Test-Retest Reliability of the Generalized Pain Questionnaire in Patients with Rheumatoid Arthritis and Preliminary Reference Values for Non-Clinical and Several Clinical Samples.

Introduction: Generalized pain hypersensitivity is a characteristic feature in many different types of chronic pain. Recently, a 7-item self-reported Generalized Pain Questionnaire (GPQ) was developed to evaluate the presence and severity of generalized pain hypersensitivity in chronic pain patients. Here, we evaluate the test-retest reliability of the GPQ and report on preliminary reference values for various patient groups and healthy subjects. Methods: Eighty-five patients diagnosed with Rheumatoid Arthritis (RA) completed the GPQ twice over a 2-week interval. Relative and absolute indicators of reliability were determined using data of 69 patients (81.2% retest response rate). Using readily available datasets, preliminary reference data were established in two nonclinical populations (NCP1; N = 30 and NCP2; N = 111), and for patients diagnosed with RA (N = 114), gout (N = 97), fibromyalgia (N=98), or neuropathy (N = 25), or participants in a pain rehabilitation program (N = 33). Results: Total GPQ scores had an ICC of 0.78 (95% CI: 0.67 to 0.86). While no systematic or proportional differences were found for the GPQ total score; two (near-)significant systematic differences were observed for the individual questions. The standard error of measurement and minimal detectable change were 2.22 and 6.2, respectively. Mean ± SD scores were found to be 0.8 ± 1.2 (NCP1), 4.0 ± 4.6 (NCP2), 6.4 ± 5.5 (Gout), 6.5 ± 5.1 (RA), 8.1 ± 4.5 (Neuropathy), 13.6 ± 4.0 (Rehabilitation) and 16.0 ± 5.0 (Fibromyalgia). Discussion: This study shows that the GPQ has acceptable reliability to be used as a tool to evaluate the presence and intensity of generalized pain hypersensitivity. The absolute measures of reliability and the preliminary reference values reported here aid in the interpretation of future studies with the GPQ.

Identification of Diabetic Small-Fiber Neuropathy Based on Electrophysiological and Psychophysical Responses to Intra-Epidermal Electric Stimulation using a Naïve Bayes Classifier.

Diagnosis and stratification of small-fiber neuropathy patients is difficult due to a lack of methods that are both sensitive and specific. Our lab recently developed a method to accurately measure psychophysical and electrophysiological responses to intra-epidermal electric stimulation, specifically targeting small nerve fibers in the skin. In this work, we study whether using one or a combination of psychophysical and electrophysiological outcome measures can be used to identify diabetic small-fiber neuropathy. It was found that classification of small-fiber neuropathy based on psychophysical and electrophysiological responses to intra-epidermal electric stimulation could match or even outperform current state-of-the-art methods for the diagnosis of small-fiber neuropathy.Clinical Relevance-Neuropathy is damage or dysfunction of nerves in the skin, often leading to the development of chronic pain. Small-fiber neuropathy is the most prevalent type of neuropathy and occurs frequently in patients with diabetes mellitus, but can also occur in other diseases or in response to chemotherapy. Early detection of neuropathy could help diabetic patients to adapt glucose management, and doctors to adjust treatment strategies to prevent nerve loss and chronic pain, but is impeded by a lack of clinical tools to monitor small nerve fiber function.

Exploring Psychophysical and Neurophysiological Responses to Intra-Epidermal Electrical Stimuli in Patients With Persistent Spinal Pain Syndrome Type 2 with a Spinal Cord Stimulator.

There is a lack of measures that provide insights into how spinal cord stimulation (SCS) modulates nociceptive function in patients with persistent spinal pain syndrome type 2 (PSPS-T2). Recently, we observed altered nociceptive detection thresholds (NDTs) in response to intra-epidermal electrical stimulation (IES) on the feet of PSPS-T2 patients when dorsal root ganglion stimulation was turned on. Furthermore, we observed altered NDTs and evoked potentials (EPs) in response to IES on the hands of PSPS-T2 patients. To explore whether EPs were obstructed by SCS artifacts, we applied IES twice to the hands of patients with SCS turned on (SCS-ON/ON group). To explore possible confounding effects of SCS outside the stimulated area, we repeated IES on the hands of these patients, once with SCS turned off and subsequently once with SCS turned on (SCS-OFF/ON group). The results demonstrated that EPs were not obstructed by SCS artifacts. Additionally, NDTs and EPs did not significantly change between measurements in the SCS-ON/ON and the SCS-OFF/ON groups. Therefore, the results suggested that possible confounding effects of SCS outside the nociceptive system did not interfere with the detection task performance. This work warrants further exploration of NDT-EP phenomena in response to IES at the painful feet of patients.Clinical Relevance-This work contributes to developing a clinical tool to explore psychophysical and neurophysiological biomarkers for observing modulating effects of SCS in patients with PSPS-T2.

Further evaluation of inflammatory and non-inflammatory aspects of pain in rheumatoid arthritis patients.

Objective: A high discrepancy between the number of tender and swollen joints (e.g. ΔTSJ ≥ 7) has previously been used as an indication for the presence of changes in central mechanisms in patients with moderate-to-high disease activity. In this study, we explored whether the ΔTSJ can also be used to obtain insights into the underlying pain mechanisms in patients with on average well-controlled disease activity. Methods: A 2 year retrospective analysis of routinely obtained 28-joint DAS (DAS28) components was performed on 45 patients with low inflammatory activity at the group level. All patients underwent pressure pain threshold (PPT) and electrical pain threshold (EPT) measurements and completed four self-report questionnaires [short-form 36 (SF-36v2); central sensitization inventory (CSI); generalized pain questionnaire (GPQ); and the pain catastrophizing scale (PCS)]. Results: Patients with a ΔTSJ ≥ 3 at least once in the past 2 years showed significantly lower EPT and PPT values and higher levels of pain and disability on the SF-36v2 compared with the ΔTSJ < 3 group. Furthermore, GPQ scores were significantly higher in those with ΔTSJ ≥ 3, while CSI and PCS scores were similar. Conclusion: These findings suggest that in patients in the ΔTSJ ≥ 3 group, mechanisms other than inflammation (only) underlie the pain. Moreover, our findings suggest that among the multiple potential underlying psychological mechanisms, pain catastrophizing (as measured by the PCS) and psychological hypervigilance (as measured by the CSI) do not play an important role. These findings could be useful in the clinical management of the patient. Depending on the dominant mechanism underlying the (persistent) pain, patients might respond differently to treatment.

Observation of nociceptive detection thresholds and cortical evoked potentials: Go/no-go versus two-interval forced choice.

Pain scientists and clinicians search for objective measures of altered nociceptive processing to study and stratify chronic pain patients. Nociceptive processing can be studied by observing a combination of nociceptive detection thresholds and evoked potentials. However, it is unknown whether the nociceptive detection threshold measured using a go-/no-go (GN) procedure can be biased by a response criterion. In this study, we compared nociceptive detection thresholds, psychometric slopes, and central evoked potentials obtained during a GN procedure with those obtained during a two-interval forced choice (2IFC) procedure to determine (1) if the nociceptive detection threshold during a GN procedure is biased by a criterion and (2) to determine if nociceptive evoked potentials observed in response to stimuli around the detection threshold are biased by a criterion. We found that the detection threshold was higher when assessed using a GN procedure in comparison with the 2IFC procedure. During a GN procedure, the average P2 component increased proportionally when averaged with respect to detection probability, but showed on-off behavior when averaged with respect to stimulus detection. During a 2IFC procedure, the average P2 component increased nonlinearly when averaged with respect to detection probability. These data suggest that nociceptive detection thresholds estimated using a GN procedure are subject to a response criterion.

Real-time estimation of perceptual thresholds based on the electroencephalogram using a deep neural network.

BACKGROUND: Perceptual thresholds are measured in scientific and clinical setting to evaluate performance of the nervous system in essential tasks such as vision, hearing, touch, and registration of pain. Current procedures for estimating perceptual thresholds depend on the analysis of pairs of stimuli and participant responses, relying on the commitment and cognitive ability of subjects to respond accurately and consistently to stimulation. Here, we demonstrate that it is possible to measure the threshold for the perception of nociceptive stimuli based on non-invasively recorded brain activity alone using a deep neural network. NEW METHOD: For each stimulus, a trained deep neural network performed a 2-interval forced choice procedure, in which the network had to choose which of two time intervals in the electroencephalogram represented post-stimulus brain activity. Network responses were used to estimate the perceptual threshold in real-time using a psychophysical method of limits. COMPARISON WITH EXISTING METHODS: Network classification was able to match participants in reporting stimulus perception, resulting in average network-estimated perceptual thresholds that matched perceptual thresholds based on participant reports. RESULTS: The neural network successfully separated trials containing brain responses from trials without and could consistently estimate perceptual thresholds in real-time during a Go-/No-Go procedure and a counting task. CONCLUSION: Deep neural networks monitoring non-invasively recorded brain activity are now able to accurately predict stimulus perception and estimate the perceptual threshold in real-time without any verbal or motor response from the participant.

Nociceptive Intra-epidermal Electric Stimulation Evokes Steady-State Responses in the Secondary Somatosensory Cortex.

Recent studies have established the presence of nociceptive steady-state evoked potentials (SSEPs), generated in response to thermal or intra-epidermal electric stimuli. This study explores cortical sources and generation mechanisms of nociceptive SSEPs in response to intra-epidermal electric stimuli. Our method was to stimulate healthy volunteers (n = 22, all men) with 100 intra-epidermal pulse sequences. Each sequence had a duration of 8.5 s, and consisted of pulses with a pulse rate between 20 and 200 Hz, which was frequency modulated with a multisine waveform of 3, 7 and 13 Hz (n = 10, 1 excluded) or 3 and 7 Hz (n = 12, 1 excluded). As a result, evoked potentials in response to stimulation onset and contralateral SSEPs at 3 and 7 Hz were observed. The SSEPs at 3 and 7 Hz had an average time delay of 137 ms and 143 ms respectively. The evoked potential in response to stimulation onset had a contralateral minimum (N1) at 115 ms and a central maximum (P2) at 300 ms. Sources for the multisine SSEP at 3 and 7 Hz were found through beamforming near the primary and secondary somatosensory cortex. Sources for the N1 were found near the primary and secondary somatosensory cortex. Sources for the N2-P2 were found near the supplementary motor area. Harmonic and intermodulation frequencies in the SSEP power spectrum remained below a detectable level and no evidence for nonlinearity of nociceptive processing, i.e. processing of peripheral firing rate into cortical evoked potentials, was found.

Simultaneous measurement of intra-epidermal electric detection thresholds and evoked potentials for observation of nociceptive processing following sleep deprivation.

Sleep deprivation has been shown to increase pain intensity and decrease pain thresholds in healthy subjects. In chronic pain patients, sleep impairment often worsens the perceived pain intensity. This increased pain perception is the result of altered nociceptive processing. We recently developed a method to quantify and monitor altered nociceptive processing by simultaneous tracking of psychophysical detection thresholds and recording of evoked cortical potentials during intra-epidermal electric stimulation. In this study, we assessed the sensitivity of nociceptive detection thresholds and evoked potentials to altered nociceptive processing after sleep deprivation in an exploratory study with 24 healthy male and 24 healthy female subjects. In each subject, we tracked nociceptive detection thresholds and recorded central evoked potentials in response to 180 single- and 180 double-pulse intra-epidermal electric stimuli. Results showed that the detection thresholds for single- and double-pulse stimuli and the average central evoked potential for single-pulse stimuli were significantly decreased after sleep deprivation. When analyzed separated by sex, these effects were only significant in the male population. Multivariate analysis showed that the decrease of central evoked potential was associated with a decrease of task-related evoked activity. Measurement repetition led to a decrease of the detection threshold to double-pulse stimuli in the mixed and the female population, but did not significantly affect any other outcome measures. These results suggest that simultaneous tracking of psychophysical detection thresholds and evoked potentials is a useful method to observe altered nociceptive processing after sleep deprivation, but is also sensitive to sex differences and measurement repetition.

Novel surface electrode design for preferential activation of cutaneous nociceptors.

Objective.Small area electrodes enable preferential activation of nociceptive fibers. It is debated, however, whether co-activation of large fibers still occurs for the existing electrode designs. Moreover, existing electrodes are limited to low stimulation intensities, for which behavioral and physiological responses may be considered less reliable. A recent optimization study showed that there is a potential for improving electrode performance and increase the range of possible stimulation intensities. Based on those results, the present study introduces and tests a novel planar concentric array electrode design for small fiber activation in healthy volunteers.Approach.Volunteers received electrical stimulation with the planar concentric array electrode and a regular patch electrode. Perception thresholds (PT) were estimated at the beginning and the end of the experiment. Evoked cortical potentials were recorded in blocks of 30 stimuli. For the patch, stimulation current intensity was set to two times PT, while three intensities, two, five, and ten times PT, were applied with the planar concentric array electrode. Sensation quality, numerical-rating scores, and reaction times were obtained for each PT estimation and during each block of evoked potential recordings.Main results.Stimulation with the patch electrode was characterized as dull, while stimulation with the planar concentric array electrode was characterized as sharp, with increased sharpness for increasing stimulus current intensity. Likewise, scores of the numerical rating scale were higher for the planar concentric array electrode compared to the patch and increased with increasing stimulation current intensity. Reaction times and ERP latencies were longer for the planar concentric array electrode compared to the patch.Significance.The presented novel planar concentric array electrode is a small, non-invasive, and single-use electrode that has the potential to investigate small fiber neuropathy and pain mechanisms, as it is small fiber preferential for a wide range of stimulation intensities.

Combining Psychophysical and EEG Biomarkers for Improved Observation of Altered Nociceptive Processing in Failed Back Surgery Syndrome.

Diagnosis and stratification of chronic pain patients is difficult due to a lack of sensitive biomarkers for altered nociceptive and pain processing. Recent developments enabled to preferentially stimulate epidermal nerve fibers and simultaneously quantify the psychophysical detection probability and neurophysiological EEG responses. In this work, we study whether using one or a combination of both outcome measures could aid in the observation of altered nociceptive processing in chronic pain. A set of features was extracted from data from a total of 66 measurements on 16 failed back surgery syndrome patients and 17 healthy controls. We assessed how well each feature discriminates both groups. Subsequently, we used a random forest classifier to study whether psychophysical features, EEG features or a combination can improve the classification accuracy. It was found that a classification accuracy of 0.77 can be achieved with psychophysical features, while a classification accuracy of 0.65 was achieved using only EEG features.Clinical Relevance-This study shows which combined features of nociceptive detection behavior and evoked EEG responses are most sensitive and specific to altered nociception in failed back surgery syndrome.

Exploring Nociceptive Detection Thresholds Combined with Evoked Potentials in Patients with Diabetes Mellitus.

There is a lack of diagnostic tools that can objectively measure small fiber neuropathy (SFN) in patients with diabetes mellitus (DM). Recently, nociceptive nerve function was observed by nociceptive detection thresholds (NDTs) and brain evoked potentials (EPs) during intra-epidermal electrical stimulation (IES) targeting Aδ-fibers. In this proof of principle, we studied whether it is possible to measure NDTs combined with EPs in DM patients with and without neuropathic pain. Furthermore, we explored the sensitivity of NDTs and EPs for polyneuropathy in these patients. Five DM patients diagnosed with painful neuropathy (DMp), five DM patients without painful neuropathy (DM), and five healthy controls (HC) were analyzed. These preliminary results showed that we can accurately measure NDTs and EPs in patients with diabetes. Strikingly, increased NDTs were found in DM and DMp compared to HC, of which the DMp showed the largest NDTs. This suggests that NDTs during IES could be a powerful biomarker for monitoring peripheral dysfunctions. Current EEG data of patients did not show any significant differences. The population needs to be enlarged before we can investigate the sensitivity of these NDTs and EPs to diabetic polyneuropathy and associated changes in nociceptive processing in more detail.Clinical Relevance- This proof of principle in a small group of patients with diabetes mellitus potentially treats the observation of the loss of nociceptive function occurring with small fiber neuropathy. That helps the development of a diagnostic measure to monitor future (early-stage) nociceptive dysfunctions in a clinical environment.

Combined Evaluation of Nociceptive Detection Thresholds and Evoked Potentials during Conditioned Pain Modulation: A Feasibility Study.

Deficient top-down inhibitory control via diffuse noxious inhibitory control (DNIC) is a mechanism known to be responsible for the maintenance and development in several chronic pain syndromes. Experimentally, DNIC is often induced by conditioned pain modulation (CPM) paradigms such as a Cold Pressor Test (CPT). Recently, a method called the NDT-EP method has been developed with the aim to evaluate the nociceptive function, which it does via simultaneous tracking of nociceptive detection thresholds (NDT) and evoked potentials (EP). It remains to be investigated whether we can evaluate DNIC via the NDT-EP method. In this study, we take the first step to investigate this by evaluating the feasibility to combine the NDT-EP method with a 7 minutes CPT. In total 20 participants of a wide age-range were measured before, during, and after a CPT. All except 1 participant were able to complete the protocol, and enough stimulus-response pairs could be obtained for psychophysical as well as electrophysiological evaluation. Preliminary analysis of the NDT's and EP's showed results in line with earlier research such as a higher threshold for nociceptive stimuli and a lower EP amplitudes. Several NDT's of mostly elderly people (59±16 years), however, exceeded the maximum applicable stimulus strength during (7/20) or after (9/20) CPT and consequently had to be excluded from the analysis. To what extent this is a consequence of the CPT or other factors such as strong habituation associated more with elderly people, is subject to further investigation. In conclusion, the results of this study show that with the present protocol, it is feasible to combine the NDT-EP method with a CPM paradigm in almost all subjects, but that the NDT data of mostly older subjects could not be properly analyzed. Further directions for research and improvements are outlined.

Multisine frequency modulation of intra-epidermal electric pulse sequences: A novel tool to study nociceptive processing.

A sustained sensory stimulus with a periodic variation of intensity creates an electrophysiological brain response at associated frequencies, referred to as the steady-state evoked potential (SSEP). The SSEPs elicited by the periodic stimulation of nociceptors in the skin may represent activity of a brain network that is primarily involved in nociceptive processing. Exploring the behavior of this network could lead to valuable insights regarding the pathway from nociceptive stimulus to pain perception. We present a method to directly modulate the pulse rate of nociceptive afferents in the skin with a multisine waveform through intra-epidermal electric stimulation. The technique was demonstrated in healthy volunteers. Each subject was stimulated using a pulse sequence modulated by a multisine waveform of 3, 7 and 13 Hz. The EEG was analyzed for the presence of the base frequencies and associated (sub)harmonics. Topographies showed significant central and contralateral SSEP responses at 3, 7 and 13 Hz in respectively 7, 4 and 3 out of the 9 participants included for analysis. As such, we found that intra-epidermal stimulation with a multisine frequency modulated pulse sequence can generate nociceptive SSEPs. The possibility to stimulate the nociceptive system using multisine frequency modulated pulses offers novel opportunities to study the temporal dynamics of nociceptive processing.

Observation of Nociceptive Processing: Effect of Intra-Epidermal Electric Stimulus Properties on Detection Probability and Evoked Potentials.

Monitoring nociceptive processing is a current challenge due to a lack of objective measures. Recently, we developed a method for simultaneous tracking of psychophysical detection probability and brain evoked potentials in response to intra-epidermal stimulation. An exploratory investigation showed that we could quantify nociceptive system behavior by estimating the effect of stimulus properties on the evoked potential (EP). The goal in this work was to accurately measure nociceptive system behavior using this method in a large group of healthy subjects to identify the locations and latencies of EP components and the effect of single- and double-pulse stimuli with an inter-pulse interval of 10 or 40 ms on these EP components and detection probability. First, we observed the effect of filter settings and channel selection on the EP. Subsequently, we compared statistical models to assess correlation of EP and detection probability with stimulus properties, and quantified the effect of stimulus properties on both outcome measures through linear mixed regression. We observed lateral and central EP components in response to intra-epidermal stimulation. Detection probability and central EP components were positively correlated to the amplitude of each pulse, regardless of the inter-pulse interval, and negatively correlated to the trial number. Both central and lateral EP components also showed strong correlation with detection. These results show that both the observed EP and the detection probability reflect the various steps of processing of a nociceptive stimulus, including peripheral nerve fiber recruitment, central synaptic summation, and habituation to a repeated stimulus.

Impact of stimulus duration on motor unit thresholds and alternation in compound muscle action potential scans.

OBJECTIVE: To investigate the impact of stimulus duration on motor unit (MU) thresholds and alternation within compound muscle action potential (CMAP) scans. METHODS: The stimulus duration (0.1, 0.2, 0.6, and 1.0 ms) in thenar CMAP scans and individual MUs of 14 healthy subjects was systematically varied. We quantified variability of individual MU's thresholds by relative spread (RS), MU thresholds by stimulus currents required to elicit target CMAPs of 5% (S5), 50% (S50) and 95% (S95) of the maximum CMAP, and relative range (RR) by 100*[S95-S5]/S50. We further assessed the strength-duration time constant (SDTC). Experimental observations were subsequently simulated to quantify alternation. RESULTS: RS, unaffected by stimulus duration, was 1.65% averaged over all recordings. RR increased for longer stimulus duration (11.4% per ms, p < 0.001). SDTC shortened with higher target CMAPs (0.007 ms per 10% CMAP, p < 0.001). Experiments and simulations supported that this may underlie the increased RR. A short compared to long stimulus duration recruited relative more MUs at S50 (more alternation) than at the tails (less alternation). CONCLUSIONS: The stimulus duration significantly affects MU threshold distribution and alternation within CMAP scans. SIGNIFICANCE: Stimulation settings can be further optimized and their standardization is preferred when using CMAP scans for monitoring neuromuscular diseases.

Interfacing With Alpha Motor Neurons in Spinal Cord Injury Patients Receiving Trans-spinal Electrical Stimulation.

Trans-spinal direct current stimulation (tsDCS) provides a non-invasive, clinically viable approach to potentially restore physiological neuromuscular function after neurological impairment, e.g., spinal cord injury (SCI). Use of tsDCS has been hampered by the inability of delivering stimulation patterns based on the activity of neural targets responsible to motor function, i.e., α-motor neurons (α-MNs). State of the art modeling and experimental techniques do not provide information about how individual α-MNs respond to electrical fields. This is a major element hindering the development of neuro-modulative technologies highly tailored to an individual patient. For the first time, we propose the use of a signal-based approach to infer tsDCS effects on large α-MNs pools in four incomplete SCI individuals. We employ leg muscles spatial sampling and deconvolution of high-density fiber electrical activity to decode accurate α-MNs discharges across multiple lumbosacral segments during isometric plantar flexion sub-maximal contractions. This is done before, immediately after and 30 min after sub-threshold cathodal stimulation. We deliver sham tsDCS as a control measure. First, we propose a new algorithm for removing compromised information from decomposed α-MNs spike trains, thereby enabling robust decomposition and frequency-domain analysis. Second, we propose the analysis of α-MNs spike trains coherence (i.e., frequency-domain) as an indicator of spinal response to tsDCS. Results showed that α-MNs spike trains coherence analysis sensibly varied across stimulation phases. Coherence analyses results suggested that the common synaptic input to α-MNs pools decreased immediately after cathodal tsDCS with a persistent effect after 30 min. Our proposed non-invasive decoding of individual α-MNs behavior may open up new avenues for the design of real-time closed-loop control applications including both transcutaneous and epidural spinal electrical stimulation where stimulation parameters are adjusted on-the-fly.

Simultaneous tracking of psychophysical detection thresholds and evoked potentials to study nociceptive processing.

Measuring altered nociceptive processing involved in chronic pain is difficult due to a lack of objective methods. Potential methods to characterize human nociceptive processing involve measuring neurophysiological activity and psychophysical responses to well-defined stimuli. To reliably measure neurophysiological activity in response to nociceptive stimulation using EEG, synchronized activation of nerve fibers and a large number of stimuli are required. On the other hand, to reliably measure psychophysical detection thresholds, selection of stimulus amplitudes around the detection threshold and many stimulus-response pairs are required. Combining the two techniques helps in quantifying the properties of nociceptive processing related to detected and non-detected stimuli around the detection threshold.The two techniques were combined in an experiment including 20 healthy participants to study the effect of intra-epidermal electrical stimulus properties (i.e. amplitude, single- or double-pulse and trial number) on the detection thresholds and vertex potentials. Generalized mixed regression and linear mixed regression were used to quantify the psychophysical detection probability and neurophysiological EEG responses, respectively.It was shown that the detection probability is significantly modulated by the stimulus amplitude, trial number, and the interaction between stimulus type and amplitude. Furthermore, EEG responses were significantly modulated by stimulus detection and trial number. Hence, we successfully demonstrated the possibility to simultaneously obtain information on psychophysical and neurophysiological properties of nociceptive processing. These results warrant further investigation of the potential of this method to observe altered nociceptive processing.

Simulating perinodal changes observed in immune-mediated neuropathies: impact on conduction in a model of myelinated motor and sensory axons.

Immune-mediated neuropathies affect myelinated axons, resulting in conduction slowing or block that may affect motor and sensory axons differently. The underlying mechanisms of these neuropathies are not well understood. Using a myelinated axon model, we studied the impact of perinodal changes on conduction. We extended a longitudinal axon model (41 nodes of Ranvier) with biophysical properties unique to human myelinated motor and sensory axons. We simulated effects of temperature and axonal diameter on conduction and strength-duration properties. We then studied effects of impaired nodal sodium channel conductance and paranodal myelin detachment by reducing periaxonal resistance, as well as their interaction, on conduction in the 9 middle nodes and enclosed paranodes. Finally, we assessed the impact of reducing the affected region (5 nodes) and adding nodal widening. Physiological motor and sensory conduction velocities and changes to axonal diameter and temperature were observed. The sensory axon had a longer strength-duration time constant. Reducing sodium channel conductance and paranodal periaxonal resistance induced progressive conduction slowing. In motor axons, conduction block occurred with a 4-fold drop in sodium channel conductance or a 7.7-fold drop in periaxonal resistance. In sensory axons, block arose with a 4.8-fold drop in sodium channel conductance or a 9-fold drop in periaxonal resistance. This indicated that motor axons are more vulnerable to developing block. A boundary of block emerged when the two mechanisms interacted. This boundary shifted in opposite directions for a smaller affected region and nodal widening. These differences may contribute to the predominance of motor deficits observed in some immune-mediated neuropathies.NEW & NOTEWORTHY Immune-mediated neuropathies may affect myelinated motor and sensory axons differently. By the development of a computational model, we quantitatively studied the impact of perinodal changes on conduction in motor and sensory axons. Simulations of increasing nodal sodium channel dysfunction and paranodal myelin detachment induced progressive conduction slowing. Sensory axons were more resistant to block than motor axons. This could explain the greater predisposition of motor axons to functional deficits observed in some immune-mediated neuropathies.

Estimation and Identifiability of Model Parameters in Human Nociceptive Processing Using Yes-No Detection Responses to Electrocutaneous Stimulation.

Healthy or pathological states of nociceptive subsystems determine different stimulus-response relations measured from quantitative sensory testing. In turn, stimulus-response measurements may be used to assess these states. In a recently developed computational model, six model parameters characterize activation of nerve endings and spinal neurons. However, both model nonlinearity and limited information in yes-no detection responses to electrocutaneous stimuli challenge to estimate model parameters. Here, we address the question whether and how one can overcome these difficulties for reliable parameter estimation. First, we fit the computational model to experimental stimulus-response pairs by maximizing the likelihood. To evaluate the balance between model fit and complexity, i.e., the number of model parameters, we evaluate the Bayesian Information Criterion. We find that the computational model is better than a conventional logistic model regarding the balance. Second, our theoretical analysis suggests to vary the pulse width among applied stimuli as a necessary condition to prevent structural non-identifiability. In addition, the numerically implemented profile likelihood approach reveals structural and practical non-identifiability. Our model-based approach with integration of psychophysical measurements can be useful for a reliable assessment of states of the nociceptive system.

Dependence of Nociceptive Detection Thresholds on Physiological Parameters and Capsaicin-Induced Neuroplasticity: A Computational Study.

Physiological properties of peripheral and central nociceptive subsystems can be altered over time due to medical interventions. The effective change for the whole nociceptive system can be reflected in changes of psychophysical characteristics, e.g., detection thresholds. However, it is challenging to separate contributions of distinct altered mechanisms with measurements of thresholds only. Here, we aim to understand how these alterations affect Aδ-fiber-mediated nociceptive detection of electrocutaneous stimuli. First, with a neurophysiology-based model, we study the effects of single-model parameters on detection thresholds. Second, we derive an expression of model parameters determining the functional relationship between detection thresholds and the interpulse interval for double-pulse stimuli. Third, in a case study with topical capsaicin treatment, we translate neuroplasticity into plausible changes of model parameters. Model simulations qualitatively agree with changes in experimental detection thresholds. The simulations with individual forms of neuroplasticity confirm that nerve degeneration is the dominant mechanism for capsaicin-induced increases in detection thresholds. In addition, our study suggests that capsaicin-induced central plasticity may last at least 1 month.