Irit Weissman-Fogel

Background: Body perception disturbances (BPDs) are highly prevalent in chronic limb pain, manifesting as hostile feelings towards the limb, reduced sensory–motor function, and altered limb ownership. Various questionnaires and tests assess BPD, but their interrelation and associations with limb disability remain underexplored. This study aimed to evaluate BPD assessments, examine whether they capture overlapping or distinct aspects of BPD, and determine their associations with upper- and lower-limb disability. Methods: This observational cross-sectional study included 92 participants with chronic limb pain. Participants completed BPD questionnaires (Bath-BPD, Neurobehavioral) and tests (Laterality Recognition, Fingers/Toe Perception, Human Figure Drawing), along with clinical pain measures and the symptom severity index. Dependent outcomes were upper- and lower-limb disability. Results: Cluster analysis grouped all measures into ‘High’ and ‘Low’ BPD severity clusters, with overall cluster quality rated as fair (silhouette = 0.40). The Neurobehavioral questionnaire emerged as the primary contributor to the cluster structure (silhouette = 1). The ‘High’ BPD cluster showed significantly greater symptom severity (t(63) = −4.13, p < 0.001). Pain severity, Bath-BPD questionnaire, and symptom severity were significantly associated with upper-limb disability (p < 0.001), whereas pain intensity alone accounted for 24% of lower-limb disability variance. Conclusions: Despite the diversity of BPD assessments, the clustering pattern suggests a partial convergence between measures, though a weak cohesiveness of BPD tests indicates that they capture partially distinct aspects of body perception. BPD questionnaires were associated with upper-limb disability, whereas lower-limb disability was associated with pain intensity. These findings emphasize the importance of assessing BPDs in musculoskeletal care and suggest their potential role as indicators of symptom severity.

Introduction: Conditioned pain modulation (CPM) is a laboratory test of the efficacy of endogenous pain inhibition. Although the vagus nerve is thought to contribute to analgesia via descending inhibitory pathways, its role in CPM remains unclear. In addition, as vagal tone fluctuates across the menstrual cycle due to hormonal changes, the menstrual cycle's influence on the vagal–CPM association warrants investigation. Methods: Sixty-seven healthy females completed psychological questionnaires and underwent psychophysical assessments (1-minute tonic heat pain [THP] given alone and during CPM). An electrocardiogram was recorded at rest, and in 1-minute segments before, during, and after the THP alone, as well as during a conditioning stimulus (CPM paradigm). Heart rate variability was assessed using time- and frequency-domain indices. Menstrual phase was categorized as either follicular or luteal based on standard cycle-length division. Results: The interaction between the resting root mean square of successive differences (RMSSD) and the menstrual cycle predicted better CPM efficiency. Post-hoc analysis revealed that the vagal–CPM association emerged solely in the follicular phase (β = −1.05, P = 0.010). Nevertheless, psychological factors did not influence the vagal–CPM association. The RMSSD broadly changed under pain with conditioning compared to baseline, with higher levels of RMSSD positively associated with CPM magnitude. Conclusions: The findings suggest a tentative menstrual cycle–dependent association between baseline vagal tone and pain inhibition in healthy females. Further, greater vagal activity contributes to more efficient pain inhibition. Future studies should use within-subject designs to examine how interactions between vagal and sympathetic activity across the menstrual cycle influence pain modulation.

Background: Body Perception Disturbances (BPD) are common in chronic limb pain conditions characterised by negative feelings toward the limb and a reduced sense of agency. Prior research has focused on isolated associations between psychological factors, pain hypersensitivity and BPD. Therefore, an integrated examination of the interconnections between these variables within a theory‐driven model is necessary. Methods: The model hypothesises that pain hypersensitivity (hyperalgesia, allodynia), directly linked with BPD (assessed by the Bath‐BPD and Neurobehavioral questionnaires) or indirectly, via symptom severity [assessed by complex regional pain syndrome (CRPS) severity score]; coping strategies (depersonalization, kinesiophobia) and psychological symptoms (somatization, depression) are directly related to BPD; and BPD is associated with pain severity and Quality of Life (QoL). Results: The model was examined using a path analysis of 92 patients with chronic limb pain. Results indicate that depersonalization was directly linked with the Bath‐BPD ( β = 0.50, p < 0.001), and depersonalization and kinesiophobia with the Neurobehavioral ( β = 0.24, p = 0.010; β = 0.22, p = 0.020, respectively). CRPS severity score accounts for the associations between hyperalgesia intensity and BPD and is directly related to the Bath‐BPD ( β = 0.25, p = 0.014), Neurobehavioral ( β = 0.24, p = 0.037), pain ( β = 0.28, p = 0.014) and QoL ( β = −0.34, p = 0.001). The Bath‐BPD marginally associated with QoL ( β = −0.20, p = 0.052) but not with pain severity. Conclusions: The theory‐driven model fits the data, suggesting that psychological copying strategies play a dominant role in BPD. The symptom severity explains the associations between pain hypersensitivity and BPD and is directly linked to BPD, pain and QoL. The model revealed potential mechanisms underlying BPD and its associated clinical outcomes. Significance Statement: This study is the first to use path analysis to examine the predictors and effects of Body Perception Disturbances (BPD) in chronic limb pain. Results identified depersonalization and kinesiophobia as key psychological predictors of BPD, while hyperalgesia has no direct effect. The Complex Regional Pain Syndrome (CRPS) severity score is negatively associated with BPD, pain and quality of life. Findings emphasise the role of dysfunctional psychological processes in BPD and suggest that targeting these processes and reducing CRPS symptoms may improve BPD and treatment outcomes.

Background: Tactile‐induced analgesia (TIA) is a phenomenon in which different types of tactile stimulation alleviate pain via different mechanisms including empathy. As TIA plays an essential role in therapeutic situations and clinical conditions, it is crucial to determine whether specific tactile stimulations confer distinct benefits.Methods: Fifty‐two subjects (31 females; 21–47 years) were exposed to four distinct experimental conditions involving three types of touch provided within a simulated supportive therapeutic setting. First, a contact heat (70 s) at a pain intensity of 60/100 Numerical Pain Scale (NPS) was applied to the forearm. The pain stimulus was then given simultaneously with vibration, gentle stroking, or handholding in random order. Pain ratings were reported at 5 and 65 s of each stimulation. Given the role of empathy in TIA, we also assessed the levels of empathy experienced by the subjects and the experimenter.Results: Handholding and vibration conditions were associated with a more rapid decrease in pain ratings compared to pain‐alone (B values: handholding = −150.94 vs. pain‐alone = −99.38, p = 0.01; vibration = −163.54 vs. pain‐alone = −99.38, p < 0.001). Higher levels of the experimenter's empathy toward the subjects were associated with greater pain alleviation during vibration vs. pain‐alone condition (B values: vibration = −56.42 vs. B pain‐alone = −9.57, p = 0.04).Conclusions: Vibration's potent analgesic effects may be attributed to its multi‐channel analgesic mechanisms, including the therapist's empathy toward the participant. On the other hand, for handholding establishing an empathic interaction should be considered in a therapeutic setting to enhance its analgesic efficacy.Significance: This article explores the effectiveness of touch‐based pain relief methods and their association with empathetic therapeutic interactions. The study emphasizes the significance of positive therapeutic interactions in facilitating tactile‐induced analgesia.

Background: Vagal activity has analgesic effects that are attributed to exercise‐induced hypoalgesia (EIH). High vagal tone and low pain sensitivity are reported in individuals who routinely exercise yet, their association is unclear. Furthermore, it is unknown if the heightened vagal tone following high physical activity predicts and intensifies EIH.Methods: Fifty‐one healthy participants (27 low–moderately physically active; 27 females) underwent a resting‐state electrocardiogram followed by heart rate variability analysis. Pain measurements, including pressure (PPT) and heat (HPT) pain thresholds, ratings of tonic heat pain (THP) and conditioned pain modulation (CPM) paradigm, were conducted pre‐ and post‐exercise on a cycle ergometer.Results: The highly active group demonstrated higher vagal tone compared to the low–moderately active (root mean square of successive differences between R–R intervals: 63.96.92 vs. 34.78 ms, p = 0.018; percentage of successive R–R intervals that exceed 50 ms: 24.41 vs. 11.52%, p = 0.012). Based on repeated‐measure ANOVA, the highly active group showed higher PPT at pre‐exercise, compared to the low–moderately active group (382 kPa vs. 327 kPa; p = 0.007). Post‐exercise, both groups demonstrated EIH, increased HPT (p = 0.013) and decreased THP ratings (p < 0.001). Linear regression revealed that only in the low–moderately active group, higher vagal tone was associated with more efficient pre‐exercise CPM and a greater reduction in THP ratings post‐exercise (p ≤ 0.01).Conclusions: Highly active individuals demonstrate greater vagal tone and lower pain sensitivity but no greater EIH. Vagal tone moderates pain inhibition efficiency and EIH only in low–moderately active individuals. These findings suggest that physical activity level moderates the vagal–pain association via the endogenous analgesia system.Significance: Highly physically active individuals exhibit greater vagal tone and reduced sensitivity to experimental pain, yet they do not benefit more from exercise‐induced hypoalgesia (EIH) compared to low–moderately active individuals. Moreover, low–moderately active individuals with greater vagal tone exhibited more efficient endogenous pain inhibition and greater EIH, suggestive of the moderation effect of physical activity level on vagal–pain associations.

Background: Dynamic mechanical allodynia (DMA) is both a symptom and a central sensitization sign, yet no standardized method for quantifying the DMA area has been reported. This study aimed to establish psychometric properties for Quantitative Dynamic Allodynography (QDA), a newly developed protocol measuring the DMA area as a percentage of the body surface. Methods: Seventy-eight patients aged 18–65 diagnosed with chronic complex regional pain syndrome (CRPS) participated in this study. Test–retest reliability was conducted twice, one week apart (N = 20), and inter-rater (N = 3) reliability was conducted on 10 participants. Disease severity (CRPS Severity Score, CSS), pain intensity (VAS), and quality of life (SF-36) measures were utilized to test construct validity. Results: High inter-rater reliability (intraclass correlation coefficient (ICC) = 0.96, p < 0.001) and test–retest reliability (r = 0.98, p < 0.001) were found. Furthermore, the QDA score was found to be correlated with the CSS (r = 0.47, p < 0.001), VAS (r = 0.37, p < 0.001), and the SF-36 physical health total (r = −0.47, p < 0.001) scores. Conclusion: The QDA is the first developed reliable and valid protocol for measuring DMA in a clinical setting and may be used as a diagnostic and prognostic measure in clinics and in research, advancing the pain precision medicine approach.

Complex regional pain syndrome (CRPS) taxonomy has been updated with reported subtypes and is defined as primary pain alongside other chronic limb pain (CLP) conditions. We aimed at identifying CRPS clinical phenotypes that distinguish CRPS from other CLP conditions. Cluster analysis was carried out to classify 61 chronic CRPS and 31 CLP patients based on evoked pain (intensity of hyperalgesia and dynamic allodynia, allodynia area, and after-sensation) and psychological (depression, kinesiophobia, mental distress, and depersonalization) measures. Pro-inflammatory cytokine IL-6 and TNF-α serum levels were measured. Three cluster groups were created: ‘CRPS’ (78.7% CRPS; 6.5% CLP); ‘CLP’ (64.5% CLP; 4.9% CRPS), and ‘Mixed’ (16.4% CRPS; 29% CLP). The groups differed in all measures, predominantly in allodynia and hyperalgesia (p < 0.001, η² > 0.58). ‘CRPS’ demonstrated higher psychological and evoked pain measures vs. ‘CLP’. ‘Mixed’ exhibited similarities to ‘CRPS’ in psychological profile and to ‘CLP’ in evoked pain measures. The serum level of TNF-αwas higher in the ‘CRPS’ vs. ‘CLP’ (p < 0.001) groups. In conclusion, pain hypersensitivity reflecting nociplastic pain mechanisms and psychological state measures created different clinical phenotypes of CRPS and possible CRPS subtypes, which distinguishes them from other CLP conditions, with the pro-inflammatory TNF-α cytokine as an additional potential biomarker.

Background: Aerobic exercise reduces pain sensitivity, a phenomenon known as exercise-induced hypoalgesia (EIH); however, little is known about EIH when the upper limbs are aerobically exercised. This study aimed to test the acute effect of a single aerobic upper-limb exercise on pain threshold and pain intensity in healthy participants, with two different protocols for controlling intensity. Methods: 31 participants performed two 20 min exercise sessions a week apart. In each session, the intensity was controlled by a target heart rate (THR) of 60% of heart rate reserve or by a rate of perceived exertion (RPE) of 7/10 on the Borg scale. Pain threshold for pressure (PPT) heat (HPT) and pain intensity in response to Tonic Heat Pain (THP) were measured pre- and post-exercise. To examine the effect of exercise in each protocol on pain sensitivity, rmANOVA was conducted. Results: Pain sensitivity remained unchanged following arm exercise in both protocols (PPT, p = 0.67; HPT, p = 0.56; and THP p = 0.39). Higher HR in the THR protocol was demonstrated with a significant protocol X time, interaction effect (F₍₃₎ = 11.194 p < 0.004). Conclusions: Moderate–high-intensity upper-limb aerobic exercise did not affect pain sensitivity in healthy individuals. Exercise intensity when controlled by THR showed a higher mean heart rate compared to exercise intensity based on RPE.

MRI-based resting-state functional connectivity (rsFC) has been shown to predict response to pharmacological and non-pharmacological treatments for chronic pain, but not yet for motor cortex transcranial magnetic stimulation (M1-rTMS). Twenty-seven fibromyalgia syndrome (FMS) patients participated in this double-blind, crossover, and sham-controlled study. Ten daily treatments of 10 Hz M1-rTMS were given over 2 weeks. Before treatment series, patients underwent resting-state fMRI and clinical pain evaluation. Significant pain reduction occurred following active, but not sham, M1-rTMS. The following rsFC patterns predicted reductions in clinical pain intensity after the active treatment: weaker rsFC of the default-mode network with the middle frontal gyrus (r = 0.76, p < 0.001), the executive control network with the rostro-medial prefrontal cortex (r = 0.80, p < 0.001), the thalamus with the middle frontal gyrus (r = 0.82, p < 0.001), and the pregenual anterior cingulate cortex with the inferior parietal lobule (r = 0.79, p < 0.001); and stronger rsFC of the anterior insula with the angular gyrus (r = − 0.81, p < 0.001). The above regions process the attentional and emotional aspects of pain intensity; serve as components of the resting-state networks; are modulated by rTMS; and are altered in FMS. Therefore, we suggest that in FMS, the weaker pre-existing interplay between pain-related brain regions and networks, the larger the pain relief resulting from M1-rTMS.