The neurons that restore walking after paralysis.

A spinal cord injury interrupts pathways from the brain and brainstem that project to the lumbar spinal cord, leading to paralysis. Here we show that spatiotemporal epidural electrical stimulation (EES) of the lumbar spinal cord1-3 applied during neurorehabilitation4,5 (EESREHAB) restored walking in nine individuals with chronic spinal cord injury. This recovery involved a reduction in neuronal activity in the lumbar spinal cord of humans during walking. We hypothesized that this unexpected reduction reflects activity-dependent selection of specific neuronal subpopulations that become essential for a patient to walk after spinal cord injury. To identify these putative neurons, we modelled the technological and therapeutic features underlying EESREHAB in mice. We applied single-nucleus RNA sequencing6-9 and spatial transcriptomics10,11 to the spinal cords of these mice to chart a spatially resolved molecular atlas of recovery from paralysis. We then employed cell type12,13 and spatial prioritization to identify the neurons involved in the recovery of walking. A single population of excitatory interneurons nested within intermediate laminae emerged. Although these neurons are not required for walking before spinal cord injury, we demonstrate that they are essential for the recovery of walking with EES following spinal cord injury. Augmenting the activity of these neurons phenocopied the recovery of walking enabled by EESREHAB, whereas ablating them prevented the recovery of walking that occurs spontaneously after moderate spinal cord injury. We thus identified a recovery-organizing neuronal subpopulation that is necessary and sufficient to regain walking after paralysis. Moreover, our methodology establishes a framework for using molecular cartography to identify the neurons that produce complex behaviours.

Convolutional neural networks for the automatic segmentation of lumbar paraspinal muscles in people with low back pain.

The size, shape, and composition of paraspinal muscles have been widely reported in disorders of the cervical and lumbar spine. Measures of size, shape, and composition have required time-consuming and rater-dependent manual segmentation techniques. Convolutional neural networks (CNNs) provide alternate timesaving, state-of-the-art performance measures, which could realise clinical translation. Here we trained a CNN for the automatic segmentation of lumbar paraspinal muscles and determined the impact of CNN architecture and training choices on segmentation performance. T2-weighted MRI axial images from 76 participants (46 female; age (SD): 45.6 (12.8) years) with low back pain were used to train CNN models to segment the multifidus, erector spinae, and psoas major muscles (left and right segmented separately). Using cross-validation, we compared 2D and 3D CNNs with and without data augmentation. Segmentation accuracy was compared between the models using the Sørensen-Dice index as the primary outcome measure. The effect of increasing network depth on segmentation accuracy was also investigated. Each model showed high segmentation accuracy (Sørensen-Dice index ≥ 0.885) and excellent reliability (ICC2,1 ≥ 0.941). Overall, across all muscles, 2D models performed better than 3D models (p = 0.012), and training without data augmentation outperformed training with data augmentation (p < 0.001). The 2D model trained without data augmentation demonstrated the highest average segmentation accuracy. Increasing network depth did not improve accuracy (p = 0.771). All trained CNN models demonstrated high accuracy and excellent reliability for segmenting lumbar paraspinal muscles. CNNs can be used to efficiently and accurately extract measures of paraspinal muscle health from MRI.

Pharmacogenetic inhibition of lumbosacral sensory neurons alleviates visceral hypersensitivity in a mouse model of chronic pelvic pain.

The study investigated the cellular and molecular mechanisms in the peripheral nervous system (PNS) underlying the symptoms of urologic chronic pelvic pain syndrome (UCPPS) in mice. This work also aimed to test the feasibility of reversing peripheral sensitization in vivo in alleviating UCPPS symptoms. Intravesical instillation of vascular endothelial growth factor A (VEGFA) was used to induce UCPPS-like symptoms in mice. Spontaneous voiding spot assays and manual Von Frey tests were used to evaluate the severity of lower urinary tract symptoms (LUTS) and visceral hypersensitivity in VEGFA-instilled mice. Bladder smooth muscle strip contractility recordings (BSMSC) were used to identify the potential changes in myogenic and neurogenic detrusor muscle contractility at the tissue-level. Quantitative real-time PCR (qPCR) and fluorescent immunohistochemistry were performed to compare the expression levels of VEGF receptors and nociceptors in lumbosacral dorsal root ganglia (DRG) between VEGFA-instilled mice and saline-instilled controls. To manipulate primary afferent activity, Gi-coupled Designer Receptors Exclusively Activated by Designer Drugs (Gi-DREADD) were expressed in lumbosacral DRG neurons of TRPV1-Cre-ZGreen mice via targeted adeno-associated viral vector (AAVs) injections. A small molecule agonist of Gi-DREADD, clozapine-N-oxide (CNO), was injected into the peritoneum (i. p.) in awake animals to silence TRPV1 expressing sensory neurons in vivo during physiological and behavioral recordings of bladder function. Intravesical instillation of VEGFA in the urinary bladders increased visceral mechanical sensitivity and enhanced RTX-sensitive detrusor contractility. Sex differences were identified in the baseline detrusor contractility responses and VEGF-induced visceral hypersensitivity. VEGFA instillations in the urinary bladder led to significant increases in the mRNA and protein expression of transient receptor potential cation channel subfamily A member 1 (TRPA1) in lumbosacral DRG, whereas the expression levels of transient receptor potential cation channel subfamily V member 1 (TRPV1) and VEGF receptors (VEGFR1 and VEGFR2) remained unchanged when compared to saline-instilled animals. Importantly, the VEGFA-induced visceral hypersensitivity was reversed by Gi-DREADD-mediated neuronal silencing in lumbosacral sensory neurons. Activation of bladder VEGF signaling causes sensory neural plasticity and visceral hypersensitivity in mice, confirming its role of an UCPPS biomarker as identified by the Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) research studies. Pharmacogenetic inhibition of lumbosacral sensory neurons in vivo completely reversed VEGFA-induced pelvic hypersensitivity in mice, suggesting the strong therapeutic potential for decreasing primary afferent activity in the treatment of pain severity in UCPPS patients.

Translumbosacral Anorectal Magnetic Stimulation Test for Fecal Incontinence.

BACKGROUND: Neuropathy may cause fecal incontinence and mixed fecal incontinence/constipation, but its prevalence is unclear, partly due to the lack of comprehensive testing of spino-anorectal innervation. OBJECTIVE: This study aimed to develop and determine the clinical usefulness of a novel test, translumbosacral anorectal magnetic stimulation for fecal incontinence. DESIGN: This observational cohort study was conducted from 2012 to 2018. SETTINGS: This study was performed at a tertiary referral center. PATIENTS: Patients with fecal incontinence, patients with mixed fecal incontinence/constipation, and healthy controls were included. INTERVENTIONS: A translumbosacral anorectal magnetic stimulation test was performed by using an anorectal probe with 4 ring electrodes and magnetic coil, and by stimulating bilateral lumbar and sacral plexuses, uses and recording 8 motor-evoked potentials at anal and rectal sites. MAIN OUTCOME MEASURES: The prevalence of lumbar and/or sacral neuropathy was examined. Secondary outcomes were correlation of neuropathy with anorectal sensorimotor function(s) and morphological changes. RESULTS: We evaluated 220 patients: 144 with fecal incontinence, 76 with mixed fecal incontinence/constipation, and 31 healthy controls. All 8 lumbar and sacral motor-evoked potential latencies were significantly prolonged (p < 0.01) in fecal incontinence and mixed fecal incontinence/constipation groups compared with controls. Neuropathy was patchy and involved 4.0 (3.0) (median (interquartile range)) sites. Lumbar neuropathy was seen in 29% to 65% of the patients in the fecal incontinence group and 22% to 61% of the patients in the mixed fecal incontinence/constipation group, and sacral neuropathy was seen in 24% to 64% and 29% to 61% of these patients. Anal neuropathy was significantly more (p < 0.001) prevalent than rectal neuropathy in both groups. There was no correlation between motor-evoked potential latencies and anal sphincter pressures, rectal sensation, or anal sphincter defects. LIMITATIONS: No comparative analysis with electromyography was performed. CONCLUSION: Lumbar or sacral plexus neuropathy was detected in 40% to 75% of patients with fecal incontinence with a 2-fold greater prevalence at the anal region than the rectum. Lumbosacral neuropathy appears to be an independent mechanism in the pathogenesis of fecal incontinence, unassociated with other sensorimotor dysfunctions. Translumbosacral anorectal magnetic stimulation has a high yield and is a safe and clinically useful neurophysiological test. See Video Abstract at http://links.lww.com/DCR/B728. PRUEBA DE ESTIMULACIN MAGNTICA TRANSLUMBOSACRAL ANORECTAL PARA LA INCONTINENCIA FECAL: ANTECEDENTES:La neuropatía puede causar incontinencia fecal y una combinación de incontinencia fe-cal/estreñimiento, pero su prevalencia no está clara, en parte debido a la falta de pruebas comple-tas de inervación espino-anorrectal.OBJETIVO:Desarrollar y determinar la utilidad clínica de una nueva prueba, estimulación magnética trans-lumbosacral anorrectal para la incontinencia fecal.DISEÑO:Estudio de cohorte observacional del 2012 al 2018.ENTORNO CLINICO:Centro de referencia terciario.PACIENTES:Pacientes con incontinencia fecal, combinación de incontinencia fecal/estreñimiento y controles sanos.INTERVENCIONES:Se realizó una prueba de estimulación magnética translumbosacral anorrectal utilizando una sonda anorrectal con 4 electrodos anulares y bobina magnética, y estimulando los plexos lumbares y sacros bilaterales y registrando ocho potenciales evocados motores las regiones anal y rectal.PRINCIPALES MEDIDAS DE RESULTADO:Se examinó la prevalencia de neuropatía lumbar y/o sacra. Los resultados secundarios fueron la correlación de la neuropatía con las funciones sensitivomotoras anorrectales y cambios morfológi-cos.RESULTADOS:Evaluamos 220 pacientes, 144 con incontinencia fecal, 76 con combinación de incontinencia fe-cal/estreñimiento y 31 sujetos sanos. Las ocho latencias de los potenciales evocadas motoras lum-bares y sacras se prolongaron significativamente (p <0,01) en la incontinencia fecal y el grupo mixto en comparación con los controles. La neuropatía fue irregular y afectaba 4,0 (3,0) (mediana (rango intercuartílico) sitios. Se observó neuropatía lumbar en 29-65% en la incontinencia fecal y 22-61% en el grupo mixto, y neuropatía sacra en 24-64% y 29-61 % de pacientes respectivamen-te. La neuropatía anal fue significativamente más prevalente (p <0,001) que la rectal en ambos grupos. No hubo correlación entre las latencias de los potenciales evocadas motoras y las presio-nes del esfínter anal, la sensación rectal o los defectos del esfínter anal.LIMITACIONES:Sin análisis comparativo con electromiografía.CONCLUSIÓNES:Se detectó neuropatía del plexo lumbar o sacro en el 40-75% de los pacientes con incontinencia fecal con una prevalencia dos veces mayor en la región anal que en el recto. La neuropatía lumbo-sacra parece ser un mecanismo independiente en la patogenia de la incontinencia fecal, no asocia-do con otras disfunciones sensitivomotoras. La estimulación magnética translumbosacral anorrec-tal tiene un alto rendimiento, es una prueba neurofisiológica segura y clínicamente útil. Consulte Video Resumen en http://links.lww.com/DCR/B728.

Co-localization of nociceptive markers in the lumbar dorsal root ganglion and spinal cord of dromedary camel.

Nociceptive markers in mice have been identified in two distinct peptidergic and nonpeptidergic neurons in the dorsal root ganglion (DRG) and distributed in different laminae of the dorsal horn of the spinal cord. Recently, however, a study in humans showed a significant overlapping in these two populations. In this study, we investigated the distribution of various nociceptive markers in the lumbar DRG and spinal cord of the dromedary camel. Immunohistochemical data showed a remarkable percentage of total neurons in the DRG expressed IB4 binding (54.5%), calcitonin gene-related peptide (CGRP; 49.5%), transient receptor potential vanilloid 1 (TRPV1; 48.2%), and nitric oxide synthase (NOS; 30.6%). The co-localization data showed that 89.6% and 74.0% of CGRP- and TRPV1-labeled neurons, respectively, were IB4 positive. In addition, 61.6% and 84.2% of TRPV1- and NOS-immunoreactive neurons, respectively, were also co-localized with CGRP. The distribution of IB4, CGRP, TRPV1, substance P, and NOS immunoreactivities in the spinal cord were observed in lamina I and outer lamina II (IIo). Quantitative data showed that 82.4% of IB4-positive nerve terminals in laminae I and IIo were co-localized with CGRP, and 86.0% of CGRP-labeled terminals were co-localized with IB4. Similarly, 85.1% of NOS-labeled nerve terminals were co-localized with CGRP. No neuropeptide Y (NPY) or cholecystokinin (CCK) immunoreactivities were detected in the DRG, and no co-localization between IB4, NPY, and CCK were observed in the spinal cord. Our results demonstrate marked convergence of nociceptive markers in the primary afferent neurons in camels, which is similar to humans rather than the mouse. The data also emphasizes the importance of interspecies differences when selecting ideal animal models for studying nociception and treating chronic pain.

Nociceptor subtypes are born continuously over DRG development.

Sensory neurogenesis in the dorsal root ganglion (DRG) occurs in two waves of differentiation with larger, myelinated proprioceptive and low-threshold mechanoreceptor (LTMR) neurons differentiating before smaller, unmyelinated (C) nociceptive neurons. This temporal difference was established from early birthdating studies based on DRG soma cell size. However, distinctions in birthdates between molecular subtypes of sensory neurons, particularly nociceptors, is unknown. Here, we assess the birthdate of lumbar DRG neurons in mice using a thymidine analog, EdU, to label developing neurons exiting mitosis combined with co-labeling of known sensory neuron markers. We find that different nociceptor subtypes are born on similar timescales, with continuous births between E9.5 to E13.5, and peak births from E10.5 to E11.5. Notably, we find that thinly myelinated Aδ-fiber nociceptors and peptidergic C-fibers are born more broadly between E10.5 and E11.5 than previously thought and that non-peptidergic C-fibers and C-LTMRs are born with a peak birth date of E11.5. Moreover, we find that the percentages of nociceptor subtypes born at a particular timepoint are the same for any given nociceptor cell type marker, indicating that intrinsic or extrinsic influences on cell type diversity are occurring similarly across developmental time. Overall, the patterns of birth still fit within the classical "two wave" description, as touch and proprioceptive fibers are born primarily at E10.5, but suggest that nociceptors have a slightly broader wave of birthdates with different nociceptor subtypes continually differentiating throughout sensory neurogenesis irrespective of myelination.

Thoracolumbar interfascial plane block for postoperative analgesia in spine surgery: A systematic review and meta-analysis.

INTRODUCTION: Thoracolumbar interfascial plane (TLIP) block has been discussed widely in spine surgery. The aim of our study is to evaluate analgesic efficacy and safety of TLIP block in spine surgery. METHOD: We performed a quantitative systematic review. Randomized controlled trials that compared TLIP block to non-block care or wound infiltration for patients undergoing spine surgery and took the pain or morphine consumption as a primary or secondary outcome were included. The primary outcome was cumulative opioid consumption during 0-24-hour. Secondary outcomes included postoperative pain intensity, rescue analgesia requirement, and adverse events. RESULT: 9 randomized controlled trials with 539 patients were included for analysis. Compared with non-block care, TLIP block was effective to decrease the opioid consumption (WMD -16.00; 95%CI -19.19, -12.81; p<0.001; I2 = 71.6%) for the first 24 hours after the surgery. TLIP block significantly reduced postoperative pain intensity at rest or movement at various time points compared with non-block care, and reduced rescue analgesia requirement ((RR 0.47; 95%CI 0.30, 0.74; p = 0.001; I2 = 0.0%) and postoperative nausea and vomiting (RR 0.58; 95%CI 0.39, 0.86; p = 0.006; I2 = 25.1%). Besides, TLIP block is superior to wound infiltration in terms of opioid consumption (WMD -17.23, 95%CI -21.62, -12.86; p<0.001; I2 = 63.8%), and the postoperative pain intensity at rest was comparable between TLIP block and wound infiltration. CONCLUSION: TLIP block improved analgesic efficacy in spine surgery compared with non-block care. Furthermore, current literature supported the TLIP block was superior to wound infiltration in terms of opioid consumption.

A shape-adjusted ellipse approach corrects for varied axonal dispersion angles and myelination in primate nerve roots.

Segmentation of axons in light and electron micrographs allows for quantitative high-resolution analysis of nervous tissues, but varied axonal dispersion angles result in over-estimates of fiber sizes. To overcome this technical challenge, we developed a novel shape-adjusted ellipse (SAE) determination of axonal size and myelination as an all-inclusive and non-biased tool to correct for oblique nerve fiber presentations. Our new resource was validated by light and electron microscopy against traditional methods of determining nerve fiber size and myelination in rhesus macaques as a model system. We performed detailed segmental mapping and characterized the morphological signatures of autonomic and motor fibers in primate lumbosacral ventral roots (VRs). An en bloc inter-subject variability for the preganglionic parasympathetic fibers within the L7-S2 VRs was determined. The SAE approach allows for morphological ground truth data collection and assignment of individual axons to functional phenotypes with direct implications for fiber mapping and neuromodulation studies.

Magnetic resonance tractography of the lumbosacral plexus: Step-by-step.

ABSTRACT: MR tractography of the lumbosacral plexus (LSP) is challenging due to the difficulty of acquiring high quality data and accurately estimating the neuronal tracts. We proposed an algorithm for an accurate visualization and assessment of the major LSP bundles using the segmentation of the cauda equina as seed points for the initial starting area for the fiber tracking algorithm.Twenty-six healthy volunteers underwent MRI examinations on a 3T MR scanner using the phased array coils with optimized measurement protocols for diffusion-weighted images and coronal T2 weighted 3D short-term inversion recovery sampling perfection with application optimized contrast using varying flip angle evaluation sequences used for LSP fiber reconstruction and MR neurography (MRN).The fiber bundles reconstruction was optimized in terms of eliminating the muscle fibers contamination using the segmentation of cauda equina, the effects of the normalized quantitative anisotropy (NQA) and angular threshold on reconstruction of the LSP. In this study, the NQA parameter has been used for fiber tracking instead of fractional anisotropy (FA) and the regions of interest positioning was precisely adjusted bilaterally and symmetrically in each individual subject.The diffusion data were processed in individual L3-S2 nerve fibers using the generalized Q-sampling imaging algorithm. Data (mean FA, mean diffusivity, axial diffusivity and radial diffusivity, and normalized quantitative anisotropy) were statistically analyzed using the linear mixed-effects model. The MR neurography was performed in MedINRIA and post-processed using the maximum intensity projection method to demonstrate LSP tracts in multiple planes.FA values significantly decreased towards the sacral region (P < .001); by contrast, mean diffusivity, axial diffusivity, radial diffusivity and NQA values significantly increased towards the sacral region (P < .001).Fiber tractography of the LSP was feasible in all examined subjects and closely corresponded with the nerves visible in the maximum intensity projection images of MR neurography. Usage of NQA instead of FA in the proposed algorithm enabled better separation of muscle and nerve fibers.The presented algorithm yields a high quality reconstruction of the LSP bundles that may be helpful both in research and clinical practice.

Lumbar medial branch cryoneurolysis under ultrasound guidance: initial report of five cases.

AIMS: To assess the feasibility and preliminary results of ultrasound guided medial branch cryoneurolysis in the management of facet joint syndrome. MATERIAL AND METHODS: Between March 2017 and August 2017, a total of 20 patients underwent medial branch blocks, 12 of which were positive. Five patients chose to participate in the study and 8 medial branch cryoneurolysis were performed. The primary endpoint of the study was the feasibility of the procedure. The secondary endpoint was the efficacy on pain assessed over the following year after the procedure. RESULTS: Technical feasibility of cryoneurolysis under ultrasound guidance was 100%. Accurate needle positioning at the accurate target in the angle between the posterior aspect of the transverse process and the lateral aspect of the facet joint was achieved in all cases. Needle progression could be depicted with US guidance in all cases. Mean pre-procedural Visual Analogue Scale and Oswestry disability Index scores were 6.8 (range 5-8) and 20.6 (range 12- 31), respectively. Follow up showed a decrease of Visual Analogue Scale score at one month (1.75, range 0-7), and at three months (1.75 range 0-3), Mean self-reported improvement at 6 months was 76% (60- 100%) and 77% at 12 months (50-100%). We report one case of failure at one month. No complications were noted during or after the procedure. CONCLUSION: Our findings suggest that ultrasound is a valid imaging modality to perform lumbar medial branch cryoneurolysis. Initial results show that cryoneurolysis under ultrasound guidance appears as a safe and effective procedure in patients suffering for facet joint pain.

Changes in lumbar kinematics and trunk muscle electromyographic activity during baseball batting under psychological pressure.

Psychological pressure during sports competition disturbs the ideal physical movement and causes injury. Baseball batting frequently causes trunk injuries. This study aimed to examine the influence of psychological pressure on the lumbar kinematics and trunk muscle activity during the baseball batting. Fourteen collegiate baseball players participated in this study. The participants performed bat swings under three different psychological conditions (non-pressure, pressure, and emphasized pressure). The lumbar kinematics and trunk muscle activity were measured during each bat swing. One- and two-way analyses of variance were performed to compare the lumbar kinematics and trunk muscle activity among different psychological pressure conditions. The lumbar flexion angle throughout the bat swing in the swing phase, from the moment of ground contact of the lead foot to the moment of ball contact, was significantly larger under the pressure and emphasized pressure conditions than under the non-pressure condition (P<0.05). The bilateral lumbar erector spinae (LES) activities in the swing and follow-through phases were significantly higher under the emphasized pressure condition than under the non-pressure condition (P<0.05). These results indicate that the baseball batting under psychological pressure influenced the lumbar kinematics and bilateral LES activities and may be related to the development of low back pain.

Cadaveric and ultrasonographic validation of needling placement in the obliquus capitis inferior muscle.

BACKGROUND: Evidence suggests that suboccipital musculature plays an important role in headache. Proper therapeutic approaches targeting this muscle are needed. OBJECTIVE: Our aim was to determine with fresh cadavers and ultrasound imaging if a solid needle is able to properly penetrate the obliquus capitis inferior muscle during the application of dry needling. DESIGN: A cadaveric and human descriptive study. METHODS: Needling insertion and ultrasound imaging of the obliquus capitis inferior muscle was conducted on 10 pain-free healthy subjects and 5 fresh cadavers. Needling insertion was performed using a 40 mm needle inserted midway between the spinous process of C2 and transverse process of C1. The needle was advanced from a posterior to anterior direction into the obliquus capitis inferior muscle with an inferior-lateral angle to reach the lamina of C2. For the cadaveric study, the obliquus capitis inferior placement was verified by resecting the superficial upper trapezius, splenius capitis, and semispinalis capitis muscles. For ultrasographic study, a linear transducer was aligned with the long axis of the obliquus capitis inferior muscle after needle insertion. RESULTS: Both the cadaveric and ultrasonic studies showed that the needle penetrated the obliquus capitis inferior muscle during its insertion and that the tip of the needle rested against C2 laminae, thereby reaching the targeted muscle. CONCLUSION: This anatomical and ultrasound imaging study supports the assertion that needling insertion of the obliquus capitis inferior muscle can be properly conducted by an experienced clinician.

Roles of the noradrenergic nucleus locus coeruleus and dopaminergic nucleus A11 region as supraspinal defecation centers in rats.

We previously demonstrated that administration of norepinephrine, dopamine, and serotonin into the lumbosacral defecation center caused propulsive contractions of the colorectum. It is known that the monoamines in the spinal cord are released mainly from descending neurons in the brainstem. In fact, stimulation of the medullary raphe nuclei, the origin of descending serotonergic neurons, enhances colorectal motility via the lumbosacral defecation center. Therefore, the purpose of this study was to examine the roles of the noradrenergic nucleus locus coeruleus (LC) and dopaminergic nucleus A11 region in the defecation reflex. Colorectal motility was measured with a balloon in anesthetized rats. Electrical stimulation of the LC and A11 region increased colorectal pressure only when a GABAA receptor antagonist was injected into the lumbosacral spinal cord. The effects of the LC stimulation and A11 region stimulation on colorectal motility were inhibited by antagonists of α1-adrenoceptors and D2-like dopamine receptors injected into the lumbosacral spinal cord, respectively. Spinal injection of a norepinephrine-dopamine reuptake inhibitor augmented the colokinetic effect of LC stimulation. The effect of stimulation of each nucleus was abolished by surgical severing of the parasympathetic pelvic nerves. Our findings demonstrate that activation of descending noradrenergic neurons from the LC and descending dopaminergic neurons from the A11 region causes enhancement of colorectal motility via the lumbosacral defecation center. The present study provides a novel concept that the brainstem monoaminergic nuclei play a role as supraspinal defecation centers.NEW & NOTEWORTHY The present study demonstrates that electrical and chemical stimulations of the locus coeruleus or A11 region augment contractions of the colorectum. The effects of locus coeruleus and A11 stimulations on colorectal motility are due to activation of α1-adrenoceptors and D2-like dopamine receptors in the lumbosacral defecation center, respectively. The present study provides a novel concept that the brainstem monoaminergic nuclei play a role as supraspinal defecation centers.

Optical recording reveals topological distribution of functionally classified colorectal afferent neurons in intact lumbosacral DRG.

Neuromodulation as a non-drug alternative for managing visceral pain in irritable bowel syndrome (IBS) may target sensitized afferents of distal colon and rectum (colorectum), especially their somata in the dorsal root ganglion (DRG). Developing selective DRG stimulation to manage visceral pain requires knowledge of the topological distribution of colorectal afferent somata which are sparsely distributed in the DRG. Here, we implemented GCaMP6f to conduct high-throughput optical recordings of colorectal afferent activities in lumbosacral DRG, that is, optical electrophysiology. Using a mouse ex vivo preparation with distal colorectum and L5-S1 DRG in continuity, we recorded 791 colorectal afferents' responses to graded colorectal distension (15, 30, 40, and 60 mmHg) and/or luminal shear flow (20-30 mL/min), then functionally classified them into four mechanosensitive classes, and determined the topological distribution of their somata in the DRG. Of the 791 colorectal afferents, 90.8% were in the L6 DRG, 8.3% in the S1 DRG, and only 0.9% in the L5 DRG. L6 afferents had all four classes: 29% mucosal, 18.4% muscular-mucosal, 34% low-threshold (LT) muscular, and 18.2% high-threshold (HT) muscular afferents. S1 afferents only had three classes: 19.7% mucosal, 34.8% LT muscular, and 45.5% HT muscular afferents. All seven L5 afferents were HT muscular. In L6 DRG, somata of HT muscular afferents were clustered in the caudal region whereas somata of the other classes did not cluster in specific regions. Outcomes of this study can directly inform the design and improvement of next-generation neuromodulation devices that target the DRG to alleviate visceral pain in IBS patients.

Differential biomechanical properties of mouse distal colon and rectum innervated by the splanchnic and pelvic afferents.

Visceral pain is one of the principal complaints of patients with irritable bowel syndrome, and this pain is reliably evoked by mechanical distension and stretch of distal colon and rectum (colorectum). This study focuses on the biomechanics of the colorectum that could play critical roles in mechanical neural encoding. We harvested the distal 30 mm of the colorectum from mice, divided evenly into three 10-mm-long segments (colonic, intermediate and rectal), and conducted biaxial mechanical stretch tests and opening-angle measurements for each tissue segment. In addition, we determined the collagen fiber orientations and contents across the thickness of the colorectal wall by nonlinear imaging via second harmonic generation (SHG). Our results reveal a progressive increase in tissue compliance and prestress from colonic to rectal segments, which supports prior electrophysiological findings of distinct mechanical neural encodings by afferents in the lumbar splanchnic nerves (LSN) and pelvic nerves (PN) that dominate colonic and rectal innervations, respectively. The colorectum is significantly more viscoelastic in the circumferential direction than in the axial direction. In addition, our SHG results reveal a rich collagen network in the submucosa and orients approximately ±30° to the axial direction, consistent with the biaxial test results presenting almost twice the stiffness in axial direction versus the circumferential direction. Results from current biomechanical study strongly indicate the prominent roles of local tissue biomechanics in determining the differential mechanical neural encoding functions in different regions of the colorectum. NEW & NOTEWORTHY Mechanical distension and stretch-not heat, cutting, or pinching-reliably evoke pain from distal colon and rectum. We report different local mechanics along the longitudinal length of the colorectum, which is consistent with the existing literature on distinct mechanotransduction of afferents innervating proximal and distal regions of the colorectum. This study draws attention to local mechanics as a potential determinant factor for mechanical neural encoding of the colorectum, which is crucial in visceral nociception.

Extradural Characteristics of the Origins of Lumbosacral Nerve Roots.

BACKGROUND AND STUDY AIMS: A great number of unsuccessful intervertebral herniated disk surgeries in the lumbosacral region have highlighted the importance of a comprehensive knowledge of the different types of nerve root anomalies. That knowledge gained by anatomical studies (and intraoperative findings) might contribute to better results. In our study we focused on intraspinal extradural lumbosacral nerve root anomalies and their possible role in radiculopathy. MATERIAL AND METHODS: The study was performed on 43 cadavers within 24 hours after death (32 men and 11 women). Bodies were dissected in the prone position, and a laminectomy exposed the entire spinal canal for the bilateral examination of each spinal nerve root from its origin to its exit through the intervertebral foramen or sacral hiatus. Uncommon extradural features in the lumbosacral region were pursued and documented. The spinal dural sac was also opened, aimed at recognizing the normotyped, prefixed, or postfixed type of plexus. RESULTS: A total of 20.93% of anomalies of extradural lumbosacral nerve root origins were observed, with the normotyped plexus prevailing. We observed atypical spacing of exits of lumbosacral roots (four cases), two roots leaving one intervertebral foramen (one case), extradural anastomoses (two cases), and missing extradural nerve root courses (two cases). The results were differentiated according to the normotyped, prefixed, or postfixed plexus type. CONCLUSION: Results of similar studies dealing with anomalies of lumbosacral nerve roots were aimed at improving the results of herniated disk surgeries because ∼ 10% of misdiagnoses are related to ignorance of anatomical variability. Our observations may help explain the differences between the clinical picture and generally accepted anatomical standards.

The nerve root sedimentation sign in diagnosis of lumbar spinal stenosis.

BACKGROUND: The nerve root sedimentation sign is a magnetic resonance (MR) sign, shown to be present in central lumbar spinal stenosis. The lack of sedimentation of the nerve roots to the dorsal part of the dural sac is consistent with the positive nerve root sedimentation sign. PURPOSE: To validate the reliability of the nerve root sedimentation sign in diagnosis of different grades of lumbar spinal canal stenosis. MATERIAL AND METHODS: This study was a retrospective review of 101 consecutive MR imaging (MRI) studies obtained on patients with clinically suspected lumbar canal stenosis. Based on the minimum anteroposterior (AP) diameter of the dural sac the study sample was classified into two groups: a group with morphological lumbar spinal stenosis; and the group of patients free from stenosis (AP > 12 mm). Patients with stenosis were further subclassified based on its severity: severe stenosis (AP ≤ 10 mm); and moderate stenosis (AP > 10 mm to ≤ 12 mm). RESULTS: Positive sedimentation sign was identified in 81% of patients with severe lumbar spinal stenosis and 14% of patients with moderate stenosis. No patients without lumbar spinal stenosis had a positive nerve root sedimentation sign. Of patients with a positive nerve root sedimentation sign, 89% presented with neurological claudication. CONCLUSION: The nerve root sedimentation is a useful tool for identification of patients with both severe clinical and morphological lumbar spinal stenosis; however, its performance in the diagnosis of patients with moderate morphological spinal stenosis is poor.

Movements of the lumbo-sacral nerve roots in the spinal canal induced by straight leg raising test: an anatomical study.

PURPOSE: The pain involved in the herniated discs could be generated by some mobility of the nerve roots during straight leg raising (SLR). SLR produces some movement of nerves, but the magnitude of this displacement needs to be thorough, that is why we have investigated lumbo-sacral nerve root displacement in the spinal canal during the passive straight leg raise (SLR). METHODS: Fourteen cadavers underwent laminectomy to mark the nerve roots of L2-S1 with lead balls. X-rays were taken during different movements imposed on the body: bilateral hip extension, left SLR then right and bilateral SLR. By superimposing these images two by two, the displacement of the nerve roots is quantified numerically during the various SLR maneuvers with respect to the reference position corresponding to the bilateral hip extension. RESULTS: The median range of the different nerve root movements ranged from 0.10 to 0.51 cm (p < 0.05 except for the L2 root) when the left SLR is applied, from 0.26 to 0.48 cm (p < 0.05) with the right SLR and from 0.30 to 0.65 cm (p < 0.05) with a bilateral SLR. No statistically significant relationship was found between age and movement value. CONCLUSIONS: The lumbo-sacral nerve roots in the spinal canal region move statistically significantly in response to the clinically applied SLR test, except for L2 root during the left SLR. This movement is symmetric and greater when a bilateral SLR is applied. These anatomical results are correlated with those observed empirically in clinical practice.

Quadratus lumborum block: are we aware of its side effects? A report of 2 cases / Bloqueio do quadrado lombar: estamos cientes de seus efeitos colaterais? Relato de dois casos

Abstract Background and objectives The quadratus lumborum block was initially described in 2007 and aims at blocking the same nerves as the ones involved on the Transverse Abdominis Plane block, while accomplishing some visceral enervation as well due to closer proximity with the neuroaxis and sympathetic trunk. Given its versatility, we have successfully used it in a wide range of procedures. We report two cases where we believe the dispersion of local anesthetic is likely to have led to a previously undescribed complication. Clinical reports We report two cases in which we performed a quadratus lumborum type II block and general anesthesia for total gastrectomy and right hemicolectomy. There were no noteworthy events while performing the block and inducing general anesthesia, but within 30-40 min serious hypotension and tachycardia were noted. As other motives for hypotension were ruled out, the event was interpreted as block-induced sympatholysis due to cephalad dispersion of the local anesthetic to the paravertebral and epidural space, and successfully managed with ephedrine and increase of the crystalloid infusion rate. Conclusions The quadratus Lumborum block is safe to execute and provides effective abdominal wall and visceral analgesia. However, the possibility of eliciting undesired episodes should prompt caution when performing this block and practitioners should thereafter remain vigilant. Questions regarding ideal dosing, volumes, timing of block and pertinence of catheters remain to be answered.

Resumo Justificativa e objetivos O bloqueio do quadrado lombar foi primeiramente descrito em 2007 e tem como objetivo o bloqueio dos mesmos nervos envolvidos no bloqueio do plano transverso abdominal, ao atingir algumas inervações viscerais, bem como devido à maior proximidade com o neuroeixo e cadeia simpática. Dada a sua versatilidade, temos usado esse bloqueio com sucesso em uma grande variedade de procedimentos. Relatamos dois casos nos quais acreditamos que a dispersão do anestésico local pode ter levado a uma complicação não descrita previamente. Relatos clínicos Relatamos dois casos nos quais realizamos o bloqueio do quadrado lombar tipo II e anestesia geral para gastrectomia total e hemicolectomia direita. Não houve eventos notáveis durante o bloqueio e a indução da anestesia geral, mas, dentro de 30 a 40 minutos, observamos grave hipotensão e taquicardia. Como outros motivos para a hipotensão foram descartados, o evento foi interpretado como simpatólise induzida pelo bloqueio devido à dispersão cefálica do anestésico local para os espaços paravertebral e epidural e tratado com sucesso com efedrina e aumento da taxa de infusão de cristaloides. Conclusões O bloqueio do quadrado lombar oferece segurança na execução e fornece analgesia eficaz à parede abdominal e vísceras. Porém, a possibilidade de provocar episódios indesejáveis requer cautela em sua execução e, por conseguinte, os médicos precisam estar atentos. As questões relacionadas à dosagem ideal, aos volumes, ao tempo de bloqueio e à pertinência dos cateteres permanecem indefinidas.

Segmental innervation of the Göttingen minipig hind body. An electrophysiological study.

The Göttingen minipig is being used increasingly in biomedical research. The anatomical structure of the porcine peripheral nervous system has been extensively characterized, but no equivalent to the dermatome map, which is so valuable in human neurophysiological research, has been created. We characterized the medullar segmental skin and muscle innervations of the minipig hind body, using neurophysiological methodology. Six adult minipigs underwent unilateral laminectomy from L2 to S3, exposing the nerve roots. The skin of the hind part of the body was divided into 36 predefined fields, based on anatomical landmarks for consistent reproducibility. We recorded the evoked potential in each exposed nerve root L2-S3 for cutaneous stimulation of each skin field, mapping the sensory innervation of the entire hind body. We subsequently recorded the motor response in seven predefined muscles during sequential stimulation of the L2-S3 nerve roots. We obtained a clear sensory evoked potential in the nerve roots during stimulation of the skin fields, allowing us to map the sensory innervation of the minipig hind body. Neurophysiological data from skin stimulation and muscle recordings enabled us to map the sensory innervation of the Göttingen minipig hind body and provide information about muscular innervation. The skin fields were sensory innervated by more than one root. The muscles each had one dominant root with minor contribution from neighboring roots. This is consistent with experimental data from human studies.