New stimulation device to drive multiple transverse intrafascicular electrodes and achieve highly selective and rich neural responses

Peripheral Nerve Stimulation (PNS) is a promising approach in functional restoration following neural impairments. Although it proves to be advantageous in the number of implantation sites provided compared with intramuscular or epimysial stimulation and the fact that it does not require daily placement, as is the case with surface electrodes, the further advancement of PNS paradigms is hampered by the limitation of spatial selectivity due to the current spread and variations of nerve physiology. New electrode designs such as the Transverse Intrafascicular Multichannel Electrode (TIME) were proposed to resolve this issue, but their use was limited by a lack of innovative multichannel stimulation devices. In this study, we introduce a new portable multichannel stimulator-called STIMEP-and implement different stimulation protocols in rats to test its versatility and unveil the potential of its combined use with TIME electrodes in rehabilitation protocols. We developed and tested various stimulation paradigms in a single fascicle and thereafter implanted two TIMEs. We also tested its stimulation using two different waveforms. The results highlighted the versatility of this new stimulation device and advocated for the parameterizing of a hyperpolarizing phase before depolarization as well as the use of small pulse widths when stimulating with multiple electrodes

Tumour compartment transcriptomics demonstrates the activation of inflammatory and odontogenic programmes in human adamantinomatous craniopharyngioma and identifies the MAPK/ERK pathway as a novel therapeutic target

Adamantinomatous craniopharyngiomas (ACPs) are clinically challenging tumours, the majority of which have activating mutations in CTNNB1. They are histologically complex, showing cystic and solid components, the latter comprised of different morphological cell types (e.g. β-catenin-accumulating cluster cells and palisading epithelium), surrounded by a florid glial reaction with immune cells. Here, we have carried out RNA sequencing on 18 ACP samples and integrated these data with an existing ACP transcriptomic dataset. No studies so far have examined the patterns of gene expression within the different cellular compartments of the tumour. To achieve this goal, we have combined laser capture microdissection with computational analyses to reveal groups of genes that are associated with either epithelial tumour cells (clusters and palisading epithelium), glial tissue or immune infiltrate. We use these human ACP molecular signatures and RNA-Seq data from two ACP mouse models to reveal that cell clusters are molecularly analogous to the enamel knot, a critical signalling centre controlling normal tooth morphogenesis. Supporting this finding, we show that human cluster cells express high levels of several members of the FGF, TGFB and BMP families of secreted factors, which signal to neighbouring cells as evidenced by immunostaining against the phosphorylated proteins pERK1/2, pSMAD3 and pSMAD1/5/9 in both human and mouse ACP. We reveal that inhibiting the MAPK/ERK pathway with trametinib, a clinically approved MEK inhibitor, results in reduced proliferation and increased apoptosis in explant cultures of human and mouse ACP. Finally, we analyse a prominent molecular signature in the glial reactive tissue to characterise the inflammatory microenvironment and uncover the activation of inflammasomes in human ACP. We validate these results by immunostaining against immune cell markers, cytokine ELISA and proteome analysis in both solid tumour and cystic fluid from ACP patients. Our data support a new molecular paradigm for understanding ACP tumorigenesis as an aberrant mimic of natural tooth development and opens new therapeutic opportunities by revealing the activation of the MAPK/ERK and inflammasome pathways in human ACP. KEYWORDS: Craniopharyngioma; IL1-β; Inflammasome; MAPK/ERK pathway; Odontogenesis; Paracrine signalling; Trametini

A high-performance 8 nV/root Hz 8-channel wearable and wireless system for real-time monitoring of bioelectrical signals

Background: It is widely accepted by the scientific community that bioelectrical signals, which can be used for the identification of neurophysiological biomarkers indicative of a diseased or pathological state, could direct patient treatment towards more effective therapeutic strategies. However, the design and realisation of an instrument that can precisely record weak bioelectrical signals in the presence of strong interference stemming from a noisy clinical environment is one of the most difficult challenges associated with the strategy of monitoring bioelectrical signals for diagnostic purposes. Moreover, since patients often have to cope with the problem of limited mobility being connected to bulky and mains-powered instruments, there is a growing demand for small-sized, high-performance and ambulatory biopotential acquisition systems in the Intensive Care Unit (ICU) and in High-dependency wards. Finally, to the best of our knowledge, there are no commercial, small, battery-powered, wearable and wireless recording-only instruments that claim the capability of recording electrocorticographic (ECoG) signals. Methods: To address this problem, we designed and developed a low-noise (8 nV/√Hz), eight-channel, battery-powered, wearable and wireless instrument (55 × 80 mm2). The performance of the realised instrument was assessed by conducting both ex vivo and in vivo experiments. Results: To provide ex vivo proof-of-function, a wide variety of high-quality bioelectrical signal recordings are reported, including electroencephalographic (EEG), electromyographic (EMG), electrocardiographic (ECG), acceleration signals, and muscle fasciculations. Low-noise in vivo recordings of weak local field potentials (LFPs), which were wirelessly acquired in real time using segmented deep brain stimulation (DBS) electrodes implanted in the thalamus of a non-human primate, are also presented. Conclusions: The combination of desirable features and capabilities of this instrument, namely its small size (~one business card), its enhanced recording capabilities, its increased processing capabilities, its manufacturability (since it was designed using discrete off-the-shelf components), the wide bandwidth it offers (0.5 – 500 Hz) and the plurality of bioelectrical signals it can precisely record, render it a versatile and reliable tool to be utilized in a wide range of applications and environments

Assessment of direct spinal cord stimulation strategies from the perspective of SCI patient's bladder and bowel functions rehabilitation

La blessure médullaire est un traumatisme aux conséquences désastreuses pour le patient. Au-delà de déficiences motrices immédiatement identifiables (paralysie des membres), l’interruption de la communication entre tissu nerveux sous-lésionnel et centres nerveux responsables de l’intégration et de la régulation des processus physiologiques, conduit souvent à un tableau clinique plus complexe. Parmi ces troubles insidieux, l’altération des fonctions urinaires et intestinales est d’une importance majeure. La régulation de ces fonctions étant sous la dépendance des segments les plus caudaux de la moelle épinière, toute altération du tissu spinal engendrera de manière quasi systématique un fonctionnement anarchique des organes conduisant à des dérèglements socialement handicapants (rétention ou/et incontinence urinaire et fécale). Bien que pour corriger cela, une stratégie basée sur la stimulation électrique fonctionnelle au niveau des racines sacrées, ait déjà été implémentée et commercialisée (Implant Brindley-Finetech), son recours ne demeure que trop marginal eu égard aux contreparties exigées (sections des racines afférentes de la moelle sacrée, avec perte de la sensibilité et des réflexes fonctionnels). Il n’est alors pas surprenant d’observer que les patients continuent à leur préférer des alternatives thérapeutiques (cathétérisme, toxine botulique…). L’objectif de cette thèse est d’évaluer les potentialités d’une stimulation directe de la moelle épinière dans la restauration des fonctions urinaires et intestinales chez le sujet lésé médullaire en proposant l’utilisation d’un nouveau modèle expérimental – le cochon domestique (40-60kg, 3-4 mois d’âge) – et une approche chirurgicale.Spinal cord injury results in the loss of movement and sensory sensations but also in the disruption of some organ functions. Nearly all spinal cord injured subjects lose bladder control and are prone to kidney failure if they do not apply intermittent (self-) catheterization. Electrical stimulation of the sacral spinal roots with an implantable neuroprosthesis is one option besides self-catheterization to become continent and control micturition. However, many persons do not ask for this neuroprosthetic device (Brindley-Finetech implant) since deafferentation and loss of sensory functions and reflexes are serious side effects and since alternative treatments are available to patients (drugs, botulinus toxin….). This PhD work aimed at investigating various techniques for spinal cord electrical stimulation in order to address dysfunctions in spinal cord injured individuals on lesion levels that have an impact on lower limb movements and bladder, bowel and sexual functions. Orderly recruitment of fibers at the spinal cord level should eventually lead to orderly recruitment of the detrusor muscle without activation of the bladder sphincter. Thereby, low pressure voiding, for example, should be obtained that is currently impossible with existing active implantable medical devices. A new large animal model – the domestic pig – was investigated to overcome size effects of rodent models and be able to translate results and technology more easily to human

Investigation of the efficiency of the shape of chopped pulses using earthworm model

International audienceIn neural electrical stimulation, limiting the charge delivered during a stimulus pulse is essential to avoid nerve tissue damage and to save power. Previous experimental and modeling studies indicated that waveforms such as non-rectangular continuous pulses or rectangular chopped pulse were able to improve stimulation efficiency. The goal of this study is to evaluate if non-rectangular chopped pulses such as quarter sine and ramp are more charge efficient than rectangular chopped pulse. We performed in vivo study on 17 lumbricus terrestris and compared the charge per stimulating phase needed to activate lateral giant fibers (LGF) and medial giant fiber (MGF) using chopped non-rectangular pulses and rectangular pulse, varying stimulation duration parameters. Results indicated that non rectangular chopped pulses activated MGF and LGF with less charge than rectangular chopped pulses. For MGF (respectively LGF), the gain of charge was up to 33.9\% (resp. 17.8\%) using chopped ramp, and up to 22.8\% (resp. 18.1\%) using chopped quarter sine

On biocompatibility and stability of transversal intrafascicular multichannel electrodes - TIME

International audienceTransversal intrafascicular multichannel electrodes (TIME) have been developed to interface with peripheral nerves after upper limb amputation. Intended use is the electrical stimulation of the median and ulnar nerve to deliver sensory feedback during phantom limb pain treatment and artificial hand control. Miniaturized electrode arrays were developed on polyimide substrates with thin film metallization using sputtered iridium oxide as electrode coating. Here, we report on the essential requirements including biocompatibility, mechanical and stimulation stability that have been investigated before permission was granted by the legal authorities to conduct subchronic first-in-man clinical trials. Explants have been investigated to identify possible first failure points and optimize the devices for chronic implantation

New Stimulation Device to Drive Multiple Transverse Intrafascicular Electrodes and Achieve Highly Selective and Rich Neural Responses

International audiencePeripheral Nerve Stimulation (PNS) is a promising approach in functional restoration following neural impairments. Although it proves to be advantageous in the number of implantation sites provided compared with intramuscular or epimysial stimulation and the fact that it does not require daily placement, as is the case with surface electrodes, the further advancement of PNS paradigms is hampered by the limitation of spatial selectivity due to the current spread and variations of nerve physiology. New electrode designs such as the Transverse Intrafascicular Multichannel Electrode (TIME) were proposed to resolve this issue, but their use was limited by a lack of innovative multichannel stimulation devices. In this study, we introduce a new portable multichannel stimulator-called STIMEP-and implement different stimulation protocols in rats to test its versatility and unveil the potential of its combined use with TIME electrodes in rehabilitation protocols. We developed and tested various stimulation paradigms in a single fascicle and thereafter implanted two TIMEs. We also tested its stimulation using two different waveforms. The results highlighted the versatility of this new stimulation device and advocated for the parameterizing of a hyperpolarizing phase before depolarization as well as the use of small pulse widths when stimulating with multiple electrodes

Functional selectivity of lumbosacral stimulation: Methodological approach and pilot study to assess visceral function in pigs

International audienceNearly all spinal cord injured (SCI) individuals lose bladder control and are prone to kidney complications if intermittent catheterization is not applied. Electrical stimulation (ES) of the sacral anterior roots with an implantable neuroprosthesis is one means to restore continence and control micturition. However, only a small percentage of the SCI population benefits from this solution because of its drawbacks, e.g. section of sacral posterior roots with loss of spared sensitivity. There has been renewed interest in spinal cord stimulation in recent years, but most studies have focused on locomotion and only few have reported the impact on visceral functions. Moreover, even though the lumbosacral spinal cord is the location of many pre-cabled neural networks (involved in locomotion, bladder, bowel management etc.), the functional selectivity of spinal stimulations has never been investigated in detail. Here we present: i) a methodology designed to study lumbosacral epispinal-intradural stimulation selectivity, ii) preliminary results assessing the impact of epispinal stimulation on bladder and bowel functions in two domestic pigs, and iii) a comparison of these visceral responses with abdominal and lower limb activities. Our experiments resulted in selective bladder and rectal responses, i.e. without hind paw responses, thus reaffirming the rehabilitation potential of spinal cord stimulation

Sacral Anterior Root Stimulation (SARS) and visceral function outcomes in spinal cord injury - a systematic review of literature over four decades

OBJECTIVES: The sacral anterior root stimulator (SARS) was developed 40 years ago to restore urinary and bowel functions to individuals with spinal cord injury (SCI). Mostly used to restore lower urinary tract function, SARS implantation is coupled with sacral deafferentation to counteract the problems of chronic detrusor sphincter dyssynergia and detrusor overactivity. In this article, we systematically review 40 years of SARS implantation and assess the medical added-value of this approach in accordance with the PRISMA guidelines (Preferred Reporting Items for Systematic reviews and Meta-Analyses). We identified four axes of investigation: i) impact on visceral functions, ii) implantation safety and device reliability, iii) individuals quality of life, and iv) additional information about the procedure. METHODS: Three databases were consulted: Pubmed, EBSCOhost and Pascal. 219 abstracts were screened and 38 publications were retained for analysis (1,147 implantations). RESULTS: The SARS technique showed good clinical results (85.9% of individuals used their implant for micturition and 67.9% to ease bowel movements) and improved individual quality of life. Conversely, several sources of complications were reported after implantation (surgical complications, failures etc.). CONCLUSIONS: Despite promising results, a decline in implantations was observed. This decline can be linked to the complication rate, as well as to the development of new therapeutics (botulinum toxin, etc.) and directions for research (spinal cord stimulation) that may have an impact on people. Nevertheless, the lack of alternatives in the short-term suggests that the SARS implant is still relevant for the restoration of visceral functions after SCI

An intermediate animal model of spinal cord stimulation

Spinal cord injuries (SCI) result in the loss of movement and sensory feedback as well as organs dysfunctions. For example, nearly all SCI subjects loose their bladder control and are prone to kidney failure if they do not proceed to intermittent (self-) catheterization. Electrical stimulation of the sacral spinal roots with an implantable neuroprosthesis is a promising approach, with commercialized products, to restore continence and control micturition. However, many persons do not ask for this intervention since a surgical deafferentation is needed and the loss of sensory functions and reflexes become serious side effects of this procedure. Recent results renewed interest in spinal cord stimulation. Stimulation of existing pre-cabled neural networks involved in physiological processes regulation is suspected to enable synergic recruitment of spinal fibers. The development of direct spinal stimulation strategies aiming at bladder and bowel functions restoration would therefore appear as a credible alternative to existent solutions. However, a lack of suitable large animal model complicates these kinds of studies. In this article, we propose a new animal model of spinal stimulation -pig- and will briefly introduce results from one first acute experimental validation session