The TiN electrodes exhibited capacitive charge transfer, a water window of  -0.6 V to 0.8 V, and a maximum charge injection capacity of 154  ±  16 µC cm-2. SIGNIFICANCE:We present the concept, fabrication and characterization of composite and flexible cuff electrodes, compatible with post-processing and MEMS packaging technologies, which allow for compact integration with control, readout and RF electronics. The fabricated TiN microelectrodes were electrochemically characterized and exhibited a comparable performance to other state-of-the-art electrodes for neural stimulation and recording. Therefore, the presented TiN-on-polyimide microelectrodes, released from silicon wafers, are a promising solution for neural interfaces targeted at sub-millimeter nerves, which may benefit from future upgrades with die-electronic modules.

Patients with focal temporal lobe seizures often experience transient episodes of impaired awareness with behavioural arrest, but the precise mechanism remains unknown. The Blumenfeld hypothesis attributes these deficits to a loss of cholinergic input to the cortex. This is presumed to result from increased activation of inhibitory regions that suppress subcortical arousal, giving rise to slow wave activity. To investigate this hypothesis – and more specifically, to characterize the relationship between propagated discharge, cortical slow waves and behavioural arrest – we performed kindling studies in rats. We found that seizure discharge took longer to spread from the amygdala than the hippocampus, and took more kindling stimulations to elicit behavioural arrest. In addition, the onset of propagated discharge in subcortical and cortical sites did not always match with the onset of behavioural arrest. Importantly, the activity seen in the cortex did not resemble the slow waves seen in deep sleep. Together, these findings suggest an additional mechanism – other than the Blumenfeld hypothesis – to explain how temporal lobe seizures may produce behavioural arrest and impair awareness.

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.

There is evidence that the right Inferior Frontal Gyrus (IFG) exerts an inhibitory influence over the left primary motor cortex (M1) when actions need to be inhibited. Patients with obsessive–compulsive disorder (OCD) present deficient motor inhibition and attentional control. We therefore hypothesized that in patients with OCD, inhibitory inter-hemispheric IFG-M1 connectivity might be impaired in proportion with clinical severity. We used dual-site neuronavigated TMS to probe resting-state IFG-M1 connectivity in 12 OCD patients and 20 healthy volunteers. A conditioning stimulus controlled by a TMS robot, was delivered over the right IFG at latencies ranging from of −0.3 to 20 ms prior to a suprathreshold test stimulus applied to the left M1. A repeated measure ANOVA on the normalized MEPs showed a significant main effect of the inter-stimulus interval (ISI) between the conditioning and test stimuli (p = 0.02) and a marginal Group (patients vs. controls) effect (p = 0.065). In controls, we found two reverberant inhibitory peaks at an ISI of 8 ms. In patients, the IFG-M1 inhibition only peaked at 8 ms with significant reduced cortico-cortical inhibition. Stepwise regression analysis revealed that the compulsion sub-score of the YBOCS predicted deficient IFG-M1 inhibition in OCD patients. Our finding that reduced resting-state IFG-M1 inhibition is positively associated with obsession severity points to a significant role of abnormal cortico-cortical premotor-to-motor connectivity in the pathophysiology of OCD.

Transcranial Magnetic Stimulation (TMS) established itself as a powerful technique for probing and treating the human brain. Major technological evolutions, such as neuronavigation and robotized systems, have continuously increased the spatial reliability and reproducibility of TMS, by minimizing the influence of human and experimental factors. However, there is still a lack of efficient set-up procedure, which prevents the automation of TMS protocols. For example, the set-up procedure for defining the stimulation intensity specific to each subject is classically done manually by experienced practitioners, by assessing the motor cortical excitability level over the motor hotspot (HS) of a targeted muscle. This is time-consuming and introduces experimental variability. Therefore, we developed a probabilistic Bayesian model (AutoHS) that automatically identifies the HS position. Using virtual and real experiments, we compared the efficacy of the manual and automated procedures. AutoHS appeared to be more reproducible, faster, and at least as reliable as classical manual procedures. By combining AutoHS with robotized TMS and automated motor threshold estimation methods, our approach constitutes the first fully automated set-up procedure for TMS protocols. The use of this procedure decreases inter-experimenter variability while facilitating the handling of TMS protocols used for research and clinical routine.

Electrical impedance tomography under spectral constraints uses a material basis decomposition to combine the different information embedded in the tissue spectra. This approach offers an alternative to static imaging while benefiting from systemic error cancellation using difference data. It suits well cases where no prior solution is known and the contrast lies entirely between frequencies, e.g. to diagnose acute stroke or cancer. In this work, a computational framework is presented to deal with the extra frequency dimensions and the constraints during reconstruction. A fraction volume approach is demonstrated with explicit Euclidean gradient, usage of a finite volume element solver and minimization over the oblique manifold. It is applied to synthetic data. Parameter estimations are compared between a mono-frequency inversion and the proposed multispectral implementation. Results suggest that the proposed workflow enables to reduce the computational workload of multispectral inversion while ensuring valid proportions of materials within each control volume.

Synchrotron-generated X-ray (SRX) microbeams deposit high radiation doses to submillimetric targets whilst minimizing irradiation of neighboring healthy tissue. We developed a new radiosurgical method which demonstrably transects cortical brain tissue without affecting adjacent regions. We made such image-guided SRX microtransections in the left somatosensory cortex in a rat model of generalized epilepsy using high radiation doses (820 Gy) in thin (200 μm) parallel slices of tissue. This procedure, targeting the brain volume from which seizures arose, altered the abnormal neuronal activities for at least 9 weeks, as evidenced by a decrease of seizure power and coherence between tissue slices in comparison to the contralateral cortex. The brain tissue located between transections stayed histologically normal, while the irradiated micro-slices remained devoid of myelin and neurons two months after irradiation. This pre-clinical proof of concept highlights the translational potential of non-invasive SRX transections for treating epilepsies that are not eligible for resective surgery.

High-frequency deep brain stimulation of the subthalamic nucleus can be used to treat severe obsessive-compulsive disorders that are refractory to conventional treatments. The mechanisms of action of this approach possibly rely on the modulation of associative-limbic subcortical–cortical loops, but remain to be fully elucidated. Here in 12 patients, we report the effects of high-frequency stimulation of the subthalamic nucleus on behavior, and on electroencephalographic responses and inferred effective connectivity during motor inhibition processes involved in the stop signal task. First, we found that patients were faster to respond and had slower motor inhibition processes when stimulated. Second, the subthalamic stimulation modulated the amplitude and delayed inhibition-related electroencephalographic responses. The power of reconstructed cortical current densities decreased in the stimulation condition in a parietal–frontal network including cortical regions of the inhibition network such as the superior parts of the inferior frontal gyri and the dorsolateral prefrontal cortex. Finally, dynamic causal modeling revealed that the subthalamic stimulation was more likely to modulate efferent connections from the basal ganglia, modeled as a hidden source, to the cortex. The connection from the basal ganglia to the right inferior frontal gyrus was significantly decreased by subthalamic stimulation. Beyond motor inhibition, our study thus strongly suggests that the mechanisms of action of high-frequency subthalamic stimulation are not restricted to the subthalamic nucleus, but also involve the modulation of distributed subcortical–cortical networks.

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.

IntroductionL’accumulation de preuves avant une prise de décision, et la capacité d’attendre avant d’agir, respectivement nommées « impulsivité décisionnelle » et « impulsivité différée », sont des formes du contrôle du comportement, dysfonctionnel dans le trouble obsessionnel compulsif (TOC). Ce travail a exploré les effets de la stimulation cérébrale profonde (SCP) du noyau sous thalamique (NST) chez ces patients et sur ces deux types d’impulsivité.Matériel et méthodesDouze patients souffrant d’un TOC traités par SCP du NST ont été inclus dans une étude randomisée en double aveugle utilisant un design croisé au cours de laquelle chacun a réalisé une évaluation comportementale en condition de stimulation ON et OFF. Leurs performances ont été comparées à celles d’un groupe de 24 sujets témoins sains appariés (âge, sexe). « L’impulsivité différée » était évaluée par la tâche de « temps de réaction en série à quatre choix », requérant une réponse motrice après avoir détecté un stimulus cible, et « l’impulsivité décisionnelle » via le « test des perles » impliquant une décision après un cumul variable d’informations laissé à l’appréciation du sujet.RésultatsLa tâche de « temps de réaction en série à quatre choix » a montré que les sujets sains avaient un nombre moindre de réponses prématurées que les patients en condition ON (p = 0,007), différence non retrouvée en condition OFF (p = 0,073), suggérant une augmentation de « l’impulsivité différée » en ON. Le test des perles a montré que les patients en condition OFF accumulaient davantage de preuves que les sujets sains avant une prise de décision (p = 0,021), et que cette différence disparaissait en condition ON (p = 0,017), témoignant d’une augmentation de « l’impulsivité décisionnelle » en ON.ConclusionL’augmentation retrouvée de ces deux types d’impulsivité pourrait être impliquée dans l’effet thérapeutique de la SCP du NST.

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.