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.

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.

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.

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.

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.

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.