Sodium leak channels in the central amygdala modulate the analgesic potency of volatile anaesthetics in mice.

BACKGROUND: Analgesia is an important effect of volatile anaesthetics, for which the spinal cord is a critical neural target. However, how supraspinal mechanisms modulate analgesic potency of volatile anaesthetics is not clear. We investigated the contribution of the central amygdala (CeA) to the analgesic effects of isoflurane and sevoflurane. METHODS: Analgesic potencies of volatile anaesthetics were tested during optogenetic and chemogenetic inhibition of CeA neurones. In vivo calcium imaging was used to measure neuronal activities of CeA neuronal subtypes under volatile anaesthesia. Contributions of the sodium leak channel (NALCN) in GABAergic CeA (CeAGABA) neurones to analgesic effects of volatile anaesthetics were explored by specific NALCN knockdown. Electrophysiological recordings on acute brain slices were applied to measure volatile anaesthetic modulation of CeA neuronal activity by NALCN. RESULTS: Optogenetic or chemogenetic silencing CeA neurones reduced the analgesic effects of isoflurane or sevoflurane in vivo. The calcium signals of CeAGABA neurones increased during exposure to isoflurane or sevoflurane at analgesic concentrations. Knockdown of NALCN in CeAGABA neurones attenuated antinociceptive effects of isoflurane, sevoflurane, or both. For example, mean concentrations of isoflurane, sevoflurane, or both that induced immobility to tail-flick stimuli were significantly increased (isoflurane: 1.17 [0.05] vol% vs 1.24 [0.04] vol%, P=0.01; sevoflurane: 2.65 [0.07] vol% vs 2.81 [0.07] vol%; P<0.001). In brain slices, isoflurane, sevoflurane, or both at clinical concentrations increased NALCN-mediated holding currents and conductance in CeAGABA neurones, which increased excitability of CeAGABA neurones in an NALCN-dependent manner. CONCLUSIONS: The analgesic potencies of volatile anaesthetics are partially mediated by modulation of NALCN in CeAGABA neurones.

Modulations in neural pathways excitability post transcutaneous spinal cord stimulation among individuals with spinal cord injury: a systematic review.

Introduction: Transcutaneous spinal cord stimulation (TSCS), a non-invasive form of spinal cord stimulation, has been shown to improve motor function in individuals living with spinal cord injury (SCI). However, the effects of different types of TSCS currents including direct current (DC-TSCS), alternating current (AC-TSCS), and spinal paired stimulation on the excitability of neural pathways have not been systematically investigated. The objective of this systematic review was to determine the effects of TSCS on the excitability of neural pathways in adults with non-progressive SCI at any level. Methods: The following databases were searched from their inception until June 2022: MEDLINE ALL, Embase, Web of Science, Cochrane Library, and clinical trials. A total of 4,431 abstracts were screened, and 23 articles were included. Results: Nineteen studies used TSCS at the thoracolumbar enlargement for lower limb rehabilitation (gait & balance) and four studies used cervical TSCS for upper limb rehabilitation. Sixteen studies measured spinal excitability by reporting different outcomes including Hoffmann reflex (H-reflex), flexion reflex excitability, spinal motor evoked potentials (SMEPs), cervicomedullay evoked potentials (CMEPs), and cutaneous-input-evoked muscle response. Seven studies measured corticospinal excitability using motor evoked potentials (MEPs) induced by transcranial magnetic stimulation (TMS), and one study measured somatosensory evoked potentials (SSEPs) following TSCS. Our findings indicated a decrease in the amplitude of H-reflex and long latency flexion reflex following AC-TSCS, alongside an increase in the amplitudes of SMEPs and CMEPs. Moreover, the application of the TSCS-TMS paired associative technique resulted in spinal reflex inhibition, manifested by reduced amplitudes in both the H-reflex and flexion reflex arc. In terms of corticospinal excitability, findings from 5 studies demonstrated an increase in the amplitude of MEPs linked to lower limb muscles following DC-TSCS, in addition to paired associative stimulation involving repetitive TMS on the brain and DC-TSCS on the spine. There was an observed improvement in the latency of SSEPs in a single study. Notably, the overall quality of evidence, assessed by the modified Downs and Black Quality assessment, was deemed poor. Discussion: This review unveils the systematic evidence supporting the potential of TSCS in reshaping both spinal and supraspinal neuronal circuitries post-SCI. Yet, it underscores the critical necessity for more rigorous, high-quality investigations.

TNFR1/p38αMAPK signaling in Nex + supraspinal neurons regulates estrogen-dependent chronic neuropathic pain.

Upregulation of soluble tumor necrosis factor (sTNF) cytokine signaling through TNF receptor 1 (TNFR1) and subsequent neuronal hyperexcitability are observed in both animal models and human chronic neuropathic pain (CNP). Previously, we have shown that estrogen modulates sTNF/TNFR1 signaling in CNP, which may contribute to female prevalence of CNP. The estrogen-dependent role of TNFR1-mediated supraspinal neuronal circuitry in CNP remains unknown. In this study, we interrogated the intersect between supraspinal TNFR1 mediated neuronal signaling and sex specificity by selectively removing TNFR1 in Nex + neurons in adult mice (NexCreERT2::TNFR1f/f). We determined that mechanical hypersensitivity induced by chronic constriction injury (CCI) decreases over time in males, but not in females. Subsequently, we investigated two downstream pathways, p38MAPK and NF-κB, important in TNFR1 signaling and injury response. We detected p38MAPK and NF-κB activation in male cortical tissue; however, p38MAPK phosphorylation was reduced in NexCreERT2::TNFR1f/f males. We observed a similar recovery from acute pain in male mice following CCI when p38αMAPK was knocked out of supraspinal Nex + neurons (NexCreERT2::p38αMAPKf/f), while chronic pain developed in female mice. To explore the intersection between estrogen and inflammation in CNP we used a combination therapy of an estrogen receptor ß (ER ß) inhibitor with a sTNF/TNFR1 or general p38MAPK inhibitor. We determined both combination therapies lends therapeutic relief to females following CCI comparable to the response evaluated in male mice. These data suggest that TNFR1/p38αMAPK signaling in Nex + neurons in CNP is male-specific and lack of therapeutic efficacy following sTNF inhibition in females is due to ER ß interference. These studies highlight sex-specific differences in pathways important to pain chronification and elucidate potential therapeutic strategies that would be effective in both sexes.

Characterizing the supraspinal sensorimotor control of walking using MRI-compatible system: a systematic review.

BACKGROUND: The regulation of gait is critical to many activities of everyday life. When walking, somatosensory information obtained from mechanoreceptors throughout body is delivered to numerous supraspinal networks and used to execute the appropriate motion to meet ever-changing environmental and task demands. Aging and age-related conditions oftentimes alter the supraspinal sensorimotor control of walking, including the responsiveness of the cortical brain regions to the sensorimotor inputs obtained from the peripheral nervous system, resulting in diminished mobility in the older adult population. It is thus important to explicitly characterize such supraspinal sensorimotor elements of walking, providing knowledge informing novel rehabilitative targets. The past efforts majorly relied upon mental imagery or virtual reality to study the supraspinal control of walking. Recent efforts have been made to develop magnetic resonance imaging (MRI)-compatible devices simulating specific somatosensory and/or motor aspects of walking. However, there exists large variance in the design and functionality of these devices, and as such inconsistent functional MRI (fMRI) observations. METHODS: We have therefore completed a systematic review to summarize current achievements in the development of these MRI-compatible devices and synthesize available imaging results emanating from studies that have utilized these devices. RESULTS: The device design, study protocol and neuroimaging observations of 26 studies using 13 types of devices were extracted. Three of these devices can provide somatosensory stimuli, eight motor stimuli, and two both types of stimuli. Our review demonstrated that using these devices, fMRI data of brain activation can be successfully obtained when participants remain motionless and experience sensorimotor stimulation during fMRI acquisition. The activation in multiple cortical (e.g., primary sensorimotor cortex) and subcortical (e.g., cerebellum) regions has been each linked to these types of walking-related sensorimotor stimuli. CONCLUSION: The observations of these publications suggest the promise of implementing these devices to characterize the supraspinal sensorimotor control of walking. Still, the evidence level of these neuroimaging observations was still low due to small sample size and varied study protocols, which thus needs to be confirmed via studies with more rigorous design.

TNFR1/p38αMAPK signaling in Nex+ supraspinal neurons regulates sex-specific chronic neuropathic pain.

Upregulation of soluble tumor necrosis factor (sTNF) cytokine signaling through TNF receptor 1 (TNFR1) and subsequent neuronal hyperexcitability are observed in both animal models and human chronic neuropathic pain (CNP) [1-4]. To test the hypothesis that supraspinal circuitry is critical to pain chronification, we studied the intersect between supraspinal TNFR1 mediated neuronal signaling and sex specificity by selectively removing TNFR1 in Nex + neurons in adult mice (NexCreERT2::TNFR1f/f). We determined that following chronic constriction injury (CCI), pain resolves in males; however, female acute pain transitions to chronic. Subsequently, we investigated two downstream pathways, p38MAPK and NF-κB, important in TNFR1 signaling and injury response. We detected p38αMAPK and NF-κB activation in male cortical tissue; however, p38αMAPK phosphorylation was reduced in NexCreERT2::TNFR1f/f males. We observed similar behavioral results following CCI in NexCreERT2::p38αMAPKf/f mice. Previously, we established estrogen's ability to modulate sTNF/TNFR1 signaling in CNP, which may contribute to female prevalence of CNP [5-9]. To explore the intersection between estrogen and inflammation in CNP we used a combination therapy of an estrogen receptor ß (ER ß) inhibitor with a sTNF/TNFR1 or general p38MAPK inhibitor. We determined both combination therapies lend "male-like" therapeutic relief to females following CCI. These data suggest that TNFR1/p38αMAPK signaling in Nex + neurons in CNP is male-specific and lack of therapeutic efficacy following sTNF inhibition in females is due to ER ß interference. These studies highlight sex-specific differences in pathways important to pain chronification and elucidate potential therapeutic strategies that would be effective in both sexes.

Abnormal Resting-State Network Presence in Females with Overactive Bladder.

Overactive bladder (OAB) is a global problem reducing the quality of life of patients and increasing the costs of any healthcare system. The etiology of OAB is understudied but likely involves supraspinal network alterations. Here, we characterized supraspinal resting-state functional connectivity in 12 OAB patients and 12 healthy controls (HC) who were younger than 60 years. Independent component analysis showed that OAB patients had a weaker presence of the salience (Cohen's d = 0.9) and default mode network (Cohen's d = 1.1) and weaker directed connectivity between the fronto-parietal network and salience network with a longer lag time compared to HC. A region of interest analysis demonstrated weaker connectivity in OAB compared to HC (Cohen's d > 1.6 or < -1.6), particularly within the frontal and prefrontal cortices. In addition, weaker seed (insula, ventrolateral prefrontal cortex) to voxel (anterior cingulate cortex, frontal gyrus, superior parietal lobe, cerebellum) connectivity was found in OAB compared to HC (Cohen's d > 1.9). The degree of deviation in supraspinal connectivity in OAB patients (relative to HC) appears to be an indicator of the severity of the lower urinary tract symptoms and an indication that such symptoms are directly related to functional supraspinal alterations. Thus, future OAB therapy options should also consider supraspinal targets, while neuroimaging techniques should be given more consideration in the quest for better phenotyping of OAB.

Bidirectional Modulation of Nociception by GlyT2+ Neurons in the Ventrolateral Periaqueductal Gray.

The midbrain periaqueductal gray (PAG), particularly its ventrolateral column (vlPAG), is part of a key descending pathway that modulates nociception, fear and anxiety behaviors in both humans and rodents. It has been previously demonstrated that inhibitory GABAergic neurons within the vlPAG have a major role in this nociceptive modulation. However, the PAG contains a diverse range of neuronal subtypes and the contribution of different subtypes of inhibitory neurons to nociceptive control has not been investigated. Here, we employed a chemogenetic strategy in mice that express Cre recombinase under the promotor for the glycine transporter 2 (GlyT2::cre) to modulate a novel group of glycinergic neurons within the vlPAG and then investigate their role in nociceptive control. We show that activation of GlyT2-PAG neurons enhances cold and noxious heat responses and increases locomotor activity (LMA) in both male and female mice. In contrast, inhibition of GlyT2-PAG neurons reduced nociceptive responses, while locomotor behaviors were unaffected. Our findings demonstrate that GlyT2+ neurons in the vlPAG modulate nociception and suggest that strategies targeting GlyT2-PAG neurons could be used to design novel analgesic therapies.

High-level motor planning allows flexible walking at different gait patterns in a neuromechanical model.

Humans can freely adopt gait parameters like walking speed, step length, or cadence on the fly when walking. Planned movement that can be updated online to account for changes in the environment rather than having to rely on habitual, reflexive control that is adapted over long timescales. Here we present a neuromechanical model that accounts for this flexibility by combining movement goals and motor plans on a kinematic task level with low-level spinal feedback loops. We show that the model can walk at a wide range of different gait patterns by choosing a small number of high-level control parameters representing a movement goal. A larger number of parameters governing the low-level reflex loops in the spinal cord, on the other hand, remain fixed. We also show that the model can generalize the learned behavior by recombining the high-level control parameters and walk with gait patterns that it had not encountered before. Furthermore, the model can transition between different gaits without the loss of balance by switching to a new set of control parameters in real time.

Single Nuclei Analyses Reveal Transcriptional Profiles and Marker Genes for Diverse Supraspinal Populations.

The mammalian brain contains numerous neurons distributed across forebrain, midbrain, and hindbrain that project axons to the lower spinal cord and work in concert to control movement and achieve homeostasis. Extensive work has mapped the anatomic location of supraspinal cell types and continues to establish specific physiological functions. The patterns of gene expression that typify and distinguish these disparate populations, however, are mostly unknown. Here, using adult mice of mixed sex, we combined retrograde labeling of supraspinal cell nuclei with fluorescence-activated nuclei sorting and single-nuclei RNA sequencing analyses to transcriptionally profile neurons that project axons from the brain to lumbar spinal cord. We identified 14 transcriptionally distinct cell types and used a combination of established and newly identified marker genes to assign an anatomic location to each. To validate the putative marker genes, we visualized selected transcripts and confirmed selective expression within lumbar-projecting neurons in discrete supraspinal regions. Finally, we illustrate the potential utility of these data by examining the expression of transcription factors that distinguish different supraspinal cell types and by surveying the expression of receptors for growth and guidance cues that may be present in the spinal cord. Collectively, these data establish transcriptional differences between anatomically defined supraspinal populations, identify a new set of marker genes of use in future experiments, and provide insight into potential differences in cellular and physiological activity across the supraspinal connectome.SIGNIFICANCE STATEMENT The brain communicates with the body through a wide variety of neuronal populations with distinct functions and differential sensitivity to damage and disease. We have used single-nuclei RNA sequencing technology to distinguish patterns of gene expression within a diverse set of neurons that project axons from the mouse brain to the lumbar spinal cord. The results reveal transcriptional differences between populations previously defined on the basis of anatomy, provide new marker genes to facilitate rapid identification of cell type in future work, and suggest distinct responsiveness of different supraspinal populations to external growth and guidance cues.

Brain-wide analysis of the supraspinal connectome reveals anatomical correlates to functional recovery after spinal injury.

The supraspinal connectome is essential for normal behavior and homeostasis and consists of numerous sensory, motor, and autonomic projections from brain to spinal cord. Study of supraspinal control and its restoration after damage has focused mostly on a handful of major populations that carry motor commands, with only limited consideration of dozens more that provide autonomic or crucial motor modulation. Here, we assemble an experimental workflow to rapidly profile the entire supraspinal mesoconnectome in adult mice and disseminate the output in a web-based resource. Optimized viral labeling, 3D imaging, and registration to a mouse digital neuroanatomical atlas assigned tens of thousands of supraspinal neurons to 69 identified regions. We demonstrate the ability of this approach to clarify essential points of topographic mapping between spinal levels, measure population-specific sensitivity to spinal injury, and test the relationships between region-specific neuronal sparing and variability in functional recovery. This work will spur progress by broadening understanding of essential but understudied supraspinal populations.

3D imaging of supraspinal inputs to the thoracic and lumbar spinal cord mapped by retrograde tracing and light-sheet microscopy.

The supraspinal inputs play a major role in tuning the hindlimb locomotion function. While most research on spinal cord injury (SCI) with rodents is based on thoracic segments, the difference in connectivity of the supraspinal centers to the thoracic and lumbar cord is still unknown. Here, we combined retrograde tracing and 3D imaging to map the connectivity of supraspinal neurons projecting to thoracic (T9-vertebral) and lumbar (T13-vertebral) spinal levels in adult female mice. We dissected the difference in connections of corticospinal neurons (CSNs), rubrospinal neurons, and reticulospinal neurons projecting to thoracic and lumbar cords. The ratio of double-labeled neurons is higher in T13-vertebral projection CSNs and parvocellular part of the red nucleus (RPC) than in T9-vertebral projection. Using the Cre-DIO system, we precisely targeted CSNs projecting to T9-vertebral or T13-vertebral. We found that abundant axon branches communicated with the red nucleus and reticular formation and distributed from cervical gray matter to the lumbar cord. Their collateral branches showed a distinct innervation pattern in thoracic and lumbar gray matters and a similar distribution pattern in the cervical spinal cord. These results revealed the difference in connectivity between the thoracic and lumbar projection supraspinal centers and clarified the collateralization of thoracic/lumbar projection CSNs throughout the brain and spinal cord. This study highlights brain-spinal cord neural networks and the complexity of the axon terminals of spinal projection CSNs, which could contribute to the development of targeted therapeutic strategies connecting CST fibers and hindlimb function recovery. Cover Image for this issue: https://doi.org/10.1111/jnc.15414.

People with multiple sclerosis have reduced TMS-evoked motor cortical output compared with healthy individuals during fatiguing submaximal contractions.

People with multiple sclerosis (PwMS) typically experience greater levels of exercise-induced fatigue compared with healthy individuals. Therefore, this study examined performance fatigability in PwMS when executing a prolonged submaximal contraction. Nine PwMS (38 ± 7 yr, 6 females) and nine healthy controls (35 ± 6 yr, 4 females) performed an elbow flexion at 15% maximal voluntary contraction (MVC) for 26 min. MVCs were performed every 2 min during, and following, the contraction to determine if maximal force was impaired by the low-intensity contraction. Single-pulse transcranial magnetic stimulation (TMS) was delivered to the primary motor cortex with a circular coil during each MVC and during the submaximal contraction. Superimposed and resting twitches were calculated from elbow flexion torque, whereas motor-evoked potentials were calculated from biceps brachii electromyography. Ratings of perceived exertion (RPE) were obtained before each MVC. During the fatiguing contraction protocol, the MS group exhibited a reduced MVC torque compared with the healthy control group (P = 0.044), which aligned with group differences in biceps brachii EMG activity (P = 0.022) and superimposed twitch amplitude (P = 0.016). Fatigue-related decrements in MVC torque (P = 0.044) and biceps brachii EMG activity (P = 0.043) demonstrated in the MS group persisted throughout recovery. However, MS did not affect the RPE during the fatigue task. These findings suggest that PwMS may have greater levels of performance fatigability due to decreased voluntary drive from the motor cortex, which is not associated with greater ratings of perceived exertion.NEW & NOTEWORTHY By combining TMS and motor nerve stimulation during a low-intensity exercise task, we were able to uncover the contribution that different levels of the CNS have during fatiguing exercise in PwMS. Our findings are novel and revealed that PwMS experienced decreased voluntary drive from the motor cortex during a low-intensity sustained fatiguing task that was associated with heightened levels of performance fatigability.

Locomotor Exercise Enhances Supraspinal Control of Lower-Urinary-Tract Activity to Improve Micturition Function after Contusive Spinal-Cord Injury.

The recovery of lower-urinary-tract activity is a top priority for patients with spinal-cord injury. Historically, locomotor training improved micturition function in both patients with spinal cord injury and animal models. We explore whether training augments such as the supraspinal control of the external urethral sphincter results in enhanced coordination in detrusor-sphincter activity. We implemented a clinically relevant contusive spinal-cord injury at the 12th thoracic level in rats and administered forced wheel running exercise for 11 weeks. Awake rats then underwent bladder cystometrogram and sphincter electromyography recordings to examine the micturition reflex. Subsequently, pseudorabies-virus-encoding red fluorescent protein was injected into the sphincter to trans-synaptically trace the supraspinal innervation of Onuf's motoneurons. Training in the injury group reduced the occurrence of bladder nonvoiding contractions, decreased the voiding threshold and peak intravesical pressure, and shortened the latency of sphincter bursting during voiding, leading to enhanced voiding efficiency. Histological analysis demonstrated that the training increased the extent of spared spinal-cord tissue around the epicenter of lesions. Compared to the group of injury without exercise, training elicited denser 5-hydroxytryptamine-positive axon terminals in the vicinity of Onuf's motoneurons in the cord; more pseudorabies virus-labeled or c-fos expressing neurons were detected in the brainstem, suggesting the enhanced supraspinal control of sphincter activity. Thus, locomotor training promotes tissue sparing and axon innervation of spinal motoneurons to improve voiding function following contusive spinal-cord injury.

OAB supraspinal control network, transition with age, and effect of treatment: A systematic review.

OBJECTIVE: In light of a better understanding of supraspinal control of nonneurogenic overactive bladder (OAB), the prevalence of which increases with age, functional imaging has gained significant momentum. The objective of this study was to perform a systematic review on the transition of supraspinal control of OAB with age, the effect of therapeutic modalities, and a coordinate-based meta-analysis of all neuroimaging evidence on supraspinal OAB control in response to bladder filling. METHODOLOGY: We performed a systematic literature search of all relevant libraries in November 2021. The coordinates of brain activity were extracted from eligible neuroimaging studies to perform an activation likelihood estimation (ALE) meta-analysis. RESULTS: A total of 16 studies out of 241 were selected for our systematic review. Coordinates were extracted from five experiments involving 70 patients. ALE meta-analysis showed activation of the insula, supplementary motor area, dorsolateral prefrontal cortex, anterior cingulate gyrus, and temporal gyrus with a transition of activation patterns with age, using a threshold of uncorrected p < 0.001. Among young patients, neuroplasticity allows the activation of accessory circuits to maintain continence, as in the cerebellum and temporoparietal lobes. Anticholinergics, pelvic floor muscle training, sacral neuromodulation, and hypnotherapy are correlated with supraspinal changes attributed to adaptability and possibly a substratum of an intrinsic supraspinal component. The latter is better demonstrated by a resting-state functional connectivity analysis, a promising tool to phenotype OAB with recent successful models of predicting severity and response to behavioral treatments. CONCLUSION: Future neuroimaging studies are necessary to better define an OAB neurosignature to allocate patients to successful treatments.

The Spino-Parabrachial Pathway for Itch.

Itch-induced scratching is an evolutionarily conserved behavioral response that protects organisms from potential parasites/irritants in their immediate vicinity. How the exposure to a pruritogen is translated to the perception of itch and how that perception drives scratching directed towards the site of exposure remains poorly understood. In this review, we focus on the recent findings that shed light on the neural pathways in the brain that underlie itch-induced scratching. We compare the molecularly defined itch pathways with the known pain circuits as they have anatomical and functional overlap. We review the roles played by the neurons in the spinoparabrachial pathway-comprising of the neurons in the spinal cord and the parabrachial nucleus (PBN), which acts as a hub for transmitting itch information across the brain. Lastly, we deliberate on scratching as a behavioral measure of the intensity of itch and its implication in unraveling the underlying supraspinal mechanisms. In summary, we provide a resource on the recent advances and discuss a path forward on our understanding of the neural circuits for itch.

Neuromuscular fatigability at high altitude: Lowlanders with acute and chronic exposure, and native highlanders.

Ascent to high altitude is accompanied by a reduction in partial pressure of inspired oxygen, which leads to interconnected adjustments within the neuromuscular system. This review describes the unique challenge that such an environment poses to neuromuscular fatigability (peripheral, central and supraspinal) for individuals who normally reside near to sea level (SL) (<1000 m; ie, lowlanders) and for native highlanders, who represent the manifestation of high altitude-related heritable adaptations across millennia. Firstly, the effect of acute exposure to high altitude-related hypoxia on neuromuscular fatigability will be examined. Under these conditions, both supraspinal and peripheral fatigability are increased compared with SL. The specific mechanisms contributing to impaired performance are dependent on the exercise paradigm and amount of muscle mass involved. Next, the effect of chronic exposure to high altitude (ie, acclimatization of ~7-28 days) will be considered. With acclimatization, supraspinal fatigability is restored to SL values, regardless of the amount of muscle mass involved, whereas peripheral fatigability remains greater than SL except when exercise involves a small amount of muscle mass (eg, knee extensors). Indeed, when whole-body exercise is involved, peripheral fatigability is not different to acute high-altitude exposure, due to competing positive (haematological and muscle metabolic) and negative (respiratory-mediated) effects of acclimatization on neuromuscular performance. In the final section, we consider evolutionary adaptations of native highlanders (primarily Himalayans of Tibet and Nepal) that may account for their superior performance at altitude and lesser degree of neuromuscular fatigability compared with acclimatized lowlanders, for both single-joint and whole-body exercise.

Predictive Clinical Decision Support System Using Machine Learning and Imaging Biomarkers in Patients With Neurostimulation Therapy: A Pilot Study.

BACKGROUND: Chronic pain is correlated with alterations in brain structure and function. The selection process for the ideal candidate for spinal cord stimulation (SCS) therapy is based on functional variables analysis and pain evaluation scores. In addition to the difficulties involved in the initial selection of patients and the predictive analysis of the trial phase, the large rate of explants is one of the most important concerns in the analysis of the suitability of implanted candidates. OBJECTIVE: To investigate the usefulness of imaging biomarkers, functional connectivity (FC) and volumetry of the whole brain in patients with Failed back surgery syndrome (FBSS) and to create a clinical patient-based decision support system (CDSS) combining neuroimaging and clinical data for predicting the effectiveness of neurostimulation therapy after a trial phase. STUDY DESIGN: A prospective, consecutive, observational, single center study. SETTING: The Multidisciplinary Pain Management Department of the General University Hospital in Valencia, Spain. METHODS: A prospective, consecutive, and observational single-center study. Using Resting-state functional magnetic resonance imaging (rs-fMRI) and Region of interest (ROI) to ROI analysis, we compared the functional connectivity between regions to detect differences in FC and volume changes. Basal magnetic resonance images were obtained in a 1.5T system and clinical variables were collected twice, at the basal condition and at 6-months post-SCS implant. We also conducted a seed-to-voxel analysis with 9 items as seed-areas characterizing the functional connectivity networks. A decreased in 10 units in the Pain Detect Questionnaire (PD-Q) score was established to define the subgroup of Responders Group (R-G) to neurostimulation therapy. The clinical variables collected and the imaging biomarkers obtained (FC and volumes) were tested on a set of 6 machine learning approaches in an effort to find the best classifier system for predicting the effectiveness of the neurostimulator. RESULTS: Twenty-four patients were analyzed and only seven were classified in the R-G. Volumetric differences were found in the left putamen, F = 34.06, P = 0.02. Four pairwise brain areas showed statistical differences in the rs-fMRI including the right insular cortex. Linear Discriminant Analysis showed the best performance for building the CDSS combining clinical variables and significant imaging biomarkers, the prediction increased diagnostic accuracy in the R-G patients from 29% in current practice to 96% of long-term success. CONCLUSION: These findings confirm a major role of the left putamen and the four pairs of brain regions in FBBS patients and suggest that a CDSS would be able to select patients susceptible to benefitting from SCS therapy adding imaging biomarkers.

Exploration of the Supraspinal Hypotheses about Spinal Cord Stimulation and Dorsal Root Ganglion Stimulation: A Systematic Review.

Despite the established efficacy and effectiveness of Spinal Cord Stimulation (SCS), there is still no consensus on the supraspinal mechanisms of action of this therapy. The purpose of this study was to systematically review previously raised hypotheses concerning supraspinal mechanisms of action of SCS based on human, animal and computational studies. Searches were conducted using four electronic databases (PubMed, EMBASE, SCOPUS and Web of Science), backward reference searching and consultation with experts. The study protocol was registered prior to initiation of the review process (PROSPERO CRD42020161531). A total of 54 publications were included, 21 of which were animal studies, and 33 were human studies. The supraspinal hypotheses (n = 69) identified from the included studies could be categorized into six groups concerning the proposed supraspinal hypothesis, namely descending pathways (n = 24); ascending medial pathway (n = 13); ascending lateral pathway (n = 10); affective/motivational influences (n = 8); spinal-cerebral (thalamic)-loop (n = 3) and miscellaneous (n = 11). Scientific support is provided for the hypotheses identified. Modulation of the descending nociceptive inhibitory pathways, medial and lateral pathways were the most frequently reported hypotheses about the supraspinal mechanisms of action of SCS. These hypotheses were mainly supported by studies with a high or moderate confidence in the body of evidence.

Effects of intrathecal and intracerebroventricular microinjection of kaempferol on pain: possible mechanisms of action.

BACKGROUND AND PURPOSE: Kaempferol (KM), a flavonoid, has an anti-inflammatory and anticancer effect and prevents many metabolic diseases. Nonetheless, very few studies have been done on the antinociceptive effects of KM. This research aimed at assessing the involvement of opioids, gamma-aminobutyric acid (GABA) receptors, and inflammatory mediators in the antinociceptive effects of KM in male Wistar rats. EXPERIMENTAL APPROACH: The intracerebroventricular and/or intrathecal administration of the compounds was done for examining their central impacts on the thermal and chemical pain by the tail-flick and formalin paw tests. For assessing the role of opioid and GABA receptors in the possible antinociceptive effects of KM, several antagonists were used. Also, a rotarod test was carried out for assessing motor performance. FINDINGS/RESULTS: The intracerebroventricular and/or intrathecal microinjections of KM (40 µg/rat) had partially antinociceptive effects in the tail-flick test in rats (P < 0.05). In the formalin paw model, the intrathecal microinjection of KM had antinociceptive effects in phase 1 (20 and 40 µg/rat; P < 0.05 and P < 0.01, respectively) and phase 2 (20 and 40 µg/rat; P < 0.01 and P < 0.001, respectively). Using naloxonazine and/or bicuculline approved the involvement of opioid and GABA receptors in the central antinociceptive effects of KM, respectively. Moreover, KM reduced the expression levels of caspase 6, interleukin-1ß, tumor necrosis factor-α, and interleukin-6. The antinociceptive effects of KM were not linked to variations in the locomotor activity. CONCLUSION AND IMPLICATIONS: It can be concluded that KM has remarkable antinociceptive effects at a spinal level, which is associated with the presence of the inflammatory state. These impacts were undetectable following injections in the lateral ventricle. The possible mechanisms of KM antinociception are possibly linked to various modulatory pathways, including opioid and GABA receptors.

No effect of passive stretching on neuromuscular function and maximum force-generating capacity in the antagonist muscle.

PURPOSE: The present study investigated whether or not passive stretching increases the force-generating capacity of the antagonist muscle, and the possible neuromuscular mechanisms behind. METHODS: To this purpose, the neuromuscular function accompanying the force-generating capacity was assessed in 26 healthy male volunteers after passive stretching and in a control session. Before and after passive intermittent static stretching of the plantar flexors consisting of five sets × 45 s + 15 s-rest, maximum voluntary isometric contraction (MVC) and surface electromyographic root mean square (sEMG RMS) were measured in the tibialis anterior (the antagonist muscle). Additionally, evoked V wave, H-reflex, and M wave were elicited by nerve stimulation at rest and during MVC. Ankle range of motion (ROM) and plantar flexors MVC and EMG RMS were measured to check for the effectiveness of the stretching manoeuvre. RESULTS: No change in MVC [p = 0.670; effect size (ES) - 0.03] and sEMG RMS/M wave during MVC (p = 0.231; ES - 0.09) was observed in the antagonist muscle after passive stretching. Similarly, no change in V wave (p = 0.531; ES 0.16), H-reflex at rest and during MVC (p = 0.656 and 0.597; ES 0.11 and 0.23, respectively) and M wave at rest and during MVC (p = 0.355 and 0.554; ES 0.04 and 0.01, respectively) was observed. An increase in ankle ROM (p < 0.001; ES 0.55) and a decrease in plantar flexors MVC (p < 0.001; ES - 1.05) and EMG RMS (p < 0.05; ES - 1.72 to - 0.13 in all muscles) indicated the effectiveness of stretching protocol. CONCLUSION: No change in the force-generating capacity and neuromuscular function of the antagonist muscle after passive stretching was observed.