The sensory gating paradigm has gained traction in child and adolescent psychiatry for assessing sensory processing deficits. However, its test-retest reliability in pediatric clinical populations remains unclear. This study evaluated the reliability of sensory gating measures in neurotypical and clinical children. Fifty-three children (26 females, ages 8-14) participated, including neurotypical children and children with attention-deficit/ hyperactivity disorder or autism spectrum disorder. Auditory P50 event-related potentials were recorded at Cz using baseline-to-peak and peak-to-peak methodology. Difference and ratio scores between paired stimuli were computed. Generalized eigendecomposition (GED) was applied as an alternative to Cz-based extraction. Reliability was assessed using intraclass correlation coefficients (ICCs). The first stimulus showed moderate-to-good reliability with both Cz and GED. The second stimulus showed poor-to-moderate reliability for Cz, but moderate-to-good for GED. Difference scores yielded moderate-to-good reliability; ratio scores showed poor-to-moderate reliability. GED produced significantly higher ICCs than Cz (mean difference = 0.15, p = 0.018). Only GEDbased measures for the first stimulus consistently revealed group differences. In sum, GED enhances the test-retest reliability of P50 gating outcomes while maintaining sensitivity to group differences. Sensory gating in children can achieve reliable short-term measurements. GED offers a robust alternative to Cz-based methods, potentially improving statistical power and reliability in clinical research.

OBJECTIVES:Directional discrimination in the nociceptive system is a measure of how temporospatial information is integrated. When investigating these mechanisms, the stimulus is typically continuously moved across the skin. However, mechanisms such as lateral inhibition may affect the discrimination if non-continuous stimuli are applied. Thus, the aim of this study was to investigate if continuous and non-continuous line stimuli are discriminated differently. METHODS:21 healthy participants were stimulated in the right forearm using linearly moving laser stimulation. The directional discrimination was estimated for three different stimulation paradigms, a continuous moving line, and two non-continuous lines (discrete). The discrete stimuli (points) were separated by either 10 or 20 mm. A computational model was used to investigate how these stimulation paradigms affected the temperature profiles at receptor level. RESULTS:The directional discrimination threshold (DDT) was higher for continuous lines (58.2 mm [95 % CI]) compared to non-continuous lines (DDT@10 mm: 41.6 mm [95 % CI], and DDT@20 mm: 29.8 mm [95 % CI]), indicating better discrimination for the discrete stimuli. The perceived intensity was significantly higher for the continuous lines (ANOVA, p<0.001). The computational model indicated that the receptor temperature is higher for continuous stimuli. But with greater temperature difference i.e. contrast along the line for non-continuous stimuli. CONCLUSIONS:In this study it was found that directional discrimination is enhanced for non-continuous lines compared to continuous. The computational model showed that continuous stimulus caused higher receptor temperature, indicating stronger activation, which appears to explain the increase perceived stimulation intensity. This may be caused by higher spatial contrast for discrete stimuli, and is comparable to what has been found in the visual and tactile systems.

Diabetic neuropathy and reduced sleep quality are both frequent complications of diabetes mellitus, yet their interaction and mutual influence remain poorly understood. This review aimed to synthesize current evidence on the association between diabetic neuropathy and sleep quality. A systematic literature search was conducted in PubMed, Embase, and the Cochrane Library. Of 1356 identified records, 32 studies met the inclusion criteria. Three randomized clinical trials were included in a post-hoc exploratory meta-analysis to evaluate the effect of gabapentinoids on Sleep Interference Scores in people with painful diabetic peripheral neuropathy. Our evidence synthesis showed that sleep disturbances were more prevalent in people with diabetic peripheral neuropathy compared to people without, especially in those experiencing neuropathic pain. Obstructive sleep apnea was common in individuals with autonomic neuropathy. Furthermore, poor sleep quality in diabetes mellitus may itself increase the risk of developing diabetic neuropathy. The pooled overall mean difference in Sleep Interference Scores was -1.07 (95% CI: -1.86 to -0.28), although heterogeneity was high (I2 = 83%). These findings indicate that poor sleep quality is highly prevalent in people with diabetic neuropathy, especially in those with neuropathic pain. Gabapentinoids appear to reduce Sleep Interference Scores in people with painful diabetic peripheral neuropathy.

Neuropathy is a severe complication of diabetes that is difficult to diagnose at an early stage. Optical coherence tomography angiography may provide an indirect measurement of assessing nerve function.

INTRODUCTION/AIMS:As corneal dendritic cells (DCs) are immune cells that can reflect systemic inflammatory activity, this study aimed to investigate whether the density and maturity of corneal DCs are associated with diabetes, diabetic peripheral neuropathy (DPN), and neuropathic pain. METHODS:Participants included individuals with type 1 diabetes mellitus (T1DM) and painful DPN (n = 19), T1DM and painless DPN (n = 15), T1DM without DPN (n = 19), and healthy controls (n = 20). Corneal confocal microscopy was used to quantify and categorize DCs as either mature or immature and based on their proximity to corneal nerves. RESULTS:No significant differences between groups were observed in total DC density (p = 0.34). Subgroup analysis revealed distinct patterns in which participants with DPN (regardless of pain status) exhibited a higher density of immature DCs distant from corneal nerves compared to those without DPN (14.4 [6.64-37.5] vs. 3.75 [0-17.7] no./mm2, p < 0.05). Healthy controls had a greater density of immature DCs near the nerves compared to the T1DM + DPN group (2.8 [0-8.44] vs. 8.3 [3.12-15.1] no./mm2), while the T1DM + DPN group had a higher density than the painful DPN (3.1 [1.25-5.62] no./mm2). For mature DCs near the nerves, individuals with painful DPN (2.5 [1.4-3.12] no./mm2) had a lower density compared to all other groups. DISCUSSION:This study demonstrates distinct patterns of corneal DC distribution in relation to painful and painless DPN. The findings suggest that immune-mediated mechanisms may play a role in the development of neuropathy and neuropathic pain in diabetes. The pathophysiological significance remains to be clarified. TRIAL REGISTRATION:ClinicalTrials.gov: NCT04078516.

INTRODUCTION/AIMS:Nerve excitability testing of small cutaneous nerve fibers has been proposed as a new tool for investigating the underlying mechanisms of small fiber neuropathy. These assessments may be performed using perception threshold tracking with pin-electrodes that preferentially activate small cutaneous nerve fibers. In this study, the test-retest reliability of two perception threshold (PT) algorithms: the Psi method and the Method of Limits (MoL), was compared. METHOD:Twenty healthy subjects completed the study. Electrical stimulation was applied using a pin electrode, and the PT to a 1 ms rectangular pulse was estimated six times during two sessions separated by 1 week. The test-retest reliability was evaluated by the intraclass correlation coefficient (ICC) and the coefficient of variation (CV). The two PT algorithms were compared by limits of agreement (LoA). RESULTS:The ICC indicated better within-session reliability (Psi: 0.77 and MoL: 0.81) than between-session reliability (Psi: 0.58 and MoL: 0.50) regardless of the algorithm used. The PTs were significantly lower when measured with the MoL (0.88 mA) compared to the estimates by the Psi (1.12 mA) method. DISCUSSION:The estimation of PT can be reliably assessed, especially within-session, with both the MoL and Psi methods. This allows for PT tracking, where PTs to different electrical stimulation provide an estimation of nerve fiber excitability. PT values obtained using different methods are not directly comparable.

To assess and describe chemotherapy-induced peripheral neuropathy (CIPN), a well-known complication to cancer treatment, using different methodologies in hematological patients. Patients scheduled for treatment with vincristine, bortezomib, or lenalidomide were included in this longitudinal observational study. The patients were examined for CIPN before treatment (baseline), before each chemotherapy cycle, one month after end of treatment, and one year after baseline using patient-reported outcomes (Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Ntx-13 (FACT/GOG-Ntx-13)) and clinician-assessed outcomes (the Common Terminology Criteria for Adverse Events (CTCAE) and the Total Neuropathy Score-clinical version (TNSc©)). A total of 23 patients with 171 examination visits were included between 2020 and 2022. Four patients were treated with vincristine, five with bortezomib, and fourteen with bortezomib and lenalidomide combined. Defining CIPN as a ≥ 10

Operant conditioning (OC) evokes behavioral changes and may be useful in pain management. However, it is unknown how alteration of a tonic painful stimulus may affect cognitive performance in an OC learning task and the associated neural activity. To address this, specific event-related potentials (ERPs) and cognitive performance were assessed after an OC task, using altered pain intensity as the operant stimulus. Two OC paradigms were designed using painful tonic pressure pain as the conditioning stimulus. 29 healthy participants received individually set tonic pressure pain corresponding to visual analogue scale 5 (VAS5; pain threshold). Pressure was maintained and a cognitive task performance yielded reward or punishment. Consequences of correct and incorrect answers in the negative reinforcement (NR) condition were pain relief (VAS3) or no pressure change (VAS5), respectively, and no pressure change (VAS5) or increased pressure (VAS7) in the positive punishment (PP) condition, respectively. The initial condition (NR or PP) was randomized, and 120 trials were conducted in three same-day sessions. 64-channel electroencephalography was recorded, and auditory-feedback ERPs (P1N1, P2N2, P3N3) were extracted. Higher ERP peak-to-peak amplitudes were found when participants received feedback that their answer was incorrect. A small OC learning behavior effect was found across trials with no difference between NR and PP. Independent of OC paradigm, learning behavior was induced, and ERP complex amplitudes increased when incorrect answers were given. These novel findings show that higher pain expectancy due to an incorrect answer, facilitated feedback-related ERPs when using pain as a conditioning stimulus.

AIMS:The aims were to quantify periventricular and deep white matter hyperintensities (WMHs) in adults with type 1 diabetes with different neuropathic phenotypes and to correlate WMH measurements to explanatory factors in diabetes. METHODS:WMH measurements were obtained from brain magnetic resonance imaging of 56 adults with type 1 diabetes in subgroups including painful diabetic peripheral neuropathy (DPN), painless DPN, without DPN and 20 healthy controls using Fazekas scale and automatic segmentation analysis. RESULTS:No differences in Fazekas assessed WMHs were found (individuals with periventricular lesions: diabetes 66 % vs. controls 40 %, p = 0.063, deep lesions: diabetes 52 % vs. controls 50 %, p = 1.0). Using automatic detection, there were no significant differences in count of periventricular (p = 0.30) or deep (p = 0.31) WMHs. Higher periventricular lesion burden was present in diabetes compared with controls (0.21 % vs. 0.06 %, p = 0.048), which was associated with more severe DPN, increased age, decreased cognitive function, and reduced volumetric and metabolic brain measures (all p < 0.05). CONCLUSIONS:Our findings indicate increased burden of periventricular WMHs in diabetes which were associated to DPN severity and measurements reflecting neurodegeneration. Deep WMHs, often considered as chronic ischemic, were not significantly different. Mechanisms reflecting neurodegeneration and accelerated brain aging could be an overlooked aspect of peripheral and central neuropathy.

Many patients with small fiber neuropathy experience elevated pain sensation for cold stimuli, and the pathophysiology is highly unknown. Therefore, the aim of this study was to evaluate a new method for probing the peripheral cold-sending fibers by combining electrical and thermal stimulation. The cold and warm detection thresholds (CDT and WDT) were measured in 17 healthy participants under the conditions with and without electrical conditioning stimulation. The electrical stimulation was tested using both 4 and 250 Hz at 50% of the electrical perception threshold. A small area cathode electrode was used for the electrical stimulation, and a thermode was placed on top of the electrode to estimate the thermal thresholds. Two-way RMANOVA was performed to analyze the results. The CDT decreased from 26.8°C (SD -4.1, +2.5, log-transformed) to 25.8°C (SD -4.9, +2.9, log-transformed) by the conditioning electrical stimulation (P = 0.006). The mean WDT was 41.6°C (SD -3.0, +4.1, log-transformed) without and 40.7°C (SD -3.1, +4.6, log10-transformed) with conditioning electrical stimulation (P = 0.12). No significant main effect was found for the frequency of electrical stimulation for the two thermal thresholds. Conditioning electrical stimulation significantly altered the CDT but not the WDT, which can be explained by the small cathode's preferential activation of Aδ fibers to a greater extent than C fibers since the cold, innoxious sensation is mainly mediated by Aδ fibers and the warm sensation by C fibers. Combining thermal and electrical stimulation may, in the future, be used for probing cold-sensing fiber excitability, but further studies are necessary to validate the results.NEW & NOTEWORTHY A novel approach is evaluated for probing peripheral cold-sensing fiber by using electrical stimulation's large variety of protocols in combination with activation of the fiber by thermal stimulation to ensure selective activation of the cold-sensing fibers. The results showed that the cold detection threshold could be altered by electrical stimulation, but no significant differences were found for warm temperatures or different frequencies of conditioning electrical stimulation. The result was promising, but further studies are needed.

Pain catastrophizing, and specifically rumination, are key components of the pain experience and a potential predictor of chronic pain. Pain trajectories in chronic pain patients can be influenced by operant conditioning paradigms, with limited knowledge of the mechanisms. Rumination and its impact on event-related potentials (ERPs) in a painful operant conditioning setting, may further elucidate how behavioral and cognitive manipulation can affect somatosensory and nociceptive processing. This study aimed to examine the impact of rumination on ERP responses to auditory feedback cues in a painful operant conditioning paradigm. 29 healthy volunteers initially completed the pain catastrophizing questionnaire followed by a cognitive task. Participants were divided into high- and low-ruminators based on the median split. Negative reinforcement (NR) and positive punishment (PP) were employed as operant conditioning paradigms, using pressure pain as the conditioning stimulus, with correct and incorrect responses resulting in pain relief/no change in pain or no change in pain/increased pain. Electroencephalographic, auditory-feedback ERP P3N3 amplitude and P300 latencies were analyzed. The group with higher rumination scores exhibited lower P3N3 amplitudes compared to the group with lower rumination scores and in response to the auditory feedback on incorrect compared to correct answers. Delayed P300 latencies were found in feedback to incorrect answers in both conditions, but unrelated to rumination. These findings suggest that individuals with higher rumination may struggle to process performance outcomes in an operant conditioning paradigm. Future studies may explore if modulation of rumination has an impact on cognitive performance and pain intensity to a painful condition.

Sodium channel variants are associated with small fiber neuropathy. While in vitro recordings allow detailed assessment of sodium channel function, their contribution to peripheral small nerve fiber excitability remains unstudied. The perception threshold tracking (PTT) method allows indirect assessment of small fiber function by transcutaneous electrical stimulation and psychophysics. Here, we developed a Sodium channel Excitability Nociceptor Test that allows for the identification of alterations in selected subtypes of sodium channels in small fibers of awake humans. We hypothesize that due to the unique dynamics of sodium channels, it is possible to derive a nerve excitability test to uniquely identify alterations in the Na v 1.7 channel. Using a multicompartmental nerve fiber model, a set of 5 electrical pulse shapes was developed. These pulse shapes consist of rectangular and ramp test pulses preceded by either a hyperpolarizing or depolarizing prepulse. To validate the predictive power of our in silico simulations, we used an automated whole-cell patch clamp on Na v 1.7 expressed in HEK293T cells and a PTT experiment in healthy participants. The computational model predicted that an alteration of Na v 1.7 can be classified with an accuracy of 92% (n = 30) when the standard deviation of the perception threshold is 11%, which was measured by the PTT experiment. The peak Na v 1.7 current elicited in vitro corresponded well with the prediction of the in silico model. The study thus provides an excitability test to predict the involvement of Na v 1.7, and potentially also Na v 1.8 and Na v 1.9, in the generation of neuropathic pain in small fiber neuropathy.

BACKGROUND:Spatial acuity concerns the ability to localize and discriminate sensory input and is often tested using the two-point discrimination threshold (2PDT). Sensitization of the pain system can affect the spatial acuity, but it is unclear how 2PDTs of different testing modalities are affected. The aim was to investigate if the 2PDTs for mechanical and heat stimulation at different intensities were modulated by topical capsaicin sensitization. METHODS:30 healthy subjects were divided into either a capsaicin or a placebo group. The 2PDT was tested using two different modalities, mechanical and thermal (laser) delivered at innocuous and noxious intensities. The 2PDT were determined at baseline and re-assessed 48 h later. In the follow-up session, the subjects either had a capsaicin patch (8%) or placebo patch placed in the testing area for 30 min before re-testing the 2PDT. RESULTS:The 2PDT was highly dependent on stimulation modality and intensity. The lowest 2PDT was found for innocuous mechanical stimuli (40.0 mm, 95% CI 38.1-41.9 mm), and the highest 2PDT was found for innocuous thermal stimuli (81.7 mm, 95% CI 73.9-89.5 mm). Topical capsaicin generally increased the 2PDT, but this was only significant for innocuous mechanical stimuli. The perceived intensity of the stimuli was increased following capsaicin and was generally higher for noxious stimuli than for innocuous stimuli (ANOVA, p < 0.001). CONCLUSIONS:This study showed that capsaicin provoked pain sensitization increased the 2PDT. The 2PDT tested using innocuous mechanical stimuli showed less variable results indicating that this test is most suitable to detect this aspect of spatial acuity. SIGNIFICANCE STATEMENT:This study investigated how the two-point discrimination threshold (2PDT) can be modulated by topical capsaicin. The 2PDT was assessed for two different modalities (thermal and mechanical) and for two different intensities (innocuous and noxious) before and after capsaicin. The results showed that the 2PDT was generally impaired following capsaicin, but this was only significant for mechanical innocuous stimuli. Furthermore, it was shown that mechanical innocuous stimuli assessed the 2PDT with lower variability than other combinations.

INTRODUCTION/AIMS:Diabetic peripheral neuropathy affects small nerve fibers early, but adequate evaluation has proven difficult. One method for functional assessment of small nerve fiber function is the axon-reflex flare (ARF) response. This study aimed to 1) validate the histamine-induced ARF response in a nonselected population with diabetes, 2) compare the response to that induced by local heating, and 3) compare both methods to an established method (quantitative sensory testing) in a nonselected population with diabetes. METHODS:Thirty-four participants with type 1 diabetes were included. The participants underwent a neurological examination, quantitative sensory testing, sural nerve conduction, and histamine- and heat-induced ARF response measurements by full-field laser speckle perfusion imaging after epidermal application of histamine and after local heating by 44° Celsius thermode, respectively. Spearman's correlations were assessed. Logistic regression was used to generate receiver operating characteristic curves using the cold detection threshold of quantitative sensory testing as reference. RESULTS:The histamine-induced ARF had an area under the curve (AUC) of 0.82, a sensitivity of 67%, and a specificity of 70%. The heat-induced ARF had an AUC of 0.40, a sensitivity of 36%, and a specificity of 57%. No significant correlation between the histamine- and the heat-induced ARF responses was found. DISCUSSION:The histamine-induced ARF response is a valid marker for small fiber neuropathy even in nonselected populations with diabetes with good agreement with established markers and can thus be used for evaluation of C-fiber function. The lack of correlation with the heat-induced ARF may be due to insufficient heating.

Objectives: The study aimed to investigate brain metabolites in type 1 diabetes and the associations with disease characteristics. We explored the metabolic profiles predicting different neuropathic phenotypes using multiple linear regression analyses. Methods: We compared brain metabolites in 55 adults with type 1 diabetes (including painful diabetic peripheral neuropathy (DPN), painless DPN, without DPN) with 20 healthy controls. Proton magnetic resonance spectroscopy measurements (N-acetylaspartate (NAA), glutamate (glu), myo-inositol (mI), and glycerophosphocholine (GPC) were obtained in ratios to creatine (cre)) from the parietal region, anterior cingulate cortex and thalamus. Results: The overall diabetes group revealed decreased parietal NAA/cre compared to healthy controls (1.41 +/- 0.12 vs. 1.55 +/- 0.13,p < 0.001) and increased mI/cre (parietal: 0.62 +/- 0.08 vs. 0.57 +/- 0.07,p = 0.025, cingulate: 0.65 +/- 0.08 vs. 0.60 +/- 0.08,p = 0.033). Reduced NAA/cre was associated with more severe DPN (all p <= 0.04) whereas increased mI/cre was associated with higher hemoglobin A(1c) (HbA(1c)) (p = 0.02). Diabetes was predicted from decreased parietal NAA/cre, increased parietal ml/cre, and decreased thalamic glu/cre. DPN was predicted from decreased parietal NAA/cre and increased GPC/cre. Painful DPN was predicted from increased parietal GPC/cre and thalamic glu/cre. Conclusions: Specific metabolic brain profiles were linked to the different phenotypes of diabetes, DPN and painful DPN. Significance: Assessment of metabolic profiles could be relevant for detailed understanding of central neuropathy in diabetes. (c) 2024 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

Objectives: Noncancer chronic pain is a clinical challenge because pharmacological treatment often fails to relieve pain. Transcranial direct current stimulation (tDCS) is a treatment that could have the potential for pain relief and improvement in quality of life. However, there is a lack of clinical trials evaluating the effects of tDCS on the pain system. The aim of the present study was to evaluate the effect of 5 days of anodal tDCS treatment on the pain system in patients with chronic noncancer pain using quantitative sensory testing and quality of life questionnaires: (1) Brief Pain Inventory-short form, (2) European Organization for Research and Treatment of Life Questionnaire-C30, and (3) Hospital Anxiety Depression Scale. Methods: Eleven patients with noncancer chronic pain (51 ± 13.6 y old, 5M) participated in the study. Anodal tDCS was applied for 5 consecutive days, followed by sham stimulation after a washout period of at least 2 weeks. Pressure pain thresholds and pain tolerance thresholds (PTT) were assessed in different body regions on days 1 and 5. Results: Anodal tDCS appeared to maintain PTT at C5 (clavicle) on day 5, but sham stimulation decreased PTT (P = 0.007). In addition, anodal tDCS increased PTT compared with sham at day 5 at Th10 ventral dermatomes (P = 0.014). Both anodal and sham tDCS decreased the Brief Pain Inventory-short form total and interference scores, and the European Organization for Research and Treatment of Life Questionnaire-C30 fatigue score, but no interaction effect was observed. Conclusion: This study adds to the evidence in the literature that tDCS may be a potential therapeutic tool for the management of noncancer chronic pain.

INTRODUCTION/AIMS:Accurate assessment of diabetic peripheral neuropathy (DPN) is essential to prevent further complications, yet current methods have limitations. Perception threshold tracking (PTT) offers promise as a novel approach for rapid evaluation of both large and small fiber dysfunction. To enhance efficiency, this study explores the Psi method compared to the Method of Limits (MoL) in estimating perception thresholds. The aim is to assess agreement, uncertainty, and the number of stimuli required for adequate estimation by each method. METHODS:Forty-three participants with diabetes underwent an estimated sural nerve conduction study, quantitative sensory testing, vibration perception threshold testing, and PTT. PTT utilized both patch and pin electrode configurations to activate large and small fibers, respectively. The uncertainty of perception thresholds was estimated as the inverse slope of the psychometric functions. RESULTS:Perception thresholds were significantly higher for the patch electrode (2.5 [2.1-3.0] mA) compared to the pin electrode (0.71 [0.56-0.91] mA; rmANOVA, p < 0.001). Bland-Altman analysis revealed a non-significant 3.3% bias between the methods, but wide limits of agreement (-42%-84%). Uncertainty was lower for the Psi method (0.80 [0.58;1.11] mA) compared to MoL (2.0 [1.2;2.9] mA; rmANOVA, p < 0.005). The Psi method achieved acceptable perception threshold estimation with only 30 stimuli. DISCUSSION:At the group level, the MoL and Psi methods produced similar perception thresholds. However, the Psi method required fewer stimuli and yielded less uncertainty in perception threshold estimation compared to MoL. Future studies should prioritize the Psi method for its efficiency and reliability.