Therapeutic Electrical Stimulation Research Articles

Bi-layered hydrogel conduit integrating microneedles for enhanced neural recording and stimulation therapy in peripheral nerve injury repair

Nerve conduit is an alternative strategy in peripheral nerve injuries (PNI) treatment both for neural signals recording and therapeutic electrical stimulation (ES). Most conventional conduits suffer from surgical suturing and lacking real-time insights of nerve recovery, as well as failing in integrating therapy strategies. Herein, we introduce a bi-layered hydrogel conduit with microneedles (BHCM), in which poly (N-isopropylacrylamide) (PNIPAm)-incorporated polyethyleneimine (PEI) forms the outer layer for conductivity and electro-driven drug loading and release, whereas PNIPAm/alginate/tannic acid hydrogel (PNIPAm/SA/TA) forms the inner layer to ensure biocompatible mechanics and strong tissue adhesion. Meanwhile, the differences in doping manipulated different critical solution temperature (LCST) and swelling between the double layers determine the self-curling performance. Therefore, the BHCM responds to temperature and self-curls into conduit to wrap and bind to sciatic nerve, avoiding the complicated suturing and enhancing the interfacial electrical transmission. By puncturing the epineurium, the microneedles strongly enhance the electrochemical performance, and synergistically facilitate controllable drug delivery as well as electrical stimulation and recording efficiency. Further, BHCM is demonstrated to regulate macrophage polarization from M1 to M2 through electrically stimulated Rhein release, thereby reducing inflammation and facilitating diabetic PNI repair. The present design aims to improve biosafety, surgical simplicity to realize overall recovery of injured nerves, making it a promising candidate for advanced peripheral nerve repair strategies.

Electroceuticals for Regeneration of Long Nerve Gap Using Biodegradable Conductive Conduits and Implantable Wireless Stimulator.

Regeneration of over 10mm long peripheral nerve defects remains a challenge due to the failure of regeneration by prolonged axotomy and denervation occurring in long-term recovery. Recent studies reveal that conductive conduits and electrical stimulation accelerate the regeneration of long nerve defects. In this study, an electroceutical platform combining a fully biodegradable conductive nerve conduit and a wireless electrical stimulator is proposed to maximize the therapeutic effect on nerve regeneration. Fully biodegradable nerve conduit fabricated using molybdenum (Mo) microparticles and polycaprolactone (PCL) can eliminate the unwanted effects of non-degradable implants, which occupy nerve paths and need to be removed through surgery increasing the risk of complications. The electrical and mechanical properties of Mo/PCL conduits are optimized by controlling the amounts of Mo and tetraglycol lubricant. The dissolution behavior and electrical conductivity of biodegradable nerve conduits in the biomimetic solutions are also evaluated. In in vivo experiments, the integrated strategy of a conductive Mo/PCL conduit with controlled therapeutic electrical stimulation shows accelerated axon regeneration for long sciatic nerve defects in rats compared to the use of the Mo/PCL conduit without stimulation and has a significant therapeutic effect based on the results obtained from the functional recovery test.

Piezoelectric effects on bone modeling for enhanced sustainability

Bone tissue possesses piezoelectric properties, allowing mechanical forces to be converted into electrical potentials. Piezoelectricity has been demonstrated to play a crucial role in bone remodelling and adaptability. Bone remodelling models that consider strain adaptation, both with and without piezoelectric effects, were simulated and validated in this study. This simulation help to better comprehend the interplay between mechanical and electrical stimulations during these processes. This study aimed to optimise the modelling of piezoelectric effects in bone modelling analysis. The connection between mechanical loads applied to bones and the resulting electrical charges generated by the piezoelectric effect was examined. Furthermore, mathematical modelling and simulation techniques were employed to enhance the piezoelectric effect and promote bone tissue growth and repair. The findings from this research have substantial implications for developing novel therapies for bone-related diseases and injuries. It was observed that electrically stimulated bone surfaces increased bone deposition. In some instances of physical disability or osteoporosis, therapeutic electrical stimulation can supplement the mechanical stresses of regular exercise to prevent bone loss. Consequently, the bone remodelling method on the software platform enables easy application and repetition of finite element analysis. This study significantly benefits bone tissue/biomedical engineering, particularly in bone remodelling, healing, and repair.

Electrical stimulation for therapeutic approach

AbstractElectrical stimulation as a therapeutic approach is widely applicable in terms of target tissues or target effects. This method can be an alternative to conventional therapies for patients who are resistant to drugs or are ineligible for surgical operations. In addition, as researchers have actively studied how to adjust the parameters for electrical stimulation in order to improve effectiveness, many patients have already received treatments with electrical stimulation. With respect to devices for electrical stimulation, recent studies are focused on developing reliability for safe and long‐term operations. From the point of view of engineers, a comprehensive understanding of how electrical stimulation modulates the biological system is essential to develop advanced strategies that provide effective therapeutic results. Herein, the fundamental mechanisms for delivering electrical stimulation on biological tissues are reviewed along with the requirements that need to be qualified by the electrodes. Furthermore, the latest advances in electrical stimulation devices are discussed followed by an introduction of representative applications of therapeutic electrical stimulation.

Comparison of Two Electrode Placement Methods in Transcranial Direct Current Stimulation for Parkinson's Disease

Purpose: Therapeutic electrical stimulation of deep brain structures, such as the subthalamic nucleus and the Globus Pallidus (GP), is widely accepted as a treatment tool for patients with Parkinson's Disease (PD). Electrical stimulation of the cerebral cortex with electrodes or transcranial stimulation can increase motor function among PD patients. The present study aimed to evaluate the effects of non-invasive cortical stimulation with simulation of transcranial Direct Current Stimulation (tDCS) technique on parts of the basal ganglia among PD patients.
 Materials and Methods: tDCS was simulated using two different electrode placement methods (anodal stimulation of the primary motor cortex (M1) and anodal stimulation of the Dorsolateral Prefrontal Cortex (DLPFC)) and We evaluated the excitation procedure in the target area based on the excitation current distribution in GP and Subthalamic Nucleus according to the patient's condition in both electrode methods. All simulations were performed using head Magnetic Resonance Imaging (MRI) images of four people with PD. Also, according to the excitation current distribution obtained from the previous step, we studied how the excitation current distributed in the target areas is affected by using a model of the basal ganglia so that based on the membrane potential of each excitation in these areas, in all four patients, we compare both electrode-installation methods in a functional way. The effectiveness of brain stimulation was also studied using a basal ganglia model. Considering the membrane potential of GP and Subthalamic Nucleus regions, the effectiveness of each electrode placement method was evaluated in the Basal Ganglia (BG) model.
 Results: According to the results, direct current stimulation was propagated through electrodes placed on the scalp throughout the model. Also, anodal stimulation of the M1 had a better stimulation of GP and subthalamic nucleus than anodal stimulation of the DLPFC.
 Conclusion: Although, the procedures for performing tDCS and invasive brain stimulation in PD are different, the results show that this treatment can be appropriate and improve motor function in patients with PD.

Electroactive Spinal Instrumentation for Targeted Osteogenesis and Spine Fusion: A Computational Study.

Direct current electrical stimulation may serve as a promising nonpharmacological adjunct promoting osteogenesis and fusion. The aim of this study was to evaluate the utility of electroactive spine instrumentation in the focal delivery of therapeutic electrical stimulation to enhance lumbar bone formation and interbody fusion. A finite element model of adult human lumbar spine (L4-L5) instrumented with single-level electroactive pedicle screws was simulated. Direct current electrical stimulation was routed through anodized electroactive pedicle screws to target regions of fusion. The electrical fields generated by electroactive pedicle screws were evaluated in various tissue compartments including isotropic tissue volumes, cortical, and trabecular bone. Electrical field distributions at various stimulation amplitudes (20-100 µA) and pedicle screw anodization patterns were analyzed in target regions of fusion (eg, intervertebral disc space, vertebral body, and pedicles). Electrical stimulation with electroactive pedicle screws at various stimulation amplitudes and anodization patterns enabled modulation of spatial distribution and intensity of electric fields within the target regions of lumbar spine. Anodized screws (50%) vs unanodized screws (0%) induced high-amplitude electric fields within the intervertebral disc space and vertebral body but negligible electric fields in spinal canal. Direct current electrical stimulation via anodized screws induced electrical fields, at therapeutic threshold of >1 mV/cm, sufficient for osteoinduction within the target interbody region. Selective anodization of electroactive pedicle screws may enable focal delivery of therapeutic electrical stimulation in the target regions in human lumbar spine. This study warrants preclinical and clinical testing of integrated electroactive system in inducing target lumbar fusion in vivo. The findings of this study provide a foundation for clinically investigating electroactive intrumentation to enhance spine fusion.

Multiple Sessions of Therapeutic Electrical Stimulation Using Implantable Thin-Film Wireless Nerve Stimulators Improve Functional Recovery after Sciatic Nerve Isograft Repair.

Although therapeutic electrical stimulation (TES) of injured peripheral nerve promotes axon regeneration and functional recovery, clinical applications of this therapy are limited to the intraoperative timeframe. Implantable, thin-film wireless nerve stimulators offer a potential solution to this problem by enabling delivery of electrical stimuli to an injured nerve over a period of several days post-surgery. The aim of this study was to determine the optimal time course of stimulation for maximizing functional recovery in a rat sciatic nerve isograft repair model. Adult male Lewis rats underwent thin-film wireless nerve stimulator implantation following sciatic nerve transection and 40 mm nerve isograft repair. Immediately after surgery, animals began a daily regimen of TES for up to 12 consecutive days. Functional recovery was assessed by compound muscle action potential (CMAP), evoked muscle force, wet muscle mass, and axon counting. Serial CMAP measurements increased in amplitude over the course of the study, yet no significant difference between cohorts for serial or terminal CMAPs was observed. Axon counts and wet muscle mass measurements were greatest in the 6-day stimulation group, which correlated with a significant increase in evoked muscle force for the 6-day stimulation group at the terminal time point. 6 daily sessions of TES were found to be most effective for augmenting functional recovery compared to other time courses of stimulation. Future studies should incorporate additional subjects and track axonal sprouting or measure neurotrophin levels during the therapeutic window to further elucidate the mechanisms behind, and ideal amount of, TES. This article is protected by copyright. All rights reserved.

Dorsal root ganglion stimulation produces differential effects on action potential propagation across a population of biophysically distinct C-neurons.

Dorsal root ganglion stimulation (DRGS) is a neurostimulation therapy used to manage chronic pain that does not respond to conventional therapies. Unfortunately, not all patients receive sufficient pain relief from DRGS, leaving them with few other treatment options. Presently, our understanding of the mechanisms of action of DRGS is incomplete, preventing us from determining why some patients do not receive analgesia from the therapy. One hypothesis suggests that DRGS augments the filtering of action potentials (APs) at the T-junction of nociceptive C-neurons. To test this hypothesis, we utilized a computational modeling approach in which we developed a population of one thousand biophysically distinct C-neuron models which each produced electrophysiological characteristics (e.g., AP height, AP duration) reported in previous experimental studies. We used this population of model C-neurons to study how morphological and electrophysiological characteristics affected the propagation of APs through the T-junction. We found that trains of APs can propagate through the T-junction in the orthodromic direction at a higher frequency than in the antidromic direction due to the decrease in axonal diameter from the peripheral to spinal axon. Including slow outward conductances in the axonal compartments near the T-junction reduced following frequencies to ranges measured experimentally. We next used the population of C-neuron models to investigate how DRGS affected the orthodromic propagation of APs through the T-junction. Our data suggest that suprathreshold DRGS augmented the filtering of APs at the T-junction of some model C-neurons while increasing the activity of other model C-neurons. However, the stimulus pulse amplitudes required to induce activity in C-neurons (i.e., several mA) fell outside the range of stimulation pulse amplitudes used clinically (i.e., typically ≤1 mA). Furthermore, our data suggest that somatic GABA currents activated directly or indirectly by the DRGS pulse may produce diverse effects on orthodromic AP propagation in C-neurons. These data suggest DRGS may produce differential effects across a population of C-neurons and indicate that understanding how inherent biological variability affects a neuron's response to therapeutic electrical stimulation may be helpful in understanding its mechanisms of action.

In situ diagnosis and simultaneous treatment of cardiac diseases using a single-device platform

The in situ diagnosis of cardiac activities with simultaneous therapeutic electrical stimulation of the heart is key to preventing cardiac arrhythmia. Here, we present an unconventional single-device platform that enables in situ monitoring even in a wet condition and control of beating heart motions without interferences to the recording signal. This platform consists of the active-matrix array of pressure-sensitive transistors for detecting cardiac beatings, biocompatible, low-impedance electrodes for cardiac stimulations, and an alginate-based hydrogel adhesive for attaching this platform conformally to the epicardium. In contrast to conventional electrophysiological sensing using electrodes, the pressure-sensitive transistors measured mechanophysiological characteristics by monitoring the spatiotemporal distributions of cardiac pressures during heart beating motions. In vivo tests show mechanophysiological readings having good correlation with electrocardiography and negligible interference with the electrical artifacts caused during cardiac stimulations. This platform can therapeutically synchronize the rhythm of abnormal heartbeats through efficient pacing of cardiac arrhythmia.

Lidocaine Nerve Block Diminishes the Effects of Therapeutic Electrical Stimulation to Enhance Nerve Regeneration in Rats.

Although electrical stimulation (ES) can improve nerve regeneration, the impact of nerve block, such as lidocaine (Lido), on the therapeutic benefits of ES remains unclear. We used a rat tibial nerve transection-and-repair model to explore how either preoperative (PreOp) or postoperative (PostOp) nerve block affects ES-related improvement in regeneration. Lewis rats were used in 1 of 2 studies. The first evaluated the effects of extraneural Lido on both healthy and injured nerves. In the second study, rats were randomized to 5 experimental groups: No ES (negative control), PreOp Lido, ES + PreOp Lido, PostOp + ES, and ES (positive control). All groups underwent tibial nerve transection and repair. In both studies, nerves were harvested for histological analysis of regeneration distal to the injury site. Application of extraneural Lido did not damage healthy or injured nerve based on qualitative histological observations. In the context of nerve transection and repair, the ES group exhibited improved axon regeneration at 21 days measured by the total number of myelinated fibers compared with No ES. Fiber density and percentage of neural tissue in the ES group were greater than those in both No ES and PreOp Lido + ES groups. ES + PostOp Lido was not different from No ES or ES group. Extraneural application of Lido did not damage nerves. Electrical stimulation augmented nerve regeneration, but Lido diminished the ES-related improvement in nerve regeneration. Clinical studies on the effects of ES to nerve regeneration may need to consider nerve block as a variable affecting ES outcome.

Distributed brain co-processor for tracking spikes, seizures and behaviour during electrical brain stimulation.

Early implantable epilepsy therapy devices provided open-loop electrical stimulation without brain sensing, computing, or an interface for synchronized behavioural inputs from patients. Recent epilepsy stimulation devices provide brain sensing but have not yet developed analytics for accurately tracking and quantifying behaviour and seizures. Here we describe a distributed brain co-processor providing an intuitive bi-directional interface between patient, implanted neural stimulation and sensing device, and local and distributed computing resources. Automated analysis of continuous streaming electrophysiology is synchronized with patient reports using a handheld device and integrated with distributed cloud computing resources for quantifying seizures, interictal epileptiform spikes and patient symptoms during therapeutic electrical brain stimulation. The classification algorithms for interictal epileptiform spikes and seizures were developed and parameterized using long-term ambulatory data from nine humans and eight canines with epilepsy, and then implemented prospectively in out-of-sample testing in two pet canines and four humans with drug-resistant epilepsy living in their natural environments. Accurate seizure diaries are needed as the primary clinical outcome measure of epilepsy therapy and to guide brain-stimulation optimization. The brain co-processor system described here enables tracking interictal epileptiform spikes, seizures and correlation with patient behavioural reports. In the future, correlation of spikes and seizures with behaviour will allow more detailed investigation of the clinical impact of spikes and seizures on patients.

Contact Separation Triboelectric Nanogenerator Based Neural Interfacing for Effective Sciatic Nerve Restoration

AbstractPeripheral nerve injuries represent one of the most common causes of permanent disabilities. Therapeutic electrical stimulation has been widely used in neural regeneration for decades. Combined with the implantation of a nerve cuff, several outcomes have proven effectiveness and feasibility in neuroprosthetic applications. However, the current electrical stimulation strategy fails to complete nerve repair. There is a lack of research on long‐term implantable nanogenerators in the neurostimulation scenario. Especially considering many disease models, those devices may not reach the in vitro simulative working setting. Thus, an implanted sciatic nerve stimulation system that spontaneously generates biphasic electric pulses in response to rats’ movement is developed. The electric signals generated by this device could stimulate injured sciatic nerve by cuff electrode. This work introduces an implantable self‐regulated neural electrical stimulation system generated by a contact separation triboelectric nanogenerator with a nerve cuff electrode and compares it with chronic therapeutic electrical stimulation for sciatic nerve restoration effect. Neural function restoration is observed in gait and histological analysis. Moreover, the upregulation of growth associated protein 43 can be a protentional target. This could have potential clinical application in facilitating closed‐loop energy harvesting for long‐term electrical stimulation.

On the Design of an Efficient Inductive Wireless Power Transfer for Passive Neurostimulation Systems.

In this paper, a minimally invasive wireless powered electronic lens (e-lens) with passive electrodes is presented for an ocular electrical stimulation. Previous research has focused on the differentiation property of the induction phenomenon and half wave rectifiers. However, these approaches are generally application specific, non efficient, suitable for low current, and deliver monophasic current stimulation. Existing rectifier-based techniques can lead to safety concerns as the offset voltage could change unpredictably. A new wireless power transfer circuit is presented for the design of an efficient system to wirelessly deliver charge-balanced biphasic waveforms through passive electrodes for transcorneal electrical stimulation. The absence of active components allows the development of a flexible e-lens system for therapeutic electrical stimulation of the eye.

Implantation and Control of Wireless, Battery-free Systems for Peripheral Nerve Interfacing

Peripheral nerve interfaces are frequently used in experimental neuroscience and regenerative medicine for a wide variety of applications. Such interfaces can be sensors, actuators, or both. Traditional methods of peripheral nerve interfacing must either tether to an external system or rely on battery power that limits the time frame for operation. With recent developments of wireless, battery-free, and fully implantable peripheral nerve interfaces, a new class of devices can offer capabilities that match or exceed those of their wired or battery-powered precursors. This paper describes methods to (i) surgically implant and (ii) wirelessly power and control this system in adult rats. The sciatic and phrenic nerve models were selected as examples to highlight the versatility of this approach. The paper shows how the peripheral nerve interface can evoke compound muscle action potentials (CMAPs), deliver a therapeutic electrical stimulation protocol, and incorporate a conduit for the repair of peripheral nerve injury. Such devices offer expanded treatment options for single-dose or repeated dose therapeutic stimulation and can be adapted to a variety of nerve locations.

Implantation and Control of Wireless, Battery-free Systems for Peripheral Nerve Interfacing.

Peripheral nerve interfaces are frequently used in experimental neuroscience and regenerative medicine for a wide variety of applications. Such interfaces can be sensors, actuators, or both. Traditional methods of peripheral nerve interfacing must either tether to an external system or rely on battery power that limits the time frame for operation. With recent developments of wireless, battery-free, and fully implantable peripheral nerve interfaces, a new class of devices can offer capabilities that match or exceed those of their wired or battery-powered precursors. This paper describes methods to (i) surgically implant and (ii) wirelessly power and control this system in adult rats. The sciatic and phrenic nerve models were selected as examples to highlight the versatility of this approach. The paper shows how the peripheral nerve interface can evoke compound muscle action potentials (CMAPs), deliver a therapeutic electrical stimulation protocol, and incorporate a conduit for the repair of peripheral nerve injury. Such devices offer expanded treatment options for single-dose or repeated dose therapeutic stimulation and can be adapted to a variety of nerve locations.

Designing a trial of early electrical stimulation to the stroke-affected arm: Qualitative findings on the barriers and facilitators

Introduction: This study aimed to explore the barriers and facilitators to implementing early therapeutic electrical stimulation (ES) treatment from both the patient and therapist perspectives as part of a feasibility study.MethodsDesign: Interviews were conducted with patients and their carers and focus groups with the therapists post-intervention period. Setting: Interviews were in the patient’s homes and for the focus groups in a specialist stroke unit in Nottinghamshire. Subjects: Fifteen patient participants (34% of sample) were interviewed (intervention n = 9; control group n = 3; carers n = 3). Sixteen therapists (9 occupational therapists; 7 physiotherapists) took part in the three focus groups. Intervention: Participants were randomized to receive usual care or usual care and ES to wrist flexors and extensors for 30 min, twice a day, 5 days a week for 3 months. Findings: The barriers to ES treatment cited by the therapists outweighed the barriers mentioned by patients. Therapists’ barriers included lack of confidence and staff knowledge regarding ES and time pressures of delivering the ES. No patients mentioned time as a barrier and considered the treatment regime to be acceptable; however, lack of staff support was mentioned 14 times by them. Conclusion: Although initially the perceived barrier for therapists was time restrictions, after analysing the data, it appears that confidence/knowledge is the real barrier, and time is the manifestation of this underlying self-doubt. Patients were able to confidently self-manage treatment, and although efficacy was not measured, patients volunteered information regarding its perceived benefit, and no adverse effects were reported.

Computational Analysis of Bone Remodeling in the Proximal Tibia Under Electrical Stimulation Considering the Piezoelectric Properties.

The piezoelectricity of bone is known to play a crucial role in bone adaptation and remodeling. The application of an external stimulus such as mechanical strain or electric field has the potential to enhance bone formation and implant osseointegration. Therefore, in the present study, the objective is to investigate bone remodeling under electromechanical stimulation as a step towards establishing therapeutic strategies. For the first time, piezoelectric bone remodeling in the human proximal tibia under electro-mechanical loads was analyzed using the finite element method in an open-source framework. The predicted bone density distributions were qualitatively and quantitatively assessed by comparing with the computed tomography (CT) scan and the bone mineral density (BMD) calculated from the CT, respectively. The effect of model parameters such as uniform initial bone density and reference stimulus on the final density distribution was investigated. Results of the parametric study showed that for different values of initial bone density the model predicted similar but not identical final density distribution. It was also shown that higher reference stimulus value yielded lower average bone density at the final time. The present study demonstrates an increase in bone density as a result of electrical stimulation. Thus, to minimize bone loss, for example, due to physical impairment or osteoporosis, mechanical loads during daily physical activities could be partially replaced by therapeutic electrical stimulation.

Implantable vagus nerve stimulator settings and short-term adverse effects in epileptic dogs.

BackgroundImplantable vagus nerve stimulation (VNS) devices can be used to treat epilepsy in dogs. Adverse effects and short‐term complications associated with delivering suggested therapeutic electrical stimulation (>1.5 mA) are not well‐described.ObjectivesTo compare complications and adverse effects observed with standard and rapid protocols of current increase.AnimalsSixteen client‐owned dogs with idiopathic epilepsy.MethodsNonrandomized, nonblinded prospective cohort study. Surgical complications, stimulation‐related adverse effects, modifications to stimulator settings, number of hospital visits, and time to reach 1.5 mA stimulation current without intolerable adverse effects were described in dogs receiving current increases every 1 to 3 weeks (slow ramping) and dogs receiving current increases every 8 to 12 hours (fast ramping).ResultsSelf‐resolving surgery site seromas formed in 6 dogs. No other surgical complications were observed. Fourteen dogs reached 1.5 mA. Coughing (11/14 dogs; 5 slow, 6 fast ramping) was the most common adverse effect. Intolerable coughing that limited current increases despite changing other stimulus parameters occurred in 6/7 of the fast‐ramping group and in none of the slow‐ramping group. Median time to 1.5 mA was 72 days (range, 28‐98) in the slow‐ramping group and 77 days (range, 3‐152) in the fast‐ramping group. Median number of clinic visits was 6 for the slow‐ramping group (range, 5‐6) and 3 for the fast‐ramping group (range, 1‐7).Conclusions and Clinical ImportanceCoughing is a common adverse effect of VNS in dogs and generally is well tolerated, particularly if current is increased slowly and other stimulation parameters are adapted for effect.

The potential of closed-loop endovascular neurostimulation as a viable therapeutic approach for drug-resistant epilepsy: A critical review.

Over the last few decades, biomedical implants have successfully delivered therapeutic electrical stimulation to reduce the frequency and severity of seizures in people with drug-resistant epilepsy. However, neurostimulation approaches require invasive surgery to implant stimulating electrodes, and surgical, medical, and hardware complications are not uncommon. An endovascular approach provides a potentially safer and less invasive surgical alternative. This article critically evaluates the feasibility of endovascular closed-loop neuromodulation for the treatment of epilepsy. By reviewing literature that reported the impact of direct electrical stimulation to reduce the frequency of epileptic seizures, we identified clinically validated extracranial, cortical, and deep cortical neural targets. We identified veins in close proximity to these targets and evaluated the potential of delivering an endovascular implant to these veins based on their diameter. We then compared the risks and benefits of existing technology to describe a benchmark of clinical safety and efficacy that would need to be achieved for endovascular neuromodulation to provide therapeutic benefit. For the majority of brain regions that have been clinically demonstrated to reduce seizure occurrence in response to delivered electrical stimulation, vessels of appropriate diameter for delivery of an endovascular electrode to these regions could be achieved. This includes delivery to the vagus nerve via the 13.2±0.9mm diameter internal jugular vein, the motor cortex via the 6.5±1.7mm diameter superior sagittal sinus, and the cerebellum via the 7.7±1.4mm diameter sigmoid sinus or 6.2±1.4mm diameter transverse sinus. Deep cerebral targets can also be accessed with an endovascular approach, with the 1.9±0.5mm diameter internal cerebral vein and 1.2-mm-diameter thalamostriate vein lying in close proximity to the anterior and centromedian nuclei of the thalamus, respectively. This work identified numerous veins that are in close proximity to conventional stimulation targets that are of a diameter large enough for delivery and deployment of an endovascular electrode array, supporting future work to assess clinical efficacy and chronic safety of an endovascular approach to deliver therapeutic neurostimulation.

Electrochemical safety limits for clinical stimulation investigated using depth and strip electrodes in the pig brain

Objective. Diagnostic and therapeutic electrical stimulation are increasingly utilized with the rise of neuromodulation devices. However, systematic investigations that depict the practical clinical stimulation paradigms (bipolar, two-electrode configuration) to determine the safety limits are currently lacking. Further, safe charge densities that were classically determined from conical sharp electrodes are generalized for cylindrical (depth) and flat (surface grid) electrodes completely ignoring geometric factors that govern current spreading and trajectories in tissue. Approach. This work reports the first investigations comparing stimulation limits for clinically used electrodes in two mediums: in benchtop experiments in saline and in vivo in a single acute experiment in the pig brain. We experimentally determine the geometric factors, the water electrolysis windows, and the current safety limits from voltage transients, for the sEEG, depth and surface strip electrodes in both mediums. Using four-electrode and three-electrode configuration measurements and comprehensive circuit models that accurately depict our measurements, we delineate the various elements of the stimulation medium, including the tissue-electrode interface impedance spectra, the medium impedance and the bias-dependent change in the interface impedance as a function of stimulation parameters. Main results. The results of our systematics studies suggest that safe currents in clinical bipolar stimulation determined in vivo can be as much as 24 times smaller than those determined from benchtop experiments (for depth electrodes at a 1 ms pulse duration). Our detailed circuit modeling attributes this drastic difference in safe limits to the greatly dissimilar electrode/tissue and electrode/saline impedances. Significance. We established the electrochemical safety limits for commonly used clinical electrodes in vivo and revealed by detailied electrochemical modeling how they differ from benchtop evaluation. We argue that electrochemical limits and currents are unique for each electrode, should be measured in vivo according to the protocols established in this work, and should be accounted for while setting the stimulation parameters for clinical applications including for chronic applications.