Relationship between Fear-Avoidance Beliefs and Reaction Time Changes Prior to and following Exercise-Induced Muscle Fatigue in Chronic Low Back Pain.

Background: Reaction time is a reliable indicator of the velocity and efficiency of neuromuscular control and may be associated with fear-avoidance beliefs. However, the effect of exercise-induced muscle fatigue on reaction time in chronic low back pain (cLBP) and its relationship with fear-avoidance beliefs remains poorly understood. Objectives: This study aimed to reveal the relationship between fear-avoidance beliefs and reaction time changes before and after exercise-induced muscle fatigue in cLBP. Methods: Twenty-five patients with cLBP were tested by the Biering-Sorensen test (BST) to induce exhaustive muscle fatigue. Total reaction time (TRT), premotor time (PMT), and electromechanical delay (EMD) of dominated deltoid muscle were recorded by surface electromyography during the arm-raising task with visual cues before and after muscle fatigue. The mean difference (MD) of TRT (MDTRT), PMT (MDPMT), and EMD (MDEMD) was calculated from the changes before and after muscle fatigue. Fear-avoidance beliefs questionnaire (FABQ) was applied to evaluate fear-avoidance beliefs before muscle fatigue. In addition, the duration time of BST was recorded for each subject. Results: TRT and PMT of dominated deltoid muscle were prolonged after exercise-induced muscle fatigue (Z = 3.511, p < 0.001; t = 3.431, p = 0.001), while there was no statistical difference in EMD (Z = 1.029, p = 0.304). Correlation analysis showed that both the MDTRT and MDPMT were positively correlated with FABQ (r = 0.418, p = 0.042; r = 0.422, p = 0.040). Conclusions: These findings suggested that we should pay attention to both muscle fatigue-induced reaction time delay in cLBP management and the possible psychological mechanism involved in it. Furthermore, this study implied that FABQ-based psychotherapy might serve as a potential approach for cLBP treatment by improving reaction time delay. This trial is registered with ChiCTR2300074348.

Cerebellar Transcranial Direct Current Stimulation Modulates Anticipatory Postural Adjustments in Healthy Adults.

During forward swinging of the arm, the central nervous system must anticipate the effect of upraising upon the body. Little is known about the cerebellar network that coordinates these anticipatory postural adjustments (APAs). Stimulating different cerebellar regions with transcranial direct current stimulation (tDCS) and with different polarities modulated the APAs. We used surface electromyography (sEMG) to measure muscle activities in a bilateral rapid shoulder flexion task. The onset of APAs was altered after tDCS over the vermis, while the postural stability and the kinematics of arm raising were not affected. To our knowledge, this is the first human cerebellar-tDCS (c-tDCS) study to separate cerebellar involvement in core muscle APAs in bilateral rapid shoulder flexion. These data contribute to our understanding of the cerebellar network supporting APAs in healthy adults. Modulated APAs of the erector spinae by tDCS on the vermis may be related to altered cerebellar brain inhibition (CBI), suggesting the importance of the vermal-cerebral connections in APAs regulation.

Effect of Cognitive Load on Anticipatory Postural Adjustment Latency and its Relationship with Pain-Related Dysfunction in Non-specific Chronic Low Back Pain: A Cross-Sectional Study.

INTRODUCTION: This study aimed to investigate the effect of cognitive load on anticipatory postural adjustment (APA) latency in patients with non-specific chronic low back pain (NCLBP) and its relationship with pain-related functional changes. METHODS: A cross-sectional study was conducted from December 15, 2022 to January 25, 2023. Participants were divided into a healthy control group (n = 29) and an NCLBP group (n = 29). Each group was assigned a single task of rapid arm raising and a dual task of rapid arm raising combined with a cognitive load. The cognitive load task was conducted using visual conflict. The APA latency for bilateral trunk muscles was observed using electromyography. The duration of electromyography recording in each task cycle was 28 s. Pain related-functional changes were evaluated using Roland-Morris Disability Questionnaire (RMDQ) before all tasks. RESULTS: The APA latency for the right multifidus was significantly delayed in the NCLBP group [25.38, 95% confidence interval (CI) 13.41-37.35] than in the healthy control group (- 5.80, 95% CI - 19.28 to 7.68) during dual task (p = 0.0416). The APA latency for the right multifidus (25.38, 95% CI 13.41-37.35) and transverse abdominis/internal oblique (29.15, 95% CI 18.81-39.50) were significantly delayed compared with on the left side in the NCLBP group during dual task (- 3.03, 95% CI - 15.18-9.13, p = 0.0220; 3.69, 95% CI - 6.81 to 14.18, p = 0.0363). The latency delay of the right and left multifidus APA in the NCLBP group under the dual-task was positively correlated with RMDQ scores (r = 0.5560, p = 0.0017; r = 0.4010, p = 0.0311). CONCLUSIONS: Cognitive load could induce APA delay in the right trunk muscles and co-activation pattern changes in bilateral trunk muscle APA in patients with NCLBP. The APA onset delay in multifidus is positively related to pain-related daily dysfunction. Trial Registration ChiCTR2300068580 (retrospectively registered in February 23, 2023).

Postural Control of Patients with Low Back Pain Under Dual-Task Conditions.

Low back pain is a major global public health problem, but the current intervention effect is not ideal. A large body of previous literature suggests that patients with chronic low back pain may have abnormal postural control, which is more evident in the dual task situation. In recent years, research on postural control in patients with low back pain under dual-task conditions has gradually become a hot topic. However, the results obtained from these studies were not entirely consistent. In this review, we summarized relevant studies on the performance of postural control in patients with low back pain under dual-task conditions, analyze it from the perspective of the theoretical model of dual-task interaction, the specific research paradigm of dual task, the performance of postural control, and the related factors affecting postural control performance, etc. It was reasonable to assume that patients with low back pain might have a certain degree of abnormal postural control, and this abnormality was affected by comprehensive factors such as age, cognitive resource capacity, attention needs, complex sensorimotor integration, external environment, etc. Furthermore, postural control performance in low back pain patients under dual-task conditions was further influenced by the nature and complexity of the different tasks. In general, the more attention resources were needed, the external environmental conditions were worse, and the age-related functions were degenerate, etc., the weaker posture control ability was. In short, a deeper understanding of postural control in patients with low back pain under dual-task conditions may shed light on more references for the rehabilitation and management of low back pain, as well as some new ideas for scientific research on cognition and postural control.

Increase of vesicular glutamate transporter 2 co-expression in the deep cerebellar nuclei related to skilled reach learning.

Motor learning induces plasticity in multiple brain regions involving the cerebellum as a crucial player. Synaptic plasticity in the excitatory collaterals to the cerebellar output, the deep cerebellar nuclei (DCN), have recently been shown to be an important part of motor learning. These synapses are composed of climbing fiber (CF) and mossy fiber synapses, with the former conveying unconditioned and the latter conditioned responses in classical conditioning paradigms. The CF synapse on to the cerebellar cortex and the DCN express vesicular transporter 2 (vGluT2), whereas mossy fibers express vGluT1 and /or vGluT2 in their terminals. However, the underlying regulatory mechanism of vGluT expression in the DCN remains unknown. Here we confirm the increase of vGluT2 in a specific part of the DCN during the acquisition of a skilled reaching task in mice. Furthermore, our findings show that this is due to an increase in co-expression of vGluT2 in vGluT1 presynapses instead of the formation of new vGluT2 synapses. Our data indicate that remodeling of synapses - in contrast to synaptogenesis - also plays an important role in motor learning and may explain the presence of both vGluT's in some mossy fiber synapses.

Effects of primary microglia and astrocytes on neural stem cells in in vitro and in vivo models of ischemic stroke.

Transplantation of neural stem cells (NSCs) can protect neurons in animal stroke models; however, their low rates of survival and neuronal differentiation limit their clinical application. Glial niches, an important location of neural stem cells, regulate survival, proliferation and differentiation of neural stem cells. However, the effects of activated glial cells on neural stem cells remain unclear. In the present study, we explored the effects of activated astrocytes and microglia on neural stem cells in vitro stroke models. We also investigated the effects of combined transplantation of neural stem cells and glial cells after stroke in rats. In a Transwell co-culture system, primary cultured astrocytes, microglia or mixed glial cells were exposed to glutamate or H2O2 and then seeded in the upper inserts, while primary neural stem cells were seeded in the lower uncoated wells and cultured for 7 days. Our results showed that microglia were conducive to neurosphere formation and had no effects on apoptosis within neurospheres, while astrocytes and mixed glial cells were conducive to neurosphere differentiation and reduced apoptosis within neurospheres, regardless of their pretreatment. In contrast, microglia and astrocytes induced neuronal differentiation of neural stem cells in differentiation medium, regardless of their pretreatment, with an exception of astrocytes pretreated with H2O2. Rat models of ischemic stroke were established by occlusion of the middle cerebral artery. Three days later, 5 × 105 neural stem cells with microglia or astrocytes were injected into the right lateral ventricle. Neural stem cell/astrocyte-treated rats displayed better improvement of neurological deficits than neural stem cell only-treated rats at 4 days after cell transplantation. Moreover, neural stem cell/microglia-, and neural stem cell/astrocyte-treated rats showed a significant decrease in ischemic volume compared with neural stem cell-treated rats. These findings indicate that microglia and astrocytes exert different effects on neural stem cells, and that co-transplantation of neural stem cells and astrocytes is more conducive to the recovery of neurological impairment in rats with ischemic stroke. The study was approved by the Animal Ethics Committee of Tongji University School of Medicine, China (approval No. 2010-TJAA08220401) in 2010.

Quantitative organization of the excitatory synapses of the primate cerebellar nuclei: further evidence for a specialized architecture underlying the primate cerebellum.

The cerebellar intrinsic connectivity is of remarkable regularity with a similar build repeated many times over. However, several modifications of this basic circuitry occur that can provide important clues to evolutionary adaptations. We have observed differences in the wiring of the cerebellar output structures (the deep cerebellar nuclei, DCN) with higher dendritic length density in the phylogenetically newer DCN. In rats, we showed that an increase in wiring is associated with an increase in the presynaptic vesicular glutamate transporter 1 (vGluT1). In this study, we have extended our analysis to the rhesus monkey and can show similarities and differences between the two species. The similarities confirm a higher density in vGluT1+ boutons in the lateral (LN/dentate) and posterior interpositus nucleus compared to the phylogenetically older DCN. In general, we also observe a lower density of vGluT1 and 2+ boutons in the monkey, which however, yields a similar number of excitatory boutons per neuron in both species. The only exception is the vGlut1+ boutons in the macaque LN/dentate, which showed a significantly lower number of vGluT1+ boutons per neuron. We also detected a higher percentage of co-labelled vGluT1 and 2 boutons in the macaque than we found in the rat. In summary, these results confirm that the hyposcalled dendrites of the monkey LN/dentate also show a lower number of vGluT1+ boutons per neuron. These results provide further support of our model relating the dendritic morphology of the LN/dentate neurons to the morphology of the specially enlarged LN/dentate nucleus in primates.

Quantitative Comparison Of Vesicular Glutamate Transporters in rat Deep Cerebellar Nuclei.

The excitatory synapses of the rat deep cerebellar nuclei (DCN) were quantitatively analyzed by vesicular glutamate transporter 1 and 2 (vGluT1 and vGluT2) immunolabeling. We calculated the number and sizes of the labeled boutons and compared them between lateral/dentate nucleus (LN/DN), posterior interposed nucleus (PIN), anterior interposed nucleus (AIN), and medial nucleus (MN). The density of vGluT1+ boutons differs significantly within these nuclei. In contrast, the vGluT2+ bouton density is more similar between different nuclei. The phylogenetically newer DCN (LN/DN and PIN) have a 39% higher density of vGluT1+ boutons than the phylogenetically older DCN (AIN and MN). The volume of vGluT1+ boutons does not differ between the DCN, however the average volume of vGluT2+ boutons is larger in MN. In summary, our current results confirm and extend our previous findings showing that the increase in dendritic and axonal wiring in phylogenetically newer DCN is associated with an increase in vGluT1+ bouton density.

Uncovering specific changes in network wiring underlying the primate cerebrotype.

Regular scaling of brain networks during evolution has been proposed to be the major process leading to enlarged brains. Alternative views, however, suggest that deviations from regular scaling were crucial to the evolution of the primate brain and the emergence of different cerebrotypes. Here, we examined the scaling within the major link between the cerebellum and the cerebral cortex by studying the deep cerebellar nuclei (DCN). We compared the major axonal and dendritic wiring in the DCN of rodents and monkeys in search of regular scaling. We were able to confirm regular scaling within the density of neurons, the general dendritic length per neuron and the Purkinje cell axon length. However, we also observed specific modification of the scaling rules within the primates' largest and phylogenetically newest DCN, the dentate nucleus (LN/dentate). Our analysis shows a deviation from regular scaling in the predicted dendritic length per neuron in the LN/dentate. This reduction in the dendritic length is also associated with a smaller dendritic region-of-influence of these neurons. We also detected specific changes in the dendritic diameter distribution, supporting the theory that there is a shift in the neuronal population of the LN/dentate towards neurons that exhibit spatially restricted, clustered branching trees. The smaller dendritic fields would enable a larger number of network modules to be accommodated in the primate LN/dentate and would provide an explanation for the unique folded structure of the primate LN/dentate. Our results show that, in some brain regions, connectivity maximization (i.e., an increase of dendritic fields) is not the sole optimum and that increases in the number of network modules may be important for the emergence of a divergent primate cerebrotype.

The hypoparathyroidism-associated mutation in Drosophila Gcm compromises protein stability and glial cell formation.

Differentiated neurons and glia are acquired from immature precursors via transcriptional controls exerted by factors such as proteins in the family of Glial Cells Missing (Gcm). Mammalian Gcm proteins mediate neural stem cell induction, placenta and parathyroid development, whereas Drosophila Gcm proteins act as a key switch to determine neuronal and glial cell fates and regulate hemocyte development. The present study reports a hypoparathyroidism-associated mutation R59L that alters Drosophila Gcm (Gcm) protein stability, rendering it unstable, and hyperubiquitinated via the ubiquitin-proteasome system (UPS). GcmR59L interacts with the Slimb-based SCF complex and Protein Kinase C (PKC), which possibly plays a role in its phosphorylation, hence altering ubiquitination. Additionally, R59L causes reduced Gcm protein levels in a manner independent of the PEST domain signaling protein turnover. GcmR59L proteins bind DNA, functionally activate transcription, and induce glial cells, yet at a less efficient level. Finally, overexpression of either wild-type human Gcmb (hGcmb) or hGcmb carrying the conserved hypoparathyroidism mutation only slightly affects gliogenesis, indicating differential regulatory mechanisms in human and flies. Taken together, these findings demonstrate the significance of this disease-associated mutation in controlling Gcm protein stability via UPS, hence advance our understanding on how glial formation is regulated.

MicroRNA role in thyroid cancer pathogenesis.

MicroRNAs (miRNAs) are a class of endogenous, non-coding RNAs approximately 22 nucleotides in length that negatively regulate translation of the protein-coding genes. As such, miRNAs are fundamental mediators of cellular differentiation, proliferation, and survival. Each miRNA may functionally interact with a multitude of target genes to exert various effects on normal physiology to support human health or pathological processes leading to disease conditions, such as cancer. Genome-wide analyses have generated specific miRNA profiles of thyroid cancers (TCs) and identified the up- and down-regulated miRNAs related to various carcinogenesis stages and prognoses. Here, we summarize the recent knowledge on aberrant miRNA expression in the various TCs, including papillary, follicular, and other rare types. In addition, we discuss the significance of miRNA profiles and individual miRNAs in the diagnosis, treatment, and prognosis of these tumors.

Increased expression of microRNA-221 inhibits PAK1 in endothelial progenitor cells and impairs its function via c-Raf/MEK/ERK pathway.

Coronary artery disease (CAD) is associated with high mortality and occurs via endothelial injury. Endothelial progenitor cells (EPCs) restore the integrity of the endothelium and protect it from atherosclerosis. In this study, we compared the expression of microRNAs (miRNAs) in EPCs in atherosclerosis patients and normal controls. We found that miR-221 expression was significantly up-regulated in patients compared with controls. We predicted and identified p21/Cdc42/Rac1-activated kinase 1 (PAK1) as a novel target of miR-221 in EPCs. We also demonstrated that miR-221 targeted a putative binding site in the 3'UTR of PAK1, and absence of this site was inversely associated with miR-221 expression in EPCs. We confirmed this relationship using a luciferase reporter assay. Furthermore, overexpression of miR-221 in EPCs significantly decreased EPC proliferation, in accordance with the inhibitory effects induced by decreased PAK1. Overall, these findings demonstrate that miR-221 affects the MEK/ERK pathway by targeting PAK1 to inhibit the proliferation of EPCs.

Gcm proteins function in the developing nervous system.

A fundamental issue during nervous system development is how individual cells are formed from the undefined precursors. Differentiated neurons and glia, two major cell types mediating neuronal function, are acquired from immature precursors via a series of explicit controls exerted by transcription factors such as proteins in the family of Glial cells missing (Gcm). In mammals, Gcm proteins are involved in placenta and parathyroid gland development, whereas in the invertebrate organism Drosophila, Gcm proteins act as fate determinants for glial cell fate, regulate neural stem cell (NSC) induction and conversion, and promote glial proliferation. In particular, Gcm protein levels are carefully tuned for Drosophila gliogenesis and their stability is under precise control via the ubiquitin-proteasome system (UPS). Here we summarize recent advances on Gcm proteins function. In addition to describe various features of Gcm protein family, the significance of their functions in the developing nervous system is also discussed.