Search

The developmental trajectory of weight-bearing locomotion and sensorimotor reflexes following a spinal cord injury, as well as the mechanisms for plasticity, remain unclear. In rats, the second postnatal week is a critical period for the development and recovery of spinal sensorimotor function. The purpose of the present study was to characterize developmental changes during this time frame to provide a basis for potential interventions and future research. Rats underwent a complete low-thoracic (T8-T10) spinal cord transection surgery, or sham procedure, on postnatal day (P)1. Spontaneous locomotion and sensorimotor reflexes (surface righting, hindlimb placing, and crossed-extensor reflex) were tested on P7, P14, or P21. Results show that spinal-transected and sham rats exhibited the same amount of spontaneous locomotion, but the degree of relative weight bearing on the hindlimbs was different between groups and changed over time. Reflex findings showed that throughout the neonatal period, the isolated lumbar spinal cord can respond to sensory input and execute coordinated motor output following spinal cord transection. These insights contribute to understanding the developmental trajectory of spinal cord function after injury and provide a foundation for interventions to enhance recovery outcomes., (© 2024 Wiley Periodicals LLC.)

Abstract: Afferents from the C2 spinal nerve (SN) and trigeminal nerve (TN) innervate neighboring cranial territories, and their convergence on the upper cervical dorsal horn neurons represents neural substrate of pain referral in primary headache disorders. Unfortunately, little is known about trigeminocervical input to the major spinal nociceptive projection area lamina I. Here, we used ex vivo brainstem-cervical cord preparation for the visually guided whole-cell recording from the upper cervical lamina I neurons. We show that 50% of them receive convergent monosynaptic input from both nerves, whereas 35% and 11% of neurons receive specific supply from the C2 SN and TN, respectively. Altogether, 10 distinct patterns of synaptic input from the C2 SN and TN to lamina I neurons could be identified. Although stimulation of both nerves evoked excitatory/inhibitory responses, more numerous pure inhibitory inputs arose from the TN. We show that cervical and trigeminal nociceptors converge on to lamina I projection and inhibitory neurons. Thus, trigeminocervical input in lamina I is processed in both nerve-specific and convergent circuitries. Afferent convergence on to inhibitory interneurons serves as a feedforward mechanism balancing excitatory drive to projection neurons. Disruption of this balance may cause pain in primary headache syndromes. [ABSTRACT FROM AUTHOR]

A model is proposed to consider sexual climax in men, women, and animals as a unitary phenomenon. Sexual climax is a stereotyped rhythmic pattern of spinally generated neural activity in the autonomic and somatic nerves innervating pelvic organs. A column of neurons in the spinal cord of the male rat is strongly activated by ejaculation (sexual climax in the male). These neurons project to the thalamus and are therefore called lumbar spinothalamic cells (LSt cells). Comprehensive studies have demonstrated that the LSt cells constitute a central pattern generator of ejaculation. These findings have been extended to female animals. Further studies identified LSt cells in the lumbar spinal cord of men and women. Strong evidence indicates that the LSt cells mediate ejaculation in men. The climax model generalizes and extends these studies. It postulates that LSt cells in the lumbar spinal cord of humans and animals of both sexes generate climax. The LSt cells generate the neural activity driving the pelvic contractions and other responses of climax. The activity is transmitted to supraspinal sites to activate orgasm. The LSt cells receive excitatory and inhibitory projections from supraspinal sites. The descending projections reflect subjective arousal and inhibitions. Spinal sensory neurons from the genitals provide excitatory and inhibitory innervation to the LSt cells. These represent pleasurable and noxious sensations. The supraspinal and spinal excitatory and inhibitory inputs are integrated by the LSt. When the sum of the excitatory inputs, minus the sum of the inhibitory inputs reaches a threshold, the LSt cells generate sexual climax. [ABSTRACT FROM AUTHOR]

Osteopetrosis is a disorder characterized by an increase in bone density and a reduction in spinal cord spaces. This change results in a defect in osteoclast function and consequent decrease in bone turnover. One of the possible local bone complications is osteomyelitis, which affects up to 10% of patients with this disorder. Platelet concentrates (L-PRF) have been used in cases of bone defects and areas of tissue necrosis, as it has the characteristic of releasing growth factors after activation. The aim of this paper is to present a clinical case of a patient with mandibular osteopetrosis, who underwent dental implantation and subsequent recurrent osteomyelitis and was treated by partial resection associated with L-PRF bone defect coverage. After 1 year of follow-up, the patient presented definitive soft tissue healing, no exposure of bone tissue or phlogistic signs at the site, and good bone repair on computed tomography scan. The present study demonstrated that the association of L-PRF with resection techniques can be a viable method for the management of patients with difficult to treat osteomyelitis, especially in cases of mandibular osteopetrosis. [ABSTRACT FROM AUTHOR]

Slow and fast movements are controlled by distinct sets of spinal V2a neurons with matching properties and connections., Competing Interests: MS No competing interests declared, (© 2024, Sengupta.)

Introduction: Toward further cerebro-spinal flow quantification in clinical practice, this study aims at assessing the variations in the cerebro spinal fluid flow pattern associated with change in the morphology of the subarachnoid space of the cervical canal of healthy humans by developing a computational fluid dynamics model., Methods: 3D T2-space MRI sequence images of the cervical spine were used to segment 11 cervical subarachnoid space. Model validation (time-step, mesh size, size and number of boundary layers, influences of parted inflow and inflow continuous velocity) was performed a 40-year-old patient-specific model. Simulations were performed using computational fluid dynamics approach simulating transient flow (Sparlart-Almaras turbulence model) with a mesh size of 0.6, 6 boundary layers of 0.05 mm, a time step of 20 ms simulated on 15 cycles. Distributions of components velocity and WSS were respectively analyzed within the subarachnoid space (intervertebral et intravertebral levels) and on dura and pia maters., Results: Mean values cerebro spinal fluid velocity in specific local slices of the canal range between 0.07 and 0.17 m.s-1 and 0.1 and 0.3 m.s-1 for maximum values. Maximum wall shear stress values vary between 0.1 and 0.5 Pa with higher value at the middle of the cervical spine on pia mater and at the lower part of the cervical spine on dura mater. Intra and inter-individual variations of the wall shear stress were highlighted significant correlation gwith compression ratio (r = 0.76), occupation ratio and cross section area of the spinal cord., Conclusion: The inter-individual variability in term of subarachnoid canal morphology and spinal cord position influence the cerebro-spinal flow pattern, highlighting the significance of canal morphology investigation before surgery., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Leblond et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Coordinated movement requires the nervous system to continuously compensate for changes in mechanical load across different conditions. For voluntary movements like reaching, the motor cortex is a critical hub that generates commands to move the limbs and counteract loads. How does cortex contribute to load compensation when rhythmic movements are sequenced by a spinal pattern generator? Here, we address this question by manipulating the mass of the forelimb in unrestrained mice during locomotion. While load produces changes in motor output that are robust to inactivation of motor cortex, it also induces a profound shift in cortical dynamics. This shift is minimally affected by cerebellar perturbation and significantly larger than the load response in the spinal motoneuron population. This latent representation may enable motor cortex to generate appropriate commands when a voluntary movement must be integrated with an ongoing, spinally-generated rhythm., (© 2024. The Author(s).)

Objective . Phantom limb pain (PLP) is debilitating and affects over 70% of people with lower-limb amputation. Other neuropathic pain conditions correspond with increased spinal excitability, which can be measured using reflexes and F -waves. Spinal cord neuromodulation can be used to reduce neuropathic pain in a variety of conditions and may affect spinal excitability, but has not been extensively used for treating PLP. Here, we propose using a non-invasive neuromodulation method, transcutaneous spinal cord stimulation (tSCS), to reduce PLP and modulate spinal excitability after transtibial amputation. Approach . We recruited three participants, two males (5- and 9-years post-amputation, traumatic and alcohol-induced neuropathy) and one female (3 months post-amputation, diabetic neuropathy) for this 5 d study. We measured pain using the McGill Pain Questionnaire (MPQ), visual analog scale (VAS), and pain pressure threshold (PPT) test. We measured spinal reflex and motoneuron excitability using posterior root-muscle (PRM) reflexes and F -waves, respectively. We delivered tSCS for 30 min d -1 for 5 d. Main Results . After 5 d of tSCS, MPQ scores decreased by clinically-meaningful amounts for all participants from 34.0 ± 7.0-18.3 ± 6.8; however, there were no clinically-significant decreases in VAS scores. Two participants had increased PPTs across the residual limb (Day 1: 5.4 ± 1.6 lbf; Day 5: 11.4 ± 1.0 lbf). F -waves had normal latencies but small amplitudes. PRM reflexes had high thresholds (59.5 ± 6.1 μ C) and low amplitudes, suggesting that in PLP, the spinal cord is hypoexcitable. After 5 d of tSCS, reflex thresholds decreased significantly (38.6 ± 12.2 μ C; p < 0.001). Significance . These preliminary results in this non-placebo-controlled study suggest that, overall, limb amputation and PLP may be associated with reduced spinal excitability and tSCS can increase spinal excitability and reduce PLP., (© 2024 IOP Publishing Ltd. All rights, including for text and data mining, AI training, and similar technologies, are reserved.)

Introduction: Spinal neurostimulation is a therapy for otherwise intractable chronic pain. Spinal neurostimulation includes stimulation of the spinal cord (SCS), dorsal root ganglion (DRGS), and dorsal root entry zone (DREZS). New paresthesia-free neurostimulation paradigms may rely on different mechanisms of action from those of conventional tonic neurostimulation. The aim of this systematic review is to assess the existing knowledge on the effect of spinal neurostimulation on somatosensory processing in patients with chronic pain. We therefore reviewed the existing literature on the effect of various spinal neurostimulation paradigms on the supraspinal somatosensory evoked response (SER)., Materials and Methods: Multiple scientific data bases were searched for studies that assessed the effect of spinal neurostimulation on the supraspinal SER, evoked by painful or nonpainful peripheral stimuli in patients with chronic pain. We found 205 studies, of which 24 were included. Demographic data, study design, and study outcome were extracted., Results: Of the 24 included studies, 23 used electroencephalography to assess the SER; one study used magnetoencephalography. Fifteen studies evaluated tonic SCS; six studies (also) evaluated paresthesia-free paradigms; three studies evaluated the effect of tonic DRGS or DREZS. Sixteen studies used nonpainful stimuli to elicit the SER, 14 observed a decreased SER amplitude. Ten studies used painful stimuli to elicit the SER, yielding mixed results., Discussion: The included studies suggest that both paresthesia-based and paresthesia-free spinal neurostimulation paradigms can decrease (part of) the SER elicited by a nonpainful peripheral stimulus. The observed SER amplitude reduction likely is the effect of various spinal and supraspinal mechanisms of spinal neurostimulation that also contribute to pain relief., Conclusions: Spinal neurostimulation modulates the processing of a peripherally applied nonpainful stimulus. For painful stimuli, the results are not conclusive. It is not yet clear whether paresthesia-free neurostimulation affects the SER differently from paresthesia-based neurostimulation., Competing Interests: Conflict of Interest Frank J.P.M. Huygen declares that he is supported in kind by Saluda Medical, receives consulting fees (payment to institution) from Boston Scientific, and receives personal fees from Abbott and Grünenthal. The remaining authors reported no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Structural neuroplasticity such as neurite extension and dendritic spine dynamics is enhanced by brain-derived neurotrophic factor (BDNF) and impaired by types of inhibitory molecules that induce growth cone collapse and actin depolymerization, for example, myelin-associated inhibitors, chondroitin sulfate proteoglycans, and negative guidance molecules. These inhibitory molecules can activate RhoA/rho-associated coiled-coil containing protein kinase (ROCK) signaling (known to restrict structural plasticity). Intermittent hypoxia (IH) and high-intensity interval training (HIIT) are known to upregulate BDNF that is associated with improvements in learning and memory and greater functional recovery following neural insults. We investigated whether the RhoA/ROCK signaling pathway is also modulated by IH and HIIT in the hippocampus, cortex, and lumbar spinal cord of male Wistar rats. The gene expression of 25 RhoA/ROCK signaling pathway components was determined following IH, HIIT, or IH combined with HIIT (30 min/day, 5 days/wk, 6 wk). IH included 10 3-min bouts that alternated between hypoxia (15% O 2 ) and normoxia. HIIT included 10 3-min bouts alternating between treadmill speeds of 50 cm·s -1 and 15 cm·s -1 . In the hippocampus, IH and HIIT significantly downregulated Acan and NgR2 mRNA that are involved in the inhibition of neuroplasticity. However, IH and IH + HIIT significantly upregulated Lingo-1 and NgR3 in the cortex. This is the first time IH and HIIT have been linked to the modulation of plasticity-inhibiting pathways. These results provide a fundamental step toward elucidating the interplay between the neurotrophic and inhibitory mechanisms involved in experience-driven neural plasticity that will aid in optimizing physiological interventions for the treatment of cognitive decline or neurorehabilitation. NEW & NOTEWORTHY Intermittent hypoxia (IH) and high-intensity interval training (HIIT) enhance neuroplasticity and upregulate neurotrophic factors in the central nervous system (CNS). We provide evidence that IH and IH + HIIT also have the capacity to regulate genes involved in the RhoA/ROCK signaling pathway that is known to restrict structural plasticity in the CNS. This provides a new mechanistic insight into how these interventions may enhance hippocampal-related plasticity and facilitate learning, memory, and neuroregeneration.

Background: Neuromuscular electrical stimulation (NMES) can generate muscle contractions and elicit excitability of neural circuits. However, the optimal stimulation frequency for effective neuromodulation remains unclear., Methods: Eleven able-bodied individuals participated in our study to examine the effects of: (1) low-frequency NMES at 25 Hz, (2) high-frequency NMES at 100 Hz; and (3) mixed-frequency NMES at 25 and 100 Hz switched every second. NMES was delivered to the right tibialis anterior (TA) muscle for 1 min in each condition. The order of interventions was pseudorandomized between participants with a washout of at least 15 min between conditions. Spinal reflexes were elicited using single-pulse transcutaneous spinal cord stimulation applied over the lumbar enlargement to evoke responses in multiple lower-limb muscles bilaterally and maximum motor responses (M max ) were elicited in the TA muscle by stimulating the common peroneal nerve to assess fatigue at the baseline and immediately, 5, 10, and 15 min after each intervention., Results: Our results showed that spinal reflexes were significantly inhibited immediately after the mixed-frequency NMES, and for at least 15 min in follow-up. Low-frequency NMES inhibited spinal reflexes 5 min after the intervention, and also persisted for at least 10 min. These effects were present only in the stimulated TA muscle, while other contralateral and ipsilateral muscles were unaffected. M max responses were not affected by any intervention., Conclusions: Our results indicate that even a short-duration (1 min) NMES intervention using low- and mixed-frequency NMES could inhibit spinal reflex excitability of the TA muscle without inducing fatigue., (© 2024 The Authors. Artificial Organs published by International Center for Artificial Organ and Transplantation (ICAOT) and Wiley Periodicals LLC.)

Prior studies suggest resistance exercise as a potential form of motor learning due to task-specific corticospinal responses observed in single sessions of motor skill and resistance training. While existing literature primarily focuses on upper limb muscles, revealing a task-dependent nature in eliciting corticospinal responses, our aim was to investigate such responses after a single session of lower limb motor skill and resistance training. Twelve participants engaged in a visuomotor force tracking task, self-paced knee extensions, and a control task. Corticospinal, spinal, and neuromuscular responses were measured using transcranial magnetic stimulation (TMS) and peripheral nerve stimulation (PNS). Assessments occurred at baseline, immediately post, and at 30-min intervals over two hours. Force steadiness significantly improved in the visuomotor task (P < 0.001). Significant fixed-effects emerged between conditions for corticospinal excitability, corticospinal inhibition, and spinal excitability (all P < 0.001). Lower limb motor skill training resulted in a greater corticospinal excitability compared to resistance training (mean difference [MD] = 35%, P < 0.001) and control (MD; 37%, P < 0.001). Motor skill training resulted in a lower corticospinal inhibition compared to control (MD; - 10%, P < 0.001) and resistance training (MD; - 9%, P < 0.001). Spinal excitability was lower following motor skill training compared to control (MD; - 28%, P < 0.001). No significant fixed effect of Time or Time*Condition interactions were observed. Our findings highlight task-dependent corticospinal responses in lower limb motor skill training, offering insights for neurorehabilitation program design., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The neural control of breathing exhibits sex differences. There is now a large effort to account for biological sex in mammalian research, but the degree to which ectothermic vertebrates exhibit sex differences in the central control of breathing is not well-established. Therefore, we compared respiratory-related neural activity in brainstem-spinal cord preparations from female and male bullfrogs to determine if important aspects of the central control of breathing vary with sex. We found that the breathing pattern was similar across males and females, but baseline frequency of the respiratory network was faster in females. The magnitude of the central response to hypercapnia was similar across sexes, but the time to reach maximum burst rate occurred more slowly in females. These results suggest that sex differences may account for variation in traits associated with the control of breathing and that future work should carefully account for sex of the animal in analysis., Competing Interests: Declaration of Competing Interest The authors declare no competing interests., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Persistent inward currents (PICs) and persistent outward currents (POCs) regulate the excitability and firing behaviours of spinal motoneurons (MNs). Given their potential role in MN excitability dysfunction in amyotrophic lateral sclerosis (ALS), PICs have been previously studied in superoxide dismutase 1 (SOD1)-G93A mice (the standard animal model of ALS); however, conflicting results have been reported on how the net PIC changes during disease progression. Also, individual PICs and POCs have never been examined before in symptomatic ALS. To fill this gap, we measured the net and individual PIC and POC components of wild-type (WT) and SOD MNs in current clamp and voltage clamp during disease progression (assessed by neuroscores). We show that SOD MNs of symptomatic mice experience a much larger net PIC, relative to WT cells from age-matched littermates. Specifically, the Na + and Ca 2+ PICs are larger, whereas the lasting SK-mediated (SK L ) POC is smaller than WT (Na + PIC is the largest and SK L POC is the smallest components in SOD MNs). We also show that PIC dysregulation is present at symptom onset, is sustained throughout advanced disease stages and is proportional to SOD MN cell size (largest dysregulation is in the largest SOD cells, the most vulnerable in ALS). Additionally, we show that studying disease progression using neuroscores is more accurate than using SOD mouse age, which could lead to misleading statistics and age-based trends. Collectively, this study contributes novel PIC and POC data, reveals ionic mechanisms contributing to the vulnerability differential among MN types/sizes, and provides insights on the roles PIC and POC mechanisms play in MN excitability dysfunction in ALS. KEY POINTS: Individual persistent inward currents (PICs) and persistent outward currents (POCs) have never been examined before in spinal motoneurons (MNs) of symptomatic amyotrophic lateral sclerosis (ALS) mice. Thus, we contribute novel PIC and POC data to the ALS literature. Male SOD MNs of symptomatic mice have elevated net PIC, with larger Na + and Ca 2+ PICs but reduced SK L POC vs. wild-type littermates. Na + PIC is the largest and SK L POC is the smallest current in SOD cells. The PIC/POC dysregulation is present at symptom onset. PIC dysregulation is sustained throughout advanced disease, and is proportional to SOD MN size (largest dysregulation is in the largest cells, the most vulnerable in ALS). Thus, we reveal ionic mechanisms contributing to the vulnerability differential among MN types/sizes in ALS. Studying disease progression using SOD mice neuroscores is more accurate than using age, which could distort the statistical differences between SOD and WT PIC/POC data and the trends during disease progression., (© 2024 The Author(s). The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.)

Objectives: This study aimed to produce an acellular spinal cord scaffold-bone marrow stromal cell (ASCS-BMSC) complex in which the growth of BMSCs transplanted into the spinal cord of rats could be simulated in vitro , facilitating the observation and evaluation of the growth of BMSCs on the ASCS for the first time., Methods: Freeze-thaw, chemical extraction and mechanical shaking approaches were used to remove the cellular components and prepare a rat ASCS containing only the extracellular matrix (ECM) structure from the rat spinal cord. BMSCs were embedded into ASCSs and freeze-dried agarose scaffolds (FASs), and cell migration and proliferation were observed via fluorescence microscopy and the MTT assay., Results: Compared with the normal rat spinal cord, the ASCS had no cell structure and retained ECM components such as type IV collagen, fibronectin and laminin, showing a three-dimensional network structure with good voids. The growth and proliferation of BMSCs on the ASCS was good, as shown by the MTT assay. Scanning electron microscopy showed that BMSCs covered 65% of the ASCS surface, and the mitochondria of BMSCs were developed and adhered to collagen fibres, as demonstrated by transmission electron microscopy. HE staining showed that BMSCs could grow inside the ASCS, and immunohistochemical staining showed that BMSCs still expressed CD44 and CD90 on the ASCS and had stem cell characteristics., Conclusions: The results of the experiment indicate that the ASCS has the ability to improve cell adhesion and proliferation. Thus, the ASCS-BMSC combination may be used to treat spinal cord injury.

Spontaneous activity refers to the firing of action potentials by neurons in the absence of external stimulation. Initially considered an artifact or "noise" in the nervous system, it is now recognized as a potential feature of neural function. Spontaneous activity has been observed in various brain areas, in experimental preparations from different animal species, and in live animals and humans using non-invasive imaging techniques. In this review, we specifically focus on the spontaneous activity of dorsal horn neurons of the spinal cord. We use a historical perspective to set the basis for a novel classification of the different patterns of spontaneous activity exhibited by dorsal horn neurons. Then we examine the origins of this activity and propose a model circuit to explain how the activity is generated and transmitted to the dorsal horn. Finally, we discuss possible roles of this activity during development and during signal processing under physiological conditions and pain states. By analyzing recent studies on the spontaneous activity of dorsal horn neurons, we aim to shed light on its significance in sensory processing. Understanding the different patterns of activity, the origins of this activity, and the potential roles it may play, will contribute to our knowledge of sensory mechanisms, including pain, to facilitate the modeling of spinal circuits and hopefully to explore novel strategies for pain treatment., (© 2024. The Author(s).)

The ventrolateral medulla (VLM) is a crucial region in the brain for visceral and somatic control, serving as a significant source of synaptic input to the spinal cord. Experimental studies have shown that gene expression in individual VLM neurons is predictive of their function. However, the molecular and cellular organization of the VLM has remained uncertain. This study aimed to create a comprehensive dataset of VLM cells using single-cell RNA sequencing in male and female mice. The dataset was enriched with targeted sequencing of spinally-projecting and adrenergic/noradrenergic VLM neurons. Based on differentially expressed genes, the resulting dataset of 114,805 VLM cells identifies 23 subtypes of neurons, excluding those in the inferior olive, and five subtypes of astrocytes. Spinally-projecting neurons were found to be abundant in seven subtypes of neurons, which were validated through in situ hybridization. These subtypes included adrenergic/noradrenergic neurons, serotonergic neurons, and neurons expressing gene markers associated with premotor neurons in the ventromedial medulla. Further analysis of adrenergic/noradrenergic neurons and serotonergic neurons identified nine and six subtypes, respectively, within each class of monoaminergic neurons. Marker genes that identify the neural network responsible for breathing were concentrated in two subtypes of neurons, delineated from each other by markers for excitatory and inhibitory neurons. These datasets are available for public download and for analysis with a user-friendly interface. Collectively, this study provides a fine-scale molecular identification of cells in the VLM, forming the foundation for a better understanding of the VLM's role in vital functions and motor control., Competing Interests: The authors declare no competing financial interests., (Copyright © 2024 the authors.)

To investigate the precise mechanism of xenon (Xe), pharmacologically isolated AMPA/KA and NMDA receptor-mediated spontaneous (s) and evoked (e) excitatory postsynaptic currents (s/eEPSC AMPA/KA and s/eEPSC NMDA ) were recorded from mechanically isolated single spinal sacral dorsal commissural nucleus (SDCN) neurons attached with glutamatergic nerve endings (boutons) using conventional whole-cell patch-clamp technique. We analysed kinetic properties of both s/eEPSC AMPA/KA and s/eEPSC NMDA by focal single- and/or paired-pulse electrical stimulation to compare them. The s/eEPSC NMDA showed smaller amplitude, slower rise time, and slower 1/e decay time constant (τ Decay ) than those of s/eEPSC AMPA/KA . We previously examined how Xe modulates s/eEPSC AMPA/KA , therefore, examined the effects on s/eEPSC NMDA in the present study. Xe decreased the frequency and amplitude of sEPSC NMDA , and decreased the amplitude but increased the failure rate and paired-pulse ratio of eEPSC NMDA without affecting their τ Decay . It was concluded that Xe might suppress NMDA receptor-mediated synaptic transmission via both presynaptic and postsynaptic mechanisms., (Copyright © 2024. Published by Elsevier B.V.)

Mature vertebrates maintain posture using vestibulospinal neurons that transform sensed instability into reflexive commands to spinal motor circuits. Postural stability improves across development. However, due to the complexity of terrestrial locomotion, vestibulospinal contributions to postural refinement in early life remain unexplored. Here we leveraged the relative simplicity of underwater locomotion to quantify the postural consequences of losing vestibulospinal neurons during development in larval zebrafish of undifferentiated sex. By comparing posture at two timepoints, we discovered that later lesions of vestibulospinal neurons led to greater instability. Analysis of thousands of individual swim bouts revealed that lesions disrupted movement timing and corrective reflexes without impacting swim kinematics, and that this effect was particularly strong in older larvae. Using a generative model of swimming, we showed how these disruptions could account for the increased postural variability at both timepoints. Finally, late lesions disrupted the fin/trunk coordination observed in older larvae, linking vestibulospinal neurons to postural control schemes used to navigate in depth. Since later lesions were considerably more disruptive to postural stability, we conclude that vestibulospinal contributions to balance increase as larvae mature. Vestibulospinal neurons are highly conserved across vertebrates; we therefore propose that they are a substrate for developmental improvements to postural control., Competing Interests: The authors declare no competing financial interests., (Copyright © 2024 the authors.)

The adult turtle spinal cord can generate multiple kinds of limb movements, including swimming, three forms of scratching, and limb withdrawal (flexion reflex), even without brain input and sensory feedback. There are many multifunctional spinal neurons, activated during multiple motor patterns, and some behaviorally specialized neurons, activated during only one. How do multifunctional and behaviorally specialized neurons each contribute to motor output? We analyzed in vivo intracellular recordings of multifunctional and specialized neurons. Neurons tended to spike in the same phase of the hip-flexor (HF) activity cycle during swimming and scratching, though one preferred opposite phases. During both swimming and scratching, a larger fraction of multifunctional neurons than specialized neurons were highly rhythmic. One group of multifunctional neurons was active during the HF-on phase and another during the HF-off phase. Thus, HF-extensor alternation may be generated by a subset of multifunctional spinal neurons during both swimming and scratching. Scratch-specialized neurons and flexion reflex-selective neurons may instead trigger their respective motor patterns, by biasing activity of multifunctional neurons. In phase-averaged membrane potentials of multifunctional neurons, trough phases were more highly correlated between swimming and scratching than peak phases, suggesting that rhythmic inhibition plays a greater role than rhythmic excitation. We also provide the first intracellular recording of a turtle swim-specialized neuron: tonically excited during swimming but inactive during scratching and flexion reflex. It displayed an excitatory postsynaptic potential following each swim-evoking electrical stimulus and thus may be an intermediary between reticulospinal axons and the swimming CPG they activate., Competing Interests: The authors declare no competing financial interests., (Copyright © 2024 Morris et al.)

The acquisition of a motor skill involves adaptations of spinal and supraspinal pathways to alpha motoneurons. In this study, we estimated the shared synaptic contributions of these pathways to understand the neural mechanisms underlying the short-term acquisition of a new force-matching task. High-density surface electromyography (HDsEMG) was acquired from the first dorsal interosseous (FDI; 7 males and 6 females) and tibialis anterior (TA; 7 males and 4 females) during 15 trials of an isometric force-matching task. For two selected trials (pre- and post-skill acquisition), we decomposed the HDsEMG into motor unit spike trains, tracked motor units between trials, and calculated the mean discharge rate and the coefficient of variation of interspike interval (COV ISI ). We also quantified the post/pre ratio of motor units' coherence within delta, alpha, and beta bands. Force-matching improvements were accompanied by increased mean discharge rate and decreased COV ISI for both muscles. Moreover, the area under the curve within alpha band decreased by ∼22% (TA) and ∼13% (FDI), with no delta or beta bands changes. These reductions correlated significantly with increased coupling between force/neural drive and target oscillations. These results suggest that short-term force-matching skill acquisition is mediated by attenuation of physiological tremor oscillations in the shared synaptic inputs. Supported by simulations, a plausible mechanism for alpha band reductions may involve spinal interneuron phase-cancelling descending oscillations. Therefore, during skill learning, the central nervous system acts as a matched filter, adjusting synaptic weights of shared inputs to suppress neural components unrelated to the specific task., Competing Interests: The authors declare no competing financial interests., (Copyright © 2024 Cabral et al.)

Neuromodulation can provide diagnostic, modulatory, and therapeutic applications. While extensive work has been conducted in the brain, modulation of the spinal cord remains relatively unexplored. The inherently delicate and mobile spinal cord tissue imposes constraints that make the precise implantation of neural probes challenging. Despite recent advances in neuromodulation devices, particularly flexible bioelectronics, opportunities to expand their use in the spinal cord have been limited by the surgical complexities of device implantation. Here, we provide a series of surgical protocols tailored specifically for the implantation of a custom-made optoelectronic device that interfaces with the spinal cord in rodents. The steps to place and anchor an optical shank on a specific segment of the spinal cord via two different surgical implantation methods are detailed here. These methods are optimized for a diverse range of devices and applications, which may or may not require direct contact with the spinal cord for optical stimulation. To elucidate the methodology, the vertebral anatomy is referenced first to identify prominent landmarks before making a skin incision. The surgical steps to secure an optical shank over the cervical spine in rodents are demonstrated. Procedures are then outlined for securing the optoelectronic device connected to the optical shank in a subcutaneous space away from the spinal cord, minimizing unnecessary direct contact. Behavioral studies comparing animals receiving the implants to those undergoing sham surgeries indicate that the optical shanks did not adversely affect hindlimb or forelimb function seven days post-implantation. The present work broadens the neuromodulation toolkit for use in future studies aimed at investigating various spinal cord interventions.

Although epidural spinal cord and muscle stimulation have each been separately used for restoration of movement after spinal cord injury, their combined use has not been widely explored. Using both approaches in combination could provide more flexible control compared to using either approach alone, but whether responses evoked from such combined stimulation can be easily predicted is unknown. We evaluate whether responses evoked by combined spinal and muscle stimulation can be predicted simply, as the linear summation of responses produced by each type of stimulation individually. Should this be true, it would simplify the prediction of co-stimulation responses and the development of control schemes for spinal cord injury rehabilitation. In healthy anesthetized rats, we measured hindlimb isometric forces in response to spinal and muscle stimulation. Force prediction errors were calculated as the difference between predicted and observed co-stimulation forces. We found that spinal and muscle co-stimulation could be closely predicted as the linear summation of the individual spinal and muscle responses and that the errors were relatively low. We discuss the implications of these results to the use of combined muscle and spinal stimulation for the restoration of movement following spinal cord injury., (© 2024. The Author(s).)

Introduction: Strength training mitigates the age-related decline in strength and muscle activation but limited evidence exists on specific motor pathway adaptations., Methods: Eleven young (22-34 years) and ten older (66-80 years) adults underwent five testing sessions where lumbar-evoked potentials (LEPs) and motor-evoked potentials (MEPs) were measured during 20 and 60% of maximum voluntary contraction (MVC). Ten stimulations, randomly delivered, targeted 25% of maximum compound action potential for LEPs and 120, 140, and 160% of active motor threshold (aMT) for MEPs. The 7-week whole-body resistance training intervention included five exercises, e.g., knee extension (5 sets) and leg press (3 sets), performed twice weekly and was followed by 4 weeks of detraining., Results: Young had higher MVC (~ 63 N·m, p = 0.006), 1-RM (~ 50 kg, p = 0.002), and lower aMT (~ 9%, p = 0.030) than older adults at baseline. Young increased 1-RM (+ 18 kg, p < 0.001), skeletal muscle mass (SMM) (+ 0.9 kg, p = 0.009), and LEP amplitude (+ 0.174, p < 0.001) during 20% MVC. Older adults increased MVC (+ 13 N·m, p = 0.014), however, they experienced decreased LEP amplitude (- 0.241, p < 0.001) during 20% MVC and MEP amplitude reductions at 120% (- 0.157, p = 0.034), 140% (- 0.196, p = 0.026), and 160% (- 0.210, p = 0.006) aMT during 60% MVC trials. After detraining, young and older adults decreased 1-RM, while young adults decreased SMM., Conclusion: Higher aMT and MEP amplitude in older adults were concomitant with lower baseline strength. Training increased strength in both groups, but divergent modifications in cortico-spinal activity occurred. Results suggest that the primary locus of adaptation occurs at the spinal level., (© 2024. The Author(s).)

Pulsatile spinal cord and CSF velocities related to the cardiac cycle can be depicted by phase-contrast MRI. Among patients with spontaneous intracranial hypotension, we have recently described relevant differences compared with healthy controls in segment C2/C3. The method might be a promising tool to solve clinical and diagnostic ambiguities. Therefore, it is important to understand the physiological range and the effects of clinical and anatomical parameters in healthy volunteers. Within a prospective study, 3D T 2 -weighted MRI for spinal canal anatomy and cardiac-gated phase-contrast MRI adapted to CSF flow and spinal cord motion for time-resolved velocity data and derivatives were performed in 70 participants (age 20-79 years) in segments C2/C3 and C5/C6. Correlations were analyzed by multiple linear regression models; p < 0.01 was required to assume a significant impact of clinical or anatomical data quantified by the regression coefficient B. Data showed that in C2/C3, the CSF and spinal cord craniocaudal velocity ranges were 4.5 ± 0.9 and 0.55 ± 0.15 cm/s; the total displacements were 1.1 ± 0.3 and 0.07 ± 0.02 cm, respectively. The craniocaudal range of the CSF flow rate was 8.6 ± 2.4 mL/s; the CSF stroke volume was 2.1 ± 0.7 mL. In C5/C5, physiological narrowing of the spinal canal caused higher CSF velocity ranges and lower stroke volume (C5/C6 B = +1.64 cm/s, p < 0.001; B = -0.4 mL, p = 0.002, respectively). Aging correlated to lower spinal cord motion (e.g., B = -0.01 cm per 10 years of aging, p < 0.001). Increased diastolic blood pressure was associated with lower spinal cord motion and CSF flow parameters (e.g., C2/C3 CSF stroke volume B = -0.3 mL per 10 mmHg, p < 0.001). Males showed higher CSF flow and spinal cord motion (e.g., CSF stroke volume B = +0.5 mL, p < 0.001; total displacement spinal cord B = +0.016 cm, p = 0.002). We therefore propose to stratify data for age and sex and to adjust for diastolic blood pressure and segmental narrowing in future clinical studies., (© 2023 The Authors. NMR in Biomedicine published by John Wiley & Sons Ltd.)

Muscle force is modulated by sequential recruitment and firing rates of motor units (MUs). However, discrepancies exist in the literature regarding the relationship between MU firing rates and their recruitment, presenting two contrasting firing-recruitment schemes. The first firing scheme, known as "onion skin," exhibits low-threshold MUs firing faster than high-threshold MUs, forming separate layers akin to an onion. This contradicts the other firing scheme, known as "reverse onion skin" or "afterhyperpolarization (AHP)," with low-threshold MUs firing slower than high-threshold MUs. To study this apparent dichotomy, we used a high-fidelity computational model that prioritizes physiological fidelity and heterogeneity, allowing versatility in the recruitment of different motoneuron types. Our simulations indicate that these two schemes are not mutually exclusive but rather coexist. The likelihood of observing each scheme depends on factors such as the motoneuron pool activation level, synaptic input activation rates, and MU type. The onion skin scheme does not universally govern the encoding rates of MUs but tends to emerge in unsaturated motoneurons (cells firing < their fusion frequency that generates peak force), whereas the AHP scheme prevails in saturated MUs (cells firing at their fusion frequency), which is highly probable for slow (S)-type MUs. When unsaturated, fast fatigable (FF)-type MUs always show the onion skin scheme, whereas S-type MUs do not show either one. Fast fatigue-resistant (FR)-type MUs are generally similar but show weaker onion skin behaviors than FF-type MUs. Our results offer an explanation for the longstanding dichotomy regarding MU firing patterns, shedding light on the factors influencing the firing-recruitment schemes. NEW & NOTEWORTHY The literature reports two contrasting schemes, namely the onion skin and the afterhyperpolarization (AHP) regarding the relationship between motor units (MUs) firing rates and recruitment order. Previous studies have examined these schemes phenomenologically, imposing one scheme on the firing-recruitment relationship. Here, we used a high-fidelity computational model that prioritizes biological fidelity and heterogeneity to investigate motoneuron firing schemes without bias toward either scheme. Our objective findings offer an explanation for the longstanding dichotomy on MU firing patterns.

Background Content: Spinal cord compression is a source of pathology routinely seen in clinical practice. However, there remain unanswered questions surrounding both the understanding of pathogenesis and the best method of treatment. This arises from limited real-life testing of the mechanical properties of the spinal cord, either through cadaveric human specimens or animal testing, both of which suffer from methodological, as well as ethical, issues., Purpose: To conduct a review of the literature on the mechanical properties of the spinal cord., Study Design/setting: A systematic review of the literature on the mechanical properties of the spinal cord is undertaken., Patient Sample: All literature reporting the testing of the mechanical properties of the spinal cord., Outcome Measures: Reported physiological mechanical properties of the spinal cord., Methods: The methodological quality of the studies has been assessed within the ARRIVE guidelines using the CAMARADES framework and SYRCLE's risk of bias tool. This paper details the methodologies and results of the reported testing., Results: We show that (1) the research quality of previous work does not follow published guidelines on animal treatment or risk of bias, (2) no standard protocol has been employed for sample preparation or mechanical testing, (3) this leads to a wide distribution of results for the tested mechanical properties, not applicable to the living human or animal, and (4) animal testing is not a good proxy for human application., Conclusions: The findings summarize the sum of current knowledge inherent to the mechanical properties of the spinal cord and may contribute to the development of a physical model which is applicable to the living human for analysis and testing in a controlled and repeatable fashion. Such a model would be the basis for further clinical research to improve outcomes from spinal cord compression., Competing Interests: Declaration of competing interest One or more of the authors declare financial or professional relationships on ICMJE-TSJ disclosure forms., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The neurophysiological effects of spinal cord stimulation (SCS) for chronic pain are poorly understood, resulting in inefficient failure-prone programming protocols and inadequate pain relief. Nonetheless, novel stimulation patterns are regularly introduced and adopted clinically. Traditionally, paresthetic sensation is considered necessary for pain relief, although novel paradigms provide analgesia without paresthesia. However, like pain relief, the neurophysiological underpinnings of SCS-induced paresthesia are unknown. Here, we paired biophysical modeling with clinical paresthesia thresholds (of both sexes) to investigate how stimulation frequency affects the neural response to SCS relevant to paresthesia and analgesia. Specifically, we modeled the dorsal column (DC) axonal response, dorsal column nucleus (DCN) synaptic transmission, conduction failure within DC fiber collaterals, and dorsal horn network output. Importantly, we found that high-frequency stimulation reduces DC fiber activation thresholds, which in turn accurately predicts clinical paresthesia perception thresholds. Furthermore, we show that high-frequency SCS produces asynchronous DC fiber spiking and ultimately asynchronous DCN output, offering a plausible biophysical basis for why high-frequency SCS is less comfortable and produces qualitatively different sensation than low-frequency stimulation. Finally, we demonstrate that the model dorsal horn network output is sensitive to SCS-inherent variations in spike timing, which could contribute to heterogeneous pain relief across patients. Importantly, we show that model DC fiber collaterals cannot reliably follow high-frequency stimulation, strongly affecting the network output and typically producing antinociceptive effects at high frequencies. Altogether, these findings clarify how SCS affects the nervous system and provide insight into the biophysics of paresthesia generation and pain relief., Competing Interests: S.F.L. has equity in CereGate, Hologram Consultants, Neuronoff, and Presidio Medical, is a member of the scientific advisory boards for CereGate and Presidio Medical, and receives research support from Abbott Neuromodulation, Medtronic, Neuromodulation Specialists, and Presidio Medical. E.R.R. and M.C. declare no competing financial interests., (Copyright © 2024 the authors.)

Many behaviors require the coordinated actions of somatic and autonomic functions. However, the underlying mechanisms remain elusive. By opto-stimulating different populations of descending spinal projecting neurons (SPNs) in anesthetized mice, we show that stimulation of excitatory SPNs in the rostral ventromedial medulla (rVMM) resulted in a simultaneous increase in somatomotor and sympathetic activities. Conversely, opto-stimulation of rVMM inhibitory SPNs decreased both activities. Anatomically, these SPNs innervate both sympathetic preganglionic neurons and motor-related regions in the spinal cord. Fiber-photometry recording indicated that the activities of rVMM SPNs correlate with different levels of muscle and sympathetic tone during distinct arousal states. Inhibiting rVMM excitatory SPNs reduced basal muscle and sympathetic tone, impairing locomotion initiation and high-speed performance. In contrast, silencing the inhibitory population abolished muscle atonia and sympathetic hypoactivity during rapid eye movement (REM) sleep. Together, these results identify rVMM SPNs as descending spinal projecting pathways controlling the tone of both the somatomotor and sympathetic systems., Competing Interests: Declaration of interests Z.H. is a co-founder of Rugen and Myrobalan and an advisor of Axonis., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Humans use their arms in complex ways that often demand two-handed coordination. Neurological conditions limit this impressive feature of the human motor system. Understanding how neuromodulatory techniques may alter neural mechanisms of bimanual coordination is a vital step towards designing efficient rehabilitation interventions. By non-invasively activating the spinal cord, transcutaneous spinal cord stimulation (tSCS) promotes recovery of motor function after spinal cord injury. A multitude of research studies have attempted to capture the underlying neural mechanisms of these effects using a variety of electrophysiological tools, but the influence of tSCS on cortical rhythms recorded via electroencephalography remains poorly understood, especially during bimanual actions. We recruited 12 neurologically intact participants to investigate the effect of cervical tSCS on sensorimotor cortical oscillations. We examined changes in the movement kinematics during the application of tSCS as well as the cortical activation level and interhemispheric connectivity during the execution of unimanual and bimanual arm reaching movements that represent activities of daily life. Behavioral assessment of the movements showed improvement of movement time and error during a bimanual common-goal movement when tSCS was delivered, but no difference was found in the performance of unimanual and bimanual dual-goal movements with the application of tSCS. In the alpha band, spectral power was modulated with tSCS in the direction of synchronization in the primary motor cortex during unimanual and bimanual dual-goal movements and in the somatosensory cortex during unimanual movements. In the beta band, tSCS significantly increased spectral power in the primary motor and somatosensory cortices during the performance of bimanual common-goal and unimanual movements. A significant increase in interhemispheric connectivity in the primary motor cortex in the alpha band was only observed during unimanual tasks in the presence of tSCS. Our observations provide, for the first time, information regarding the supra-spinal effects of tSCS as a neuromodulatory technique applied to the spinal cord during the execution of bi- and unimanual arm movements. They also corroborate the suppressive effect of tSCS at the cortical level reported in previous studies. These findings may guide the design of improved rehabilitation interventions using tSCS for the recovery of upper-limb function in the future., (© 2024. The Author(s).)

Objective . Spinal cord stimulation (SCS) is a well-established treatment for managing certain chronic pain conditions. More recently, it has also garnered attention as a means of modulating neural activity to restore lost autonomic or sensory-motor function. Personalized modeling and treatment planning are critical aspects of safe and effective SCS (Rowald and Amft 2022 Front. Neurorobotics 16 983072, Wagner et al 2018 Nature 563 65-71). However, the generation of spine models at the required level of detail and accuracy requires time and labor intensive manual image segmentation by human experts. This study aims to develop a maximally automated segmentation routine capable of producing high-quality anatomical models, even with limited data, to facilitate safe and effective personalized SCS treatment planning. Approach . We developed an automated image segmentation and model generation pipeline based on a novel convolutional neural network (CNN) architecture trained on feline spinal cord magnetic resonance imaging data. The pipeline includes steps for image preprocessing, data augmentation, transfer learning, and cleanup. To assess the relative importance of each step in the pipeline and our choice of CNN architecture, we systematically dropped steps or substituted architectures, quantifying the downstream effects in terms of tissue segmentation quality (Jaccard index and Hausdorff distance) and predicted nerve recruitment (estimated axonal depolarization). Main results . The leave-one-out analysis demonstrated that each pipeline step contributed a small but measurable increment to mean segmentation quality. Surprisingly, minor differences in segmentation accuracy translated to significant deviations (ranging between 4% and 13% for each pipeline step) in predicted nerve recruitment, highlighting the importance of careful workflow design. Additionally, transfer learning techniques enhanced segmentation metric consistency and allowed generalization to a completely different spine region with minimal additional training data. Significance . To our knowledge, this work is the first to assess the downstream impacts of segmentation quality differences on neurostimulation predictions. It highlights the role of each step in the pipeline and paves the way towards fully automated, personalized SCS treatment planning in clinical settings., (Creative Commons Attribution license.)

A variation of the longitudinal relaxation time T 1 in brain regions that differ in their main fiber direction has been occasionally reported, however, with inconsistent results. Goal of the present study was to clarify such inconsistencies, and the origin of potential T 1 orientation dependence, by applying direct sample rotation and comparing the results from different approaches to measure T 1 . A section of fixed porcine spinal cord white matter was investigated at 3 T with variation of the fiber-to-field angle θ FB . The experiments included one-dimensional inversion-recovery, MP2RAGE, and variable flip-angle T 1 measurements at 22 °C and 36 °C as well as magnetization-transfer (MT) and diffusion-weighted acquisitions. Depending on the technique, different degrees of T 1 anisotropy (between 2 and 10%) were observed as well as different dependencies on θ FB (monotonic variation or T 1 maximum at 30-40°). More pronounced anisotropy was obtained with techniques that are more sensitive to MT effects. Furthermore, strong correlations of θ FB -dependent MT saturation and T 1 were found. A comprehensive analysis based on the binary spin-bath model for MT revealed an interplay of several orientation-dependent parameters, including the transverse relaxation times of the macromolecular and the water pool as well as the longitudinal relaxation time of the macromolecular pool., (© 2024. The Author(s).)

Contraction intensity is a key factor determining the development of muscle fatigue, and it has been shown to induce distinct changes along the motor pathway. The role of cortical and spinal inputs that regulate motor unit (MU) behavior during fatiguing contractions is poorly understood. We studied the cortical, spinal, and neuromuscular response to sustained fatiguing isometric tasks performed at 20% and 70% of the maximum isometric voluntary contraction (MVC), together with MU behavior of knee extensors in healthy active males. Neuromuscular function was assessed before and after performance of both tasks. Cortical and spinal responses during exercise were measured via stimulation of the motor cortex and spinal cord. High-density electromyography was used to record individual MUs from the vastus lateralis (VL). Exercise at 70%MVC induced greater decline in MVC ( P = 0.023) and potentiated twitch force compared with 20%MVC ( P < 0.001), with no difference in voluntary activation ( P = 0.514). Throughout exercise, corticospinal responses were greater during the 20%MVC task ( P < 0.001), and spinal responses increased over time in both tasks ( P ≤ 0.042). MU discharge rate increased similarly after both tasks ( P ≤ 0.043), whereas recruitment and derecruitment thresholds were unaffected ( P ≥ 0.295). These results suggest that increased excitability of cortical and spinal inputs might be responsible for the increase in MU discharge rate. The increase in evoked responses together with the higher MU discharge rate might be required to compensate for peripheral adjustments to sustain fatiguing contractions at different intensities. NEW & NOTEWORTHY Changes in central nervous system and muscle function occur in response to fatiguing exercise and are specific to exercise intensity. This study measured corticospinal, neuromuscular, and motor unit behavior to fatiguing isometric tasks performed at different intensities. Both tasks increased corticospinal excitability and motor unit discharge rate. Our findings suggest that these acute adjustments are required to compensate for the exercise-induced decrements in neuromuscular function caused by fatiguing tasks.

Objective: Functional MRI (fMRI) can be employed to assess neuronal activity in the central nervous system. However, investigating the spinal cord using fMRI poses several technical difficulties. Enhancing the fMRI signal intensity in the spinal cord can improve the visualization and analysis of different neural pathways, particularly those involved in bladder function. The bulbocavernosus reflex (BCR) is an excellent method for evaluating the integrity of the sacral spinal cord. Instead of stimulating the glans penis or clitoris, the BCR can be simulated comfortably by tapping the suprapubic region. In this study, we explain the necessity and development of a device to elicit the simulated BCR (sBCR) via suprapubic tapping while conducting an fMRI scan., Methods: The device was successfully tested on a group of 20 healthy individuals. Two stimulation task block protocols were administered (empty vs. full bladder). Each block consisted of 40 s of suprapubic tapping followed by 40 s of rest, and the entire sequence was repeated four times., Results: Our device can reliably and consistently elicit sBCR noninvasively as demonstrated by electromyographic recording of pelvic muscles and anal winking. Participants did note mild to moderate discomfort and urge to void during the full bladder task., Conclusion: Our device demonstrates an efficacious approach to elicit sBCR within an MRI bore to assess sacral spinal cord functional activity without generating any significant motion artifacts., Significance: This device can explore the mechanisms and processes controlling urinary, digestive, or sexual function within this region in humans., (© 2024 Wiley Periodicals LLC.)

The jump smash is badminton's most aggressive technical manoeuvre, which is often the key to winning a match. This paper aims to explore the neuromuscular control strategies of advanced and beginner players when jumping smash in different ways. Collecting sEMG and kinematic data from 18 subjects with different motor experiences when jumping smash. Nonnegative Matrix Factorization and K-Means clustering were used to extract muscle synergies and exclude irrelevant combined synergies. Uncontrolled manifold analysis was then used to explore the association between synergies and shoulder stability. In addition, motor output at the spinal cord level was assessed by mapping sEMG to each spinal cord segment. The study found that advanced subjects could respond to different jump smash styles by adjusting the coordinated activation strategies of the upper-limb and postural muscles. Long-term training can induce a rapid decrease in the degree of co-variation of the synergies before contact with a shuttlecock to better cope with an upcoming collision. It is recommended that beginners should focus more on training the coordination of upper-limb muscles and postural muscles., (Copyright © 2023. Published by Elsevier B.V.)

Volitional movement requires descending input from the motor cortex and sensory feedback through the spinal cord. We previously developed a paired brain and spinal electrical stimulation approach in rats that relies on convergence of the descending motor and spinal sensory stimuli in the cervical cord. This approach strengthened sensorimotor circuits and improved volitional movement through associative plasticity. In humans, it is not known whether posterior epidural spinal cord stimulation targeted at the sensorimotor interface or anterior epidural spinal cord stimulation targeted within the motor system is effective at facilitating brain evoked responses. In 59 individuals undergoing elective cervical spine decompression surgery, the motor cortex was stimulated with scalp electrodes and the spinal cord was stimulated with epidural electrodes, with muscle responses being recorded in arm and leg muscles. Spinal electrodes were placed either posteriorly or anteriorly, and the interval between cortex and spinal cord stimulation was varied. Pairing stimulation between the motor cortex and spinal sensory (posterior) but not spinal motor (anterior) stimulation produced motor evoked potentials that were over five times larger than brain stimulation alone. This strong augmentation occurred only when descending motor and spinal afferent stimuli were timed to converge in the spinal cord. Paired stimulation also increased the selectivity of muscle responses relative to unpaired brain or spinal cord stimulation. Finally, clinical signs suggest that facilitation was observed in both injured and uninjured segments of the spinal cord. The large effect size of this paired stimulation makes it a promising candidate for therapeutic neuromodulation. KEY POINTS: Pairs of stimuli designed to alter nervous system function typically target the motor system, or one targets the sensory system and the other targets the motor system for convergence in cortex. In humans undergoing clinically indicated surgery, we tested paired brain and spinal cord stimulation that we developed in rats aiming to target sensorimotor convergence in the cervical cord. Arm and hand muscle responses to paired sensorimotor stimulation were more than five times larger than brain or spinal cord stimulation alone when applied to the posterior but not anterior spinal cord. Arm and hand muscle responses to paired stimulation were more selective for targeted muscles than the brain- or spinal-only conditions, especially at latencies that produced the strongest effects of paired stimulation. Measures of clinical evidence of compression were only weakly related to the paired stimulation effect, suggesting that it could be applied as therapy in people affected by disorders of the central nervous system., (© 2024 The Authors. The Journal of Physiology © 2024 The Physiological Society.)

Alpha band oscillations in shared synaptic inputs to the alpha motor neuron pool can be considered an involuntary source of noise that hinders precise voluntary force production. This study investigated the impact of changing muscle length on the shared synaptic oscillations to spinal motor neurons, particularly in the physiological tremor band. Fourteen healthy individuals performed low-level dorsiflexion contractions at ankle joint angles of 90° and 130°, while high-density surface electromyography (HDsEMG) was recorded from the tibialis anterior (TA). We decomposed the HDsEMG into motor units spike trains and calculated the motor units' coherence within the delta (1-5 Hz), alpha (5-15 Hz), and beta (15-35 Hz) bands. Additionally, force steadiness and force spectral power within the tremor band were quantified. Results showed no significant differences in force steadiness between 90° and 130°. In contrast, alpha band oscillations in both synaptic inputs and force output decreased as the length of the TA was moved from shorter (90°) to longer (130°), with no changes in delta and beta bands. In a second set of experiments (10 participants), evoked twitches were recorded with the ankle joint at 90° and 130°, revealing longer twitch durations in the longer TA muscle length condition compared to the shorter. These experimental results, supported by a simple computational simulation, suggest that increasing muscle length enhances the muscle's low-pass filtering properties, influencing the oscillations generated by the Ia afferent feedback loop. Therefore, this study provides valuable insights into the interplay between muscle biomechanics and neural oscillations. KEY POINTS: We investigated whether changes in muscle length, achieved by changing joint position, could influence common synaptic oscillations to spinal motor neurons, particularly in the tremor band (5-15 Hz). Our results demonstrate that changing muscle length from shorter to longer induces reductions in the magnitude of alpha band oscillations in common synaptic inputs. Importantly, these reductions were reflected in the oscillations of muscle force output within the alpha band. Longer twitch durations were observed in the longer muscle length condition compared to the shorter, suggesting that increasing muscle length enhances the muscle's low-pass filtering properties. Changes in the peripheral contractile properties of motor units due to changes in muscle length significantly influence the transmission of shared synaptic inputs into muscle force output. These findings prove the interplay between muscle mechanics and neural adaptations., (© 2024 The Authors. The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.)

Introduction/purpose: Recently, the use of transcutaneous spinal cord stimulation (TSCS) has been proposed as a viable alternative to the H-reflex. The aim of the current study was to investigate to what extent the two modes of spinal cord excitability investigation would be similarly sensitive to the well-known vibration-induced depression., Methods: Fourteen healthy participants (8 men and 6 women; age: 26.7 ± 4.8 years) were engaged in the study. The right soleus H-reflex and TSCS responses were recorded at baseline (PRE), during right Achilles tendon vibration (VIB) and following 20 min of vibration exposure (POST-VIB). Care was taken to match H-reflex and TSCS responses amplitude at PRE and to maintain effective stimulus intensities constant throughout time points., Results: The statistical analysis showed a significant effect of time for the H-reflex, with VIB (13 ± 5% of maximal M-wave (M max ) and POST-VIB (36 ± 4% of M max ) values being lower than PRE-values (48 ± 6% of M max ). Similarly, TSCS responses changed over time, VIB (9 ± 5% of M max ) and POST-VIB (27 ± 5% of M max ) values being lower than PRE-values (46 ± 6% of M max ). Pearson correlation analyses revealed positive correlation between H-reflex and TSCS responses PRE-to-VIB changes, but not for PRE- to POST-VIB changes., Conclusion: While the sensitivity of TSCS seems to be similar to the gold standard H-reflex to highlight the vibratory paradox, both responses showed different sensitivity to the effects of prolonged vibration, suggesting slightly different pathways may actually contribute to evoked responses of both stimulation modalities., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Krause corpuscles, which were discovered in the 1850s, are specialized sensory structures found within the genitalia and other mucocutaneous tissues 1-4 . The physiological properties and functions of Krause corpuscles have remained unclear since their discovery. Here we report the anatomical and physiological properties of Krause corpuscles of the mouse clitoris and penis and their roles in sexual behaviour. We observed a high density of Krause corpuscles in the clitoris compared with the penis. Using mouse genetic tools, we identified two distinct somatosensory neuron subtypes that innervate Krause corpuscles of both the clitoris and penis and project to a unique sensory terminal region of the spinal cord. In vivo electrophysiology and calcium imaging experiments showed that both Krause corpuscle afferent types are A-fibre rapid-adapting low-threshold mechanoreceptors, optimally tuned to dynamic, light-touch and mechanical vibrations (40-80 Hz) applied to the clitoris or penis. Functionally, selective optogenetic activation of Krause corpuscle afferent terminals evoked penile erection in male mice and vaginal contraction in female mice, while genetic ablation of Krause corpuscles impaired intromission and ejaculation of males and reduced sexual receptivity of females. Thus, Krause corpuscles of the clitoris and penis are highly sensitive mechanical vibration detectors that mediate sexually dimorphic mating behaviours., (© 2024. The Author(s).)

The soleus H-reflex modulation pattern was investigated during stepping following transspinal stimulation over the thoracolumbar region at 15, 30, and 50 Hz with 10 kHz carry-over frequency above and below the paresthesia threshold. The soleus H-reflex was elicited by posterior tibial nerve stimulation with a single 1 ms pulse at an intensity that the M-wave amplitudes ranged from 0 to 15% of the maximal M-wave evoked 80 ms after the test stimulus, and the soleus H-reflex was half the size of the maximal H-reflex evoked on the ascending portion of the recruitment curve. During treadmill walking, the soleus H-reflex was elicited every 2 or 3 steps, and stimuli were randomly dispersed across the step cycle which was divided in 16 equal bins. For each subject and condition, the soleus M-wave and H-reflex were normalized to the maximal M-wave. The soleus background electromyographic (EMG) activity was estimated as the linear envelope for 50 ms duration starting at 100 ms before posterior tibial nerve stimulation for each bin. The gain was determined as the slope of the relationship between the soleus H-reflex and the soleus background EMG activity. The soleus H-reflex phase-dependent amplitude modulation remained unaltered during transspinal stimulation, regardless frequency, or intensity. Similarly, the H-reflex slope and intercept remained the same for all transspinal stimulation conditions tested. Locomotor EMG activity was increased in knee extensor muscles during transspinal stimulation at 30 and 50 Hz throughout the step cycle while no effects were observed in flexor muscles. These findings suggest that transspinal stimulation above and below the paresthesia threshold at 15, 30, and 50 Hz does not block or impair spinal integration of proprioceptive inputs and increases activity of thigh muscles that affect both hip and knee joint movement. Transspinal stimulation may serve as a neurorecovery strategy to augment standing or walking ability in upper motoneuron lesions., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: The spinal cord and its interactions with the brain are fundamental for movement control and somatosensation. However, brain and spinal electrophysiology in humans have largely been treated as distinct enterprises, in part due to the relative inaccessibility of the spinal cord. Consequently, there is a dearth of knowledge on human spinal electrophysiology, including the multiple pathologies that affect the spinal cord as well as the brain., New Method: Here we exploit recent advances in the development of wearable optically pumped magnetometers (OPMs) which can be flexibly arranged to provide coverage of both the spinal cord and the brain in relatively unconstrained environments. This system for magnetospinoencephalography (MSEG) measures both spinal and cortical signals simultaneously by employing custom-made scanning casts., Results: We evidence the utility of such a system by recording spinal and cortical evoked responses to median nerve stimulation at the wrist. MSEG revealed early (10 - 15 ms) and late (>20 ms) responses at the spinal cord, in addition to typical cortical evoked responses (i.e., N20)., Comparison With Existing Methods: Early spinal evoked responses detected were in line with conventional somatosensory evoked potential recordings., Conclusion: This MSEG system demonstrates the novel ability for concurrent non-invasive millisecond imaging of brain and spinal cord., Competing Interests: Declaration of Competing Interest The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Transspinal (or transcutaneous spinal cord) stimulation is a noninvasive, cost-effective, easily applied method with great potential as a therapeutic modality for recovering somatic and nonsomatic functions in upper motor neuron disorders. However, how transspinal stimulation affects motor neuron depolarization is poorly understood, limiting the development of effective transspinal stimulation protocols for rehabilitation. In this study, we characterized the responses of soleus α motor neurons to single-pulse transspinal stimulation using single-motor unit (SMU) discharges as a proxy given the 1:1 discharge activation between the motor neuron and the motor unit. Peristimulus time histogram, peristimulus frequencygram, and surface electromyography (sEMG) were used to characterize the postsynaptic potentials of soleus motor neurons. Transspinal stimulation produced short-latency excitatory postsynaptic potentials (EPSPs) followed by two distinct phases of inhibitory postsynaptic potentials (IPSPs) in most soleus motor neurons and only IPSPs in others. Transspinal stimulation generated double discharges at short interspike intervals in a few motor units. The short-latency EPSPs were likely mediated by muscle spindle group Ia and II afferents, and the IPSPs via excitation of group Ib afferents and recurrent collaterals of motor neurons leading to activation of diverse spinal inhibitory interneuronal circuits. Further studies are warranted to understand better how transspinal stimulation affects depolarization of α motor neurons over multiple spinal segments. This knowledge will be seminal for developing effective transspinal stimulation protocols in upper motor neuron lesions. NEW & NOTEWORTHY Transspinal stimulation produces distinct actions on soleus motor neurons: an early short-latency excitation followed by two inhibitions or only inhibition and doublets. These results show how transspinal stimulation affects depolarization of soleus α motor neurons in healthy humans.

Motor behaviors such as breathing required temporal coordination of different muscle groups to insured efficient ventilation and provide oxygen to the body. This action is the result of interactions between neural networks located within the brainstem. Inspiration and expiration depend at least in part on interactions between two separate oscillators: inspiration is driven by a neural network located in the preBötzinger complex (PreBötC) and active expiration is driven by a network in the parafacial respiratory group (pFRG). Neurons of the pFRG are silent at rest and become active when the respiratory drive increased. This study investigated the temporal coordination between the brainstem respiratory network and the lumbar spinal network that generates spontaneous activities that is different of the induced fictive locomotion. The remaining question is how these activities coordinate early during the development. Results of this study show that brainstem networks contribute to the temporal coordination of the lumbar spontaneous activity during inspiration since lumbar motor activity occurs exclusively during the expiratory time. This study also investigated the role of the β-noradrenergic modulation on the respiratory activities. β-noradrenergic receptors activation increased the frequency of the double bursts and increased expiratory activity at the lumbar level. These results suggest interactions between brainstem and spinal networks and reveal a descending drive that may contribute to the coordination of the respiratory and lumbar spontaneous activities., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Objectives: Low-intensity, focused ultrasound (FUS) is an emerging noninvasive neuromodulation approach, with improved spatial and temporal resolution and penetration depth compared to other noninvasive electrical stimulation strategies. FUS has been used to modulate circuits in the brain and the peripheral nervous system, however, its potential to modulate spinal circuits is unclear. In this study, we assessed the effect of trans-spinal FUS (tsFUS) on spinal reflexes in healthy rats., Materials and Methods: tsFUS targeting different spinal segments was delivered for 1 minute, under anesthesia. Monosynaptic H-reflex of the sciatic nerve, polysynaptic flexor reflex of the sural nerve, and withdrawal reflex tested with a hot plate were measured before, during, and after tsFUS., Results: tsFUS reversibly suppresses the H-reflex in a spinal segment-, acoustic pressure- and pulse-repetition frequency (PRF)-dependent manner. tsFUS with high PRF augments the degree of homosynaptic depression of the H-reflex observed with paired stimuli. It suppresses the windup of components of the flexor reflex associated with slower, C-afferent, but not faster, A- afferent fibers. Finally, it increases the latency of the withdrawal reflex. tsFUS does not elicit neuronal loss in the spinal cord., Conclusions: Our study provides evidence that tsFUS reversibly suppresses spinal reflexes and suggests that tsFUS could be a safe and effective strategy for spinal cord neuromodulation in disorders associated with hyperreflexia, including spasticity after spinal cord injury and painful syndromes., Competing Interests: Conflict of Interest The authors reported no conflict of interest., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Alzheimer's disease is the most common cause of dementia worldwide, and longitudinal studies are crucial to find the factors affecting disease development. Here, we describe a novel initiative from southern Spain designed to contribute in the identification of the genetic component of the cognitive decline of Alzheimer's disease patients. The germline variant rs9320913 is a C>A substitution mapping within a gene desert. Although it has been previously associated to a higher educational achievement and increased fluid intelligence, its role on Alzheimer's disease risk and progression remains elusive. A total of 407 subjects were included in the study, comprising 153 Alzheimer disease patients and 254 healthy controls. We have explored the rs9320913 contribution to both Alzheimer disease risk and progression according to the Mini-Mental State Exams. We found that rs9320913 maps within a central nervous system lincRNA AL589740.1. eQTL results show that rs9320913 correlated with the brain-frontal cortex (beta = − 0.15 , p value = 0.057) and brain-spinal cord (beta of -0.23, p value = 0.037). We did not find rs9320913 to be associated to AD risk, although AA patients seemed to exhibit a less pronounced Mini-Mental State Exam score decline. [ABSTRACT FROM AUTHOR]

Epidural spinal cord stimulation (ESCS) is widely used for chronic pain treatment, and is also a promising tool for restoring motor function after spinal cord injury. Despite significant positive impact of ESCS, currently available protocols provide limited specificity and efficiency partially due to the limited number of contacts of the leads and to the limited flexibility to vary the spatial distribution of the stimulation field in respect to the spinal cord. Recently, we introduced Orientation Selective (OS) stimulation strategies for deep brain stimulation, and demonstrated their selectivity in rats using functional MRI (fMRI). The method achieves orientation selectivity by controlling the main direction of the electric field gradients using individually driven channels. Here, we introduced a similar OS approach for ESCS, and demonstrated orientation dependent brain activations as detected by brain fMRI. The fMRI activation patterns during spinal cord stimulation demonstrated the complexity of brain networks stimulated by OS-ESCS paradigms, involving brain areas responsible for the transmission of the motor and sensory information. The OS approach may allow targeting ESCS to spinal fibers of different orientations, ultimately making stimulation less dependent on the precision of the electrode implantation. [ABSTRACT FROM AUTHOR]

Purpose: Neuroimaging provides great utility in complex spinal surgeries, particularly when anatomical geometry is distorted by pathology (tumour, degeneration, etc.). Spinal cord MRI diffusion tractography can be used to generate streamlines; however, it is unclear how well they correspond with white matter tract locations along the cord microstructure. The goal of this work was to evaluate the spatial correspondence of DTI tractography with anatomical MRI in healthy anatomy (where anatomical locations can be well defined in T1-weighted images). Methods: Ten healthy volunteers were scanned on a 3T system. T1-weighted (1 × 1 × 1 mm) and diffusion-weighted images (EPI readout, 2 × 2 × 2 mm, 30 gradient directions) were acquired and subsequently registered (Spinal Cord Toolbox (SCT)). Atlas-based (SCT) anatomic label maps of the left and right lateral corticospinal tracts were identified for each vertebral region (C2–C6) from T1 images. Tractography streamlines were generated with a customized approach, enabling seeding of specific spinal tract regions corresponding to individual vertebral levels. Spatial correspondence of generated fibre streamlines with anatomic tract segmentations was compared in unseeded regions of interest (ROIs). Results: Spatial correspondence of the lateral corticospinal tract streamlines was good over a single vertebral ROI (Dice's similarity coefficient (DSC) = 0.75 ± 0.08, Hausdorff distance = 1.08 ± 0.17 mm). Over larger ROI, fair agreement between tractography and anatomical labels was achieved (two levels: DSC = 0.67 ± 0.13, three levels: DSC = 0.52 ± 0.19). Conclusion: DTI tractography produced good spatial correspondence with anatomic white matter tracts, superior to the agreement between multiple manual tract segmentations (DSC ~ 0.5). This supports further development of spinal cord tractography for computer-assisted neurosurgery. [ABSTRACT FROM AUTHOR]

The study aimed to establish the spinal cord occupation rate of the dural sac during flexion and extension. We measured the cross-sectional area of the dural sac and the spinal cord between C2/C3 and C7/T1 disc levels in 100 patients with cervical spondylotic myelopathy and 1211 asymptomatic subjects. The spinal cord occupation rate of the dural sac in the cross-sectional area was higher on extension than on flexion at the mid-lower cervical spine. The spinal cord occupation rate of the dural sac in the cross-sectional area was highest at the C4/C5 and C5/C6 levels on extension. [ABSTRACT FROM AUTHOR]

Sulf2a belongs to the Sulf family of extracellular sulfatases which selectively remove 6-O-sulfate groups from heparan sulfates, a critical regulation level for their role in modulating the activity of signalling molecules. Data presented here define Sulf2a as a novel player in the control of Sonic Hedgehog (Shh)-mediated cell type specification during spinal cord development. We show that Sulf2a depletion in zebrafish results in overproduction of V3 interneurons at the expense of motor neurons and also impedes generation of oligodendrocyte precursor cells (OPCs), three cell types that depend on Shh for their generation. We provide evidence that Sulf2a, expressed in a spatially restricted progenitor domain, acts by maintaining the correct patterning and specification of ventral progenitors. More specifically, Sulf2a prevents Olig2 progenitors to activate high-threshold Shh response and, thereby, to adopt a V3 interneuron fate, thus ensuring proper production of motor neurons and OPCs. We propose a model in which Sulf2a reduces Shh signalling levels in responding cells by decreasing their sensitivity to the morphogen factor. More generally, our work, revealing that, in contrast to its paralog Sulf1, Sulf2a regulates neural fate specification in Shh target cells, provides direct evidence of non-redundant functions of Sulfs in the developing spinal cord. [ABSTRACT FROM AUTHOR]