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BACKGROUND: The Zic family of transcription factors (TFs) promote both proliferation and maturation of cerebellar granule neurons (CGNs), raising the question of how a single, constitutively expressed TF family can support distinct developmental processes. Here we use an integrative experimental and bioinformatic approach to discover the regulatory relationship between Zic TF binding and changing programs of gene transcription during postnatal CGN differentiation. RESULTS: We first established a bioinformatic pipeline to integrate Zic ChIP-seq data from the developing mouse cerebellum with other genomic datasets from the same tissue. In newborn CGNs, Zic TF binding predominates at active enhancers that are co-bound by developmentally regulated TFs including Atoh1, whereas in mature CGNs, Zic TF binding consolidates toward promoters where it co-localizes with activity-regulated TFs. We then performed CUT&RUN-seq in differentiating CGNs to define both the time course of developmental shifts in Zic TF binding and their relationship to gene expression. Mapping Zic TF binding sites to genes using chromatin looping, we identified the set of Zic target genes that have altered expression in RNA-seq from Zic1 or Zic2 knockdown CGNs. CONCLUSIONS: Our data show that Zic TFs are required for both induction and repression of distinct, developmentally regulated target genes through a mechanism that is largely independent of changes in Zic TF binding. We suggest that the differential collaboration of Zic TFs with other TF families underlies the shift in their biological functions across CGN development.
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Neuronas , Factores de Transcripción , Animales , Factores de Transcripción/metabolismo , Factores de Transcripción/genética , Ratones , Neuronas/metabolismo , Cerebelo/metabolismo , Diferenciación Celular/genética , Genoma , Regulación del Desarrollo de la Expresión GénicaRESUMEN
The integration of Spiking Neural Networks (SNNs) into the analysis and interpretation of physiological and speech signals has emerged as a groundbreaking approach, offering enhanced performance and deeper insights into the underlying biological processes. This review aims to summarize key advances, methodologies, and applications of SNNs within these domains, highlighting their unique ability to mimic the temporal dynamics and efficiency of the human brain. We dive into the core principles of SNNs, their neurobiological underpinnings, and the computational advantages they bring to signal processing, particularly in handling the temporal and spatial complexities inherent in physiological and speech data. Comparative analyses with conventional neural network models are presented to underscore the superior efficiency, lower power consumption, and higher temporal resolution of SNNs. The review further explores challenges and future prospects, highlighting the potential of SNNs to revolutionize wearable healthcare monitoring systems, neuroprosthetic devices, and natural language processing technologies. By providing a comprehensive overview of current strategies, this review aims to inspire innovative approaches in the field, fostering advances in real-time and energy-efficient processing of complex biological signals.
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Peripheral nerve injury is a major challenge in clinical treatment due to the limited intrinsic capacity for nerve regeneration. Tissue engineering approaches offer promising solutions by providing biomimetic scaffolds and cell sources to promote nerve regeneration. In the present work, we investigated the potential role of skin-derived progenitors (SKPs), which are induced into neurons and Schwann cells (SCs), and their extracellular matrix in tissue-engineered nerve grafts (TENGs) to enhance peripheral neuroregeneration. SKPs were induced to differentiate into neurons and SCs in vitro and incorporated into nerve grafts composed of a biocompatible scaffold including chitosan neural conduit and silk fibroin filaments. In vivo experiments using a rat model of peripheral nerve injury showed that TENGs significantly enhanced nerve regeneration compared to the scaffold control group, catching up with the autograft group. Histological analysis showed improved axonal regrowth, myelination and functional recovery in animals treated with these TENGs. In addition, immunohistochemical staining confirmed the presence of induced neurons and SCs within the regenerated nerve tissue. Our results suggest that SKP-induced neurons and SCs in tissue-engineered nerve grafts have great potential for promoting peripheral nerve regeneration and represent a promising approach for clinical translation in the treatment of peripheral nerve injury. Further optimization and characterization of these engineered constructs is warranted to improve their clinical applicability and efficacy.
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A zoonotic disease called brucellosis can cause flu-like symptoms and heart inflammation. The bacteria responsible for this disease can also enter the brain, causing a condition called neurobrucellosis that can result in long-term neurological problems. In this study, researchers aimed to determine the changes in the hippocampal cells of rats infected with Brucella. For the study, 24 adult male albino rats were inoculated with 1 × 106 CFU Brucella abortus 544. The rats were then deeply anesthetized, and their hippocampus samples were taken for stereological, histological, and molecular studies. The results showed that the infected rats had increased microgliosis and astrogliosis. Furthermore, a high level of caspase-3 in their hippocampal tissue indicated their susceptibility to apoptosis. Additionally, there was a decrease in expression of Ki67, which further supported this. Sholl's analysis confirmed a significant failure in glial morphology. The study demonstrated that the pathogen has the ability to destroy the hippocampus and potentially affect its normal physiology. However, more research is needed to clarify various aspects of neurobrucellosis.
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Astrocyte-microglia crosstalk is vital for neuronal survival and clearing aggregate accumulation in neurodegenerative diseases. While interleukin-3 (IL-3) has been reported to exert both protective and detrimental effects in neurodegenerative diseases, however, its role in α-synuclein pathology remains unclear. In this study, it is found that astrocytic IL-3 and microglial IL-3R are positively responsive to α-synuclein pathology in the brains of transgenic A53T Parkinson's disease (PD) mice and in an adeno-associated virus (AAV)-human α-synuclein (AAV-hα-Syn)-injected PD mouse model. Exogenous IL-3 infusion reduces behavioral abnormities and nigrostriatal α-synuclein pathology. Mechanistically, IL-3 induces microglial phagocytosis of pathological α-synuclein while simultaneously stimulating dopaminergic (DA) neurons to clear pathological α-synuclein via induction of autophagy through the IFN-ß/Irgm1 pathway. Due to its limited efficiency in crossing the blood-brain barrier, a precise IL-3 delivery strategy is developed by cross-linking IL-3 and RVG29 with PEG-Linker (RVG-modified IL-3 nanogels-RVG-IL3 NGs). Intravenous administration of RVG-IL3 NGs shows efficient uptake by microglia and DA neurons within the brain. RVG-IL3 NGs ameliorate motor deficits and pathological α-synuclein by improving microglial and neuronal function in the AAV-hα-Syn mouse model of PD. Collectively, IL-3 may represent a feasible therapeutic strategy for PD.
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Teaching aspects of neuroscience to large undergraduate classes can be difficult in terms of the cost of equipment involved such as microscopes and electrophysiology equipment, the time taken to master techniques such as dissection or intracellular recording, and ethical concerns when using vertebrates. Here, I describe a practical that uses behavioral readouts and optogenetics on Drosophila that can be implemented with minimal cost as well as reduced ethical concerns and uses mostly observational techniques. The practical can be used to teach aspects of genetics and the tools for manipulating neuronal activity for ascribing neuronal function. The practical can be customized to fit different undergraduate levels and learning objectives.
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In neurons and myocytes, selective ion channels in the plasma membrane play a pivotal role in transducing chemical or sensory stimuli into electrical signals, underpinning neural and cardiac functionality. Recent advancements in biomedical research have increasingly spotlighted the interaction between ion channels and electromagnetic fields, especially terahertz (THz) radiation. This review synthesizes current findings on the impact of THz radiation, known for its deep penetration and non-ionizing properties, on ion channel kinetics and membrane fluid dynamics. It is organized into three parts: the biophysical effects of THz exposure on cells, the specific modulation of ion channels by THz radiation, and the potential pathophysiological consequences of THz exposure. Understanding the biophysical mechanisms underlying these effects could lead to new therapeutic strategies for diseases.
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Sensorineural hearing loss is one of the most prevalent sensory deficits. Spiral ganglion neurons (SGNs) exhibit very limited regeneration capacity and their degeneration leads to profound hearing loss. Mesenchymal stem cell-derived small extracellular vesicles (MSC-sEV) have been demonstrated to repair tissue damage in various degenerative diseases. However, the effects of MSC-sEV on SGN degeneration remain unclear. In this study, we investigated the efficacy of MSC-sEV for protection against ouabain-induced SGN degeneration. MSC-sEV were derived from rat bone marrow and their components related to neuron growth were determined by proteomic analysis. In primary culture SGNs, MSC-sEV significantly promoted neurite growth and growth cone development. The RNA-Seq analysis of SGNs showed that enriched pathways include neuron development and axon regeneration, consistent with proteomics. In ouabain induced SGN degeneration rat model, MSC-sEV administration via intratympanic injection significantly enhanced SGN survival and mitigated hearing loss. Furthermore, after ouabain treatment, SGNs displayed evident signs of apoptosis, including nuclei condensation and fragmentation, with numerous cells exhibiting TUNEL-positive. However, administration of MSC-sEV effectively decreased the number of TUNEL-positive cells and reduced caspase-3 activation. In conclusion, our findings demonstrate the potential of MSC-sEV in preventing SGN degeneration and promoting neural growth, suggesting intratympanic injection of MSC-sEV is a specific and efficient strategy for neural hearing loss.
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Dragonflies are poikilothermic animals with limited thermoregulation; therefore, their entire bodies, including the brain, experience a range of temperatures during their daily activities.1,2 These flying insects exhibit hunting prowess, pursuing prey or conspecifics whether in direct sunlight or under the cover of cloud.3,4 Likely to underlie these aerobatic feats are the small target motion detector (STMD) neurons.5 These visual neurons are sensitive to target contrast and tuned to the target's size and velocity, with some neurons exhibiting complex predictive and selective properties, well suited for prey interception and feeding amid swarms.3,4,6,7,8,9 Increased temperature can modulate the biochemical processes underlying neuronal processing, increasing sensitivity and quickening the responsiveness of insect photoreceptors and downstream optic flow neurons,10,11,12 while in other neuronal pathways, compensatory processes have been shown to account for temperature changes.13,14 We determined the ethological range of temperatures experienced by the dragonfly, Hemicordulia tau, in its natural environment. Across this behaviorally relevant range, we showed increased temperatures having a large 8.7-fold increase in the contrast sensitivity of STMD neurons. However, suppression of responses to larger targets was unaltered. STMD tuning for target velocities was changed remarkably, not only increasing the optimum but extending the fastest velocities encoded by an order of magnitude. These results caution against interpreting functionality underlying spike rates at constrained, experimental temperatures. Moreover, they raise intriguing new questions about how information is represented within the brain of these flying insects, given the relationship between visual stimulus parameters and neuronal activity varies so dramatically depending on current environmental conditions.
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INTRODUCTION: Ultrasound changes in the cross-sectional area of the median nerve (CSAmn) could be of interest as biomarkers in patients with amyotrophic lateral sclerosis (ALS). METHODS: Eighty-four ALS patients (51 men [60.7%]; mean 62.0 [SD 11.46] years old) and forty-six controls (27 men [58.7%]; mean 59.9 [SD 8.08] years old) of two different cohorts were recruited between September 2013 and February 2018. The CSAmn was measured bilaterally in each cohort, by two different examiners with two different ultrasound machines (one in each cohort). Its association with clinical variables (disease duration, muscle strength, disability, progression rate and tracheostomy-free survival) was assessed. RESULTS: The CSAmn was smaller in patients than in controls, and the study cohort did not influence its values. A mild correlation between the strength of the wrist flexor and the CSAmn was found. In the multivariable analysis, the probability of this association being true was 90%. In the cox regression, both a faster progression rate and a larger CSAmn independently predicted poor survival (HR=4.29, [Cr.I95%: 2.71-6.80], p<0.001; and HR=1.14, [Cr.I95%: 1.03-1.25], p=0.01), after adjusting by age, body mass index, bulbar onset, and diagnostic delay. CONCLUSIONS: The CSAmn is an easy to assess biomarker that seems reliable and reproducible. Our data also suggest that it could act as a progression and prognostic biomarker in ALS patients. Longitudinal studies with repeated measures are warranted to confirm its usefulness in the clinical practice.
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Esclerosis Amiotrófica Lateral , Biomarcadores , Nervio Mediano , Ultrasonografía , Humanos , Masculino , Persona de Mediana Edad , Femenino , Nervio Mediano/diagnóstico por imagen , Pronóstico , Anciano , Progresión de la Enfermedad , Estudios de CohortesRESUMEN
The integration of artificial spiking neurons based on steep-switching logic devices and artificial synapses with neuromorphic functions enables an energy-efficient computer architecture that mimics the human brain well, known as a spiking neural network (SNN). 2D materials with impact ionization or ferroelectric characteristics have the potential for use in such devices. However, research on 2D spiking neurons remains limited and investigations of 2D artificial synapses far more common. An innovative 2D spiking neuron is implemented using a WSe2 impact ionization transistor (I2FET), while a spiking neural network is formed by combining it with a 2D ferroelectric synaptic device (FeFET). The suggested 2D spiking neuron demonstrates precise spiking behavior that closely resembles that of actual neurons. In addition, it achieves a low energy consumption of 2 pJ/spike. The better impact ionization properties of WSe2 are responsible for this efficiency. Furthermore, an all-2D SNN consisting of 2D I2FET neurons and 2D FeFET synapses is constructed, which achieves high accuracy of 87.5% in a face classification task by unsupervised learning. The integration of a 2D SNN with 2D steep-switching spiking neuronal devices and 2D synaptic devices shows great potential for the development of neuromorphic systems with improved energy efficiency and computational capabilities.
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The purpose of this study is to identify the therapeutic effect of electroacupuncture (EA) on cerebral ischemia-reperfusion (I/R) injury, and to clarify the regulatory mechanism related to telomerase reverse transcriptase (TERT)-mediated telomerase activity. A Middle cerebral artery occlusion/reperfusion (MCAO/R) animal model was constructed and rats were treated by EA invention at the Baihui (GV20) and Fengchi (GB20) acupoints. Neurological deficits were assessed via rotarod test and Morris water maze test. 2,3,5-Triphenyltertrazolium chloride (TTC) staining was performed to evaluate infarct volume. Histological changes were observed under H&E staining and Nissl staining. TERT expression was examined using qRT-PCR and western blot. Telomerase activity was assessed with TRAP method. Neuron apoptosis and senescence were assessed by TUNEL and immunofluorescence assays. Inflammatory cytokines and oxidative stress-indicators were examined using commercial kits. EA intervention at both GV20 and GB20 acupoints reduced infarct volumes (2.48 ± 1.89 vs. 29.56 ± 2.55), elevated the telomerase activity (0.84 ± 0.08 vs. 0.34 ± 0.09), and upregulated the levels of total TERT protein (0.61 ± 0.09 vs. 0.21 ± 0.05) and mitochondrial TERT (Mito-TERT; 0.54 ± 0.03 vs. 0.27 ± 0.03) in hippocampus tissues of MCAO/R rats. EA intervention attenuated motor dysfunction (112.00 ± 6.69 vs. 30.02 ± 2.60) and improved spatial learning (23.87 ± 1.90 vs. 16.23 ± 1.45) and memory ability (8.38 ± 1.06 vs. 4.13 ± 1.13) of rats with cerebral I/R injury. In addition, EA intervention significantly attenuated histopathological changes of injured neurons, mitigated neuron apoptosis (32.27 ± 5.52 vs. 65.83 ± 4.31) and senescence in MCAO/R rats, as well as inhibited excessive production of inflammatory cytokines and attenuated oxidative stress. However, the above therapeutic efficiency of EA intervention in MCAO/R rats was partly eliminated by TERT knockdown. EA intervention at GB20 and GV20 acupoints exerted a protective role in cerebral I/R injury partly through restoring TERT function, implying the clinical potential of EA treatment in the treatment of ischemic stroke.
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OBJECTIVES: To investigate the relationship among patients' apathy, cognitive impairment, depression, anxiety, and caregiver burden in amyotrophic lateral sclerosis (ALS). DESIGN: A cross-sectional study design was used. SETTING: The study was conducted at a tertiary hospital in Wuhan, Hubei, China. PARTICIPANTS: A total of 109 patients with ALS and their caregivers were included. OUTCOME MEASURES: Patients with ALS were screened using the Edinburgh Cognitive and Behavioural Screen, Beck Depression Inventory-II, Generalised Anxiety Disorder-7 and Apathy Scale to assess their cognition, depression, anxiety and apathy, respectively. The primary caregivers completed the Zarit Burden Interview. The association between apathy, cognitive impairment, depression, anxiety and caregiver burden was analysed using logistic regression. Mediation models were employed to investigate the mediating effect of patients' apathy on the relationship between depression/anxiety and caregiver burden. RESULTS: Patients in the high caregiver burden group exhibited significantly higher levels of depression, anxiety and apathy compared with those in the low caregiver burden group (p<0.05). There was a positive association observed between caregiver burden and disease course (rs=0.198, p<0.05), depression (rs=0.189, p<0.05), anxiety (rs=0.257, p<0.05) and apathy (rs=0.388, p<0.05). There was a negative association between caregiver burden and the Revised ALS Functional Rating Scale (rs=-0.275, p<0.05). Apathy was an independent risk factor for higher caregiver burden (OR 1.121, 95% CI 1.041 to 1.206, p<0.05). Apathy fully mediated the relationship between depression and caregiver burden (ß=0.35, 95% CI 0.16 to 0.54, p<0.05) while partially mediating the relationship between anxiety and caregiver burden (ß=0.34, 95% CI 0.16 to 0.52, p<0.05). CONCLUSIONS: Apathy, depression and anxiety exerted a detrimental impact on caregiver burden in individuals with ALS. Apathy played a mediating role in the relationship between depression and caregiver burden and between anxiety and caregiver burden. These findings underscore the importance of identifying apathy and developing interventions for its management within the context of ALS.
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Esclerosis Amiotrófica Lateral , Ansiedad , Apatía , Carga del Cuidador , Depresión , Humanos , Esclerosis Amiotrófica Lateral/psicología , Masculino , Femenino , Estudios Transversales , Persona de Mediana Edad , Ansiedad/psicología , Ansiedad/etiología , Depresión/psicología , Depresión/etiología , China/epidemiología , Carga del Cuidador/psicología , Anciano , Cuidadores/psicología , Adulto , Disfunción Cognitiva/etiología , Disfunción Cognitiva/psicología , Escalas de Valoración Psiquiátrica , Modelos Logísticos , Costo de EnfermedadRESUMEN
Many RNA-binding proteins (RBPs) are linked to the dysregulation of RNA metabolism in motor neuron diseases (MNDs). However, the molecular mechanisms underlying MN vulnerability have yet to be elucidated. Here, we found that such an RBP, Quaking5 (Qki5), contributes to formation of the MN-specific transcriptome profile, termed "MN-ness," through the posttranscriptional network and maintenance of the mature MNs. Immunohistochemical analysis and single-cell RNA sequencing (scRNA-seq) revealed that Qki5 is predominantly expressed in MNs, but not in other neuronal populations of the spinal cord. Furthermore, comprehensive RNA sequencing (RNA-seq) analyses revealed that Qki5-dependent RNA regulation plays a pivotal role in generating the MN-specific transcriptome through pre-messenger ribonucleic acid (mRNA) splicing for the synapse-related molecules and c-Jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK) signaling pathways. Indeed, MN-specific ablation of the Qki5 caused neurodegeneration in postnatal mice and loss of Qki5 function resulted in the aberrant activation of stress-responsive JNK/SAPK pathway both in vitro and in vivo. These data suggested that Qki5 plays a crucial biological role in RNA regulation and safeguarding of MNs and might be associated with pathogenesis of MNDs.
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Neuronas Motoras , Proteínas de Unión al ARN , Médula Espinal , Transcriptoma , Animales , Proteínas de Unión al ARN/metabolismo , Proteínas de Unión al ARN/genética , Neuronas Motoras/metabolismo , Ratones , Médula Espinal/metabolismo , Precursores del ARN/metabolismo , Precursores del ARN/genética , Empalme del ARN , Ratones NoqueadosRESUMEN
In this study, we develop an in silico model of a neuron's behaviour under demyelination caused by a cytokine storm to investigate the effects of viral infections in the brain. We use a comprehensive model to measure how cytokine-induced demyelination affects the propagation of action potential (AP) signals within a neuron. We analysed the effects of neuron-neuron communications by applying information and communication theory at different levels of demyelination. Our simulations demonstrate that virus-induced degeneration can play a role in the signal power and spiking rate, which compromise the propagation and processing of information between neurons. We propose a transfer function to model the weakening effects on the AP. Our results show that demyelination induced by a cytokine storm not only degrades the signal but also impairs its propagation within the axon. Our proposed in silico model can analyse virus-induced neurodegeneration and enhance our understanding of virus-induced demyelination.
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Simulación por Computador , Enfermedades Desmielinizantes , Neuronas , Enfermedades Desmielinizantes/patología , Enfermedades Desmielinizantes/metabolismo , Enfermedades Desmielinizantes/virología , Neuronas/metabolismo , Humanos , Modelos Neurológicos , Potenciales de Acción , Síndrome de Liberación de Citoquinas , Animales , Citocinas/metabolismo , Axones/metabolismo , Axones/patologíaRESUMEN
Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease leading to motor neuron loss. Currently mutations in > 40 genes have been linked to ALS, but the contribution of many genes and genetic mutations to the ALS pathogenic process remains poorly understood. Therefore, we first performed comparative interactome analyses of five recently discovered ALS-associated proteins (C21ORF2, KIF5A, NEK1, TBK1, and TUBA4A) which highlighted many novel binding partners, and both unique and shared interactors. The analysis further identified C21ORF2 as a strongly connected protein. The role of C21ORF2 in neurons and in the nervous system, and of ALS-associated C21ORF2 variants is largely unknown. Therefore, we combined human iPSC-derived motor neurons with other models and different molecular cell biological approaches to characterize the potential pathogenic effects of C21ORF2 mutations in ALS. First, our data show C21ORF2 expression in ALS-relevant mouse and human neurons, such as spinal and cortical motor neurons. Further, the prominent ALS-associated variant C21ORF2-V58L caused increased apoptosis in mouse neurons and movement defects in zebrafish embryos. iPSC-derived motor neurons from C21ORF2-V58L-ALS patients, but not isogenic controls, show increased apoptosis, and changes in DNA damage response, mitochondria and neuronal excitability. In addition, C21ORF2-V58L induced post-transcriptional downregulation of NEK1, an ALS-associated protein implicated in apoptosis and DDR. In all, our study defines the pathogenic molecular and cellular effects of ALS-associated C21ORF2 mutations and implicates impaired post-transcriptional regulation of NEK1 downstream of mutant C21ORF72 in ALS.
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Esclerosis Amiotrófica Lateral , Células Madre Pluripotentes Inducidas , Mitocondrias , Neuronas Motoras , Quinasa 1 Relacionada con NIMA , Pez Cebra , Humanos , Esclerosis Amiotrófica Lateral/genética , Esclerosis Amiotrófica Lateral/metabolismo , Esclerosis Amiotrófica Lateral/patología , Quinasa 1 Relacionada con NIMA/genética , Quinasa 1 Relacionada con NIMA/metabolismo , Animales , Neuronas Motoras/metabolismo , Neuronas Motoras/patología , Células Madre Pluripotentes Inducidas/metabolismo , Ratones , Mitocondrias/metabolismo , Mitocondrias/patología , Reparación del ADN/genética , Daño del ADN , MutaciónRESUMEN
INTRODUCTION: Hindfoot varus deformity is common in people with unilateral upper motor neuron syndrome (UMNS) and can be dynamic or persistent. The aims of this study were (1) to gain insight into plantar pressure characteristics of people with chronic UMNS in relation to hindfoot varus and (2) to propose a quantitative outcome measure, based on plantar pressure, for the scientific evaluation of surgical interventions. METHODS: In this retrospective study, a cohort comprising plantar pressure data of 49 people with UMNS (22 "no hindfoot varus", 18 "dynamic hindfoot varus", and 9 "persistent hindfoot varus"), and 586 healthy controls was analyzed. As an indication of plantigrade foot contact, the ratio between the plantar contact area of the affected and the non-affected foot was calculated. To investigate spatial and temporal aspects of plantar pressure, normalized plantar pressure patterns and center of pressure trajectories were computed. RESULTS: People with UMNS had lower plantar pressure area ratios compared to healthy controls. Additionally, increased plantar pressure underneath the lateral foot was found in people with a persistent hindfoot varus. Center of pressure trajectories were more lateral during the first 26% of the stance phase in people with a dynamic hindfoot varus and during the first 82% of the stance phase in people with a persistent hindfoot varus compared to healthy controls. CONCLUSION: Spatial and temporal differences in plantar pressure were found in people with dynamic or persistent hindfoot varus deformity. We propose to primarily use the medio-lateral center of pressure trajectory as outcome measure for the scientific evaluation of surgical interventions targeting hindfoot varus.
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Pie , Enfermedad de la Neurona Motora , Presión , Humanos , Femenino , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Pie/fisiopatología , Enfermedad de la Neurona Motora/fisiopatología , Enfermedad de la Neurona Motora/complicaciones , Adulto , Anciano , Estudios de Casos y Controles , Deformidades Adquiridas del Pie/fisiopatología , Deformidades Adquiridas del Pie/etiología , Deformidades Adquiridas del Pie/cirugía , Fenómenos BiomecánicosRESUMEN
Hyperreflexia associated with spasticity is a prevalent neurological condition characterized by excessive and exaggerated reflex responses to stimuli. Hyperreflexia can be caused by several diseases including multiple sclerosis, stroke and spinal cord injury (SCI). Although we have previously identified the contribution of the RAC1-PAK1 pathway underlying spinal hyperreflexia with SCI-induced spasticity, a feasible druggable target has not been validated. To assess the utility of targeting PAK1 to attenuate H-reflex hyperexcitability, we administered Romidepsin, a clinically available PAK1 inhibitor, in Thy1-YFP reporter mice. We performed longitudinal EMG studies with a study design that allowed us to assess pathological H-reflex changes and drug intervention effects over time, before and after contusive SCI. As expected, our results show a significant loss of rate-dependent depression - an indication of hyperreflexia and spasticity - 1 month following SCI as compared with baseline, uninjured controls (or before injury). Romidepsin treatment reduced signs of hyperreflexia in comparison with control cohorts and in pre- and post-drug intervention in SCI animals. Neuroanatomical study further confirmed drug response, as romidepsin treatment also reduced the presence of SCI-induced dendritic spine dysgenesis on α-motor neurons. Taken together, our findings extend previous work demonstrating the utility of targeting PAK1 activity in SCI-induced spasticity and support the novel use of romidepsin as an effective tool for managing spasticity. KEY POINTS: PAK1 plays a role in contributing to the development of spinal cord injury (SCI)-induced spasticity by contributing to dendritic spine dysgenesis. In this study, we explored the preclinical utility of inhibiting PAK1 to reduce spasticity and dendritic spine dysgenesis in an SCI mouse model. Romidepsin is a PAK1 inhibitor approved in the US in 2009 for the treatment of cutaneous T-cell lymphoma. Here we show that romidepsin treatment after SCI reduced SCI-induced H-reflex hyperexcitability and abnormal α-motor neuron spine morphology. This study provides compelling evidence that romidepsin may be a promising therapeutic approach for attenuating SCI-induced spasticity.
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The maturation of cerebral cortical networks during early life involves a major reorganization of long-range axonal connections. In a recent study, Bragg-Gonzalo, Aguilera, et al. discovered that in mice, the interhemispheric connections sent by S1L4 callosal projection neurons are pruned via the tight control of their ipsilateral synaptic integration, which relies on the early activity of specific interneurons.