Optimized Electrical Stimulation of C-Nociceptors in Humans Based on the Chronaxie of Porcine C-Fibers.

Classically, to electrically excite C-nociceptors, rectangular pulses are used with a duration close to the estimated chronaxie of C-fibres (about 2 ms). Recent results using slow depolarizing stimuli suggest longer chronaxies. We therefore set out to optimize C-fiber stimulation based on recordings of single C-nociceptors in-vivo and C-fiber compound-action-potentials (C-CAP) ex-vivo using half-sine shaped stimuli of durations between 1 and 250ms. Single fiber (n = 45) recording in pigs revealed high chronaxie values for C-touch fibers (15.8 ms), polymodal- (14.2 ms) and silent-nociceptors (16.8 ms). Activation thresholds decreased 2 to 3-fold in all fibre classes when increasing the duration of half-sine pulses from 1 to 25 ms (P < .05). C-CAPs strength-duration curves of the pig saphenous nerve (n = 7) showed the highest sensitivity for half-sine durations between 10 and 25 ms. Half-maximum currents for C-CAPS were reduced 3-fold compared to rectangular pulses (P < .01) whereas the opposite was found for A-fiber compound action potentials. Psychophysics in humans (n = 23) revealed that half-sine stimulus durations >10 ms reduced detection thresholds, pain thresholds, and stimulus current amplitudes required to generate a pain rating of 3 on an 11-point Numeric Rating Scale (NRS) as compared to 1 ms rectangular pulses (P < 0.05). Increasing the duration from 1 to 25 ms led to a 4-fold amplitude reduction for pain-thresholds and stimuli caused an axon-reflex flare. Excitability of single polymodal nociceptors in animals paralleled human psychophysics and we conclude optimized half-sine pulses facilitate C-nociceptor activation. PERSPECTIVE: Electrical stimulation with longer lasting half-sine wave pulses preferentially activates C-nociceptors and changes in the strength duration curve may identify nociceptor hyperexcitability in patients with neuropathic pain.

Aplicação da técnica de eletrodiagnóstico em pacientes críticos: uma revisão sistemática / Application of electrodiagnostic technique in critically ill patients: a systematic review

O ambiente de terapia intensiva está evoluindo em tecnologias para avaliação e tratamento sendo uma das técnicas mais atuais aplicadas neste ambiente o eletrodiagnóstico. Esta é uma revisão sistemática desenvolvida com base nos resultados de pesquisa das principais bases de dados, seguindo o PRISMA. Neste foram incluídos somente artigos observacionais que utilizaram a técnica de eletrodiagnóstico em pacientes críticos, para os mais diferentes objetivos e desfechos. As bases de dados consultadas foram: MEDLINE (acessado via PubMed), Fisioterapia Evidence banco de dados (Pedro), Registro de Ensaios Controlados (CENTRAL Cochrane) e EMBASE além de uma busca manual de referências adicionais. Um total de 10 artigos foram encontrados, sendo que dois apresentaram-se repetidos e outros seis foram excluídos por não contemplarem os critérios de inclusão obtendo-se ao final um total de dois artigos totalizando 33 pacientes. Um dos artigos apresentou resultados seguros, sem lesão muscular e o protocolo foi viável para ser aplicado em terapia intensiva. O outro artigo que após lesão cerebral traumática os pacientes podem apresentar distúrbios eletrofisiológicos, além de atrofia muscular generalizada sendo evidenciados pela técnica de eletrodiagnóstico. (AU)

The intensive care environment is evolving in technologies for evaluation and treatment, and these include a recent technique named electrodiagnosis. This systematic review was based on search results from major databases, following PRISMA guidelines. Only observational studies using the electrodiagnostic technique in critically patients for different objectives and outcomes were included. The following databases were searched: MEDLINE (accessed via PubMed), Physiotherapy Evidence database (Pedro), Controlled Trials Registry (CENTRAL Cochrane) and EMBASE, in addition to a manual search for additional references. Ten articles were found, two of which were repeated and six were excluded because they did not meet the inclusion criteria; thus, two articles were selected, with a total of 33 patients. One of the articles showed safe results, without any muscle injury, and the protocol was applicable in intensive care. The other article demonstrated that, after traumatic brain injury, patients may present with electrophysiological disorders and generalized muscle atrophy, which can be revealed by the electrodiagnostic technique. (AU)

Intraoperative direct cortical stimulation motor evoked potentials: Stimulus parameter recommendations based on rheobase and chronaxie.

OBJECTIVE: To determine optimal interstimulus interval (ISI) and pulse duration (D) for direct cortical stimulation (DCS) motor evoked potentials (MEPs) based on rheobase and chronaxie derived with two techniques. METHODS: In 20 patients under propofol/remifentanil anesthesia, 5-pulse DCS thenar MEP rheobase and chronaxie with 2, 3, 4 and 5ms ISI were measured by linear regression of five charge thresholds at 0.05, 0.1, 0.2, 0.5 and 1msD, and estimated from two charge thresholds at 0.1 and 1msD using simple arithmetic. Optimal parameters were defined by minimum threshold energy: the ISI with lowest rheobase2×chronaxie, and D at its chronaxie. Near-optimal was defined as threshold energy <25% above minimum. RESULTS: The optimal ISI was 3 or 4 (n=7 each), 2 (n=4), or 5ms (n=2), but only 4ms was always either optimal or near-optimal. The optimal D was ∼0.2 (n=12), ∼0.1 (n=7) or ∼0.3ms (n=1). Two-point estimates closely approximated five-point measurements. CONCLUSIONS: Optimal ISI/D varies, with 4ms/0.2ms being most consistently optimal or near-optimal. Two-point estimation is sufficiently accurate. SIGNIFICANCE: The results endorse 4ms ISI and 0.2msD for general use. Two-point estimation could enable quick individual optimization.

Electrical Stimulation Based on Chronaxie Increases Fibrosis and Modulates TWEAK/Fn14, TGF-ß/Myostatin, and MMP Pathways in Denervated Muscles.

OBJECTIVE: The aim of this work was to investigate the effects of electrical stimulation (ES) of denervated muscles of rat in neuromuscular performance, muscle atrophy, and fibrosis formation. DESIGN: Wistar rats were divided into normal (N), 7- or 15-day denervation (D7d and D15d), D7d or D15d plus ES (DES7d and DES15d, respectively). Sciatic nerves were crushed causing muscle denervation. Two hundred muscle contractions were electrically induced daily by surface electrodes, considering muscle chronaxie. Sciatic functional index was used to determine neuromuscular performance during walking. The muscle fiber cross-sectional area and percentage of connective tissue were assessed by light microscopy. Molecular markers of extracellular matrix production and remodeling were evaluated. Metalloproteinase (MMP) activity was assessed by zymography, and TWEAK, Fn14, myostatin, and transforming growth factor (TGF)-ß gene expressions were determined by real-time PCR. RESULTS: Electrical stimulation impaired natural recovery of walking at 15 days. In addition, ES induced fibrosis and accentuated muscle atrophy in denervated muscles. Although ES reduced the accumulation of TWEAK and myostatin expressions, it up-regulated Fn14 and TGF-ß in a time-dependent manner. Electrical stimulation also increased the activity of MMP-2 compared to the other groups (P < 0.05). CONCLUSIONS: Electrical stimulation applied to denervated muscles induced muscle fibrosis and atrophy, as well as loss of performance. The TWEAK/Fn14 system, TGF-beta/myostatin pathway, and MMP activity seem to be involved in these deleterious changes.

Safety and feasibility of a neuromuscular electrical stimulation chronaxie-based protocol in critical ill patients: A prospective observational study.

PURPOSE: The aim of this study was to evaluate the safety and feasibility of a neuromuscular electrical stimulation (NMES) protocol based on neuromuscular excitability and applied in numerous muscle groups of critical ill patients. MATERIALS AND METHODS: We performed a prospective observational study using an NMES applied daily and bilaterally into 5 muscle groups in lower limbs for 3 consecutive days. The characteristics of NMES were 90 contractions per muscle, pulse width equal to chronaxie, and a pulse frequency of 100 Hz. We assessed safety with central venous oxygen saturation, serum lactate, and creatine phosphokinase measurements. To evaluate feasibility, we recorded the time spent for the entire NMES protocol and the number of NMES sessions completed. RESULTS: Eleven male patients finished the study. There were no significant changes observed in creatine phosphokinase from baseline up to 96 hours: 470(±270) IU/L and 455(±240) IU/L (P>.99). Central venous oxygen saturation and serum lactate had the same pattern with no significant variations (P=.23 and P=.8, respectively). The time spent during the whole procedure and the number of complete NMES sessions performed were 107±24 minutes and 84 sessions (85%), respectively. CONCLUSIONS: We demonstrated that NMES chronaxie-based protocol is safe and feasible.

Chronaxie Measurements in Patterned Neuronal Cultures from Rat Hippocampus.

Excitation of neurons by an externally induced electric field is a long standing question that has recently attracted attention due to its relevance in novel clinical intervention systems for the brain. Here we use patterned quasi one-dimensional neuronal cultures from rat hippocampus, exploiting the alignment of axons along the linear patterned culture to separate the contribution of dendrites to the excitation of the neuron from that of axons. Network disconnection by channel blockers, along with rotation of the electric field direction, allows the derivation of strength-duration (SD) curves that characterize the statistical ensemble of a population of cells. SD curves with the electric field aligned either parallel or perpendicular to the axons yield the chronaxie and rheobase of axons and dendrites respectively, and these differ considerably. Dendritic chronaxie is measured to be about 1 ms, while that of axons is on the order of 0.1 ms. Axons are thus more excitable at short time scales, but at longer time scales dendrites are more easily excited. We complement these studies with experiments on fully connected cultures. An explanation for the chronaxie of dendrites is found in the numerical simulations of passive, realistically structured dendritic trees under external stimulation. The much shorter chronaxie of axons is not captured in the passive model and may be related to active processes. The lower rheobase of dendrites at longer durations can improve brain stimulation protocols, since in the brain dendrites are less specifically oriented than axonal bundles, and the requirement for precise directional stimulation may be circumvented by using longer duration fields.

Essential oil of Croton zehntneri and its main constituent anethole block excitability of rat peripheral nerve.

Croton zehntneri is an aromatic plant native to Northeast Brazil and employed by local people to treat various diseases. The leaves of this plant have a rich content of essential oil. The essential oil of C. zehntneri samples, with anethole as the major constituent and anethole itself, have been reported to have several pharmacological activities such as antispasmodic, cardiovascular, and gastroprotective effects and inducing the blockade of neuromuscular transmission and antinociception. Since several works have demonstrated that essential oils and their constituents block cell excitability and in view of the multiple effects of C. zehntneri essential oil and anethole on biological tissues, we undertook this investigation aiming to characterize and compare the effects of this essential oil and its major constituent on nerve excitability. Sciatic nerves of Wistar rats were used. They were mounted in a moist chamber, and evoked compound action potentials were recorded. Nerves were exposed in vitro to the essential oil of C. zehntneri and anethole (0.1-1 mg/mL) up to 180 min, and alterations in excitability (rheobase and chronaxie) and conductibility (peak-to-peak amplitude and conduction velocity) parameters of the compound action potentials were evaluated. The essential oil of C. zehntneri and anethole blocked, in a concentration-dependent manner with similar pharmacological potencies (IC50: 0.32 ± 0.07 and 0.22 ± 0.11 mg/mL, respectively), rat sciatic nerve compound action potentials. Strength-duration curves for both agents were shifted upward and to the right compared to the control curve, and the rheobase and chronaxie were increased following essential oil and anethole exposure. The time courses of the essential oil of C. zehntneri and anethole effects on peak-to-peak amplitude of compound action potentials followed an exponential decay and reached a steady state. The essential oil of C. zehntneri and anethole caused a similar reduction in conduction velocities of the compound action potential waves investigated. In conclusion, we demonstrated here that the essential oil of C. zehntneri blocks neuronal excitability and that this effect, which can be predominantly attributable to its major constituent, anethole, is important since these agents have several pharmacological effects likely related to the alteration of excitability. This finding is relevant due to the use of essential oils in aromatherapy and the low acute toxicity of this agent, which exhibits other effects of potential therapeutic usefulness.

Limb immobilization alters functional electrophysiological parameters of sciatic nerve.

Immobilization, used in clinical practice to treat traumatologic problems, causes changes in muscle, but it is not known whether changes also occur in nerves. We investigated the effects of immobilization on excitability and compound action potential (CAP) and the ultrastructure of the rat sciatic nerve. Fourteen days after immobilization of the right leg of adult male Wistar rats (n=34), animals were killed and the right sciatic nerve was dissected and mounted in a moist chamber. Nerves were stimulated at a baseline frequency of 0.2 Hz and tested for 2 min at 20, 50, and 100 Hz. Immobilization altered nerve excitability. Rheobase and chronaxy changed from 3.13 ± 0.05 V and 52.31 ± 1.95 µs (control group, n=13) to 2.84 ± 0.06 V and 59.71 ± 2.79 µs (immobilized group, n=15), respectively. Immobilization altered the amplitude of CAP waves and decreased the conduction velocity of the first CAP wave (from 93.63 ± 7.49 to 79.14 ± 5.59 m/s) but not of the second wave. Transmission electron microscopy showed fragmentation of the myelin sheath of the sciatic nerve of immobilized limbs and degeneration of the axon. In conclusion, we demonstrated that long-lasting leg immobilization can induce alterations in nerve function.

Limb immobilization alters functional electrophysiological parameters of sciatic nerve

Immobilization, used in clinical practice to treat traumatologic problems, causes changes in muscle, but it is not known whether changes also occur in nerves. We investigated the effects of immobilization on excitability and compound action potential (CAP) and the ultrastructure of the rat sciatic nerve. Fourteen days after immobilization of the right leg of adult male Wistar rats (n=34), animals were killed and the right sciatic nerve was dissected and mounted in a moist chamber. Nerves were stimulated at a baseline frequency of 0.2 Hz and tested for 2 min at 20, 50, and 100 Hz. Immobilization altered nerve excitability. Rheobase and chronaxy changed from 3.13±0.05 V and 52.31±1.95 µs (control group, n=13) to 2.84±0.06 V and 59.71±2.79 µs (immobilized group, n=15), respectively. Immobilization altered the amplitude of CAP waves and decreased the conduction velocity of the first CAP wave (from 93.63±7.49 to 79.14±5.59 m/s) but not of the second wave. Transmission electron microscopy showed fragmentation of the myelin sheath of the sciatic nerve of immobilized limbs and degeneration of the axon. In conclusion, we demonstrated that long-lasting leg immobilization can induce alterations in nerve function.

Strength-duration relationship for intra- versus extracellular stimulation with microelectrodes.

Chronaxie, a historically introduced excitability time parameter for electrical stimulation, has been assumed to be closely related to the time constant of the cell membrane. Therefore, it is perplexing that significantly larger chronaxies have been found for intracellular than for extracellular stimulation. Using compartmental model analysis, this controversy is explained on the basis that extracellular stimulation also generates hyperpolarized regions of the cell membrane hindering a steady excitation as seen in the intracellular case. The largest inside/outside chronaxie ratio for microelectrode stimulation is found in close vicinity of the cell. In the case of monophasic cathodic stimulation, the length of the primarily excited zone which is situated between the hyperpolarized regions increases with electrode-cell distance. For distant electrodes this results in an excitation process comparable to the temporal behavior of intracellular stimulation. Chronaxie also varies along the neural axis, being small for electrode positions at the nodes of Ranvier and axon initial segment and larger at the soma and dendrites. As spike initiation site can change for short and long pulses, in some cases strength-duration curves have a bimodal shape, and thus, they deviate from a classical monotonic curve as described by the formulas of Lapicque or Weiss.

Potencial de ação: do estímulo à adaptação neural / Action potential: from excitation to neural adaptation

INTRODUÇÃO: O potencial de ação (PA) origina-se graças a uma perturbação do estado de repouso da membrana celular, com consequente fluxo de íons, por meio da membrana e alteração da concentração iônica nos meios intra e extracelular. OBJETIVOS: Sintetizar o conhecimento científico acumulado até o presente sobre o potencial de ação neural e o seu processo de adaptação sob aplicação de um estímulo constante. MATERIAIS E MÉTODOS: Busca realizada nas bases Springer, ScienceDirect, PubMed, IEEE Xplore, Google Acadêmico, Portal de Periódicos da Capes, além de livros referentes ao assunto. O idioma de preferência selecionado foi o inglês, com as keywords: action potential; adaptation; accommodation; rheobase; chronaxy; nerve impulse. Efetuou-se a procura de artigos com uma janela de tempo de 1931 a 2010 e livros de 1791 a 2007. RESULTADOS: Dos trabalhos selecionados, foram extraídas informações a respeito dos seguintes tópicos: potencial de ação e suas fases; condução nervosa; reobase; cronaxia; acomodação; e adaptação neuronal. CONCLUSÃO: Um estímulo que crie PA, se aplicado de maneira constante, pode reduzir a frequência de despolarizações em função do tempo e, consequentemente, adaptar a célula. O tempo que a célula demora, na ausência de estímulos, para recuperar sua frequência original é definido como desadaptação.

INTRODUCTION: The action potential (AP) arises due to a disturbance of the resting state of the cell membrane with consequent flow of ions across the membrane and ion concentration changes in intra and extra cellular space. OBJECTIVES: This article aims to summarize the scientific knowledge accumulated to date on the action potential and neural adaptation in the process of applying a constant stimulus. MATERIALS AND METHODS: This is a literature review on the bases Springer, ScienceDirect, PubMed, IEEE Xplore, Google Scholar, Capes Periodicals Portal as well as books on the topic. The selected preferred language was English with the keywords: action potential; adaptation, accommodation; rheobase; chronaxy; nerve impulse. We conducted a search of articles with a wide time window from 1931 to 2010 and books from 1791 to 2007. RESULTS: In the selected studies was extracted information about the following topics: action potential and its stages; nerve conduction; rheobase; chronaxie, accommodation, and adaptation. CONCLUSION: A stimulus that creates AP, if applied consistently, can reduce the frequency of depolarization as a function of time and, consequently, to adapt the cell. The time it takes the cell in the absence of stimuli, to recover its original frequency, is defined as a disadaptation.

A comparison of the excitability of motor axons innervating the APB and ADM muscles.

OBJECTIVE: Threshold tracking allows the non-invasive assessment of axonal excitability. This study aimed to determine whether axonal excitability of the motor axons of the median nerve (to APB) and ulnar nerve (to ADM) to the small muscles of the hands is sufficiently similar to be interchangeable; confirm the feasibility and reproducibility of ulnar studies and obtain control data for a young population for this site of stimulation. METHODS: Twenty normal subjects between the ages of 23-43 were studied using the TRONDF protocol of QTRACS, (©Prof Hugh Bostock, London). The median and ulnar nerves were stimulated at the wrist and the compound muscle action potentials were recorded from abductor pollicis brevis and abductor digiti minimi, respectively. Repeat studies were performed in four subjects to confirm reproducibility of the recordings. RESULTS: Stimulus intensity was greater and strength duration time constant was longer for the median nerve. Threshold electrotonus showed there was a greater change in threshold in the hyperpolarising direction for the median nerve compared with the ulnar nerve. There was however little difference in the recovery cycle and current threshold relationship. CONCLUSIONS: Although recovery cycles and the current thresholds are similar for APB and ADM, there are definite differences in stimulus threshold, SDTC and threshold electrotonus which question the interchangeability of studies for these two sites. SIGNIFICANCE: This study demonstrates reproducibility of motor axonal excitability studies of the ulnar nerve at the wrist, provides young control data for this site of stimulation and suggests that although certain excitability indices are similar for the median nerve to APB and ulnar nerve to ADM there are definite differences making the interchangeability of the data questionable.

The discrepancy between human peripheral nerve chronaxie times as measured using magnetic and electric field stimuli: the relevance to MRI gradient coil safety.

Peripheral nerve stimulation (PNS) resulting from electric fields induced from the rapidly changing magnetic fields of gradient coils is a concern in MRI. Nerves exposed to either electric fields or changing magnetic fields would be expected to display consistent threshold characteristics, motivating the direct application of electric field exposure criteria from the literature to guide the development of gradient magnetic field exposure criteria for MRI. The consistency of electric and magnetic field exposures was tested by comparing chronaxie times for electric and magnetic PNS curves for 22 healthy human subjects. Electric and magnetic stimulation thresholds were measured for exposure of the forearm using both surface electrodes and a figure-eight magnetic coil, respectively. The average chronaxie times for the electric and magnetic field conditions were 109 +/- 11 micros and 651 +/- 53 micros (+/-SE), respectively. We do not propose that these results call into question the basic mechanism, namely that rapidly switched gradient magnetic fields induce electric fields in human tissues, resulting in PNS. However, this result does motivate us to suggest that special care must be taken when using electric field exposure data from the literature to set gradient coil PNS safety standards in MRI.

A comparison of chronaxies for ventricular fibrillation induction, defibrillation, and cardiac stimulation: unexpected findings and their implications.

INTRODUCTION: A low-energy (

A model for transcutaneous current stimulation: simulations and experiments.

Complex nerve models have been developed for describing the generation of action potentials in humans. Such nerve models have primarily been used to model implantable electrical stimulation systems, where the stimulation electrodes are close to the nerve (near-field). To address if these nerve models can also be used to model transcutaneous electrical stimulation (TES) (far-field), we have developed a TES model that comprises a volume conductor and different previously published non-linear nerve models. The volume conductor models the resistive and capacitive properties of electrodes, electrode-skin interface, skin, fat, muscle, and bone. The non-linear nerve models were used to conclude from the potential field within the volume conductor on nerve activation. A comparison of simulated and experimentally measured chronaxie values (a measure for the excitability of nerves) and muscle twitch forces on human volunteers allowed us to conclude that some of the published nerve models can be used in TES models. The presented TES model provides a first step to more extensive model implementations for TES in which e.g., multi-array electrode configurations can be tested.

The hyperbolic strength-duration relationship of defibrillation threshold.

Defibrillation with square-wave pulses has proved to possess hyperbolic strength-duration relationship. Does such a hyperbolic relation also exist for exponentially decaying pulses as they are commonly used today? This paper hypothesizes that exponentially decaying pulses obey hyperbolic strength-duration relationship, calculates the consequences, and advises of how such thresholds should be investigated. If the strength-duration relationship exists for current, the corresponding charge threshold must be a Weiss' straight threshold line. In analogy, for exponentially decaying pulses, the integral of the amplitude over pulse duration (PD) must be calculated as a function of PD. If this function is linearly correlated, the mean voltage possesses a hyperbolic strength-duration relationship, whereas the peak voltage does not. Peak amplitude curves possess minima shifting to the right with increasing time constant RC limiting the allowed range of useful PDs. To prove that exponentially decaying pulses have a hyperbolic relationship, testing must be done in six steps that are demonstrated with results published in literature. Mean voltages have, indeed, hyperbolic strength-duration relationship. Chronaxie is not calculated correctly as long as peak voltage thresholds are correlated and PDs are greater than allowed.

Multichannel surface recordings on the visual cortex: implications for a neuroprosthesis.

Using a multi-channel platinum surface electrode array, recordings from cat primary visual cortex were obtained in response to visual stimuli, and electrical stimuli delivered using the elements of the array itself. Neural responses to electrical stimuli were consistent, regardless of stimulus polarity or leading phase (biphasic), although thresholds were lower for monophasic than biphasic pulses. Both visual and electrical stimuli reliably evoked responses with characteristic components, which interacted with each other in a nonlinear summation showing first facilitation then suppression during the window of interaction. The chronaxie for eliciting threshold cortical responses was about 100 mus, and the charge density with a pulse width of 50-100 mus was around 55 muC cm(-2). These data form the basis of understanding the types of cortical responses to stimuli delivered by devices suitable for chronic implantation.