Peculiarities of Neurostimulation by Intense Nanosecond Pulsed Electric Fields: How to Avoid Firing in Peripheral Nerve Fibers.

Intense pulsed electric fields (PEF) are a novel modality for the efficient and targeted ablation of tumors by electroporation. The major adverse side effects of PEF therapies are strong involuntary muscle contractions and pain. Nanosecond-range PEF (nsPEF) are less efficient at neurostimulation and can be employed to minimize such side effects. We quantified the impact of the electrode configuration, PEF strength (up to 20 kV/cm), repetition rate (up to 3 MHz), bi- and triphasic pulse shapes, and pulse duration (down to 10 ns) on eliciting compound action potentials (CAPs) in nerve fibers. The excitation thresholds for single unipolar but not bipolar stimuli followed the classic strength-duration dependence. The addition of the opposite polarity phase for nsPEF increased the excitation threshold, with symmetrical bipolar nsPEF being the least efficient. Stimulation by nsPEF bursts decreased the excitation threshold as a power function above a critical duty cycle of 0.1%. The threshold reduction was much weaker for symmetrical bipolar nsPEF. Supramaximal stimulation by high-rate nsPEF bursts elicited only a single CAP as long as the burst duration did not exceed the nerve refractory period. Such brief bursts of bipolar nsPEF could be the best choice to minimize neuromuscular stimulation in ablation therapies.

Roles of central orexinergic system on cardiovascular function and acupuncture on intervention of cardiovascular risk: Orexinergic system mediate the role of acupuncture?

Central orexinergic system contributes to the regulation of cardiovascular function. Orexinergic neurons receiving projections of nerve fibers from multiple structures of brain which involved in control and regulation of cardiovascular function locate in hypothalamus, and their axon terminals widely project to various central structures where orexins receptors are expressed. Here, we summarize the present knowledge that describes the influence of central orexinergic system on cardiovascular activity, the relevance of dysfunction in central orexinergic system with hypertension and psychological stress induced cardiovascular reactivity which are serious risk factors for cardiovascular disease and cardiovascular death. We propose that central orexinergic system may be potentially important targets for the prevention of cardiovascular disease and cardiovascular death, and different orexinergic system involved neuronal circuits may be involved in distinct cardiovascular functions. Acupuncture having bidirectional regulatory ability and a much lower incidence of side effects can prevent disease. We review the improvement of acupuncture on hypertension and psychological stress induced cardiovascular reactivity. We think that acupuncture intervenes hypertension and psychological stress induced cardiovascular reactivity to prevent cardiovascular disease and cardiovascular death. We also summarize relation between acupuncture and central orexinergic system. We propose a hypothesis that acupuncture improve hypertension and psychological stress induced cardiovascular reactivity through regulating central orexinergic system. The knowledge is beneficial for the development of potential therapeutic targets and methods to prevent cardiovascular disease and cardiovascular death.

The Electric Shock during Acupuncture: A Normal Needling Sensation or a Warning Sign.

The electric shock has been proposed as one of the new needling sensations in recent years. In acupuncture sensation scales, the electric shock is included by ASS and SNQS, but not SASS, MASS, and C-MMASS. Some scholars argue that the electric shock is a normal needling sensation, but some researchers do not agree with this view. This problem has not been resolved due to a lack of evidence from basic research. Literature and research point out that the electric shock is caused by inserting a needle into the nerve directly. A question of considerable scientific and practical interest is whether the electric shock should be a normal needling sensation. In this article, we review the historical documentation of the needling sensation and the process of formulating and improving acupuncture sensation scales to suggest that the electric shock may not be a normal needling sensation. Secondly, we collected and analyzed cases of nerve injury caused by acupuncture accompanied by the electric shock and why acupuncture caused the electric shock without nerve injury. It suggests that there may be a correlation between the electric shock and peripheral nerve injury, and acupuncture manipulation is an essential factor in adverse acupuncture events. Finally, we put forward that the electric shock during acupuncture is a warning sign that the peripheral nerve may be injured, rather than a normal needling sensation. In the future, we hope to have experimental studies on the mechanism of the electric shock or observational studies on the correlation between the electric shock and peripheral nerve injury to verify.

Efficacy of Electrical Stimulation on Nerve Fiber Growth in Small Fiber Neuropathy.

OBJECTIVES: To define whether electrical nerve stimulation (ENS) therapy would promote intraepidermal nerve growth and nerve regeneration in patients with small fiber neuropathy (SFN). METHODS: This was a prospective study conducted on 8 subjects with previously diagnosed SFN. Nerve conduction testing, punch biopsies, and clinical examinations with a calculation of revised total neuropathy score were conducted on subjects before beginning ENS therapy and at 30 and 60 days after the start of ENS therapy. RESULTS: Clinical examination findings and intraepidermal nerve fiber density measurements on day 30 and day 60 did not show statistically significant changes in the treated group compared with the untreated group. CONCLUSIONS: Despite the success of previous animal studies, no meaningful nerve growth and regeneration in SFN was demonstrated with ENS therapy in this study. Studies of larger subject larger populations with longer duration of ENS treatment are warranted to confirm our findings.

Melanin-concentrating hormone (MCH) in the median raphe nucleus: Fibers, receptors and cellular effects.

Serotonergic neurons of the median raphe nucleus (MnR) and hypothalamic melanin-concentrating hormone (MCH)-containing neurons, have been involved in the control of REM sleep and mood. In the present study, we examined in rats and cats the anatomical relationship between MCH-containing fibers and MnR neurons, as well as the presence of MCHergic receptors in these neurons. In addition, by means of in vivo unit recording in urethane anesthetized rats, we determined the effects of MCH in MnR neuronal firing. Our results showed that MCH-containing fibers were present in the central and paracentral regions of the MnR. MCHergic fibers were in close apposition to serotonergic and non-serotonergic neurons. By means of an indirect approach, we also analyzed the presence of MCHergic receptors within the MnR. Accordingly, we microinjected MCH conjugated with the fluorophore rhodamine (R-MCH) into the lateral ventricle. R-MCH was internalized into serotonergic and non-serotonergic MnR neurons; some of these neurons were GABAergic. Furthermore, we determined that intracerebroventricular administration of MCH induced a significant decrease in the firing rate of 53 % of MnR neurons, while the juxtacellular administration of MCH reduced the frequency of discharge in 67 % of these neurons. Finally, the juxtacellular administration of the MCH-receptor antagonist ATC-0175 produced an increase in the firing rate in 78 % of MnR neurons. Hence, MCH produces a strong regulation of MnR neuronal activity. We hypothesize that MCHergic modulation of the MnR neuronal activity may be involved in the promotion of REM sleep and in the pathophysiology of depressive disorders.

Modulation of sensory nerve fiber excitability by transcutaneous cathodal direct current stimulation.

OBJECTIVE: To assess the lasting effects on sensory nerve membrane excitability of transcutaneous peripheral nerve stimulation with cathodal direct currents (pDCS). METHODS: We performed pDCS in 10 healthy subjects with the active electrode placed over the distal right forearm and the reference electrode on the back of the right hand. We used 5×5cm rubber electrodes and the current applied was 2.5mA during 15min. Three pDCS sessions were performed on the same day: first, a baseline stimulation was performed, followed by a sham stimulation and lastly a cathodal stimulation. Median sensory nerve excitability measurements were performed at baseline and immediately after each pDCS session using the TRONDNF nerve excitability protocol of the QTRAC program (measurement on the second finger). RESULTS: The protocol was completed and well tolerated in all subjects. RRP (relative refractory period) and refractoriness at 2.5ms were significantly different across the three study conditions, with a significant increase of RRP immediately following cathodal stimulation compared with baseline assessment (mean 4.2 versus 5.3, P=0.002). Other measurements were not modulated by the intervention. Sham-stimulation did not change axonal excitability. CONCLUSIONS: Cathodal pDCS stimulation increased RRP of sensory fibers, but no other consistent long-lasting effect was observed. This finding might suggest a reduction of sensory fiber excitability induced by cathodal pDCS.

Excitation and electroporation by MHz bursts of nanosecond stimuli.

Intense nanosecond pulsed electric field (nsPEF) is a novel modality for cell activation and nanoelectroporation. Applications of nsPEF in research and therapy are hindered by a high electric field requirement, typically from 1 to over 50 kV/cm to elicit any bioeffects. We show how this requirement can be overcome by engaging temporal summation when pulses are compressed into high-rate bursts (up to several MHz). This approach was tested for excitation of ventricular cardiomyocytes and peripheral nerve fibers; for membrane electroporation of cardiomyocytes, CHO, and HEK cells; and for killing EL-4 cells. MHz compression of nsPEF bursts (100-1000 pulses) enables excitation at only 0.01-0.15 kV/cm and electroporation already at 0.4-0.6 kV/cm. Clear separation of excitation and electroporation thresholds allows for multiple excitation cycles without membrane disruption. The efficiency of nsPEF bursts increases with the duty cycle (by increasing either pulse duration or repetition rate) and with increasing the total time "on" (by increasing either pulse duration or number). For some endpoints, the efficiency of nsPEF bursts matches a single "long" pulse whose amplitude and duration equal the time-average amplitude and duration of the bursts. For other endpoints this rule is not valid, presumably because of nsPEF-specific bioeffects and/or possible modification of targets already during the burst. MHz compression of nsPEF bursts is a universal and efficient way to lower excitation thresholds and facilitate electroporation.

A simulation environment for studying transcutaneous electrotactile stimulation.

Transcutaneous electrical nerve stimulation (TENS) allows the artificial excitation of nerve fibres by applying electric-current pulses through electrodes on the skin's surface. This work involves the development of a simulation environment that can be used for studying transcutaneous electrotactile stimulation and its dependence on electrode layout and excitation patterns. Using an eight-electrode array implementation, it is shown how nerves located at different depths and with different orientations respond to specific injected currents, allowing the replication of already reported experimental findings and the creation of new hypotheses about the tactile sensations associated with certain stimulation patterns. The simulation consists of a finite element model of a human finger used to calculate the distribution of the electric potential in the finger tissues neglecting capacitive effects, and a cable model to calculate the excitation/inhibition of action potentials in each nerve.

The frontal aslant tract (FAT) and its role in speech, language and executive function.

In this review, we examine the structural connectivity of a recently-identified fiber pathway, the frontal aslant tract (FAT), and explore its function. We first review structural connectivity studies using tract-tracing methods in non-human primates, and diffusion-weighted imaging and electrostimulation in humans. These studies suggest a monosynaptic connection exists between the lateral inferior frontal gyrus and the pre-supplementary and supplementary motor areas of the medial superior frontal gyrus. This connection is termed the FAT. We then review research on the left FAT's putative role in supporting speech and language function, with particular focus on speech initiation, stuttering and verbal fluency. Next, we review research on the right FAT's putative role supporting executive function, namely inhibitory control and conflict monitoring for action. We summarize the extant body of empirical work by suggesting that the FAT plays a domain general role in the planning, timing, and coordination of sequential motor movements through the resolution of competition among potential motor plans. However, we also propose some domain specialization across the hemispheres. On the left hemisphere, the circuit is proposed to be specialized for speech actions. On the right hemisphere, the circuit is proposed to be specialized for general action control of the organism, especially in the visuo-spatial domain. We close the review with a discussion of the clinical significance of the FAT, and suggestions for further research on the pathway.

Thalamocortical and Intracortical Inputs Differentiate Layer-Specific Mouse Auditory Corticocollicular Neurons.

Long-range descending projections from the auditory cortex play key roles in shaping response properties in the inferior colliculus. The auditory corticocollicular projection is massive and heterogeneous, with axons emanating from cortical layers 5 and 6, and plays a key role in directing plastic changes in the inferior colliculus. However, little is known about the cortical and thalamic networks within which corticocollicular neurons are embedded. Here, laser scanning photostimulation glutamate uncaging and photoactivation of channelrhodopsin-2 were used to probe the local and long-range network differences between preidentified layer 5 and layer 6 auditory corticocollicular neurons from male and female mice in vitro Layer 5 corticocollicular neurons were found to vertically integrate supragranular excitatory and inhibitory input to a substantially greater degree than their layer 6 counterparts. In addition, all layer 5 corticocollicular neurons received direct and large thalamic inputs from channelrhodopsin-2-labeled thalamocortical fibers, whereas such inputs were less common in layer 6 corticocollicular neurons. Finally, a new low-calcium/synaptic blockade approach to separate direct from indirect inputs using laser photostimulation was validated. These data demonstrate that layer 5 and 6 corticocollicular neurons receive distinct sets of cortical and thalamic inputs, supporting the hypothesis that they have divergent roles in modulating the inferior colliculus. Furthermore, the direct connection between the auditory thalamus and layer 5 corticocollicular neurons reveals a novel and rapid link connecting ascending and descending pathways.SIGNIFICANCE STATEMENT Descending projections from the cortex play a critical role in shaping the response properties of sensory neurons. The projection from the auditory cortex to the inferior colliculus is a massive, yet poorly understood, pathway emanating from two distinct cortical layers. Here we show, using a range of optical techniques, that mouse auditory corticocollicular neurons from different layers are embedded into different cortical and thalamic networks. Specifically, we observed that layer 5 corticocollicular neurons integrate information across cortical lamina and receive direct thalamic input. The latter connection provides a hyperdirect link between acoustic sensation and descending control, thus demonstrating a novel mechanism for rapid "online" modulation of sensory perception.

Dependence of excitability indices on membrane channel dynamics, myelin impedance, electrode location and stimulus waveforms in myelinated and unmyelinated fibre models.

Neuronal excitability is determined in a complex way by several interacting factors, such as membrane dynamics, fibre geometry, electrode configuration, myelin impedance, neuronal terminations[Formula: see text] This study aims to increase understanding in excitability, by investigating the impact of these factors on different models of myelinated and unmyelinated fibres (five well-known membrane models are combined with three electrostimulation models, that take into account the spatial structure of the neuron). Several excitability indices (rheobase, polarity ratio, bi/monophasic ratio, time constants[Formula: see text]) are calculated during extensive parameter sweeps, allowing us to obtain novel findings on how these factors interact, e.g. how the dependency of excitability indices on the fibre diameter and myelin impedance is influenced by the electrode location and membrane dynamics. It was found that excitability is profoundly impacted by the used membrane model and the location of the neuronal terminations. The approximation of infinite myelin impedance was investigated by two implementations of the spatially extended non-linear node model. The impact of this approximation on the time constant of strength-duration plots is significant, most importantly in the Frankenhaeuser-Huxley membrane model for large electrode-neuron separations. Finally, a multi-compartmental model for C-fibres is used to determine the impact of the absence of internodes on excitability. Graphical Abstract Electrostimulation models, obtained by combining five membrane models with three representations of the neuronal cable equation, are fed with electrode and stimulus input parameters. The dependency of neuronal excitability on the interaction of these input parameters is determined by deriving excitability indices from the spatiotemporal model response. The impact of the myelin impedance and the fibre diameter on neural excitability is also considered.

Joint nociceptor nerve activity and pain in an animal model of acute gout and its modulation by intra-articular hyaluronan.

The mechanisms whereby deposition of monosodium urate (MSU) crystals in gout activates nociceptors to induce joint pain are incompletely understood. We tried to reproduce the signs of painful gouty arthritis, injecting into the knee joint of rats suspensions containing amorphous or triclinic, needle MSU crystals. The magnitude of MSU-induced inflammation and pain behavior signs were correlated with the changes in firing frequency of spontaneous and movement-evoked nerve impulse activity recorded in single knee joint nociceptor saphenous nerve fibers. Joint swelling, mechanical and cold allodynia, and hyperalgesia appeared 3 hours after joint injection of MSU crystals. In parallel, spontaneous and movement-evoked joint nociceptor impulse activity raised significantly. Solutions containing amorphous or needle-shaped MSU crystals had similar inflammatory and electrophysiological effects. Intra-articular injection of hyaluronan (HA, Synvisc), a high-MW glycosaminoglycan present in the synovial fluid with analgesic effects in osteoarthritis, significantly reduced MSU-induced behavioral signs of pain and decreased the enhanced joint nociceptor activity. Our results support the interpretation that pain and nociceptor activation are not triggered by direct mechanical stimulation of nociceptors by MSU crystals, but are primarily caused by the release of excitatory mediators by inflammatory cells activated by MSU crystals. Intra-articular HA decreased behavioral and electrophysiological signs of pain, possibly through its viscoelastic filtering effect on the mechanical forces acting over sensitized joint sensory endings and probably also by a direct interaction of HA molecules with the transducing channels expressed in joint nociceptor terminals.

Topography of the human acoustic radiation as revealed by ex vivo fibers micro-dissection and in vivo diffusion-based tractography.

The acoustic radiation is a compact bundle of fibers conveying auditory information from the medial geniculate nucleus of the thalamus to the auditory cortex. Topographical knowledge of this bundle in primates is scarce and in vivo diffusion-based tractography reconstructions in humans remains challenging, especially with the most widely used MRI acquisition protocols. Therefore, the AR represents a notable anatomical omission in the neurobiological investigation of acoustic and linguistic functional mechanisms in humans. In this study, we combine blunt micro-dissections and advanced diffusion tractography methods to provide novel insights into the topographical anatomy of this bundle in humans. Evidences from ex vivo blunt micro-dissection in three human (two right) hemispheres are compared to the 3D profile of this bundle as reconstructed by tractography techniques in four healthy adult data sets provided by the Human Connectome Project. Both techniques show the unique trajectory of the AR, a transversal course from the midline to the lateral convexity of the posterior temporal lobe. Blunt dissections demonstrated three portions of this bundle that we defined as the genu, stem, and fan, revealing the intimate relationships that each of these components has with neighboring association and projection pathways. Probabilistic tractography and ultra-high b values provided results comparable to blunt micro-dissections and highlighted the main limitations in tracking the AR. This is, to our knowledge, the first ex vivo/in vivo integrated study providing novel and reliable information about the precise anatomy of the AR, which will be important for future investigations in the neuroscientific, clinical, and surgical field.

Selective recurrent laryngeal nerve stimulation using a penetrating electrode array in the feline model.

OBJECTIVES/HYPOTHESIS: Laryngeal muscles (LMs) are controlled by the recurrent laryngeal nerve (RLN), injury of which can result in vocal fold (VF) paralysis (VFP). We aimed to introduce a bioelectric approach to selective stimulation of LMs and graded muscle contraction responses. STUDY DESIGN: Acute experiments in cats. METHODS: The study included six anesthetized cats. In four cats, a multichannel penetrating microelectrode array (MEA) was placed into an uninjured RLN. For RLN injury experiments, one cat received a standardized hemostat-crush injury, and one cat received a transection-reapproximation injury 4 months prior to testing. In each experiment, three LMs (thyroarytenoid, posterior cricoarytenoid, and cricothyroid muscles) were monitored with an electromyographic (EMG) nerve integrity monitoring system. Electrical current pulses were delivered to each stimulating channel individually. Elicited EMG voltage outputs were recorded for each muscle. Direct videolaryngoscopy was performed for visualization of VF movement. RESULTS: Stimulation through individual channels led to selective activation of restricted nerve populations, resulting in selective contraction of individual LMs. Increasing current levels resulted in rising EMG voltage responses. Typically, activation of individual muscles was successfully achieved via single placement of the MEA by selection of appropriate stimulation channels. VF abduction was predominantly observed on videolaryngoscopy. Nerve histology confirmed injury in cases of RLN crush and transection experiments. CONCLUSIONS: We demonstrated the ability of a penetrating MEA to selectively stimulate restricted fiber populations within the feline RLN and selectively elicit contractions of discrete LMs in both acute and injury-model experiments, suggesting a potential role for intraneural MEA implantation in VFP management. LEVEL OF EVIDENCE: NA. Laryngoscope, 128:1606-1614, 2018.

Geometric Navigation of Axons in a Cerebral Pathway: Comparing dMRI with Tract Tracing and Immunohistochemistry.

Brain fiber pathways are presumed to follow smooth curves but recent high angular resolution diffusion MRI (dMRI) suggests that instead they follow 3 primary axes often nearly orthogonal. To investigate this, we analyzed axon pathways under monkey primary motor cortex with (1) dMRI tractography, (2) axon tract tracing, and (3) axon immunohistochemistry. dMRI tractography shows the predicted crossings of axons in mediolateral and dorsoventral orientations and does not show axon turns in this region. Axons labeled with tract tracer in the motor cortex dispersed in the centrum semiovale by microscopically sharp axonal turns and/or branches (radii ≤15 µm) into 2 sharply defined orientations, mediolateral and dorsoventral. Nearby sections processed with SMI-32 antibody to label projection axons and SMI-312 antibody to label all axons revealed axon distributions parallel to the tracer axons. All 3 histological methods confirmed preponderant axon distributions parallel with dMRI axes with few axons (<20%) following smooth curves or diagonal orientations. These findings indicate that axons navigate deep white matter via microscopic sharp turns and branches between primary axes. They support dMRI observations of primary fiber axes, as well as the prediction that fiber crossings include navigational events not yet directly resolved by dMRI. New methods will be needed to incorporate coherent microscopic navigation into dMRI of connectivity.

Probabilistic vs. deterministic fiber tracking and the influence of different seed regions to delineate cerebellar-thalamic fibers in deep brain stimulation.

This study compared tractography approaches for identifying cerebellar-thalamic fiber bundles relevant to planning target sites for deep brain stimulation (DBS). In particular, probabilistic and deterministic tracking of the dentate-rubro-thalamic tract (DRTT) and differences between the spatial courses of the DRTT and the cerebello-thalamo-cortical (CTC) tract were compared. Six patients with movement disorders were examined by magnetic resonance imaging (MRI), including two sets of diffusion-weighted images (12 and 64 directions). Probabilistic and deterministic tractography was applied on each diffusion-weighted dataset to delineate the DRTT. Results were compared with regard to their sensitivity in revealing the DRTT and additional fiber tracts and processing time. Two sets of regions-of-interests (ROIs) guided deterministic tractography of the DRTT or the CTC, respectively. Tract distances to an atlas-based reference target were compared. Probabilistic fiber tracking with 64 orientations detected the DRTT in all twelve hemispheres. Deterministic tracking detected the DRTT in nine (12 directions) and in only two (64 directions) hemispheres. Probabilistic tracking was more sensitive in detecting additional fibers (e.g. ansa lenticularis and medial forebrain bundle) than deterministic tracking. Probabilistic tracking lasted substantially longer than deterministic. Deterministic tracking was more sensitive in detecting the CTC than the DRTT. CTC tracts were located adjacent but consistently more posterior to DRTT tracts. These results suggest that probabilistic tracking is more sensitive and robust in detecting the DRTT but harder to implement than deterministic approaches. Although sensitivity of deterministic tracking is higher for the CTC than the DRTT, targets for DBS based on these tracts likely differ.

Muscle Activation During Peripheral Nerve Field Stimulation Occurs Due to Recruitment of Efferent Nerve Fibers, Not Direct Muscle Activation.

BACKGROUND: Peripheral nerve field stimulation (PNFS) is a potential treatment for chronic low-back pain. Pain relief using PNFS is dependent on activation of non-nociceptive Aß-fibers. However, PNFS may also activate muscles, causing twitches and discomfort. In this study, we developed a mathematical model, to investigate the activation of sensory and motor nerves, as well as direct muscle fiber activation. METHODS: The extracellular field was estimated using a finite element model based on the geometry of CT scanned lumbar vertebrae. The electrode was modeled as being implanted to a depth of 10-15 mm. Three implant directions were modeled; horizontally, vertically, and diagonally. Both single electrode and "between-lead" stimulation between contralateral electrodes were modeled. The extracellular field was combined with models of sensory Aß-nerves, motor neurons and muscle fibers to estimate their activation thresholds. RESULTS: The model showed that sensory Aß fibers could be activated with thresholds down to 0.563 V, and the lowest threshold for motor nerve activation was 7.19 V using between-lead stimulation with the cathode located closest to the nerves. All thresholds for direct muscle activation were above 500 V. CONCLUSIONS: The results suggest that direct muscle activation does not occur during PNFS, and concomitant motor and sensory nerve fiber activation are only likely to occur when using between-lead configuration. Thus, it may be relevant to investigate the location of the innervation zone of the low-back muscles prior to electrode implantation to avoid muscle activation.

Investigation of assumptions underlying current safety guidelines on EM-induced nerve stimulation.

An intricate network of a variety of nerves is embedded within the complex anatomy of the human body. Although nerves are shielded from unwanted excitation, they can still be stimulated by external electromagnetic sources that induce strongly non-uniform field distributions. Current exposure safety standards designed to limit unwanted nerve stimulation are based on a series of explicit and implicit assumptions and simplifications. This paper demonstrates the applicability of functionalized anatomical phantoms with integrated coupled electromagnetic and neuronal dynamics solvers for investigating the impact of magnetic resonance exposure on nerve excitation within the full complexity of the human anatomy. The impact of neuronal dynamics models, temperature and local hot-spots, nerve trajectory and potential smoothing, anatomical inhomogeneity, and pulse duration on nerve stimulation was evaluated. As a result, multiple assumptions underlying current safety standards are questioned. It is demonstrated that coupled EM-neuronal dynamics modeling involving realistic anatomies is valuable to establish conservative safety criteria.

Why intra-epidermal electrical stimulation achieves stimulation of small fibres selectively: a simulation study.

The in situ electric field in the peripheral nerve of the skin is investigated to discuss the selective stimulation of nerve fibres. Coaxial planar electrodes with and without intra-epidermal needle tip were considered as electrodes of a stimulator. From electromagnetic analysis, the tip depth of the intra-epidermal electrode should be larger than the thickness of the stratum corneum, the electrical conductivity of which is much lower than the remaining tissue. The effect of different radii of the outer ring electrode on the in situ electric field is marginal. The minimum threshold in situ electric field (rheobase) for free nerve endings is estimated to be 6.3 kV m(-1). The possible volume for electrostimulation, which can be obtained from the in situ electric field distribution, becomes deeper and narrower with increasing needle depth, suggesting that possible stimulation sites may be controlled by changing the needle depth. The injection current amplitude should be adjusted when changing the needle depth because the peak field strength also changes. This study shows that intra-epidermal electrical stimulation can achieve stimulation of small fibres selectively, because Aß-, Aδ-, and C-fibre terminals are located at different depths in the skin.

Inhibitory effects of heterotopic noxious counter-stimulation on perception and brain activity related to Aß-fibre activation.

Heterotopic noxious counter-stimulation (HNCS) inhibits pain and pain processes through cerebral and cerebrospinal mechanisms. However, it is unclear whether HNCS inhibits non-nociceptive processes, which needs to be clarified for a better understanding of HNCS analgesia. The aim of this study was to examine the effects of HNCS on perception and scalp somatosensory evoked potentials (SEPs). Seventeen healthy volunteers participated in two counter-balanced sessions, including non-nociceptive (selective Aß-fibre activation) or nociceptive electrical stimulation, combined with HNCS. HNCS was produced by a 20-min cold pressor test (left hand) adjusted individually to produce moderate pain (mean ± SEM: 42.5 ± 5.3 on a 0-100 scale, where 0 is no pain and 100 the worst pain imaginable). Non-nociceptive electrical stimulation was adjusted individually at 80% of pain threshold and produced a tactile sensation in every subject. Nociceptive electrical stimulation was adjusted individually at 120% of RIII-reflex threshold and produced moderate pain (45.3 ± 4.5). Shock sensation was significantly decreased by HNCS compared with baseline for non-nociceptive (P < 0.001) and nociceptive (P < 0.001) stimulation. SEP peak-to-peak amplitude at Cz was significantly decreased by HNCS for non-nociceptive (P < 0.01) and nociceptive (P < 0.05) stimulation. These results indicate that perception and brain activity related to Aß-fibre activation are inhibited by HNCS. The mechanisms of this effect remain to be investigated to clarify whether it involves inhibition of spinal wide-dynamic-range neurons by diffuse noxious inhibitory controls, supraspinal processes or both.