Neurophysiological oscillatory markers of hypoalgesia in conditioned pain modulation

Introduction:Conditioned pain modulation (CPM) is an experimental procedure that consists of an ongoing noxious stimulus attenuating the pain perception caused by another noxious stimulus. A combination of the CPM paradigm with concurrent electrophysiological recordings can establish whether an association exists between experimentally modified pain perception and modulations of neural oscillations.Objectives:We aimed to characterize how CPM modifies pain perception and underlying neural oscillations. We also interrogated whether these perceptual and/or neurophysiological effects are distinct in patients affected by chronic pain.Methods:We presented noxious electrical stimuli to the right ankle before, during, and after CPM induced by an ice pack placed on the left forearm. Seventeen patients with chronic pain and 17 control participants rated the electrical pain in each experimental condition. We used magnetoencephalography to examine the anatomy-specific effects of CPM on the neural oscillatory responses to the electrical pain.Results:Regardless of the participant groups, CPM induced a reduction in subjective pain ratings and neural responses (beta-band [15-35 Hz] oscillations in the sensorimotor cortex) to electrical pain.Conclusion:Our findings of pain-induced beta-band activity may be associated with top-down modulations of pain, as reported in other perceptual modalities. Therefore, the reduced beta-band responses during CPM may indicate changes in top-down pain modulations.</p

Heterogeneous Cortical Effects of Spinal Cord Stimulation

Objectives: The understanding of the cortical effects of spinal cord stimulation (SCS) remains limited. Multiple studies have investigated the effects of SCS in resting-state electroencephalography. However, owing to the large variation in reported outcomes, we aimed to describe the differential cortical responses between two types of SCS and between responders and nonresponders using magnetoencephalography (MEG). Materials and Methods: We conducted 5-minute resting-state MEG recordings in 25 patients with chronic pain with active SCS in three sessions, each after a one-week exposure to tonic, burst, or sham SCS. We extracted six spectral features from the measured neurophysiological signals: the alpha peak frequency; alpha power ratio (power 7–9 Hz/power 9–11 Hz); and average power in the theta (4–7.5 Hz), alpha (8–12.5 Hz), beta (13–30 Hz), and low-gamma (30.5–60 Hz) frequency bands. We compared these features (using nonparametric permutation t-tests) for MEG sensor and cortical map effects across stimulation paradigms, between participants who reported low (&lt; 5, responders) vs high (≥ 5, nonresponders) pain scores, and in three representative participants. Results: We found statistically significant (p &lt; 0.05, false discovery rate corrected) increased MEG sensor signal power below 3 Hz in response to burst SCS compared with tonic and sham SCS. We did not find statistically significant differences (all p &gt; 0.05) between the power spectra of responders and nonresponders. Our data did not show statistically significant differences in the spectral features of interest among the three stimulation paradigms or between responders and nonresponders. These results were confirmed by the MEG cortical maps. However, we did identify certain trends in the MEG source maps for all comparisons and several features, with substantial variation across participants. Conclusions: The considerable variation in cortical responses to the various SCS treatment options necessitates studies with sample sizes larger than commonly reported in the field and more personalized treatment plans. Studies with a finer stratification between responders and nonresponders are required to advance the knowledge on SCS treatment effects.</p

The Effect of Various Spinal Neurostimulation Paradigms on the Supraspinal Somatosensory Evoked Response:A Systematic Review

Introduction: Spinal neurostimulation is a therapy for otherwise intractable chronic pain. Spinal neurostimulation includes stimulation of the spinal cord (SCS), dorsal root ganglion (DRGS), and dorsal root entry zone (DREZS). New paresthesia-free neurostimulation paradigms may rely on different mechanisms of action from those of conventional tonic neurostimulation. The aim of this systematic review is to assess the existing knowledge on the effect of spinal neurostimulation on somatosensory processing in patients with chronic pain. We therefore reviewed the existing literature on the effect of various spinal neurostimulation paradigms on the supraspinal somatosensory evoked response (SER). Materials and Methods: Multiple scientific data bases were searched for studies that assessed the effect of spinal neurostimulation on the supraspinal SER, evoked by painful or nonpainful peripheral stimuli in patients with chronic pain. We found 205 studies, of which 24 were included. Demographic data, study design, and study outcome were extracted. Results: Of the 24 included studies, 23 used electroencephalography to assess the SER; one study used magnetoencephalography. Fifteen studies evaluated tonic SCS; six studies (also) evaluated paresthesia-free paradigms; three studies evaluated the effect of tonic DRGS or DREZS. Sixteen studies used nonpainful stimuli to elicit the SER, 14 observed a decreased SER amplitude. Ten studies used painful stimuli to elicit the SER, yielding mixed results. Discussion: The included studies suggest that both paresthesia-based and paresthesia-free spinal neurostimulation paradigms can decrease (part of) the SER elicited by a nonpainful peripheral stimulus. The observed SER amplitude reduction likely is the effect of various spinal and supraspinal mechanisms of spinal neurostimulation that also contribute to pain relief. Conclusions: Spinal neurostimulation modulates the processing of a peripherally applied nonpainful stimulus. For painful stimuli, the results are not conclusive. It is not yet clear whether paresthesia-free neurostimulation affects the SER differently from paresthesia-based neurostimulation.</p

Spinal cord stimulation for the management of painful diabetic neuropathy: a systematic review and meta-analysis of individual patient and aggregate data

Spinal cord stimulation (SCS) has been suggested as a treatment option for patients with painful diabetic neuropathy (PDN). We conducted a systematic review and undertook a meta-analysis on individual patient data from randomised controlled trials (RCTs) to assess the effectiveness of SCS for the management of PDN. Electronic databases were searched from inception to May 2020 for RCTs of SCS for PDN. Searches identified 2 eligible RCTs (total of 93 patients with PDN) and 2 long-term follow-up studies of one of the RCTs. Individual patient data were obtained from the authors of one of these RCTs. Meta-analysis showed significant and clinically meaningful reductions in pain intensity for SCS compared with best medical therapy alone, pooled mean difference (MD) -3.13 (95% confidence interval [CI]: -4.19 to -2.08) on a 10-point scale at the 6-month follow-up. More patients receiving SCS achieved at least a 50% reduction in pain intensity compared with best medical therapy, pooled risk ratio 0.08 (95% CI: 0.02-0.38). Increases were observed for health-related quality of life assessed as EQ-5D utility score (pooled MD 0.16, 95% CI: 0.02-0.30) and visual analogue scale (pooled MD 11.21, 95% CI: 2.26-20.16). Our findings demonstrate that SCS is an effective therapeutic adjunct to best medical therapy in reducing pain intensity and improving health-related quality of life in patients with PDN. Large well-reported RCTs with long-term follow-up are required to confirm these results.</p

Systematic review and network meta-analysis of neurostimulation for painful diabetic neuropathy

Background: Different waveforms of spinal cord stimulation (SCS) have now been evaluated for the management of painful diabetic neuropathy (PDN). However, no direct or indirect comparison between SCS waveforms has been performed to date. Purpose: To conduct a systematic review and network meta-analysis to evaluate the effectiveness of SCS for PDN. Data Sources: MEDLINE, CENTRAL, Embase, and WikiStim were searched from inception until December 2021. Study Selection: Randomized controlled trials (RCTs) of SCS for PDN were included. Data Extraction: Pain intensity, proportion of patients achieving at least a 50% reduction in pain intensity, and health-related quality of life (HRQoL) data were extracted. Data Synthesis: Significant reductions in pain intensity were observed for low-frequency SCS (LF-SCS) (mean difference [MD] −3.13 [95% CI −4.19 to −2.08], moderate certainty) and high-frequency SCS (HF-SCS) (MD −5.20 [95% CI −5.77 to −4.63], moderate certainty) compared with conventional medical management (CMM) alone. There was a significantly greater reduction in pain intensity on HF-SCS compared with LF-SCS (MD −2.07 [95% CI −3.26 to −0.87], moderate certainty). Significant differences were observed for LF-SCS and HF-SCS compared with CMM for the outcomes proportion of patients with at least 50% pain reduction and HRQoL (very low to moderate certainty). No significant differences were observed between LF-SCS and HF-SCS (very low to moderate certainty). Limitations: Limited number of RCTs and no head-to-head RCTs conducted. Conclusions: Our findings confirm the pain relief and HRQoL benefits of the addition of SCS to CMM for patients with PDN. However, in the absence of head-to-head RCT evidence, the relative benefits of HF-SCS compared with LF-SCS for patients with PDN remain uncertain

Examining the Duration of Carryover Effect in Patients With Chronic Pain Treated With Spinal Cord Stimulation (EChO Study):An Open, Interventional, Investigator-Initiated, International Multicenter Study

Objectives: Spinal cord stimulation (SCS) is a surgical treatment for severe, chronic, neuropathic pain. It is based on one to two lead(s) implanted in the epidural space, stimulating the dorsal column. It has long been assumed that when deactivating SCS, there is a variable interval before the patient perceives the return of the pain, a phenomenon often termed echo or carryover effect. Although the carryover effect has been problematized as a source of error in crossover studies, no experimental investigation of the effect has been published. This open, prospective, international multicenter study aimed to systematically document, quantify, and investigate the carryover effect in SCS. Materials and Methods: Eligible patients with a beneficial effect from their SCS treatment were instructed to deactivate their SCS device in a home setting and to reactivate it when their pain returned. The primary outcome was duration of carryover time defined as the time interval from deactivation to reactivation. Central clinical parameters (age, sex, indication for SCS, SCS treatment details, pain score) were registered and correlated with carryover time using nonparametric tests (Mann-Whitney/Kruskal-Wallis) for categorical data and linear regression for continuous data. Results: In total, 158 patients were included in the analyses. A median carryover time of five hours was found (interquartile range 2.5;21 hours). Back pain as primary indication for SCS, high-frequency stimulation, and higher pain score at the time of deactivation were correlated with longer carryover time. Conclusions: This study confirms the existence of the carryover effect and indicates a remarkably high degree of interindividual variation. The results suggest that the magnitude of carryover may be correlated to the nature of the pain condition and possibly stimulation paradigms. Clinical Trial Registration: The Clinicaltrials.gov registration number for the study is NCT03386058.</p

Search for dark matter produced in association with bottom or top quarks in √s = 13 TeV pp collisions with the ATLAS detector

A search for weakly interacting massive particle dark matter produced in association with bottom or top quarks is presented. Final states containing third-generation quarks and miss- ing transverse momentum are considered. The analysis uses 36.1 fb−1 of proton–proton collision data recorded by the ATLAS experiment at √s = 13 TeV in 2015 and 2016. No significant excess of events above the estimated backgrounds is observed. The results are in- terpreted in the framework of simplified models of spin-0 dark-matter mediators. For colour- neutral spin-0 mediators produced in association with top quarks and decaying into a pair of dark-matter particles, mediator masses below 50 GeV are excluded assuming a dark-matter candidate mass of 1 GeV and unitary couplings. For scalar and pseudoscalar mediators produced in association with bottom quarks, the search sets limits on the production cross- section of 300 times the predicted rate for mediators with masses between 10 and 50 GeV and assuming a dark-matter mass of 1 GeV and unitary coupling. Constraints on colour- charged scalar simplified models are also presented. Assuming a dark-matter particle mass of 35 GeV, mediator particles with mass below 1.1 TeV are excluded for couplings yielding a dark-matter relic density consistent with measurements