Pain Sensitivity Research Articles

Effect of individualized anesthesia and analgesia on postoperative pain in patients stratified for pain sensitivity: A study protocol for the PeriOPerative individualization trial randomized controlled trial.

Despite advancements in surgical and anesthesia techniques, acute and persistent postoperative pain are still a common challenge. Postoperative pain has direct effects on individual patient care and outcome, as well as putting strain on limited health care resources. Several prediction methods for postoperative pain have been described. One such method is the assessment of pain during peripheral venous cannulation (VCP). It is not known if different approaches to anesthesia and analgesia, depending on the evaluation of risk for postoperative pain, can improve outcome. The aim of this study is to evaluate if individualized anesthesia and analgesia can affect postoperative pain and recovery after surgery, in patients stratified by VCP. Adult patients scheduled for laparoscopic surgery undergo pain-sensitivity stratification using VCP on the day of surgery. Patients scoring VCP ≥2.0 on the visual analogue scale (pain-sensitive) are randomized to multimodal anaesthesia and analgesia with opioids or standard of care. Patients scoring VCP ≤1.9 (pain-tolerant) are randomized to opioid-free anaesthesia or standard of care. The primary outcome is acute postoperative pain measured with numeric rating scale in the postoperative care unit. Secondary outcomes include analysis of pain after 24 h, persistent postoperative pain and quality of recovery. Individualized perioperative pain management has the potential to improve patient care. This study will examine the impact of different anesthesia and analgesia regimes, in patients with differing pain sensitivity, on postoperative pain. Prospectively posted at ClinicalTrials.gov, identifier NCT04751812.

Topical capsaicin modulates the two-point discrimination threshold-Modulation depends on stimulation modality and intensity.

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

Transcranial Direct Current Stimulation Reduces Pressure Pain Sensitivity in Patients With Noncancer Chronic Pain

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

When thinking about pain contributes to suffering: the example of pain catastrophizing

Abstract The extensive literature on the potent role negative thoughts about pain have on the experience of pain and pain-related suffering has documented associations with important neurobiological processes involved in amplifying nociceptive signals. We focus this review on pain catastrophizing (pCAT)— appraisals of pain as threatening, overwhelming, and unmanageable— and review the evidence that these thoughts are learned in childhood through experience and observation of others, particularly caretakers and parents. For children who have learned pCAT, repeated exposures to pain over time activate pCAT and likely contribute to further amplification of pain through changes in the neurobiological pain regulatory systems, which overlap with those regulating the stress response. We propose that repeated pain and stress exposures throughout childhood, adolescence, and into adulthood alter the neurobiology of pain via a repetitive positive feedback loop that increases risk for heightened pain sensitivity over time with repeated exposures. At some point, often precipitated by an acute episode of pain and possibly influenced by allostatic load, pCAT contributes to persistence of episodic or acute pain and exacerbates pain-related suffering. This developmental trajectory is not inevitable, as the impact of pCAT on pain and pain-related suffering can be influenced by various factors. We also present future directions for work in this area.

Effects of Apnea-Induced Hypoxia on Hypoalgesia in Healthy Subjects

Introduction: Exercise-induced hypoalgesia is a phenomenon in which exercise bouts induce a reduction in pain sensitivity. Apnea training involves similar characteristics that could potentially induce hypoalgesia. Objectives: The objectives of this study are to explore the effect of apnea training on hypoalgesia; assess the correlation between conditioned pain modulation (CPM) response and apnea-induced hypoalgesia; and examine the association between hypoalgesia with hypoxemia, and heart rate (HR) during apnea. Methods: A randomized controlled trial was conducted comparing a walking protocol employing intermittent apnea compared with normal breathing in healthy volunteers. Hypoalgesia was tested with pressure pain thresholds (PPTs) and CPM. Oxygen saturation (SpO2) and HR were also tested. Results: Relevant but not significant changes were detected in the thumb (MD = 0.678 kg/cm2), and tibialis (MD = 0.718 kg/cm2) in favor of the apnea group. No significant differences were detected in CPM. The apnea group presented lower SpO2, but HR values similar to those of the control group during the intervention. Basal CPM and intrasession hypoxemia significantly correlated with the PPT response. However, HR did not correlate with the PPT response. Conclusions: The current results suggest a trend, though not statistically significant, toward an improvement in the PPT in favor of apnea training compared to normal breathing. Nevertheless, subjects who presented greater basal CPM and lower oxygen saturation during the session presented a greater PPT response, suggesting the possibility of mediators of response. Future investigations should clarify this phenomenon.

The effect of stretching intensity on pain sensitivity: A randomized crossover study on healthy adults.

Stretching exercises have effects on local and widespread pain sensitivity. A dose-response relationship may exist between the analgesic effect and the intensity of stretching, such that a higher intensity of stretching may generate a larger reduction in analgesic response, but this remains to be studied. This study aimed to examine the dose-response relationship between stretching intensity and the analgesic effect. A randomized, repeated-measures crossover study was performed to examine the effect of stretching to the first point of pain onset and stretching to the point of a sensation of stretching (discomfort). The primary outcome was regional and distant pressure pain thresholds. Thirty-one participants (n = 24 female) were available for analysis. We observed a 22.2% increase in regional pressure pain thresholds (93.2 kPa, p = 0.001) and a 15.0% increase in distant pressure pain thresholds (50.9 kPa, p = 0.012) following stretching to the point of stretch. We observed a 20.0% increase in regional pressure pain thresholds (90.3 kPa, p = 0.001) and a 15.1% increase in distant pressure pain thresholds (52.1 kPa, p = 0.004) following stretching to the point of pain. The results showed that local and widespread pain sensitivity decreased following acute stretching, regardless of stretching intensity. No differences in pain sensitivity were found between stretching to the point of stretch or stretching to the first onset of pain. Thus, the results showed no evidence of a dose-response relationship between stretching intensity and the analgesic effect. The study showed a significant acute hypoalgesic effect of stretching exercises regardless of stretching intensity. This may have appropriate clinical implications for patients with musculoskeletal and nociplastic pain.

Effectiveness of high-frequency vibration, cotton rolls and elastomeric wafers in alleviating debonding pain of orthodontic metal brackets: a randomized clinical trial

This study aimed to evaluate the effectiveness of different pain mitigation methods during orthodontic debonding and to evaluate pain sensitivity across various regions of the dentition. A total of 144 participants (50 males and 94 females) with metal brackets were randomly assigned to one of four groups: High-Frequency Vibration (V), Cotton Roll (CR), Elastomeric Wafer (EW), and Open Mouth group (OM). Pain levels were measured using the Visual Analog Scale (VAS) across different sextants of the dentition. The Kruskal-Wallis test and post hoc analyses were conducted to compare VAS scores between groups. The Mann-Whitney test was used to analyse sex-based differences. The V group, utilizing high-frequency vibration, had the lowest total VAS score, indicating superior pain relief compared to CR, EW, and OM groups. No significant difference was observed between the CR and EW groups. Median VAS scores were highest in the lower front sextant, followed by the upper front sextants, and lowest in the posterior regions, indicating greater pain sensitivity in the anterior regions during debonding. High-frequency vibration was the most effective method for reducing pain during orthodontic debonding, particularly in the anterior dental regions. Both CR and EW methods were also effective but to a lesser extent. These findings suggest that high-frequency vibration could significantly improve patient comfort during orthodontic procedures. Utilizing high-frequency vibration for orthodontic debonding can enhance patient comfort, especially in the more sensitive anterior dental regions, thereby potentially improving treatment compliance and experience.Trial registration: NCT05904587.

Arginine vasopressin induces analgesic effects and inhibits pyramidal cells in the anterior cingulate cortex in spared nerve injured mice.

Neuropathic pain (NP) is a severe disease caused by a primary disease or lesion affecting the somatosensory nervous system. It`s reported that NP is related to the increased activity of glutamatergic pyramidal cells and changed neural oscillations in the anterior cingulate cortex (ACC). Arginine vasopressin (AVP), a neurohypophyseal hormone, has been shown to cause pain-alleviating effects when applied to peripheral system. However, the extent to which, and the mechanisms by which, AVP induces analgesic effects in the central nervous system remain unclear. In the present study, we observed that intranasal delivery of AVP inhibited mechanical pain, thermal pain and spontaneous pain sensitivity in mice with spared nerve injury. Meanwhile, AVP application exclusively reduced the FOS expression in the pyramidal cells but not interneurons in the ACC. In vivo electrophysiological recording of the ACC further showed that AVP application not only inhibited the theta oscillation in local field potential analysis, but also reduced the firing rate of spikes of pyramidal cells in the ACC in neuropathic pain mice. In summary, AVP induce analgesic effects by inhibiting neural theta oscillations and the spiking of pyramidal cells of the ACC in mice with neuropathic pain, which should provide new potential noninvasive methods for clinical treatment of chronic pain.

Regional Sensorimotor Effects of Chiropractic Spinal Manipulation: Preliminary Results From an Experimental Study.

The purpose of this study was to assess the effects of different spinal manipulation (SM) techniques and target segments on a specific dermatome and myotome, when compared with a remote spinal cord segment that served as a control location. Twenty-nine healthy volunteers were randomized to receive instrumental (Activator IV, Activator Methods International Ltd) or manual SM at the C6, C1, and T4 vertebral segments in 3 independent sessions. Pressure pain thresholds (PPTs) and muscle strength were examined at the C6 (test) and L4 (control) dermatomes and myotomes, at baseline and after intervention. Linear mixed-effects models were used to analyze changes over time and interindividual variability. Pressure pain thresholds significantly increased at both proximal and distal C6 dermatome locations (P < .05), irrespective of the technique and segment of application (P > .2). No significant changes were observed at the L4 dermatome. Muscle strength remained unchanged throughout the study. Multilevel modeling revealed significant associations between increased PPTs along the C6 dermatome (P < .001), whereas the combination of technique and target segment predicted PPT increases at the proximal C6 dermatome. These findings support regional, rather than segmental mechanisms underlying the sensory effects of SM. Specifically, significant increases in PPTs along the C6 dermatome suggest localized effects on pain sensitivity, which may depend on the target spinal region. Further investigation is needed to better understand these regional changes of SM and their potential clinical implications.

Lifestyle factors as predictors of incident functional somatic disorder. Five-year follow-up of The DanFunD study.

To assess whether lifestyle factors, including sleep pattern, are predictors for the development of functional somatic disorder (FSD). A population-based prospective cohort of 9656 men and women aged 18-76 years was established in 2011-2015 and invited for re-examination in 2017-2020, when 5738 participated. Median follow-up period was 65 months. Participants filled in validated questionnaires on lifestyle, sleep pattern and various delimitations of FSD, which were operationalized using two different approaches: bodily distress syndrome (BDS) and functional somatic syndromes (FSS) (i.e. chronic fatigue, chronic widespread pain (CWP), irritable bowel, and multiple chemical sensitivity (MCS)). Baseline lifestyle and sleep pattern in relation to incidence of BDS and FSS (chronic fatigue, CWP, irritable bowel, MCS) was analysed by logistic regressions, adjusted for age, sex and subjective social status. Inferior sleep quality at baseline predicted both incidence of BDS and all FSS delimitations except MCS. Smoking, alcohol intake, and low physical activity, but not diet, were predictors for the development of BDS. No uniform pattern was observed for the FSS. Smoking predicted development of chronic fatigue, CWP and irritable bowel, but not MCS. Alcohol and food quality only influenced the development of chronic fatigue whereas low physical activity only influenced the development of chronic fatigue and CWP. Lifestyle factors and sleep pattern seem to be predictors for some delimitations of FSD, but the importance of the various lifestyle factors is different for the different delimitations. The study shows the importance of analysing the various FSSs separately.

High-Fat Diet-Induced Blood-Brain Barrier Dysfunction: Impact on Allodynia and Motor Coordination in Rats.

The associations among increased pain sensitivity, obesity, and systemic inflammation have not been described as related to BBB dysfunctions. To analyze the metabolic, behavioral, and inflammatory effects of a high-fat diet (HFD) and ultrastructural modifications in brain regions, we used an in vivo experimental model. Adult male Wistar rats were randomly assigned to one of two conditions, an ad libitum control group or an HFD (60%)-fed group, for eight weeks. At the end of the protocol, glucose and insulin tolerance tests were performed. Additionally, we analyzed the response to a normally innocuous mechanical stimulus and changes in motor coordination. At the end of the protocol, HFD-fed rats presented increased HOMA-IR and metabolic syndrome (MetS) prevalence. HFD-fed rats also developed an increased nociceptive response to mechanical stimuli and neurological injury, resulting in impaired motor function. Hypothalamus and cerebellum neurons from HFD-fed rats presented with nuclear swelling, an absence of nucleoli, and karyolysis. These results reveal that HFD consumption affects vital brain structures such as the cerebellum, hippocampus, and hypothalamus. This, in turn, could be producing neuronal damage, impairing cellular communication, and consequently altering motricity and pain sensitivity. Although direct evidence of a causal link between BBB dysfunction and sensory-motor changes was not observed, understanding the association uncovered in this study could lead to targeted therapeutic strategies.

Brown Sequard Syndrome: A Case Report

A very unusual neurological disorder known as Brown-Séquard Syndrome (BSS) may develop when the spinal cord is severed or damaged on one side. Ipsilateral motor paralysis, loss of proprioception, and a lack of pain and temperature sensitivity on the opposite side are hallmarks of this disorder's distinctive pattern of neurological impaired functions. A 45-year-old man with a history of severe injuries who acquired Brown-Séquard Syndrome is the subject of this case report.

Alpha transcranial alternating current stimulation modulates pain anticipation and perception in a context-dependent manner.

Pain perception is closely tied to the brain's anticipatory processes, particularly involving the suppression of sensorimotor α-oscillations, which reflect the system's readiness for incoming pain. Higher sensorimotor α-oscillation levels are correlated with lower pain sensitivity. Alpha transcranial alternating current stimulation (α-tACS) can enhance these oscillations, potentially reducing pain perception, with effects that may be sustained and influenced by the certainty of pain expectations. Hence, this study investigated the immediate and sustained effects of α-tACS on pain anticipation and perception, focusing on how these effects are shaped by the certainty of expectations. In a double-blind, sham-controlled design, 80 healthy participants underwent a 20-minute session of real or sham α-tACS over the right sensorimotor region. Behavioral and neural responses related to pain anticipation and perception were recorded before, immediately after, and 30 minutes poststimulation under both certain and uncertain conditions. Compared with sham stimulation, real α-tACS disrupted the habituation of laser-evoked potentials (N2-P2 complex), particularly under certain expectations, with effects persisting 30 minutes poststimulation. In anticipatory brain oscillations, real α-tACS enhanced somatosensory α1-oscillations and increased midfrontal θ-oscillations in conditions of certainty, with θ-oscillation modulation showing sustained effects. Mediation analysis revealed that α-tACS reduced pain reactivity by enhancing somatosensory α1-oscillations but increased pain reactivity through the enhancement of midfrontal θ-oscillations, with the latter effect being more pronounced. These findings suggest that while α-tACS may provide pain relief through somatosensory α-oscillation augmentation, its stronger and longer-lasting impact on midfrontal θ-oscillations could lead to hyperalgesia, particularly in the context of certain pain expectations.

Yoga, Physical Therapy and Home Exercise Effects on Chronic Low Back Pain: Pain Perception, Function, Stress, and Quality of Life in a Randomized Trial.

Low back pain is a common health problem. In this study, we investigated the effects of yoga, physical therapy (PT), and home exercise (HE) on pain perception, function, stress, and quality of life in chronic low back pain (cLBP). We randomly assigned 54 participants to three distinct treatment groups: (a) a physical therapy group (PT) who received spinal stabilization exercises (SSE) combined with local heat and transcutaneous electrical stimulation; (b) a home exercise group (HE) who received SSE as part of the home program; and (c) a yoga group who received yoga exercises. The primary outcome measures were a Visual Analog Scale (VAS) for measuring pain, and the Oswestry Disability Index (ODI) to measure function. Secondary outcome measures were the Tampa Kinesiophobia Scale (TKS), Central Sensitization Inventory (CSI), pain sensitivity (L3 and deltoid R/L PPTs), Spielberger State-Trait Anxiety Inventory (STAI), plasma cortisol and DHEA-S levels, Transversus Abdominis (TrA) muscle activation, and the Nottingham Health Profile (NHP). Assessments were conducted before and after a six-week intervention period. All three groups demonstrated improvements in pain on the VAS, function on the ODI, pain sensitivity on the L3 and deltoid R/L PPTs, CSI, anxiety on the STAI, TrA muscle activation, and quality of life on the NHP (p < .05). The PT group exhibited a more pronounced improvement on the ODI score (p < .05) than the other groups. Cortisol levels only decreased in the PT group (p < .05). The exercises did not impact DHEA-S and NHP-S parameters. Thus, all interventions resulted in decreased stress, pain intensity, pain sensitivity, central sensitization, and improved function and quality of life; there was no singularly superior approach between interventions. These findings will aid in tailoring treatment programs for managing cLBP according to individual needs.

Isolated during adolescence: long-term impact on social behavior, pain sensitivity, and the oxytocin system in male and female rats

BackgroundAdolescent social isolation (ASI) has profound long-term effects on behavioral and neural development. Despite this, the specific long-term impact of ASI during different adolescent stages and across sexes remain underexplored.MethodsOur study addresses this gap by examining the effects of early- and late- adolescent social isolation on both male and female rats. Rats were either isolated (or group-housed) starting from PD 21 (early) or PD 42 (late) for three weeks and then rehoused into groups. In adulthood (PD 90), rats underwent a battery of tests: elevated plus-maze, open field, novel object recognition, social interaction and social recognition memory and hotplate tests. Finally, we analyzed oxytocin receptor binding in several regions in the brains of a second cohort of rats.ResultsBoth, male and female rats from the late adolescent social isolation (LASI) groups spent significantly less time interacting in the social interaction test. Additionally, we observed a general decrease in social recognition memory regardless of sex. Both male ASI groups demonstrated heightened thermal pain sensitivity, while the opposite was observed in early adolescent social isolation (EASI) female rats. In the brain, we observed changes in oxytocin receptor (OTR) binding in the paraventricular nucleus of the hypothalamus (PVN) and paraventricular nucleus of the thalamus (PVT) and central amygdala (CeA) with the largest changes in EASI and LASI female rats.ConclusionOur model demonstrates long-lasting alterations on behavior and oxytocin receptor binding levels following ASI providing insights into the long-term effects of ASI in a time- and sex-specific manner.

Non-Invasive Brain Stimulation Beyond the Motor Cortex: A Systematic Review and Meta-Analysis Exploring Effects on Quantitative Sensory Testing in Clinical Pain.

Non-invasive brain stimulation (NIBS) has been investigated increasingly as a means of treating pain. The effectiveness of NIBS in the treatment of pain has traditionally focused upon protocols targeting the primary motor cortex (M1). However, over time, the effectiveness of M1 NIBS has been attributed to effects on interconnected cortical and subcortical sites rather than M1 itself. While previous reviews have demonstrated the effectiveness of non-M1 NIBS in improving subjective reports of pain intensity, the neurophysiological mechanisms underlying these effects remain incompletely understood. As chronic pain is associated with pain hypersensitivity and impaired endogenous descending pain modulation, it is plausible that non-M1 NIBS promotes analgesic effects by influencing these processes. The aim of this systematic review and meta-analysis was therefore to evaluate the effect of NIBS over non-M1 sites on quantitative sensory testing measures in clinical pain populations. A systematic search of electronic databases was conducted from inception to January 2024. Included articles (13trials, n = 565 participants) were appraised using PEDro and GRADE and a random effects model was used to meta-analyse outcomes where possible. A small number of studies found that NIBS applied to DLPFC may improve pain modulation in patients with fibromyalgia, and that stimulation of the posterior superior insula and prefrontal cortex could improve pain sensitivity in chronic neuropathic and osteoarthritic pain, respectively. However, findings varied between studies and there remains a paucity of primary research. This review indicates that current literature does not provide clear evidence that NIBS over non-M1 sites influences pain processing.

Pain sensitization and pain-related psychological factors in patients with temporomandibular disorders: an observational cross-sectional study.

There is conflicting evidence on how central processing impairments affect patients with temporomandibular disorders (TMD). Moreover, there is sparse research on the assessment of endogenous pain modulation in this population through conditioned pain modulation (CPM) testing. The main objective of this observational study was to evaluate the possible differences between myofascial TDM patients and healthy pain-free controls on psychophysical variables suggestive of central processing impairments (including temporal summation (TSP), pressure pain threshold (PPT) and conditioned pain modulation (CPM)). This is a cross-sectional observational study including a sample of patients with TMD and pain-free controls recruited from private and university clinics in Spain. Outcome measures included local and distal PPTs, temporal summation, conditioned pain modulation and psychological factors of depression, anxiety, kinesiophobia, fear avoidance beliefs and pain catastrophizing. Fifty-nine patients with TMD of myofascial origin (32 years [IR: 25-43]) and 30 healthy, pain-free controls (29.5 years [IR: 25-41]) participated in the study and completed the evaluations. Patients with TMD showed significantly reduced CPM (p = 0.001; t = 3.31) and both local and distal PPTs (p < 0.05) when compared with controls, after adjusting for the influence of age and sex. TSP did not show any difference between the groups (p = 0.839; Z = 0.20). All psychological factors were higher in patients with TMD (p < 0.005), except for anxiety (p = 0.134). Patients with myofascial TMD included in this study exhibited signs of altered central processing, linked to impaired descending pain modulation, distal hyperalgesia and psychological factors like depression, kinesiophobia, fear avoidance beliefs and pain catastrophizing but not anxiety.

Disturbances of Interoception in Schizophrenia – Focus on Neuroimaging

Abstract: The current paper presents the most recent theoretical understanding of interoception (INTC) in light of the predictive processing framework and the Embodied Predictive Interoceptive Coding model and reviews recent experimental data on different interoceptive disturbances in schizophrenia (SCZ) such as lower interoceptive accuracy, nociceptive dysfunction reflected by reduced pain sensitivity, disturbed thermoregulation, impaired gastrointestinal regulation, cardiovascular and respiratory dysfunction, and immune disturbances. The immense clinical implications of these disturbances are discussed in the context of the high rates of morbidity and mortality in SCZ related to suicide and cardiac death. Next, the potential of INTC-related treatments is reviewed, and conclusions are made on the evidence for the use of vagus nerve stimulation, mindfulness-based interventions, and exercise therapy. The neuroimaging perspective is given in a brief account of the INTC-related findings in healthy individuals suggesting the right anterior insula and anterior cingulate cortex as key brain areas for interoceptive awareness, accuracy, and sensibility, by supporting higher-order representation and integration of visceral, and somatosensory interoception with exteroceptive information. In SCZ, on the other hand, neuroimaging research on specific interoceptive abilities is lacking but indirect evidence points to disrupted activation of major INTC network hubs. There is converging evidence of changes in these hubs in terms of both structure and function (volume reductions, aberrant activation, and connectivity). This narrative review identifies several gaps in contemporary INTC-related research in SCZ that need to be addressed in future experimental and clinical studies to elucidate the exact nature of the disturbances of interoceptive abilities in modalities other than cardioception; the interactions between different interoceptive modalities; the association between interoceptive abilities and other mental functions (such as emotion recognition and regulation, decision making, learning, memory, etc.); the efficacy of nonpharmacological and pharmacological INTC-based interventions; and the relation of disturbed interoceptive abilities with brain structure and function.

Pain profiles and variability in temporal summation of pain and conditioned pain modulation in pain-free individuals and patients with low back pain, osteoarthritis, and fibromyalgia.

Pain profiles (e.g. pro- and anti-nociceptive) can be developed using quantitative sensory testing (QST) but substantial variability exists. This study describes the variability in temporal summation of pain (TSP) and conditioned pain modulation (CPM) in chronic musculoskeletal pain patients, proposes cut-off values, and explores the association with clinical pain intensity. This is a secondary analysis in which TSP and CPM were assessed using cuff algometry in pain-free subjects (n = 69), and patients with chronic low back pain (cLBP, n = 267), osteoarthritis (n = 134), and fibromyalgia (n = 101). Using TSP and CPM from the pain-free subjects as a reference, four distinct pain profiles TSP (low/high) and CPM (low/high) were created, and differences in clinical pain between pain profiles were explored. Individual data revealed large inter-person variability. High TSP and low CPM were found in fibromyalgia (p < 0.01) and osteoarthritis (p < 0.01) but not cLBP when compared to pain-free subjects. The proportion of patients classified into the distinct pain profiles was significantly different (p < 0.001) with the largest proportion in the high TSP and low CPM group in fibromyalgia (52.5%) and osteoarthritis (41.4%). Clinical pain was not significantly different comparing the pain profiles, and no significant correlations were observed between clinical pain and TSP or CPM. These results demonstrated substantial inter-person variability in TSP and CPM in patients with different chronic pain conditions and pain-free subjects. The proportion of patients with a pro-nociceptive profile appears larger in fibromyalgia and osteoarthritis, but we found no association to clinical pain. This analysis shows that there is variability when assessing TSP and CPM in both pain-free subjects and patients with chronic pain. A cut-off for determining when a person is pain-sensitive is proposed, and data based on this cut-off approach suggest that significantly more patients with osteoarthritis and fibromyalgia are pain-sensitive (i.e. higher TSP and lower CPM) compared to pain-free subjects. This analysis does not find an association between pain sensitivity and clinical pain.

Investigating the effects of artificial baroreflex stimulation on pain perception: A comparative study in no-pain and chronic low back pain individuals.

The autonomic nervous system (ANS) and pain exhibit a reciprocal relationship, where acute pain triggers ANS responses, whereas resting ANS activity can influence pain perception. Nociceptive signalling can also be altered by 'top-down' processes occurring in the brain, brainstem and spinal cord, known as 'descending modulation'. By employing the conditioned pain modulation (CPM) paradigm, we previously revealed a connection between reduced low-frequency heart rate variability and CPM. Individuals with chronic pain often experience both ANS dysregulation and impaired CPM. Baroreceptors, which contribute to blood pressure and heart rate variability regulation, may play a significant role in this relationship, although their involvement in pain perception and their functioning in chronic pain have not been sufficiently explored. In the present study, we combined artificial 'baroreceptor stimulation' in both pressure pain and CPM paradigms, seeking to explore the role of baroreceptors in pain perception and descending modulation. In total, 22 individuals with chronic low back pain (CLBP) and 29 individuals with no-pain (NP) took part in the present study. We identified a differential modulation of baroreceptor stimulation on pressure pain between the groups of NP and CLBP participants. Specifically, NP participants perceived less pain in response to baroreflex activation, whereas CLBP participants exhibited increased pain sensitivity. CPM scores were associated with baseline measures of baroreflex sensitivity in both CLBP and NP participants. Our data support the importance of the baroreflex in chronic pain and a possible mechanism of dysregulation involving the interaction between the ANS and descending pain modulation. KEY POINTS: Baroreflex stimulation has different effects on pressure pain in participants with chronic pain compared to matched individuals with no-pain. Baroreceptor activation decreases pain in participants with no-pain but increases pain perception in participants with chronic pain. Baroreflex sensitivity is associated with conditioned pain modulation in both groups of chronic pain and no-pain participants. The reactivity of the baroreflex during autonomic stress demonstrated a positive correlation with Pain Trait scores in participants with chronic back pain.