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.

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.

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.

Sensory phenotypes in complex regional pain syndrome and chronic low back pain-indication of common underlying pathomechanisms.

Introduction: First-line pain treatment is unsatisfactory in more than 50% of chronic pain patients, likely because of the heterogeneity of mechanisms underlying pain chronification. Objectives: This cross-sectional study aimed to better understand pathomechanisms across different chronic pain cohorts, regardless of their diagnoses, by identifying distinct sensory phenotypes through a cluster analysis. Methods: We recruited 81 chronic pain patients and 63 age-matched and sex-matched healthy controls (HC). Two distinct chronic pain cohorts were recruited, ie, complex regional pain syndrome (N = 20) and low back pain (N = 61). Quantitative sensory testing (QST) was performed in the most painful body area to investigate somatosensory changes related to clinical pain. Furthermore, QST was conducted in a pain-free area to identify remote sensory alterations, indicating more widespread changes in somatosensory processing. Results: Two clusters were identified based on the QST measures in the painful area, which did not represent the 2 distinct pain diagnoses but contained patients from both cohorts. Cluster 1 showed increased pain sensitivities in the painful and control area, indicating central sensitization as a potential pathomechanism. Cluster 2 showed a similar sensory profile as HC in both tested areas. Hence, either QST was not sensitive enough and more objective measures are needed to detect sensitization within the nociceptive neuraxis or cluster 2 may not have pain primarily because of sensitization, but other factors such as psychosocial ones are involved. Conclusion: These findings support the notion of shared pathomechanisms irrespective of the pain diagnosis. Conversely, different mechanisms might contribute to the pain of patients with the same diagnosis.

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.

Pain-autonomic measures reveal nociceptive sensitization in complex regional pain syndrome.

BACKGROUND: Allodynia and hyperalgesia are common signs in individuals with complex regional pain syndrome (CRPS), mainly attributed to sensitization of the nociceptive system. Appropriate diagnostic tools for the objective assessment of such hypersensitivities are still lacking, which are essential for the development of mechanism-based treatment strategies. OBJECTIVES: This study investigated the use of pain-autonomic readouts to objectively detect sensitization processes in CRPS. METHODS: Twenty individuals with chronic CRPS were recruited for the study alongside 16 age- and sex-matched healthy controls (HC). All individuals underwent quantitative sensory testing and neurophysiological assessments. Sympathetic skin responses (SSRs) were recorded in response to 15 pinprick and 15 noxious heat stimuli of the affected (CRPS hand/foot) and a control area (contralateral shoulder/hand). RESULTS: Individuals with CRPS showed increased mechanical pain sensitivity and increased SSR amplitudes compared with HC in response to pinprick and heat stimulation of the affected (p < 0.001), but not in the control area (p > 0.05). Habituation of pinprick-induced SSRs was reduced in CRPS compared to HC in both the affected (p = 0.018) and slightly in the control area (p = 0.048). Habituation of heat-induced SSR was reduced in CRPS in the affected (p = 0.008), but not the control area (p = 0.053). CONCLUSIONS: This is the first study demonstrating clinical evidence that pain-related autonomic responses may represent objective tools to quantify sensitization processes along the nociceptive neuraxis in CRPS (e.g. widespread hyperexcitability). Pain-autonomic readouts could help scrutinize mechanisms underlying the development and maintenance of chronic pain in CRPS and provide valuable metrics to detect mechanism-based treatment responses in clinical trials. SIGNIFICANCE: This study provides clinical evidence that autonomic measures to noxious stimuli can objectively detect sensitization processes along the nociceptive neuraxis in complex regional pain syndrome (CRPS) (e.g. widespread hyperexcitability). Pain-autonomic readouts may represent valuable tools to explore pathophysiological mechanisms in a variety of pain patients and offer novel avenues to help guide mechanism-based therapeutic strategies.

Cold evoked potentials elicited by rapid cooling of the skin in young and elderly healthy individuals.

Cold-evoked potentials (CEPs) constitute a novel electrophysiological tool to assess cold-specific alterations in somatosensory function. As an important step towards the clinical implementation of CEPs as a diagnostic tool, we evaluated the feasibility and reliability of CEPs in response to rapid cooling of the skin (-300 °C/s) and different stimulation sites in young and elderly healthy individuals. Time-locked electroencephalographic responses were recorded from at vertex in fifteen young (20-40 years) and sixteen elderly (50-70 years), individuals in response to 15 rapid cold stimuli (-300 °C/s) applied to the skin of the hand dorsum, palm, and foot dorsum. High CEP proportions were shown for young individuals at all sites (hand dorsum/palm: 100% and foot: 79%) and elderly individuals after stimulation of the hand dorsum (81%) and palm (63%), but not the foot (44%). Depending on the age group and stimulation site, test-retest reliability was "poor" to "substantial" for N2P2 amplitudes and N2 latencies. Rapid cooling of the skin enables the recording of reliable CEPs in young individuals. In elderly individuals, CEP recordings were only robust after stimulation of the hand, but particularly challenging after stimulation of the foot. Further improvements in stimulation paradigms are warranted to introduce CEPs for clinical diagnostics.

Clinical trials and tribulations: lessons from spinal cord injury studies registered on ClinicalTrials.gov.

STUDY DESIGN: Article. OBJECTIVE: ClinicalTrials.gov is an online trial registry that provides public access to information on past, present, and future clinical trials. While increasing transparency in research, the quality of the information provided in trial registrations is highly variable. The objective of this study is to assess key areas of information on ClinicalTrials.gov in interventional trials involving people with spinal cord injuries. SETTING: Interventional trials on ClinicalTrials.gov involving people with spinal cord injuries. METHODS: A subset of data on interventional spinal cord injury trials was downloaded from ClinicalTrials.gov. Reviewers extracted information pertaining to study type, injury etiology, spinal cord injury characteristics, timing, study status, and results. RESULTS: Of the interventional trial registrations reviewed, 62.5%, 58.6%, and 24.3% reported injury level, severity, and etiology, respectively. The timing of intervention relative to injury was reported in 72.8% of registrations. Most trials identified a valid study status (89.2%), but only 23.5% of those completed studies had posted results. CONCLUSIONS: Our review provides a snapshot of interventional clinical trials conducted in the field of spinal cord injury and registered in ClinicalTrials.gov. Areas for improvement were identified with regards to reporting injury characteristics, as well as posting results.

Combined Neurophysiologic and Neuroimaging Approach to Reveal the Structure-Function Paradox in Cervical Myelopathy.

OBJECTIVE: To explore the so-called "structure-function paradox" in individuals with focal spinal lesions by means of tract-specific MRI coupled with multi-modal evoked potentials and quantitative sensory testing. METHODS: Individuals with signs and symptoms attributable to cervical myelopathy (i.e., no evidence of competing neurological diagnosis) were recruited in the Balgrist University Hospital, Zurich, Switzerland between February 2018 and March 2019. We evaluated the relationship between the extent of structural damage within spinal nociceptive pathways (i.e., dorsal horn, spinothalamic tract, anterior commissure) assessed with atlas-based MRI , and 1) the functional integrity of spinal nociceptive pathways measured with contact heat-, cold-, and pinprick- evoked potentials and 2) clinical somatosensory phenotypes assessed with quantitative sensory testing. RESULTS: Sixteen individuals (mean age 61 years) with either degenerative (N=13) or post-traumatic (N=3) cervical myelopathy participated in the study. Most individuals presented with mild myelopathy (modified Japanese Orthopaedic Association score (mJOA)>15; N=13). 71% of individuals presented with structural damage within spinal nociceptive pathways on MRI. Yet, 50% of these individuals presented with complete functional sparing (i.e., normal contact heat-, cold-, and pinprick- evoked potentials). The extent of structural damage within spinal nociceptive pathways was neither associated with functional integrity of thermal (heat: p=0.57; cold: p=0.49) and mechano-nociceptive pathways (p=0.83) nor with the clinical somatosensory phenotype (heat: p=0.16; cold: p=0.37; mechanical: p=0.73). The amount of structural damage to the spinothalamic tract did not correlate with spinothalamic conduction velocity (p>0.05; rho=-0.11). CONCLUSIONS: Our findings provide neurophysiological evidence to substantiate that structural damage in the spinal cord does not equate to functional somatosensory deficits. This study recognizes the pronounced structure-function paradox in cervical myelopathies and underlines the inevitable need for a multi-modal phenotyping approach to reveal the eloquence of lesions within somatosensory pathways.

A Systematic Review of Safety Reporting in Acute Spinal Cord Injury Clinical Trials: Challenges and Recommendations.

Accurate safety information in published clinical trials guides the assessment of risk-benefit, as well as the design of future clinical trials. Comprehensive reporting of adverse events, toxicity, and discontinuations from acute spinal cord injury clinical trials is an essential step in this process. Here, we sought to assess the degree of "satisfactoriness" of reporting in past clinical trials in spinal cord injury. A review of citations from MEDLINE and EMBASE identified eligible clinical trials in acute (within 30 days) spinal cord injury. English language studies, published between 1980 and 2020, with sensory, motor, or autonomic neurological assessments as the primary outcome measure were eligible for inclusion. Criteria were then established to qualify the safety reporting as satisfactory (i.e., distinguished severe/life-threatening events), partially satisfactory, or unsatisfactory (i.e., only mentioned in general statements, or reported but without distinguishing severe events). A total of 40 trials were included. Satisfactory reporting for clinical adverse events was observed in 30% of trials; partially satisfactory was achieved by 10% of the trials, and the remaining 60% were unsatisfactory. The majority of trials were determined to be unsatisfactory for the reporting of laboratory-defined toxicity (82.5%); only 17.5% were satisfactory. Discontinuations were satisfactorily reported for the majority of trials (80%), with the remaining partially satisfactory (5%) or unsatisfactory (15%). Reporting of safety in clinical trials for acute spinal cord injury is suboptimal. Due to the complexities of acute spinal cord injury (e.g., polytrauma, multiple systems affected), tailored and specific standards for tracking adverse events and safety reporting should be established.

Pain-autonomic interaction: A surrogate marker of central sensitization.

BACKGROUND: Central sensitization represents a key pathophysiological mechanism underlying the development of neuropathic pain, often manifested clinically as mechanical allodynia and hyperalgesia. Adopting a mechanism-based treatment approach relies highly on the ability to assess the presence of central sensitization. The aim of the study was to investigate potential pain-autonomic readouts to operationalize experimentally induced central sensitization in the area of secondary hyperalgesia. METHODS: Pinprick evoked potentials (PEPs) and sympathetic skin responses (SSRs) were recorded in 20 healthy individuals. Three blocks of PEP and SSR recordings were performed before and after heat-induced secondary hyperalgesia. All measurements were also performed before and after a control condition. Multivariate analyses were performed using linear mixed-effect regression models to examine the effect of experimentally induced central sensitization on PEP and SSR parameters (i.e. amplitudes, latencies and habituation) and on pinprick pain ratings. RESULTS: The noxious heat stimulation induced robust mechanical hyperalgesia with a significant increase in PEP and SSR amplitudes (p < 0.001) in the area of secondary hyperalgesia. Furthermore, PEP and SSR habituation were reduced (p < 0.001) after experimentally induced central sensitization. CONCLUSIONS: The findings demonstrate that combined recordings of PEPs and SSRs are sensitive to objectify experimentally induced central sensitization and may have a great potential to reveal its presence in clinical pain conditions. Corroborating current pain phenotyping with pain-autonomic markers has the potential to unravel central sensitization along the nociceptive neuraxis and might provide a framework for mechanistically founded therapies. SIGNIFICANCE: Our findings provide evidence that combined recordings of sympathetic skin responses (SSRs) and pinprick evoked potentials (PEPs) might be able to unmask central sensitization induced through a well-established experimental pain model in healthy individuals. As such, these novel readouts of central sensitization might attain new insights towards complementing clinical pain phenotyping.

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.

New life for an old idea: Assessing tonic heat pain by means of participant controlled temperature.

BACKGROUND: Temporal changes of pain perception to prolonged tonic heat pain are conventionally assessed using a computerized visual analog scale. Such a rating-based approach is, however, prone to floor and ceiling effects, which limit the assessment of temporal changes in perception. Thus, alternative methods that overcome these shortcomings are warranted. NEW METHOD: The aim of this study was to assess the feasibility and reliability of a psychophysical approach, i.e., participant-controlled temperature (PCT), to evaluate ongoing human perception of tonic heat pain. Fifty participants were presented with a 45 °C stimulus on the non-dominant hand, and were instructed to maintain their initial sensation for two minutes via a feedback controller in the dominant hand. A subset of participants (n = 17) performed PCT tonic heat protocols on two different days to determine the test-retest reliability. As participants controlled temperature to maintain a stable pain perception, any adjustments made reflected shifts in their perception of heat. RESULTS: In 33 (71.7%) participants, we observed an initial adaptation (participant increased temperature) followed by temporal summation of pain (participant decreased temperature). Twelve participants (26.1%) showed only adaptation and one (2.2%) only temporal summation. No sex differences were observed, nor did the initial rating of pain have an effect on PCT outcomes. Temporal summation of pain showed moderate to substantial reliability upon retest. CONCLUSIONS: PCT represents can be reliably performed using a contact heat stimulator to measure the temporal summation of pain. The standardized setup and overall good reliability of the outcome measures facilitate a sound implementation into the clinical work-up of patients with pain conditions.

Tracking Changes in Neuropathic Pain After Acute Spinal Cord Injury.

Neuropathic pain represents a primary detrimental outcome of spinal cord injury. A major challenge facing effective management is a lack of surrogate measures to examine the physiology and anatomy of neuropathic pain. To this end, we investigated the relationship between psychophysical responses to tonic heat stimulation and neuropathic pain rating after traumatic spinal cord injury. Subjects provided a continuous rating to 2 min of tonic heat at admission to rehabilitation and again at discharge. Adaptation, temporal summation of pain, and modulation profile (i.e., the relationship between adaptation and temporal summation of pain) were extracted from tonic heat curves for each subject. There was no association between any of the tonic heat outcomes and neuropathic pain severity at admission. The degree of adaptation, the degree of temporal summation of pain, and the modulation profile did not change significantly from admission to discharge. However, changes in modulation profiles between admission and discharge were significantly correlated with changes in neuropathic pain severity (p = 0.027; R 2 = 0.323). The modulation profile may represent an effective measure to track changes in neuropathic pain severity from early to later stages of spinal cord injury.