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.

A novel approach to pharmaco-EEG for investigating analgesics: assessment of spectral indices in single-sweep evoked brain potentials.

AIMS: To compare results from analysis of averaged and single-sweep evoked brain potentials (EPs) by visual inspection and spectral analysis in order to identify an objective measure for the analgesic effect of buprenorphine and fentanyl. METHODS: Twenty-two healthy males were included in a randomized study to assess the changes in EPs after 110 sweeps of painful electrical stimulation to the median nerve following treatment with buprenorphine, fentanyl or placebo patches. Bone pressure, cutaneous heat and electrical pain ratings were assessed. EPs and pain assessments were obtained before drug administration, 24, 48, 72 and 144 h after beginning of treatment. Features from EPs were extracted by three different approaches: (i) visual inspection of amplitude and latency of the main peaks in the average EPs, (ii) spectral distribution of the average EPs and (iii) spectral distribution of the EPs from single-sweeps. RESULTS: Visual inspection revealed no difference between active treatments and placebo (all P > 0.05). Spectral distribution of the averaged potentials showed a decrease in the beta (12-32 Hz) band for fentanyl (P = 0.036), which however did not correlate with pain ratings. Spectral distribution in the single-sweep EPs revealed significant increases in the theta, alpha and beta bands for buprenorphine (all P < 0.05) as well as theta band increase for fentanyl (P = 0.05). For buprenorphine, beta band activity correlated with bone pressure and cutaneous heat pain (both P = 0.04, r = 0.90). CONCLUSION: In conclusion single-sweep spectral band analysis increases the information on the response of the brain to opioids and may be used to identify the response to analgesics.

Alterations in Functional Connectivity of Thalamus and Primary Somatosensory Cortex in Painful and Painless Diabetic Peripheral Neuropathy.

OBJECTIVE: In this study we aimed to investigate the functional connectivity of brain regions involved in sensory processing in diabetes with and without painful and painless diabetic peripheral neuropathy (DPN) and the association with peripheral nerve function and pain intensity. RESEARCH DESIGN AND METHODS: In this cross-sectional study we used resting-state functional MRI (fMRI) to investigate functional brain connectivity of 19 individuals with type 1 diabetes and painful DPN, 19 with type 1 diabetes and painless DPN, 18 with type 1 diabetes without DPN, and 20 healthy control subjects. Seed-based connectivity analyses were performed for thalamus, postcentral gyrus, and insula, and the connectivity z scores were correlated with peripheral nerve function measurements and pain scores. RESULTS: Overall, compared with those with painful DPN and healthy control subjects, subjects with type 1 diabetes without DPN showed hyperconnectivity between thalamus and motor areas and between postcentral gyrus and motor areas (all P ≤ 0.029). Poorer peripheral nerve functions and higher pain scores were associated with lower connectivity of the thalamus and postcentral gyrus (all P ≤ 0.043). No connectivity differences were found in insula (all P ≥ 0.071). CONCLUSIONS: Higher functional connectivity of thalamus and postcentral gyrus appeared only in diabetes without neuropathic complications. Thalamic/postcentral gyral connectivity measures demonstrated an association with peripheral nerve functions. Based on thalamic connectivity, it was possible to group the phenotypes of type 1 diabetes with painful/painless DPN and type 1 diabetes without DPN. The results of the current study support that fMRI can be used for phenotyping, and with validation, it may contribute to early detection and prevention of neuropathic complications.

Cognitive function in individuals with and without painful and painless diabetic polyneuropathy-A cross-sectional study in type 1 diabetes.

INTRODUCTION: Previous studies suggest that cognitive impairment is more prevalent in individuals with painful and painless diabetic peripheral neuropathy (DPN). However, the current evidence is not well described. This study investigated cognitive function in adults with type 1 diabetes mellitus (T1DM) and the association to painful/painless DPN and clinical parameters. METHODS: This cross-sectional, observational, case-control study included 58 participants with T1DM, sub-grouped into 20 participants with T1DM and painful DPN, 19 participants with T1DM and painless DPN, 19 participants with T1DM without DPN, and 20 healthy controls were included. The groups were matched for sex and age. The participants performed Addenbrooke's examination III (ACE-III), which assesses attention, memory, verbal fluency, language and visuospatial skills. Working memory was evaluated using an N-back task. Cognitive scores were compared between the groups and correlated to age, diabetes duration, HbA1c and nerve conduction measurements. RESULTS: Compared to healthy controls, T1DM participants showed lower total ACE-III (p = .028), memory (p = .013) and language scores (p = .028), together with longer reaction times in the N-back task (p = .041). Subgroup analyses demonstrated lower memory scores in those with painless DPN compared with healthy controls (p = .013). No differences were observed between the three T1DM subgroups. Cognitive scores and clinical parameters were not associated. CONCLUSIONS: This study supports the notion of cognitive alterations in T1DM and indicates that cognitive function is altered in T1DM regardless of underlying neuropathic complications. The memory domain appears altered in T1DM, particularly in those with painless DPN. Further studies are needed to verify the findings.

Gray Matter Brain Alterations in Type 1 Diabetes - Findings Based on Detailed Phenotyping of Neuropathy Status.

AIMS: This study investigated brain structure in patients of type 1 diabetes with diabetic peripheral neuropathy (DPN) and type 1 diabetes with neuropathic pain and the associations to clinical, peripheral, and cognitive measurements. METHODS: Sixty individuals with type 1 diabetes and 20 healthy controls were included in the study. Nineteen individuals with type 1 diabetes and neuropathic pain, 19 with type 1 diabetes and DPN, 18 with type 1 diabetes without DPN, and 20 healthy controls were included in the brain analyses. We utilized structural brain magnetic resonance imaging to investigate total and regional gray matter volume. RESULTS: Significant lower gray matter volume was found in type 1 diabetes with neuropathic pain and in type 1 diabetes without DPN compared to healthy controls (p=0.024 and p=0.019, respectively). Lower insula volume was observed in all three diabetes groups (all p≤0.050). Thalamus and hippocampus volume was lower in type 1 diabetes with neuropathic pain, cerebellum volume was lower in type 1 diabetes with DPN, and somatosensory cortex volume was lower in type 1 diabetes without DPN (all p≤0.018). Attenuated memory was associated with lower gray matter volume in type 1 diabetes with DPN. No associations were found between gray matter volume and clinical/peripheral measurements. CONCLUSION: We demonstrated lower gray matter volume in individuals with type 1 diabetes regardless of the presence of DPN and neuropathic pain. Hence, central gray matter alteration was not associated with peripheral alterations.

New diagnostic measures of oxaliplatin-induced peripheral sensory neuropathy.

OBJECTIVE: Oxaliplatin-induced peripheral neuropathy (OIPN) is an unwanted side effect of oxaliplatin chemotherapy treatment. OIPN manifests in an acute phase that lasts a few days after injection and a persistent phase that may become chronic. Currently, there is no consensus about a clinically applicable, quantitative, and objective measure of OIPN. METHODS: Seventeen patients treated with oxaliplatin containing adjuvant chemotherapy for stage III colon cancer, but otherwise healthy, were tested with six quantitative sensory tests (QST) and five large fibre perception threshold tracking (PTT) measures (quantified by, e.g., rheobase and electrotonus threshold) one hour before each of the 12 chemotherapy cycles given at two weeks' intervals. These measures were repeated at 3, 6, and 12-month follow-ups. The temporal development of OIPN assessed by the Common Terminology Criteria for Adverse Events (CTCAE) scale, QST, and PTT measures was calculated by linear regression. RESULTS: The CTCAE score showed a tri-phasic increase during the treatment and remained increased during the follow-up. The vibration threshold (R = 0.25, p<0.001), the cold pain threshold (R = 0.17, p = 0.02), and the rheobase (R = 0.28, p < 0.001) increased during treatment, whereas the cold detection threshold (R=-0.16, p = 0.002) decreased. The cold pain threshold and the rheobase remained increased, and the cold detection and heat pain threshold remained decreased during follow-up. CONCLUSIONS: Increased cold pain sensitivity and decreased large fibre sensitivity (increased rheobase) correlate to the persistent OIPN, whereas the CTCAE score assesses both acute and persistent OIPN. Furthermore, the novel PTT method assessed the nerve excitability changes caused by the oxaliplatin.

A new self-understanding as chemo sufferer - a phenomenological study of everyday life with chemotherapy induced neuropathy among survivors after colorectal cancer.

PURPOSE: To explore the essential meaning of how sensory disturbances caused by Oxaliplatin influence self-understanding and freedom to live an everyday life among survivors after colorectal cancer. METHODS: Data was generated by means of a semi-structured individual interview with eight survivors after colorectal cancer who continued to experience chemotherapy-induced peripheral neuropathy at least one year after completing chemotherapy with Oxaliplatin. Data analysis was guided by existential phenomenology and descriptive life-world research. RESULTS: The essential meaning was structured by four constituents. 1) An unpleasant fluctuating sensation which is impossible to ignore, 2) Breaking through of noise and pain despite struggling to keep them at bay, 3) Continuously feeling ill despite being cured, and 4) Bodily constraints that impact self-understanding and limit enjoyment of life. CONCLUSION: The survivors used distraction to keep the sensory disturbances at bay but were forced to adapt to a new self-understanding as sufferers after chemotherapy despite being cured of their cancer disease. This way of being-in-the-world was understood by survivors, their families and healthcare professionals as a necessary price to pay to be alive. However, marked as sufferer after chemotherapy, the participants' everyday style of experience and life revealed as an ill health condition, which limited their ability to accomplish everyday activities as before and their freedom to realize their potential-the "I can".

Spatial temperature distribution in human hairy and glabrous skin after infrared CO2 laser radiation.

BACKGROUND: CO2 lasers have been used for several decades as an experimental non-touching pain stimulator. The laser energy is absorbed by the water content in the most superficial layers of the skin. The deeper located nociceptors are activated by passive conduction of heat from superficial to deeper skin layers. METHODS: In the current study, a 2D axial finite element model was developed and validated to describe the spatial temperature distribution in the skin after infrared CO2 laser stimulation. The geometry of the model was based on high resolution ultrasound scans. The simulations were compared to the subjective pain intensity ratings from 16 subjects and to the surface skin temperature distributions measured by an infrared camera. RESULTS: The stimulations were sensed significantly slower and less intense in glabrous skin than they were in hairy skin (MANOVA, p < 0.001). The model simulations of superficial temperature correlated with the measured skin surface temperature (r > 0.90, p < 0.001). Of the 16 subjects tested; eight subjects reported pricking pain in the hairy skin following a stimulus of 0.6 J/cm2 (5 W, 0.12 s, d1/e2 = 11.4 mm) only two reported pain to glabrous skin stimulation using the same stimulus intensity. The temperature at the epidermal-dermal junction (depth 50 µm in hairy and depth 133 µm in glabrous skin) was estimated to 46°C for hairy skin stimulation and 39°C for glabrous skin stimulation. CONCLUSIONS: As compared to previous one dimensional heat distribution models, the current two dimensional model provides new possibilities for detailed studies regarding CO2 laser stimulation intensity, temperature levels and nociceptor activation.

Unexplained Bone Pain Is an Independent Risk Factor for Bone Metastases in Newly Diagnosed Prostate Cancer: A Prospective Study.

OBJECTIVE: To determine the relationship between bone pain and bone metastases in newly diagnosed prostate cancer. PATIENTS AND METHODS: This prospective study of bone scintigraphy enrolled 567 consecutive patients with newly diagnosed prostate cancer. The presence of all-cause bone pain, known benign bone disease, and unexplained bone pain (ie, not related to known benign bone disease) was derived from a patient questionnaire. Univariate logistic regression models (LRMs) were used to assess the relationship between individual clinical variables (all-cause bone pain, unexplained bone pain, prostate-specific antigen, Gleason grade, T stage, and age) and bone metastases. A multivariate LRM was used to assess the relationship between bone metastases and all factors in combination. Agreement between the LRMs and bone metastases was estimated by accuracy and by Cohen's κ. RESULTS: All-cause bone pain predicted bone metastasis in univariate but not multivariate analysis. Unexplained bone pain remained an independent predictor of bone metastases in multivariate analysis (odds ratio: 4.5; P < .001). Prostate-specific antigen was the single most important predictor of bone metastases (P < .001). CONCLUSION: Unexplained bone pain was a strong independent risk factor for bone metastasis. Guidelines should recommend staging bone scintigraphy in patients with unexplained bone pain, regardless of other risk factors.

On the use of information theory for the analysis of synchronous nociceptive withdrawal reflexes and somatosensory evoked potentials elicited by graded electrical stimulation.

BACKGROUND: To date, few studies have combined the simultaneous acquisition of nociceptive withdrawal reflexes (NWR) and somatosensory evoked potentials (SEPs). In fact, it is unknown whether the combination of these two signals acquired simultaneously could provide additional information on somatosensory processing at spinal and supraspinal level compared to individual NWR and SEP signals. NEW METHOD: By using the concept of mutual information (MI), it is possible to quantify the relation between electrical stimuli and simultaneous elicited electrophysiological responses in humans based on the estimated stimulus-response signal probability distributions. RESULTS: All selected features from NWR and SEPs were informative in regard to the stimulus when considered individually. Specifically, the information carried by NWR features was significantly higher than the information contained in the SEP features (p<0.05). Moreover, the joint information carried by the combination of features showed an overall redundancy compared to the sum of the individual contributions. Comparison with existing methods MI can be used to quantify the information that single-trial NWR and SEP features convey, as well as the information carried jointly by NWR and SEPs. This is a model-free approach that considers linear and non-linear correlations at any order and is not constrained by parametric assumptions. CONCLUSIONS: The current study introduces a novel approach that allows the quantification of the individual and joint information content of single-trial NWR and SEP features. This methodology could be used to decode and interpret spinal and supraspinal interaction in studies modulating the responsiveness of the nociceptive system.

On the Agreement between Manual and Automated Methods for Single-Trial Detection and Estimation of Features from Event-Related Potentials.

The agreement between humans and algorithms on whether an event-related potential (ERP) is present or not and the level of variation in the estimated values of its relevant features are largely unknown. Thus, the aim of this study was to determine the categorical and quantitative agreement between manual and automated methods for single-trial detection and estimation of ERP features. To this end, ERPs were elicited in sixteen healthy volunteers using electrical stimulation at graded intensities below and above the nociceptive withdrawal reflex threshold. Presence/absence of an ERP peak (categorical outcome) and its amplitude and latency (quantitative outcome) in each single-trial were evaluated independently by two human observers and two automated algorithms taken from existing literature. Categorical agreement was assessed using percentage positive and negative agreement and Cohen's κ, whereas quantitative agreement was evaluated using Bland-Altman analysis and the coefficient of variation. Typical values for the categorical agreement between manual and automated methods were derived, as well as reference values for the average and maximum differences that can be expected if one method is used instead of the others. Results showed that the human observers presented the highest categorical and quantitative agreement, and there were significantly large differences between detection and estimation of quantitative features among methods. In conclusion, substantial care should be taken in the selection of the detection/estimation approach, since factors like stimulation intensity and expected number of trials with/without response can play a significant role in the outcome of a study.

Is the conditioned pain modulation paradigm reliable? A test-retest assessment using the nociceptive withdrawal reflex.

The aim of this study was to determine the reliability of the conditioned pain modulation (CPM) paradigm assessed by an objective electrophysiological method, the nociceptive withdrawal reflex (NWR), and psychophysical measures, using hypothetical sample sizes for future studies as analytical goals. Thirty-four healthy volunteers participated in two identical experimental sessions, separated by 1 to 3 weeks. In each session, the cold pressor test (CPT) was used to induce CPM, and the NWR thresholds, electrical pain detection thresholds and pain intensity ratings after suprathreshold electrical stimulation were assessed before and during CPT. CPM was consistently detected by all methods, and the electrophysiological measures did not introduce additional variation to the assessment. In particular, 99% of the trials resulted in higher NWR thresholds during CPT, with an average increase of 3.4 mA (p<0.001). Similarly, 96% of the trials resulted in higher electrical pain detection thresholds during CPT, with an average increase of 2.2 mA (p<0.001). Pain intensity ratings after suprathreshold electrical stimulation were reduced during CPT in 84% of the trials, displaying an average decrease of 1.5 points in a numeric rating scale (p<0.001). Under these experimental conditions, CPM reliability was acceptable for all assessment methods in terms of sample sizes for potential experiments. The presented results are encouraging with regards to the use of the CPM as an assessment tool in experimental and clinical pain. Trial registration: Clinical Trials.gov NCT01636440.

Long-term facilitation of nociceptive withdrawal reflexes following low-frequency conditioning electrical stimulation: a new model for central sensitization in humans.

Central sensitization is believed to be one of the key mechanisms behind chronic pain conditions, and several models have been developed in order to characterize this phenomenon in humans. One of these models relies on conditioning electrical stimulation to elicit long-lasting effects on the nociceptive system. The aim of this study was to evaluate these effects using an objective electrophysiological measurement, the nociceptive withdrawal reflex (NWR). Long-term changes in spinal nociception after high- and low-frequency conditioning electrical stimulation were assessed in 13 healthy volunteers. Perceptual intensity ratings to mechanical stimuli and blood flow variations were assessed in the conditioned area (dorsum of the foot) and surroundings. To evaluate the excitability of the nociceptive system, the NWR was elicited within the same innervation area (superficial peroneal nerve) at graded stimulation intensities and recorded in the hamstrings. Following low-frequency stimulation, an intensity-independent long-lasting facilitation of the NWR was observed, with a significant increase in the reflex size (average of 31+/-4%, p<0.001) and in the number of reflexes (average increase of 22+/-10%, p<0.01), accompanied by a significant increase in the blood flow (average increase of 40+/-10%, p<0.001). These findings suggest that activity-dependent central sensitization can be elicited using conditioning electrical stimulation with a stimulation frequency that lies within the physiological firing range of primary afferents, and that it can be objectively assessed in humans using the NWR.

The saltation illusion demonstrates integrative processing of spatiotemporal information in thermoceptive and nociceptive networks.

In sensory saltation, first reported by Geldard and Sherrick (Science 178:178-179, 1972), a stimulus is displaced towards a second one following closely in time and space as a function of the delay between the stimuli. The distance between stimulus locations is restricted by the extension of sensory fields in the primary somatosensory cortex. Saltation is assumed to reflect dynamic changes in these cortical representations. The present study demonstrates for the first time saltation in thermoceptive and nociceptive pathways with CO(2) laser stimulation. Stimuli were presented to the dorsal forearms of 18 healthy subjects at two intensities. Saltation patterns consisted of a reference stimulus S0 near the wrist, the first test stimulus S1 at the reference location after a fixed onset delay of 1,000 ms, and a second test stimulus S2 at a location 105 mm distant from reference after a variable onset delay of 60-516 ms. Perceived positions were indicated by the subjects without skin contact with a 3D tracker. As expected, subjects mislocalized S1 towards S2. Mean S1 displacement was 51+/-36 mm. Decreasing delays between S1 and S2 resulted in increasing displacements, independent of intensity. However, since no clear-cut discrimination of thermal versus nociceptive activation could be achieved definite conclusions about differences between the two modalities cannot be drawn. In addition, effects of body site on the saltation characteristics were observed. The saltation paradigm constitutes a promising approach to the functional analysis of spatiotemporal dynamics in thermoceptive and nociceptive networks to supplement brain-mapping approaches to cortical sensory fields.