Brain macrophage senescence in glioma.

Gliomas are a diverse group of primary central nervous system neoplasms with no curative therapies available. Brain macrophages comprise microglia in the brain parenchyma, border-associated macrophages in the meningeal-choroid plexus-perivascular space and monocyte-derived macrophages infiltrating the brain. With the great improvement of our recognition of brain macrophages, diverse macrophage populations have been found in the context of glioma, which exhibit functional and phenotypic heterogeneity. We have long thought that brain macrophage senescence is detrimental, manifested by specialized forms of persistent cell cycle arrest and chronic low-grade inflammation. Persistent senescence of macrophages may result in immune dysfunction, potentially contributing to glioma initiation and development. Given the crucial roles played by brain macrophages in glioma, we unravel how brain macrophages undergo reprogramming and their contribution to glioma. We outline general molecular alterations and specific biomarkers in senescent brain macrophages, as well as functional changes (such as metabolism, autophagy, phagocytosis, antigen presentation, and infiltration and recruitment). In addition, recent advances in genetic regulation and mechanisms linked to senescent brain macrophages are discussed. In particular, this review emphasizes the contribution of senescent brain macrophages to glioma, which may drive translational efforts to utilize brain macrophages as a prognostic marker or/and treatment target in glioma. An in-depth comprehending of how brain macrophage senescence functionally influences the tumor microenvironment will be key to our development of innovative therapeutics for glioma.

Phenotypic and genetic characterization of children with Wilson Disease from Northeast China.

BACKGROUND: Wilson disease (WD) is an autosomal recessive inherited disease caused by ATP7B variants and characterized by copper metabolism defects. However, children with WD are often asymptomatic, making the clinical diagnosis difficult. Therefore, more accurate methods are required for clinical diagnosis. The objective of this study was to highlight the phenotypic and genetic characteristics of children with WD in northeast China. METHODS: We retrospectively analyzed the clinical data and gene sequencing results of 65 children with WD from January 1, 2014, to December 31, 2022, at the Shengjing Hospital of China Medical University. All data refer to the time of diagnosis before treatment. RESULTS: The median age at diagnosis was 5 years (range 1.2-15 years). In 50 cases (50/65, 76.9%) patients, routine physical examinations revealed only abnormal liver function. However, they had a significantly negative (p < 0.05) Kayser-Fleischer ring (KF). Children with acute liver failure had significantly increased 24 h urinary copper excretion (p < 0.05). We detected 46 genetic variants of ATP7B, including seven novel variants. The most frequent variant was p.R778L with an allele frequency of 38.7%. Phenotype-genotype correlation analysis suggested that p.R778L was significantly associated with lower serum ceruloplasmin levels and higher zinc levels (p < 0.05). The loss-of-function (LOF) variant was associated with significantly lower albumin levels (p < 0.05). CONCLUSION: Most children with WD are asymptomatic, which makes early diagnosis of WD difficult. Therefore, clinical and laboratory characteristics as well as genetic testing are essential. p.R778L is the most frequent variant of ATP7B in China and may play an important role in lowering serum ceruloplasmin levels.

Ninety-Hz Spinal Cord Stimulation-Induced Analgesia Is Dependent on Active Charge Balance and Is Nonlinearly Related to Amplitude: A Sham-Controlled Behavioral Study in a Rodent Model of Chronic Neuropathic Pain.

BACKGROUND: Ninety-Hz active-recharge spinal cord stimulation (SCS) applied at below sensory-threshold intensity, as used with fast-acting subperception therapy spinal cord stimulation, has been shown clinically to produce significant analgesia, but additional characterization is required to better understand the therapy. This preclinical study investigates the behavioral effect of multiple 90-Hz SCS variants in a rodent model of neuropathic pain, focusing on charge balance and the relationship between 90-Hz efficacy and stimulation intensity. MATERIALS AND METHODS: Rats (n = 24) received a unilateral partial sciatic nerve ligation to induce neuropathic pain and were implanted with a quadripolar lead at T13. Mechanical hypersensitivity was assessed before, during, and after 60 minutes of SCS. After a prescreen with 50-Hz SCS 67% motor threshold ([MT], the positive control), rats underwent a randomized-crossover study including sham SCS and several 90-Hz SCS paradigms (at 40% MT or 60% MT, either using active or pseudopassive recharge) (experiment 1, n = 16). A second, identical experiment (experiment 2) was performed to supplement data with 90-Hz SCS at 20% and 80% MT (experiment 2, n = 8). RESULTS: Experiment 1: At 40% MT, 90-Hz active-recharge SCS produced a significantly larger recovery to baseline than did 90-Hz pseudopassive SCS at both tested intensities and sham SCS. Experiment 2: Only the 90-Hz SCS active recharge at 40% MT and 50-Hz SCS positive control caused mean recovery to baseline that was statistically better than that of sham SCS. CONCLUSIONS: The degree to which 90-Hz SCS reduced mechanical hypersensitivity during stimulation depended on the nature of charge balance, with 90-Hz active-recharge SCS generating better responses than did 90-Hz pseudopassive recharge SCS. In addition, our findings suggest that the amplitude of 90-Hz active-recharge SCS must be carefully configured for efficacy.

Network model of nociceptive processing in the superficial spinal dorsal horn reveals mechanisms of hyperalgesia, allodynia, and spinal cord stimulation.

The spinal dorsal horn (DH) processes sensory information and plays a key role in transmitting nociception to supraspinal centers. Loss of DH inhibition during neuropathic pain unmasks a pathway from nonnociceptive Aß-afferent inputs to superficial dorsal horn (SDH) nociceptive-specific (NS) projection neurons, and this change may contribute to hyperalgesia and allodynia. We developed and validated a computational model of SDH neuronal circuitry that links nonnociceptive Aß-afferent inputs in lamina II/III to a NS projection neuron in lamina I via a network of excitatory interneurons. The excitatory pathway and the NS projection neuron were in turn gated by inhibitory interneurons with connections based on prior patch-clamp recordings. Changing synaptic weights in the computational model to replicate neuropathic pain states unmasked a low-threshold excitatory pathway to NS neurons similar to experimental recordings. Spinal cord stimulation (SCS) is an effective therapy for neuropathic pain, and accumulating experimental evidence indicates that NS neurons in the SDH also respond to SCS. Accounting for these responses may inform therapeutic improvements, and we quantified responses to SCS in the SDH network model and examined the role of different modes of inhibitory control in modulating NS neuron responses to SCS. We combined the SDH network model with a previously published model of the deep dorsal horn (DDH) and identified optimal stimulation frequencies across different neuropathic pain conditions. Finally, we found that SCS-generated inhibition did not completely suppress model NS activity during simulated pinch inputs, providing an explanation of why SCS does not eliminate acute pain.NEW & NOTEWORTHY Chronic pain is a severe public health problem that reduces the quality of life for those affected and exacts an enormous socio-economic burden worldwide. Spinal cord stimulation (SCS) is an effective treatment for chronic pain, but SCS efficacy has not significantly improved over time, in part because the mechanisms of action remain unclear. Most preclinical studies investigating pain and SCS mechanisms have focused on the responses of deep dorsal horn (DDH) neurons, but neural networks in the superficial dorsal horn (SDH) are also important for processing nociceptive information. This work synthesizes heterogeneous experimental recordings from the SDH into a computational model that replicates experimental responses and that can be used to quantify neuronal responses to SCS under neuropathic pain conditions.

Active Recharge Burst and Tonic Spinal Cord Stimulation Engage Different Supraspinal Mechanisms: A Functional Magnetic Resonance Imaging Study in Peripherally Injured Chronic Neuropathic Rats.

OBJECTIVES: To assess the supraspinal working mechanisms of the burst spinal cord stimulation (SCS) mode, we used functional magnetic resonance imaging (fMRI) in chronic neuropathic rats. We hypothesized that active recharge burst SCS would induce a more profound blood oxygenation level-dependent (BOLD) signal increase in areas associated with cognitive-emotional aspects of pain, as compared to tonic SCS. METHODS: Sprague Dawley rats (n = 17) underwent a unilateral partial sciatic nerve ligation, which resulted in chronic neuropathic pain. Quadripolar SCS electrodes were epidurally positioned on top of the dorsal columns at Th13. Isoflurane-anesthetized (1.5%) rats received either tonic SCS (n = 8) or burst SCS (n = 9) at 66% of motor threshold. BOLD fMRI was conducted before, during, and after SCS using a 9.4-T horizontal bore scanner. RESULTS: Overall, both tonic and burst SCS induced a significant increase of BOLD signal levels in areas associated with the location and intensity of pain, and areas associated with cognitive-emotional aspects of pain. Additionally, burst SCS significantly increased BOLD signal levels in the raphe nuclei, nucleus accumbens, and caudate putamen. Tonic SCS did not induce a significant increase in BOLD signal levels in these areas. CONCLUSIONS: In conclusion, active recharge burst and tonic SCS have different effects on the intensity and localization of SCS-induced activation responses in the brain. This work demonstrates that active recharge burst is another waveform that can engage brain areas associated with cognitive-emotional aspects of pain as well as areas associated with location and intensity of pain. Previous studies showing similar engagement used only passive recharge burst.

Burst and Tonic Spinal Cord Stimulation Both Activate Spinal GABAergic Mechanisms to Attenuate Pain in a Rat Model of Chronic Neuropathic Pain.

BACKGROUND: Experimental and clinical studies have shown that tonic spinal cord stimulation (SCS) releases gamma-aminobutyric acid (GABA) in the spinal dorsal horn. Recently, it was suggested that burst SCS does not act via spinal GABAergic mechanisms. Therefore, we studied spinal GABA release during burst and tonic SCS, both anatomically and pharmacologically, in a well-established chronic neuropathic pain model. METHODS: Animals underwent partial sciatic nerve ligation (PSNL). Quantitative immunohistochemical (IHC) analysis of intracellular GABA levels in the lumbar L4 to L6 dorsal spinal cord was performed after 60 minutes of burst, tonic, or sham SCS in rats that had undergone PSNL (n = 16). In a second pharmacological experiment, the effects of intrathecal administration of the GABAA antagonist bicuculline (5 µg) and the GABAB antagonist phaclofen (5 µg) were assessed. Paw withdrawal thresholds to von Frey filaments of rats that had undergone PSNL (n = 20) were tested during 60 minutes of burst and tonic SCS 30 minutes after intrathecal administration of the drugs. RESULTS: Quantitative IHC analysis of GABA immunoreactivity in spinal dorsal horn sections of animals that had received burst SCS (n = 5) showed significantly lower intracellular GABA levels when compared to sham SCS sections (n = 4; P = 0.0201) and tonic SCS sections (n = 7; P = 0.0077). Intrathecal application of the GABAA antagonist bicuculline (5 µg; n = 10) or the GABAB antagonist phaclofen (5 µg; n = 10) resulted in ablation of the analgesic effect for both burst SCS and tonic SCS. CONCLUSIONS: In conclusion, our anatomical and pharmacological data demonstrate that, in this well-established chronic neuropathic animal model, the analgesic effects of both burst SCS and tonic SCS are mediated via spinal GABAergic mechanisms.

Electrophysiology equipment for reliable study of kHz electrical stimulation.

Characterizing the cellular targets of kHz (1-10 kHz) electrical stimulation remains a pressing topic in neuromodulation because expanding interest in clinical application of kHz stimulation has surpassed mechanistic understanding. The presumed cellular targets of brain stimulation do not respond to kHz frequencies according to conventional electrophysiology theory. Specifically, the low-pass characteristics of cell membranes are predicted to render kHz stimulation inert, especially given the use of limited-duty-cycle biphasic pulses. Precisely because kHz frequencies are considered supra-physiological, conventional instruments designed for neurophysiological studies such as stimulators, amplifiers and recording microelectrodes do not operate reliably at these high rates. Moreover, for pulsed waveforms, the signal frequency content is well above the pulse repetition rate. Thus, the very tools used to characterize the effects of kHz electrical stimulation may themselves be confounding factors. We illustrate custom equipment design that supports reliable electrophysiological recording during kHz-rate stimulation. Given the increased importance of kHz stimulation in clinical domains and compelling possibilities that mechanisms of actions may reflect yet undiscovered neurophysiological phenomena, attention to suitable performance of electrophysiological equipment is pivotal.

Assessment of axonal recruitment using model-guided preclinical spinal cord stimulation in the ex vivo adult mouse spinal cord.

Spinal cord stimulation (SCS) is used clinically to limit chronic pain, but fundamental questions remain on the identity of axonal populations recruited. We developed an ex vivo adult mouse spinal cord preparation to assess recruitment following delivery of clinically analogous stimuli determined by downscaling a finite element model of clinical SCS. Analogous electric field distributions were generated with 300-µm × 300-µm electrodes positioned 200 µm above the dorsal column (DC) with stimulation between 50 and 200 µA. We compared axonal recruitment using electrodes of comparable size and stimulus amplitudes when contacting the caudal thoracic DC and at 200 or 600 µm above. Antidromic responses recorded distally from the DC, the adjacent Lissauer tract (LT), and in dorsal roots (DRs) were found to be amplitude and site dependent. Responses in the DC included a unique component not seen in DRs, having the lowest SCS recruitment amplitude and fastest conduction velocity. At 200 µm above, mean cathodic SCS recruitment threshold for axons in DRs and LT were 2.6 and 4.4 times higher, respectively, than DC threshold. SCS recruited primary afferents in all (up to 8) caudal segments sampled. Whereas A and C fibers could be recruited at nearby segments, only A fiber recruitment and synaptically mediated dorsal root reflexes were observed in more distant (lumbar) segments. In sum, clinically analogous SCS led to multisegmental recruitment of several somatosensory-encoding axonal populations. Most striking is the possibility that the lowest threshold recruitment of a nonprimary afferent population in the DC are postsynaptic dorsal column tract cells (PSDCs) projecting to gracile nuclei.NEW & NOTEWORTHY Spinal cord stimulation (SCS) is used clinically to control pain. To identify axonal populations recruited, finite element modeling identified scaling parameters to deliver clinically analogous SCS in an ex vivo adult mouse spinal cord preparation. Results showed that SCS first recruited an axonal population in the dorsal column at a threshold severalfold lower than primary afferents. These putative postsynaptic dorsal column tract cells may represent a previously unconsidered population responsible for SCS-induced paresthesias necessary for analgesia.

Dependence of c-fos Expression on Amplitude of High-Frequency Spinal Cord Stimulation in a Rodent Model.

OBJECTIVES: Clinical high-frequency spinal cord stimulation (hfSCS) (>250 Hz) applied at subperception amplitudes reduces leg and low back pain. This study investigates, via labeling for c-fos-a marker of neural activation, whether 500 Hz hfSCS applied at amplitudes above and below the dorsal column (DC) compound action potential (CAP) threshold excites dorsal horn neurons. MATERIALS AND METHODS: DC CAP thresholds in rats were determined by applying single biphasic pulses of SCS to T12 -T13 segments using pulse widths of 40 or 200 µsec via a ball electrode placed over the left DC and increasing amplitude until a short latency CAP was observed on the L5 DC and sciatic nerve. The result of this comparison allowed us to substitute sciatic nerve CAP for DC CAP. SCS at T12 -T13 was applied continuously for two hours using: sham or hfSCS at 500 Hz SCS, 40 µsec pulse width, and 50, 70, 90, or 140% CAP threshold. Spinal cord slices from T11 -L1 were immunolabeled for c-fos, and the number of c-fos-positive cells was quantified. RESULTS: 500 Hz hfSCS applied at 90 and 140% CAP threshold produced substantial (≥6 c-fos + neurons on average per slice per segment) c-fos expression in more segments between T11 and L1 than did sham stimulation (p < 0.025, 90% CAP; p < 0.001, 140% CAP, Fisher's Exact Tests) and resulted in more c-fos-positive neurons on average per slice per segment ipsilateral to than contralateral to the SCS electrode at 70, 90, and 140% CAP threshold (p < 0.01, Wilcoxon Signed Rank Tests). CONCLUSIONS: The finding of enhanced c-fos expression in the ipsilateral superficial dorsal horn provides evidence for activation/modulation of neuronal circuitry associated with subperception hfSCS.

Conventional-SCS vs. Burst-SCS and the Behavioral Effect on Mechanical Hypersensitivity in a Rat Model of Chronic Neuropathic Pain: Effect of Amplitude.

OBJECTIVE: Various spinal cord stimulation (SCS) modes are used in the treatment of chronic neuropathic pain disorders. Conventional (Con) and Burst-SCS are hypothesized to exert analgesic effects through different stimulation-induced mechanisms. Preclinical electrophysiological findings suggest that stimulation intensity is correlated with the effectiveness of Burst-SCS. Therefore, we aimed to investigate the relation between amplitude (charge per second) and behavioral effects in a rat model of chronic neuropathic pain, for both Conventional Spinal Cord Stimulation (Con-SCS) and biphasic Burst-SCS. MATERIALS AND METHODS: Animals (n = 12 rats) received a unilateral partial sciatic nerve ligation, after which they were implanted with quadripolar electrodes in the epidural space at thoracic level 13. Mechanical hypersensitivity was assessed using paw withdrawal thresholds (WTs) to von Frey monofilaments, at various SCS intensities (amplitudes) and multiple time points during 60 minutes of stimulation and 30 minutes post stimulation. RESULTS: Increasing amplitude was shown to improve the efficacy of Con-SCS, whereas the efficacy of Burst-SCS showed a non-monotonic relation with amplitude. Con-SCS at 66% MT (n = 5) and Burst-SCS at 50% MT (n = 6) were found to be equally effective in normalizing mechanical hypersensitivity. However, in the assessed time period Burst-SCS required significantly more mean charge per second to do so (p < 0.01). When applied at comparable mean charge per second, Con-SCS resulted in a superior behavioral outcome (p < 0.01), compared with Burst-SCS. CONCLUSION: Biphasic Burst-SCS requires significantly more mean charge per second in order to achieve similar pain relief, as compared with Con-SCS, in an experimental model of chronic neuropathic pain.

Burst Spinal Cord Stimulation in Peripherally Injured Chronic Neuropathic Rats: A Delayed Effect.

OBJECTIVE: Two well-known spinal cord stimulation (SCS) paradigms, conventional (Con) and burst SCS, are hypothesized to exert their antinociceptive effects through different stimulation-induced mechanisms. We studied the course of the behavioral antinociceptive effect during 60 minutes of SCS and 30 minutes post-SCS in a rat model of chronic neuropathic pain. METHODS: Animals underwent a unilateral partial sciatic nerve ligation, after which quadripolar electrodes were implanted into the epidural space at vertebral level T13 (n = 43 rats). While receiving either Con SCS or biphasic burst SCS, the pain behavior of the rats was assessed by means of paw withdrawal thresholds (WTs) in response to the application of von Frey monofilaments. RESULTS: After 15 minutes of Con SCS (n = 21), WTs significantly differed from baseline (P = 0.04), whereas WTs of the burst SCS group (n = 22) did not. After 30 minutes of SCS, WTs of the Con SCS and burst SCS groups reached similar levels, both significantly different from baseline, indicating a comparable antinociceptive effect for these SCS paradigms. Yet, the WTs of the burst SCS group were still significantly increased compared with baseline at 30 minutes post-stimulation, whereas the WTs of the Con SCS group were not. CONCLUSIONS: To conclude, biphasic burst SCS results in a delayed antinociceptive effect after onset of the stimulation, as compared with Con SCS, in a chronic neuropathic pain model. Furthermore, biphasic burst SCS seems to exhibit a delayed wash-out of analgesia after stimulation is turned off.

Spinal sensory projection neuron responses to spinal cord stimulation are mediated by circuits beyond gate control.

Spinal cord stimulation (SCS) is a therapy used to treat intractable pain with a putative mechanism of action based on the Gate Control Theory. We hypothesized that sensory projection neuron responses to SCS would follow a single stereotyped response curve as a function of SCS frequency, as predicted by the Gate Control circuit. We recorded the responses of antidromically identified sensory projection neurons in the lumbar spinal cord during 1- to 150-Hz SCS in both healthy rats and neuropathic rats following chronic constriction injury (CCI). The relationship between SCS frequency and projection neuron activity predicted by the Gate Control circuit accounted for a subset of neuronal responses to SCS but could not account for the full range of observed responses. Heterogeneous responses were classifiable into three additional groups and were reproduced using computational models of spinal microcircuits representing other interactions between nociceptive and nonnociceptive sensory inputs. Intrathecal administration of bicuculline, a GABAA receptor antagonist, increased spontaneous and evoked activity in projection neurons, enhanced excitatory responses to SCS, and reduced inhibitory responses to SCS, suggesting that GABAA neurotransmission plays a broad role in regulating projection neuron activity. These in vivo and computational results challenge the Gate Control Theory as the only mechanism underlying SCS and refine our understanding of the effects of SCS on spinal sensory neurons within the framework of contemporary understanding of dorsal horn circuitry.

Modeling effects of spinal cord stimulation on wide-dynamic range dorsal horn neurons: influence of stimulation frequency and GABAergic inhibition.

Spinal cord stimulation (SCS) is a clinical therapy for chronic, neuropathic pain, but an incomplete understanding of the mechanisms underlying SCS contributes to the lack of improvement in SCS efficacy over time. To study the mechanisms underlying SCS, we constructed a biophysically based network model of the dorsal horn circuit consisting of interconnected dorsal horn interneurons and a wide-dynamic range (WDR) projection neuron and representations of both local and surround receptive field inhibition. We validated the network model by reproducing cellular and network responses relevant to pain processing including wind-up, A fiber-mediated inhibition, and surround receptive field inhibition. We then simulated the effects of SCS on the activity of the WDR projection neuron and found that the response of the model WDR neuron to SCS depends on the SCS frequency; SCS frequencies of 30-100 Hz maximally inhibited the model WDR neuron, while frequencies under 30 Hz and over 100 Hz excited the model WDR neuron. We also studied the impacts on the effects of SCS of loss of inhibition due to the loss of either GABA or KCC2 function. Reducing the influence of local and surround GABAergic interneurons by weakening their inputs or their connections to the WDR neuron and shifting the anionic reversal potential of the WDR neurons upward each reduced the range of optimal SCS frequencies and changed the frequency at which SCS had a maximal effect. The results of this study provide insights into the mechanisms of SCS and pave the way for improved SCS parameter selection.

Comparative Assessment of In Vitro Xanthine Oxidase and α-Glucosidase Inhibitory Activities of Cultured Cambial Meristematic Cells, Adventitious Roots, and Field-Cultivated Ginseng.

Panax ginseng, a traditional Chinese medicine with a history spanning thousands of years, faces overexploitation and challenges related to extended growth periods. Tissue-cultured adventitious roots and stem cells are alternatives to wild and field-cultivated ginseng. In this study, we assessed the in vitro xanthine oxidase and α-glucosidase inhibitory activities of saponin extracts among cultured cambial meristematic cells (CMC), adventitious ginseng roots (AGR), and field-cultivated ginseng roots (CGR). The xanthine oxidase (XO) and α-glucosidase inhibitory activities were determined by uric acid estimation and the p-NPG method, respectively. Spectrophotometry and the Folin-Ciocalteu, aluminum nitrate, and Bradford methods were employed to ascertain the total saponins and phenolic, flavonoid, and protein contents. The calculated IC50 values for total saponin extracts against XO and α-glucosidase were 0.665, 0.844, and >1.6 mg/mL and 0.332, 0.745, and 0.042 mg/mL for AGR, CMC, CGR, respectively. Comparing the total saponin, crude protein, and total phenolic contents revealed that AGR > CMC > CGR. To the best of our knowledge, this study presents the first report on the in vitro comparison of xanthine oxidase and α-glucosidase inhibitory activities among AGR, CMC, and CGR. The findings offer valuable insights into the development of hypoglycemic and antihyperuricemic medicinal, nutraceutical, and functional products utilizing AGR and CMC.

Predictive value of NCCT quantitative analysis for proximal and middle impacted ureteral stones.

The purpose of the study was to explore the predictive value of preoperative quantitative NCCT analysis for proximal and middle ureteral stone impaction. Data of 128 patients who diagnosed with proximal and middle ureteral stones were analyzed. Stone size, upper diameter of the ureter(D1), lower diameter of the ureter (D2), CT attenuation of the ureter above the stone (HA, 'HU above'), CT attenuation of the ureter below the stone (HB, 'HU below'), CT attenuation values of the stone's proximal segments (C1), CT attenuation values of the stone's distal segments (C2), and ureteral wall thickness(UWT)were recorded. Logistic regression was used to perform univariate and multivariate analyses of the data to determine the independent predictors of proximal and middle ureteral stone impaction. The receiver operating characteristic (ROC) curve was plotted to evaluate the predictive performance. Among the 128 patients, 52 (40.6%) had impacted stones, while 76 (59.4%) did not. Multivariate logistic regression analysis showed that stone size > 9.45 mm (OR = 1.372, 95% CI = 1.071-1.756, P = 0.012), UWT > 3.22 mm (OR = 4.217, 95% CI = 2.165 ~ 8.213, P < 0.001)、DDR > 2.10 (OR = 4.901, 95% CI = 1.797 ~ 13.365, P = 0.002)and HBA > 1.58 (OR = 5.237,95% CI = 1.502 ~ 18.259, P = 0.009)were independent risk factors for predicting ureteral stone impaction. In conclusion, stone size, UWT, DDR, and HBA show crucial predictive value for impaction of stones.

Absence of paresthesia during high-rate spinal cord stimulation reveals importance of synchrony for sensations evoked by electrical stimulation.

Electrically activating mechanoreceptive afferents inhibits pain. However, paresthesia evoked by spinal cord stimulation (SCS) at 40-60 Hz becomes uncomfortable at high pulse amplitudes, limiting SCS "dosage." Kilohertz-frequency SCS produces analgesia without paresthesia and is thought, therefore, not to activate afferent axons. We show that paresthesia is absent not because axons do not spike but because they spike asynchronously. In a pain patient, selectively increasing SCS frequency abolished paresthesia and epidurally recorded evoked compound action potentials (ECAPs). Dependence of ECAP amplitude on SCS frequency was reproduced in pigs, rats, and computer simulations and is explained by overdrive desynchronization: spikes desychronize when axons are stimulated faster than their refractory period. Unlike synchronous spikes, asynchronous spikes fail to produce paresthesia because their transmission to somatosensory cortex is blocked by feedforward inhibition. Our results demonstrate how stimulation frequency impacts synchrony based on axon properties and how synchrony impacts sensation based on circuit properties.

In Vivo Measurements Reveal that Both Low- and High-frequency Spinal Cord Stimulation Heterogeneously Modulate Superficial Dorsal Horn Neurons.

Current sub-perception spinal cord stimulation (SCS) is characterized by the use of high-frequency pulses to achieve paresthesia-free analgesic effects. High-frequency SCS demonstrates distinctive properties from paresthesia-based SCS, such as a longer time course to response, implying the existence of alternative mechanism(s) of action beyond gate control theory. We quantified the responses to SCS of single neurons within the superficial dorsal horn (SDH), a structure in close proximity to SCS electrodes, to investigate the mechanisms underlying high-frequency SCS in 62 urethane-anesthetized male rats. Sciatic nerve stimulation was delivered to isolate lumbar SDH neurons with evoked C-fiber activity. The evoked C-fiber activity before and after the application of SCS was compared to quantify the effects of SCS across stimulation intensity and stimulation duration at three different stimulation frequencies. We observed heterogeneous responses of SDH neurons which depended primarily on the type of unit. Low-threshold units with spontaneous activity, putatively inhibitory interneurons, tended to be facilitated by SCS while the other unit types were suppressed. The effects of SCS were more prominent with increased stimulation duration from 30 s to 30 m across frequencies. Our results highlight the importance of inhibitory interneurons in modulating local circuits of the SDH and the importance of local circuit contributions to the analgesic mechanisms of SCS.

Novel Evoked Synaptic Activity Potentials (ESAPs) Elicited by Spinal Cord Stimulation.

Spinal cord stimulation (SCS) evokes fast epidural evoked compound action potential (ECAP) that represent activity of dorsal column axons, but not necessarily a spinal circuit response. Using a multimodal approach, we identified and characterized a delayed and slower potential evoked by SCS that reflects synaptic activity within the spinal cord. Anesthetized female Sprague Dawley rats were implanted with an epidural SCS lead, epidural motor cortex stimulation electrodes, an epidural spinal cord recording lead, an intraspinal penetrating recording electrode array, and intramuscular electromyography (EMG) electrodes in the hindlimb and trunk. We stimulated the motor cortex or the epidural spinal cord and recorded epidural, intraspinal, and EMG responses. SCS pulses produced characteristic propagating ECAPs (composed of P1, N1, and P2 waves with latencies <2 ms) and an additional wave ("S1") starting after the N2. We verified the S1-wave was not a stimulation artifact and was not a reflection of hindlimb/trunk EMG. The S1-wave has a distinct stimulation-intensity dose response and spatial profile compared with ECAPs. 6-Cyano-7-nitroquinoxaline-2,3-dione (CNQX; a selective competitive antagonist of AMPA receptors (AMPARs)] significantly diminished the S1-wave, but not ECAPs. Furthermore, cortical stimulation, which did not evoke ECAPs, produced epidurally detectable and CNQX-sensitive responses at the same spinal sites, confirming epidural recording of an evoked synaptic response. Finally, applying 50-Hz SCS resulted in dampening of S1-wave but not ECAPs. Therefore, we hypothesize that the S1-wave is synaptic in origin, and we term the S1-wave type responses: evoked synaptic activity potentials (ESAPs). The identification and characterization of epidurally recorded ESAPs from the dorsal horn may elucidate SCS mechanisms.

Evaluating optimized temporal patterns of spinal cord stimulation (SCS).

BACKGROUND: Temporal patterns of stimulation represent a novel dimension for improving the efficacy of spinal cord stimulation to treat chronic neuropathic pain. OBJECTIVE: We hypothesized that nonregular temporal patterns of stimulation designed using a computational model would be superior to conventional stimulation at constant frequencies or completely random patterns of stimulation. METHODS: Using a computational model of the dorsal horn network and an optimization algorithm based on biological evolution, we designed an optimized pattern of spinal cord stimulation with comparable efficacy and increased efficiency relative to constant frequency (CF) stimulation. We evaluated the effect of different temporal patterns on individual neurons recorded in the dorsal horn of urethane-anesthetized rats. RESULTS: The optimized pattern and 50 Hz CF stimulation produced greater inhibition of spontaneously firing neurons recorded in vivo than random 50 Hz stimulation or a pattern designed intentionally with poor fitness. Spinal Cord Stimulation (SCS) led to significant changes in the firing patterns of recorded units, and stimulation patterns that generated significant inhibition also tended to reduce entropy and regularize the firing patterns of units, suggesting that patterns of dorsal horn neuron activity may be important for pain perception in addition to the firing rate. CONCLUSIONS: These results demonstrate that the computational model can be used as a tool for optimizing stimulation parameters and suggest that optimized temporal patterns may increase the efficacy of spinal cord stimulation.