Intra- and inter-session reliability of electrical detection and pain thresholds of cutaneous and muscle primary afferents in the lower back of healthy individuals.

To advance evidence-based practice and targeted treatments of low back pain (LBP), a better pathophysiological understanding and reliable outcome measures are required. The processing of nociceptive information from deeper somatic structures (e.g., muscle, fascia) might play an essential role in the pathophysiology of LBP. In this study, we measured the intra- and inter-session reliability of electrical detection and pain thresholds of cutaneous and muscle primary afferents of the lower back. Twenty healthy participants attended two study visits separated by 27.7 ± 1.7 days. To determine the location-specific electrical detection threshold (EDT) and pain threshold (EPT), needle electrodes were inserted in the epidermal layer over, and in the lumbar erector spinae muscle. Additionally, established quantitative sensory testing (QST) parameters were assessed. Reliability was determined by differences between measurements, intraclass correlation coefficients (ICC2,1), Bland-Altman plots, and standard error of measurement (SEM). Correspondence between QST parameters and electrical thresholds was assessed using Pearson's correlation. Except for cutaneous EPT, no significant (p ≤ 0.05) intra- and inter-session differences were observed. Excellent intra-session reliability was shown for cutaneous and intramuscular electrical stimulations and all QST parameters (ICC: 0.76-0.93). Inter-session reliabilities were good (ICC: 0.74-0.75) except for electrical stimulations (ICC: 0.08-0.36). Limits of agreement and SEM were higher for inter-session than intra-session. A medium to strong relationship was found between electrical and mechanical/pressure pain thresholds. In conclusion, cutaneous and intramuscular electrical stimulation will potentially close an important diagnostic gap regarding the selective examination of deep tissue afferents and provide location-specific information for the excitability of non-nociceptive and nociceptive afferents.

BackWards - Unveiling the brain's topographic organization of paraspinal sensory input.

Cortical reorganization and its potential pathological significance are being increasingly studied in musculoskeletal disorders such as chronic low back pain (CLBP) patients. However, detailed sensory-topographic maps of the human back are lacking, and a baseline characterization of such representations, reflecting the somatosensory organization of the healthy back, is needed before exploring potential sensory map reorganization. To this end, a novel pneumatic vibrotactile stimulation method was used to stimulate paraspinal sensory afferents, while studying their cortical representations in unprecedented detail. In 41 young healthy participants, vibrotactile stimulations at 20 Hz and 80 Hz were applied bilaterally at nine locations along the thoracolumbar axis while functional magnetic resonance imaging (fMRI) was performed. Model-based whole-brain searchlight representational similarity analysis (RSA) was used to investigate the organizational structure of brain activity patterns evoked by thoracolumbar sensory inputs. A model based on segmental distances best explained the similarity structure of brain activity patterns that were located in different areas of sensorimotor cortices, including the primary somatosensory and motor cortices and parts of the superior parietal cortex, suggesting that these brain areas process sensory input from the back in a "dermatomal" manner. The current findings provide a sound basis for testing the "cortical map reorganization theory" and its pathological relevance in CLBP.

Central sensitization in CRPS patients with widespread pain: a cross-sectional study.

OBJECTIVE: Widespread pain hypersensitivity and enhanced temporal summation of pain (TSP) are commonly reported in patients with complex regional pain syndrome (CRPS) and discussed as proxies for central sensitization. This study aimed to directly relate such signs of neuronal hyperexcitability to the pain phenotype of CRPS patients. METHODS: Twenty-one CRPS patients and 20 healthy controls (HC) were recruited. The pain phenotype including spatial pain extent (assessed in % body surface) and intensity were assessed and related to widespread pain hypersensitivity, TSP, and psychological factors. Quantitative sensory testing (QST) was performed in the affected, the contralateral and a remote (control) area. RESULTS: CRPS patients showed decreased pressure pain thresholds in all tested areas (affected: t(34) = 4.98, P < .001, contralateral: t(35) = 3.19, P = .005, control: t(31) = 2.65, P = .012). Additionally, patients showed increased TSP in the affected area (F(3,111) = 4.57, P = .009) compared to HC. TSP was even more enhanced in patients with a high compared to a low spatial pain extent (F(3,51) = 5.67, P = .008), suggesting pronounced spinal sensitization in patients with extended pain patterns. Furthermore, the spatial pain extent positively correlated with the Bath Body Perception Disturbance Scale (ρ = 0.491; P = .048). CONCLUSIONS: Overall, we provide evidence that the pain phenotype in CRPS, that is, spatial pain extent, might be related to sensitization mechanism within the central nociceptive system. This study points towards central neuronal excitability as a potential therapeutic target in patients with more widespread CRPS.

In vivo measurements of spinal stiffness according to a stepwise increase of axial load.

BACKGROUND: The spine has a complex motor control. Its different stabilization mechanisms through passive, active, and neurological subsystems may result in spinal stiffness. To better understand lumbar spinal motor control, this study aimed to measure the effects of increasing the axial load on spinal stiffness. METHODS: A total of 19 healthy young participants (mean age, 24 ± 2.1 years; 8 males and 11 females) were assessed in an upright standing position. Under different axial loads, the posterior-to-anterior spinal stiffness of the thoracic and lumbar spine was measured. Loads were 0%, 10%, 45%, and 80% of the participant's body weight. RESULTS: Data were normally distributed and showed excellent reliability. A repeated-measures analysis of variance with a Greenhouse-Geisser correction showed an effect of the loading condition on the mean spinal stiffness [F (2.6, 744) = 3.456, p < 0.001]. Vertebrae and loading had no interaction [F (2.6, 741) = 0.656, p = 0.559]. Post hoc tests using Bonferroni correction revealed no changes with 10% loading (p = 1.000), and with every additional step of loading, spinal stiffness decreased: 0% or 10-45% loading (p < 0.001), 0% or 10-80% loading (p < 0.001), and 45-80% (p < 0.001). CONCLUSION: We conclude that a load of ≥ 45% of the participant's body weight can lead to changes in the spinal motor control. An axial load of 10% showed no significant changes. Rehabilitation should include high-axial-load exercise if needed in everyday living.

Translation and validation of the German version of the Young Spine Questionnaire.

BACKGROUND: Back pain in childhood and adolescence increases the risk for back pain in adulthood, but validated assessment tools are scarce. The aim of this study was to validate the Young Spine Questionnaire (YSQ) in a German version (G-YSQ) in children and adolescents. METHODS: Children and adolescents between 10 and 16 years (N = 240, 166 females, mean age = 13.05 ± 1.70 years), recruited in chiropractic practices and schools, completed the G-YSQ (translated according to scientific guidelines) and the KIDSCREEN-10 (assessing health-related quality of life) at three time points. Test-retest reliability was determined calculating intraclass correlation coefficients [ICC(3,1)] using start and two week-data. Construct validity was investigated testing a priori hypotheses. To assess responsiveness, the patients additionally filled in the Patient Global Impression of Change (PGIC) after three months and the area under the curve (AUC) of receiver operating curves was calculated. RESULTS: The ICC(3,1) was 0.88 for pain intensity and pain frequency, indicating good reliability, 0.68 for week prevalence and 0.60 for point prevalence, indicating moderate reliability. Pain intensity, frequency and prevalence differed between patients and controls (p < 0.001) and, except point prevalence, between older (> 12 years) and younger control participants (p < 0.01). Health-related quality of life of participants with severe pain (in one or several spinal regions) was lower (KIDSCREEN-10, total score: F(4,230) = 7.26, p < 0.001; KIDSCREEN-10, self-rated general health: H(4) = 51.94, p < 0.001) than that of participants without pain or with moderate pain in one spinal region. Thus, altogether these findings indicate construct validity of the G-YSQ. The AUC was 0.69 (95 % CI = 0.57-0.82) and 0.67 (95 % CI = 0.54-0.80) for week and point prevalence, respectively, indicating insufficient responsiveness of the G-YSQ. CONCLUSIONS: Apart from the question on point prevalence, construct validity and sufficient test-retest reliability was shown for the G-YSQ. However, its responsiveness needs to be improved, possibly by asking for pain frequency during the last week instead of (dichotomous) week prevalence. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02955342, registered 07/09/2016, https://clinicaltrials.gov/ct2/results?cond=&term=NCT02955342&cntry=CH&state=&city=Zurich&dist= .

Default mode network changes in fibromyalgia patients are largely dependent on current clinical pain.

Differences in fMRI resting-state connectivity of the default mode network (DMN) seen in chronic pain patients are often interpreted as brain reorganization due to the chronic pain condition. Nevertheless, patients' pain at the time of fMRI might influence the DMN because pain, like cognitive stimuli, engages attentional mechanisms and cognitive engagement is known to alter DMN activity. Here, we aimed to dissociate the influence of chronic pain condition (trait) from the influence of current pain experience (state) on DMN connectivity in patients with fibromyalgia (FM). We performed resting-state fMRI scans to test DMN connectivity in FM patients and matched healthy controls in two separate cohorts: (1) in a cohort not experiencing pain during scanning (27 FM patients and 27 controls), (2) in a cohort with current clinical pain during scanning (16 FM patients and 16 controls). In FM patients without pain during scanning, the connectivity of the DMN did not differ significantly from controls. By contrast, FM patients with current clinical pain during the scan had significantly increased DMN connectivity to bilateral anterior insula (INS) similar to previous studies. Regression analysis showed a positive relationship between DMN-midINS connectivity and current pain. We therefore suggest that transient DMN disruptions due to current clinical pain during scanning (current pain state) may be a substantial contributor to DMN connectivity disruptions observed in chronic pain patients.

Excitatory and inhibitory responses in the brain to experimental pain: A systematic review of MR spectroscopy studies.

BACKGROUND: The role of the brain in processing pain has been extensively investigated using various functional imaging techniques coupled with well controlled noxious stimuli. Studies applying experimental pain have also used proton magnetic resonance spectroscopy (1H-MRS). The advantage of MRS compared to other techniques is the capacity to non-invasively examine metabolites involved in neurotransmission of pain, including glutamate, γ-aminobutyric acid (GABA), glutamate â€‹+ â€‹glutamine (Glx), and glutamine. OBJECTIVE: To systematically review MRS studies used in the context of studying experimental pain in healthy human participants. DATA SOURCES: PubMed, Ovid Medline, and Embase databases were searched using pre-specified search terms. ELIGIBILITY CRITERIA: Studies investigating glutamate, GABA, Glx and/or glutamine in relation to experimental pain (e.g., heat) in healthy participants via MRS. APPRAISAL CRITERIA: Each study was evaluated with a modified quality criterion (used in previous imaging systematic reviews) as well as a risk of bias assessment. RESULTS: From 5275 studies, 14 met the selection criteria. Studies fell into two general categories, those examining changes in metabolites triggered by noxious stimulation or examining the relationship between sensitivity to pain and resting metabolite levels. In five (out of ten) studies, glutamate, Glx and/or glutamine increased significantly in response to experimental pain (compared to baseline) in three different brain areas. To date, there is no evidence to suggest Glx, glutamate or glutamine levels decrease, suggesting an overall effect in favour of increased excitation to pain. In addition to no changes, both increases and decreases were reported for levels of GABA+ (=GABA â€‹+ â€‹macromolecules). A positive correlation between pain sensitivity and resting glutamate and Glx levels were reported across three studies (out of three). Further research is needed to examine the relationship of GABA+ and pain sensitivity. LIMITATIONS: A major limitation of our review was a limited number of studies that used MRS to examine experimental pain. In light of this and major differences in study design, we did not attempt to aggregate results in a meta-analysis. As for the studies we reviewed, there was a limited number of brain areas were examined by studies included in our review. Moreover, the majority of studies included lacked an adequate control condition (i.e., non-noxious stimulation) or blinding, which represent a major source of potential bias. CONCLUSION: MRS represents a promising tool to examine the brain in pain, functionally, and at rest with support for increased glutamate, glutamine and Glx levels in relation to pain. IMPLICATIONS: Resting and functional MRS should be viewed as complementary to existing neuroimaging techniques, and serve to investigate the brain in pain. Systematic review registration number- CRD42018112917.

The Effect of Conditioned Pain Modulation on Tonic Heat Pain Assessed Using Participant-Controlled Temperature.

OBJECTIVE: Descending pain modulation can be experimentally assessed by way of testing conditioned pain modulation. The application of tonic heat as a test stimulus in such paradigms offers the possibility of observing dynamic pain responses, such as adaptation and temporal summation of pain. Here we investigated conditioned pain modulation effects on tonic heat employing participant-controlled temperature, an alternative tonic heat pain assessment. Changes in pain perception are thereby represented by temperature adjustments performed by the participant, uncoupling this approach from direct pain ratings. Participant-controlled temperature has emerged as a reliable and sex-independent measure of tonic heat. METHODS: Thirty healthy subjects underwent a sequential conditioned pain modulation paradigm, in which a cold water bath was applied as the conditioning stimulus and tonic heat as a test stimulus. Subjects were instructed to change the temperature of the thermode in response to variations in perception to tonic heat in order to maintain their initial rating over a two-minute period. Two additional test stimuli (i.e., lower limb noxious withdrawal reflex and pressure pain threshold) were included as positive controls for conditioned pain modulation effects. RESULTS: Participant-controlled temperature revealed conditioned pain modulation effects on temporal summation of pain (P = 0.01). Increased noxious withdrawal reflex thresholds (P = 0.004) and pressure pain thresholds (P < 0.001) in response to conditioning also confirmed inhibitory conditioned pain modulation effects. CONCLUSIONS: The measured interaction between conditioned pain modulation and temporal summation of pain supports the participant-controlled temperature approach as a promising method to explore dynamic inhibitory and facilitatory pain processes previously undetected by rating-based approaches.

Influence of body position and axial load on spinal stiffness in healthy young adults.

PURPOSE: This study aimed at investigating the effects of different body positions and axial loads on spinal stiffness to better understand spinal stabilisation mechanisms. METHODS: The posterior-to-anterior lumbar and thoracic spinal stiffness of 100 young healthy adults (mean age 23 years; 50 females) were measured in three test situations: prone, standing and standing while carrying a load equal to 50% of the subject's body weight. Each test situation comprised three trials. RESULTS: Spinal stiffness in all test situations showed good reliability. Repeated measures analysis of covariance showed significantly higher spinal stiffness in standing than in the prone position [F(1/1694) = 433.630, p < 0.001]. However, spinal stiffness was significantly lower when standing while carrying a load of 50% of the body weight than when standing without additional load [F(1/1494) = 754.358, p < 0.001]. CONCLUSION: This study showed that spinal lumbar and thoracic stiffness increases when body position is changed from prone to standing. Additional axial load of 50% of the subject's body weight results in reduced spinal stiffness during standing. These slides can be retrieved under Electronic Supplementary Material.

A prospective observational study on trajectories and prognostic factors of mid back pain.

BACKGROUND: Although mid back pain (MBP) is a common condition that causes significant disability, it has received little attention in research and knowledge about trajectories and prognosis of MBP is limited. The purpose of this study was to identify trajectories of MBP and baseline risk factors for an unfavorable outcome in MBP patients undergoing chiropractic treatment. METHODS: This prospective-observational study analyzes outcome data of 90 adult MBP patients (mean age = 37.0 ± 14.6 years; 49 females) during one year (at baseline, after 1 week, 1 month, 3, 6 and 12 months) after start of chiropractic treatment. Patients completed an 11-point (0 to 10) numeric pain rating scale (NRS) at baseline and one week, one month, three, six and twelve months after treatment start and the Patient's Global Impression of Change (PGIC) questionnaire at all time points except baseline. To determine trajectories, clustering with the package kml (software R), a variant of k-means clustering adapted for longitudinal data, was performed using the NRS-data. The identified NRS-clusters and PGIC data after three months were tested for association with baseline variables using univariable logistic regression analyses, conditional inference trees and random forest plots. RESULTS: Two distinct NRS-clusters indicating a favourable (rapid improvement within one month from moderate pain to persistent minor pain or recovery after one year, 80% of patients) and an unfavourable trajectory (persistent moderate to severe pain, 20% of patients) were identified. Chronic (> 3 months) pain duration at baseline significantly predicted that a patient was less likely to follow a favourable trajectory [OR = 0.16, 95% CI = 0.05-0.50, p = 0.002] and to report subjective improvement after twelve months [OR = 0.19, 95% CI = 0.07-0.51, p = 0.001], which was confirmed by the conditional inference tree and the random forest analyses. CONCLUSIONS: This prospective exploratory study identified two distinct MBP trajectories, representing a favourable and an unfavourable outcome over the course of one year after chiropractic treatment. Pain chronicity was the factor that influenced outcome measures using NRS or PGIC.

Role of brain imaging in disorders of brain-gut interaction: a Rome Working Team Report.

Imaging of the living human brain is a powerful tool to probe the interactions between brain, gut and microbiome in health and in disorders of brain-gut interactions, in particular IBS. While altered signals from the viscera contribute to clinical symptoms, the brain integrates these interoceptive signals with emotional, cognitive and memory related inputs in a non-linear fashion to produce symptoms. Tremendous progress has occurred in the development of new imaging techniques that look at structural, functional and metabolic properties of brain regions and networks. Standardisation in image acquisition and advances in computational approaches has made it possible to study large data sets of imaging studies, identify network properties and integrate them with non-imaging data. These approaches are beginning to generate brain signatures in IBS that share some features with those obtained in other often overlapping chronic pain disorders such as urological pelvic pain syndromes and vulvodynia, suggesting shared mechanisms. Despite this progress, the identification of preclinical vulnerability factors and outcome predictors has been slow. To overcome current obstacles, the creation of consortia and the generation of standardised multisite repositories for brain imaging and metadata from multisite studies are required.

Histological Underpinnings of Grey Matter Changes in Fibromyalgia Investigated Using Multimodal Brain Imaging.

Chronic pain patients present with cortical gray matter alterations, observed with anatomical magnetic resonance (MR) imaging. Reduced regional gray matter volumes are often interpreted to reflect neurodegeneration, but studies investigating the cellular origin of gray matter changes are lacking. We used multimodal imaging to compare 26 postmenopausal women with fibromyalgia with 25 healthy controls (age range: 50-75 years) to test whether regional gray matter volume decreases in chronic pain are associated with compromised neuronal integrity. Regional gray matter decreases were largely explained by T1 relaxation times in gray matter, a surrogate measure of water content, and not to any substantial degree by GABAA receptor concentration, an indirect marker of neuronal integrity measured with [18F] flumazenil PET. In addition, the MR spectroscopy marker of neuronal viability, N-acetylaspartate, did not differ between patients and controls. These findings suggest that decreased gray matter volumes are not explained by compromised neuronal integrity. Alternatively, a decrease in neuronal matter could be compensated for by an upregulation of GABAA receptors. The relation between regional gray matter and T1 relaxation times suggests decreased tissue water content underlying regional gray matter decreases. In contrast, regional gray matter increases were explained by GABAA receptor concentration in addition to T1 relaxation times, indicating perhaps increased neuronal matter or GABAA receptor upregulation and inflammatory edema. By providing information on the histological origins of cerebral gray matter alterations in fibromyalgia, this study advances the understanding of the neurobiology of chronic widespread pain. SIGNIFICANCE STATEMENT: Regional gray matter alterations in chronic pain, as detected with voxel-based morphometry of anatomical magnetic resonance images, are commonly interpreted to reflect neurodegeneration, but this assumption has not been tested. We found decreased gray matter in fibromyalgia to be associated with T1 relaxation times, a surrogate marker of water content, but not with GABAA receptor concentration, a surrogate of neuronal integrity. In contrast, regional gray matter increases were partly explained by GABAA receptor concentration, indicating some form of neuronal plasticity. The study emphasizes that voxel-based morphometry is an exploratory measure, demonstrating the need to investigate the histological origin of gray matter alterations for every distinct clinical entity, and advances the understanding of the neurobiology of chronic (widespread) pain.

Different Brain Circuitries Mediating Controllable and Uncontrollable Pain.

UNLABELLED: Uncontrollable, compared with controllable, painful stimulation can lead to increased pain perception and activation in pain-processing brain regions, but it is currently unknown which brain areas mediate this effect. When pain is controllable, the lateral prefrontal cortex (PFC) seems to inhibit pain processing, although it is unclear how this is achieved. Using fMRI in healthy volunteers, we examined brain activation during controllable and uncontrollable stimulation to answer these questions. In the controllable task, participants self-adjusted temperatures applied to their hand of pain or warm intensities to provoke a constant sensation. In the uncontrollable task, the temperature time courses of the controllable task were replayed (yoked control) and participants rated their sensation continuously. During controllable pain trials, participants significantly downregulated the temperature to keep their sensation constant. Despite receiving the identical nociceptive input, intensity ratings increased during the uncontrollable pain trials. This additional sensitization was mirrored in increased activation of pain-processing regions such as insula, anterior cingulate cortex, and thalamus. Further, increased connectivity between the anterior insula and medial PFC (mPFC) in the uncontrollable and increased negative connectivity between dorsolateral PFC (dlPFC) and insula in the controllable task were observed. This suggests a pain-facilitating role of the mPFC during uncontrollable pain and a pain-inhibiting role of the dlPFC during controllable pain, both exerting their respective effects via the anterior insula. These results elucidate neural mechanisms of context-dependent pain modulation and their relation to subjective perception. SIGNIFICANCE STATEMENT: Pain control is of uttermost importance and stimulus controllability is an important way to achieve endogenous pain modulation. Here, we show differential effects of controllability and uncontrollability on pain perception and cerebral pain processing. When pain was controllable, the dorsolateral prefrontal cortex downregulated pain-evoked activation in important pain-processing regions. In contrast, sensitization during uncontrollable pain was mediated by increased connectivity of the medial prefrontal cortex with the anterior insula and other pain-processing regions. These novel insights into cerebral pain modulation by stimulus controllability have the potential to improve treatment approaches in pain patients.

Is a Responsive Default Mode Network Required for Successful Working Memory Task Performance?

In studies of cognitive processing using tasks with externally directed attention, regions showing increased (external-task-positive) and decreased or "negative" [default-mode network (DMN)] fMRI responses during task performance are dynamically responsive to increasing task difficulty. Responsiveness (modulation of fMRI signal by increasing load) has been linked directly to successful cognitive task performance in external-task-positive regions but not in DMN regions. To investigate whether a responsive DMN is required for successful cognitive performance, we compared healthy human subjects (n = 23) with individuals shown to have decreased DMN engagement (chronic pain patients, n = 28). Subjects performed a multilevel working-memory task (N-back) during fMRI. If a responsive DMN is required for successful performance, patients having reduced DMN responsiveness should show worsened performance; if performance is not reduced, their brains should show compensatory activation in external-task-positive regions or elsewhere. All subjects showed decreased accuracy and increased reaction times with increasing task level, with no significant group differences on either measure at any level. Patients had significantly reduced negative fMRI response (deactivation) of DMN regions (posterior cingulate/precuneus, medial prefrontal cortex). Controls showed expected modulation of DMN deactivation with increasing task difficulty. Patients showed significantly reduced modulation of DMN deactivation by task difficulty, despite their successful task performance. We found no evidence of compensatory neural recruitment in external-task-positive regions or elsewhere. Individual responsiveness of the external-task-positive ventrolateral prefrontal cortex, but not of DMN regions, correlated with task accuracy. These findings suggest that a responsive DMN may not be required for successful cognitive performance; a responsive external-task-positive network may be sufficient. SIGNIFICANCE STATEMENT: We studied the relationship between responsiveness of the brain to increasing task demand and successful cognitive performance, using chronic pain patients as a probe. fMRI working memory studies show that two main cognitive networks ["external-task positive" and "default-mode network" (DMN)] are responsive to increasing task difficulty. The responsiveness of both of these brain networks is suggested to be required for successful task performance. The responsiveness of external-task-positive regions has been linked directly to successful cognitive task performance, as we also show here. However, pain patients show decreased engagement and responsiveness of the DMN but can perform a working memory task as well as healthy subjects, without demonstrable compensatory neural recruitment. Therefore, a responsive DMN might not be needed for successful cognitive performance.

Metabolic brain activity suggestive of persistent pain in a rat model of neuropathic pain.

Persistent pain is a central characteristic of neuropathic pain conditions in humans. Knowing whether rodent models of neuropathic pain produce persistent pain is therefore crucial to their translational applicability. We investigated the spared nerve injury (SNI) model of neuropathic pain and the formalin pain model in rats using positron emission tomography (PET) with the metabolic tracer [18F]fluorodeoxyglucose (FDG) to determine if there is ongoing brain activity suggestive of persistent pain. For the formalin model, under brief anesthesia we injected one hindpaw with 5% formalin and the FDG tracer into a tail vein. We then allowed the animals to awaken and observed pain behavior for 30min during the FDG uptake period. The rat was then anesthetized and placed in the scanner for static image acquisition, which took place between minutes 45 and 75 post-tracer injection. A single reference rat brain magnetic resonance image (MRI) was used to align the PET images with the Paxinos and Watson rat brain atlas. Increased glucose metabolism was observed in the somatosensory region associated with the injection site (S1 hindlimb contralateral), S1 jaw/upper lip and cingulate cortex. Decreases were observed in the prelimbic cortex and hippocampus. Second, SNI rats were scanned 3weeks post-surgery using the same scanning paradigm, and region-of-interest analyses revealed increased metabolic activity in the contralateral S1 hindlimb. Finally, a second cohort of SNI rats was scanned while anesthetized during the tracer uptake period, and the S1 hindlimb increase was not observed. Increased brain activity in the somatosensory cortex of SNI rats resembled the activity produced with the injection of formalin, suggesting that the SNI model may produce persistent pain. The lack of increased activity in S1 hindlimb with general anesthetic demonstrates that this effect can be blocked, as well as highlights the importance of investigating brain activity in awake and behaving rodents.

Exogenously applied muscle metabolites synergistically evoke sensations of muscle fatigue and pain in human subjects.

NEW FINDINGS: What is the central question of this study? Can physiological concentrations of metabolite combinations evoke sensations of fatigue and pain when injected into skeletal muscle? If so, what sensations are evoked? What is the main finding and its importance? Low concentrations of protons, lactate and ATP evoked sensations related to fatigue. Higher concentrations of these metabolites evoked pain. Single metabolites evoked no sensations. This suggests that the combination of an ASIC receptor and a purinergic P2X receptor is required for signalling fatigue and pain. The results also suggest that two types of sensory neurons encode metabolites; one detects low concentrations of metabolites and signals sensations of fatigue, whereas the other detects higher levels of metabolites and signals ache and hot. The perception of fatigue is common in many disease states; however, the mechanisms of sensory muscle fatigue are not understood. In mice, rats and cats, muscle afferents signal metabolite production in skeletal muscle using a complex of ASIC, P2X and TRPV1 receptors. Endogenous muscle agonists for these receptors are combinations of protons, lactate and ATP. Here we applied physiological concentrations of these agonists to muscle interstitium in human subjects to determine whether this combination could activate sensations and, if so, to determine how the subjects described these sensations. Ten volunteers received infusions (0.2 ml over 30 s) containing protons, lactate and ATP under the fascia of a thumb muscle, abductor pollicis brevis. Infusion of individual metabolites at maximal amounts evoked no fatigue or pain. Metabolite combinations found in resting muscles (pH 7.4 + 300 nm ATP + 1 mm lactate) also evoked no sensation. The infusion of a metabolite combination found in muscle during moderate endurance exercise (pH 7.3 + 400 nm ATP + 5 mm lactate) produced significant fatigue sensations. Infusion of a metabolite combination associated with vigorous exercise (pH 7.2 + 500 nm ATP + 10 mm lactate) produced stronger sensations of fatigue and some ache. Higher levels of metabolites (as found with ischaemic exercise) caused more ache but no additional fatigue sensation. Thus, in a dose-dependent manner, intramuscular infusion of combinations of protons, lactate and ATP leads to fatigue sensation and eventually pain, probably through activation of ASIC, P2X and TRPV1 receptors. This is the first demonstration in humans that metabolites normally produced by exercise act in combination to activate sensory neurons that signal sensations of fatigue and muscle pain.

Personalized assessment and management of non-specific low back pain.

BACKGROUND AND OBJECTIVE: Low back pain (LBP), and in particular non-specific low back pain (NSLBP), which accounts for approximately 90% of LBP, is the leading cause of years lived with disability worldwide. In clinical trials, LBP is often poorly categorized into 'specific' versus 'non-specific' and 'acute' versus 'chronic' pain. However, a better understanding of the underlying pain mechanisms might improve study results and reduce the number of NSLBP patients. DATABASES AND DATA TREATMENT: Narrative review. RESULTS: NSLBP is a multi-dimensional, biopsychosocial condition that requires all contributing dimensions to be assessed and prioritized. Thereby, the assessment of the contribution of nociceptive, neuropathic and nociplastic pain mechanisms forms the basis for personalized management. In addition, psychosocial (e.g. anxiety, catastrophizing) and contextual factors (e.g. work situation) as well as comorbidities need to be assessed and individually weighted. Personalized treatment of NSLBP further requires individually choosing treatment modalities, for example, exercising, patient education, cognitive-behavioural advice, pharmacotherapy, as well as tailoring treatment within these modalities, for example, the delivery of tailored psychological interventions or exercise programs. As the main pain mechanism and psychosocial factors may vary over time, re-assessment is necessary and treatment success should ideally be assessed quantitatively and qualitatively. CONCLUSIONS: The identification of the main contributing pain mechanism and the integration of the patients' view on their condition, including beliefs, preferences, concerns and expectations, are key in the personalized clinical management of NSLBP. In research, particular importance should be placed on accurate characterization of patients and on including outcomes relevant to the individual patient. SIGNIFICANCE STATEMENT: Here, a comprehensive review of the challenges associated with the diagnostic label 'non-specific low back pain' is given. It outlines what is lacking in current treatment guidelines and it is summarized what is currently known with respect to individual phenotyping. It becomes clear that more research on clinically meaningful subgroups is needed to best tailor treatment approaches.

Healthy women show more experimentally induced central sensitization compared with men.

ABSTRACT: Women more often experience chronic pain conditions than men. Central sensitization (CS) is one key mechanism in chronic pain that can differ between the sexes. It is unknown whether CS processes are already more pronounced in healthy women than in men. In 66 subjects (33 women), a thermal CS induction protocol was applied to the dorsum of one foot and a sham protocol to the other. Spatial extent [cm 2 ] of secondary mechanical hyperalgesia (SMH) and dynamic mechanical allodynia were assessed as subjective CS proxy measures, relying on verbal feedback. Changes in nociceptive withdrawal reflex magnitude (NWR-M) and response rate (NWR-RR) recorded through surface electromyography at the biceps and rectus femoris muscles were used as objective CS proxies. The effect of the CS induction protocol on SMH was higher in women than in men (effect size 2.11 vs 1.68). Nociceptive withdrawal reflex magnitude results were statistically meaningful for women (effect size 0.31-0.36) but not for men (effect size 0.12-0.29). Differences between men and women were not meaningful. Nociceptive withdrawal reflex response rate at the rectus femoris increased in women after CS induction and was statistically different from NWR-RR in men (median differences of 13.7 and 8.4% for 120 and 140% reflex threshold current). The objective CS proxy differences indicate that dorsal horn CS processes are more pronounced in healthy women. The even larger sex differences in subjective CS proxies potentially reflect greater supraspinal influence in women. This study shows that sex differences are present in experimentally induced CS in healthy subjects, which might contribute to women's vulnerability for chronic pain.

A descriptive evaluation of a job analysis survey in the chiropractic profession in Switzerland - an update after more than 10 years.

OBJECTIVES: The aim of this cross-sectional study was to update the results of the first Swiss Job Analysis Survey in 2009 with regard to the demographics of the chiropractors and their patients, practice characteristics, interprofessional collaboration, the importance of imaging, and job satisfaction. METHODS: In April 2020, the adapted 2009 questionnaire was electronically sent to all members of the Swiss Chiropractic Association ChiroSuisse (N = 316). Only complete questionnaires were included in the descriptive analysis. Demographic data were compared to all ChiroSuisse members. RESULTS: The response rate was 76.3%. The mean age of the participants was 49.9 ± 12.3 years and 62.2% were male. Among the younger chiropractors (≤ 15 years of professional experience), 51.6% were male. Almost half of the participants worked in a joint office and one in five worked in a multidisciplinary setting. The typical chiropractic patient was middle-aged, female and suffered most frequently from acute lower back/pelvis pain and second most frequently from neck pain. Diversified osseous adjustment was the most commonly used technique, followed by advice on activities of daily living and trigger point therapy. Images (X-ray, CT, MRI) were ordered in less than 20% of the patients. 95% of the chiropractors were satisfied with their career choice. CONCLUSIONS: No changes to 2009 were observed in terms of the typical patient or the applied techniques. However, the Swiss chiropractors were more experienced, to a larger proportion female, more often worked in multidisciplinary settings, and ordered fewer images. Job satisfaction among Swiss chiropractors was high.