Excitation Of Nerve Fibers Research Articles

Auditory nerve fiber excitability for alternative electrode placement in the obstructed human cochlea: electrode insertion in scala vestibuli versus scala tympani

Objective. The cochlear implant (CI) belongs to the most successful neuro-prostheses. Traditionally, the stimulating electrode arrays are inserted into the scala tympani (ST), the lower cochlear cavity, which enables simple surgical access. However, often deep insertion is blocked, e.g. by ossification, and the auditory nerve fibers (ANFs) of lower frequency regions cannot be stimulated causing severe restrictions in speech understanding. As an alternative, the CI can be inserted into the scala vestibuli (SV), the other upper cochlear cavity. Approach. In this computational study, the excitability of 25 ANFs are compared for stimulation with ST and SV implants. We employed a 3-dimensional realistic human cochlear model with lateral wall electrodes based on a μ-CT dataset and manually traced fibers. A finite element approach in combination with a compartment model of a spiral ganglion cell was used to simulate monophasic stimulation with anodic (ANO) and cathodic (CAT) pulses of 50 μs. Main results. ANO thresholds are lower in ST (mean/std = μ/σ = 189/55 μA) stimulation compared to SV (μ/σ = 323/119 μA) stimulation. Contrary, CAT thresholds are higher for the ST array (μ/σ = 165/42 μA) compared to the SV array (μ/σ = 122/46 μA). The threshold amplitude depends on the specific fiber-electrode spatial relationship, such as lateral distance from the cochlear axis, the angle between electrode and target ANF, and the curvature of the peripheral process. For CAT stimulation the SV electrodes show a higher selectivity leading to less cross-stimulation of additional fibers from different cochlear areas. Significance. We present a first simulation study with a human cochlear model that investigates an additional CI placement into the SV and its impact on the excitation behavior. Results predict comparable outcomes to ST electrodes which confirms that SV implantation might be an alternative for patients with a highly obstructed ST.

Numerical simulation of neural excitation during brain tumor ablation by microsecond pulses

Replacing monopolar pulse with bipolar pulses of the same energized time can minimize unnecessary neurological side effects during irreversible electroporation (IRE). An improved neural excitation model that considers dynamic conductivity and thermal effects during brain tumor IRE ablation was proposed for the first time in this study. Nerve fiber excitation during IRE ablation by applying a monopolar pulse (100 μs) and a burst of bipolar pulses (energized time of 100 μs with both the sub-pulse length and interphase delay of 1 μs) was investigated. Our results suggest that both thermal effects and dynamic conductivity change the onset time of action potential (AP), and dynamic conductivity also changes the hyperpolarization amplitude. Considering both thermal effects and dynamic conductivity, the hyperpolarization amplitude in nerve fibers located 2 cm from the tumor center was reduced by approximately 23.8 mV and the onset time of AP was delayed by approximately 17.5 μs when a 500 V monopolar pulse was applied. Moreover, bipolar pulses decreased the excitable volume of brain tissue by approximately 68.8 % compared to monopolar pulse. Finally, bipolar pulses cause local excitation with lesser damage to surrounding healthy tissue in complete tumor ablation, demonstrating the potential benefits of bipolar pulses in brain tissue ablation.

Estimation of electric field inside a neural spheroid by low‐frequency magnetic field exposure

AbstractExposure to time‐varying, low‐frequency and high‐intensity magnetic field (MF) induce electric field (EF) inside the human body, producing stimulus effects such as nerve fiber excitation or synaptic modulation. To measure such stimulus effects by low‐frequency MF exposure in real‐time, we developed a fluorescent recording system using optical fibers that is neither affected by the MF nor affects the MF distribution. In this study, a numerical calculation model composed of voxels with a 6.25 µm spatial resolution was developed. Using this numerical model, we evaluated the distribution of the EF generated inside three‐dimensional neuronal tissue called neural spheroid, under 50 Hz sinusoidal wave, 300 mT (root mean square) uniform MF exposure. We also investigated the influence of the optical fiber on the electric field distribution in neural spheroid. As a result, MF produced an induced EF in the neural spheroid of more than 4 V/m, well above the theoretical threshold of synaptic modulation. These results indicated that our experimental system was suitable for the evaluation of the threshold of stimulus effects using neural spheroid.

BRUXISM AS A CAUSE OF NEUROPHYSIOLOGICAL ALTERATIONS IN THE TRIGEMINAL COMPLEX

All components of the dentoalveolar structures demonstrate close interconnections, especially in the intricate relationship between the nervous and muscular aspects of the temporomandibular joint (TMJ). The muscular system relies hierarchically on the regulatory mechanisms of the nervous system. Consequently, any disruption in the interaction between these components can lead to pathology affecting the overall function of the TMJ. One of the most prevalent myogenic disorders is bruxism, impacting 6-20% of the global population. However, pronounced signs of this condition are observed in only 3-5% of individuals. Bruxism is a multifactorial disorder, and its exact etiology remains unclear. Currently, a primary factor in bruxism is considered to be a disturbance in the body's adaptive capacity to cope with stress. Psychological stress induces hyperactivity in the masticatory muscles, leading to intense clenching of the dentition. This, in turn, results in an overload of the supporting tooth tissues, pathological abrasion of the dentition, dysfunction of the temporomandibular joint (TMJ), and the emergence of general clinical symptoms such as headaches, orofacial issues, and neurological symptoms. The pathophysiological foundation of bruxism lies in the excessive strain on the masticatory muscles, causing ischemia and inflammation in the muscle fibers. The inflammatory process in these fibers triggers a persistent excitation of afferent nerve fibers of type C, giving rise to a dull, aching pain. As bruxism is a chronic condition, there is a physiological restructuring of nerve fibers. This involves the initial peripheral and subsequent central sensitization of C-type nerve fibers, resulting in an inappropriate response of the body to physiological stimuli. For instance, the nervous system begins to interpret minor stimuli as painful (hyperalgesia). Currently, no treatment methods completely eliminate bruxism. Modern treatment approaches involve the use of intraoral dental appliances, pharmacotherapy (with muscle relaxants such as botulinum toxin type A and drugs from the benzodiazepine group), and psychotherapy courses aims to teach patients sleep hygiene, self-control, and the elimination of detrimental habits, including clenching the dentition as a response to psychological stress.

Modeling the excitation of nerve axons under transcutaneous stimulation

Computational models enable a safe and convenient way to study the excitation of nerve fibers under external stimulation. Contemporary models calculate the electric field distribution from transcutaneous stimulation and the resulting neuronal response separately. This study uses finite element methods to develop a multi-scale model that couples electric fields within macroscopic tissue layers and microscopic nerve fibers in a single-stage computational framework. The model included a triaxial myelinated nerve fiber bundle embedded within a volume conductor of tissue layers to represent the median nerve innervating the forearm muscles. The model captured the excitability of nerve fibers under transcutaneous stimulation and their nerve-tissue interactions to a transient external stimulus. The determinants of the strength-duration curve, rheobase, and chronaxie for the proposed model had close correlations with in-vivo experimentation on human participants. Additionally, the excitability indices for the triaxial myelinated nerve fiber implemented using the finite element method agreed well with experimental data from the literature. The validity of the proposed model encourages its use for applications involving transcutaneous stimulation. Capable of capturing field distribution across realistic morphologies, the model can serve as a testbed to improve stimulation protocols and electrode designs with subject-level specificity.

Potent dual MAGL/FAAH inhibitor AKU-005 engages endocannabinoids to diminish meningeal nociception implicated in migraine pain

BackgroundEngaging the endocannabinoid system through inhibition of monoacylglycerol lipase (MAGL) and fatty acid amide hydrolase (FAAH), degrading endocannabinoids (endoCBs) 2-arachidonoylglycerol (2-AG) and anandamide (AEA), was proposed as a promising approach to ameliorate migraine pain. However, the activity of MAGL and FAAH and action of endoCB on spiking activity of meningeal afferents, from which migraine pain originates, has not been explored thus far. Therefore, we here explored the analgesic effects of endoCB enhancement in rat and human meningeal tissues.MethodsBoth MAGL and FAAH activity and local 2-AG and AEA levels were measured by activity-based protein profiling (ABPP) and LC–MS/MS, respectively, in rat meninges obtained from hemiskulls of P38-P40 Wistar rats and human meninges from elderly patients undergoing non-migraine related neurosurgery. The action on endoCBs upon administration of novel dual MAGL/FAAH inhibitor AKU-005 on meningeal afferents excitability was tested by investigating paired KCl-induced spiking and validation with local (co-)application of either AEA or 2-AG. Finally, the specific TRPV1 agonist capsaicin and blocker capsazepine were tested.ResultsThe basal level of 2-AG exceeded that of AEA in rat and human meninges. KCl-induced depolarization doubled the level of AEA. AKU-005 slightly increased spontaneous spiking activity whereas the dual MAGL/FAAH inhibitor significantly decreased excitation of nerve fibres induced by KCl. Similar inhibitory effects on meningeal afferents were observed with local applications of 2-AG or AEA. The action of AKU-005 was reversed by CB1 antagonist AM-251, implying CB1 receptor involvement in the anti-nociceptive effect. The inhibitory action of AEA was also reversed by AM-251, but not with the TRPV1 antagonist capsazepine. Data cluster analysis revealed that both AKU-005 and AEA largely increased long-term depression-like meningeal spiking activity upon paired KCl-induced spiking.ConclusionsIn the meninges, high anti-nociceptive 2-AG levels can tonically counteract meningeal signalling, whereas AEA can be engaged on demand by local depolarization. AEA-mediated anti-nociceptive effects through CB1 receptors have therapeutic potential. Together with previously detected MAGL activity in trigeminal ganglia, dual MAGL/FAAH inhibitor AKU-005 appears promising as migraine treatment.Graphical

Do long-lasting effects of epidural polarization of afferent fibres depend on persistent sodium current?

Few attempts have so far been made to define the mechanisms underlying the hour-long effects of trans-spinal stimulation combined with epidural polarization. In the present study, we investigated the potential involvement of non-inactivating sodium channels in afferent fibres. To this end, riluzole, a blocker of these channels, was administered locally to the dorsal columns close to the site of the excitation of afferent nerve fibres by epidural stimulation in deeply anaesthetized rats in vivo. Riluzole did not prevent the induction of the polarization-evoked sustained increase in the excitability of dorsal column fibres but tended to weaken it. It likewise weakened but did not abolish the sustained polarization-evoked shortening of the refractory period of these fibres. These results lead to the conclusion that the persistent sodium current may contribute to the sustained post-polarization-evoked effects but is only partly involved in both the induction and the expression of these effects.

Apical Reference Stimulation: A Possible Solution to Facial Nerve Stimulation.

Postimplantation facial nerve stimulation is a common side-effect of intracochlear electrical stimulation. Facial nerve stimulation occurs when electric current intended to stimulate the auditory nerve, spread beyond the cochlea to excite the nearby facial nerve, causing involuntarily facial muscle contractions. Facial nerve stimulation can often be resolved through adjustments in speech processor fitting but, in some instances, these measures exhibit limited benefit or may have a detrimental effect on speech perception. In this study, apical reference stimulation mode was investigated as a potential intervention to facial nerve stimulation. Apical reference stimulation is a bipolar stimulation strategy in which the most apical electrode is used as the reference electrode for stimulation on all the other intracochlear electrodes. A person-specific model of the human cochlea, facial nerve and electrode array, coupled with a neural model, was used to predict excitation of auditory and facial nerve fibers. These predictions were used to evaluate the effectiveness in reducing facial nerve stimulation using apical reference stimulation. Predictions were confirmed in psychoacoustic tests by determining auditory comfort and threshold levels for the apical reference stimulation mode while capturing electromyography data in two participants. Models predicted a favorable outcome for apical reference stimulation, as facial nerve fiber thresholds were higher and auditory thresholds were lower, in direct comparison to conventional monopolar stimulation. Psychophysical tests also illustrated decreased auditory thresholds and increased dynamic range during apical reference stimulation. Furthermore, apical reference stimulation resulted in lower electromyography energy levels, compared to conventional monopolar stimulation, which suggests a reduction in facial nerve stimulation. Subjective feedback corroborated that apical reference stimulation alleviated facial nerve stimulation. Apical reference stimulation may be a viable strategy to alleviate facial nerve stimulation considering the improvements in dynamic range and auditory thresholds, complemented with a reduction in facial nerve stimulation symptoms.

Sensitivity Study of Neuronal Excitation and Cathodal Blocking Thresholds of Myelinated Axons for Percutaneous Auricular Vagus Nerve Stimulation.

Excitation of myelinated nerve fibers is investigated by means of numerical simulations, for the application of percutaneous auricular vagus nerve stimulation (pVNS). High sensitivity to axon diameter is of interest regarding the goal of targeting thicker fibers. Excitation and blocking thresholds for different pulse types, phase durations, axon depths, axon-electrode distances, temperatures and axon diameters are investigated. The used model consists of a 50mm long axon and a centrally located needle electrode in a layered medium representing the auricle. Neuronal excitation is simulated using the Frankenhaeuser-Huxley equations for all combinations of parameter values. Multiple modes and locations of excitation along the axon were observed, depending on the pulse type and amplitude. When increasing the axon-electrode distance from 1mm to 2mm, sensitivity of thresholds to axon depth decreased with ca. 50%, while sensitivity to axon-electrode distance, axon diameter and phase duration each increased with ca. 15% to 20%, except from monophasic anodal pulses, showing a 45% decrease for axon-electrode distance. These trends for axon diameter and axon-electrode distance allow for more selective stimulation of thicker target fibers using monophasic anodal pulses at higher axon-electrode distances. Cathodal monophasic pulses did not perform well due to blocking of the thicker fibers, which was only rarely seen for other pulse types. Sensitivities of stimulation thresholds to these parameters by numerical simulation reveal how the stimulation parameters can be changed in order to increase therapeutic effect and comfort during pVNS by enabling more selective stimulation.

Purinergic Modulation of Activity in the Developing Auditory Pathway.

Purinergic P2 receptors, activated by endogenous ATP, are prominently expressed on neuronal and non-neuronal cells during development of the auditory periphery and central auditory neurons. In the mature cochlea, extracellular ATP contributes to ion homeostasis, and has a protective function against noise exposure. Here, we focus on the modulation of activity by extracellular ATP during early postnatal development of the lower auditory pathway. In mammals, spontaneous patterned activity is conveyed along afferent auditory pathways before the onset of acoustically evoked signal processing. During this critical developmental period, inner hair cells fire bursts of action potentials that are believed to provide a developmental code for synaptic maturation and refinement of auditory circuits, thereby establishing a precise tonotopic organization. Endogenous ATP-release triggers such patterned activity by raising the extracellular K+ concentration and contributes to firing by increasing the excitability of auditory nerve fibers, spiral ganglion neurons, and specific neuron types within the auditory brainstem, through the activation of diverse P2 receptors. We review recent studies that provide new models on the contribution of purinergic signaling to early development of the afferent auditory pathway. Further, we discuss potential future directions of purinergic research in the auditory system.

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

To assess the lasting effects on sensory nerve membrane excitability of transcutaneous peripheral nerve stimulation with cathodal direct currents (pDCS). 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). 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. 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.

Altered excitability of small cutaneous nerve fibers during cooling assessed with the perception threshold tracking technique

BackgroundThere is a need for new approaches to increase the knowledge of the membrane excitability of small nerve fibers both in healthy subjects, as well as during pathological conditions. Our research group has previously developed the perception threshold tracking technique to indirectly assess the membrane properties of peripheral small nerve fibers. In the current study, a new approach for studying membrane excitability by cooling small fibers, simultaneously with applying a slowly increasing electrical stimulation current, is evaluated. The first objective was to examine whether altered excitability during cooling could be detected by the perception threshold tracking technique. The second objective was to computationally model the underlying ionic current that could be responsible for cold induced alteration of small fiber excitability. The third objective was to evaluate whether computational modelling of cooling and electrical simulation can be used to generate hypotheses of ionic current changes in small fiber neuropathy.ResultsThe excitability of the small fibers was assessed by the perception threshold tracking technique for the two temperature conditions, 20 °C and 32 °C. A detailed multi-compartment model was developed, including the ionic currents: NaTTXs, NaTTXr, NaP, KDr, KM, KLeak, KA, and Na/K-ATPase. The perception thresholds for the two long duration pulses (50 and 100 ms) were reduced when the skin temperature was lowered from 32 to 20 °C (p < 0.001). However, no significant effects were observed for the shorter durations (1 ms, p = 0.116; 5 ms p = 0.079, rmANOVA, Sidak). The computational model predicted that the reduction in the perception thresholds related to long duration pulses may originate from a reduction of the KLeak channel and the Na/K-ATPase. For short durations, the effect cancels out due to a reduction of the transient TTX resistant sodium current (Nav1.8). Additionally, the result from the computational model indicated that cooling simultaneously with electrical stimulation, may increase the knowledge regarding pathological alterations of ionic currents.ConclusionCooling may alter the ionic current during electrical stimulation and thereby provide additional information regarding membrane excitability of small fibers in healthy subjects and potentially also during pathological conditions.

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.

Ephaptic interactions between myelinated nerve fibres of rodent peripheral nerves.

We report evidence that ephaptic interactions may occur between intact mammalian myelinated nerve fibres and not only between demyelinated or damaged mammalian nerve fibres or nerve cells as analysed in previous studies. The ephaptic interactions were investigated between nerve fibres traversing the lumbar dorsal roots and between bundles of fibres in the sciatic nerve in anaesthetized rats in vivo. The interactions were estimated by comparing the excitability of nerve fibres originating from one of the hindlimb nerves (peroneal or sural) under control conditions and when the stimulation of these fibres was combined with stimulation of another nerve (tibial). An increase in nerve volleys recorded from group I muscle afferents in the peroneal nerve and of the fastest skin afferents in the sural nerve was used as a measure of the increase in the excitability. The excitability of these fibres was increased during a fraction of a millisecond, coinciding with the period of passage of nerve impulses evoked by the conditioning stimulation of the tibial nerve. The degree of the increase was comparable to the increases in the excitability evoked by 1-2min lasting fibre polarization. Ephaptic interactions were found to be more potent and with longer lasting after-effects within the dorsal roots than within the sciatic nerve. We postulate that ephaptic interactions may result in the synchronization of information forwarded via neighbouring afferent nerve fibres prior to their entry into the spinal cord and thereby securing the propagation of nerve impulses across branching points within the spinal grey matter.

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.

Chapter 8 - Clinical neurophysiology of pain

Clinical neurophysiologic investigation of pain pathways in humans is based on specific techniques and approaches, since conventional methods of nerve conduction studies and somatosensory evoked potentials do not explore these pathways. The proposed techniques use various types of painful stimuli (thermal, laser, mechanical, or electrical) and various types of assessments (measurement of sensory thresholds, study of nerve fiber excitability, or recording of electromyographic reflexes or cortical potentials). The two main tests used in clinical practice are quantitative sensory testing and pain-related evoked potentials (PREPs). In particular, PREPs offer the possibility of an objective assessment of nociceptive pathways. Three types of PREPs can be distinguished depending on the type of stimulation used to evoke pain: laser-evoked potentials, contact heat evoked potentials, and intraepidermal electrical stimulation evoked potentials (IEEPs). These three techniques investigate both small-diameter peripheral nociceptive afferents (mainly Aδ nerve fibers) and spinothalamic tracts without theoretically being able to differentiate the level of lesion in the case of abnormal results. In routine clinical practice, PREP recording is a reliable method of investigation for objectifying the existence of a peripheral or central lesion or loss of function concerning the nociceptive pathways, but not the existence of pain. Other methods, such as nerve fiber excitability studies using microneurography, more directly reflect the activities of nociceptive axons in response to provoked pain, but without detecting or quantifying the presence of spontaneous pain. These methods are more often used in research or experimental study design. Thus, it should be kept in mind that most of the results of neurophysiologic investigation performed in clinical practice assess small fiber or spinothalamic tract lesions rather than the neuronal mechanisms directly at the origin of pain and they do not provide objective quantification of pain.

To flourish or perish: evolutionary TRiPs into the sensory biology of plant-herbivore interactions.

The interactions between plants and their herbivores are highly complex systems generating on one side an extraordinary diversity of plant protection mechanisms and on the other side sophisticated consumer feeding strategies. Herbivores have evolved complex, integrative sensory systems that allow them to distinguish between food sources having mere bad flavors from the actually toxic ones. These systems are based on the senses of taste, olfaction and somatosensation in the oral and nasal cavities, and on post-ingestive chemosensory mechanisms. The potential ability of plant defensive chemical traits to induce tissue damage in foragers is mainly encoded in the latter through chemesthetic sensations such as burning, pain, itch, irritation, tingling, and numbness, all of which induce innate aversive behavioral responses. Here, we discuss the involvement of transient receptor potential (TRP) channels in the chemosensory mechanisms that are at the core of complex and fascinating plant-herbivore ecological networks. We review how "sensory" TRPs are activated by a myriad of plant-derived compounds, leading to cation influx, membrane depolarization, and excitation of sensory nerve fibers of the oronasal cavities in mammals and bitter-sensing cells in insects. We also illustrate how TRP channel expression patterns and functionalities vary between species, leading to intriguing evolutionary adaptations to the specific habitats and life cycles of individual organisms.

P15. Multimodal mapping of nerve pathology with a multichannel approach

Objective Clinical electroneurography, the diagnostic standard for the assessment of thickly myelinated peripheral nerves, is of limited spatial resolution since it provides only average data (nerve conduction velocity [NCV], nerve or muscle action potential amplitude) on relatively large nerve segments. Accordingly, different distribution patterns of axonal or myelin pathologies cannot be distinguished. But precisely this is relevant to ensure correct diagnosis and therapies. These can pose a relevant burden on the patient ranging from spontaneous recovery over surgical to medical, partly highly expensive, treatment. Hence, our main objective is to optimize the diagnostic specificity via a multichannel neurographical approach. By adding ultrasound data, a functional-structural model can be developed as a novel basis for medical decision making. Methods Based on ultrasound, eight electrodes are positioned along the course of the median and ulnar nerve, respectively, and nerve depth (distance to skin) profiles are recorded. Bipolar direct current stimulation is applied close to the M. abductor pollicis brevis and the M. abductor digiti minimi, resulting in the excitation of both motor and sensory nerve fibers (mixed nerve technique) ( Buschbacher, 1999 ) such that eight mixed nerve action potentials (NAPs) can be recorded along the nerve. We performed reference measurements in 10 healthy volunteers. Results Median nerve depth ranged from 2 to 23 mm, and we recorded reproducible signals at all locations with a maximum of 8 averages (at 20 mm) in good correspondence with previously published values ( Fig. 1 ) ( Watson et al., 2002 ). Fig. 2 reports the (inverse) relationship between NAP amplitudes and depth. Discussion Using the setup described, we reliably obtain NAP and their latencies of two peripheral nerves along their course with slight or no averaging. The interesting question is, if and how different pathologies influence the amplitude level. The next step will be the assessment of nerve pathologies to test that diagnostic and therapeutic decision making benefits from structural-functional nerve mapping with high spatial resolution.

Long-term effects of direct current are reproduced by intermittent depolarization of myelinated nerve fibers.

Direct current (DC) potently increases the excitability of myelinated afferent fibers in the dorsal columns, both during DC polarization of these fibers and during a considerable (>1 h) postpolarization period. The aim of the present study was to investigate whether similarly long-lasting changes in the excitability of myelinated nerve fibers in the dorsal columns may be evoked by field potentials following stimulation of peripheral afferents and by subthreshold epidurally applied current pulses. The experiments were performed in deeply anesthetized rats. The effects were monitored by changes in nerve volleys evoked in epidurally stimulated hindlimb afferents and in the synaptic actions of these afferents. Both were found to be facilitated during as well as following stimulation of a skin nerve and during as well as following epidurally applied current pulses of 5- to 10-ms duration. The facilitation occurring ≤2 min after skin nerve stimulation could be linked to both primary afferent depolarization and large dorsal horn field potentials, whereas the subsequent changes (up to 1 h) were attributable to effects of the field potentials. The findings lead to the conclusion that the modulation of spinal activity evoked by DC does not require long-lasting polarization and that relatively short current pulses and intrinsic field potentials may contribute to plasticity in spinal activity. These results suggest the possibility of enhancing the effects of epidural stimulation in human subjects by combining it with polarizing current pulses and peripheral afferent stimulation and not only with continuous DC. NEW & NOTEWORTHY The aim of this study was to define conditions under which a long-term increase is evoked in the excitability of myelinated nerve fibers. The results demonstrate that a potent and long-lasting increase in the excitability of afferent fibers traversing the dorsal columns may be induced by synaptically evoked intrinsic field as well as by epidurally applied intermittent current pulses. They thus provide a new means for the facilitation of the effects of epidural stimulation.

NaV1.1 inhibition can reduce visceral hypersensitivity.

Functional bowel disorder patients can suffer from chronic abdominal pain, likely due to visceral hypersensitivity to mechanical stimuli. As there is only a limited understanding of the basis of chronic visceral hypersensitivity (CVH), drug-based management strategies are ill defined, vary considerably, and include NSAIDs, opioids, and even anticonvulsants. We previously reported that the 1.1 subtype of the voltage-gated sodium (NaV; NaV1.1) channel family regulates the excitability of sensory nerve fibers that transmit a mechanical pain message to the spinal cord. Herein, we investigated whether this channel subtype also underlies the abdominal pain that occurs with CVH. We demonstrate that NaV1.1 is functionally upregulated under CVH conditions and that inhibiting channel function reduces mechanical pain in 3 mechanistically distinct mouse models of chronic pain. In particular, we use a small molecule to show that selective NaV1.1 inhibition (a) decreases sodium currents in colon-innervating dorsal root ganglion neurons, (b) reduces colonic nociceptor mechanical responses, and (c) normalizes the enhanced visceromotor response to distension observed in 2 mouse models of irritable bowel syndrome. These results provide support for a relationship between NaV1.1 and chronic abdominal pain associated with functional bowel disorders.