Organic electrolytic photocapacitors for stimulation of the mouse somatosensory cortex

Objective. For decades electrical stimulation has been used in neuroscience to investigate brain networks and been deployed clinically as a mode of therapy. Classically, all methods of electrical stimulation require implanted electrodes to be connected in some manner to an apparatus which provides power for the stimulation itself. Approach. We show the use of novel organic electronic devices, specifically organic electrolytic photocapacitors (OEPCs), which can be activated when illuminated with deep-red wavelengths of light and correspondingly do not require connections with external wires or power supplies when implanted at various depths in vivo. Main results. We stimulated cortical brain tissue of mice with devices implanted subcutaneously, as well as beneath both the skin and skull to demonstrate a wireless stimulation of the whisker motor cortex. Devices induced both a behavior response (whisker movement) and a sensory response in the corresponding sensory cortex. Additionally, we showed that coating OEPCs with a thin layer of a conducting polymer formulation (PEDOT:PSS) significantly increases their charge storage capacity, and can be used to further optimize the applied photoelectrical stimulation. Significance. Overall, this new technology can provide an on-demand electrical stimulation by simply using an OEPC and a deep-red wavelength illumination. Wires and interconnects to provide power to implanted neurostimulation electrodes are often problematic in freely-moving animal research and with implanted electrodes for long-term therapy in patients. Our wireless brain stimulation opens new perspectives for wireless electrical stimulation for applications in fundamental neurostimulation and in chronic therapy

Behavioral, neural and ultrastructural alterations in a graded-dose 6-OHDA mouse model of early-stage Parkinson's disease

Studying animal models furthers our understanding of Parkinson’s disease (PD) pathophysiology by providing tools to investigate detailed molecular, cellular and circuit functions. Different versions of the neurotoxin-based 6-hydroxydopamine (6-OHDA) model of PD have been widely used in rats. However, these models typically assess the result of extensive and definitive dopaminergic lesions that reflect a late stage of PD, leading to a paucity of studies and a consequential gap of knowledge regarding initial stages, in which early interventions would be possible. Additionally, the better availability of genetic tools increasingly shifts the focus of research from rats to mice, but few mouse PD models are available yet. To address these, we characterize here the behavioral, neuronal and ultrastructural features of a graded-dose unilateral, single-injection, striatal 6-OHDA model in mice, focusing on early-stage changes within the first two weeks of lesion induction. We observed early onset, dose-dependent impairments of overall locomotion without substantial deterioration of motor coordination. In accordance, histological evaluation demonstrated a partial, dose-dependent loss of dopaminergic neurons of substantia nigra pars compacta (SNc). Furthermore, electron microscopic analysis revealed degenerative ultrastructural changes in SNc dopaminergic neurons. Our results show that mild ultrastructural and cellular degradation of dopaminergic neurons of the SNc can lead to certain motor deficits shortly after unilateral striatal lesions, suggesting that a unilateral dose-dependent intrastriatal 6-OHDA lesion protocol can serve as a successful model of the early stages of Parkinson’s disease in mice

On-invasive electrical stimulation using temporal interference for the central and peripheral nervous systems

Les interférences temporelles (TI) ont émergé comme nouvelle technique de stimulation non-invasive en 2017 avec les travaux de Grossman et son équipe. Cette technique promettait cependant de pouvoir remplacer des moyens de neuromodulation invasifs pour des cibles cérébrales profondes.Dans ce travail de thèse, la possibilité de stimuler un nerf périphérique, le nerf sciatique a été investigué. Pour ce faire, différents paramètres de stimulations avec des enveloppes allant de 0.5 à 5 Hz ont été appliqué de manières non-invasives sur la jambe de souris. Les mouvements de jambes et contractions musculaires provoquées correspondaient à la fréquence des enveloppes. Aussi, l'impact de l'orientation du champ électrique lors de la stimulation via TI a été étudié dans un modèle murin dit "kindling". Il a été démontré que l'orientation joue un rôle clé dans la stimulation via TI et qu'une orientation parallèle des champs électrique par apport au collatérales de Schaffer était plus efficace qu'une orientation perpendiculaire. Enfin, la focalité et l'évolutivité de la stimulation TI a été étudiée au travers de plusieurs modèles animaux et des cadavres grâce à une nouvelle technique de stimulation: les interférences temporelles multipolaires (mTI). Le principe de la technique repose sur l'ajout d’enveloppes supplémentaires ayant la même fréquence mais des fréquences porteuses différentes interagissant constructivement à la cible thérapeutique et destructivement ailleurs. Il a été démontré que le focalité de la mTI est supérieure à la TI ce qui ouvre la voie à l'utilisation de la mTI comme un outil de neuromodulation focal adapté dans un environnement clinique ou de recherche.Temporal interference (TI) emerged as a new non-invasive stimulation technique in 2017 with the work of Grossman and his team. However, this technique held the promise of being able to replace invasive neuromodulation means for deep brain targets.In this thesis, the possibility of stimulating a peripheral nerve, the sciatic nerve, was investigated. To do so, different stimulation parameters with envelopes ranging from 0.5 to 5 Hz were applied in a non-invasive way on the leg of mice. The leg movements and muscle contractions induced corresponded to the frequency of the envelopes. Also, the impact of the orientation of the electric field during TI stimulation was studied in a "kindling" mouse model. It was shown that orientation plays a key role in TI stimulation and that a parallel orientation of the electric fields with respect to Schaffer's collaterals was more effective than a perpendicular orientation. Finally, the focality and scalability of TI stimulation was studied in several animal models and cadavers using a new stimulation technique: multipolar temporal interference (mTI). The principle of the technique is based on the addition of additional envelopes with the same frequency but different carrier frequencies interacting constructively at the therapeutic target and destructively elsewhere. It has been demonstrated that the mTI focus is superior to the TI which opens the way to the use of mTI as a suitable focal neuromodulation tool in a clinical or research environment

Orientation of Temporal Interference for Non-invasive Deep Brain Stimulation in Epilepsy

In patients with focal drug-resistant epilepsy, electrical stimulation from intracranial electrodes is frequently used for the localization of seizure onset zones and related pathological networks. The ability of electrically stimulated tissue to generate beta and gamma range oscillations, called rapid-discharges, is a frequent indication of an epileptogenic zone. However, a limit of intracranial stimulation is the fixed physical location and number of implanted electrodes, leaving numerous clinically and functionally relevant brain regions unexplored. Here, we demonstrate an alternative technique relying exclusively on non-penetrating surface electrodes, namely an orientation-tunable form of temporally interfering (TI) electric fields to target the CA3 of the mouse hippocampus which focally evokes seizure-like events (SLEs) having the characteristic frequencies of rapid-discharges, but without the necessity of the implanted electrodes. The orientation of the topical electrodes with respect to the orientation of the hippocampus is demonstrated to strongly control the threshold for evoking SLEs. Additionally, we demonstrate the use of Pulse-width-modulation of square waves as an alternative to sine waves for TI stimulation. An orientation-dependent analysis of classic implanted electrodes to evoke SLEs in the hippocampus is subsequently utilized to support the results of the minimally invasive temporally interfering fields. The principles of orientation-tunable TI stimulation seen here can be generally applicable in a wide range of other excitable tissues and brain regions, overcoming several limitations of fixed electrodes which penetrate tissue and overcoming several limitations of other non-invasive stimulation methods in epilepsy, such as transcranial magnetic stimulation (TMS).Funding Agencies|European Research Council (ERC) under the European Unions Horizon 2020 Research and Innovation ProgramEuropean Research Council (ERC) [716867]; Excellence Initiative of Aix- Marseille University-AMIDEX, a French "Investissements dAvenir" programFrench National Research Agency (ANR); Knut and Alice Wallenberg FoundationKnut &amp; Alice Wallenberg Foundation</p

Laser‐Driven Wireless Deep Brain Stimulation using Temporal Interference and Organic Electrolytic Photocapacitors

International audienceDeep brain stimulation (DBS) is a technique commonly used both in clinical and fundamental neurosciences. Classically, brain stimulation requires an implanted and wired electrode system to deliver stimulation directly to the target area. Although techniques such as temporal interference (TI) can provide stimulation at depth without involving any implanted electrodes, these methods still rely on a wired apparatus which limits free movement. Herein organic photocapacitors as untethered light-driven electrodes which convert deep-red light into electric current are reported. Pairs of these ultrathin devices can be driven using lasers at two different frequencies to deliver stimulation at depth via temporally interfering fields. This concept of laser TI stimulation using numerical modeling, tests with phantom brain samples, and finally in vivo tests is validated. Wireless organic photocapacitors are placed on the cortex and elicit stimulation in the hippocampus, while not delivering off-target stimulation in the cortex. This laser-driven wireless TI evokes a neuronal response at depth that is comparable to control experiments induced with deep brain stimulation protocols using implanted electrodes. This work shows that a combination of these two techniques-temporal interference and organic electrolytic photocapacitors-provides a reliable way to target brain structures requiring neither deeply implanted electrodes nor tethered stimulator devices. The laser TI protocol demonstrated here addresses two of the most important drawbacks in the field of DBS and thus holds potential to solve many issues in freely moving animal experiments or for clinical chronic therapy application

Non-thermal Electroporation Ablation of Epileptogenic Zones Stops Seizures in Mice While Providing Reduced Vascular Damage and Accelerated Tissue Recovery

International audienceIn epilepsy, the most frequent surgical procedure is the resection of brain tissue in the temporal lobe, with seizure-free outcomes in approximately two-thirds of cases. However, consequences of surgery can vary strongly depending on the brain region targeted for removal, as surgical morbidity and collateral damage can lead to significant complications, particularly when bleeding and swelling are located near delicate functional cortical regions. Although focal thermal ablations are well-explored in epilepsy as a minimally invasive approach, hemorrhage and edema can be a consequence as the blood-brain barrier is still disrupted. Non-thermal irreversible electroporation (NTIRE), common in many other medical tissue ablations outside the brain, is a relatively unexplored method for the ablation of neural tissue, and has never been reported as a means for ablation of brain tissue in the context of epilepsy. Here, we present a detailed visualization of non-thermal ablation of neural tissue in mice and report that NTIRE successfully ablates epileptic foci in mice, resulting in seizure-freedom, while causing significantly less hemorrhage and edema compared to conventional thermal ablation. The NTIRE approach to ablation preserves the blood-brain barrier while pathological circuits in the same region are destroyed. Additionally, we see the reinnervation of fibers into ablated brain regions from neighboring areas as early as day 3 after ablation. Our evidence demonstrates that NTIRE could be utilized as a precise tool for the ablation of surgically challenging epileptogenic zones in patients where the risk of complications and hemorrhage is high, allowing not only reduced tissue damage but potentially accelerated recovery as vessels and extracellular matrix remain intact at the point of ablation

Focal non-invasive deep-brain stimulation with temporal interference for the suppression of epileptic biomarkers

International audienceIntroduction Neurostimulation applied from deep brain stimulation (DBS) electrodes is an effective therapeutic intervention in patients suffering from intractable drug-resistant epilepsy when resective surgery is contraindicated or failed. Inhibitory DBS to suppress seizures and associated epileptogenic biomarkers could be performed with high-frequency stimulation (HFS), typically between 100 and 165 Hz, to various deep-seated targets, such as the Mesio-temporal lobe (MTL), which leads to changes in brain rhythms, specifically in the hippocampus. The most prominent alterations concern high-frequency oscillations (HFOs), namely an increase in ripples, a reduction in pathological Fast Ripples (FRs), and a decrease in pathological interictal epileptiform discharges (IEDs). Materials and methods In the current study, we use Temporal Interference (TI) stimulation to provide a non-invasive DBS (130 Hz) of the MTL, specifically the hippocampus, in both mouse models of epilepsy, and scale the method using human cadavers to demonstrate the potential efficacy in human patients. Simulations for both mice and human heads were performed to calculate the best coordinates to reach the hippocampus. Results This non-invasive DBS increases physiological ripples, and decreases the number of FRs and IEDs in a mouse model of epilepsy. Similarly, we show the inability of 130 Hz transcranial current stimulation (TCS) to achieve similar results. We therefore further demonstrate the translatability to human subjects via measurements of the TI stimulation vs. TCS in human cadavers. Results show a better penetration of TI fields into the human hippocampus as compared with TCS. Significance These results constitute the first proof of the feasibility and efficiency of TI to stimulate at depth an area without impacting the surrounding tissue. The data tend to show the sufficiently focal character of the induced effects and suggest promising therapeutic applications in epilepsy

Noninvasive Stimulation of Peripheral Nerves using Temporally-Interfering Electrical Fields

Electrical stimulation of peripheral nerves is a cornerstone of bioelectronic medicine. Effective ways to accomplish peripheral nerve stimulation (PNS) noninvasively without surgically implanted devices are enabling for fundamental research and clinical translation. Here, it is demonstrated how relatively high-frequency sine-wave carriers (3 kHz) emitted by two pairs of cutaneous electrodes can temporally interfere at deep peripheral nerve targets. The effective stimulation frequency is equal to the offset frequency (0.5 - 4 Hz) between the two carriers. This principle of temporal interference nerve stimulation (TINS) in vivo using the murine sciatic nerve model is validated. Effective actuation is delivered at significantly lower current amplitudes than standard transcutaneous electrical stimulation. Further, how flexible and conformable on-skin multielectrode arrays can facilitate precise alignment of TINS onto a nerve is demonstrated. This method is simple, relying on the repurposing of existing clinically-approved hardware. TINS opens the possibility of precise noninvasive stimulation with depth and efficiency previously impossible with transcutaneous techniques.Funding Agencies|European Research Council (ERC) under the European Union [716867, 949191]; City Council of Brno, Czech Republic; European Research Council [834677]; Swedish Research Council; MedTechLabs</p