How far does electrical stimulation activate white matter tracts? A computational modeling study.

OBJECTIVE: The aim of this study was to model how the different parameters of electrical stimulation (intensity, pulse shape, probe geometry) influence the extent of white matter activation. METHODS: The electrical potentials generated by the stimulating electrodes were determined by solving Laplace equation. The temporal evolution of membrane potentials at each nodes of Ranvier of an axon was then computed by solving the coupled system of differential equations describing membrane dynamics and cable propagation. RESULTS: Regions of unilateral propagation were observed for monophasic pulses delivered with a bipolar probe aligned along the tract. For biphasic pulses, the largest activation areas and depths were found with a high inter-electrode-distance (IED) bipolar probe, oriented orthogonally to the tract. The smallest activation areas and depths were found for bipolar stimulations with the probe aligned parallel to the tract and low IED. For isotropic white matter regions, the activation area and depth were three times larger than for anisotropic white matter tracts. CONCLUSIONS: Bipolar probes with biphasic pulses offer the greatest versatility: an orthogonal orientation acts as two monopolars (increased sensitivity when searching for a tract), whereas a parallel orientation corresponds to a single monopolar (increased specificity). Activation is more superficial when stimulating highly anisotropic tracts. SIGNIFICANCE: This knowledge is essential for interpreting the behavorial effects of stimulation and the recordings of axono-cortical evoked potentials.

Short-range axono-cortical evoked-potentials in brain tumor surgery: Waveform characteristics as markers of direct connectivity.

OBJECTIVE: Intraoperative measurement of axono-cortical evoked potentials (ACEP) has emerged as a promising tool for studying neural connectivity. However, it is often difficult to determine if the activity recorded by cortical grids is generated by stimulated tracts or by spurious phenomena. This study aimed to identify criteria that would indicate a direct neurophysiological connection between a recording contact and a stimulated pathway. METHODS: Electrical stimulation was applied to white matter fascicles within the resection cavity, while the evoked response was recorded at the cortical level in seven patients. RESULTS: By analyzing the ACEP recordings, we identified a main epicenter characterized by a very early positive (or negative) evoked response occurring just after the stimulation artifact (<5 ms, |Amplitude| > 100 µV) followed by an early and large negative (or positive) monophasic evoked response (<40 ms; |Amplitude| > 300 µV). The neighboring activity had a different waveform and was attenuated compared to the hot-spot activity. CONCLUSIONS: It is possible to distinguish the hotspot with direct connectivity to the stimulated site from neighboring activity using the identified criteria. SIGNIFICANCE: The electrogenesis of the ACEP at the hotspot and neighboring activity is discussed.

Quantitative assessment of near-infrared spectroscopy time course under hypercapnia using an a priori model-based fitting.

BACKGROUND: Partial arterial pressure of carbon dioxide (CO2) modulates cerebral blood flow through a vasoreactivity mechanism. Near infrared spectroscopy (NIRS) can be used to record these changes in cerebral hemodynamics. However, no laterality comparison of the NIRS signal has been performed despite being a prerequisite for the use of such a method in a vasoreactivity monitoring context. We propose to investigate the NIRS signal laterality in response to a CO2-inhalation-based hypercapnia paradigm in healthy volunteers. METHODS: Eleven healthy volunteers (6 women, 5 men, mean age: 31 ± 11) underwent a 3-block-design inhalation paradigm: normoxia (5min, "baseline") - hypercapnia (2min, "stimulation") - normoxia (5min, "post-stimulation"). NIRS signal was measured using a two-channel oximeter (INVOS 5100C, Medtronic, USA) with sensors placed symmetrically on both left and right sides on each subject's forehead. Additional heart rate (HR) monitoring was performed simultaneously. Based on the NIRS mean signal pattern, an a priori model of parametric identification was applied for each channel to quantify parameters of interest (amplitude, time delay, excitation and post-stimulation time) for each inhalation block. RESULTS: HR increased significantly during the stimulation block. The quality of the model was satisfactory: mean absolute errors between modeled and experimental signals were lower than the resolution of the device. No significant lateralization was found between left and right values of most of the parameters. CONCLUSION: Due to the lack of lateralization, this parametric identification of NIRS responses to hypercapnia could bring light to a potential asymmetry and be used as a biomarker in patients with cerebrovascular diseases.

Relevance of selective neural stimulation with a multicontact cuff electrode using multicriteria analysis.

Neural multicontact cuff electrodes have the potential to activate selectively different groups of muscles and offer more possibilities of electrical configurations compared to whole ring cuffs. Several previous studies explored multicontact electrodes with a limited set of configurations which were sorted using a selectivity index only. The objective of the present study is to classify a larger number of configurations, i.e. the way the current is spread over the 12 contacts of the cuff electrode, using additional criteria such as robustness (i.e. ability to maintain selectivity within a range of current amplitudes) and efficiency (i.e. electrical consumption of the considered multipolar configuration versus the electrical consumption of the reference whole-ring configuration). Experiments were performed on the sciatic nerve of 4 rabbits. Results indicated that the optimal configuration depends on the weights applied to selectivity, robustness and efficiency criteria. Tripolar transverse is the most robust configuration and the less efficient, whereas tripolar longitudinal ring is efficient but not robust. New configurations issued from a previous theoretical study we carried out such as steering current ring appears as good compromise between the 3 criteria.

Comparison of the efficiency of chopped and non-rectangular electrical stimulus waveforms in activating small vagus nerve fibers.

BACKGROUND: In the context of morbid obesity, vagus nerve stimulation could be used to control gastric function targeting the small afferent B-fibers and C-fibers. Compared to large A-fibers, activation thresholds of these small efferent fibers are 10 to 100 times greater, inducing technical constraints and possible nerve damages. Although rectangular waveform is commonly used in nerve stimulation, recent modeling and experimental studies suggest that non-rectangular waveforms could reduced the charge injected by the stimulator. NEW METHOD: The objective of the present study is to evaluate the charge injection of complex waveforms such as the ramp, quarter sine and chopped pulses in the context of vagus nerve stimulation. We performed in-vivo study on the porcine abdominal vagus nerves and evaluated charge injection at activation thresholds. A modeling study was performed to further extent the results obtained in-vivo. COMPARISON WITH EXISTING METHOD: Compared to the rectangular pulse, the ramp and quarter sine waveforms activated gastric fibers with the lowest charge injection: -23.2% and -30.1% respectively. The efficacy of chopped pulses is questioned through the consideration of the strength-duration curve. CONCLUSION: Continuous ramp and quarter sine waveforms effectively activate small diameter fibers. These pulse shapes may be considered for long-term vagus nerve stimulation. The results predicted by computational models were qualitatively consistent with experiments. This suggested the relevance of using modeling in the context of complex waveforms prior to future in-vivo tests.

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

In 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.

Model based optimal multipolar stimulation without a priori knowledge of nerve structure: application to vagus nerve stimulation.

OBJECTIVE: Multipolar cuff electrode can selectively stimulate areas of peripheral nerves and therefore enable to control independent functions. However, the branching and fascicularization are known for a limited set of nerves and the specific organization remains subject-dependent. This paper presents general modeling and optimization methods in the context of multipolar stimulation using a cuff electrode without a priori knowledge of the nerve structure. Vagus nerve stimulation experiments based on the optimization results were then investigated. APPROACH: The model consisted of two independent components: a lead field matrix representing the transfer function from the applied current to the extracellular voltage present on the nodes of Ranvier along each axon, and a linear activation model. The optimization process consisted in finding the best current repartition (ratios) to reach activation of a targeted area depending on three criteria: selectivity, efficiency and robustness. MAIN RESULTS: The results showed that state-of-the-art configurations (tripolar transverse, tripolar longitudinal) were part of the optimized solutions but new ones could emerge depending on the trade-off between the three criteria and the targeted area. Besides, the choice of appropriate current ratios was more important than the choice of the stimulation amplitude for a stimulation without a priori knowledge of the nerve structure. We successfully assessed the solutions in vivo to selectively induce a decrease in cardiac rhythm through vagus nerve stimulation while limiting side effects. Compared to the standard whole ring configuration, a selective solution found by simulation provided on average 2.6 less adverse effects. SIGNIFICANCE: The preliminary results showed the rightness of the simulation, using a generic nerve geometry. It suggested that this approach will have broader applications that would benefit from multicontact cuff electrodes to elicit selective responses. In the context of the vagus nerve stimulation for heart failure therapy, we show that the simulation results were confirmed and improved the therapy while decreasing the side effects.

Fast Simulation and Optimization Tool to Explore Selective Neural Stimulation.

In functional electrical stimulation, selective stimulation of axons is desirable to activate a specific target, in particular muscular function. This implies to simulate a fascicule without activating neighboring ones i.e. to be spatially selective. Spatial selectivity is achieved by the use of multicontact cuff electrodes over which the stimulation current is distributed. Because of the large number of parameters involved, numerical simulations provide a way to find and optimize electrode configuration. The present work offers a computation effective scheme and associated tool chain capable of simulating electrode-nerve interface and find the best spread of current to achieve spatial selectivity.

Exploring Selective Neural Electrical Stimulation for Upper Limb Function Restoration.

This article introduces a new approach of selective neural electrical stimulation of the upper limb nerves. Median and radial nerves of individuals with tetraplegia are stimulated via a multipolar cuff electrode to elicit movements of wrist and hand in acute conditions during a surgical intervention. Various configurations corresponding to various combinations of a 12-poles cuff electrode contacts are tested. Video recording and electromyographic (EMG) signals recorded via sterile surface electrodes are used to evaluate the selectivity of each stimulation configuration in terms of activated muscles. In this abstract we introduce the protocol and preliminary results will be presented during the conference.

Vagus nerve stimulation: state of the art of stimulation and recording strategies to address autonomic function neuromodulation.

OBJECTIVE: Neural signals along the vagus nerve (VN) drive many somatic and autonomic functions. The clinical interest of VN stimulation (VNS) is thus potentially huge and has already been demonstrated in epilepsy. However, side effects are often elicited, in addition to the targeted neuromodulation. APPROACH: This review examines the state of the art of VNS applied to two emerging modulations of autonomic function: heart failure and obesity, especially morbid obesity. MAIN RESULTS: We report that VNS may benefit from improved stimulation delivery using very advanced technologies. However, most of the results from fundamental animal studies still need to be demonstrated in humans.

A phantom axon setup for validating models of action potential recordings.

Electrode designs and strategies for electroneurogram recordings are often tested first by computer simulations and then by animal models, but they are rarely implanted for long-term evaluation in humans. The models show that the amplitude of the potential at the surface of an axon is higher in front of the nodes of Ranvier than at the internodes; however, this has not been investigated through in vivo measurements. An original experimental method is presented to emulate a single fiber action potential in an infinite conductive volume, allowing the potential of an axon to be recorded at both the nodes of Ranvier and the internodes, for a wide range of electrode-to-fiber radial distances. The paper particularly investigates the differences in the action potential amplitude along the longitudinal axis of an axon. At a short radial distance, the action potential amplitude measured in front of a node of Ranvier is two times larger than in the middle of two nodes. Moreover, farther from the phantom axon, the measured action potential amplitude is almost constant along the longitudinal axis. The results of this new method confirm the computer simulations, with a correlation of 97.6 %.

A measure of cortico-cortical potentials evoked by 10 Hz direct electrical stimulation of the brain and by means of a differential recording mode of electrocorticographic signals.

Direct electrical stimulation (DES) at 60 Hz is used to perform real-time functional mapping of the brain during wide-awake neurosurgery. The electrophysiological effects of DES are largely unknown, locally and at a more remote distance. Here, by lowering the DES frequency to 10 Hz and by using a differential recording mode of electro-corticographic (ECoG) signals to improve the focality, we were able to record cortico-cortical evoked potentials easily with standard current amplitude of stimulation (2 mA). DES applied at 10 Hz and differential recording of ECoG could be used to map on-line the connectivity between different sub-cortical and cortical areas with a higher spatial accuracy.

Numerical simulation of multipolar configuration and prepulse technique to obtain spatially reverse recruitment order.

In the context of functional electrical stimulation of peripheral nerves, the control of a specific motor or sensory functions may need selective stimulation to target the desired effect without others. In implanted stimulation, spatial selectivity is obtained using multipolar CUFF electrodes with specific spread of the current over each contact. Furthermore, electrical stimulation recruits large fibers before small ones, whereas the targeted function could be elicited by a specific fiber type i.e. fiber diameter. In our work, numerical simulations were used to investigate the combination of multipolar configuration and prepulses, in order to obtain spatially reverse recruitment order. Multipolar stimulation provides efficient spatial selectivity, whereas sub-threshold prepulses were used to reverse recruitment order with a reasonable increase of the injected charges. We compared several selective configurations combined with prepulses to show that some are able to guarantee both the spatial selectivity while one fiber's diameter can be preferentially activated.

The difference between electrical microstimulation and direct electrical stimulation - towards new opportunities for innovative functional brain mapping?

Both electrical microstimulation (EMS) and direct electrical stimulation (DES) of the brain are used to perform functional brain mapping. EMS is applied to animal fundamental neuroscience experiments, whereas DES is performed in the operating theatre on neurosurgery patients. The objective of the present review was to shed new light on electrical stimulation techniques in brain mapping by comparing EMS and DES. There is much controversy as to whether the use of DES during wide-awake surgery is the 'gold standard' for studying the brain function. As part of this debate, it is sometimes wrongly assumed that EMS and DES induce similar effects in the nervous tissues and have comparable behavioural consequences. In fact, the respective stimulation parameters in EMS and DES are clearly different. More surprisingly, there is no solid biophysical rationale for setting the stimulation parameters in EMS and DES; this may be due to historical, methodological and technical constraints that have limited the experimental protocols and prompted the use of empirical methods. In contrast, the gap between EMS and DES highlights the potential for new experimental paradigms in electrical stimulation for functional brain mapping. In view of this gap and recent technical developments in stimulator design, it may now be time to move towards alternative, innovative protocols based on the functional stimulation of peripheral nerves (for which a more solid theoretical grounding exists).

Fascicle-selective multi-contact cuff electrode.

Neural recording is one of the main issues to be addressed in order to allow closed-loop functional electrical stimulation systems. Because each fascicle in nerves carry specific information, new sensors providing high spatial selectivity are required for chronic implantable devices. This work aims at evaluating the feasibility of a new device using a highly spatial-selective multi-contact cuff electrode. The proposed electrode configuration is evaluated based on simulations using a model of a nerve comprising multiple fascicles. Study of the electrode selectivity is done and compared with a state-of-the-art electrode designed for the same purpose and shows that activity of two fascicles separated by as little as 1 mm can be distinguished. Implementation challenges and perspectives for such electrodes are also discussed.

Sensitivity of a frequency-selective electrode based on spatial spectral properties of the extracellular AP of myelinated nerve fibers.

In the context of functional electrical stimulation, neural recording is one of the main issues. For instance, the control of the limbs in people with motor deficiencies needs information about the muscle lengths and speeds that can be extracted from electroneurograms (ENG) carried on afferent peripheral nerves. The aim of this study is to propose an non-invasive and spatial-selective electrode (because specific informations are carried into different fascicles). To do so, we investigate the spatial properties of an extracellular action potential (AP). This properties are described qualitatively and quantitatively using analytical study on an inhomogeneous an anisotropic nerve model. Then, a spectral analysis on this spatial signal discriminates the different frequency components. Low spatial frequencies represent the global shape of the signal, whereas high frequencies are related to the type of fibers. We show that the latter is rapidly attenuated with the distance and thus, being a local phenomenon, can be used as a selective measurement. Finally, we propose a spatial filtering based on electrode design and an electronic architecture to extract this high frequencies.

New electrode layout for internal selectivity of nerves.

A nerve is an enclosed, cable-like bundle of peripheral axons. Each axon or set of axons carries neural afferent or efferent information. Many applications need to detect or record these specific nervous data inside the nerve but it is a big challenge. The main issue is to achieve a good selectivity inside the nerve without being invasive. In this context, we propose a new layout of multipolar electrode allowing a very high level of spatial selectivity. This electrode has a flat-interface electrode with an array of poles. The idea is to find the best value for the inter-pole distance and the most suitable post processing in order to both improve selectivity in the nerve and reject external parasitic signals. In this preliminary work, we put emphasis on the simulation of the action potential as a method to help the electrode specification.