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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).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, that is, 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 used. CPM and TSP magnitudes were related to intensity and spatial extent of spontaneous NP.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.Our results do not support altered above-level anti- or pro-nociceptive mechanisms in SCI-NP compared with HC; however, they also highlight the relevance of spontaneous NP intensity with regards to the capacity of endogenous pain modulation in SCI subjects.Central sensitization encompasses deficient endogenous pain modulation and increased nociceptive excitability. These two mechanisms can be assessed in humans by conditioned pain modulation and temporal summation of pain, respectively. Our data demonstrates a lack of descending pain inhibition only in subjects with severe neuropathic pain which may hint towards central sensitization at spinal and/or supra-spinal levels. Disentangling the mechanisms of endogenous pain modulation and neuronal hyperexcitability might improve mechanism-based treatment of neuropathic pain in subjects with spinal cord injury.

PurposeFunctional understanding of the periaqueductal grey (PAG), a physiologically and clinically highly relevant brainstem region, can be advanced using proton magnetic resonance spectroscopy (1H-MRS). However, the PAG’s small size and high levels of physiological noise are methodologically challenging. This study aimed to (1) improve1H-MRS data quality in the PAG using spectral registration for frequency and phase error correction, (2) investigate whether spectral registration is particularly useful in cases of greater head motion and (3) examine two metabolite quantification approaches using literature-based or individual-based water relaxation times.MethodsSpectra were acquired in 33 healthy volunteers (50.1 years, SD=17.19, 18 females) on a 3T Philipps MR system using a point-resolved spectroscopy sequence optimized with very selective saturation pulses (OVERPRESS) and voxel-based flip angle calibration (effective volume of interest size: 8.8×10.2×12.2 mm3).ResultsSpectral registration significantly improved signal-to-noise ratios (SNR;p=0.048, median value [interquartile range]: 18.0 [17.00-20.00]) and spectral linewidth (N-acetylaspartate peak:pp’sp=0.002) recorded with a markerless motion tracking system. Metabolite concentrations were higher when quantified using individual-based compared to literature-based water relaxation times (p’sConclusionThis study demonstrates that high-quality1H-MRS can be acquired in the PAG using spectral registration. This offers new opportunities for future1H-MRS studies in the PAG and possibly also other clinically relevant brain regions with similar methodological challenges.

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 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.

Background New therapeutic approaches in neurological disorders are progressing into clinical development. Past failures in translational research have underlined the critical importance of selecting appropriate inclusion criteria and primary outcomes. Narrow inclusion criteria provide sensitivity, but increase trial duration and cost to the point of infeasibility, while broader requirements amplify confounding, increasing the risk of trial failure. This dilemma is perhaps most pronounced in spinal cord injury (SCI), but applies to all neurological disorders with low frequency and/or heterogeneous clinical manifestations. Objective Stratification of homogeneous patient cohorts to enable the design of clinical trials with broad inclusion criteria. Methods Prospectively–gathered data from patients with acute cervical SCI were analysed using an unbiased recursive partitioning conditional inference tree (URP–CTREE) approach. Performance in the 6-minute walk test at 6 months after injury was classified based on standardized neurological assessments within the first 15 days of injury. Functional and neurological outcomes were tracked throughout rehabilitation up to 6 months after injury. Results URP–CTREE identified homogeneous outcome cohorts in a study group of 309 SCI patients. These cohorts were validated by an internal, yet independent, validation group of 172 patients. The study group cohorts identified demonstrated distinct recovery profiles throughout rehabilitation. The baseline characteristics of the analysed groups were compared to a reference group of 477 patients. Conclusion URP–CTREE enables inclusive trial design by revealing the distribution of outcome cohorts, discerning distinct recovery profiles and projecting potential patient enrolment by providing estimates of the relative frequencies of cohorts to improve the design of clinical trials in SCI and beyond., Neurorehabilitation and Neural Repair, 36 (4-5), ISSN:1545-9683, ISSN:0888-4390, ISSN:1552-6844

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.

Contact heat evoked potentials (CHEPs) have become an acknowledged research tool in the assessment of the integrity of the nociceptive system and gained importance in the diagnostic work-up of patients with suspected small fiber neuropathy. For the latter, normative values for CHEP amplitude and latency are indispensable for a clinically meaningful interpretation of the results gathered in patients. To this end, CHEPs were recorded in 100 healthy subjects over a wide age range (20–80 years) and from three different dermatomes of the lower extremities (L2, L5, and S2). A normal baseline (35–52 °C) and increased baseline stimulation (42–52 °C) were applied. Statistical analysis revealed significant effects of stimulation site, stimulation intensity, and sex on CHEP parameters (N2 latency, N2P2 amplitude, and NRS). Significant positive correlations of body height with N2 latency, and pain ratings with N2P2 amplitudes were observed. This is the first time that normative values have been obtained from multiple dermatomes of the lower extremities. The present dataset will facilitate the clinical application of CHEPs in the neurophysiological diagnosis of small fiber neuropathy and by discerning pathological findings help establish a proximal-distal gradient of nerve degeneration in polyneuropathies.

Supplemental Digital Content is Available in the Text. Endogenous opioids are involved in the pleasant feeling of pain relief. This might enhance reinforcing effects on behavior providing pain relief., Endogenous opioids mediate the pleasurable responses to positively reinforcing stimuli such as palatable food. Yet, the reduction or omission of a negative experience can also be rewarding (negative reinforcement). As such, pain relief leads to negative reinforcement and evokes a pleasant feeling in humans. Although it has been shown that the feeling of pleasure associated with positive reinforcement is at least partly mediated through endogenous opioids, it is currently unknown whether similar neurochemical mechanisms are involved in the pleasant feeling evoked by pain relief. In this study, 27 healthy participants completed 2 identical experimental sessions, 1 with placebo and 1 with naltrexone, an endogenous opioid antagonist. Pain relief was induced by superficial cooling after heat stimulation of capsaicin-sensitized skin. Participants rated the relief and pleasantness in response to the cooling. Endogenous opioid blockade by naltrexone decreased relief and pleasantness ratings compared with placebo (P = 0.0027). This study provides evidence that endogenous opioids play a role in mediating the pleasant feeling of pain relief in humans. Clinically, the rewarding nature of pain relief and its underlying mechanisms require consideration because of their potential reinforcing effects on behaviors that might be beneficial short-term but maladaptive long-term.