Pressure Stimuli Research Articles

Catastrophizing and chronic low back pain: A functional magnetic resonance study

Pain depends on the interaction of cognitive, and emotional factors. Individuals with negative coping strategies such as catastrophizing are prone to develop chronic pain syndromes, and poor functional outcomes. This maladapted behavior may be caused by abnormalities in attention systems and amplification of pain processing. Low back pain (LBP) is a disabling pain syndrome, but it is poorly known how catastrophizing affects brain activity. To explore catastrophizing neural correlates in LBP, we performed an fMRI study to verify the central pain system (pain matrix), and anticipation responses. Under unpredictable stimuli, we expected to see catastrophizing LBP showing lower ability to disengage attention to pain and lower pain threshold. We studied 43 LBP and 27 C subjects. LBP responded catastrophizing questionnaires (FABQ, CSQ). We used a pressure-pain device, to deliver stimuli in the thumbnail. Pain thresholds detected a priori, for moderate pain. Subjects performed 2 event-related fMRI experiments: 1 - Supraliminal Pain for the pain matrix study; 2 – Variable Pain for anticipation at unpredictable stimuli. T2* images acquired in a 3 T Siemens scanner. FMRI data was preprocessed and carried out using FSL tool. Corrected cluster significance threshold: P = 0.05. Both groups were similar for demographics. LBP had lower threshold for pressure stimulus. Both groups activated pain matrix areas, and had the same pattern during anticipation. When covarying with FABQ during experiment 2, LBP showed greater posterior cingulate cortex activation, indicating that in LBP, FABQ reduces brain activity. LBP had lower pain threshold, suggesting central sensitization. Although both groups activated the pain matrix and had the same anticipation pattern, catastrophizing LBP had decreased activity in posterior cingulate cortex, suggesting negative coping skill influences pain appraisal in anticipation. The area belongs to the attention system and antinociception pathways in healthy subjects. Our results are in line with previous data showing greater posterior cingulate activity in low catastrophizers.

An Artificial Sensory Neuron with Tactile Perceptual Learning.

Sensory neurons within skin form an interface between the external physical reality and the inner tactile perception. This interface enables sensory information to be organized identified, and interpreted through perceptual learning-the process whereby the sensing abilities improve through experience. Here, an artificial sensory neuron that can integrate and differentiate the spatiotemporal features of touched patterns for recognition is shown. The system comprises sensing, transmitting, and processing components that are parallel to those found in a sensory neuron. A resistive pressure sensor converts pressure stimuli into electric signals, which are transmitted to a synaptic transistor through interfacial ionic/electronic coupling via a soft ionic conductor. Furthermore, the recognition error rate can be dramatically decreased from 44% to 0.4% by integrating with the machine learning method. This work represents a step toward the design and use of neuromorphic electronic skin with artificial intelligence for robotics and prosthetics.

Dynamic Covalent Chemistry under High-Pressure:A New Route to Disulfide Metathesis.

This work describes, for the first time, the application of combined pressure and temperature stimuli in disulfide metathesis reactions. In the system studied, above a pressure of 0.2 GPa, equimolar amounts of symmetric disulfides bis 4-chlorophenyl disulfide [(4-ClPhS)2 ] and bis 2-nitrophenyl disulfide [(2-NO2 PhS)2 ] react to give the heterodimeric product 4-Cl-PhSSPh-2-NO2 . In contrast to experiments conducted in solution at atmospheric pressure or in mechanochemical experiments under ball-mill grinding conditions, there is no necessity to use a base or thiolate anion as a catalyst for the exchange reaction under investigated conditions. Single-crystal and powder X-ray diffraction revealed also that, despite the high-pressure conditions of this reaction, the heterodimeric-disulfide product unexpectedly crystallizes into the low-density polymorph A. This counterintuitive result contrasts with the high-pressure stability of the higher-density polymorph B, confirmed by its compression up to 2.8 GPa with no signs of a phase transition.

Ultrathin, flexible and multimodal tactile sensors based on organic field-effect transistors

In this study, a novel approach to the fabrication of a multimodal temperature and force sensor on ultrathin, conformable and flexible substrates is presented. This process involves coupling a charge-modulated organic field-effect transistor (OCMFET) with a pyro/piezoelectric element, namely a commercial film of poly-vinylene difluoride (PVDF). The proposed device is able to respond to both pressure stimuli and temperature variations, demonstrating the feasibility of the approach for the development of low-cost, highly sensitive and conformable multimodal sensors. The overall thickness of the device is 1.2 μm, being thus able to conform to any surface (including the human body), while keeping its electrical performance. Furthermore, it is possible to discriminate between simultaneously applied temperature and pressure stimuli by coupling sensing surfaces made of poled and unpoled spin-coated PVDF-trifluoroethylene (PVDF-TrFE, a PVDF copolymer) with OCMFETs. This demonstrates the possibility of creating multimodal sensors that can be employed for applications in several fields, ranging from robotics to wearable electronics.

Predicting Severity of Acute Pain After Cesarean Delivery: A Narrative Review.

Cesarean delivery is one of the most common surgical procedures in the United States, with over 1.3 million performed annually. One-fifth of women who undergo cesarean delivery will experience severe pain in the acute postoperative period, increasing their risk of developing chronic pain and postpartum depression, and negatively impacting breastfeeding and newborn care. A growing body of research has investigated tools to predict which patients will experience more severe pain and have increased analgesic consumption after cesarean delivery. These include quantitative sensory testing, assessment of wound hyperalgesia, response to local anesthetic infiltration, and preoperative psychometric evaluations such as validated psychological questionnaires and simple screening tools. For this review, we searched MEDLINE, the Cochrane database, and Google Scholar to identify articles that evaluated the utility of various tools to predict severe pain and/or opioid consumption in the first 48 hours after cesarean delivery. Thirteen articles were included in the final review: 5 utilizing quantitative sensory testing, including patient responses to pressure, electrical, and thermal stimuli; 1 utilizing hyperalgesia testing; 1 using response to local anesthetic wound infiltration; 4 utilizing preoperative psychometric evaluations including the State-Trait Anxiety Inventory, the Pain Catastrophizing Scale, the Pittsburgh Sleep Quality Index, the Hospital Anxiety and Depression Scale, and simple questionnaires; and 2 utilizing a combination of quantitative sensory tests and psychometric evaluations. A number of modalities demonstrated statistically significant correlations with pain outcomes after cesarean delivery, but most correlations were weak to modest, and many modalities might not be clinically feasible. Response to local anesthetic infiltration and a tool using 3 simple questions enquiring about anxiety and anticipated pain and analgesic needs show potential for clinical use, but further studies are needed to evaluate the utility of these predictive tests in clinical practice.

Spectroscopic differences in posterior insula in patients with chronic temporomandibular pain.

Background and aims Chronic pain including temporomandibular disorder (TMD) pain involves a complex interplay between peripheral and central sensitization, endogenous modulatory pathways, cortical processing and integration and numerous psychological, behavioral and social factors. The aim of this study was to compare spectroscopic patterns of N-Acetyl-aspartate (NAA), total creatine (tCr), choline (Cho), myo-inositol (MI), glutamate (Glu), and the combination of Glu and glutamine in the posterior insula in patients with chronic generalized or regional chronic TMD pain (gTMD and rTMD, respectively) compared to healthy individuals (HI) in relation to clinical findings of TMD pain. Methods Thirty-six female patients with chronic rTMD or gTMD with at least 3 months duration were included in the study. Ten healthy women were included as controls. All participants completed a questionnaire that comprised assessment of degrees of depression, anxiety, stress, catastrophizing, pain intensity, disability and locations. A clinical Diagnostic Criteria for Temporomandibular Disorders examination that comprised assessment of pain locations, headache, mouth opening capacity, pain on mandibular movement, pain on palpation and temporomandibular joint noises was performed. Pressure-pain threshold (PPT) over the masseter muscle and temporal summation to pressure stimuli were assessed with an algometer. Within a week all participants underwent non-contrast enhanced MRI on a 3T MR scanner assessing T1-w and T2-w fluid attenuation inversion recovery. A single-voxel 1H-MRS examination using point-resolved spectroscopy was performed. The metabolite concentrations of NAA, tCr, Cho, MI, Glu and Glx were analyzed with the LC model. Metabolite levels were calculated as absolute concentrations, normalized to the water signal. Metabolite concentrations were used for statistical analysis from the LC model if the Cramér-Rao bounds were less than 20%. In addition, the ratios NAA/tCr, Cho/tCr, Glu/tCr and MI/tCr were calculated. Results The results showed significantly higher tCr levels within the posterior insula in patients with rTMD or gTMD pain than in HI (p=0.029). Cho was negatively correlated to maximum mouth opening capacity with or without pain (rs=-0.42, n=28, p=0.031 and rs=-0.48, n=28, p=0.034, respectively) as well as pressure-pain threshold on the hand (rs=-0.41, n=28, p=0.031). Glu was positively correlated to temporal summation to painful mechanical stimuli (rs=0.42, n=26, p=0.034). Conclusions The present study found that increased concentrations of Cho and Glu in the posterior insular cortex is related to clinical characteristics of chronic TMD pain, including generalized pain. These findings provide new evidence about the critical involvement of the posterior insular cortex and the neurobiology underlying TMD pain in both regional and generalized manifestations. Implications The findings in this study have indirect implications for the diagnosis and management of TMD patients. That said, the findings provide new evidence about the critical involvement of the posterior insular cortex and the neurobiology underlying TMD pain in both regional and generalized manifestations. It is also a further step towards understanding and accepting chronic pain as a disorder in itself.

Cerebral Vascular KIR2.x Channels are Distinctly Regulated by Membrane Lipids and Hemodynamic Forces.

This study examined membrane lipid (phosphatidylinositol‐bis‐phosphate (PIP2) and cholesterol) regulation of cerebral arterial KIR and whether these signaling molecules enable distinct channel pools to uniquely sense hemodynamic forces. Endothelial and smooth muscle cells were freshly isolated from rat cerebral arteries; patch‐clamp electrophysiology, Q‐PCR and immunohistochemistry delineated KIR channel activity and expression. Electrophysiology revealed a Ba2+‐sensitive KIR current in smooth muscle and endothelial cells, while Q‐PCR and immunohistochemistry confirmed KIR2.x mRNA and protein expression respectively. Each cellular pool of KIR channels was sensitive to particular membrane lipids and hemodynamic forces. Endothelial KIR responded dynamically to PIP2 manipulations, and laminar flow activated this channel pool in a PIP2 dependent manner. In contrast, smooth muscle KIR reacted to cholesterol perturbations, and pressure stimuli (e.g. hyposmotic challenge or negative pressure application) modulated this channel pool in a cholesterol dependent manner. The flow and pressure sensitivity of KIR channels was confirmed in intact cerebral arteries using vessel myography. In summary, while both vascular cell types express KIR2.x channels, each pool is distinctly regulated by membrane lipids and hemodynamic stimuli. This emerging picture of KIR regulation advances our mechanistic understanding of how hemodynamic forces interact to control arterial tone development.Support or Funding InformationThis research was supported by an operating grant from the Canadian Institute of Health Research. DG Welsh is Rorabeck Chair of Molecular Neuroscience and Vascular Biology at the University of Western Ontario.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

The influence of isometric exercise on endogenous pain modulation: comparing exercise-induced hypoalgesia and offset analgesia in young, active adults.

Background and aims Impairment of endogenous analgesia has been associated with the development, maintenance and persistence of pain. Endogenous analgesia can be evaluated using exercise-induced hypoalgesia (EIH) and offset analgesia (OffA) paradigms, which measure temporal filtering of sensory information. It is not clear if these paradigms are underpinned by common mechanisms, as EIH and OffA have not previously been directly compared. A further understanding of the processes responsible for these clinically relevant phenomena may have future diagnostic and therapeutic utility in management of individuals with persistent pain conditions. The primary aim of this study was to investigate if there is a correlation between the magnitudes of EIH and OffA. The secondary aim of the study was to examine whether exercise influences OffA. Methods Thirty-six healthy, pain-free participants were recruited. EIH was evaluated using pressure pain thresholds (PPT) and pain ratings to suprathreshold pressure stimuli over tibialis anterior and the cervical spine. OffA evaluation utilised a three-step protocol, whereby individualised heat pain thermal stimuli [Numerical Rating Scale (NRS)=50/100] were applied (T1), before increasing 1 °C (T2), followed by 1 °C reduction (T3). The magnitude of OffA was calculated as the percentage reduction in the NRS from T2 to T3. PPT/suprathreshold pain ratings and OffA measures were recorded, before and after 5 min of isometric quadriceps exercise performed at 20-25% maximum voluntary contraction (MVC); and following a 15 min rest period. Data were analysed using repeated measures (RM) ANCOVA and correlational analyses. Results There was no correlation between EIH measures (PPTs or pain ratings to suprathreshold pressure stimuli over tibialis anterior or the cervical spine) and OffA (p>0.11 for all). OffA was induced and not modulated by exercise (p=0.28). Conclusions Five minutes of 20-25% MVC lower limb isometric exercise provided non-pharmacological pain modulation in young, active adults. Magnitude of EIH was not correlated with that of OffA, and exercise did not influence magnitude of OffA. Implications These results suggest that in young, pain-free individuals, separate testing of these two paradigms is required to comprehensively evaluate efficacy of endogenous analgesia. If these results are replicated in patient populations, alternative or complementary methods to exercise interventions may be required to modulate impaired OffA.

Pain Adaptability in Individuals With Chronic Musculoskeletal Pain Is Not Associated With Conditioned Pain Modulation

Healthy humans can be divided into the pain adaptive (PA) and the pain nonadaptive (PNA) groups; PA showed a greater decrease in pain rating to a cold pressor test (CPT) than PNA. This study examined if the dichotomy of pain adaptability existed in individuals with chronic musculoskeletal pain. CPTs at 2°C and 7°C were used to assess the status of pain adaptability in participants with either chronic nonspecific low back pain or knee osteoarthritis. The participants' potency of conditioned pain modulation (CPM) and local inhibition were measured. The strengths of pain adaptability at both CPTs were highly correlated. PA and PNA did not differ in their demographic characteristics, pain thresholds from thermal and pressure stimuli, or potency of local inhibition or CPM. PA reached their maximum pain faster than PNA (t41 = −2.76, P < .01), and had a gradual reduction of pain unpleasantness over 7 days whereas PNA did not (F6,246 = 3.01, P = .01). The dichotomy of pain adaptability exists in musculoskeletal pain patients. Consistent with the healthy human study, the strength of pain adaptability and potency of CPM are not related. Pain adaptability could be another form of endogenous pain inhibition of which clinical implication is yet to be understood. PerspectiveThe dichotomy of pain adaptability was identified in healthy humans. The current study confirms that this dichotomy also exists in individuals with chronic musculoskeletal pain, and could be reliably assessed with CPTs at 2°C and 7°C. Similar to the healthy human study, pain adaptability is not associated with CPM, and may reflect the temporal aspect of pain inhibition.

The influence of the carotid baroreflex on dynamic regulation of cerebral blood flow and cerebral tissue oxygenation in humans at rest and during exercise.

This preliminary study tested the hypothesis that the carotid baroreflex (CBR) mediated sympathoexcitation regulates cerebral blood flow (CBF) at rest and during dynamic exercise. In seven healthy subjects (26 ± 1years), oscillatory neck pressure (NP) stimuli of + 40mmHg were applied to the carotid baroreceptors at a pre-determined frequency of 0.1Hz at rest, low (10 ± 1W), and heavy (30 ± 3W) exercise workloads (WLs) without (control) and with α - 1 adrenoreceptor blockade (prazosin). Spectral power analysis of the mean arterial blood pressure (MAP), mean middle cerebral artery blood velocity (MCAV), and cerebral tissue oxygenation index (ScO2) in the low-frequency range (0.07-0.20Hz) was estimated to examine NP stimuli responses. From rest to heavy exercise, WLs resulted in a greater than three-fold increase in MCAV power (42 ± 23.8-145.2 ± 78, p < 0.01) and an almost three-fold increase in ScO2 power (0.51 ± 0.3-1.53 ± 0.8, p = 0.01), even though there were no changes in MAP power (from 24.5 ± 21 to 22.9 ± 11.9) with NP stimuli. With prazosin, the overall MAP (p = 0.0017), MCAV (p = 0.019), and ScO2 (p = 0.049) power was blunted regardless of the exercise conditions. Prazosin blockade resulted in increases in the Tf gain index between MAP and MCAV compared to the control (p = 0.03). CBR-mediated changes in sympathetic activity contribute to dynamic regulation of the cerebral vasculature and CBF at rest and during dynamic exercise in humans.

Design and Evaluation of a Wearable Haptic Device for Skin Stretch, Pressure, and Vibrotactile Stimuli

This letter presents a wearable haptic device for the forearm and its application in robotic teleoperation. The device is able to provide skin stretch, pressure, and vibrotactile stimuli. Two servo motors, housed in a 3D printed lightweight platform, actuate an elastic fabric belt, wrapped around the arm. When the two servo motors rotate in opposite directions, the belt is tightened (or loosened), thereby compressing (or decompressing) the arm. On the other hand, when the two motors rotate in the same direction, the belt applies a shear force to the arm skin. Moreover, the belt houses four vibrotactile motors, positioned evenly around the arm at 90° from each other. The device weights 220 g for 115 × 122 × 50 mm of dimensions, making it wearable and unobtrusive. We carried out a perceptual characterization of the device as well as two human-subjects teleoperation experiments in a virtual environment, employing a total of 34 subjects. In the first experiment, participants were asked to control the motion of a robotic manipulator for grasping an object; in the second experiment, participants were asked to teleoperate the motion of a quadrotor fleet along a given path. In both scenarios, the wearable haptic device provided feedback information about the status of the slave robot(s) and of the given task. Results showed the effectiveness of the proposed device. Performance on completion time, length trajectory, and perceived effectiveness when using the wearable device improved of 19.8%, 25.1%, and 149.1% than when wearing no device, respectively. Finally, all subjects but three preferred the conditions including wearable haptics.

(104) - Order of heat and pressure tests impacts pain responsivity ratings

Considering the volume and variety of trials that use quantitative sensory testing (QST), accounting for potential order effects is imperative when determining the study protocol as well as for accurate data analysis. The present secondary data analyses examined whether the order of two common testing methods (heat and pressure) affected subsequent subjective participant pain ratings. 106 participants (50 females, mean age 30) underwent both thermal pain threshold and tolerance testing and pressure pain threshold testing in randomized order. Thermal pain threshold and tolerance was administered to the right ventral forearm using the Medoc Pathway with a .5 sec/minute rate of rise. Participants indicated when they first felt pain (threshold) and when it became intolerable (tolerance) by pressing a mouse button, which turned the device off. The temperature for each was recorded. Pressure was applied to the left and right trapezius muscle and the left and right thumb joint using an SBMedic algometer. Participants were instructed to say “pain” when they first felt pain as a result of the pressure stimulus. Heat and pressure were measured twice for each area, and an average was calculated for each testing method. T-tests revealed a significant order effect for pressure ratings, such that thermal testing performed first resulted in higher pressure ratings for both the trapezius (P = .013) and thumb (P = .025). Testing order was also significant for heat pain threshold (P = .049) and marginally significant for heat pain tolerance (P = .067), such that performing thermal testing first resulted in higher heat pain temperatures. These data suggest that order of testing impacts overall levels of pain responsivity, particularly in relation to heat and pressure, and could have implications for the interaction of other types of sensory testing (e.g. cold pain tolerance) as well. The current findings speak to the importance of controlling for testing order in QST data.

Psychosocial factors partially mediate the relationship between mechanical hyperalgesia and self-reported pain.

Amplification of sensory signalling within the nervous system along with psychosocial factors contributes to the variation and severity of knee pain. Quantitative sensory testing (QST) is a non-invasive test battery that assesses sensory perception of thermal, pressure, mechanical and vibration stimuli used in the assessment of pain. Psychosocial factors also have an important role in explaining the occurrence of pain. The aim was to determine whether QST measures were associated with self-reported pain, and whether those associations were mediated by psychosocial factors. Participants with knee pain identified from a population-based cohort completed a tender point count and a reduced QST battery of thermal, mechanical and pressure pain thresholds, temporal summation, mechanical pain sensitivity (MPS), dynamic mechanical allodynia (DMA) and vibration detection threshold performed following the protocol by the German Research Network on Neuropathic Pain. QST assessments were performed at the most painful knee and opposite forearm (if pain-free). Participants were asked to score for their global and knee pain intensities within the past month (range 0-10), and complete questionnaire items investigating anxiety, depression, illness perceptions, pain catastrophising, and physical functioning. QST measures (independent variable) significantly correlated (Spearman's rho) with self-reported pain intensity (dependent variable) were included in structural equation models with psychosocial factors (latent mediators). Seventy-two participants were recruited with 61 participants (36 women; median age 64 years) with complete data included in subsequent analyses. Tender point count was significantly correlated with global pain intensity. DMA at the knee and MPS at the most painful knee and opposite pain-free forearm were significantly correlated with both global pain and knee pain intensities. Psychosocial factors including pain catastrophising sub-scales (rumination and helplessness) and illness perceptions (consequences and concern) were significant partial mediators of the association with global pain intensity when loaded on to a latent mediator for: tender point count [75% total effect; 95% confidence interval (CI) 22%, 100%]; MPS at the knee (49%; 12%, 86%); and DMA at the knee (63%; 5%, 100%). Latent psychosocial factors were also significant partial mediators of the association between pain intensity at the tested knee with MPS at the knee (30%; 2%, 58%), but not for DMA at the knee. Measures of mechanical hyperalgesia at the most painful knee and pain-free opposite forearm were associated with increased knee and global pain indicative of altered central processing. Psychosocial factors were significant partial mediators, highlighting the importance of the central integration of emotional processing in pain perception. Associations between mechanical hyperalgesia at the forearm and knee, psychosocial factors and increased levels of clinical global and knee pain intensity provide evidence of altered central processing as a key mechanism in knee pain, with psychological factors playing a key role in the expression of clinical pain.

Comparison of combined therapy with ultrasound-associated interferential current in healthy subjects

ABSTRACT BACKGROUND AND OBJECTIVES: Although used in the therapeutic field, there is a shortage of studies that evaluate combined therapy or the association of electrical currents with therapeutic ultrasound, the present study aimed to compare the two forms in healthy individuals, analyzing the pain, number of accommodations and current intensity. METHODS: Thirty healthy volunteers took turns for three weeks in three groups. Nociception was evaluated by means of pressure and thermal stimuli in the lumbar spine and respective dermatomes. Then, the volunteer's dominant foot was submerged in cold water to evaluate the threshold of pain and its intensity. Shortly after, electroanalgesia (combined therapy, only current association with ultrasound, or placebo) was applied for 15 minutes. The application of the bipolar interferential current used a frequency of 4kHz, and amplitude modulation frequency of 100Hz, with one electrode on L3 and the other on S1. When combined therapy was used, the ultrasound head (1MHz) played the role of the electrode positioned over the L5-S1 region, in continuous form, at a dose of 0.4W/cm2. The intensity of the initial and final current was evaluated, as well as the number of accommodations. RESULTS: There was no significant difference between the pain thresholds of pressure and cold, but the combined therapy required more current intensity despite having a smaller number of accommodations. CONCLUSION: None of the therapies produced a difference in pain thresholds, but the combined therapy had fewer accommodations.

Comparison of combined therapy with ultrasound-associated interferential current in healthy subjects

ABSTRACT BACKGROUND AND OBJECTIVES: Although used in the therapeutic field, there is a shortage of studies that evaluate combined therapy or the association of electrical currents with therapeutic ultrasound, the present study aimed to compare the two forms in healthy individuals, analyzing the pain, number of accommodations and current intensity. METHODS: Thirty healthy volunteers took turns for three weeks in three groups. Nociception was evaluated by means of pressure and thermal stimuli in the lumbar spine and respective dermatomes. Then, the volunteer's dominant foot was submerged in cold water to evaluate the threshold of pain and its intensity. Shortly after, electroanalgesia (combined therapy, only current association with ultrasound, or placebo) was applied for 15 minutes. The application of the bipolar interferential current used a frequency of 4kHz, and amplitude modulation frequency of 100Hz, with one electrode on L3 and the other on S1. When combined therapy was used, the ultrasound head (1MHz) played the role of the electrode positioned over the L5-S1 region, in continuous form, at a dose of 0.4W/cm2. The intensity of the initial and final current was evaluated, as well as the number of accommodations. RESULTS: There was no significant difference between the pain thresholds of pressure and cold, but the combined therapy required more current intensity despite having a smaller number of accommodations. CONCLUSION: None of the therapies produced a difference in pain thresholds, but the combined therapy had fewer accommodations.

Rare NaV1.7 variants associated with painful diabetic peripheral neuropathy.

Diabetic peripheral neuropathy (DPN) is a common disabling complication of diabetes. Almost half of the patients with DPN develop neuropathic pain (NeuP) for which current analgesic treatments are inadequate. Understanding the role of genetic variability in the development of painful DPN is needed for improved understanding of pain pathogenesis for better patient stratification in clinical trials and to target therapy more appropriately. Here, we examined the relationship between variants in the voltage-gated sodium channel NaV1.7 and NeuP in a deeply phenotyped cohort of patients with DPN. Although no rare variants were found in 78 participants with painless DPN, we identified 12 rare NaV1.7 variants in 10 (out of 111) study participants with painful DPN. Five of these variants had previously been described in the context of other NeuP disorders and 7 have not previously been linked to NeuP. Those patients with rare variants reported more severe pain and greater sensitivity to pressure stimuli on quantitative sensory testing. Electrophysiological characterization of 2 of the novel variants (M1852T and T1596I) demonstrated that gain of function changes as a consequence of markedly impaired channel fast inactivation. Using a structural model of NaV1.7, we were also able to provide further insight into the structural mechanisms underlying fast inactivation and the role of the C-terminal domain in this process. Our observations suggest that rare NaV1.7 variants contribute to the development NeuP in patients with DPN. Their identification should aid understanding of sensory phenotype, patient stratification, and help target treatments effectively.

Functional resonance magnetic imaging (fMRI) in adolescents with idiopathic musculoskeletal pain: a paradigm of experimental pain

BackgroundStudies on functional magnetic resonance imaging (fMRI) have shown that adults with musculoskeletal pain syndromes tolerate smaller amount of pressure (pain) as well as differences in brain activation patterns in areas related to pain.The objective of this study was to evaluate, through fMRI, the brain activation in adolescents with idiopathic musculoskeletal pain (IMP) while performing an experimental paradigm of pain.MethodsThe study included 10 consecutive adolescents with idiopathic musculoskeletal pain (average age 16.3±1.0) and 10 healthy adolescents age-matched. fMRI exams were performed in a 3 T scanner (Magnetom Trio, Siemens) using an event-related design paradigm. Pressure stimuli were performed in the nondominant hand thumb, divided into two stages, fixed pain and variable pain.The two local Research Ethics Committees (Ethics Committee from Universidade Federal de São Paulo- Brazil, process number 0688/11, on July 1st, 2011 and Ethics Committee from Hospital Israelita Albert Einsten – Brazil, process number 1673, on October 19th, 2011) approved the study.ResultsThe idiopathic musculoskeletal pain (IMP) group showed a reduced threshold for pain (3.7 kg/cm2 versus 4.45 kg/cm2, p = 0.005). Control group presented increased bain activation when compared to IMP group in the following areas: thalamus (p = 0.00001), precentral gyrus (p = 0.0004) and middle frontal gyrus (p = 0.03). In intragroup analysis, IMP group showed greater brain activation during the unpredictable stimuli of the variable pain stage, especially in the lingual gyrus (p = 0.0001), frontal lobe (p = 0.0001), temporal gyrus (p = 0.0001) and precentral gyrus (p = 0.03), when compared to predictable stimulus of fixed pain. The same intragroup analysis with the control group showed greater activation during the unpredictable stimuli in regions of the precentral gyrus (p = 0.0001), subcallosal area (p = 0.0001), right and left occipital fusiform gyrus (p = 0.0001; (p = 0.0007), middle gyrus (p = 0.01) and precuneus p = (0.02).ConclusionAdolescents with idiopathic musculoskeletal pain (IMP) tend to request higher brain function in cognitive-emotional areas when interpreting unpredictable sensory-perceptual situations. Therefore, it is assumed that this difference in pain processing in adolescents with IMP make the subjective experience of pain something more intense and unpleasant.

An All-Silk-Derived Dual-Mode E-skin for Simultaneous Temperature-Pressure Detection.

Flexible skin-mimicking electronics are highly desired for development of smart human-machine interfaces and wearable human-health monitors. Human skins are able to simultaneously detect different information, such as touch, friction, temperature, and humidity. However, due to the mutual interferences of sensors with different functions, it is still a big challenge to fabricate multifunctional electronic skins (E-skins). Herein, a combo temperature-pressure E-skin is reported through assembling a temperature sensor and a strain sensor in both of which flexible and transparent silk-nanofiber-derived carbon fiber membranes (SilkCFM) are used as the active material. The temperature sensor presents high temperature sensitivity of 0.81% per centigrade. The strain sensor shows an extremely high sensitivity with a gauge factor of ∼8350 at 50% strain, enabling the detection of subtle pressure stimuli that induce local strain. Importantly, the structure of the SilkCFM in each sensor is designed to be passive to other stimuli, enabling the integrated E-skin to precisely detect temperature and pressure at the same time. It is demonstrated that the E-skin can detect and distinguish exhaling, finger pressing, and spatial distribution of temperature and pressure, which cannot be realized using single mode sensors. The remarkable performance of the silk-based combo temperature-pressure sensor, together with its green and large-scalable fabrication process, promising its applications in human-machine interfaces and soft electronics.

Flexible Bimodal Sensor for Simultaneous and Independent Perceiving of Pressure and Temperature Stimuli

AbstractSimultaneous bimodal perceiving of pressure and temperature stimuli is widely desired for artificial intelligence electronics, such as electronic skin and health monitoring. In multiparametric sensing, it is a challenge to detect different stimuli independently and expediently without cross coupling. Here, this study reports a pressure–temperature bimodal tactile sensor composed of two sinuous thermosensitive platinum (Pt) ribbons fabricated on a flexible polyimide substrate, which is covered by a porous elastomer membrane to provide a handy solution for multimodal detection. By operating two Pt ribbons in a constant temperature difference feedback circuit, the sensor implements simultaneous and independent detections of pressure and temperature stimuli automatically and efficiently. High sensitivity, lower detection limit, high resolution, good stability, and low hysteresis are achieved for dual parametric sensing. The sensor shows competence in health monitoring for bimodal perceiving of wrist pulse and artery temperature simultaneously and independently. The smart sensing design and self‐sustained circuit simplify the bimodal sensor, and thus provide a fast and expedient approach for multimodal sensation applications.

Altered Behavioral and Autonomic Pain Responses in Alzheimer's Disease Are Associated with Dysfunctional Affective, Self-Reflective and Salience Network Resting-State Connectivity.

While pain behaviors are increased in Alzheimer’s disease (AD) patients compared to healthy seniors (HS) across multiple disease stages, autonomic responses are reduced with advancing AD. To better understand the neural mechanisms underlying these phenomena, we undertook a controlled cross-sectional study examining behavioral (Pain Assessment in Advanced Dementia, PAINAD scores) and autonomic (heart rate, HR) pain responses in 24 HS and 20 AD subjects using acute pressure stimuli. Resting-state fMRI was utilized to investigate how group connectivity differences were related to altered pain responses. Pain behaviors (slope of PAINAD score change and mean PAINAD score) were increased in patients vs. controls. Autonomic measures (HR change intercept and mean HR change) were reduced in severe vs. mildly affected AD patients. Group functional connectivity differences associated with greater pain behavior reactivity in patients included: connectivity within a temporal limbic network (TLN) and between the TLN and ventromedial prefrontal cortex (vmPFC); between default mode network (DMN) subcomponents; between the DMN and ventral salience network (vSN). Reduced HR responses within the AD group were associated with connectivity changes within the DMN and vSN—specifically the precuneus and vmPFC. Discriminant classification indicated HR-related connectivity within the vSN to the vmPFC best distinguished AD severity. Thus, altered behavioral and autonomic pain responses in AD reflects dysfunction of networks and structures subserving affective, self-reflective, salience and autonomic regulation.