Central Nervous System Mechanisms Research Articles

Unraveling neuroprotection with Kv1.3 potassium channel blockade by a scorpion venom peptide

Voltage-gated potassium channels play a crucial role in cellular repolarization and are potential therapeutic targets in neuroinflammatory disorders and neurodegenerative diseases. This study explores Tityus bahiensis scorpion venom for neuroactive peptides. We identified the αKtx12 peptide as a potent neuroprotective agent. In SH-SY5Y cells, αKtx12 significantly enhances viability, validating its pharmacological potential. And in the animal model, we elucidate central nervous system (CNS) mechanism of αKtx12 through neuroproteomic analyses highlighting αKtx12 as a valuable tool for characterizing neuroplasticity and neurotropism, revealing its ability to elicit more physiological responses. The peptide’s potential to promote cell proliferation and neuroprotection suggests a role in functional recovery from nervous system injury or disease. This research unveils the neuroactive potential of scorpion venom-derived αKtx12’s, offering insights into its pharmacological utility. The peptide’s impact on neuronal processes suggests a promising avenue for therapeutic development, particularly in neurodegenerative conditions.

Distinct mechanisms for online and offline motor skill learning across human development.

The human central nervous system (CNS) undergoes tremendous changes from childhood to adulthood and this may affect how individuals at different stages of development learn new skills. Here, we studied motor skill learning in children, adolescents, and young adults to test the prediction that differences in the maturation of different learning mechanisms lead to distinct temporal patterns of motor learning during practice and overnight. We found that overall learning did not differ between children, adolescents, and young adults. However, we demonstrate that adult-like skill learning is characterized by rapid and large improvements in motor performance during practice (i.e., online) that are susceptible to forgetting and decay over time (i.e., offline). On the other hand, child-like learning exhibits slower and less pronounced improvements in performance during practice, but these improvements are robust against forgetting and lead to gains in performance overnight without further practice. The different temporal dynamics of motor skill learning suggest an engagement of distinct learning mechanisms in the human CNS during development. In conclusion, adult-like skill learning mechanisms favor online improvements in motor performance whereas child-like learning mechanisms favors offline behavioral gains. RESEARCH HIGHLIGHTS: Many essential motor skills, like walking, talking, and writing, are acquired during childhood, and it is colloquially thought that children learn better than adults. We investigated dynamics of motor skill learning in children, adolescents, and young adults. Adults displayed substantial improvements during practice that was susceptible to forgetting over time. Children displayed smaller improvements during practice that were resilient against forgetting. The distinct age-related characteristics of these processes of acquisition and consolidation suggest that skill learning relies on different mechanisms in the immature and mature central nervous system.

Exploring low- and high-order functional connectivity in chronic ankle instability through resting-state fMRI.

The functional connectivity (FC) has emerged as a valuable tool for comprehending the cerebral operational mechanism. Understanding the FC changes in patients with chronic ankle instability (CAI) helps reveal the underlying central nervous system mechanisms of the disease and provides clues for developing personalized treatment plans. To explore differences between low- and high-order FC in patients with CAI and healthy controls, as well as the correlation among the feature connections and clinical data. In our study, we recruited 40 patients with CAI and 42 healthy individuals who had not experienced ankle injuries. All participants underwent clinical assessments of ankle joints, collected the number of ankle sprains within the past 6 months, and performed resting-state functional magnetic resonance imaging (rs-fMRI) scans. Pearson correlation and matrix variate normal distribution (MVND) were used to construct low-order and high-order FC networks, respectively. Feature selections between groups were performed by two-sample t-tests, and a multi-kernel support vector machine (MK-SVM) was subsequently applied to combine the multiple connection patterns for the classification. Using leave-one-out cross-validation (LOOCV) to assess classification performance and identify the consensus connections contributing most to classification. FC was reduced in certain brain regions of CAI patients. More consensus connections were recognized in low-order FC network than in high-order FC network. The highest classification accuracy of 91.30% was achieved by combining three connection patterns. The most discriminating functional connections were primarily centered on the default mode network and spanned the visual network, sensorimotor network, ventral attention network, and central executive network. In addition, FC strength in the left cingulate and paracingulate gyrus (DCG.L) and right superior temporal gyrus (STG.R) was negatively correlated with the number of ankle sprains in the past 6 months in all FC networks (p<0.05). Abnormalities in connectivity in patients with CAI were observed in both low- and high-order FC networks. The adaptive changes in the brain related to CAI may extend beyond the sensorimotor networks, primarily involving higher-level default mode networks associated with attention. Moreover, the FC strength between DCG.L and STG.R may predict the risk of ankle re-sprains and help clinicians develop personalized treatment plans.

Analgesic effect of dance movement therapy: An fNIRS study

ObjectiveThis study aims to explores the physiological and psychological mechanisms of exercise-induced hypoalgesia (EIH) by combining the behavioral results with neuroimaging data on changes oxy-hemoglobin (HbO) in prefrontal cortex (PFC). MethodsA total of 97 healthy participants were recruited and randomly divided into three groups: a single dance movement therapy (DMT) group, a double DMT group, and control group. Evaluation indicators included the pressure pain threshold (PPT) test, the color-word stroop task (CWST) for wearing functional near-infrared spectroscopy (fNIRS), and the self-assessment manikin (SAM). The testing time is before intervention, after intervention, and one hour of sit rest after intervention. Results1) Repeated measures ANOVA revealed that, there is a time * group effect on the PPT values of the three groups of participants at three time points. After 30 min of acute dance intervention, an increase in the PPT values of 10 test points occurred in the entire body of the participants in the experimental group with a significant difference than the control group. 2) In terms of fNIRS signals, bilateral DLPFC and left VLPFC channels were significantly activated in the experimental group. 3) DMT significantly awakened participants and brought about pleasant emotions, but cognitive improvement was insignificant. 4) Mediation effect analysis found that the change in HbO concentration in DLPFC may be a mediator in predicting the degree of improvement in pressure pain threshold through dance intervention (total effect β = 0.7140). ConclusionIn healthy adults, DMT can produce a diffuse EIH effect on improving pressure pain threshold, emotional experience but only showing an improvement trend in cognitive performance. Dance intervention significantly activates the left ventrolateral and bilateral dorsolateral prefrontal cortex. This study explores the central nervous system mechanism of EIH from a physiological and psychological perspective.

Prioritized adjustments in posture stabilization and adaptive reaching during neuromuscular fatigue of lower-limb muscles.

Neuromuscular fatigue (NMF) induces temporary reductions in muscle force production capacity, affecting various aspects of motor function. Although studies have extensively explored NMF's impact on muscle activation patterns and postural stability, its influence on motor adaptation processes remains less understood. This article investigates the effects of localized NMF on motor adaptation during upright stance, focusing on reaching tasks. Using a force-field perturbation paradigm, participants performed reaching movements while standing upright before and after inducing NMF in the ankle dorsiflexor muscles. Results revealed that despite maintained postural stability, participants in the NMF group exhibited larger movement errors during reaching tasks, suggesting impaired motor adaptation. This was evident in both initial and terminal phases of adaptation, indicating a disruption in learning processes rather than a decreased adaptation rate. Analysis of electromyography activation patterns highlighted distinct strategies between groups, with the NMF group showing altered activation of both fatigued and nonfatigued muscles. In addition, differences in coactivation patterns suggested compensatory mechanisms to prioritize postural stability despite NMF-induced disruptions. These findings underscore the complex interplay between NMF, motor adaptation, and postural control, suggesting a potential role for central nervous system mechanisms in mediating adaptation processes. Understanding these mechanisms has implications for sports performance, rehabilitation, and motor skill acquisition, where NMF may impact the learning and retention of motor tasks. Further research is warranted to elucidate the transient or long-term effects of NMF on motor adaptation and its implications for motor rehabilitation interventions.NEW & NOTEWORTHY We assessed motor adaptation during force-field reaching following exercise-induced neuromuscular fatigue (NMF) on postural muscles. NMF impaired adaptation in performance. Similarly, diverging activation strategies were observed in the muscles. No effects were seen on measures of postural control. These results suggest the remodulation of motor commands to the muscles in the presence of NMF, which may be relevant in settings where participants could be exposed to NMF while learning, such as sports and rehabilitation.

Goat Milk Supplementation Modulates the Mitochondrial Metabolic Flexibility and Orexin-A Levels Influencing the Inflammatory Pattern in Rats.

Milk and its derivatives are included in a balanced diet of humans as excellent sources of proteins, vitamins, and essential minerals that are functional nutrients. Knowledge about the nutritional benefits or harms due to milk consumption has been expanding in recent years. We previously explored, in rodent models, the metabolic effects of isoenergetic intake of milk derived from cows, donkeys, or humans, while the impact of goat's milk intake has remained unexplored. The aim of this work was to investigate, in an animal model, the effects of dietary supplementation with goat's milk on energy homeostasis and inflammatory state, focusing on the modulation of mitochondrial functions in most metabolically active organs, such as skeletal muscle and the liver. In addition, we highlighted a link between nutrient intake, substrate metabolism, and the orexinergic system. Our results indicate that goat milk improves mitochondrial oxidative capacity and reduces inflammation and oxidative stress in both organs. Notably, goat milk lowers the circulating levels of Orexin-A, a neuropeptide that plays a crucial role in regulating peripheral energy balance and central nervous system mechanisms. These data provide the first evidence that the anti-inflammatory and antioxidant effects of goat milk are mediated by the modulation of mitochondrial functions and orexinergic signaling.

Neural Circuit Mechanisms of Sinisan formula for the Treatment of adolescent Depression: prefrontal cortex to dorsal raphe nucleus

Ethnopharmacological relevanceSinisan formula (SNSF), documented in the classic books Shanghan Lun, is known for its ability to regulate liver-qi and treat depression. However, its underlying mechanism, particularly its effects on dynamic real-time neuron activity and circuits remains to be fully elucidated. Aim of the studyThis study aimed to investigate the antidepressant effect of SNSF and its central nervous system mechanism on depression-like behaviors, focusing on the prefrontal cortex (PFC) to dorsal raphe nucleus (DRN) neural circuit in a stress-induced adolescent animal model. Materials and methodsSNSF comprised four herbs, the root of Bupleurum chinense DC., the root of Paeonia lactiflora Pall., the fruit of Citrus aurantium L., the rhizome of Glycyrrhiza uralensis Fisch., in equal propotions. The adolescent depression animal model was induced by maternal separation (MS) and chronic restraint stress (CRS). In-vivo multichannel physiological electrodes were implanted into the PFC on PND 28 and animals were recorded 5 times during PND 35–46. From PND 47, the behavioral tests were performed to evaluate the antidepressant efficacy of SNSF. Subsequently, brain tissue was collected for Western blot and immunofluorescence staining analysis. Retro virus was injected into the DRN to explore sources of projections received by serotonergic (5-HTergic) neurons. And the PFC-to-DRN circuit was activated or inhibited through chemogenetic techniques to investigate the effects of SNSF on depression-like behaviors. ResultsAdministration of SNSF for 18 days effectively alleviated depression-like behaviors in MS&CRS adolescent mice. The PFC emerged as the primary glutamatergic projection source of the DRN5−HT neurons. Following SNSF administration for 13/15/18 days, there was an increase in the firing rate of excitatory neurons and excitatory/inhibitory (E/I) ratio in the PFC. MS&CRS stress let to a reduction in the density of 5-HT+ and CaMKII + neurons in the DRN, accompanied by an increase in the density of GAD + neurons in the DRN, while SNSF administration reversed the alterations. Chemogenetic activation of the PFC-to-DRN circuit rescued the depression-like behaviors induced by MS&CRS, whereas suppression of this circuit attenuated the antidepressant effect of SNSF. ConclusionsSNSF significantly mitigated depression-like behaviors in MS&CRS mice. SNSF exerts its antidepressant effects by increasing the E/I ratio in the PFC and enhancing glutamatergic projections from the PFC to the DRN.

The role of afferent renal nerves in regulating sympathetic outflow via central nervous system mechanisms.

The role of afferent renal nerves in regulating sympathetic outflow via central nervous system mechanisms.

Role of mitochondrial dysfunction and biogenesis in fibromyalgia syndrome: Molecular mechanism in central nervous system

A critical role for mitochondrial dysfunction has been shown in the pathogenesis of fibromyalgia. It is a chronic pain syndrome characterized by neuroinflammation and impaired oxidative balance in the central nervous system. Boswellia serrata (BS), a natural polyphenol, is a well-known able to influence the mitochondrial metabolism. The objective of this study was to evaluate the mitochondrial dysfunction and biogenesis in fibromyalgia and their modulation by BS. To induce the model reserpine (1 mg/Kg) was subcutaneously administered for three consecutive days and BS (100 mg/Kg) was given orally for twenty-one days. BS reduced pain like behaviors in reserpine-injected rats and the astrocytes activation in the dorsal horn of the spinal cord and prefrontal cortex that are recognized as key regions associated with the neuropathic pain. Vulnerability to neuroinflammation and impaired neuronal plasticity have been described as consequences of mitochondrial dysfunction. BS administration increased PGC-1α expression in the nucleus of spinal cord and brain tissues, promoting the expression of regulatory genes for mitochondrial biogenesis (NRF-1, Tfam and UCP2) and cellular antioxidant defence mechanisms (catalase, SOD2 and Prdx 3). According with these data BS reduced lipid peroxidation and the GSSG/GSH ratio and increased SOD activity in the same tissues. Our results also showed that BS administration mitigates cytochrome-c leakage by promoting mitochondrial function and supported the movement of PGC-1α protein into the nucleus restoring the quality control of mitochondria. Additionally, BS reduced Drp1 and Fis1, preventing both mitochondrial fission and cell death, and increased the expression of Mfn2 protein, facilitating mitochondrial fusion. Overall, our results showed important mitochondrial dysfunction in central nervous system in fibromyalgia syndrome and the role of BS in restoring mitochondrial dynamics.

Analgesic Activity Combination of Dry Extract of Meniran Leaves (Phyllanthus niruri L.) and Moringa Leaves (Moringa oleifera L.) Using the Chemical Induction Method: Invivo Study

Analgesics are drugs that selectively reduce pain in the central nervous system or peripheral pain mechanisms without significantly changing consciousness. This study aims to determine the analgesic activity of a combination of dry extracts of meniran leaves (Phyllanthus niruri l.) and moringa leaves (Moringa oleifera l.) against Swiss Webster rats with chemical induction methods. This research proves the presence of secondary metabolite content in the dry extract of meniran leaves and moringa leaves which have analgesic activity. The research used 30 male Swiss Webster rats divided into 5 groups. Group 1 is the negative control (CMC-Na 0.5%), group 2 is the positive control (diclofenac Na), group 3 (Dry extract of meniran leaves), group 4 (Dry extract of moringa leaves) and Group 5 (Combination of dry extracts). meniran and moringa leaves). Each was given 1 mL of 1% acetic acid induction chemical stimulation, then the writhing response was observed and recorded at 5-minute intervals for 30 minutes. The results showed that the K3 group combined dry extract of meniran leaves (Phyllanthus niruri L.) and moringa leaves (Moringa oleifera L) is not statistically significantly different from the positive control diclofenac sodium, p-value = 0.183. In conclusion, dry extract of meniran leaves (Phyllanthus niruri L.) and Moringa leaves (Moringa oleifera L.) has been proven to contain secondary metabolites of flavonoids, alkaloids, tannins, and saponins which have analgesic activity.

Tumor cells impair immunological synapse formation via central nervous system-enriched metabolite

Tumors employ various strategies to evade immune surveillance. Central nervous system (CNS) has multiple features to restrain immune response. Whether tumors and CNS share similar programs of immunosuppression is elusive. Here, we analyze multi-omics data of tumors from HER2+ breast cancer patients receiving trastuzumab and anti-PD-L1 antibody and find that CNS-enriched N-acetyltransferase 8-like (NAT8L) and its metabolite N-acetylaspartate (NAA) are overexpressed in resistant tumors. In CNS, NAA is released during brain inflammation. NAT8L attenuates brain inflammation and impairs anti-tumor immunity by inhibiting cytotoxicity of natural killer (NK) cells and CD8+ Tcells via NAA. NAA disrupts the formation of immunological synapse by promoting PCAF-induced acetylation of lamin A-K542, which inhibits the integration between lamin A and SUN2 and impairs polarization of lytic granules. We uncover that tumor cells mimic the anti-inflammatory mechanism of CNS to evade anti-tumor immunity and NAT8L is a potential target to enhance efficacy of anti-cancer agents.

Changes in motor behavior and lumbar motoneuron morphology following repeated chlorpyrifos exposure in rats.

Chlorpyrifos is an organophosphate pesticide associated with numerous health effects including motor performance decrements. While many studies have focused on the health effects following acute chlorpyrifos poisonings, almost no studies have examined the effects on motoneurons following occupational-like exposures. The main objective of this study was to examine the broad effects of repeated occupational-like chlorpyrifos exposures on spinal motoneuron soma size relative to motor activity. To execute our objective, adult rats were exposed to chlorpyrifos via oral gavage once a day, five days a week for two weeks. Chlorpyrifos exposure effects were assessed either three days or two months following the last exposure. Three days following the last repeated chlorpyrifos exposure, there were transient effects in open-field motor activity and plasma cholinesterase activity levels. Two months following the chlorpyrifos exposures, there were delayed effects in sensorimotor gating, pro-inflammatory cytokines and spinal lumbar motoneuron soma morphology. Overall, these results offer support that subacute repeated occupational-like chlorpyrifos exposures have both short-term and longer-term effects in motor activity, inflammation, and central nervous system mechanisms.

Inflammatory Demyelinating Diseases of the Central Nervous System.

Over the past decades, a large number of immunomodulatory or immunosuppressive treatments have been approved to treat central nervous system (CNS) demyelinating disorders such as multiple sclerosis (MS). Owing to the heterogeneity of patients with CNS demyelinating diseases, there is no clinical treatment that can adequately control all disease subtypes. Although significant progress has been made for relapsing-remitting MS, effective management of the progressive phase of MS has not yet been achieved. This is at least in part caused by our incomplete understanding of the mechanisms driving disease progression, despite our increasing knowledge regarding the underlying cellular and molecular mechanisms. Here, we summarized our current knowledge regarding the mechanisms of CNS demyelinating disorders and their animal models to identify open questions and challenges for existing concepts. We also discussed potential strategies for the future design of immune therapies to treat CNS demyelinating disorders.

Alpha-synuclein expression in GnRH neurons of young and old bovine hypothalami.

Context Understanding of central nervous system mechanisms related to age-related infertility remains limited. Fibril α-synuclein, distinct from its monomer form, is implicated in age-related diseases and propagates among neurons akin to prions. Aims We compared α-synuclein expression in gonadotropin-releasing hormone-expressing neurons (GnRH neurons) in the pre-optic area, arcuate nucleus, and median eminence of healthy heifers and aged cows to determine its role in age-related infertility. Methods We analysed mRNA and protein expression, along with fluorescent immunohistochemistry for GnRH and α-synuclein, followed by Congo red staining to detect amyloid deposits, and confocal microscopy. Key results Both mRNA and protein expressions of α-synuclein were confirmed by reverse transcription-polymerase chain reaction (RT-PCR) and western blots in bovine cortex, hippocampus, and anterior and posterior hypothalamus tissues. Significant differences in α-synuclein mRNA expression were observed in the cortex and hippocampus between young and old cows. Western blots showed five bands of α-synuclein, probably reflecting monomer, dimer, and oligomers, in the cortex, hippocampus, hypothalamus tissues, and there were significant differences in some bands between young and old cows. Bright-field and polarised light microscopy did not detect obvious amyloid deposition in aged hypothalami; however, higher-sensitive confocal microscopy unveiled strong positive signal of Congo red and α-synuclein in GnRH neurons in aged hypothalami. Additionally, α-synuclein expression was detected in immortalised GnRH neurons, GT1-7 cells. Conclusion Alpha-synuclein was expressed in GnRH neurons, and some differences were observed between young and old hypothalami. Implications Alpha-synuclein may play an important role in aging-related infertility.

Alpha-synuclein expression in oxytocin neurons of young and old bovine brains.

Understanding of central nervous system mechanisms underlying age-related infertility remains limited. Fibril α-synuclein, distinct from its monomeric form, is implicated in age-related diseases. Notably, fibril α-synuclein spreads among neurons, similar to prions, from damaged old neurons in cortex and hippocampus to healthy neurons. However, less is known whether α-synuclein propagates into oxytocin neurons, which play crucial roles in reproduction. We compared α-synuclein expression in the oxytocin neurons in suprachiasmatic nucleus (SCN), supraoptic nucleus (SON), paraventricular hypothalamic nucleus (PVN), and posterior pituitary (PP) gland of healthy heifers and aged cows to determine its role in age-related infertility. We analyzed mRNA and protein expression, along with Congo red histochemistry and fluorescent immunohistochemistry for oxytocin and α-synuclein, followed by confocal microscopy with Congo red staining. Both mRNA and protein expressions of α-synuclein were confirmed in the bovine cortex, hippocampus, SCN, SON, PVN, and PP tissues. Significant differences in α-synuclein mRNA expressions were observed in the cortex and hippocampus between young heifers and old cows. Western blots showed five bands of α-synuclein, probably reflecting monomers, dimers, and oligomers, in the cortex, hippocampus, SCN, SON, PVN, and PP tissues, and there were significant differences in some bands between the young heifers and old cows. Bright-field and polarized light microscopy did not detect obvious amyloid deposition in the aged hypothalami; however, higher-sensitive confocal microscopy unveiled strong positive signals for Congo red and α-synuclein in oxytocin neurons in the aged hypothalami. α-synuclein was expressed in oxytocin neurons, and some differences were observed between young and old hypothalami.

Characteristics of multi-channel intermuscular directional coupling based on time-varying partial directional coherence analysis

The human body transmits directional information between muscles during upper limb movements, and this will be particularly evident when the dominant muscle changes during movement transitions. By capturing the electromyography (EMG) signals of wrist flexion and extension continuous transition movements, we investigated the characteristics of multichannel intermuscular directional coupling and directional information transmission, and consequently explored the control mechanism of Central nervous system (CNS) and the coordination mechanism of motor muscles. Multi-channel EMG was collected from 12 healthy subjects under continuous translational movements of wrist flexion and extension, and the time-varying biased directional coherence analysis (TVPDC) model was constructed using partial directional coherence analysis (PDC) frequency domain directionality to study the directional information transfer characteristics in the time–frequency domain, screen closely related muscle pairs and perform directional coupling significance analysis. Palmaris longus (PL) played a dominant role under wrist flexion movements(WF), Extensor Carpi Radialis (ECR) played a dominant role under wrist extension movements(WE), and the remaining muscles responded to them with information and Biceps Brachii (BB) played a responsive role throughout the movement; flexor pairs had the highest positive coupling values in the beta band during Conversion action1 (MC1) and WF phases, and extensor pairs had the highest positive coupling values in the gamma band during Conversion action2(MC2) phase and the highest coupling values in the beta band during WE phase. TVPDC can effectively analyze the multichannel intermuscular directional coupling and information transmission relationship of surface electromyography under wrist flexion and extension transition movements, providing a reference for exploring the control mechanism of CNS and abnormal control mechanism in patients with motor dysfunction in a new perspective.

Experience influences kinematic motor synergies: an Uncontrolled manifold approach to simulated Nordic skiing

ABSTRACT Motor synergies are defined as central nervous system mechanisms which adjust participating degrees of freedom to ensure dynamic stability (control) of certain performance variables and have been identified during many motor tasks. The potential for synergistic control of individual segments during full-body tasks is often overlooked. Thus, this study compared individual differences in the potential stabilization of multiple performance variables on the basis of experience during a full-body sport activity. Normalized time series of synergy indices from Uncontrolled Manifold analyses on experienced (n = 9) and inexperienced (n = 19) participants were analysed using statistical parametric mapping during simulated Nordic skiing. Regardless of experience, hand, upper arm, and whole-body centre of mass (COM) kinematics were found to be stabilized by kinematic motor synergies. Only experienced Nordic skiers stabilized trunk COM position at all, while trunk COM velocity was stabilized for a longer duration than inexperienced participants. However, inexperienced participants stabilized hand velocity for a greater duration overall and to a greater magnitude during early pull phase than the experienced skiers. That motor synergies for hand and trunk COM velocity differed between experience groups suggests potential utility for these performance variables as indicators of motor skill development for full-body tasks such as Nordic skiing.

Contribution of neural circuits tested by transcranial magnetic stimulation in corticomotor control of low back muscle: a systematic review.

Transcranial magnetic stimulation (TMS) is widely used to investigate central nervous system mechanisms underlying motor control. Despite thousands of TMS studies on neurophysiological underpinnings of corticomotor control, a large majority of studies have focused on distal muscles, and little is known about axial muscles (e.g., low back muscles). Yet, differences between corticomotor control of low back and distal muscles (e.g., gross vs. fine motor control) suggest differences in the neural circuits involved. This systematic review of the literature aims at detailing the organisation and neural circuitry underlying corticomotor control of low back muscles tested with TMS in healthy humans. The literature search was performed in four databases (CINAHL, Embase, Medline (Ovid) and Web of science) up to May 2022. Included studies had to use TMS in combination with EMG recording of paraspinal muscles (between T12 and L5) in healthy participants. Weighted average was used to synthesise quantitative study results. Forty-four articles met the selection criteria. TMS studies of low back muscles provided consistent evidence of contralateral and ipsilateral motor evoked potentials (with longer ipsilateral latencies) as well as of short intracortical inhibition/facilitation. However, few or no studies using other paired pulse protocols were found (e.g., long intracortical inhibition, interhemispheric inhibition). In addition, no study explored the interaction between different cortical areas using dual TMS coil protocol (e.g., between primary motor cortex and supplementary motor area). Corticomotor control of low back muscles are distinct from hand muscles. Our main findings suggest: (i) bilateral projections from each single primary motor cortex, for which contralateral and ipsilateral tracts are probably of different nature (contra: monosynaptic; ipsi: oligo/polysynaptic) and (ii) the presence of intracortical inhibitory and excitatory circuits in M1 influencing the excitability of the contralateral corticospinal cells projecting to low back muscles. Understanding of these mechanisms are important for improving the understanding of neuromuscular function of low back muscles and to improve the management of clinical populations (e.g., low back pain, stroke).

Epidrugs in the Therapy of Central Nervous System Disorders: A Way to Drive on?

The polygenic nature of neurological and psychiatric syndromes and the significant impact of environmental factors on the underlying developmental, homeostatic, and neuroplastic mechanisms suggest that an efficient therapy for these disorders should be a complex one. Pharmacological interventions with drugs selectively influencing the epigenetic landscape (epidrugs) allow one to hit multiple targets, therefore, assumably addressing a wide spectrum of genetic and environmental mechanisms of central nervous system (CNS) disorders. The aim of this review is to understand what fundamental pathological mechanisms would be optimal to target with epidrugs in the treatment of neurological or psychiatric complications. To date, the use of histone deacetylases and DNA methyltransferase inhibitors (HDACis and DNMTis) in the clinic is focused on the treatment of neoplasms (mainly of a glial origin) and is based on the cytostatic and cytotoxic actions of these compounds. Preclinical data show that besides this activity, inhibitors of histone deacetylases, DNA methyltransferases, bromodomains, and ten-eleven translocation (TET) proteins impact the expression of neuroimmune inflammation mediators (cytokines and pro-apoptotic factors), neurotrophins (brain-derived neurotropic factor (BDNF) and nerve growth factor (NGF)), ion channels, ionotropic receptors, as well as pathoproteins (β-amyloid, tau protein, and α-synuclein). Based on this profile of activities, epidrugs may be favorable as a treatment for neurodegenerative diseases. For the treatment of neurodevelopmental disorders, drug addiction, as well as anxiety disorders, depression, schizophrenia, and epilepsy, contemporary epidrugs still require further development concerning a tuning of pharmacological effects, reduction in toxicity, and development of efficient treatment protocols. A promising strategy to further clarify the potential targets of epidrugs as therapeutic means to cure neurological and psychiatric syndromes is the profiling of the epigenetic mechanisms, which have evolved upon actions of complex physiological lifestyle factors, such as diet and physical exercise, and which are effective in the management of neurodegenerative diseases and dementia.

Mechanisms of cancer pain.

Personalised and targeted interventions have revolutionised cancer treatment and dramatically improved survival rates in recent decades. Nonetheless, effective pain management remains a problem for patients diagnosed with cancer, who continue to suffer from the painful side effects of cancer itself, as well as treatments for the disease. This problem of cancer pain will continue to grow with an ageing population and the rapid advent of more effective therapeutics to treat the disease. Current pain management guidelines from the World Health Organisation are generalised for different pain severities, but fail to address the heterogeneity of mechanisms in patients with varying cancer types, stages of disease and treatment plans. Pain is the most common complaint leading to emergency unit visits by patients with cancer and over one-third of patients that have been diagnosed with cancer will experience under-treated pain. This review summarises preclinical models of cancer pain states, with a particular focus on cancer-induced bone pain and chemotherapy-associated pain. We provide an overview of how preclinical models can recapitulate aspects of pain and sensory dysfunction that is observed in patients with persistent cancer-induced bone pain or neuropathic pain following chemotherapy. Peripheral and central nervous system mechanisms of cancer pain are discussed, along with key cellular and molecular mediators that have been highlighted in animal models of cancer pain. These include interactions between neuronal cells, cancer cells and non-neuronal cells in the tumour microenvironment. Therapeutic targets beyond opioid-based management are reviewed for the treatment of cancer pain.