High efficacy treatment of murine Pseudomonas aeruginosa catheter-associated urinary tract infections using the c-di-GMP modulating anti-biofilm compound Disperazol in combination with ciprofloxacin.

Persistent urinary tract infections (UTIs) in hospitalized patients constitute an important medical problem. It is estimated that 75% of nosocomial UTIs are associated with urinary tract catheters with P. aeruginosa being a species that forms biofilms on these catheters. These infections are highly resistant to standard-of-care antibiotics, and the effects of the host immune defenses, which allows for development of persistent infections. With antibiotics losing their efficacy, new treatment options against resilient infections, such as catheter-associated urinary tract infections (CAUTIs), are critically needed. Central to our anti-biofilm approach is the manipulation of the c-di-GMP signaling pathway in P. aeruginosa to switch bacteria from the protective biofilm to the unprotected planktonic mode of life. We recently identified a compound (H6-335-P1), that stimulates the c-di-GMP degrading activity of the P. aeruginosa BifA protein which plummets the intracellular c-di-GMP content and induces dispersal of P. aeruginosa biofilm bacteria into the planktonic state. In the present study, we formulated H6-335-P1 as a hydrochloride salt (Disperazol), which is water-soluble and facilitates delivery via injection or oral administration. Disperazol can work as a monotherapy, but we observed a 100-fold improvement in efficacy when treating murine P. aeruginosa CAUTIs with a Disperazol/ciprofloxacin combination. Biologically active Disperazol reached the bladder 30 min after oral administration. Our study provides proof of concept that Disperazol can be used in combination with a relevant antibiotic for effective treatment of CAUTIs.

Facilitation of Early and Middle Latency SEP after tDCS of M1: No Evidence of Primary Somatosensory Homeostatic Plasticity.

Homeostatic plasticity is a mechanism that stabilizes cortical excitability within a physiological range. Most homeostatic plasticity protocols have primed and tested the homeostatic response of the primary motor cortex (M1). This study investigated if a homeostatic response could be recorded from the primary sensory cortex (S1) after inducing homeostatic plasticity in M1. In 31 healthy participants, homeostatic plasticity was induced over M1 with a priming and testing block of transcranial direct current stimulation (tDCS) in two different sessions (anodal and cathodal). S1 excitability was assessed by early (N20, P25) and middle-latency (N33-P45) somatosensory evoked potentials (SEP) extracted from 4 electrodes (CP5, CP3, P5, P3). Baseline and post-measures (post-priming, 0-min, 10-min, and 20-min after homeostatic induction) were taken. Anodal M1 homeostatic plasticity induction significantly facilitated the N20-P25, P45 peak, and N33-P45 early SEP components up to 20-min post-induction, without any indication of a homeostatic response (i.e., reduced SEP). Cathodal homeostatic induction did not induce any significant effect on early or middle latency SEPs. M1 homeostatic plasticity induction by anodal stimulation protocol to the primary motor cortex did not induce a homeostatic response in SEPs.

Porcine Model of Cerebral Ischemic Stroke Utilizing Intracortical Recordings for the Continuous Monitoring of the Ischemic Area.

PURPOSE: Our aim was to use intracortical recording to enable the tracking of ischemic infarct development over the first few critical hours of ischemia with a high time resolution in pigs. We employed electrophysiological measurements to obtain quick feedback on neural function, which might be useful for screening, e.g., for the optimal dosage and timing of agents prior to further pre-clinical evaluation. METHODS: Micro-electrode arrays containing 16 (animal 1) or 32 electrodes (animal 2-7) were implanted in the primary somatosensory cortex of seven female pigs, and continuous electrical stimulation was applied at 0.2 Hz to a cuff electrode implanted on the ulnar nerve. Ischemic stroke was induced after 30 min of baseline recording by injection of endothelin-1 onto the cortex adjacent to the micro-electrode array. Evoked responses were extracted over a moving window of 180 s and averaged across channels as a measure of cortical excitability. RESULTS: Across the animals, the cortical excitability was significantly reduced in all seven 30 min segments following endothelin-1 injection, as compared to the 30 min preceding this intervention. This difference was not explained by changes in the anesthesia, ventilation, end-tidal CO2, mean blood pressure, heart rate, blood oxygenation, or core temperature, which all remained stable throughout the experiment. CONCLUSIONS: The animal model may assist in maturing neuroprotective approaches by testing them in an accessible model of resemblance to human neural and cardiovascular physiology and body size. This would constitute an intermediate step for translating positive results from rodent studies into human application, by more efficiently enabling effective optimization prior to chronic pre-clinical studies in large animals.

Evoked oscillatory cortical activity during acute pain: Probing brain in pain by transcranial magnetic stimulation combined with electroencephalogram.

Temporal dynamics of local cortical rhythms during acute pain remain largely unknown. The current study used a novel approach based on transcranial magnetic stimulation combined with electroencephalogram (TMS-EEG) to investigate evoked-oscillatory cortical activity during acute pain. Motor (M1) and dorsolateral prefrontal cortex (DLPFC) were probed by TMS, respectively, to record oscillatory power (event-related spectral perturbation and relative spectral power) and phase synchronization (inter-trial coherence) by 63 EEG channels during experimentally induced acute heat pain in 24 healthy participants. TMS-EEG was recorded before, during, and after noxious heat (acute pain condition) and non-noxious warm (Control condition), delivered in a randomized sequence. The main frequency bands (α, ß1, and ß2) of TMS-evoked potentials after M1 and DLPFC stimulation were recorded close to the TMS coil and remotely. Cold and heat pain thresholds were measured before TMS-EEG. Over M1, acute pain decreased α-band oscillatory power locally and α-band phase synchronization remotely in parietal-occipital clusters compared with non-noxious warm (all p < .05). The remote (parietal-occipital) decrease in α-band phase synchronization during acute pain correlated with the cold (p = .001) and heat pain thresholds (p = .023) and to local (M1) α-band oscillatory power decrease (p = .024). Over DLPFC, acute pain only decreased ß1-band power locally compared with non-noxious warm (p = .015). Thus, evoked-oscillatory cortical activity to M1 stimulation is reduced by acute pain in central and parietal-occipital regions and correlated with pain sensitivity, in contrast to DLPFC, which had only local effects. This finding expands the significance of α and ß band oscillations and may have relevance for pain therapies.

Effects of pain on cortical homeostatic plasticity in humans: a systematic review.

Homeostatic plasticity (HP) is a negative feedback mechanism that prevents excessive facilitation or depression of cortical excitability (CE). Cortical HP responses in humans have been investigated by using 2 blocks of noninvasive brain stimulation with a no-stimulation block in between. A healthy HP response is characterized by reduced CE after 2 excitatory stimulation blocks and increased CE when using inhibitory stimulation. Conversely, impaired HP responses have been demonstrated in experimental and chronic pain conditions. Therefore, this systematic review aimed to provide an overview of the effect of pain on cortical HP in humans. Scopus, Embase, and PubMed were searched from inception until November 20, 2023. The included studies (1) compared experimental or clinical pain conditions with healthy controls, (2) induced HP using 2 blocks of stimulation with a no-stimulation interval, and (3) evaluated CE measures such as motor-evoked potentials. Four studies were included, consisting of 5 experiments and 146 participants, of whom 63 were patients with chronic pain and 48 were subjected to an experimental pain model. This systematic review found support for an HP impairment in pain compared with that in pain-free states, reflected by a lack of CE reduction after excitatory-excitatory HP induction over the primary motor cortex. Inhibitory-inhibitory HP induction did not produce a consistent HP response across studies, independent of pain or pain-free states. Standardization of HP induction protocols and outcome calculations is needed to ensure reproducibility and study comparison. Future HP studies may consider investigating sensory domains including nociception, which would further our understanding of abnormal HP regulation in pain conditions.

Ex-vivo systems for neuromodulation: A comparison of ex-vivo and in-vivo large animal nerve electrophysiology.

BACKGROUND: Little research exists on extending ex-vivo systems to large animal nerves, and to the best of our knowledge, there has yet to be a study comparing these against in-vivo data. This paper details the first ex-vivo system for large animal peripheral nerves to be compared with in-vivo results. NEW METHOD: Detailed ex-vivo and in-vivo closed-loop neuromodulation experiments were conducted on pig ulnar nerves. Temperatures from 20 °C to 37 °C were evaluated for the ex-vivo system. The data were analysed in the time and velocity domains, and a regression analysis established how evoked compound action potential amplitude and modal conduction velocity (CV) varied with temperature and time after explantation. MAIN RESULTS: Pig ulnar nerves were sustained ex-vivo up to 5 h post-explantation. CV distributions of ex-vivo and in-vivo data were compared, showing closer correspondence at 37 °C. Regression analysis results also demonstrated that modal CV and time since explantation were negatively correlated, whereas modal CV and temperature were positively correlated. COMPARISON WITH EXISTING METHODS: Previous ex-vivo systems were primarily aimed at small animal nerves, and we are not aware of an ex-vivo system to be directly compared with in-vivo data. This new approach provides a route to understand how ex-vivo systems for large animal nerves can be developed and compared with in-vivo data. CONCLUSION: The proposed ex-vivo system results were compared with those seen in-vivo, providing new insights into large animal nerve activity post-explantation. Such a system is crucial for complementing in-vivo experiments, maximising collected experimental data, and accelerating neural interface development.

A study on the risk stratification for patients within 24 hours of admission for risk of hospital-acquired urinary tract infection using Bayesian network models.

Early identification of patients at risk of hospital-acquired urinary tract infections (HA-UTI) enables the initiation of timely targeted preventive and therapeutic strategies. Machine learning (ML) models have shown great potential for this purpose. However, existing ML models in infection control have demonstrated poor ability to support explainability, which challenges the interpretation of the result in clinical practice, limiting the adaption of the ML models into a daily clinical routine. In this study, we developed Bayesian Network (BN) models to enable explainable assessment within 24 h of admission for risk of HA-UTI. Our dataset contained 138,250 unique hospital admissions. We included data on admission details, demographics, lifestyle factors, comorbidities, vital parameters, laboratory results, and urinary catheter. Models developed from a reduced set of five features were characterized by transparency compared to models developed from a full set of 50 features. The expert-based clinical BN model over the reduced feature space showed the highest performance (area under the curve = 0.746) compared to the naïve- and tree-augmented-naïve BN models. Moreover, models developed from expert-based knowledge were characterized by enhanced explainability.

Assessment of Dementia in Minority Ethnic Groups in Scotland: Results of a Survey of Cognitive Specialists.

OBJECTIVE: Minority ethnic groups (MEGs) in Europe receive suboptimal dementia evaluation, yet related research in Scotland is lacking. This research examined the evaluation of dementia in MEGs in Scotland and compared it with previous research to highlight the changes in the clinical evaluation of dementia over the decade. DESIGN AND SETTING: A self-administered survey was created online and emailed to 14 Heads of the boards under the Scottish National Health Service and dementia-associated settings and organizations. RESULTS: Most surveyed centers (85.6%) received MEG referrals. Although 92.9% of the centers used professional translators when needed, 85.7% thought assessing dementia in MEGs was difficult, mostly due to the suitability of test instruments and rating scales and patients' linguistic abilities. Very few found their skills to be good in evaluating MEGs. There was no mention of specialized dementia services for MEGs. CONCLUSIONS: The lack of culturally appropriate instruments and specialized dementia services reveals that the services are not ready to meet the demand for evaluating patients from diverse cultural and language backgrounds. Inadequate clinical evaluation may lead to misdiagnoses. Therefore, although significant work has been carried out in the past few years, improvements must be continued to enhance the current practices and apply suitable evaluation methods for MEGs.

Impact of Chronic Pain on Use-Dependent Plasticity: Corticomotor Excitability and Motor Representation in Musicians With and Without Pain.

Long-term musical training induces adaptive changes in the functional representation of the motor cortex. It is unknown if the maladaptive plasticity associated with chronic pain, frequently affecting trained musicians, may alter the use-dependent plasticity in the motor cortex. This study investigated the interaction between adaptive and maladaptive plasticity in the motor pathways, in particular how chronic pain influences long-term use-dependent plasticity. Using transcranial magnetic stimulation (TMS), corticospinal excitability was assessed by measuring the amplitude of the motor-evoked potential (MEP), area of the motor map, volume, and center of gravity of the first dorsal interosseous muscle in 19 pain-free musicians, 17 upper limb/neck pain chronic pain musicians, and 19 pain-free non-musicians as controls. Motor map volume and MEP amplitude were smaller for both pain-free and chronic pain musicians compared to pain-free controls (P < 0.011). No significant differences were found between musicians with and without chronic pain. These findings confirm that long-term musical training can lead to focalized and specialized functional organization of the primary motor cortex. Moreover, the adaptive use-dependent plasticity acquired through fine-motor skill acquisition is not significantly compromised by the maladaptive plasticity typically associated with chronic pain, highlighting the potential of long-term sensorimotor training to counteract the effects of chronic pain in the motor system.

Early mortality in children with cancer in Denmark and Sweden: The role of social background in a setting with universal healthcare.

Socioeconomic differences in overall survival from childhood cancer have been shown previously, but the underlying mechanisms remain unclear. We aimed to investigate if social inequalities were seen already for early mortality in settings with universal healthcare. From national registers, all children diagnosed with cancer at ages 0-19 years, during 1991-2014, in Sweden and Denmark, were identified, and information on parental social characteristics was collected. We estimated odds ratios (OR) and 95% confidence intervals (CI) of early mortality (death within 90 days after cancer diagnosis) by parental education, income, employment, cohabitation, and country of birth using logistic regression. For children with acute lymphoblastic leukaemia (ALL), clinical characteristics were obtained. Among 13,926 included children, 355 (2.5%) died within 90 days after diagnosis. Indications of higher early mortality were seen among the disadvantaged groups, with the most pronounced associations observed for maternal education (ORadj_Low_vs_High 1.65 [95% CI 1.22-2.23]) and income (ORadj_Q1(lowest)_vs_Q4(highest) 1.77 [1.25-2.49]). We found attenuated or null associations between social characteristics and later mortality (deaths occurring 1-5 years after cancer diagnosis). In children with ALL, the associations between social factors and early mortality remained unchanged when adjusting for potential mediation by clinical characteristics. In conclusion, this population-based cohort study indicated differences in early mortality after childhood cancer by social background, also in countries with universal healthcare. Social differences occurring this early in the disease course requires further investigation, also regarding the timing of diagnosis.

Morphology and morphometry of the ulnar nerve in the forelimb of pigs.

The knowledge of the morphology and morphometry of peripheral nerves is essential for developing neural interfaces and understanding nerve regeneration in basic and applied research. Currently, the most adopted animal model is the rat, even though recent studies have suggested that the neuroanatomy of large animal models is more comparable to humans. The present knowledge of the morphological structure of large animal models is limited; therefore, the present study aims to describe the morphological characteristics of the Ulnar Nerve (UN) in pigs. UN cross-sections were taken from seven Danish landrace pigs at three distinct locations: distal UN, proximal UN and at the dorsal cutaneous branch of the UN (DCBUN). The nerve diameter, fascicle diameter and number, number of fibres and fibre size were quantified. The UN diameter was larger in the proximal section compared to the distal segment and the DCBUN. The proximal branch also had a more significant number of fascicles (median: 15) than the distal (median: 10) and the DCBUN (median: 11) segments. Additionally, the mean fascicle diameter was smaller at the DCBUN (mean: 165 µm) than at the distal (mean: 197 µm) and proximal (mean: 199 µm) segments of the UN. Detailed knowledge of the microscopical structure of the UN in pigs is critical for further studies investigating neural interface designs and computational models of the peripheral nervous system.

Distal subsartorial compartment block of the saphenous nerve - A dissection study and a patient case series.

STUDY OBJECTIVE: A saphenous nerve block is an important tool for analgesia after foot and ankle surgery. The conventional midthigh approach to saphenous nerve block in the femoral triangle may impede ambulation by impairing quadriceps motor function. PRIMARY OBJECTIVE: Developing a selective saphenous nerve block targeting the nerve distal to its emergence from the adductor canal in the subsartorial compartment. DESIGN: This study consists of A) a dissection study and B) Data from a clinical case series. SETTING: A) Medical University of Innsbruck, Austria (dissection of 15 cadaver sides) and. B) Aarhus University Hospital, Denmark (5 patients). INTERVENTIONS: A) Five mL of methylene blue was injected into the subsartorial compartment distal to the intersection of the saphenous nerve and the tendon of the adductor magnus guided by ultrasound. B) Five patients undergoing major hindfoot and ankle surgery had a subsartorial compartment block with 10 mL of local anesthetic in addition to a popliteal sciatic nerve block. MEASUREMENT: A) The frequencies of staining the saphenous and medial vastus nerves. B) Assessment of postoperative pain by NRS score (0-10) and success rate of saphenous nerve block by presence of cutaneous anesthesia in the anteromedial lower leg, and motor impairment by ability to ambulate. MAIN RESULTS: A) The saphenous nerve was stained in 15/15 cadaver sides. A terminal branch of the medial vastus nerve was stained in 2/15 cadaver sides. B) All patients were fully able to ambulate without support. No patients had any post-surgical pain from the anteromedial aspect of the ankle and foot (NRS score 0). The success rate of saphenous nerve block was 100%. CONCLUSION: The saphenous nerve can be targeted in the subsartorial compartment distal to the intersection of the nerve and the tendon of the adductor magnus. The subsartorial compartment block provided efficient analgesia without quadriceps motor impairment.

Pain history and experimental pressure pain responses in adolescents: Results from a population-based birth cohort.

BACKGROUND: Sensitized pain mechanisms are often reported in musculoskeletal pain conditions, but population-based paediatric studies are lacking. We assessed whether adolescents with musculoskeletal pain history had evidence of increased responsiveness to experimental pressure stimuli. METHODS: Data were from 1496 adolescents of the Generation XXI birth cohort. Pain history was collected using the Luebeck Pain Questionnaire (self-reported at 13, parent-reported at 7 and 10 years). Two case definitions for musculoskeletal pain were considered: (1) cross-sectional-musculoskeletal pain lasting more than 3 months at age 13 and (2) longitudinal-musculoskeletal pain at age 13 with musculoskeletal pain reports at ages 7 and/or 10. Lower limb cuff pressure algometry was used to assess pain detection and tolerance thresholds, conditioned pain modulation effects (CPM, changes in thresholds in the presence on painful conditioning) and temporal summation of pain effects (TSP, changes in pain intensity to 10 phasic painful cuff stimulations). RESULTS: Adolescents with musculoskeletal pain at age 13 plus a history of pain in previous evaluations (longitudinal definition) had lower pain tolerance thresholds compared to the remaining sample (40.2 v. 49.0 kPa, p = 0.02), but showed no differences in pain detection threshold, CPM effect and TSP effect. Pain sensitivity, CPM effects and TSP effects were not significantly different when the current pain only case definition (cross-sectional) was used. CONCLUSIONS: Adolescents with current musculoskeletal pain who had a history of pain since childhood had lower tolerance to cuff stimulation. This may suggest long-standing musculoskeletal pain since childhood may contribute to sensitisation, rather than the presence of current pain only. SIGNIFICANCE: Repeated musculoskeletal pain up to age 13 years may contribute to higher pain sensitivity (particularly lowered pressure pain tolerance) in the general adolescent population. This does not seem to be the case when reported pain experiences are recent or when the outcomes are temporal pain summation or CPM. In this community-based paediatric sample, the vast majority showed no sign of altered pain processing, but a small fraction may reveal some pain sensitization at 13 years of age.

Efficacy of iliopsoas plane block for patients undergoing hip arthroscopy: a prospective, triple-blind, randomized, placebo-controlled trial.

BACKGROUND: Intraoperative stretching of the hip joint capsule often generates severe pain during the first 3 hours after hip arthroscopy. The short-lived severe pain mandates high opioid consumption, which may result in adverse events and delay recovery. The femoral nerve nociceptors are located anteriorly in the hip joint capsule. A femoral nerve block reduces pain and opioid demand after hip arthroscopy. It impedes, however, ambulation and home discharge after outpatient surgery. The iliopsoas plane block selectively anesthetizes the femoral sensory nerve branches innervating the hip joint capsule without compromising ambulation. We aimed to assess reduction of opioid consumption after iliopsoas plane block during the short-lived painful postsurgical period of time after hip arthroscopy. METHODS: In a randomized, triple-blind trial, 50 patients scheduled for hip arthroscopy in general anesthesia were allocated to active or placebo iliopsoas plane block. The primary outcome was opioid consumption during the first three postoperative hours in the postanesthesia care unit. Secondary outcomes included pain, nausea, and ability to ambulate. RESULTS: Forty-nine patients were analyzed for the primary outcome. The mean 3-hour intravenous morphine equivalent consumption in the iliopsoas plane block group was 10.4 mg vs 23.8 mg in the placebo group (p<0.001). No intergroup differences were observed for the secondary outcomes during the postoperative follow-up. CONCLUSION: An iliopsoas plane block reduces opioid consumption after hip arthroscopy. The reduction of opioid consumption during the clinically relevant 3-hour postsurgical period of time was larger than 50% for active versus placebo iliopsoas plane block in this randomized, triple-blind trial.

Employment, occupation, and income in adults with neurofibromatosis 1 in Denmark: a population- and register-based cohort study.

BACKGROUND: Little is known about employment status, occupation, and disposable income in adults with NF1. METHODS: From the Danish National Patient Registry and database of two national Centers for Rare Diseases, we identified 1469 adults with NF1, who were matched to 11,991 randomly selected population comparisons on sex and birth year and month. Annual information on employment, occupation and disposable income was ascertained from national registries in 1980-2019. RESULTS: Adults with NF1 had a lower odds ratio (OR) for employment [OR 0.71, 95% confidence interval (CI) 0.61-0.83] and higher OR for health-related unemployment (OR 2.94, 95% CI 2.16-3.96) at age 30 years than population comparisons, which persisted at age 40 and 50 years. Somatic diagnoses were associated with a higher OR for health-related unemployment in adults with NF1 than in the population comparisons. Adults with NF1 had a slightly lower disposable income, with a 14% (0.82-0.89) reduction observed among the youngest birth cohort. Furthermore, adults with NF1 were less likely to be in a high skilled occupation at ages 30, 40 and 50 years. CONCLUSION: Adults with NF1 have a lower employment rate, which was mainly due to health-related reasons and a slightly lower disposable income than adults without NF1. Thus, anticipation guidance for employment should be part of the management of NF1 families.

Disrupted Cortical Homeostatic Plasticity Due to Prolonged Capsaicin-induced Pain.

Homeostatic plasticity (HP) regulates cortical excitability (CE) stability but is disrupted in persistent pain conditions. This study investigated how prolonged experimental pain affects HP and if pain relief modulates disrupted HP. Twenty-four healthy participants were randomised into a PainRelief or NoPainRelief group and attended four sessions; two sessions on consecutive days, separated by two weeks. Transcranial magnetic stimulation motor-evoked potentials reflecting CE and quantitative sensory testing (QST) measures were recorded. A capsaicin (pain condition) or placebo (control condition) patch was applied to the hand. HP was induced by cathodal-cathodal transcranial direct current stimulation (HP1) with CE assessment before and after. The PainRelief group had ice applied to the patch, while the NoPainRelief group waited for five minutes; subsequently another HP induction (HP2) and CE assessment were performed. After 24 h with the patch on, HP induction (HP3), QST, and CE recordings were repeated. Capsaicin reduced CE and the pain condition showed disrupted homeostatic responses at all time points (HP1: showed CE inhibition instead of facilitation; HP2 & HP3: lack of CE facilitation). Conversely, homeostatic responses were induced at all time points for the placebo condition. Capsaicin pain disrupts HP which is not restored by ice-induced pain relief. Future research may explore the prevention of HP disruption by targeting capsaicin-induced nociception but not pain perception.

Acute pain drives different effects on local and global cortical excitability in motor and prefrontal areas: insights into interregional and interpersonal differences in pain processing.

Pain-related depression of corticomotor excitability has been explored using transcranial magnetic stimulation-elicited motor-evoked potentials. Transcranial magnetic stimulation-electroencephalography now enables non-motor area cortical excitability assessments, offering novel insights into cortical excitability changes during pain states. Here, pain-related cortical excitability changes were explored in the dorsolateral prefrontal cortex and primary motor cortex (M1). Cortical excitability was recorded in 24 healthy participants before (Baseline), during painful heat (Acute Pain), and non-noxious warm (Warm) stimulation at the right forearm in a randomized sequence, followed by a pain-free stimulation measurement. Local cortical excitability was assessed as the peak-to-peak amplitude of early transcranial magnetic stimulation evoked potential, whereas global-mean field power measured the global excitability. Relative to the Baseline, Acute Pain decreased the peak-to-peak amplitude in M1 and dorsolateral prefrontal cortex compared with Warm (both P < 0.05). A reduced global-mean field power was only found in M1 during Acute Pain compared with Warm (P = 0.003). Participants with the largest reduction in local cortical excitability under Acute Pain showed a negative correlation between dorsolateral prefrontal cortex and M1 local cortical excitability (P = 0.006). Acute experimental pain drove differential pain-related effects on local and global cortical excitability changes in motor and non-motor areas at a group level while also revealing different interindividual patterns of cortical excitability changes, which can be explored when designing personalized treatment plans.

Adynamic response to cold pain reflects dysautonomia in type 1 diabetes and polyneuropathy.

Cardiac autonomic neuropathy (CAN), widely assessed by heart rate variability (HRV), is a common complication of long-term diabetes. We hypothesized that HRV dynamics during tonic cold pain in individuals with type 1 diabetes mellitus (T1DM) could potentially demask CAN. Forty-eight individuals with long-term T1DM and distal symmetrical polyneuropathy and 21 healthy controls were included. HRV measures were retrieved from 24-h electrocardiograms. Moreover, ultra-short-term HRV recordings were used to assess the dynamic response to the immersion of the hand into 2 °C cold water for 120 s. Compared to healthy, the T1DM group had expectedly lower 24-h HRV measures for most components (p < 0.01), indicating dysautonomia. In the T1DM group, exposure to cold pain caused diminished sympathetic (p < 0.001) and adynamic parasympathetic (p < 0.01) HRV responses. Furthermore, compared to healthy, cold pain exposure caused lower parasympathetic (RMSSD: 4% vs. 20%; p = 0.002) and sympathetic responses (LF: 11% vs. 73%; p = 0.044) in the T1MD group. QRISK3-scores are negatively correlated with HRV measures in 24-h and ultra-short-term recordings. In T1DM, an attenuated sympathovagal response was shown as convincingly adynamic parasympathetic responses and diminished sympathetic adaptability, causing chronometric heart rhythm and rigid neurocardiac regulation threatening homeostasis. The findings associate with an increased risk of cardiovascular disease, emphasizing clinical relevance.