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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 to HC in response to pinprick and heat stimulation of the affected (p.05). Habituation of pinprick-induced SSRs was reduced in CRPS compared to HC in both the affected (p=.018) and slightly in the control area (p=.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 hyperaxcitability). 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.

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 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.

Background and purpose: The timing of decision-making for a surgical intervention in patients with mild degenerative cervical myelopathy (DCM) is challenging. Spinal cord motion phase contrast MRI (PC-MRI) measurements can reveal the extent of dynamic mechanical strain on the spinal cord to potentially identify high-risk patients. This study aims to determine the comparability of axial and sagittal PC-MRI measurements of spinal cord motion with the prospect of improving the clinical workup.Methods: Sixty-four DCM patients underwent a PC-MRI scan assessing spinal cord motion. The agreement of axial and sagittal measurements was determined by means of intraclass correlation coefficients (ICCs) and Bland-Altman analyses.Results: The comparability of axial and sagittal PC-MRI measurements was good to excellent at all cervical levels (ICCs motion amplitude: .810-.940; p < .001). Significant differences between axial and sagittal amplitude values could be found at segments C3 and C4, while its magnitude was low (C3: 0.07 ± 0.19 cm/second; C4: -0.12 ± 0.30 cm/second). Bland-Altman analysis showed a good agreement between axial and sagittal PC-MRI scans (coefficients of repeatability: minimum -0.23 cm/second at C2; maximum -0.58 cm/second at C4). Subgroup analysis regarding anatomic conditions (stenotic vs. nonstenotic segments) and different velocity encoding (2 vs. 3 cm/second) showed comparable results.Conclusions: This study demonstrates good comparability between axial and sagittal spinal cord motion measurements in DCM patients. To this end, axial and sagittal PC-MRI are both accurate and sensitive in detecting pathologic cord motion. Therefore, such measures could identify high-risk patients and improve clinical decision-making (ie, timing of decompression).

BACKGROUND Deficient endogenous pain modulation and increased nociceptive excitability are key features of central sensitization and can be assessed in humans by conditioned pain modulation (CPM, anti-nociceptive) and temporal summation of pain (TSP, pro-nociceptive), respectively. This study aimed to investigate these measures as proxies for central sensitization in subjects with chronic neuropathic pain (NP) after spinal cord injury (SCI). METHODS In paraplegic subjects with NP (SCI-NP; n=17) and healthy controls (HC; n=17), parallel and sequential sham-controlled CPM paradigms were performed using pressure pain threshold at the hand, i.e., above lesion level, as test stimulus. The conditioning stimulus was a noxious cold (verum) or lukewarm water bath (sham) applied contralaterally. Regarding pro-nociceptive mechanisms, a TSP protocol with individually-adjusted pressure pain stimuli at the thenar eminence was employed. CPM and TSP magnitudes were related to intensity and spatial extent of spontaneous NP. RESULTS Neither the parallel nor sequential sham-controlled CPM paradigm showed any significant inhibition of above-level pressure pain thresholds for SCI-NP or HC. Accordingly, no group difference in CPM capacity was found, however, subjects with more intense spontaneous NP showed lower inhibitory CPM capacity. TSP was observed for both groups, but was not enhanced in SCI-NP. CONCLUSIONS Our results do not support altered above-level anti- or pro-nociceptive mechanisms in SCI-NP compared to HC, however, they also highlight the relevance of spontaneous NP intensity with regard to the capacity of endogenous pain modulation in SCI subjects.

BACKGROUND Central sensitization is considered a key mechanism underlying neuropathic pain (NP) after spinal cord injury (SCI). METHODS Two novel proxies for central sensitization were investigated in thoracic SCI subjects with (SCI-NP) and without NP (SCI-nonNP) compared to healthy controls (HC). Specifically, temporal summation of pain (TSP) was investigated by examining pain ratings during a 2-min tonic heat application to the volar forearm. Additionally, palmar heat-induced sympathetic skin responses (SSR) were recorded in order to reveal changes in pain-autonomic interaction above the lesion level. Pain extent was assessed as the percentage of body area and the number of body regions being affected by NP. RESULTS Enhanced TSP was observed in SCI-NP (+66%) compared to SCI-nonNP (-75%, p=0.009) and HC (-59%, p=0.021). In contrast, no group differences were found (p=0.685) for SSR habituation. However, pain extent in SCI-NP was positively correlated with deficient SSR habituation (body area: r=0.561, p=0.024; body regions: r=0.564, p=0.023). CONCLUSIONS These results support the value of TSP and heat-induced SSRs as proxies for central sensitization in widespread neuropathic pain syndromes after SCI. Measures of pain-autonomic interaction emerged as a promising tool for the objective investigation of sensitized neuronal states in chronic pain conditions.