Effects of Background Noise and Linguistic Violations on Frontal Theta Oscillations During Effortful Listening.

OBJECTIVES: Background noise and linguistic violations have been shown to increase the listening effort. The present study aims to examine the effects of the interaction between background noise and linguistic violations on subjective listening effort and frontal theta oscillations during effortful listening. DESIGN: Thirty-two normal-hearing listeners participated in this study. The linguistic violation was operationalized as sentences versus random words (strings). Behavioral and electroencephalography data were collected while participants listened to sentences and strings in background noise at different signal to noise ratios (SNRs) (-9, -6, -3, 0 dB), maintained them in memory for about 3 sec in the presence of background noise, and then chose the correct sequence of words from a base matrix of words. RESULTS: Results showed the interaction effects of SNR and speech type on effort ratings. Although strings were inherently more effortful than sentences, decreasing SNR from 0 to -9 dB (in 3 dB steps), increased effort rating more for sentences than strings in each step, suggesting the more pronounced effect of noise on sentence processing that strings in low SNRs. Results also showed a significant interaction between SNR and speech type on frontal theta event-related synchronization during the retention interval. This interaction indicated that strings exhibited higher frontal theta event-related synchronization than sentences at SNR of 0 dB, suggesting increased verbal working memory demand for strings under challenging listening conditions. CONCLUSIONS: The study demonstrated that the interplay between linguistic violation and background noise shapes perceived effort and cognitive load during speech comprehension under challenging listening conditions. The differential impact of noise on processing sentences versus strings highlights the influential role of context and cognitive resource allocation in the processing of speech.

Low energy availability reduces myofibrillar and sarcoplasmic muscle protein synthesis in trained females.

Low energy availability (LEA) describes a state where the energy intake is insufficient to cover the energy costs of both exercise energy expenditure and basal physiological body functions. LEA has been associated with various physiological consequences, such as reproductive dysfunction. However, the effect of LEA on skeletal muscle protein synthesis in females performing exercise training is still poorly understood. We conducted a randomized controlled trial to investigate the impact of LEA on daily integrated myofibrillar and sarcoplasmic muscle protein synthesis in trained females. Thirty eumenorrheic females were matched based on training history and randomized to undergo 10 days of LEA (25 kcal · kg fat-free mass (FFM)-1  · day-1 ) or optimal energy availability (OEA, 50 kcal · kg FFM-1  · day-1 ). Before the intervention, both groups underwent a 5-day 'run-in' period with OEA. All foods were provided throughout the experimental period with a protein content of 2.2 g kg lean mass-1  · day-1 . A standardized, supervised combined resistance and cardiovascular exercise training programme was performed over the experimental period. Daily integrated muscle protein synthesis was measured by deuterium oxide (D2 O) consumption along with changes in body composition, resting metabolic rate, blood biomarkers and 24 h nitrogen balance. We found that LEA reduced daily integrated myofibrillar and sarcoplasmic muscle protein synthesis compared with OEA. Concomitant reductions were observed in lean mass, urinary nitrogen balance, free androgen index, thyroid hormone concentrations and resting metabolic rate following LEA. These results highlight that LEA may negatively affect skeletal muscle adaptations in females performing exercise training. KEY POINTS: Low energy availability (LEA) with potential health and performance impairments is widespread among female athletes. We investigated the impact of 10 days of LEA on daily integrated myofibrillar and sarcoplasmic muscle protein synthesis in young, trained females. We show that LEA impairs myofibrillar and sarcoplasmic muscle protein synthesis in trained females performing exercise training. These findings suggest that LEA may have negative consequences for skeletal muscle adaptations and highlight the importance of ensuring adequate energy availability in female athletes.

Phase-locking of Neural Activity to the Envelope of Speech in the Delta Frequency Band Reflects Differences between Word Lists and Sentences.

The envelope of a speech signal is tracked by neural activity in the cerebral cortex. The cortical tracking occurs mainly in two frequency bands, theta (4-8 Hz) and delta (1-4 Hz). Tracking in the faster theta band has been mostly associated with lower-level acoustic processing, such as the parsing of syllables, whereas the slower tracking in the delta band relates to higher-level linguistic information of words and word sequences. However, much regarding the more specific association between cortical tracking and acoustic as well as linguistic processing remains to be uncovered. Here, we recorded EEG responses to both meaningful sentences and random word lists in different levels of signal-to-noise ratios (SNRs) that lead to different levels of speech comprehension as well as listening effort. We then related the neural signals to the acoustic stimuli by computing the phase-locking value (PLV) between the EEG recordings and the speech envelope. We found that the PLV in the delta band increases with increasing SNR for sentences but not for the random word lists, showing that the PLV in this frequency band reflects linguistic information. When attempting to disentangle the effects of SNR, speech comprehension, and listening effort, we observed a trend that the PLV in the delta band might reflect listening effort rather than the other two variables, although the effect was not statistically significant. In summary, our study shows that the PLV in the delta band reflects linguistic information and might be related to listening effort.

Validity and reliability of self-reported and neural measures of listening effort.

Listening effort can be defined as a measure of cognitive resources used by listeners to perform a listening task. Various methods have been proposed to measure this effort, yet their reliability remains unestablished, a crucial step before their application in research or clinical settings. This study encompassed 32 participants undertaking speech-in-noise tasks across two sessions, approximately a week apart. They listened to sentences and word lists at varying signal-to-noise ratios (SNRs) (-9, -6, -3 and 0 dB), then retaining them for roughly 3 s. We evaluated the test-retest reliability of self-reported effort ratings, theta (4-7 Hz) and alpha (8-13 Hz) oscillatory power, suggested previously as neural markers of listening effort. Additionally, we examined the reliability of correct word percentages. Both relative and absolute reliability were assessed using intraclass correlation coefficients (ICC) and Bland-Altman analysis. We also computed the standard error of measurement (SEM) and smallest detectable change (SDC). Our findings indicated heightened frontal midline theta power for word lists compared to sentences during the retention phase under high SNRs (0 dB, -3 dB), likely indicating a greater memory load for word lists. We observed SNR's impact on alpha power in the right central region during the listening phase and frontal theta power during the retention phase in sentences. Overall, the reliability analysis demonstrated satisfactory between-session variability for correct words and effort ratings. However, neural measures (frontal midline theta power and right central alpha power) displayed substantial variability, even though group-level outcomes appeared consistent across sessions.

Lowered muscle glycogen reduces body mass with no effect on short-term exercise performance in men.

Performance in short-duration sports is highly dependent on muscle glycogen, but the total degradation is only moderate and considering the water-binding property of glycogen, unnecessary storing of glycogen may cause an unfavorable increase in body mass. To investigate this, we determined the effect of manipulating dietary carbohydrates (CHO) on muscle glycogen content, body mass, and short-term exercise performance. In a randomized and counterbalanced cross-over design, twenty-two men completed two maximal cycle tests of either 1-min (n = 10) or 15-min (n = 12) duration with different pre-exercise muscle glycogen levels. Glycogen manipulation was initiated three days prior to the tests by exercise-induced glycogen depletion followed by ingestion of a moderate (M-CHO) or high (H-CHO) CHO-diet. Subjects were weighed before each test, and muscle glycogen content was determined in biopsies from m. vastus lateralis before and after each test. Pre-exercise muscle glycogen content was lower following M-CHO than H-CHO (367 mmol · kg-1 DW vs. 525 mmol · kg-1 DW, p < 0.00001), accompanied by a 0.7 kg lower body mass (p < 0.00001). No differences were observed in performance between diets in neither the 1-min (p = 0.33) nor the 15-min (p = 0.99) test. In conclusion, pre-exercise muscle glycogen content and body mass were lower after ingesting moderate compared with high amounts of CHO, while short-term exercise performance was unaffected. This demonstrates that adjusting pre-exercise glycogen levels to the requirements of competition may provide an attractive weight management strategy in weight-bearing sports, particularly in athletes with high resting glycogen levels.

Determining primary stability for adhesively stabilized dental implants.

OBJECTIVES: To examine factors influencing the primary stability of dental implants when stabilized in over-sized osteotomies using a calcium phosphate-based adhesive cement was the objective. METHODS: Using implant removal torque measurements as a surrogate for primary stability, we examined the influence of implant design features (diameter, surface area, and thread design), along with cement gap size and curing time, on the resulting primary implant stability. RESULTS: Removal torque values scaled with implant surface area and increasing implant diameters. Cement gap size did not alter the median removal torque values; however, larger gaps were associated with an increased spread of the measured values. Among the removal torque values measured, all were found to be above 32 Ncm which is an insertion torque threshold value commonly recommended for immediate loading protocols. CONCLUSION: The adhesive cement show potential for offering primary implant stability for different dental implant designs. In this study, the primary parameters influencing the measured removal torque values were the implant surface area and diameter. As the liquid cement prevents the use of insertion torque, considering the relationship between insertion and removal torque, removal torque can be considered a reliable surrogate for primary implant stability for bench and pre-clinical settings. CLINICAL RELEVANCE: At present, the primary stability of dental implants is linked to the quality of the host bone, the drill protocol, and the specific implant design. The adhesive cement might find applications in future clinical settings for enhancing primary stability of implants under circumstances where this cannot be achieved conventionally.

Fibre type- and localisation-specific muscle glycogen utilisation during repeated high-intensity intermittent exercise.

Glycogen particles are situated in key areas of the muscle cell in the vicinity of the main energy-consumption sites and may be utilised heterogeneously dependent on the nature of the metabolic demands. The present study aimed to investigate the time course of fibre type-specific utilisation of muscle glycogen in three distinct subcellular fractions (intermyofibrillar, IMF; intramyofibrillar, Intra; and subsarcolemmal, SS) during repeated high-intensity intermittent exercise. Eighteen moderately to well-trained male participants performed three periods of 10 × 45 s cycling at ∼105% watt max (EX1-EX3) coupled with 5 × 6 s maximal sprints at baseline and after each period. Muscle biopsies were sampled at baseline and after EX1 and EX3. A higher glycogen breakdown rate in type 2 compared to type 1 fibres was found during EX1 for the Intra (-72 vs. -45%) and IMF (-59 vs. -35%) glycogen fractions (P < 0.001) but with no differences for SS glycogen (-52 vs. -40%). In contrast, no fibre type differences were observed during EX2-EX3, where the utilisation of Intra and IMF glycogen in type 2 fibres was reduced, resulting in depletion of all three subcellular fractions to very low levels post-exercise within both fibre types. Importantly, large heterogeneity in single-fibre glycogen utilisation was present with an early depletion of especially Intra glycogen in individual type 2 fibres. In conclusion, there is a clear fibre type- and localisation-specific glycogen utilisation during high-intensity intermittent exercise, which varies with time course of exercise and is characterised by exacerbated pool-specific glycogen depletion at the single-fibre level. KEY POINTS: Muscle glycogen is the major fuel during high-intensity exercise and is stored in distinct subcellular areas of the muscle cell in close vicinity to the main energy consumption sites. In the present study quantitative electron microscopy imaging was used to investigate the utilisation pattern of three distinct subcellular muscle glycogen fractions during repeated high-intensity intermittent exercise. It is shown that the utilisation differs dependent on fibre type, subcellular localisation and time course of exercise and with large single-fibre heterogeneity. These findings expand on our understanding of subcellular muscle glycogen metabolism during exercise and may help us explain how reductions in muscle glycogen can attenuate muscle function even at only moderately lowered whole-muscle glycogen concentrations.

Priming of central and peripheral mechanisms with heat and cutaneous capsaicin facilitates secondary hyperalgesia to high-frequency electrical stimulation.

Heat/capsaicin sensitization and electrical high-frequency stimulation (HFS) are well-known models of secondary hyperalgesia, a phenomenon related to chronic pain conditions. This study investigated whether priming with heat/capsaicin would facilitate hyperalgesia to HFS in healthy subjects. Heat/capsaicin priming consisted of a 45°C heat stimulation for 5 min followed by a topical capsaicin patch (4 × 4 cm) for 30 min on the volar forearm of 20 subjects. HFS (100 Hz, 5 times 1 s, minimum 1.5 mA) was subsequently delivered through a transcutaneous pin electrode approximately 1.5 cm proximal to the heat/capsaicin application. Two sessions were applied in a crossover design; traditional HFS (HFS) and heat/capsaicin sensitization followed by HFS (HFS + HEAT/CAPS). Heat pain threshold (HPT), mechanical pain sensitivity (MPS), and superficial blood perfusion were assessed at baseline, after capsaicin removal, and up to 40 min after HFS. MPS was assessed with pin-prick stimulation (128 mN and 256 mN) in the area adjacent to both HFS and heat/capsaicin, distal but adjacent to heat/capsaicin and in a distal control area. HPT was assessed in the area of heat/capsaicin. Higher sensitivity to 128 mN pin-prick stimulation (difference from baseline and control area) was observed in the HFS + HEAT/CAPS session than in the HFS session 20 and 30 min after HFS. Furthermore, sensitivity was increased after HFS + HEAT/CAPS compared with after heat/capsaicin in the area adjacent to both paradigms, but not in the area distal to heat/capsaicin. Results indicate that heat/capsaicin causes priming of the central and peripheral nervous system, which facilitates secondary mechanical hyperalgesia to HFS.NEW & NOTEWORTHY High-frequency electrical stimulation (HFS) and heat/capsaicin sensitization are well-known models of secondary hyperalgesia. The results from the current study indicate that increased sensitivity to 128 mN pin-prick stimulation can be obtained when HFS is delivered following an already established heightened central hyperexcitability provoked by heat/capsaicin sensitization.

An analytical method to separate modality-specific and nonspecific sensory components of event-related potentials.

Several models have been developed to analyse cortical activity in response to salient events constituted by multiple sensory modalities. In particular, additive models compare event-related potentials (ERPs) in response to stimuli from two or more concomitant sensory modalities with the ERPs evoked by unimodal stimuli, in order to study sensory interactions. In this approach, components that are not specific to a sensory modality are commonly disregarded, although they likely carry information about stimulus expectation and evaluation, attentional orientation and other cognitive processes. In this study, we present an analytical method to assess the contribution of modality-specific and nonspecific components to the ERP. We developed an experimental setup that recorded ERPs in response to four stimulus types (visual, auditory, and two somatosensory modalities to test for stimulus specificity) in three different conditions (unimodal, bimodal and trimodal stimulation) and recorded the saliency of these stimuli relative to the sensory background. Stimuli were delivered in pairs, in order to study the effects of habituation. To this end, spatiotemporal features (peak amplitudes and latencies at different scalp locations) were analysed using linear mixed models. Results showed that saliency relative to the sensory background increased with the number of concomitant stimuli. We also observed that the spatiotemporal features of modality-specific components derived from this method likely reflect the amount and type of sensory input. Furthermore, the nonspecific component reflected habituation occurring for the second stimulus in the pair. In conclusion, this method provides an alternative to study neural mechanisms of responses to multisensory stimulation.

Tempo-spatial integration of nociceptive stimuli assessed via the nociceptive withdrawal reflex in healthy humans.

Spatial information of nociceptive stimuli applied in the skin of healthy humans is integrated in the spinal cord to determine the appropriate withdrawal reflex response. Double-simultaneous stimulus applied in different skin sites are integrated, eliciting a larger reflex response. The temporal characteristics of the stimuli also modulate the reflex, e.g., by temporal summation. The primary aim of this study was to investigate how the combined tempo-spatial aspects of two stimuli are integrated in the nociceptive system. This was investigated by delivering single- and double-simultaneous stimulation and sequential stimulation with different interstimulus intervals (ISIs ranging 30-500 ms) to the sole of the foot of 15 healthy subjects. The primary outcome measure was the size of the nociceptive withdrawal reflex (NWR) recorded from the tibialis anterior (TA) and biceps femoris (BF) muscles. Pain intensity was measured using a numerical rating scale (NRS) scale. Results showed spatial summation in both TA and BF when delivering simultaneous stimulation. Simultaneous stimulation provoked larger reflexes than sequential stimulation in TA, but not in BF. Larger ISIs elicited significantly larger reflexes in TA, whereas the opposite pattern occurred in BF. This differential modulation between proximal and distal muscles suggests the presence of spinal circuits eliciting a functional reflex response based on the specific tempo-spatial characteristics of a noxious stimulus. No modulation was observed in pain intensity ratings across ISIs. Absence of modulation in the pain intensity ratings argues for an integrative mechanism located within the spinal cord governed by a need for efficient withdrawal from a potentially harmful stimulus.NEW & NOTEWORTHY Tempo-spatial integration of electrical noxious stimuli was studied using the nociceptive withdrawal reflex and a perceived intensity. Tibialis anterior and biceps femoris muscles were differentially modulated by the temporal characteristics of the stimuli and stimulated sites. These findings suggest that spinal neurons are playing an important role in the tempo-spatial integration of nociceptive information, leading to a reflex response that is distributed across multiple spinal cord segments and governed by an efficient defensive withdrawal strategy.

Variability and effect sizes of intracranial current source density estimations during pain: Systematic review, experimental findings, and future perspectives.

Pain arises from the integration of sensory and cognitive processes in the brain, resulting in specific patterns of neural oscillations that can be characterized by measuring electrical brain activity. Current source density (CSD) estimation from low-resolution brain electromagnetic tomography (LORETA) and its standardized (sLORETA) and exact (eLORETA) variants, is a common approach to identify the spatiotemporal dynamics of the brain sources in physiological and pathological pain-related conditions. However, there is no consensus on the magnitude and variability of clinically or experimentally relevant effects for CSD estimations. Here, we systematically examined reports of sample size calculations and effect size estimations in all studies that included the keywords pain, and LORETA, sLORETA, or eLORETA in Scopus and PubMed. We also assessed the reliability of LORETA CSD estimations during non-painful and painful conditions to estimate hypothetical sample sizes for future experiments using CSD estimations. We found that none of the studies included in the systematic review reported sample size calculations, and less than 20% reported measures of central tendency and dispersion, which are necessary to estimate effect sizes. Based on these data and our experimental results, we determined that sample sizes commonly used in pain studies using CSD estimations are suitable to detect medium and large effect sizes in crossover designs and only large effects in parallel designs. These results provide a comprehensive summary of the effect sizes observed using LORETA in pain research, and this information can be used by clinicians and researchers to improve settings and designs of future pain studies.

Characterization of Source-Localized EEG Activity During Sustained Deep-Tissue Pain.

Musculoskeletal pain is a clinical condition that is characterized by ongoing pain and discomfort in the deep tissues such as muscle, bones, ligaments, nerves, and tendons. In the last decades, it was subject to extensive research due to its high prevalence. Still, a quantitative description of the electrical brain activity during musculoskeletal pain is lacking. This study aimed to characterize intracranial current source density (CSD) estimations during sustained deep-tissue experimental pain. Twenty-three healthy volunteers received three types of tonic stimuli for three minutes each: computer-controlled cuff pressure (1) below pain threshold (sustained deep-tissue no-pain, SDTnP), (2) above pain threshold (sustained deep-tissue pain, SDTP) and (3) vibrotactile stimulation (VT). The CSD in response to these stimuli was calculated in seven regions of interest (ROIs) likely involved in pain processing: contralateral anterior cingulate cortex, contralateral primary somatosensory cortex, bilateral anterior insula, contralateral dorsolateral prefrontal cortex, posterior parietal cortex and contralateral premotor cortex. Results showed that participants exhibited an overall increase in spectral power during SDTP in all seven ROIs compared to both SDTnP and VT, likely reflecting the differences in the salience of these stimuli. Moreover, we observed a difference is CSD due to the type of stimulus, likely reflecting somatosensory discrimination of stimulus intensity. These results describe the different contributions of neural oscillations within these brain regions in the processing of sustained deep-tissue pain.

Evaluation of rest-activity cycles in patients with severe acquired brain injury: an observational study.

BACKGROUND: There is little knowledge about rest-activity cycles (RAC) in patients with severe-acquired brain injury (sABI) during early in-hospital rehabilitation. This study aimed to investigate if patients with sABI displayed unconsolidated RACs at the beginning of in-hospital rehabilitation, and how these changed over time. METHODS: This study was a prospective observational study. All patients consecutively admitted to one ward were screened for eligibility. We recorded accelerometric activity for 20 days. The Daytime Activity Ratio (DAR) of activity between daytime (7-22) and the total activity during the entire day was calculated and used to estimate consolidation. RESULTS: Fifty-five patients were screened and 20 patients were included. Complete day 1 & 2 data was obtained on 18 patients. Fifty-six percentage of these had a consolidated RAC at the beginning of rehabilitation. On day 19 & 20, complete data could be obtained from 15 patients, 80% of these had consolidation of RAC. When comparing these a significant mean increase of 5.8% 95%CI(0.52; 11.01) in DAR was found p < .05, and the model of all data also showed a significant increase in median DAR over time p < .01. CONCLUSION: RAC consolidation improves over time in patients admitted for in-hospital early neurorehabilitation.

Stimulus predictability moderates the withdrawal strategy in response to repetitive noxious stimulation in humans.

Nociceptive withdrawal reflex (NWR) is a protective reaction to a noxious stimulus, resulting in withdrawal of the affected area and thus preventing potential tissue damage. This involuntary reaction consists of neural circuits, biomechanical strategies, and muscle activity that ensure an optimal withdrawal. Studies of lower limb NWR indicate that the amplitude of the NWR is highly modulated by extrinsic and intrinsic factors, such as stimulation site, intensity, frequency, and supraspinal activity, among others. Whether the predictability of the stimulus has an effect on the biomechanical strategies is still unclear. This study aimed to evaluate how the predictability of impending noxious stimuli modulate the NWR reaction in the lower limb. NWR was evoked on fifteen healthy participants by trains of electrical stimuli on the sole of the foot and was measured in one distal (tibialis anterior) and one proximal (biceps femoris) muscle. The predictability was manipulated by giving participants prior information about the onset of the stimulus trains and the number of delivered stimuli per train. Results showed that the predictability of the incoming stimuli differentially modulates the muscle activity involved in the NWR reaction. For the most unpredictable stimulus train, larger NWR at distal muscles were evoked. Furthermore, the stereotyped temporal summation profile to repeated stimulation was observed when the stimulus train was completely predictable, while it was disrupted in proximal muscles in unpredictable conditions. It is inferred that the reflex response is shaped by descending control, which dynamically tunes the activity of the muscles involved in the resulting reaction.NEW & NOTEWORTHY Innate defensive behaviors such as reflexes are found across all species, constituting preprogrammed responses to external threats that are not anticipated. Previous studies indicated that the excitability of the reflex arcs like spinal nociceptive withdrawal reflex (NWR) pathways in humans are modulated by several cognitive factors. This study assesses how the predictability of a threat affects the biomechanical pattern of the withdrawal response, showing that distal and proximal muscles are differentially modulated by descending control.

Long-term risk of colorectal cancer after screen-detected adenoma: Experiences from a Danish gFOBT-positive screening cohort.

Fecal occult blood test (FOBT) screening for colorectal cancer (CRC) is implemented in several countries. Approximately half of all FOBT-positive persons have screen-detected adenomas. Despite removal of these, patients with large/multiple adenomas have increased risk of later developing new advanced adenomas and CRC. International guidelines exist for colonoscopic surveillance following adenoma removal. These divide patients into low-, intermediate- and high-risk groups. We followed 711 FOBT-positive patients with screening adenoma identified during population-based CRC screening in two Danish counties in 2005-2006. As reference population, we included 1,240,348 persons in the same age group from the rest of Denmark not included in the screening. We estimated the long-term CRC risk stratified by adenoma findings during screening and compared to the reference group. After 12 years follow-up, the CRC incidence among all adenoma patients was 322 cases per 100,000 person-years (95% confidence interval [CI]: 212-489) ranging from 251 (95% CI: 94-671) to 542 (95% CI: 300-978) cases per 100,000 person-years in the low- and high-risk groups, respectively. In the reference population, the CRC incidence was 244 (95% CI: 242-247) per 100,000. Patients with screen-detected high-risk adenomas after a positive FOBT had an almost doubled risk of CRC compared to the reference population (adjusted hazard ratio [aHR] 1.95, 95% CI: 1.08-3.51), and the incidence in those with no follow-up visits was over 3.6 (aHR 3.64, 95% CI: 1.82-7.29) times the incidence in the reference population. The increased CRC risk could be controlled if high-risk patients underwent follow-up colonoscopy (aHR 0.87, 95% CI: 0.28-2.69).

Agreement between the Danish Cancer Registry and the Danish Colorectal Cancer Group Database.

Background: The Danish Cancer Registry (DCR) and the Danish Colorectal Cancer Group (DCCG) database are population-based registries collecting information on Danish patients with colorectal cancer (CRC). DCR registers all patients with incident CRC whereas DCCG records patients with first time CRC. The registries use different inclusion criteria. The consequencenses of this are unknown and not previously evaluated. The aim of this study was to examine the agreement between patients registered in DCR and DCCG and to evaluate its influence on estimated survival and mortality.Material and methods: Patients registered in DCR and DCCG with CRC in 2014-2015 were included. Because of different inclusion criteria, DCCG's inclusion criteria were applied to DCR. Descriptive statistics were used for comparisons. One-year relative survival (1-year RS) was calculated, and the Cox proportional hazard model used for calculating 1-year mortality rate ratios (1-year MRR).Results: In 2014-2015, DCR registered 9678 Danish residents with CRC that fulfilled DCCG's inclusion criteria, while DCCG registered 10,312 Danish residents with CRC. Allowing ±180 days between dates of diagnosis, 10,688 patients were registered with CRC in the merger of the two registries. Of these, 86% were included in both registers, 4% only in DCR, and 10% only in DCCG. No difference was found in 1-year RS between patients in DCR 86% (95% CI: 85-87) and DCCG 85% (95% CI: 84-86). However, patients registered in DCCG had a 1-year MRR of 1.09 (95% CI: 1.01-1.17) compared to DCR.Conclusion: An agreement of 86% of patients was found between the two registries. The discrepancy did not influence 1-year RS. DCCG registered more patients than DCR, and 1-year MRR of patients in DCCG was increased compared to patients in DCR. Regular linkage of the registries is recommended to improve data quality of both registries.

From Perception Threshold to Ion Channels-A Computational Study.

Small-surface-area electrodes have successfully been used to preferentially activate cutaneous nociceptors, unlike conventional large area-electrodes, which preferentially activate large non-nociceptor fibers. Assessments of the strength-duration relationship, threshold electrotonus, and slowly increasing pulse forms have displayed different perception thresholds between large and small surface electrodes, which may indicate different excitability properties of the activated cutaneous nerves. In this study, the origin of the differences in perception thresholds between the two electrodes was investigated. It was hypothesized that different perception thresholds could be explained by the varying distributions of voltage-gated ion channels and by morphological differences between peripheral nerve endings of small and large fibers. A two-part computational model was developed to study activation of peripheral nerve fibers by different cutaneous electrodes. The first part of the model was a finite-element model, which calculated the extracellular field delivered by the cutaneous electrodes. The second part of the model was a detailed multicompartment model of an Aδ-axon as well as an Aß-axon. The axon models included a wide range of voltage-gated ion channels: NaTTXs, NaTTXr, Nap, Kdr, KM, KA, and HCN channel. The computational model reproduced the experimentally assessed perception thresholds for the three protocols, the strength-duration relationship, the threshold electrotonus, and the slowly increasing pulse forms. The results support the hypothesis that voltage-gated ion channel distributions and morphology differences between small and large fibers were sufficient to explain the difference in perception thresholds between the two electrodes. In conclusion, assessments of perception thresholds using the three protocols may be an indirect measurement of the membrane excitability, and computational models may have the possibility to link voltage-gated ion channel activation to perception threshold measurements.

Investigating stimulation parameters for preferential small-fiber activation using exponentially rising electrical currents.

Electrical stimulation is widely used in pain research and profiling, but current technologies lack selectivity toward small sensory fibers. Pin electrodes deliver high current density in upper skin layers, and it has been proposed that slowly rising exponential pulses can elevate large-fiber activation threshold and thereby increase preferential small-fiber activation. Optimal stimulation parameters for the combined pin electrode and exponential pulse stimulation have so far not been established, which is the aim of this study. Perception thresholds were compared between pin and patch electrodes using single 1- to 100-ms exponential and rectangular pulses. Stimulus-response functions were evaluated for both pulse shapes delivered as single pulses and pulse trains of 10 Hz using intensities from 0.1 to 20 times perception threshold. Perception thresholds (mA) decreased when duration was increased for both electrodes with rectangular pulses and the pin electrode with exponential pulses. For the patch electrode, perception thresholds for exponential pulses decreased for durations ≤10 ms but increased for durations ≥15 ms, indicating accommodation of large fibers. Stimulus-response curves for single pulses were similar for the two pulse shapes. For pulse trains, the slope of the curve was higher for rectangular pulses. Maximal large-fiber accommodation to exponential pulses was observed for 100-ms pulses, indicating that 100-ms exponential pulses should be applied for preferential small-fiber activation. Intensity of 10 times perception threshold was sufficient to cause maximal pain ratings. The developed methodology may open new opportunities for using electrical stimulation paradigms for small-fiber stimulation and diagnostics.NEW & NOTEWORTHY Selective activation of small cutaneous nerve fibers is pivotal for investigations of the pain system. The present study demonstrated that patch electrode perception thresholds increase with increased duration of exponential currents from 20 to 100 ms. This is likely caused by large-fiber accommodation, which can be utilized to activate small fibers preferentially through small-diameter pin electrodes. This finding may be utilized in studies of fundamental pain mechanisms and, for example, in small-fiber neuropathy.

Intense and sustained pain reduces cortical responses to auditory stimuli: Implications for the interpretation of the effects of heterotopic noxious conditioning stimulation in humans.

Phasic pain stimuli are inhibited when they are applied concomitantly with a conditioning tonic stimulus at another body location (heterotopic noxious conditioning stimulation, HNCS). While the effects of HNCS are thought to rely on a spino-bulbo-spinal mechanism in animals (termed diffuse noxious inhibitory controls, DNIC), the underlying neurophysiology in humans may involve other pathways. In this study, we investigated the role of concomitant supraspinal mechanisms during HNCS by presenting auditory stimuli during a conditioning tonic painful stimulus (the cold pressor test, CPT). Considering that auditory stimuli are not conveyed through the spinal cord, any changes in brain responses to auditory stimuli during HNCS can be ascribed entirely to supraspinal mechanisms. Electroencephalography (EEG) was recorded during HNCS, and auditory stimuli were administered in three blocks, before, during and after HNCS. Nociceptive withdrawal reflexes (NWRs) were recorded at the same time points to investigate spinal processing. Our results showed that AEPs were significantly reduced during HNCS. Moreover, the amplitude of the NWR was significantly diminished during HNCS in most participants. Given that spinal and supraspinal mechanisms operate concomitantly during HNCS, the possibility of isolating their individual contributions in humans is questionable. We conclude that the net effects of HCNS are not independent from attentional/cognitive influences.

Preferential activation of small cutaneous fibers through small pin electrode also depends on the shape of a long duration electrical current.

BACKGROUND: Electrical stimulation is widely used in experimental pain research but it lacks selectivity towards small nociceptive fibers. When using standard surface patch electrodes and rectangular pulses, large fibers are activated at a lower threshold than small fibers. Pin electrodes have been designed for overcoming this problem by providing a higher current density in the upper epidermis where the small nociceptive fibers mainly terminate. At perception threshold level, pin electrode stimuli are rather selectively activating small nerve fibers and are perceived as painful, but for high current intensity, which is usually needed to evoke sufficient pain levels, large fibers are likely co-activated. Long duration current has been shown to elevate the threshold of large fibers by the mechanism of accommodation. However, it remains unclear whether the mechanism of accommodation in large fibers can be utilized to activate small fibers even more selectively by combining pin electrode stimulation with a long duration pulse. RESULTS: In this study, perception thresholds were determined for a patch- and a pin electrode for different pulse shapes of long duration. The perception threshold ratio between the two different electrodes was calculated to estimate the ability of the pulse shapes to preferentially activate small fibers. The perception threshold ratios were compared between stimulation pulses of 5- and 50 ms durations and shapes of: exponential increase, linear increase, bounded exponential, and rectangular. Qualitative pain perception was evaluated for all pulse shapes delivered at 10 times perception threshold. The results showed a higher perception threshold ratio for long duration 50 ms pulses than for 5 ms pulses. The highest perception threshold ratio was found for the 50 ms, bounded exponential pulse shape. Results furthermore revealed different strength-duration relation between the bounded exponential- and rectangular pulse shapes. Pin electrode stimulation at high intensity was mainly described as "stabbing", "shooting", and "sharp". CONCLUSION: These results indicate that long duration pulses with a bounded exponential increase preferentially activate the small nociceptive fibers with a pin electrode and concurrently cause elevated threshold of large non-nociceptive fibers with patch electrodes.