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Study Design: Retrospective review of prospectively collected data., Objective: This study aimed to accurately map the lower extremity muscles innervated by the lumbar spinal roots by directly stimulating the spinal roots during surgery., Summary of Background Data: Innervation of the spinal roots in the lower extremities has been estimated by clinical studies, anatomic studies, and animal experiments. However, there have been discrepancies between studies. Moreover, there are no studies that have studied the laterality of lower limb innervation., Materials and Methods: In 73 patients with lumbar degenerative disease, a total of 147 spinal roots were electrically stimulated and the electromyographic response was recorded at the vastus medialis (VM), gluteus medius (GM), tibialis anterior (TA), biceps femoris (BF), and gastrocnemius (GC). The asymmetry index (AI) was obtained using the following equation to represent the left-right asymmetry in the compound muscle action potential (CMAP) amplitude. Paired t tests were used to compare CMAP amplitudes on the right and left sides. Differences in the AI among the same spinal root groups were determined using one-way analysis of variance., Results: The frequency of CMAP elicitation in VM, GM, TA, BF, and GC were 100%, 75.0%, 50.0%, 83.3%, and 33.3% in L3 spinal root stimulation, 90.4%, 78.8%, 59.6%, 73.1%, and 59.6% in L4 spinal root stimulation, 32.2%, 78.0%, 93.2%, 69.5%, and 83.1% in L5 spinal root stimulation, and 40.0%, 100%, 80.0%, 70.0%, and 80.0% in S1 spinal root stimulation, respectively. The most frequent muscle with maximum amplitude of the CMAP in L3, L4, L5, and S1 spinal root stimulation was the VM, GM, TA, and GM, respectively. Unilateral innervation occurred at high rates in the TA in L4 root stimulation and the VM in L5 root stimulation in 37.5% and 42.3% of patients, respectively. Even in patients with bilateral innervation, a 20% to 38% AI of CMAP amplitude was observed., Conclusions: The spinal roots innervated a much larger range of muscles than what is indicated in general textbooks. Furthermore, a non-negligible number of patients showed asymmetric innervation of lower limb by the lumbar spinal roots., Competing Interests: The authors report no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

On demand and localized treatment for excessive muscle tone after spinal cord injury (SCI) is currently not available. Here, we examine the reduction in leg hypertonus in a person with mid-thoracic, motor complete SCI using a commercial transcutaneous electrical stimulator (TES) applied at 50 or 150 Hz to the lower back and the possible mechanisms producing this bilateral reduction in leg tone. Hypertonus of knee extensors without and during TES, with both cathode (T11-L2) and anode (L3-L5) placed over the spinal column (midline, MID) or 10 cm to the left of midline (lateral, LAT) to only active underlying skin and muscle afferents, was simultaneously measured in both legs with the pendulum test. Spinal reflexes mediated by proprioceptive (H-reflex) and cutaneomuscular reflex (CMR) afferents were examined in the right leg opposite to the applied LAT TES. Hypertonus disappeared in both legs but only during thoracolumbar TES, and even during LAT TES. The marked reduction in tone was reflected in the greater distance both lower legs first dropped to after being released from a fully extended position, increasing by 172.8% and 94.2% during MID and LAT TES, respectively, compared with without TES. Both MID and LAT (left) TES increased H-reflexes but decreased the first burst, and lengthened the onset of subsequent bursts, in the cutaneomuscular reflex of the right leg. Thoracolumbar TES is a promising method to decrease leg hypertonus in chronic, motor complete SCI without activating spinal cord structures and may work by facilitating proprioceptive inputs that activate excitatory interneurons with bilateral projections that in turn recruit recurrent inhibitory neurons. NEW & NOTEWORTHY We present proof of concept that surface stimulation of the lower back can reduce severe leg hypertonus in a participant with motor complete, thoracic spinal cord injury (SCI) but only during the applied stimulation. We propose that activation of skin and muscle afferents from thoracolumbar transcutaneous electrical stimulation (TES) may recruit excitatory spinal interneurons with bilateral projections that in turn recruit recurrent inhibitory networks to provide on demand suppression of ongoing involuntary motoneuron activity.

Objective: This study aimed at determining whether stimulation of sacral spinal roots can induce penile erection in cats., Materials and Methods: In anesthetized cats, a 20-gauge catheter was inserted into the corpus cavernosum to measure the penile pressure. Stimulus pulses (5-80 Hz, 0.2 ms) were applied through bipolar hook electrodes to sacral ventral roots alone or to combined ventral and dorsal roots of a single S1-S3 segment to induce penile pressure increases and penile erection., Results: Stimulation of the S1 or S2 ventral root at 30 to 40 Hz induced observable penile erection with rigidity and the largest increase (169 ± 11 cmH 2 O) in penile pressure. Continuous stimulation (10 minutes) of afferent and efferent axons by simultaneous stimulation of the S1 or S2 dorsal and ventral roots at 30 Hz also produced a large increase (190 ± 8 cmH 2 O) in penile pressure that was sustainable during the entire stimulation period. After a complete spinal cord transection at the T9-T10 level, simultaneous stimulation of the S1 or S2 dorsal and ventral roots induced large (186 ± 9 cmH 2 O) and sustainable increases in penile pressure., Conclusion: This study indicates the possibility to develop a novel neuromodulation device to restore penile erection after spinal cord injury using a minimally invasive surgical approach to insert a lead electrode through the sacral foramen to stimulate a sacral spinal root., (Copyright © 2022 International Neuromodulation Society. Published by Elsevier Inc. All rights reserved.)

Background: Cervical radiculopathy is a common cause of neck pain with resultant intraneural edema and impaired nerve function. One strategy to treat radiculopathy is neurodynamic mobilization (NDM); however, little is known about the effect of this treatment on nerve tissue fluid dynamics., Objective: Investigate the impact of upper limb, median nerve-biased NDM on longitudinal intraneural fluid dispersion in the C5,C6,C7 nerve roots in un-embalmed cadavers., Design: In situ repeated measures., Methods: Human cadavers (n = 8) were dissected to expose and inject C5,C6,C7 cervical nerve roots with a dying agent. Initial longitudinal dye spread was recorded after dye spread stabilization. Cadavers were taken through 150 repetitions of upper limb, median nerve-biased NDM followed by dye spread re-measurement. Paired-samples t-tests with Bonferroni correction (α = 0.017) were used to compare pre-vs post-NDM dye spread measurements at C5,C6,C7 nerve roots; a one-way repeated measures ANOVA (α = 0.05) was used to examine differences between change scores for C5,C6,C7 nerve roots., Results: Median nerve-biased NDM resulted in significant intraneural longitudinal dye spread at C5 and C6 nerve roots of 0.6 ± 0.6 mm and 3.4 ± 3.9 mm, respectively (p < 0.014). Dye spread was not significant at C7 nerve root (0.4 ± 0.7 mm). There was no between root difference in change of longitudinal dye spread between C5, C6, and C7 nerve roots., Conclusions: The results of this study show median nerve-biased NDM produced internal fluid movement within C5 and C6 cervical nerve roots. Results provide insight regarding possible mechanism of action and feasibility of NDM in treatment of patients with cervical radiculopathy., Competing Interests: Declaration of competing interest None., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Supra-sacral spinal cord injury (SCI) causes loss of bladder fullness sensation and bladder over-activity, leading to retention and incontinence respectively. Velocity selective recording (VSR) of nerve roots innervating the bladder might enable identification of bladder activity. A 10-electrode nerve cuff for sacral nerve root VSR was developed and tested in a sheep model during acute surgeries and chronic implantation for 6 months. The cuff performed well, with 5.90±1.90 kΩ electrode, and <~800 Ω tissue impedance after 189 days implantation with a stable device and tissues. This is important information for assessing the feasibility of chronic VSR.Clinical Relevance-This demonstrates the manufacturing and performance of a neural interface for chronic monitoring of bladder nerve afferents with applications in urinary incontinence and retention management following SCI.

Exercise modifies respiratory functions mainly through the afferent feedback provided by exercising limbs and the descending input from suprapontine areas, two contributions that are still underestimated in vitro. To better characterize the role of limb afferents in modulating respiration during physical activity, we designed a novel experimental in vitro platform. The whole central nervous system was isolated from neonatal rodents and kept with hindlimbs attached to an ad-hoc robot (Bipedal Induced Kinetic Exercise, BIKE) driving passive pedaling at calibrated speeds. This setting allowed extracellular recordings of a stable spontaneous respiratory rhythm for more than 4 h, from all cervical ventral roots. BIKE reversibly reduced the duration of single respiratory bursts even at lower pedaling speeds (2 Hz), though only an intense exercise (3.5 Hz) modulated the frequency of breathing. Moreover, brief sessions (5 min) of BIKE at 3.5 Hz augmented the respiratory rate of preparations with slow bursting in control (slower breathers) but did not change the speed of faster breathers. When spontaneous breathing was accelerated by high concentrations of potassium, BIKE reduced bursting frequency. Regardless of the baseline respiratory rhythm, BIKE at 3.5 Hz always decreased duration of single bursts. Surgical ablation of suprapontine structures completely prevented modulation of breathing after intense training. Albeit the variability in baseline breathing rates, intense passive cyclic movement tuned fictive respiration toward a common frequency range and shortened all respiratory events through the involvement of suprapontine areas. These observations contribute to better define how the respiratory system integrates sensory input from moving limbs during development, opening new rehabilitation perspectives., (© 2023. The Author(s).)

Spinal cord injuries result in severe neurological deficits and neuronal loss, with poor functional recovery. Mesenchymal stem cells have shown promising results; therefore the present objective of this work was to compare motor recovery after treatment with human dental pulp stem cells (hDPSC) cultivated in monolayer (2D) or as spheroids (3D), following avulsion and reimplantation of spinal motor roots in adult rats. Thus, 72 adult female Lewis rats were divided into 4 groups: avulsion (AV); avulsion followed by reimplantation (AR); avulsion associated with reimplant and 2D cell therapy (AR + 2D), and avulsion associated with reimplant and 3D cell therapy (AR + 3D). The application of the cells in 2D and 3D was performed by microsurgery, with subsequent functional assessment using a walking track test (Catwalk system), immunohistochemistry, neuronal survival, and qRT-PCR in 1-, 4-, and 12-weeks post-injury. The animals in the AR + 2D and AR + 3D groups showed the highest neuronal survival rates, and immunofluorescence revealed downregulation of GFAP, and Iba-1, with preservation of synaptophysin, indicating a reduction in glial reactivity, combined with the maintenance of pre-synaptic inputs. There was an increase in anti-inflammatory (IL-4, TGFβ) and a reduction of pro-inflammatory factors (IL-6, TNFα) in animals treated with reimplantation and hDPSC. As for the functional recovery, in all analyzed parameters, the AR + 2D group performed better and was superior to the avulsion alone. Overall, our results indicate that the 2D and 3D cell therapy approaches provide successful immunomodulation and motor recovery, consistent with advanced therapies after spinal cord injury., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Objective. Spinal cord neuromodulation has gained much attention for demonstrating improved motor recovery in people with spinal cord injury, motivating the development of clinically applicable technologies. Among them, transcutaneous spinal cord stimulation (tSCS) is attractive because of its non-invasive profile. Many tSCS studies employ a high-frequency (10 kHz) carrier, which has been reported to reduce stimulation discomfort. However, these claims have come under scrutiny in recent years. The purpose of this study was to determine whether using a high-frequency carrier for tSCS is more comfortable at therapeutic amplitudes, which evoke posterior root-muscle (PRM) reflexes. Approach. In 16 neurologically intact participants, tSCS was delivered using a 1 ms long monophasic pulse with and without a high-frequency carrier. Stimulation amplitude and pulse duration were varied and PRM reflexes were recorded from the soleus, gastrocnemius, and tibialis anterior muscles. Participants rated their discomfort during stimulation from 0 to 10 at PRM reflex threshold. Main Results. At PRM reflex threshold, the addition of a high-frequency carrier (0.87 ± 0.2) was equally comfortable as conventional stimulation (1.03 ± 0.18) but required approximately double the charge to evoke the PRM reflex (conventional: 32.4 ± 9.2 µ C; high-frequency carrier: 62.5 ± 11.1 µ C). Strength-duration curves for tSCS with a high-frequency carrier had a rheobase that was 4.8× greater and a chronaxie that was 5.7× narrower than the conventional monophasic pulse, indicating that the addition of a high-frequency carrier makes stimulation less efficient in recruiting neural activity in spinal roots. Significance. Using a high-frequency carrier for tSCS is equally as comfortable and less efficient as conventional stimulation at amplitudes required to stimulate spinal dorsal roots., (Creative Commons Attribution license.)

Aim: To analyze the increase in diameter of the nerve roots C5 and C6 in early childhood., Methods: The nerve roots of 56 children aged 0 days to 10 years (47 younger than 2 years) were examined by high-resolution ultrasound imaging. The correlation of diameter and age was statistically tested and a logarithmic regression analysis was performed to develop a logarithmic growth model., Results: The increase in nerve root diameter is greatest during the first 2 years of life and then the growth rate decreases steadily. The relationship between age and diameter follows a logarithmic curve (p < 10 -8 )., Interpretation: The main increase in the diameter of the nerve roots happens in the first 2 years of life. Comparing data from a previous study, our data also suggest that the maturation of the proximal part of the median nerve is comparable to the maturation of its distal segments. This suggests a synchronous maturation of the axons and myelin sheath for the whole extent of the nerve, from the radix to its very distal part., What This Paper Adds: Normative values for the size of the cervical nerve roots C5 and C6; an insight into the maturation of the proximal parts of the peripheral nervous system; and the correlation between age and cervical root diameter., (© 2022 The Authors. Brain and Behavior published by Wiley Periodicals LLC.)

The classic view of the vertebrate dorsal root ganglion is that it arises from trunk neural crest cells that migrate to positions lateral to the spinal cord, sending axons dorsally into the spinal cord and dendrites ventrally to meet with motor axons in the ventral root to form spinal nerves. As a result, the ganglion ends up lying in the dorsal root of the spinal nerve. Serial histological sections of parts of the trunk of juveniles of different snake species revealed that the ganglia lie distal to the junction of dorsal and ventral roots of spinal nerves and outside the neural canal. The anatomical position of spinal ganglia in snakes suggests that regulation of trunk neural crest migration in snakes differs from that in the model endotherms in which it has been most thoroughly explored. Dorsal roots have no distinct rootlets and the span of root entry to the spinal cord is short compared to that of ventral rootlets in the same segment. Comparing early developmental stages to juvenile spinal cords shows an increased separation of spinal nerve root sites and ventral migration of the ganglion in later development. Dorsal rami of the spinal nerves leave directly from the dorsal edge of the ganglion, and the ventral ramus leaves from the ventral tip of the ganglion. How these features relate to the developmental regulation of ganglion form and position and the extraordinary locomotor capabilities of the snake trunk are unclear., (© 2022 Wiley Periodicals LLC.)

This study aimed to identify potential lateralization of bladder function. Electrical stimulation of spinal roots or the pelvic nerve's anterior vesical branch was performed bilaterally in female dogs. The percent difference between the left and right stimulation-induced increased detrusor pressure was determined. Bladders were considered left or right-sided if differences were greater or less than 25% or 10%. Based on differences of 25%, upon stimulation of spinal roots, bladders were left-sided in 17/44 (38.6%), right-sided in 12/44 (27.2%) and bilateral in 15/44 (34.2%). Using ± 10%, 48% had left side dominance (n = 21/44), 39% had right side dominance (n = 17/44), and 14% were bilateral (n = 6/44). With stimulation of the pelvic nerve's anterior vesical branch in 19 dogs, bladders were left-sided in 8 (42.1%), right-sided in 6 (31.6%) and bilateral in 5 (26.3%) using 25% differences and left side dominance in 8 (43%), right sided in 7 (37%) and bilateral in 4 (21%) using 10% differences. These data suggest lateralization of innervation of the female dog bladder with left- and right-sided lateralization occurring at similar rates. Lateralization often varied at different spinal cord levels within the same animal., Competing Interests: The authors have declared that no competing interests exist.

Background: Axo-axonic contacts onto central terminals of primary afferents modulate sensory inputs to the spinal cord. These contacts produce primary afferent depolarization (PAD), which serves as a mechanism for presynaptic inhibition, and also produce dorsal root reflexes (DRRs), which may regulate the excitability of peripheral terminals and second order neurons. We aimed to identify changes in these responses as a consequence of peripheral inflammation., Methods: In vitro spinal cord recordings of spontaneous activities in dorsal and ventral roots were performed in control mice and following paw inflammation. We also used pharmacological assays to define the neurotransmitter systems implicated in such responses., Results: Paw inflammation increased the frequency and amplitude of spontaneous dorsal root depolarizations, the occurrence of DRRs and the amplitude of ventral roots depolarizations. PAD was classified in two different patterns based on their relation to ventral activity: time-locked and independent events. Both patterns increased in amplitude after paw inflammation, and independent events also increased in frequency. The circuits that were responsible for this activity implicated both glutamatergic and GABAergic transmission. Adrenergic modulation differentially affected both types of PAD, and this modulation changed after paw inflammation., Conclusions: Our findings suggest the existence of independent spinal circuits at the origin of PAD and DRRs. Inflammation modulates these circuits differentially, unveiling varied mechanisms of spinal sensitization. This in vitro approach provides an isolated model for the study of the mechanisms of central sensitization and for the performance of pharmacological assays with the purpose of identifying and testing novel antinociceptive targets., Significance: Spinal circuits modulate activity of primary afferents acting on central terminals. Under in vitro conditions, dorsal roots show spontaneous activity in the form of depolarizations and action potentials. Our findings are consistent with the existence of several independent generator circuits. Experimental paw inflammation reduced mechanical withdrawal threshold and significantly increased the spontaneous activity of dorsal roots, which may be secondary to an enhanced output of spinal generators. This can be considered as a novel sign of central sensitization., (© 2021 The Authors. European Journal of Pain published by John Wiley & Sons Ltd on behalf of European Pain Federation - EFIC ®.)

Background: Spinal cord injuries induce a critical loss of motoneurons followed by irreversible locomotor function impairment. Surgical approaches combined with neuroprotective agents effectively rescue the damaged motoneurons and improve locomotor function. Our aim was to develop a reliable method which is able to provide quantifiable and in-depth data on the locomotor recovery during skeletal muscle reinnervation., New Method: Sprague-Dawley rats underwent lumbar 4 ventral root avulsion and reimplantation followed by riluzole treatment in order to rescue the injured motoneurons of the damaged pool. Control animals were operated, but received no riluzole treatment. The locomotor pattern of the hind limb was recorded biweekly on a special runway equipped with high resolution and high speed digital cameras producing both lateral and rear views simultaneously. All together 12 parameters of the hind limb movement pattern were evaluated by measuring specific joint angles, footprints and gait parameters in single video frames. Four months after the operation Fast Blue, a fluorescent retrograde tracer was applied to the L4 spinal nerve in order to label the reinnervating motoneurons., Results: Our results confirmed the sensitivity of our arrangement and established strong relationship between the functional improvement and the morphological reinnervation. Moreover, we developed a correction method to make the system tolerant to the differences in the weight, step duration and step length., Comparison With Existing Methods: There are no commercially available cheap, multi-parametric analysing equipment to characterise the gait in its complexity., Conclusions: Our system offers a modular, adaptable and expandable analysis on the reinnervation of the limb musculature in rodents., (Copyright © 2021. Published by Elsevier B.V.)

The aim of this study was to determine whether stimulation of sacral spinal nerve roots can induce defecation in cats. In anesthetized cats, bipolar hook electrodes were placed on the S1-S3 dorsal and/or ventral roots. Stimulus pulses (1-50 Hz, 0.2 ms) were applied to an individual S1-S3 root to induce proximal/distal colon contractions and defecation. Balloon catheters were inserted into the proximal and distal colon to measure contraction pressure. Glass marbles were inserted into the rectum to demonstrate defecation by videotaping the elimination of marbles. Stimulation of the S2 ventral root at 7 Hz induced significantly ( P < 0.05) larger contractions (32 ± 9 cmH 2 O) in both proximal and distal colon than stimulation of the S1 or S3 ventral root. Intermittent (5 times) stimulation (1 min on and 1 min off) of both dorsal and ventral S2 roots at 7 Hz produced reproducible colon contractions without fatigue, whereas continuous stimulation of 5-min duration caused significant fatigue in colon contractions. Stimulation (7 Hz) of both dorsal and ventral S2 roots together successfully induced defecation that eliminated 1 or 2 marbles from the rectum. This study indicates the possibility to develop a novel neuromodulation device to restore defecation function after spinal cord injury using a minimally invasive surgical approach to insert a lead electrode via the sacral foramen to stimulate a sacral spinal root. NEW & NOTEWORTHY This study in cats determined the optimal stimulation parameters and the spinal segment for sacral spinal root stimulation to induce colon contraction. The results have significant implications for design of a novel neuromodulation device to restore defecation function after spinal cord injury (SCI) and for optimizing sacral neuromodulation parameters to treat non-SCI people with chronic constipation.

FK1706 is a novel non-immunosuppressive immunophilin ligand with neurotrophic activity and exerts its neurotrophic effect through NGF. The present study aimed to elaborate on the neurotrophic activity and the mechanism of action of FK1706 in end-to-side neurorrhaphy rats and SH-SY5Y cells. In the regenerating nerves of neurorrhaphy rats, FK1706 increased the thickness of myelin sheath and the level of nerve regeneration-related proteins. The mechanism of action of FK1706 on neurite regrowth was elucidated in vitro by incubating SH-SY5Y cells in different conditions (Control, NGF, FK1706, NGF + FK1706, NGF + FK1706 + geldanamycin). Under the conditions where NGF was used, the phosphorylation level of major proteins (Raf-1 and ERK) in the Ras/Raf/MAPK/ERK signaling pathway related to SH-SY5Y cell proliferation was significantly enhanced following the application of FK1706. The number of viable cells, cell viability and neurite length of SH-SY5Y cells was maximal when NGF and FK1706 were used simultaneously. The binding level of HSP90 and Raf-1 in FK1706 group was the highest. These results indicated that FK1706 could significantly promote nerve regeneration after neurorrhaphy. The putative mechanism of action stated that FK1706 could promote the binding of HSP90 and Raf-1, make Raf-1 continue to be activated, thereby affecting key proteins in the Ras/Raf/MAPK/ERK signaling pathway related to the neurotrophic effects of NGF to promote the proliferation and neurite regrowth of nerve cells., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: While palsy of the L5 nerve root due to stretch injury is a known complication in complex lumbosacral spine surgery, the underlying pathophysiology remains unclear. The goal of this cadaveric study was to quantify movement of the L5 nerve root during flexion/extension of the hip and lower lumbar spine., Methods: Five fresh-frozen human cadavers were dissected on both sides to expose the lumbar vertebral bodies and the L5 nerve roots. Movement of the L5 nerve root was tested during flexion and extension of the hip and lower lumbar spine. Four steps were undertaken to characterize these movements: (1) removal of the bilateral psoas muscles, (2) removal of the lumbar vertebral bodies including the transforaminal ligaments from L3 to L5, (3) opening and removing the dura mater laterally to visualize the rootlets, and (4) removal of remaining soft tissue surrounding the L5 nerve root. Two metal bars were inserted into the sacral body at the level of S1 as fixed landmarks. The tips of these bars were connected to make a line for the ruler that was used to measure movement of the L5 nerve roots. Movement was regarded as measurable when there was an L5 nerve excursion of at least 1 mm., Results: The mean age at death was 86.6 years (range 68-89 years). None of the four steps revealed any measurable movement after flexion/extension of the hip and lower lumbar spine on either side (< 1 mm). Flexion of the hip and lower lumbar spine revealed lax L5 nerve roots. Extension of the hip and lower lumbar spine showed taut ones., Conclusion: Significant movement or displacement of the L5 nerve root could not be quantified in this study. No mechanical cause for L5 nerve palsy could be identified so the etiology of the condition remains unclear.

This study aimed to clarify whether the reflex excitation of muscle sympathetic nerves induced by contractions of the skeletal muscles modulates their contractility. In anesthetized rats, isometric tetanic contractions of the triceps surae muscles were induced by electrical stimulation of the intact tibial nerve before and after transection of the lumbar sympathetic trunk (LST), spinal cord, or dorsal roots. The amplitude of the tetanic force (TF) was reduced by approximately 10% at 20 min after transection of the LST, spinal cord, or dorsal roots. The recorded postganglionic sympathetic nerve activity from the lumbar gray ramus revealed that both spinal and supraspinal reflexes were induced in response to the contractions. Repetitive electrical stimulation of the cut peripheral end of the LST increased the TF amplitude. Our results indicated that the spinal and supraspinal somato-sympathetic nerve reflexes induced by contractions of the skeletal muscles contribute to the maintenance of their own contractile force.

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.

Previous studies suggested that the mode of donor transection is a critical factor affecting the efficacy of the contralateral C7 (CC7) nerve transfer. Nevertheless, the mechanism underlying this phenomenon remains elusive. The aim of this study was to investigate the relationship between the division modes of the CC7 nerve and cortical functional reorganization of Sprague-Dawley rats. We hypothesized that different methods of CC7 nerve transection might induce differences in cortical functional reorganization, thus resulting in differences in surgery efficacy. BDNF, TNF- α /IL-6, and miR-132/134 were selected as indicators of cortical functional reorganization. No significant differences in all these indicators were noted between the entire group and the entire root+posterior division group ( P > 0.05). BDNF and miR-132/134 levels in the entire group and the entire root+posterior division group were significantly increased compared with their levels in the posterior group and the blank control group ( P < 0.001). In all groups, BDNF, TNF- α /IL-6, and miR-132/134 levels in both hemispheres initially increased and subsequently decreased until week 40. In conclusion, this study provided the evidence of dynamic changes in BDNF, TNF- α /IL-6, and miR-132/134 in the cortex of rats after CC7 nerve transfer using different transecting modes, demonstrating that different CC7 nerve divisions might result in different surgical effects through modulation of cortical reorganization., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2021 Jinding Guo et al.)

After a dorsal root crush injury, centrally-projecting sensory axons fail to regenerate across the dorsal root entry zone (DREZ) to extend into the spinal cord. We find that chemogenetic activation of adult dorsal root ganglion (DRG) neurons improves axon growth on an in vitro model of the inhibitory environment after injury. Moreover, repeated bouts of daily chemogenetic activation of adult DRG neurons for 12 weeks post-crush in vivo enhances axon regeneration across a chondroitinase-digested DREZ into spinal gray matter, where the regenerating axons form functional synapses and mediate behavioral recovery in a sensorimotor task. Neuronal activation-mediated axon extension is dependent upon changes in the status of tubulin post-translational modifications indicative of highly dynamic microtubules (as opposed to stable microtubules) within the distal axon, illuminating a novel mechanism underlying stimulation-mediated axon growth. We have identified an effective combinatory strategy to promote functionally-relevant axon regeneration of adult neurons into the CNS after injury.

Background: The anatomical distribution of the extraforaminal ligaments in the cervical intervertebral foramina has been well studied. However, detailed descriptions of the biomechanical characteristics of these ligaments are lacking., Methods: The paravertebral muscles were dissected, and the extraforaminal ligaments and nerve roots were identified. The C5 and C7 or C6 and C8 cervical nerve roots on both sides were randomly selected, and a window was opened on the vertebral lamina to expose the posterior spinal nerve root segments. Five needles were placed on the nerve root and the bone structure around the intervertebral foramen; the distal end of the nerve root was then tied with silk thread, and the weights were connected across the pulley. A weight load was gradually applied to the nerve root (50 g/time, 60 times in total). At the end of the experiment, segments of the extraforaminal ligaments were selectively cut off to compare the changes in nerve root displacement., Results: The displacement of the C5, C6, C7, and C8 nerve roots increases with an increasing traction load, and the rate of change of nerve root displacement in the intervertebral foramen is smaller than that in the nerve root on the outside area (p < 0.05). Extraforaminal ligaments can absorb part of the pulling load of the nerve root; the C5 nerve root has the largest load range., Conclusions: Cervical extraforaminal ligaments can disperse the tension load on the nerve root and play a role in protecting the nerve root. The protective effect of the C5 nerve root was the strongest, and this may anatomically explain why the C5 nerve roots are less prone to simple avulsion.

Plastic adaptations are known to take place in muscles, tendons, joints, and the nervous system in response to changes in muscle activity. However, few studies have addressed how these plastic adaptations are related. Thus this study focuses on changes in the mechanical properties of the ankle plantarflexor muscle-tendon unit, stretch reflex activity, and spinal neuronal pathways in relation to cast immobilization. The left rat hindlimb from toes to hip was immobilized with a plaster cast for 1, 2, 4, or 8 wk followed by acute electrophysiological recordings to investigate muscle stiffness and stretch reflex torque. Moreover, additional acute experiments were performed after 4 wk of immobilization to investigate changes in the central gain of the stretch reflex. Monosynaptic reflexes (MSR) were recorded from the L4 and L5 ventral roots following stimulation of the corresponding dorsal roots. Rats developed reduced range of movement in the ankle joint 2 wk after immobilization. This was accompanied by significant increases in the stiffness of the muscle-tendon complex as well as an arthrosis at the ankle joint at 4 and 8 wk following immobilization. Stretch reflexes were significantly reduced at 4-8 wk following immobilization. This was associated with increased central gain of the stretch reflex. These data show that numerous interrelated plastic changes occur in muscles, connective tissue, and the central nervous system in response to changes in muscle use. The findings provide an understanding of coordinated adaptations in multiple tissues and have important implications for prevention and treatment of the negative consequences of immobilization following injuries of the nervous and musculoskeletal systems. NEW & NOTEWORTHY Immobilization leads to multiple simultaneous adaptive changes in muscle, connective tissue, and central nervous system.

Objective: The rate of neuronal apoptosis increases after spinal cord injury (SCI). Anastomosing the normal nerve roots above the SCI level to the injured sacral nerve roots can enhance the functional recovery of neurons. Therefore, we evaluated the effect of sacral nerve root transfer after SCI on pontine neuronal survival., Methods: Sprague-Dawley rats were randomly divided into three groups: Group A, reconstruction of afferent and efferent nerve pathways of the bladder after SCI; Group B, SCI only; and Group C, control group. We examined pontine neuronal morphology using hematoxylin and eosin (H&E) staining after SCI and nerve transfer. Bcl-2 and Bax protein expression changes in the pontine micturition center were quantified by immunohistochemistry. The number of apoptotic neurons was determined by TUNEL staining. We examined pontine neuronal apoptosis by transmission electron microscopy (TEM) at different time points., Results: H&E staining demonstrated that the number of neurons had increased in Group A, but more cells in Group B displayed nuclear pyknosis, with the disappearance of the nucleus. Compared with Group B, Group A had significantly higher Bcl-2 expression, significantly lower Bax expression, and a significantly higher Bcl-2/Bax ratio. The number of apoptotic neurons and neuron bodies in Group A was significantly lower than that in Group B, as indicated by TUNEL staining and TEM., Conclusions: These findings demonstrate that lumbosacral nerve transfer can reduce neuronal apoptosis in the pontine micturition center and enhance functional recovery of neurons. This result further suggests that lumbosacral nerve transfer can be used as a new approach for reconstructing bladder function after spinal cord injury., Competing Interests: All authors declare that they have no conflicts of interest., (Copyright © 2020 Ronghua Yu et al.)

Ventral root avulsion leads to severe motoneuron degeneration and prolonged distal nerve denervation. After a critical period, a state of chronic denervation develops as repair Schwann cells lose their pro-regenerative properties and inhibitory factors such as CSPGs accumulate in the denervated nerve. In rats with ventral root avulsion injuries, we combined timed GDNF gene therapy delivered to the proximal nerve roots with the digestion of inhibitory CSPGs in the distal denervated nerve using sustained lentiviral-mediated chondroitinase ABC (ChABC) enzyme expression. Following reimplantation of lumbar ventral roots, timed GDNF-gene therapy enhanced motoneuron survival up to 45 weeks and improved axonal outgrowth, electrophysiological recovery, and muscle reinnervation. Despite a timed GDNF expression period, a subset of animals displayed axonal coils. Lentiviral delivery of ChABC enabled digestion of inhibitory CSPGs for up to 45 weeks in the chronically denervated nerve. ChABC gene therapy alone did not enhance motoneuron survival, but led to improved muscle reinnervation and modest electrophysiological recovery during later stages of the regeneration process. Combining GDNF treatment with digestion of inhibitory CSPGs did not have a significant synergistic effect. This study suggests a delicate balance exists between treatment duration and concentration in order to achieve therapeutic effects., (© 2020 The Authors. The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.)

Descending neuromodulators from the brainstem play a major role in the development and regulation of spinal sensorimotor functions. Here, the contribution of serotonergic signaling in the lumbar spinal cord was investigated in the context of the generation of locomotor activity. Experiments were performed on in vitro spinal cord preparations from newborn rats (0-5 days). Rhythmic locomotor episodes (fictive locomotion) triggered by tonic electrical stimulations (2Hz, 30s) of a single sacral dorsal root were recorded from bilateral flexor-dominated (L2) and extensor-dominated (L5) ventral roots. We found that the activity pattern induced by sacral stimulation evolves over the 5 post-natal (P) day period. Although alternating rhythmic flexor-like motor bursts were expressed at all ages, the locomotor pattern of extensor-like bursting was progressively lost from P1 to P5. At later stages, serotonin (5-HT) and quipazine (5-HT2A receptor agonist) at concentrations sub-threshold for direct locomotor network activation promoted sacral stimulation-induced fictive locomotion. The 5-HT2A receptor antagonist ketanserin could reverse the agonist's action but was ineffective when fictive locomotion was already expressed in the absence of 5-HT (mainly before P2). Although inhibiting 5-HT7 receptors with SB266990 did not affect locomotor pattern organization, activating 5-HT1A receptors with 8-OH-DPAT specifically deteriorated extensor phase motor burst activity. We conclude that during the first 5 post-natal days in rat, serotonergic signaling in the lumbar cord becomes increasingly critical for the expression of fictive locomotion. Our findings therefore further underline the importance of both descending serotonergic and sensory afferent pathways in shaping locomotor activity during postnatal development. This article is part of the special issue entitled 'Serotonin Research: Crossing Scales and Boundaries'., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Objective: Most of knowledge on muscle radicular innervation was from explorations in root/spinal cord pathologies. Direct and individual access to each of the lumbar-sacral -ventral and dorsal- nerve roots during dorsal rhizotomy for spastic diplegia allows precise study of the corresponding muscle innervation. Authors report the lumbo-sacral segmental myotomal organization obtained from recordings of muscle responses to root stimulation in a 20-children prospective series., Methods: Seven key-muscles in each lower limb and anal sphincter were Electromyography (EMG)-recorded and clinically observed by physiotherapist during L2-to-S2 dorsal rhizotomy. Ventral roots (VR), for topographical mapping, and dorsal roots (DR), for segmental excitability testing, were stimulated, just above threshold for eliciting muscular response., Results: In 70% of the muscles studied, VR innervation was pluri-radicular, from 2-to-4 roots, with 1 or 2 roots being dominant at each level. Overlapping was important. Muscle responses to DR stimulation were 1.75 times more extended compared to VR stimulation. Inter-individual variability was important., Conclusions: Accuracy of root identification and stimulation with the used method brings some more precise information to radicular functional anatomy., Significance: Those neurophysiological findings plead for performing Intra-Operative Neuromonitoring when dealing with surgery in the lumbar-sacral roots., Competing Interests: Declaration of competing interest The authors have no conflict of interest, ethical adherence and any financial disclosures., (Copyright © 2020 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

We investigated the usefulness of diffusion tensor imaging using single-shot turbo spin-echo sequence (TSE-DTI) in detecting the responsible nerve root by multipoint measurements of fractional anisotropy (FA) values. Five patients with bilateral lumbar spinal stenosis showing unilateral neurological symptoms were examined using TSE-DTI. In the spinal canal, FA values in the symptomatic side were lower than those in the asymptomatic side. TSE-DTI using multipoint measurements of FA values can differentiate the responsible lumbar nerve root.

Background Context: Motor evoked potentials (MEPs) have excellent sensitivity for monitoring the functional integrity of the lateral corticospinal tract of the spinal cord. The sensitivity for nerve root function, however, is not as well established; consequently, MEPs are often not utilized for posterior extradural spine procedures distal to the conus. Spontaneous electromyography (sEMG) and somatosensory evoked potentials (SSEPs) are often included for these procedures, but their limited sensitivity has been well documented. Given the risk of motor nerve root injuries during spine procedures, and specifically increased vulnerability of the L4 and L5 nerves, the sensitivity of MEPs was evaluated for diagnostic accuracy and therapeutic impact., Purpose: To determine the diagnostic sensitivity of MEPs during lumbosacral spine procedures and the potential therapeutic impact of the resolution of MEP alerts., Study Design: A total of 4,386 posterior extradural lumbosacral spine procedures utilizing multimodality intraoperative neuromonitoring (IONM) with sEMG, SSEPs, and MEPs were abstracted from a multi-institutional database. All cases took place between October 2015 and October 2017. No external funding was provided., Outcome Measures: Sensitivity and specificity, as well as positive and negative likelihood ratios for new postoperative neurologic deficits were calculated for each modality individually as well as when combined (multimodality)., Patient Sample: Age 18 and older METHODS: Data entered in the electronic medical record were analyzed. Alerts to sEMG activity, decreases in SSEP amplitude, or decreases in MEP amplitude were documented as well as the status of the alerts at closure: resolved or unresolved. The presence of an sEMG alert or an unresolved MEP or SSEP alert at closure was considered a positive diagnostic result, and these results were assessed relative to presence of new immediate onset neurologic deficits as documented in the electronic record., Results: The sensitivity and specificity of multimodality IONM for new immediate-onset lower extremity motor deficits were 100.0% (95% confidence interval: [64.6, 100.0]) and 92.2% (91.1, 93.1), respectively. Looking at the modalities in isolation, the sensitivity of MEPs was considerably better than either lower extremity sEMG or posterior tibial nerve SSEPs: 100.0% (78.5, 100.0) versus just 14.3% (4.0, 39.9) and 28.6% (8.2, 64.1), respectively. Surprisingly, the specificity of lower extremity MEPs was better than sEMG, 97.9% (97.5, 98.3) versus 95.4% (94.7, 96.0) (χ 2 =43.0, p<.001). The specificity of lower extremity SSEPs was 99.0% (98.5, 99.3). Only 4.4% of all procedures had a lower extremity MEP alert. There were 14 significant new nerve root injuries and all 14 had unresolved MEPs at closure. Total 85.7% of those nerve root injuries were dorsiflexion foot drop injuries and all had unresolved tibialis anterior MEP alerts. Although the overall rate of nerve root injuries was 0.32% (14/4,386), the rate for procedures with unresolved isolated tibialis anterior MEP alerts was 44.4% (12/27). The therapeutic impact is evident in the 2.0% of cases (87/4,386) with lower extremity MEP alerts that were able to be fully resolved by closure and for which the rate of injury was zero., Conclusions: The diagnostic accuracy of MEPs for anterior tibialis-related nerve root dysfunction supports the inclusion of this modality during routine posterior extradural lumbosacral procedures, especially when the L4 or L5 nerve roots are at risk. Moreover, therapeutic interventions that lead to the resolution of MEP alerts avert postoperative neurologic injuries., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: The rat has served usefully as a model for fecal incontinence and exploration of the mechanism of action of sacral neuromodulation. However, there is a gap in knowledge concerning representation(s) on the primary sensory cortex of this anatomical region., Methods: Multi-electrode array (32 channels) and intrinsic optical signal (IOS) processing were used to map cortical activation sites following anorectal electrical stimulation in the rat. A simple method for expanding a 32-electrode array to a virtual 2700 array was refined., Key Results: The IOS method identified activation of parietal cortex following anorectal or first sacral nerve root (S1) stimulation; however, the signal was poorly localized and large spontaneous vasomotion was observed in pial vessels. In contrast, the resulting high-density maps showed two anatomically distinct cortical activation sites to anorectal stimulation., Conclusions & Inferences: There are two distinct sites of activation on the parietal cortex following anorectal stimulation in the rat. The implications for sacral neuromodulation as a therapy for fecal incontinence are discussed., (© 2019 John Wiley & Sons Ltd.)

Interneurons (INs) coordinate motoneuron activity to generate appropriate patterns of muscle contractions, providing animals with the ability to adjust their body posture and to move over a range of speeds. In Drosophila larvae several IN subtypes have been morphologically described and their function well documented. However, the general lack of molecular characterization of those INs prevents the identification of evolutionary counterparts in other animals, limiting our understanding of the principles underlying neuronal circuit organization and function. Here we characterize a restricted subset of neurons in the nerve cord expressing the Maf transcription factor Traffic Jam (TJ). We found that TJ + neurons are highly diverse and selective activation of these different subtypes disrupts larval body posture and induces specific locomotor behaviors. Finally, we show that a small subset of TJ + GABAergic INs, singled out by the expression of a unique transcription factors code, controls larval crawling speed.

We report evidence that ephaptic interactions may occur between intact mammalian myelinated nerve fibres and not only between demyelinated or damaged mammalian nerve fibres or nerve cells as analysed in previous studies. The ephaptic interactions were investigated between nerve fibres traversing the lumbar dorsal roots and between bundles of fibres in the sciatic nerve in anaesthetized rats in vivo. The interactions were estimated by comparing the excitability of nerve fibres originating from one of the hindlimb nerves (peroneal or sural) under control conditions and when the stimulation of these fibres was combined with stimulation of another nerve (tibial). An increase in nerve volleys recorded from group I muscle afferents in the peroneal nerve and of the fastest skin afferents in the sural nerve was used as a measure of the increase in the excitability. The excitability of these fibres was increased during a fraction of a millisecond, coinciding with the period of passage of nerve impulses evoked by the conditioning stimulation of the tibial nerve. The degree of the increase was comparable to the increases in the excitability evoked by 1-2 min lasting fibre polarization. Ephaptic interactions were found to be more potent and with longer lasting after-effects within the dorsal roots than within the sciatic nerve. We postulate that ephaptic interactions may result in the synchronization of information forwarded via neighbouring afferent nerve fibres prior to their entry into the spinal cord and thereby securing the propagation of nerve impulses across branching points within the spinal grey matter., (© 2019 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

Spinal dorsal roots can be affected by a wide range of lesions, leading to a significant loss of proprioceptive information transmission and greatly affecting motor behavior. In this context, the reimplantation of lesioned roots with platelet-rich plasma (PRP) may allow nerve regeneration. Therefore, the present study evaluated sensorimotor improvement following dorsal root rhizotomy and repair with PRP. For this purpose, female Lewis rats were subjected to unilateral rhizotomy (RZ) of the L4-L6 dorsal roots and divided into the following groups: (1) the unlesioned control group; (2) the group that underwent rhizotomy (RZ) without repair; and (3) the group that underwent RZ followed by root repair with PRP. PRP was obtained from human blood and characterized regarding platelet concentration, integrity, and viability. Reflex arc recovery was evaluated weekly for eight weeks by the electronic von Frey method. The spinal cords were processed 1 week postlesion to evaluate the in vivo gene expression of TNFα, TGF-β, BDNF, GDNF, VEGF, NGF, IL-4, IL-6, IL-13 by qRT-PCR and eight weeks postlesion to evaluate changes in the glial response (GFAP and Iba-1) and excitatory synaptic circuits (VGLUT1) by immunofluorescence. The results indicated that PRP therapy partially restores the paw withdrawal reflex over time, indicating the reentry of primary afferents from the dorsal root ganglia into the spinal cord without exacerbating glial reactivity. Additionally, the analysis of mRNA levels showed that PRP therapy has immunomodulatory properties. Overall, the present data suggest that the repair of dorsal roots with PRP may be considered a promising approach to improve sensorimotor recovery following dorsal rhizotomy., (Copyright © 2019. Published by Elsevier Inc.)

Objective: To investigate how electroacupuncture (EA) at Zusanli (ST 36) with varying intensities of stimulation affects dorsal root nerve signals in normal rats., Methods: Adult female Wistar rats were examined after drug-induced anesthesia and isolation of the L4 dorsal root associated with the Zusanli (ST 36) acupoint, using bipolar platinum electrodes. We applied EA at Zusanli (ST 36) with a continuous wave waveform for 1 min, and recorded action potentials in the L4 spinal cord dorsal root nerve with a frequency of 5 Hz and various current intensity levels (approximately 1-4 mA). In addition, we tested EA with a frequency of 15 Hz and current intensity of 1-4 mA. The L4 spinal cord dorsal nerve bundle action potentials were measured for 1 min of EA. To analyze the discharge frequency, we used the maximum Lyapunov exponent and Lempel-Ziv (LZ) complexity., Results: At a fixed frequency, with increasing intensity of EA, dorsal root nerve filament discharge frequency revealed an initial increase, followed by a decreasing trend. A stimulation intensity of 3 mA induced a significantly greater discharge frequency, compared with stimulation intensities of 2 and 4 mA. EA stimulation evoked neuroelectric signals with chaotic characteristics. Increased intensity led to an initial increase in LZ complexity which then decreased, with a stimulation strength of 3 mA inducing the highest level of LZ complexity., Conclusion: EA of different intensities can induce nerve action potential encoding with different features.

In the mouse spinal cord, V1 interneurons are a heterogeneous population of inhibitory spinal interneurons that have been implicated in regulating the frequency of the locomotor rhythm and in organizing flexor and extensor alternation. By introducing archaerhodopsin into engrailed-1-positive neurons, we demonstrate that the function of V1 neurons in locomotor-like activity is more complex than previously thought. In the whole cord, V1 hyperpolarization increased the rhythmic synaptic drive to flexor and extensor motoneurons, increased the spiking in each cycle, and slowed the locomotor-like rhythm. In the hemicord, V1 hyperpolarization accelerated the rhythm after an initial period of tonic activity, implying that a subset of V1 neurons are active in the hemicord, which was confirmed by calcium imaging. Hyperpolarizing V1 neurons resulted in an equalization of the duty cycle in flexor and extensors from an asymmetrical pattern in control recordings in which the extensor bursts were longer than the flexor bursts. Our results suggest that V1 interneurons are composed of several subsets with different functional roles. Furthermore, during V1 hyperpolarization, the default state of the locomotor central pattern generator (CPG) is symmetrical, with antagonist motoneurons each firing with an approximately 50% duty cycle. We hypothesize that one function of the V1 population is to set the burst durations of muscles to be appropriate to their biomechanical function and to adapt to the environmental demands, such as changes in locomotor speed., Competing Interests: The authors have declared that no competing interests exist.

Objectives: High-frequency (kHz) stimulation of preganglionic pelvic nerve afferents can inhibit voiding in both anesthetized and conscious rats. The afferents travel via the S1 sacral nerve root, which is easier to access than the distal pelvic nerve fibers within the abdominal cavity. We therefore investigated whether voiding could be inhibited by high-frequency stimulation at S1 and how this compared to distal pelvic nerve stimulation., Methods: Urethane-anesthetized rats were instrumented to record bladder pressure and abdominal wall electromyogram and to stimulate the distal preganglionic pelvic nerve bundle and S1 sacral root. Saline was infused continuously into the bladder to evoke repeated voiding. Stimulation was initiated within 1-2 sec of the onset of the steep rise in bladder pressure signaling an imminent void., Results: In six rats, stimulation of the distal pelvic nerve bundle (1-3 kHz sinusoidal waveform 1 mA, 60 sec) supressed the occurrence of an imminent void. Voiding resumed within 70 ± 13.0 sec (mean ± SEM) of stopping stimulation. Stimulation (using the same parameters) of the S1 root at the level of the sacral foramen suppressed voiding for the entire stimulation period in three rats and deferred voiding for 35-56 sec (mean 44.0 ± 3.2 sec) in the remaining three. Stimulation at either site when the bladder was approximately half full, as estimated from previous intervoid intervals, had no effect on voiding., Conclusions: This preliminary study provides proof-of-concept for the sacral root as an accessible target for high-frequency stimulation that may be developed as an "on demand" neuromodulation paradigm to suppress unwanted urinary voids., Conflict of Interest: The authors reported no conflict of interest., (© 2019 International Neuromodulation Society.)

As animals forage for food and water or evade predators, they must rapidly decide what visual features in the environment deserve attention. In vertebrates, this visuomotor computation is implemented within the neural circuits of the optic tectum (superior colliculus in mammals). However, the mechanisms by which tectum decides whether to approach or evade remain unclear, and also which neural mechanisms underlie this behavioral choice. To address this problem, we used an eye-brain-spinal cord preparation to evaluate how the lamprey responds to visual inputs with distinct stimulus-dependent motor patterns. Using ventral root activity as a behavioral readout, we classified 2 main types of fictive motor responses: ( i ) a unilateral burst response corresponding to orientation of the head toward slowly expanding or moving stimuli, particularly within the anterior visual field, and ( ii ) a unilateral or bilateral burst response triggering fictive avoidance in response to rapidly expanding looming stimuli or moving bars. A selective pharmacological blockade revealed that the brainstem-projecting neurons in the deep layer of the tectum in interaction with local inhibitory interneurons are responsible for selecting between these 2 visually triggered motor actions conveyed through downstream reticulospinal circuits. We suggest that these visual decision-making circuits had evolved in the common ancestor of vertebrates and have been conserved throughout vertebrate phylogeny., Competing Interests: The authors declare no conflict of interest.

Transcutaneous and epidural electrical spinal cord stimulation techniques are becoming more valuable as electrophysiological and clinical tools. Recently, remarkable recovery of the upper limb sensorimotor function during cervical spinal stimulation was demonstrated. In the present study, we sought to elucidate the neural mechanisms underlying the effects of transcutaneous spinal cord stimulation (tSCS) of the cervical spine. We hypothesized that cervical tSCS can be used to selectively activate the sensory route entering the spinal cord and transsynaptically converge on upper limb motor pools. To test this hypothesis, we applied cervical tSCS using paired stimuli (homosynaptic depression) and during passive muscle stretching of the wrist flexor (presynaptic inhibition via Ia afferents), voluntary hand muscle contraction (descending facilitation of motoneuron pool), and muscle-tendon vibration of the wrist (presynaptic inhibition via afferent occlusion). Our results demonstrate significant inhibition of the second evoked response during paired stimulus delivery, inhibition of responses during passive muscle stretching and muscle-tendon vibration, and facilitation during voluntary muscle contraction, which share similarities with responses evoked during lumbosacral tSCS. These results indicate that the route of the stimulation current transmission passes via afferents in the dorsal roots through the spinal cord to activate the motor pools and potentially interneuronal networks projecting to upper limb muscles. Using a novel stimulation paradigm, our study is the first to present evidence of the sensory neuronal pathway of the cervical tSCS propagation. Overall, our work demonstrates the utility and sensitivity of cervical tSCS to engage the sensory pathway projecting to the upper limbs. NEW & NOTEWORTHY Despite therapeutic effects that have been demonstrated previously using noninvasive cervical spinal stimulation, it has been unclear whether, and to what degree, the stimulation can activate the sensory afferent system. Our study presents evidence that cervical transcutaneous spinal cord stimulation can engage the sensory pathways and transsynaptically converge on motor pools projecting to upper limb muscles, demonstrating the utility and sensitivity of cervical spinal stimulation for electrophysiological assessments and neurorehabilitation.

Objective: We aimed to refine electroneurogram techniques for monitoring hypogastric nerve activity during bladder filling, and then examined nerve activity in normal intact versus acutely decentralized bladders., Methods: Effects of electrical stimulation of hypogastric nerves or lumbar ventral roots on detrusor pressure were examined, as were effects of isoflurane versus propofol anesthetics on hypogastric nerve stimulation evoked pressure. Hypogastric nerve activity was then recorded using custom-made bipolar cuff electrodes during bladder filling before and after its transection between the spinal cord and electrode to eliminate efferent nerve signals., Results: Electrical stimulation of hypogastric nerves evoked low amplitude detrusor pressures that did not differ between the two anesthetics. Upper lumbar (L2) ventral root stimulation evoked detrusor pressures were suppressed, yet not eliminated, after transection of hypogastric nerves and all spinal roots below L5. Afferent and efferent hypogastric nerve activity did not change with bladder filling in neuronally intact bladders yet decreased in decentralized bladders. No change in afferent activity was observed during bladder filling in either intact or decentralized bladders., Conclusions: These findings indicate that a more complete decentralized bladder model should include transection of lumbosacral spinal roots innervating the bladder as well as hypogastric nerves. These refined electroneurogram recording methods may be suitable for evaluating the effectiveness of nerve transfer surgeries for bladder reinnervation by monitoring sensory activity in the transferred nerve., Competing Interests: The authors have declared that no competing interests exist.

Ia excitation and recurrent inhibition are basic neuronal circuits in motor control in hind limb. Renshaw cells receive synaptic inputs from axon collaterals of motoneurons and inhibit motoneurons and Ia inhibitory interneurons. It is important to know properties of Ia excitation and recurrent inhibition of trunk muscle such as abdominal muscles. The abdominal muscles have many roles and change those roles for different kind of functions. Intracellular recordings were obtained from the abdominal motoneurons of the upper lumbar segments in cats anesthetized. First, dorsal roots were left intact, and sensory and motor axons were electrically stimulated. Ia excitatory post-synaptic potentials were elicited in five of eight motoneurons at same segment stimulated. Second, dorsal roots were sectioned, and motor axons were electrically stimulated. Recurrent inhibitory post-synaptic potentials were elicited in one of 11 abdominal motoneurons. Renshaw cells extracellularly fired high-frequency bursts at short latency and at same segment stimulated.

The inspiratory motor activities are greater in the intercostal muscles positioned at more rostral thoracic segments. This rostro-caudal gradient of the thoracic inspiratory motor activity is thought to be generated by the spinal interneurons. To clarify the involvement of the inhibitory thoracic interneurons in this rostro-caudal gradient, we examined the effects of 10 μM strychnine, an antagonist of glycine and GABA A receptors, applied to the neonatal rat thoracic spinal cord. The respiratory-related interneuron activities were optically recorded from thoracic segments in the isolated neonatal rat brainstem-spinal cord preparations stained with voltage-sensitive dye, and the electrical inspiratory motor activities were obtained from the third and eleventh thoracic ventral roots (T3VR, T11VR). Although strychnine caused seizure-like activities in all of the ventral roots recorded, the inspiratory motor activities continued. The inspiratory optical signals in the rostral thoracic segments (T2-T5) were significantly larger than those in the caudal thoracic segments (T9-T11) regardless of the existence of strychnine. Similarly, the percent ratio of the amplitude of the inspiratory electrical activity in the T3VR under control and strychnine was significantly larger than that in the T11VR regardless of the existence of strychnine. Strychnine significantly increased the inspiratory activity in both the T3VR and T11VR. These results suggest that the glycinergic and GABAergic inhibitory interneurons are not essential to generate the rostro-caudal gradient in the neonatal rat thoracic inspiratory motor outputs, but these interneurons are likely to play a role in the inhibitory control of inspiratory motor output., (Copyright © 2018 IBRO. Published by Elsevier Ltd. All rights reserved.)

The objective of this article is to examine dynamic changes of ischial blood perfusion during sacral nerve root stimulation against surface functional electrical stimulation (FES). Fourteen adults with suprasacral spinal cord injury (SCI) were recruited. The gluteal maximus was activated by surface FES or stimulating sacral nerve roots by functional magnetic stimulation (FMS) or a sacral anterior root stimulator implant (SARS). Ischial skin index of hemoglobin (IHB) and oxygenation (IOX) was measured.Skin blood perfusion was significantly higher during FMS than the baseline (IHB 1.05 ± 0.21 before vs.1.08 ± 0.02 during stimulation, p = 0.03; IOX 0.18 ± 0.21 before vs. 0.46 ± 0.30, p = 0.01 during stimulation). Similarly, when using the SARS implant, we also observed blood perfusion significantly increased (IHB 1.01 ± 0.02 before vs.1.07 ± 0.02 during stimulation, p = 0.003; IOX 0.79 ± 0.81 before vs. 2.2 ± 1.21 during stimulation, p = 0.036). Among four participants who completed both the FMS and FES studies, the magnitude of increase in both parameters was significantly higher during FMS. This study demonstrates sacral nerve root stimulation confer better benefit on blood perfusion than applying traditional FES in SCI population.

Introduction: Contralateral cervical seventh nerve root (CC7) transfer has been widely applied for treatment of traumatic brachial plexus injury. The purpose of the study was to evaluate outcomes of patients with global brachial plexus avulsion (GBPA) after CC7 transfer and compare the recoveries of median nerve as the only recipient nerve and one of the multiple recipient nerves., Methods: A retrospective review of 51 patients treated with CC7 transfers after GBPA was carried out. The British Medical Research Council (MRC) grading system and range of joint motion (ROM) were used for motor and sensory assessment., Results: The effective rates of FCR were 57.7%, 45.5%, and 36.4% in CC7 transfer to median nerve (CC7-Md), CC7 transfer to median nerve and biceps branch (CC7-Md+Bic) and CC7 transfer to median nerve and triceps branch (CC7-Md+Tric) groups, respectively. There were no statistical differences no matter in FCR or FDS among groups. The effective rate in biceps had no significant difference with that in triceps. The effective sensory recovery rate was 65.4%, 54.5%, and 36.4% in CC7-Md, CC7-Md+Bic, and CC7-Md+Tric groups. There were no statistical differences in the sensory effective recovery rate among groups. All the ROMs were improved significantly after surgery. The improvement of ROM of elbow flexion after surgery in CC7-Md+Bic group was significantly larger than that of elbow extension after surgery in CC7-Md+Tric group (p = 0.047)., Conclusions: The CC7 transfer contributed to the functional improvement of the hand and wrist for the patients with global brachial plexus avulsion. The whole CC7 could be used to repair more than one recipient nerve (including median nerve) without affecting the recovery of median nerve. When CC7 was used to repair two nerves, biceps branch might be preferred to choose as one recipient nerve rather than triceps branch., (© 2018 The Authors. Brain and Behavior published by Wiley Periodicals, Inc.)

Locomotor patterns are mainly modulated by afferent feedback, but its actual contribution to spinal network activity during continuous passive limb training is still unexplored. To unveil this issue, we devised a robotic in vitro setup (Bipedal Induced Kinetic Exercise, BIKE) to induce passive pedaling, while simultaneously recording low-noise ventral and dorsal root (VR and DR) potentials in isolated neonatal rat spinal cords with hindlimbs attached. As a result, BIKE evoked rhythmic afferent volleys from DRs, reminiscent of pedaling speed. During BIKE, spontaneous VR activity remained unchanged, while a DR rhythmic component paired the pedaling pace. Moreover, BIKE onset rarely elicited brief episodes of fictive locomotion (FL) and, when trains of electrical pulses were simultaneously applied to a DR, it increased the amplitude, but not the number, of FL cycles. When BIKE was switched off after a 30-min training, the number of electrically induced FL oscillations was transitorily facilitated, without affecting VR reflexes or DR potentials. However, 90 min of BIKE no longer facilitated FL, but strongly depressed area of VR reflexes and stably increased antidromic DR discharges. Patch clamp recordings from single motoneurons after 90-min sessions indicated an increased frequency of both fast- and slow-decaying synaptic input to motoneurons. In conclusion, hindlimb rhythmic and alternated pedaling for different durations affects distinct dorsal and ventral spinal networks by modulating excitatory and inhibitory input to motoneurons. These results suggest defining new parameters for effective neurorehabilitation that better exploits spinal circuit activity., (Copyright © 2018 IBRO. Published by Elsevier Ltd. All rights reserved.)

Nearly all spinal cord injured (SCI) individuals lose bladder control and are prone to kidney complications if intermittent catheterization is not applied. Electrical stimulation of the sacral anterior roots with an implantable neuroprosthesis is one means to restore continence and control micturition. However, only a small percentage of the SCI population benefits from this solution because of its drawbacks, e.g., section of sacral posterior roots with loss of spared sensitivity. There has been renewed interest in spinal cord stimulation in recent years, but most studies have focused on locomotion and only few have reported the impact on visceral functions. Moreover, even though the lumbosacral spinal cord is the location of many pre-cabled neural networks (involved in locomotion, bladder, and bowel management), the functional selectivity of spinal stimulations has never been investigated in detail. Here, we present: 1) a methodology designed to study lumbosacral epispinal-intradural stimulation selectivity; 2) preliminary results assessing the impact of epispinal stimulation on bladder and bowel functions in two domestic pigs; and 3) a comparison of these visceral responses with abdominal and lower limb activities. Our experiments resulted in selective bladder and rectal responses, i.e., without hind paw responses, thus reaffirming the rehabilitation potential of spinal cord stimulation.

To understand neural circuits that control limbs, one must measure their activity during behavior. Until now this goal has been challenging, because limb premotor and motor circuits have been largely inaccessible for large-scale recordings in intact, moving animals-a constraint that is true for both vertebrate and invertebrate models. Here, we introduce a method for 2-photon functional imaging from the ventral nerve cord (VNC) of behaving adult Drosophila melanogaster. We use this method to reveal patterns of activity across nerve cord populations during grooming and walking and to uncover the functional encoding of moonwalker ascending neurons (MANs), moonwalker descending neurons (MDNs), and a previously uncharacterized class of locomotion-associated A1 descending neurons. Finally, we develop a genetic reagent to destroy the indirect flight muscles and to facilitate experimental access to the VNC. Taken together, these approaches enable the direct investigation of circuits associated with complex limb movements.

Background: Transcranial motor evoked potential (TcMEP) is widely used intraoperatively to monitor spinal cord and nerve root function. To our knowledge, there is no report regarding TcMEP signal loss purely caused by patient positioning during the spinal procedure., Purpose: The objective of this article is to report an intraoperative TcMEP signal loss of a patient with fixed sagittal imbalance posture along with mild hip contractures., Study Design: A retrospective case report., Methods: A 57-year-old man had fixed sagittal imbalance and flexed hip contractures. For a reconstruction surgery of T10 to the sacrum/ilium and L5 pedicle subtraction osteotomy (PSO), he was put in a prone position on a Jackson table. In order to accommodate his fixed hip flexion contracture, thigh pads were not used and pillows were placed under his bilateral thighs for cushioning. TcMEPs were used to assess lumbar nerve root function. Ten minutes after incision, bilateral vastus medialis TcMEPs were lost during spine exposure whereas all other data remained normal at baseline. The bilateral lower extremities were repositioned, with the knees flexed into a sling position to increase hip flexion. Five minutes after repositioning, the bilateral vastus medialis TcMEPs gradually improved and maintained baseline amplitude during the remainder of the surgery., Results: No muscle weakness was detected immediately after surgery. The patient was discharged day 6 postoperatively with markedly improved posture and alignment., Conclusion: Insufficient hip flexion in patients with fixed sagittal imbalance and hip flexion contractures may cause TcMEP signal changes in the quadriceps response. TcMEP monitoring of bilateral lower extremities is highly recommended for patients with sagittal imbalance and hip contractures, with consideration for lower extremity repositioning when data degradation does not correlate with the actual spinal procedure being performed., (Copyright © 2018 Scoliosis Research Society. Published by Elsevier Inc. All rights reserved.)

Cerebrospinal fluid (CSF) dynamics are thought to play a vital role in central nervous system (CNS) physiology. The objective of this study was to investigate the impact of spinal cord (SC) nerve roots (NR) on CSF dynamics. A subject-specific computational fluid dynamics (CFD) model of the complete spinal subarachnoid space (SSS) with and without anatomically realistic NR and nonuniform moving dura wall deformation was constructed. This CFD model allowed detailed investigation of the impact of NR on CSF velocities that is not possible in vivo using magnetic resonance imaging (MRI) or other noninvasive imaging methods. Results showed that NR altered CSF dynamics in terms of velocity field, steady-streaming, and vortical structures. Vortices occurred in the cervical spine around NR during CSF flow reversal. The magnitude of steady-streaming CSF flow increased with NR, in particular within the cervical spine. This increase was located axially upstream and downstream of NR due to the interface of adjacent vortices that formed around NR.

Purpose: Diffusion tensor imaging (DTI) based on a single-shot echo planer imaging (EPI-DTI) is an established method that has been used for evaluation of lumbar nerve disorders in previous studies, but EPI-DTI has problems such as a long acquisition time, due to a lot of axial slices, and geometric distortion. To solve these problems, we attempted to apply DTI based on a single-shot turbo spin echo (TSE-DTI) with direct coronal acquisition. Our purpose in this study was to investigate whether TSE-DTI may be more useful for evaluation of lumbar nerve disorders than EPI-DTI., Materials and Methods: First, lumbar nerve roots of five healthy volunteers were evaluated for optimization of imaging parameters with TSE-DTI including b-values and the number of motion proving gradient (MPG) directions. Subsequently, optimized TSE-DTI was quantitatively compared with conventional EPI-DTI by using fractional anisotropy (FA) values and visual scores in subjective visual evaluation of tractography. Lumbar nerve roots of six patients, who had unilateral neurologic symptoms in one leg, were evaluated by the optimized TSE-DTI., Results: TSE-DTI with b-value of 400 s/mm 2 and 32 diffusion-directions could reduce the image distortion compared with EPI-DTI, and showed that the average FA values on the symptomatic side for six patients were significantly lower than those on the non-symptomatic side (P < 0.05)., Conclusion: Tractography with TSE-DTI might show damaged areas of lumbar nerve roots without severe image distortion. TSE-DTI might improve the reproducibility in measurements of FA values for quantification of a nerve disorder, and would become a useful tool for diagnosis of low back pain., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Spinal motoneurons and locomotor networks are regulated by monoamines, among which, the contribution of histamine has yet to be fully addressed. The present study investigates histaminergic regulation of spinal activity, combining intra- and extracellular electrophysiological recordings from neonatal rat spinal cord in vitro preparations. Histamine dose-dependently and reversibly generated motoneuron depolarization and action potential firing. Histamine (20 µM) halved the area of dorsal root reflexes and always depolarized motoneurons. The majority of cells showed a transitory repolarization, while 37% showed a sustained depolarization maintained with intense firing. Extracellularly, histamine depolarized ventral roots (VRs), regardless of blockage of ionotropic glutamate receptors. Initial, transient glutamate-mediated bursting was synchronous among VRs, with some bouts of locomotor activity in a subgroup of preparations. After washout, the amplitude of spontaneous tonic discharges increased. No desensitization or tachyphylaxis appeared after long perfusion or serial applications of histamine. On the other hand, histamine induced single motoneuron and VR depolarization, even in the presence of tetrodotoxin (TTX). During chemically induced fictive locomotion (FL), histamine depolarized VRs. Histamine dose-dependently increased rhythm periodicity and reduced cycle amplitude until near suppression. This study demonstrates that histamine induces direct motoneuron membrane depolarization and modulation of locomotor output, indicating new potential targets for locomotor neurorehabilitation., (© 2017 Wiley Periodicals, Inc.)

Introduction: Neurophysiologic monitoring can improve autonomic nerve sparing during critical phases of rectal cancer surgery., Objectives: To develop a system for extracorporeal stimulation of sacral nerve roots., Methods: Dedicated software controlled a ten-electrode stimulation array by switching between different electrode configurations and current levels. A built-in impedance and current level measurement assessed the effectiveness of current injection. Intra-anal surface electromyography (sEMG) informed on targeting the sacral nerve roots. All tests were performed on five pig specimens., Results: During switching between electrode configurations, the system delivered 100% of the set current (25 mA, 30 Hz, 200 μs cathodic pulses) in 93% of 250 stimulation trains across all specimens. The impedance measured between single stimulation array contacts and corresponding anodes across all electrode configurations and specimens equaled 3.7 ± 2.5 kΩ. The intra-anal sEMG recorded a signal amplitude increase as previously observed in the literature. When the stimulation amplitude was tested in the range from 1 to 21 mA using the interconnected contacts of the stimulation array and the intra-anal anode, the impedance remained below 250 Ω and the system delivered 100% of the set current in all cases. Intra-anal sEMG showed an amplitude increase for current levels exceeding 6 mA., Conclusion: The system delivered stable electric current, which was proved by built-in impedance and current level measurements. Intra-anal sEMG confirmed the ability to target the branches of the autonomous nervous system originating from the sacral nerve roots., Significance: Stimulation outside of the operative field during rectal cancer surgery is feasible and may improve the practicality of pelvic intraoperative neuromonitoring.