Assessing the modulation of cutaneous sensory fiber excitability using a fast perception threshold tracking technique.

INTRODUCTION: Topical application of lidocaine-and-prilocaine (LP) cream attenuates the functionality of small cutaneous nerve fibers. The aim of this human study was to measure the underlying excitability modulation of small cutaneous nerve fibers using a novel and fast perception threshold tracking (PTT) technique. METHODS: Small sensory fibers were selectively blocked by 120-minute topical application of LP and confirmed by quantitative sensory testing. Excitability changes of small (activated by a specially designed pin electrode) and large (patch electrode) nerve fibers were assessed as the strength-duration relation and threshold electrotonus. RESULTS: The excitability assessed by the strength-duration relation and threshold electrotonus was significantly modulated for the small afferents (P < 0.05, Wilcoxon's test) but not the large afferents. DISCUSSION: This novel PTT technique was able to assess inhibition of membrane properties of small cutaneous fibers, suggesting the usefulness of the technique as a diagnostic method for assessing impairment of small fibers, as seen in many types of polyneuropathies.

A Novel Stimulation Paradigm to Limit the Habituation of the Nociceptive Withdrawal Reflex.

In gait rehabilitation, combining gait therapy with functional electrical stimulation based on the nociceptive withdrawal reflex (NWR) improves walking velocity and gait symmetry of hemiparetic patients. However, habituation of the NWR can affect the efficacy of training. The current study aimed at identifying the stimulation parameters that would limit, in healthy participants, the habituation of the NWR. The NWR was elicited at every heel-off while the participants walked on a treadmill. Three stimulation paradigms were tested: deterministic paradigm (fixed parameters), stochastic pulse duration paradigm (varying the pulse duration of the stimuli), and stochastic frequency paradigm (varying the frequency of the stimuli). The charge delivered for the three paradigms was identical. The reflex response was quantified by the EMG activity of the tibialis anterior (TA) muscle and as ankle and hip joints angle changes. The ankle dorsiflexion and TA EMG responses were not significantly reduced with the stochastic pulse duration paradigm, in contrast to the two other paradigms. Hence, using a stochastic pulse duration stimulation paradigm seemed to be effective in limiting the habituation of the NWR in heathy individuals. This might be highly relevant for effective gait rehabilitation.

Membrane properties in small cutaneous nerve fibers in humans.

INTRODUCTION: Assessment of membrane properties is important for understanding the mechanisms of painful peripheral neuropathy, developing new diagnostic techniques, and screening/profiling of analgesics that target ion channels. METHODS: Small cutaneous nerves were activated electrically by small diameter (0.2 mm) cathodes, and large nerves were activated by ordinary patch electrodes. This new perception threshold tracking method combines perception threshold assessment and stimulation paradigms from conventional threshold tracking. RESULTS: The strength-duration time-constant of large fibers (580 µs ± 160 µs) was lower than the time constant of small fibers (1060 µs ± 690 µs; P < 0.01, paired t-test). Threshold electrotonus showed similar threshold reductions to sub-threshold prepulses, except for 80 ms hyperpolarizing prepulses, to which small fibers showed less threshold reduction than large fibers (repeated-measures analysis of variance, Bonferroni, P = 0.006). CONCLUSIONS: This is a reliable method to investigate the membrane properties of small cutaneous nerve fibers in humans and may be used in clinical settings as a diagnostic or profiling tool. Muscle Nerve 55: 195-201, 2017.

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.

Nerve Fiber Activation During Peripheral Nerve Field Stimulation: Importance of Electrode Orientation and Estimation of Area of Paresthesia.

INTRODUCTION AND AIM: Low back pain is one of the indications for using peripheral nerve field stimulation (PNFS). However, the effect of PNFS varies between patients; several stimulation parameters have not been investigated in depth, such as orientation of the nerve fiber in relation to the electrode. While placing the electrode parallel to the nerve fiber may give lower activation thresholds, anodal blocking may occur when the propagating action potential passes an anode. METHODS: A finite element model was used to simulate the extracellular potential during PNFS. This was combined with an active cable model of Aß and Aδ nerve fibers. It was investigated how the angle between the nerve fiber and electrode affected the nerve activation and whether anodal blocking could occur. Finally, the area of paresthesia was estimated and compared with any concomitant Aδ fiber activation. RESULTS: The lowest threshold was found when nerve and electrode were in parallel, and that anodal blocking did not appear to occur during PNFS. The activation of Aß fibers was within therapeutic range (<10V) of PNFS; however, within this range, Aδ fiber activation also may occur. The combined area of activated Aß fibers (paresthesia) was at least two times larger than Aδ fibers for similar stimulation intensities. CONCLUSION: No evidence of anodal blocking was observed in this PNFS model. The thresholds were lowest when the nerves and electrodes were parallel; thus, it may be relevant to investigate the overall position of the target nerve fibers prior to electrode placement.

A human experimental model of episodic pain.

An experimental model of daily episodic pain was developed to investigate peripheral sensitization and cortical reorganization in healthy individuals. Two experiments (A and B) were conducted. Experiments A and B consisted of one and five consecutive days, respectively, in which the participants were subjected to 45 min of intense painful cutaneous electrical stimulation (episodic pain session), using a stimulus paradigm that in animals has been shown to induce long-term potentiation. These electrical stimulations produced a verbal pain rating of approximately 85 on a 0-100 verbal rating scale (VRS). Physiological (blood flow and axon flare reflex), psychophysical (perception threshold and verbal pain ratings) and electrophysiological (128 channels recorded somatosensory evoked potential (SEP)) measurements were recorded. The stimulation evoked a visible axon flare reflex and caused significantly increased cutaneous blood flow around the site of the stimulation. Axon flare reflex and blood flow reached a plateau on day one in all the subjects and no significant changes between the days were observed. The results showed that the effect of the electrical stimulations changed over the five days; pain potentiation was induced on the first day (significant increase in the verbal pain ratings during the 45 min stimulation) but not on any of the subsequent days. After five days of subsequent pain induction, the global field power showed a significant reduction in P2 amplitude in the late stage (200-370 ms, in the central-parietal area). In conclusion, the results suggest that in healthy individuals this model of episodic pain produces a rapid adaptation after day one and that generates significant SEP changes at day five.

Activation of peripheral nerve fibers by electrical stimulation in the sole of the foot.

BACKGROUND: Human nociceptive withdrawal reflexes (NWR) can be evoked by electrical stimulation applied to the sole of the foot. However, elicitation of NWRs is highly site dependent, and NWRs are especially difficult to elicit at the heel. The aim of the present study was to investigate potential peripheral mechanisms for any site dependent differences in reflex thresholds. RESULTS: The first part of the study investigated the neural innervation in different sites of the sole of the foot using two different staining techniques. 1) Staining for the Nav1.7 antigen (small nociceptive fibers) and 2) the Sihler whole nerve technique (myelinated part of the nerve). No differences in innervation densities were found across the sole of the foot using the two staining techniques: Nav1.7 immunochemistry (small nociceptive fibers (1-way ANOVA, NS)) and the Sihler's method (myelinated nerve fibers (1-way ANOVA, NS)). However, the results indicate that there are no nociceptive intraepidermal nerve fibers (IENFs) innervating the heel.Secondly, mathematical modeling was used to investigate to what degree differences in skin thicknesses affect the activation thresholds of Aδ and Aß fibers in the sole of the foot. The modeling comprised finite element analysis of the volume conduction combined with a passive model of the activation of branching cutaneous nerve fibers. The model included three different sites in the sole of the foot (forefoot, arch and heel) and three different electrode sizes (diameters: 9.1, 12.9, and 18.3 mm). For each of the 9 combinations of site and electrode size, a total of 3000 Aß fibers and 300 Aδ fibers was modeled. The computer simulation of the effects of skin thicknesses and innervation densities on thresholds of modeled Aδ and Aß fibers did not reveal differences in pain and perception thresholds across the foot sole as have been observed experimentally. Instead a lack of IENFs at the heel decreased the electrical activation thresholds compared to models including IENFs. CONCLUSIONS: The nerve staining and modeling results do not explain differences in NWR thresholds across the sole of the foot which may suggest that central mechanisms contribute to variation in NWR excitability across the sole of the foot.

Estimating nerve excitation thresholds to cutaneous electrical stimulation by finite element modeling combined with a stochastic branching nerve fiber model.

Electrical stimulation of cutaneous tissue through surface electrodes is an often used method for evoking experimental pain. However, at painful intensities both non-nociceptive Aß-fibers and nociceptive Aδ- and C-fibers may be activated by the electrical stimulation. This study proposes a finite element (FE) model of the extracellular potential and stochastic branching fiber model of the afferent fiber excitation thresholds. The FE model described four horizontal layers; stratum corneum, epidermis, dermis, and hypodermal used to estimate the excitation threshold of Aß-fibers terminating in dermis and Aδ-fibers terminating in epidermis. The perception thresholds of 11 electrodes with diameters ranging from 0.2 to 20 mm were modeled and assessed on the volar forearm of healthy human volunteers by an adaptive two-alternative forced choice algorithm. The model showed that the magnitude of the current density was highest for smaller electrodes and decreased through the skin. The excitation thresholds of the Aδ-fibers were lower than the excitation thresholds of Aß-fibers when current was applied through small, but not large electrodes. The experimentally assessed perception threshold followed the lowest excitation threshold of the modeled fibers. The model confirms that preferential excitation of Aδ-fibers may be achieved by small electrode stimulation due to higher current density in the dermoepidermal junction.

Multichannel matching pursuit validation and clustering--a simulation and empirical study.

INTRODUCTION: Multichannel matching pursuit (MMP) is a relatively new method that can be applied to electroencephalogram (EEG) signals in combination with inverse modelling. However, limitations of MMP have not been adequately tested. The aims of this study were to investigate how the accuracy of MMP algorithm is altered due to increased number of brain sources and increased noise level, and to implement and test a modified K-means clustering algorithm in order to group similar MMP atoms in time-frequency and space between subjects together. METHODS: Four groups of 20 EEG signals were simulated. The groups consisted of simulations with 5, 10, 15, and 20 brain sources. The accuracy of MMP algorithm was first tested on increasing number of sources. Then, different levels of noise were added to the simulations and accuracy of the algorithm was tested on increasing noise level. K-means clustering algorithm was tested on 4 datasets (5, 10, 15, and 20 sources) of 10 similar phantom subjects. Finally, the clustering algorithm was tested on empirical somatosensory evoked potential and brainstem evoked potential data. RESULTS: The MMP accuracy decreased as the number of sources increased and MMP accuracy was robust to noise. Furthermore, we found that when applying the clustering method to a subject group's MMP data, the clustering method grouped the similar atoms between subjects correctly. CONCLUSION: The MMP and clustering method proved to be an efficient way to group similar brain activity and thus study differences in brain activation sequence to sensory stimulation between groups of subjects.

The effect of visuo-spatial organisation in recognition-memory tasks.

We investigated whether recognition memory benefits when stimuli are organised in a visuo-spatial array. Three different memory tasks were compared: (a) verbal task (what); (b) spatial task (where); (c) combination task, where both verbal and spatial informations were combined together (what/where). We hypothesised that when visual stimuli are organised in a spatial array the recognition is better. Recognition memory was assessed by quantifying the speed of correct responses and the total number of correct responses in a group of male volunteers (N = 20). Subjects' task was to recognise a stimulus probe from sequences (one versus three) of stimuli. All stimuli appeared randomly in one of nine locations on a 3 x 3 grid. The results show that subjects were faster and more accurate when they had to recognise only spatial information (where) than when they had to recognise verbal information (what) or the combination of both verbal and spatial information (what/where). Additionally, when the stimuli were presented in a spatial array there were benefits for the spatial task, whilst verbal and combination tasks were unaffected. Additionally, asymmetry between left and right hemifields has been found. These findings are discussed with regard to different memory processes that operate independently.

An automated method for micro-state segmentation of evoked potentials.

We present a method for segmenting evoked potentials into functional micro-states. The method is based on measuring the similarity between all the topographic maps in the evoked potential and grouping them into functional micro-states based on minimizing an error function. The similarity is measured as the normalized cross-correlation coefficient. The method was validated on simulated data and tested on its ability to segment a visual evoked potential. On simulated data the method missed from 1% to 8.5% of the micro-state boundaries for evoked potentials with a signal-to-noise ratio of 20-1dB, respectively. The proposed segmentation method was compared with segmentation based on K-mean clustering. It was found that the proposed method was better at detecting the correct number of micro-states and was computationally more efficient. The automatic segmentation of the visual evoked potential was compared to the manual segmentation performed by eleven EEG specialists. No significant difference in the deviation of micro-state boundaries was observed between two random EEG specialists and between a random EEG specialist and the automatic method. Thus it was found that the method could reliably segment evoked potentials into their functional micro-states.

Velocity recovery function of the compound muscle action potential assessed with doublet and triplet stimulation.

Normative values of muscle fiber conduction velocity depend on the conditions in which conduction velocity is measured due to the velocity recovery function (VRF) of muscle fibers. In this study the VRF of the compound muscle action potential (CMAP) was assessed following doublet and triplet stimulation in order to investigate the effect of repetitive muscle activation on muscle fiber conduction velocity. The VRF from doublet and triplet activation showed a peak of 4.6%-15.0% and 6.4%-25.9%, respectively, which is not significantly different. The VRF of the CMAP with doublet stimulation had a plateau between 25-75 ms, similar to that reported for single muscle fibers, and changed as a consequence of previous activation. The VRFs with doublet and triplet stimulation were different for interstimulus intervals in the range of 12-250 ms, where the triplet resulted in a plateau of supernormal conduction velocity. The VRF of the triplet could be explained by linear summation of the effects from doublet stimulations only for small distances between the two conditioning stimuli. These results provide new information on the adaptation of membrane properties of muscle fibers to repetitive activation. Changes in CMAP properties due to repeated activation may influence the accuracy of techniques based on CMAP recordings, such as collision methods.

The recruitment order of electrically activated motor neurons investigated with a novel collision technique.

OBJECTIVE: The development of a novel collision technique for assessment of the activation order of electrically activated nerve fibers, which is an important question in functional electrical therapy or for interpretation of results of motor unit number estimates. METHODS: Compound muscle action potentials were recorded with the belly-tendon configuration from the abductor digiti minimi. A novel modified Hopf's collision technique was applied on ten healthy male subjects to determine the distributions of conduction velocities (DCV) of all ulnar nerve fibers and of the fibers activated by electrical stimuli eliciting 20%, 50%, and 80% of the maximal muscle response. RESULTS: The maximum nerve conduction velocity was (means+/-SE) 64.1+/-0.85m/s. The median conduction velocity of estimated DCV was 58.9+/-0.97m/s (stimulus at 20%), 58.0+/-0.98m/s (50%), 57.2+/-0.91m/s (80%), and 56.5+/-0.84m/s (whole nerve) (all different between each other, P<0.001). CONCLUSIONS: The proposed collision technique allows the assessment of nerve conduction velocity distributions at maximal and sub-maximal stimulation levels and provided evidence for an inverse activation order of nerve fibers with electrical stimulation. SIGNIFICANCE: The excessive fatigue seen with nerve electrical stimulation can be explained by a preferential activation of large diameter nerve fibers. The motor units first activated with electrical stimulation are likely not representative of the motor unit pool in the muscle, which poses limitations in the reliability of some of the proposed methods for motor unit counting.

Breakdown of accommodation in nerve: a possible role for persistent sodium current.

BACKGROUND: Accommodation and breakdown of accommodation are important elements of information processing in nerve fibers, as they determine how nerve fibers react to natural slowly changing stimuli or electrical stimulation. The aim of the present study was to elucidate the biophysical mechanism of breakdown of accommodation, which at present is unknown. RESULTS: A model of a space-clamped motor nerve fiber was developed. It was found that this new model could reproduce breakdown of accommodation when it included a low-threshold, rapidly activating, persistent sodium current. However, the phenomenon was not reproduced when the persistent sodium current did not have fast activation kinetics or a low activation threshold. CONCLUSION: The present modeling study suggests that persistent, low-threshold, rapidly activating sodium currents have a key role in breakdown of accommodation, and that breakdown of accommodation can be used as a tool for studying persistent sodium current under normal and pathological conditions.

Orderly activation of human motor neurons using electrical ramp prepulses.

OBJECTIVE: Conventional electrical stimulation (rectangular pulses) recruits large before small diameter motor neurons and motor neurons close to the electrode before more distant motor neurons. The present study investigated the possibility for changing the recruitment order of electrical stimuli with sub-threshold ramp prepulses. METHODS: The median nerve was stimulated using surface electrodes at the wrist and elbow. Compound motor action potentials were recorded from abductor pollicis brevis and flexor carpi radialis. Stimulus-response curves, nerve conduction velocity and excitation thresholds of abductor pollicis brevis and flexor carpi radials, with and without ramp prepulses, were recorded in order to study the effect of ramp prepulses on axonal excitability. RESULTS: The conduction velocity of the initial response (10% of the maximal response) was decreased by 4.3+/-0.83m/s with ramp prepulses (500ms, 80% of the excitation threshold). The ramp prepulses also had a differential effect on the excitation thresholds of abductor pollicis brevis and flexor carpi radialis. In addition, ramp prepulses increased the threshold of 10% of the maximal response more than the threshold of 90% of the maximal response. CONCLUSIONS: These results demonstrate that large diameter and motor neurons close to the electrode accommodate more to ramp prepulses than small diameter and distant motor neurons, which suggests that ramp prepulses may be used to change the recruitment order of rectangular pulses. SIGNIFICANCE: This technique of ramp prepulses allows stimulation of alternate subsets of motor nerves.