Priming of the autonomic nervous system after an experimental human pain model.

Modulated autonomic responses to noxious stimulation have been reported in experimental and clinical pain. These effects are likely mediated by nociceptive sensitization, but may also, more simply reflect increased stimulus-associated arousal. To disentangle between sensitization- and arousal-mediated effects on autonomic responses to noxious input, we recorded sympathetic skin responses (SSRs) in response to 10 pinprick and heat stimuli before (PRE) and after (POST) an experimental heat pain model to induce secondary hyperalgesia (EXP) and a control model (CTRL) in 20 healthy females. Pinprick and heat stimuli were individually adapted for pain perception (4/10) across all assessments. Heart rate, heart rate variability, and skin conductance level (SCL) were assessed before, during, and after the experimental heat pain model. Both pinprick- and heat-induced SSRs habituated from PRE to POST in CTRL, but not EXP (P = 0.033). Background SCL (during stimuli application) was heightened in EXP compared with CTRL condition during pinprick and heat stimuli (P = 0.009). Our findings indicate that enhanced SSRs after an experimental pain model are neither fully related to subjective pain, as SSRs dissociated from perceptual responses, nor to nociceptive sensitization, as SSRs were enhanced for both modalities. Our findings can, however, be explained by priming of the autonomic nervous system during the experimental pain model, which makes the autonomic nervous system more susceptible to noxious input. Taken together, autonomic readouts have the potential to objectively assess not only nociceptive sensitization but also priming of the autonomic nervous system, which may be involved in the generation of distinct clinical pain phenotypes.NEW & NOTEWORTHY The facilitation of pain-induced sympathetic skin responses observed after experimentally induced central sensitization is unspecific to the stimulation modality and thereby unlikely solely driven by nociceptive sensitization. In addition, these enhanced pain-induced autonomic responses are also not related to higher stimulus-associated arousal, but rather a general priming of the autonomic nervous system. Hence, autonomic readouts may be able to detect generalized hyperexcitability in chronic pain, beyond the nociceptive system, which may contribute to clinical pain phenotypes.

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.

Descending pain modulatory efficiency in healthy subjects is related to structure and resting connectivity of brain regions.

The descending pain modulatory system in humans is commonly investigated using conditioned pain modulation (CPM). Whilst variability in CPM efficiency, i.e., inhibition and facilitation, is normal in healthy subjects, exploring the inter-relationship between brain structure, resting-state functional connectivity (rsFC) and CPM readouts will provide greater insight into the underlying CPM efficiency seen in healthy individuals. Thus, this study combined CPM testing, voxel-based morphometry (VBM) and rsFC to identify the neural correlates of CPM in a cohort of healthy subjects (n =40), displaying pain inhibition (n = 29), facilitation (n = 10) and no CPM effect (n = 1). Clusters identified in the VBM analysis were implemented in the rsFC analysis alongside key constituents of the endogenous pain modulatory system. Greater pain inhibition was related to higher volume of left frontal cortices and stronger rsFC between the motor cortex and periaqueductal grey. Conversely, weaker pain inhibition was related to higher volume of the right frontal cortex - coupled with stronger rsFC to the primary somatosensory cortex, and rsFC between the amygdala and posterior insula. Overall, healthy subjects showed higher volume and stronger rsFC of brain regions involved with descending modulation, while the lateral and medial pain systems were related to greater pain inhibition and facilitation during CPM, respectively. These findings reveal structural alignments and functional interactions between supraspinal areas involved in CPM efficiency. Ultimately understanding these underlying variations and how they may become affected in chronic pain conditions, will advance a more targeted subgrouping in pain patients for future cross-sectional studies investigating endogenous pain modulation.

Single-trial averaging improves the physiological interpretation of contact heat evoked potentials.

Laser and contact heat evoked potentials (LEPs and CHEPs, respectively) provide an objective measure of pathways and processes involved in nociception. The majority of studies analyzing LEP or CHEP outcomes have done so based on conventional, across-trial averaging. With this approach, evoked potential components are potentially confounded by latency jitter and ignore relevant information contained within single trials. The current study addressed the advantage of analyzing nociceptive evoked potentials based on responses to noxious stimulations within each individual trial. Single-trial and conventional averaging were applied to data previously collected in 90 healthy subjects from 3 stimulation locations on the upper limb. The primary analysis focused on relationships between single and across-trial averaged CHEP outcomes (i.e., N2P2 amplitude and N2 and P2 latencies) and subject characteristics (i.e., age, sex, height, and rating of perceived intensity), which were examined by way of linear mixed model analysis. Single-trial averaging lead to larger N2P2 amplitudes and longer N2 and P2 latencies. Age and ratings of perceived intensity were the only subject level characteristics associated with CHEPs outcomes that significantly interacted with the method of analysis (conventional vs single-trial averaging). The strength of relationships for age and ratings of perceived intensity, measured by linear fit, were increased for single-trial compared to conventional across-trial averaged CHEP outcomes. By accounting for latency jitter, single-trial averaging improved the associations between CHEPs and physiological outcomes and should be incorporated as a standard analytical technique in future studies.

Supraspinal nociceptive networks in neuropathic pain after spinal cord injury.

Neuropathic pain following spinal cord injury involves plastic changes along the whole neuroaxis. Current neuroimaging studies have identified grey matter volume (GMV) and resting-state functional connectivity changes of pain processing regions related to neuropathic pain intensity in spinal cord injury subjects. However, the relationship between the underlying neural processes and pain extent, a complementary characteristic of neuropathic pain, is unknown. We therefore aimed to reveal the neural markers of widespread neuropathic pain in spinal cord injury subjects and hypothesized that those with greater pain extent will show higher GMV and stronger connectivity within pain related regions. Thus, 29 chronic paraplegic subjects and 25 healthy controls underwent clinical and electrophysiological examinations combined with neuroimaging. Paraplegics were demarcated based on neuropathic pain and were thoroughly matched demographically. Our findings indicate that (a) spinal cord injury subjects with neuropathic pain display stronger connectivity between prefrontal cortices and regions involved with sensory integration and multimodal processing, (b) greater neuropathic pain extent, is associated with stronger connectivity between the posterior insular cortex and thalamic sub-regions which partake in the lateral pain system and (c) greater intensity of neuropathic pain is related to stronger connectivity of regions involved with multimodal integration and the affective-motivational component of pain. Overall, this study provides neuroimaging evidence that the pain phenotype of spinal cord injury subjects is related to the underlying function of their resting brain.

Feedback improves compliance of pressure relief activities in wheelchair users with spinal cord injury.

STUDY DESIGN: Prospective cross-sectional pre-post pilot study. OBJECTIVES: This pilot study aimed to evaluate the potential for improving pressure relief behaviour in wheelchair users with spinal cord injury (SCI) using a novel feedback system based on textile pressure sensor technology. SETTING: In- and out-patient clinic of the Spinal Cord Injury Center, Balgrist University Hospital, Zurich, Switzerland. METHODS: Nine wheelchair users with SCI (3 females, 50 ± 12 years of age, 2 tetra- and 7 paraplegics) were equipped with a feedback system (sensomativewheelchair) for three continuous weeks. The system consists of a textile pressure mat and a mobile smartphone application that reminds participants to perform missing pressure reliefs during regular and unobserved wheelchair usage in a customized manner. Pressure reliefs were detected using a subject-specific random forest classifier. Improvements of relief quality, duration and frequency were analysed by comparing week 1 (baseline) with no feedback, i.e., only pressure data recorded, against week 2 (with feedback). Carry-over effects of improved relief behaviour were studied in week 3 (no feedback, pressure data only recorded). RESULTS: All participants increased their relief frequency and performed in median 82% (IQRs: 55%-99%) of the required reliefs while using the feedback system, whereas the median relief frequency was only 11% (IQRs: 10%-31%) during the baseline condition. Every participant who did not perform reliefs of sufficient duration (based on the recommendations of the therapist) during week 1 showed a significant improvement while using the feedback system. CONCLUSION: Subject-specific feedback using the novel feedback system may have the potential for improving the regularity of an individual's relief activities, and may ultimately be an instrument for reducing the risk of developing pressure ulcers.

Assessment of neuropathic pain after spinal cord injury using quantitative pain drawings.

STUDY DESIGN: Clinimetric cross-sectional cohort study in adults with paraplegic spinal cord injury (SCI) and neuropathic pain (NP). OBJECTIVE: To assess the reliability of standardized quantitative pain drawings in patients with NP following SCI. SETTING: Hospital-based research facility at the Spinal Cord Injury Center, Balgrist University Hospital, Zurich, Switzerland. METHODS: Twenty individuals with chronic thoracic spinal cord injury and neuropathic pain were recruited from a national and local SCI registry. A thorough clinical examination and pain assessments were performed. Pain drawings were acquired at subsequent timepoints, 13 days (IQR 7.8-14.8) apart, in order to assess test-retest reliability. RESULTS: The average extent [%] and intensity [NRS 0-10] of spontaneous NP were 11.3% (IQR 4.9-35.8) and 5 (IQR 3-7), respectively. Pain extent showed excellent inter-session reliability (intraclass correlation coefficient 0.96). Sensory loss quantified by light touch and pinprick sensation was associated with larger pain extent (rpinprick = -0.47, p = 0.04; rlight touch = -0.64, p < 0.01). CONCLUSION: Assessing pain extent using quantitative pain drawings is readily feasible and reliable in human SCI. Relating information of sensory deficits to the presence of pain may provide distinct insights into the interaction of sensory deafferentation and the development of neuropathic pain after SCI.

Construct validation of the leisure time physical activity questionnaire for people with SCI (LTPAQ-SCI).

STUDY DESIGN: Cross-sectional construct validation study. OBJECTIVES: To test the construct validity of the Leisure Time Physical Activity Questionnaire for People with Spinal Cord Injury (LTPAQ-SCI) by examining associations between the scale responses and cardiorespiratory fitness (CRF) in a sample of adults living with spinal cord injury (SCI). SETTING: Three university-based laboratories in Canada. METHODS: Participants were 39 adults (74% male; M age: 42 ± 11 years) with SCI who completed the LTPAQ-SCI and a graded exercise test to volitional exhaustion using an arm-crank ergometer. One-tailed Pearson's correlation coefficients were computed to examine the association between the LTPAQ-SCI measures of mild-, moderate-, heavy-intensity and total minutes per week of LTPA and CRF (peak volume of oxygen consumption [V̇O2peak] and peak power output [POpeak]). RESULTS: Minutes per week of mild-, moderate- and heavy-intensity LTPA and total LTPA were all positively correlated with V̇O2peak. The correlation between minutes per week of mild intensity LTPA and V̇O2peak was small-medium (r = 0.231, p = 0.079) while all other correlations were medium-large (rs ranged from 0.276 to 0.443, ps < 0.05). Correlations between the LTPAQ-SCI variables and POpeak were also positive but small (rs ranged from 0.087 to 0.193, ps > 0.05), except for a medium-sized correlation between heavy-intensity LTPA and POpeak (r = 0.294, p = 0.035). CONCLUSIONS: People with SCI who report higher levels of LTPA on the LTPAQ-SCI also demonstrate greater levels of CRF, with stronger associations between moderate- and heavy-intensity LTPA and CRF than between mild-intensity LTPA and CRF. These results provide further support for the construct validity of the LTPAQ-SCI as a measure of LTPA among people with SCI.

Pinprick Evoked Potentials-Reliable Acquisition in Healthy Human Volunteers.

OBJECTIVE: Pinprick evoked potentials (PEPs) represent a novel tool to assess the functional integrity of mechano-nociceptive pathways with a potential toward objectifying sensory deficits and gain seen in neurological disorders. The aim of the present study was to evaluate the feasibility and reliability of PEPs with respect to age, stimulation site, and skin type. METHODS: Electroencephalographic responses evoked by two pinprick stimulation intensities (128 mN and 256 mN) applied at three sites (hand dorsum, palmar digit II, and foot dorsum) were recorded in 30 healthy individuals. Test-retest reliability was performed for the vertex negative-positive complex amplitudes, N-latencies, and pain ratings evoked by the 256mN stimulation intensity. RESULTS: Feasibility of PEP acquisition was demonstrated across age groups, with higher proportions of evoked potentials (>85%) for the 256mN stimulation intensity. Reliability analyses, that is, Bland-Altman and intraclass correlation coefficients, revealed poor to excellent reliability upon retest depending on the stimulation sites. CONCLUSIONS: This study highlights the reliability of PEP acquisition from cervical and lumbar segments across clinically representative age groups. Future methodological improvements might further strengthen PEP reliability in order to complement clinical neurophysiology of sensory nerve fibers by a more specific assessment of mechano-nociceptive pathways. Beyond looking at sensory deficits, PEPs may also become applicable to revealing signs of central sensitization, complementing the clinical assessment of mechanical hyperalgesia.

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.

Associations between arterial stiffness and blood pressure fluctuations after spinal cord injury.

STUDY DESIGN: Cross-sectional. OBJECTIVE: To examine the relationship between arterial stiffness and daily fluctuations in blood pressure (BP) owing to hypotensive events and autonomic dysreflexia (AD) in individuals with a T6 and above spinal cord injury (SCI). SETTING: University-based laboratory in Vancouver, BC, Canada. METHODS: Twenty-six individuals (73% male; 43 (11) years) with a chronic (> 1 year post SCI), traumatic, motor-complete SCI with a neurological level of injury of C4-T6 participated in this study. Arterial stiffness was assessed using carotid-to-femoral pulse wave velocity (cfPWV). BP was measured over a 24-hr period using ambulatory BP monitoring. AD was defined as an increase in systolic BP > 20 mmHg above baseline BP. Hypotensive events were defined as a decrease in systolic BP ≥ 20 mmHg and/or diastolic BP ≥ 10 mmHg below baseline. The severity and frequency of these events were quantified and Pearson and Spearman's correlations between them and cfPWV were performed. RESULTS: AD severity and frequency were not were correlated with cfPWV. For hypotensive events, both the frequency (r = 0.412, P = 0.04) and severity (Δsystolic BP; r = -0.425, P = 0.03) of these events were correlated with cfPWV. The combined total of AD and hypotensive events (9 (5) events/day) was also correlated with cfPWV (r = 0.480, P = 0.01). CONCLUSIONS: Hypotensive events, and the combined frequency of both hypo- and hypertensive events within a 24-hr period are associated with increased arterial stiffness in individuals with T6 and above SCI, suggesting BP instability may play a role in arterial stiffening post SCI.

Application of electrophysiological measures in spinal cord injury clinical trials: a narrative review.

STUDY DESIGN: Narrative review. OBJECTIVES: To discuss how electrophysiology may contribute to future clinical trials in spinal cord injury (SCI) in terms of: (1) improvement of SCI diagnosis, patient stratification and determination of exclusion criteria; (2) the assessment of adverse events; and (3) detection of therapeutic effects following an intervention. METHODS: An international expert panel for electrophysiological measures in SCI searched and discussed the literature focused on the topic. RESULTS: Electrophysiology represents a valid method to detect, track, and quantify readouts of nerve functions including signal conduction, e.g., evoked potentials testing long spinal tracts, and neural processing, e.g., reflex testing. Furthermore, electrophysiological measures can predict functional outcomes and thereby guide rehabilitation programs and therapeutic interventions for clinical studies. CONCLUSION: Objective and quantitative measures of sensory, motor, and autonomic function based on electrophysiological techniques are promising tools to inform and improve future SCI trials. Complementing clinical outcome measures, electrophysiological recordings can improve the SCI diagnosis and patient stratification, as well as the detection of both beneficial and adverse events. Specifically composed electrophysiological measures can be used to characterize the topography and completeness of SCI and reveal neuronal integrity below the lesion, a prerequisite for the success of any interventional trial. Further validation of electrophysiological tools with regard to their validity, reliability, and sensitivity are needed in order to become routinely applied in clinical SCI trials.

Cold pressor test in spinal cord injury-revisited.

STUDY DESIGN: Systematic review. OBJECTIVES: A spinal cord injury (SCI) commonly results in alterations of cardiovascular physiology. In order to investigate such alterations, the cold pressor test (CPT) has been used as an established challenge test. This review summarizes the basic physiology underlying a CPT, discusses potential mechanisms responsible for abnormal pressor responses following SCI, and highlights the utility of CPT in the SCI population. SETTING: Canada and Switzerland. METHODS: We have completed a comprehensive review of studies that have investigated the effect of foot or hand CPT on hemodynamic indices in individuals with SCI. RESULTS: Depending on the level of spinal cord lesion and the location of cold application, i.e., above or below the lesion, mean arterial pressure typically increases (ranging between 4 and 23 mmHg), while heart rate responses demonstrated either a decrease or an increase (ranging between -4 and 24 bpm) during CPT. The increase in blood pressure during foot CPT in high-level lesions might not necessarily be attributed to a physiological CPT response as seen in able-bodied individuals, but rather due to a reflexic sympathetic discharge below the level of lesion, known as autonomic dysreflexia. CONCLUSIONS: Further investigations in a wider range of individuals with SCI including incomplete injuries might be helpful to examine the ability of CPT assessing the integrity of the autonomic nervous system following SCI. Furthermore, additional autonomic tests are needed to emphasize the integrity of autonomic pathways and to account for the complexity of the autonomic nervous system.

How reliable are sympathetic skin responses in subjects with spinal cord injury?

OBJECTIVE: To determine the test-retest reliability of sympathetic skin responses (SSR) in individuals with spinal cord injury (SCI). METHODS: Fourteen men and four women with traumatic SCI (age: 44 ± 18 years; C2-T11; AIS A-D; 1-383 months post-injury) participated in two electrophysiological testing sessions separated by an average of 1 day. During each session, sudomotor function was tested supine by recordings of SSRs in both hands and feet. Two stimulation approaches were chosen: median nerve stimulation and a deep breath maneuver. SSR recordings were analyzed as SSR scores representing the presence or absence of responses. In addition, SSR amplitude and latencies were calculated. Test-retest reliability for the SSR score was calculated by the intraclass correlation coefficient (ICC) and its confidence interval. Coefficient of variation (CV) was calculated for SSR amplitudes and latencies. RESULTS: SSR score to median nerve stimulation demonstrated 'almost perfect' reliability with ICCs of 0.97 and 0.96, for both hands and feet, respectively. The SSR score to deep breath maneuver was slightly lower, such as 0.89 and 0.74 for hands and feet. The CV of SSR amplitudes to median nerve stimulation was 48 and 18% for hands and feet, respectively, and 7 and 12% for the latency. INTERPRETATION: The qualitative interpretation of SSR by its presence or absence is a reliable way to assess sudomotor function in individuals with SCI. Although methodical procedures try to standardize SSR testings, quantitative SSR outcomes (amplitude, latency) are still highly variable.

Physical exercise improves arterial stiffness after spinal cord injury.

OBJECTIVE/BACKGROUND: Aortic pulse wave velocity (PWV), the gold-standard assessment of central arterial stiffness, has prognostic value for cardiovascular disease risk in able-bodied individuals. The aim of this study was to compare aortic PWV in athletes and non-athletes with spinal cord injury (SCI). DESIGN: Cross-sectional comparison. METHODS: Aortic PWV was assessed in 20 individuals with motor-complete, chronic SCI (C2-T5; 18 ± 8 years post-injury) using applanation tonometry at the carotid and femoral arterial sites. Ten elite hand-cyclists were matched for sex to 10 non-athletes; age and time since injury were comparable between the groups. Heart rate and discrete brachial blood pressure measurements were collected throughout testing. OUTCOME MEASURES: Aortic PWV, blood pressure, heart rate. RESULTS: Aortic PWV was significantly lower in athletes vs. non-athletes (6.9 ± 1.0 vs. 8.7 ± 2.5 m/second, P = 0.044). There were no significant between-group differences in resting supine mean arterial blood pressure (91 ± 19 vs. 81 ± 10 mmHg) and heart rate (60 ± 10 vs. 58 ± 6 b.p.m.). CONCLUSION: Athletes with SCI exhibited improved central arterial stiffness compared to non-athletes, which is in agreement with the previous able-bodied literature. This finding implies that chronic exercise training may improve arterial health and potentially lower cardiovascular disease risk in the SCI population.

Unraveling the physiological and psychosocial signatures of pain by machine learning.

BACKGROUND: Pain is a complex subjective experience, strongly impacting health and quality of life. Despite many attempts to find effective solutions, present treatments are generic, often unsuccessful, and present significant side effects. Designing individualized therapies requires understanding of multidimensional pain experience, considering physical and emotional aspects. Current clinical pain assessments, relying on subjective one-dimensional numeric self-reports, fail to capture this complexity. METHODS: To this aim, we exploited machine learning to disentangle physiological and psychosocial components shaping the pain experience. Clinical, psychosocial, and physiological data were collected from 118 chronic pain and healthy participants undergoing 40 pain trials (4,697 trials). FINDINGS: To understand the objective response to nociception, we classified pain from the physiological signals (accuracy >0.87), extracting the most important biomarkers. Then, using multilevel mixed-effects models, we predicted the reported pain, quantifying the mismatch between subjective level and measured physiological response. From these models, we introduced two metrics: TIP (subjective index of pain) and Φ (physiological index). These represent possible added value in the clinical process, capturing psychosocial and physiological pain dimensions, respectively. Patients with high TIP are characterized by frequent sick leave from work and increased clinical depression and anxiety, factors associated with long-term disability and poor recovery, and are indicated for alternative treatments, such as psychological ones. By contrast, patients with high Φ show strong nociceptive pain components and could benefit more from pharmacotherapy. CONCLUSIONS: TIP and Φ, explaining the multidimensionality of pain, might provide a new tool potentially leading to targeted treatments, thereby reducing the costs of inefficient generic therapies. FUNDING: RESC-PainSense, SNSF-MOVE-IT197271.

Contact-Heat Evoked Potentials: Insights into Pain Processing in CRPS Type I.

Purpose: The pathophysiological mechanisms underlying the development of chronic pain in complex regional pain syndrome (CRPS) are diverse and involve both peripheral and central changes in pain processing, such as sensitization of the nociceptive system. The aim of this study was to objectively distinguish the specific changes occurring at both peripheral and central levels in nociceptive processing in individuals with chronic CRPS type I. Patients and Methods: Nineteen individuals with chronic CRPS type I and 16 age- and sex-matched healthy controls (HC) were recruited. All individuals underwent a clinical examination and pain assessment in the most painful limb, the contralateral limb, and a pain-free control area to distinguish between peripheral and central mechanisms. Contact-heat evoked potentials (CHEPs) were recorded after heat stimulation of the three different areas and amplitudes and latencies were analyzed. Additionally, quantitative sensory testing (QST) was performed in all three areas. Results: Compared to HC, CHEP amplitudes in CRPS were only increased after stimulation of the painful area (p=0.025), while no increases were observed for the pain-free control area (p=0.14). None of the CHEP latencies were different between the two cohorts (all p>0.23). Furthermore, individuals with CRPS showed higher pain ratings after stimulation of the painful limb compared to their contralateral limb (p=0.013). Lastly, compared to HC, mechanical (p=0.012) and thermal (p=0.046) sensitivity was higher in the painful area of the CRPS cohort. Conclusion: This study provides neurophysiological evidence supporting an intact thermo-nociceptive pathway with signs of peripheral sensitization, such as hyperexcitable primary afferent nociceptors, in individuals with CRPS type I. This is further supported by the observation of mechanical and thermal gain of sensation only in the painful limb. Additionally, the increased CHEP amplitudes might be related to fear-induced alterations of nociceptive processing.

Novel neurophysiological evidence for preserved pain habituation across chronic pain conditions.

OBJECTIVE: The present study aimed to investigate whether subjective and objective measures of pain habituation can be used as potential markers for central sensitization across various chronic pain patients. METHODS: Two blocks of contact-heat stimuli were applied to a non-painful area in 93 chronic pain patients (low back pain, neuropathic pain, and complex regional pain syndrome) and 60 healthy controls (HC). Habituation of pain ratings, contact-heat evoked potentials (CHEP), and sympathetic skin responses (SSR) was measured. RESULTS: There was no significant difference in any measure of pain habituation between patients and HC. Even patients with apparent clinical signs of central sensitization showed no reduced pain habituation. However, prolonged baseline CHEP and SSR latencies (stimulation block 1) were found in patients compared to HC (CHEP: Δ-latency = 23 ms, p = 0.012; SSR: Δ-latency = 100 ms, p = 0.022). CONCLUSION: Given the performed multimodal neurophysiological testing protocol, we provide evidence indicating that pain habituation may be preserved in patients with chronic pain and thereby be of limited use as a sensitive marker for central sensitization. These results are discussed within the framework of the complex interactions between pro- and antinociceptive mechanism as well as methodological issues. The prolonged latencies of CHEP and SSR after stimulation in non-painful areas may indicate subclinical changes in the integrity of thermo-nociceptive afferents, or a shift towards antinociceptive activity. This shift could potentially affect the relay of ascending signals. SIGNIFICANCE: Our findings challenge the prevailing views in the literature and may encourage further investigations into the peripheral and central components of pain habituation, using advanced multimodal neurophysiological techniques.

Indication for spinal sensitization in chronic low back pain: mechanical hyperalgesia adjacent to but not within the most painful body area.

Introduction: In 85% of patients with chronic low back pain (CLBP), no specific pathoanatomical cause can be identified. Besides primary peripheral drivers within the lower back, spinal or supraspinal sensitization processes might contribute to the patients' pain. Objectives: The present study conceptualized the most painful area (MP) of patients with nonspecific CLBP as primarily affected area and assessed signs of peripheral, spinal, and supraspinal sensitization using quantitative sensory testing (QST) in MP, a pain-free area adjacent to MP (AD), and a remote, pain-free control area (CON). Methods: Fifty-nine patients with CLBP (51 years, SD = 16.6, 22 female patients) and 35 pain-free control participants individually matched for age, sex, and testing areas (49 years, SD = 17.5, 19 female participants) underwent a full QST protocol in MP and a reduced QST protocol assessing sensory gain in AD and CON. Quantitative sensory testing measures, except paradoxical heat sensations and dynamic mechanical allodynia (DMA), were Z-transformed to the matched control participants and tested for significance using Z-tests (α = 0.001). Paradoxical heat sensations and DMA occurrence were compared between cohorts using Fisher's exact tests (α = 0.05). The same analyses were performed with a high-pain and a low-pain CLBP subsample (50% quantile). Results: Patients showed cold and vibration hypoesthesia in MP (all Ps < 0.001) and mechanical hyperalgesia (P < 0.001) and more frequent DMA (P = 0.044) in AD. The results were mainly driven by the high-pain CLBP subsample. In CON, no sensory alterations were observed. Conclusion: Mechanical hyperalgesia and DMA adjacent to but not within MP, the supposedly primarily affected area, might reflect secondary hyperalgesia originating from spinal sensitization in patients with CLBP.

Potential thresholds of critically increased cardiac-related spinal cord motion in degenerative cervical myelopathy.

Introduction: New diagnostic techniques are a substantial research focus in degenerative cervical myelopathy (DCM). This cross-sectional study determined the significance of cardiac-related spinal cord motion and the extent of spinal stenosis as indicators of mechanical strain on the cord. Methods: Eighty-four DCM patients underwent MRI/clinical assessments and were classified as MRI+ [T2-weighted (T2w) hyperintense lesion in MRI] or MRI- (no T2w-hyperintense lesion). Cord motion (displacement assessed by phase-contrast MRI) and spinal stenosis [adapted spinal canal occupation ratio (aSCOR)] were related to neurological (sensory/motor) and neurophysiological readouts [contact heat evoked potentials (CHEPs)] by receiver operating characteristic (ROC) analysis. Results: MRI+ patients (N = 31; 36.9%) were more impaired compared to MRI- patients (N = 53; 63.1%) based on the modified Japanese Orthopedic Association (mJOA) subscores for upper {MRI+ [median (Interquartile range)]: 4 (4-5); MRI-: 5 (5-5); p < 0.01} and lower extremity [MRI+: 6 (6-7); MRI-: 7 (6-7); p = 0.03] motor dysfunction and the monofilament score [MRI+: 21 (18-23); MRI-: 24 (22-24); p < 0.01]. Both patient groups showed similar extent of cord motion and stenosis. Only in the MRI- group displacement identified patients with pathologic assessments [trunk/lower extremity pin prick score (T/LEPP): AUC = 0.67, p = 0.03; CHEPs: AUC = 0.73, p = 0.01]. Cord motion thresholds: T/LEPP: 1.67 mm (sensitivity 84.6%, specificity 52.5%); CHEPs: 1.96 mm (sensitivity 83.3%, specificity 65.6%). The aSCOR failed to show any relation to the clinical assessments. Discussion: These findings affirm cord motion measurements as a promising additional biomarker to improve the clinical workup and to enable timely surgical treatment particularly in MRI- DCM patients. Clinical trial registration: www.clinicaltrials.gov, NCT02170155.