Central Nervous System Excitability Research Articles

Reliability of Corticospinal and Motoneuronal Excitability Evaluation During Unfatiguing and Fatiguing Cycling Exercise.

Central nervous system excitability depends on the task performed, muscle group solicited, and contraction type. However, little is known on corticospinal and motoneuronal excitability measured during locomotor exercise. This study aimed at determining the reliability of motor-evoked potentials (MEP) and thoracic motor-evoked potentials (TMEP) in dynamic mode during unfatiguing and fatiguing cycling exercise. Twenty-two participants completed four visits. Visit 1 comprised familiarization and a maximal incremental test to determine maximal power output (Wmax). The remaining visits encompassed unfatiguing evaluations, which included 8 brief bouts of moderate (50% Wmax) and high intensity cycling (80% Wmax). In each bout, a set of two TMEPs, five MEPs and one M-max were obtained. Subsequently, a fatiguing exercise to exhaustion at 80% Wmax was performed, with four sets of measurements 3 min through the exercise and 4 additional sets at exhaustion, both measured at 50% Wmax. Intraclass correlation coefficients (ICCs) for 5, 10, 15 and 20 MEP·Mmax-1 revealed excellent reliability at both intensities and during fatiguing exercise (ICC ≥ 0.92). TMEP·Mmax-1 showed ICCs ≥0.82 for moderate and high intensity, and it was not affected by fatigability. Overall standard error of measurement was 0.090 [0.083, 0.097] for MEP·Mmax-1 and 0.114 [0.105, 0.125] for TMEP·Mmax-1. A systematic bias associated to the number of stimulations, especially at high intensity, suggested the evaluation itself may be influenced by fatigability. A mean reduction of 8% was detected in TMEP·Mmax-1 at exhaustion. Motoneuronal and corticospinal excitability measured in dynamic mode presented good to excellent reliability in unfatiguing and fatiguing exercise. Further studies inducing greater fatigability must be conducted to assess the sensitivity of central nervous system excitability during cycling.

GABAergic signaling beyond synapses: an emerging target for cancer therapy.

Traditionally, γ-aminobutyric acid (GABA) is best known for its role as a primary inhibitory neurotransmitter reducing neuronal excitability in the mammalian central nervous system (CNS), thereby producing calming effects. However, an emerging body of data now supports a function for GABA beyond neurotransmission as a potent factor regulating cancer cell growth and metastasis, as well as the antitumor immune response, by shaping the tumor microenvironment (TME). Here, we review the current knowledge on GABA's effects on the function of tumor cells, tumor-immune interactions, and the underlying molecular mechanisms. Since altered GABAergic signaling is now recognized as a feature of certain types of solid tumors, we also discuss the potential of repurposing existing GABAergic agents as a new class of anticancer therapy.

Acute effects of conventional versus wide-pulse neuromuscular electrical stimulation on quadriceps evoked torque and neuromuscular function.

The effectiveness of a neuromuscular electrical stimulation (NMES) program is proportional to the level of evoked torque, which can be achieved with either conventional or wide-pulse stimulations. The aim of this study was to compare evoked torque, objective fatigability, and related peripheral and central alterations, as well as changes in central nervous system (CNS) excitability induced by an acute session of conventional versus wide-pulse NMES. Seventeen young men underwent three 20-min NMES sessions: conventional (0.2 ms/50 Hz), wide-pulse at 50 Hz (1 ms/50 Hz), and wide-pulse at 100 Hz (1 ms/100 Hz). Neuromuscular measurements (i.e., maximal voluntary contraction, voluntary activation, evoked responses to femoral nerve stimulation, and CNS excitability) were performed on the right quadriceps femoris muscle before and after each NMES session. CNS excitability was measured using transcranial magnetic, thoracic, and transcutaneous spinal cord stimulations. The level of evoked torque was not significantly different between conventional and wide-pulse protocols applied at the maximal tolerable current intensity. All NMES protocols induced objective fatigability (~14% decrease in maximal voluntary contraction torque, p < 0.001) associated with peripheral (decrease in doublet torque and potentiated M-wave amplitude, p = 0.002 and p < 0.001, respectively) but not central (unchanged voluntary activation, p = 0.79) alterations. However, these acute changes did not differ between NMES protocols and none of the NMES protocols modified markers of CNS excitability. These results may allow to conjecture that chronic effects and treatment effectiveness could be comparable between conventional and wide-pulse NMES.

Effects of 10 Hz individualized repetitive transcranial magnetic stimulation on patients with disorders of consciousness: a study protocol for an exploratory double-blind crossover randomized sham-controlled trial

BackgroundRepetitive transcranial magnetic stimulation (rTMS), as a non-invasive brain stimulation technique, has shown potentials for consciousness recovery of patients with disorders of consciousness (DoC), as, to a certain extent, it is effective in regulating the excitability of central nervous system. However, it is difficult to achieve satisfactory effect with “one size fits all” rTMS treatment due to different clinical conditions of patients. There is an urgent need to develop individualized strategy to improve the effectiveness of rTMS on patients with DoC.MethodsOur protocol is a randomized double-blind sham-controlled crossover trial that includes 30 DoC patients. Each patient will received 20 sessions, in which 10 sessions will be rTMS-active stimulus, and the other 10 sessions will be sham stimulus, separated by no less than 10 days’ washout period. The rTMS-active will include 10 Hz rTMS over the individualized-targeted selection area for each patient according to the different insult regions of the brain. Coma Recovery Scale-Revised (CRS-R) will be used as primary outcome at baseline, after the first stage of stimulation, at the end of the washout period, and after the second stage of stimulation. Secondary outcomes will be measured at the same time, including efficiency, relative spectral power, and functional connectivity of high-density electroencephalograph (EEG). Adverse events will be recorded during the study.DiscussionrTMS has obtained grade A evidence in treating patients with several central nervous system diseases, and there has been some evidence showing partial improvement on level of consciousness in DoC patients. However, the effectiveness of rTMS in DoC is only 30~36%, mostly due to the non-specific target selection. In this protocol, we present a double-blind crossover randomized sham-controlled trial based on the individualized-targeted selection strategy that aims to study the effectiveness of rTMS therapy for DoC, and the result may provide new insights to non-invasive brain stimulation.Trial registrationClinicalTrials.gov: NCT05187000. Registered on January 10, 2022.

The main non-invasive neuromodulatory techniques: an infographic

INTRODUCTION: This infographic aims to present the main non-invasive neuromodulatory techniques that can be used to assess and/or modulate central nervous system excitability. Single- and paired-pulse transcranial magnetic stimulation (TMS) can be used to assess brain excitability through the delivery of magnetic pulses over the cerebral cortex. The motor evoked potential is an indirect measure of motor cortex excitability and is the most used cortical measure of excitability. RESULTS: Neuromodulation may be achieved through several techniques, which may be used to promote top-down or bottom-up effects. Among the top-down techniques is direct current stimulation (DCS) which can change its nomenclature according to the stimulation target, for example, transcranial (tDCS), or cerebellar (ctDCS). In addition, also can be included in top-down techniques the transcranial random noise stimulation (tRNS), transcranial alternate current stimulation (tACS), and repetitive TMS (rTMS). On other hand, the bottom-up techniques include the peripheral electrical stimulation (PES), transcutaneous auricular vagus nerve stimulation (taVNS), transcutaneous spinal direct current stimulation (tsDCS), and repetitive peripheral magnetic stimulation (rPMS). CONCLUSION: The neuromodulatory effects are dependent on several parameters that can be specific to physical principles (electrical or magnetic). For example, in repetitive P/TMS the frequency, type and angular orientation of coil, distance between the coil and the brain, pulse waveform, and pattern of stimulation are presented as important parameters able to interfere with the quality of stimulation. The same can be observed in tDCS, ctDCS, and tsDCS with the polarity and shape and montage of electrode, intensity, site and duration of stimulation, and current density.

Effects of prolonged local vibration superimposed to muscle contraction on motoneuronal and cortical excitability.

Introduction: Acute effects of prolonged local vibration (LV) at the central nervous system level have been well investigated demonstrating an altered motoneuronal excitability with a concomitant increase in cortical excitability. While applying LV during isometric voluntary contraction is thought to optimize the effects of LV, this has never been addressed considering the acute changes in central nervous system excitability. Materials and Methods: In the present study, nineteen healthy participants were engaged in four randomized sessions. LV was applied for 30min to the relaxed flexor carpi radialis muscle (VIBRELAXED) or during wrist flexions (i.e. intermittent contractions at 10% of the maximal voluntary contraction: 15s ON and 15s OFF; VIBCONTRACT). A control condition and a condition where participants only performed repeated low-contractions at 10% maximal force (CONTRACT) were also performed. For each condition, motor evoked potentials (MEPs) elicited by transcranial magnetic stimulation and cervicomedullary evoked potentials (CMEPs) elicited by corticospinal tract electrical stimulation were measured before (PRE) and immediately after prolonged LV (POST) to investigate motoneuronal and corticospinal excitability, respectively. We further calculated the MEP/CMEP ratio as a proxy of cortical excitability. Results: No changes were observed in the control nor CONTRACT condition. At POST, CMEP decreased similarly in VIBRELAXED (-32% ± 42%, p < .001) and VIBCONTRACT (-41% ± 32%, p < .001). MEP/CMEP increased by 110% ± 140% (p = .01) for VIBRELAXED and by 120% ± 208% (p = .02) for VIBCONTRACT without differences between those conditions. Discussion: Our results suggest that LV to the flexor carpi radialis muscle, either relaxed or contracted, acutely decreases motoneuronal excitability and induces some priming of cortical excitability.

Alcohol withdrawal produces changes in excitability, population discharge probability, and seizure threshold.

Alcohol withdrawal syndrome (AWS) results from the sudden cessation of chronic alcohol use and is associated with high morbidity and mortality. Alcohol withdrawal-induced central nervous system (CNS) hyperexcitability results from complex, compensatory changes in synaptic efficacy and intrinsic excitability. These changes in excitability counteract the depressing effects of chronic ethanol on neural transmission and underlie symptoms of AWS, which range from mild anxiety to seizures and death. The development of targeted pharmacotherapies for treating AWS has been slow, due in part to the lack of available animal models that capture the key features of human AWS. Using a unique optogenetic method of probing network excitability, we examined electrophysiologic correlates of hyperexcitability sensitive to early changes in CNS excitability. This method is sensitive to pharmacologic treatments that reduce excitability and may represent a platform for AWS drug development. We applied a newly developed method, the optogenetic population discharge threshold (oPDT), which uses light intensity response curves to measure network excitability in chronically implanted mice. Excitability was tracked using the oPDT before, during, and after the chronic intermittent exposure (CIE) model of alcohol withdrawal (WD). Alcohol withdrawal produced a dose-dependent leftward shift in the oPDT curve (denoting increased excitability), which was detectable in as few as three exposure cycles. This shift in excitability mirrored an increase in the number of spontaneous interictal spikes during withdrawal. In addition, Withdrawal lowered seizure thresholds and increased seizure severity in optogenetically kindled mice. We demonstrate that the oPDT provides a sensitive measure of alcohol withdrawal-induced hyperexcitability. The ability to actively probe the progression of excitability without eliciting potentially confounding seizures promises to be a useful tool in the preclinical development of next-generation pharmacotherapies for AWS.

Investigation on property differences of ginseng and American ginseng by spatial metabolomics of neurochemicals with desorption electrospray ionization mass spectrometry imaging

Ethnopharmacological relevanceThe properties are the body's response to traditional Chinese medicine (TCM). The essence of traditional Chinese medicine properties are cold, hot, warm, and cool. In the theory of traditional Chinese medicine, ginseng is warm and American ginseng is cool, they present two opposite properties. The material basis of property differences and effect mechanism of property degree need further investigation. Aim of the studyThe aim of this work was to screen out the neurochemicals related to warm and cool properties of ginseng and American ginseng, and investigate the distributions of identified neurochemicals in rat brain and the metabolic mechanism. Materials and methodsSpatial metabolomics was applied to study the effects of ginseng and American ginseng on the distributions of neurochemicals in rat brain by desorption electrospray ionization mass spectrometry imaging (DESI-MSI). Based on discriminant coefficients in partial least square discriminant analysis (PLS-DA) processing, neurochemicals related to warm and cool properties were classified. In addition, the score contributions of the neurochemicals markers could be used to evaluate the warm and cool property degrees. ResultsA total of 25 neurochemicals were imaged and identified in brain section. The distribution regions of main neurochemicals were consistent with in sagittal and coronal sections of brain reported in literature. 17 neurochemicals were classified as warm markers. Meanwhile, 8 neurochemicals were identified as cool markers, correlated with the cool properties of American ginseng. It demonstrated that the score contributions of the 25 neurochemicals markers could be used to evaluate the warm and cool property degrees. Based on the regulatory effects of neurochemicals, the warm markers could promote the body's energy metabolism, improve the function of endocrine system, and enhance the excitability of central nervous system. The cool property markers have reduced excitability of central nervous system, weakened metabolism and stress response ability, thus presented the biological activity of cool and cold. ConclusionsOur findings provided a rapid and effective visualization method for the spatial distribution and metabolism of small molecular neurochemicals in rat brain. DESI-MSI was a reference methodology for evaluating the properties of TCM.

Pre-pregnancy migraine diagnosis, medication use, and spontaneous abortion: a prospective cohort study

BackgroundMigraine is common among females of reproductive age (estimated prevalence:17–24%) and may be associated with reproductive health through underlying central nervous system excitability, autoimmune conditions, and autonomic dysfunction. We evaluated the extent to which pre-pregnancy migraine diagnosis and medication use are associated with risk of spontaneous abortion (SAB).MethodsWe analyzed data from a preconception study of pregnancy planners (2013–2021). Eligible participants self-identified as female, were aged 21–45 years, resided in the USA or Canada, and conceived during follow-up (n = 7890). Participants completed baseline and bimonthly follow-up questionnaires for up to 12 months or until a reported pregnancy, whichever occurred first. Pregnant participants then completed questionnaires during early (~ 8–9 weeks) and late (~ 32 weeks) gestation. We defined migraineurs as participants who reported a migraine diagnosis or use of a medication to treat migraine. Preconception questionnaires elicited migraine medication use during the past 4 weeks, and SAB on follow-up and pregnancy questionnaires. We used Cox regression models with gestational weeks as the time scale to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for associations among preconception migraine, migraine medication use, and SAB, controlling for potential demographic, medical, and lifestyle confounders.ResultsNineteen percent of study pregnancies ended in SAB. History of migraine before conception was not appreciably associated with SAB risk (HR = 1.03, 95% CI: 0.91–1.06). Use of any migraine medication was associated with a modest increase in SAB risk overall (HR = 1.14, 95% CI: 0.96–1.36). We observed the greatest increase in risk among those taking migraine medications daily (HR = 1.38, 95% CI: 0.81–2.35) and those taking prescription migraine prophylaxis (HR = 1.43, 95% CI: 0.72–2.84) or combination analgesic and caffeine medications (HR = 1.42, 95% CI: 0.99–2.04).ConclusionsMigraine medication use patterns suggesting greater underlying migraine severity were associated with increased risk of SAB. This research adds to the limited information available on the reproductive effects of migraine.

Evidence of a sudden increase in α-chloralose poisoning in dogs and cats in the Netherlands between 2018 and 2021.

After changes in European Union biocide legislation, the Dutch Poisons Information Center observed a strong increase in information requests concerning dogs and cats exposed to α-chloralose. To investigate whether α-chloralose-based rodenticides are safe for non-professional use, additional information regarding poisoning scenarios and clinical course was collected. Veterinarians reporting α-chloralose exposure over a 2.5-year period were contacted by mail for follow-up information concerning exposure scenario, product formulation, clinical course and treatment, and outcome. In total, information was collected for 96 dogs and 41 cats. Fifty-three of 96 dogs and 17 of 19 cats known to have been exposed to α-chloralose-based rodenticides developed signs of central nervous system (CNS) depression or sensory-induced CNS excitation. Mortality in dogs and cats following exposure was 1% and 18%, respectively. An additional 22 cats presented with clinical signssuggestive of α-chloralose poisoning, with a mortality of 5%. Exposure to α-chloralose was not confirmed by biochemical analyses. Dogs and especially cats were at risk of poisoning from α-chloralose. If criteria such as acute toxicity and risk of (secondary) poisoning are applied during the approval of α-chloralose-based rodenticides, similar to anticoagulant-based rodenticides, it can be concluded that α-chloralose is also not safe for non-professional use.

Effective corticospinal excitability neuromodulation elicited by short-duration concurrent and synchronized associative cortical and neuromuscular stimulations

Optimal parameters of combined repetitive associative transcranial magnetic stimulation (rTMS) and neuromuscular electrical stimulation (NMES) for neuromodulation of central nervous system (CNS) excitability are not well understood. We examined corticospinal excitability after short-duration concurrent and synchronized associative stimulation applied using primary motor cortex rTMS and upper-limb NMES. Intermittent theta burst stimulation (iTBS) was delivered with burst at 50 Hz and repeated at 5 Hz over the course of 192 s as an established cortical facilitation rTMS protocol. NMES was applied to activate the extensor carpi radialis muscle over the same 192 s duration. Four interventions were compared: (1) iTBS with concurrent and synchronized 50 Hz NMES; (2) iTBS with concurrent and synchronized 5 Hz NMES; (3) iTBS with concurrent and asynchronized 41 Hz NMES; (4) iTBS with 5 s delayed and synchronized 50 Hz NMES. Single-pulse motor evoked potential (MEP) responses elicited by transcranial magnetic stimulation of the primary motor cortex and maximum motor responses (Mmax) elicited by radial nerve stimulation were compared before and for 30 min after each intervention. Our results showed that corticospinal excitability (MEP/Mmax) was only facilitated after the iTBS and concurrent 50 Hz NMES intervention, but the responses returned to baseline within 10 min of completing the intervention. This result demonstrates that short-duration concurrent and synchronized stimulation could be applied to effectively neuromodulate corticospinal excitability. Therefore, repetitive synchronized associative stimulation of the primary motor cortical networks and sensorimotor peripheral circuits may be enhanced using synchronized 50 Hz frequency of activation during concurrent stimulation.

Acute effects of quadriceps muscle versus tendon prolonged local vibration on force production capacities and central nervous system excitability.

The present study aimed to directly compare the effects of 30min muscle (VIBmuscle) vs. tendon (VIBtendon) local vibration (LV) to the quadriceps on maximal voluntary isometric contraction (MVIC) and rate of torque development (RTD) as well as on central nervous system excitability (i.e. motoneuron and cortical excitability). Before (PRE) and immediately after (POST) LV applied to the quadriceps muscle or its tendon, we investigated MVIC and RTD (STUDY #1; n = 20) or vastus lateralis (VL), vastus medialis (VM) and rectus femoris (RF) electromyography responses to thoracic electrical stimulation (TMEPs; motoneuron excitability) and transcranial magnetic stimulation (MEPs; corticospinal excitability) (STUDY #2; n = 17). MEP/TMEP ratios were further calculated to quantify changes in cortical excitability. MVIC decreased at POST (P = 0.017) without any difference between VIBtendon and VIBmuscle, while RTD decreased for VIBtendon (P = 0.013) but not VIBmuscle. TMEP amplitudes were significantly decreased for all muscles (P = 0.014, P < 0.001 and P = 0.004 for VL, VM and RF, respectively) for both LV sites. While no changes were observed for MEP amplitude, MEP/TMEP ratios increased at POST for VM and RF muscles (P = 0.009 and P = 0.013, respectively) for both VIBtendon and VIBmuscle. The present results suggest that prolonged muscle and tendon LV are similarly effective in modulating central nervous system excitability and decreasing maximal force. Yet, altered explosive performance after tendon but not muscle LV suggests greater neural alterations when tendons are vibrated.

Morphine with or without Acepromazine in Horses: A Kinematic Evaluation.

Simple SummaryMorphine is an opioid agonist drug and produces a significant analgesic effect in horses but besides the evidenced analgesic effect, the use of morphine is not routine due to the potential excitatory effects described in the literature. To minimize these effects, neuroleptanalgesia, or the combination of opioids and sedative drugs, is encouraged. Our aim was to describe changes occurring in the locomotor pattern after co-administration of a tranquilizer, acepromazine, and morphine in horses. Six mature horses were used and received four different treatments with saline solution, morphine, acepromazine, or a combination of morphine and acepromazine. A three-dimensional accelerometric device was used to collect data and objectivize those findings moreover the sedative effect of the treatments was also measured. Significant differences were observed when comparing all the treatments in the majority of accelerometric variables, except the regularity of the pattern, some energetic parameters, and tranquilization. An evident counteraction of the effects caused by both morphine and acepromazine was observed. Due to these effects, the possibility of adding acepromazine to an additional analgesic treatment with morphine in the clinical setting ensures the absence of the supplemental instability caused by other sedatives and minimizes the potential opioid excitatory effects.The objective was to demonstrate walking locomotor pattern alterations after co-administration of acepromazine and morphine in horses. Six mature horses receiving four different treatments were used. Treatments consisted of a single dose of saline solution, 0.2 mg/kg bwt of morphine hydrochloride, 0.02 mg/kg bwt of acepromazine maleate, and a combination of 0.2 mg/kg bwt of morphine hydrochloride with 0.02 mg/kg bwt of acepromazine maleate. A three-dimensional accelerometric device was used to collect data. Walking tests were performed 10 min prior to injection, and then at 5, 10, 15, and 20 min after the injection, and then every 10 min for 3 h. Eight variables were calculated including stride kinematic, coordination, and energetic parameters; moreover ground-to-lip distance (GLD), as a tranquilization parameter, was also measured. A significant interaction was observed in all the variables studied but regularity, mediolateral power, the propulsive part of the power, and the GLD. An evident counteraction of the effects caused by both, opioids and phenothiazines, in the gait pattern was observed. The co-administration of acepromazine and morphine could allow a safe opiate administration while minimizing the possible central nervous system (CNS) excitation and reducing potential locomotor adverse effects.

Transcranial electrical stimulation of dorsolateral prefrontal cortex in substance use disorder therapy

There is a growing interest in therapeutic applications of non-invasive brain stimulation methods. Transcranial electrical stimulation is a non-invasive brain stimulation method used to modulate central nervous system excitability. The procedure involves placing two electrodes on the patient’s head through which very low-intensity electrical current is sent. Transcranial electrical stimulation methods include transcranial direct current stimulation and transcranial alternating current stimulation. These methods are considered to be safe and relatively inexpensive, and can be used in home settings. Research conducted in recent years suggests that transcranial electrical stimulation can be applied to support substance use disorder therapy. The positive effects of stimulation include decreased craving and frequency of substance use, an improved quality of life and changes in the activity of functional brain networks. Transcranial direct current stimulation with the anode being placed over the right dorsolateral prefrontal cortex and the cathode being placed over the left dorsolateral prefrontal cortex is considered to be of a particularly high therapeutic potential. There are a limited number of studies which indicate that not only direct current stimulation, but also alternating current stimulation can be used for substance use disorder therapy.

Low-Intensity and Short-Duration Continuous Cervical Transcutaneous Spinal Cord Stimulation Intervention Does Not Prime the Corticospinal and Spinal Reflex Pathways in Able-Bodied Subjects.

Cervical transcutaneous spinal cord stimulation (tSCS) has been utilized in applications for improving upper-limb sensory and motor function in patients with spinal cord injury. Although therapeutic effects of continuous cervical tSCS interventions have been reported, neurophysiological mechanisms remain largely unexplored. Specifically, it is not clear whether sub-threshold intensity and 10-min duration continuous cervical tSCS intervention can affect the central nervous system excitability. Therefore, the purpose of this study was to investigate effects of sub-motor-threshold 10-min continuous cervical tSCS applied at rest on the corticospinal and spinal reflex circuit in ten able-bodied individuals. Neurophysiological assessments were conducted to investigate (1) corticospinal excitability via transcranial magnetic stimulation applied on the primary motor cortex to evoke motor-evoked potentials (MEPs) and (2) spinal reflex excitability via single-pulse tSCS applied at the cervical level to evoke posterior root muscle (PRM) reflexes. Measurements were recorded from multiple upper-limb muscles before, during, and after the intervention. Our results showed that low-intensity and short-duration continuous cervical tSCS intervention applied at rest did not significantly affect corticospinal and spinal reflex excitability. The stimulation duration and/or intensity, as well as other stimulating parameters selection, may therefore be critical for inducing neuromodulatory effects during cervical tSCS.

Specific inhibition of α5 subunit-containing GABAA receptors enhances locomotor activity and neuronal activity in the motor cortex.

Gamma-aminobutyric acid (GABA) is a major inhibitory neurotransmitter in the central nervous system (CNS). This study examined the effect of specific inhibition of α5 subunit-containing GABAA receptors (α5GABAAR) on the behavioral profile and neuronal activity of the CNS using a compound called L-655,708, which is a selective negative allosteric modulator of α5GABAAR. L-655,708 administration significantly increased locomotor activity without anxiety-related behavior. Furthermore, L-655,708 administration significantly increased c-Fos mRNA expression (a neuronal activity marker) in motor area of the cerebral cortex, whereas it hardly altered c-Fos mRNA expression in the sensory cortex, hippocampus, and spinal cord. This study revealed for the first time that alteration of neuronal activity with specific inhibition of α5GABAAR differs depending on each CNS region. α5GABAAR could be a potential target for modulating CNS excitability and behavioral activity.

The role of intranasal esketamine in treatment-resistant depression

IntroductionMajor depressive disorder (MDD) is a highly prevalent clinical condition with a leading cause of disability worldwide. Unfortunately, about 1/3 of patients with MDD fail to achieve remission despite treatment with multiple antidepressants and are considered to have treatment-resistant depression (TRD). Research showed abnormalities in glutamatergic transmission in neural circuits and antidepressant efficacy with the N-methyl-D-aspartate (NMDA) receptor antagonist, ketamine.ObjectivesThe authors elaborate a narrative literature review on the intranasal esketamine as a new-class antidepressant.MethodsPubMed database searched using the terms “treatment-resistant depression” and “esketamine”.ResultsKetamine, synthetized from PCP, acts as an antagonist of NMDA receptor, reducing Central Nervous System excitability. One limitation of ketamine for treating depression is that requires intravenous administration, reducing its applicability in outpatient settings. Esketamine, the S-enantiomer of ketamine, developed as an intranasal formulation has a higher affinity for the NMDA receptor. The evidence of the rapid antidepressant effect of intranasal esketamine was first made by Lapidus et al, that demonstrated intranasal esketamine ability to reduce depressive symptomatology. However, some recent studies reported significant acute cardiovascular, psychotomimetic and neurological side-effects. Thus, drug formulation, delivery device, insufflation technique, and individual factors seem to contribute importantly to the tolerability and efficacy of the intranasal administration rote.ConclusionsThere is the need to develop novel treatments providing effective, more rapid-acting, and sustained relief of depressive symptoms, especially in patients with TRD. Intranasal esketamine has shown antidepressant effects in patients with TRD but further investigation is required to strongly reinforce this potential and safety.

Acute effects of weighted plyometric exercise on sprint, agility and jump performance in university football players

Background: Conditioning activities such as resistance training can cause excitation of central nervous system resulting in Post-activation Potentiation phenomenon. Plyometric exercise also has an important role to develop Post-activation Potentiation following a resistance stimulus. So the purpose the study was to investigate the immediate effects of weighted plyometric exercise on sprint, agility and jump performance. Materials and methods: Twenty male university football players (age=21.3±1.5 years, body mass=63.3±9.5 kg, height=169.8±6.4 m) participated in this Single group pre-test post-test study. Agility Time (AT), Sprint Time (ST) and Counter-Movement Jump (CMJ) height were measured prior to and 1st and 5th minutes following plyometric exercise. Results: A repeated measures ANOVA employed at baseline (T0), 1 minute (T1), and 5 minutes (T5) post intervention showed significant effect for all the three outcome measures (p&lt;0.001). Post-hoc Bonferroni pairwise comparison showed a significant decrease in both AT and ST from baseline to assessments at both T1 (p&lt;0.001) and T5 (p&lt;0.001), whereas there was a significant increase in the CMJ height. However, no statistical difference was found between T1 and T5 (p=0.058) in ST, but AT was significantly lower at T5 than at T1 (p=0.008), and CMJ height showed significant increase from T1 to T5 (p=0.001). Conclusion: Our results suggest that weighted plyometric exercises have an acute response on sprint, agility and counter movement jump (CMJ Height) following Post-Activation Potentiation (PAP) effect developed after plyometric exercises.

Effects of lactate and carbon monoxide interactions on neuroprotection and neuropreservation.

Lactate, historically considered a waste product of anerobic metabolism, is a metabolite in whole-body metabolism needed for normal central nervous system (CNS) functions and a potent signaling molecule and hormone in the CNS. Neuronal activity signals normally induce its formation primarily in astrocytes and production is dependent on anerobic and aerobic metabolisms. Functions are dependent on normal dynamic, expansive, and evolving CNS functions. Levels can change under normal physiologic conditions and with CNS pathology. A readily combusted fuel that is sshuttled throughout the body, lactate is used as an energy source and is needed for CNS hemostasis, plasticity, memory, and excitability. Diffusion beyond the neuron active zone impacts activity of neurons and astrocytes in other areas of the brain. Barriergenesis, function of the blood-brain barrier, and buffering between oxidative metabolism and glycolysis and brain metabolism are affected by lactate. Important to neuroprotection, presence or absence is associated with L-lactate and heme oxygenase/carbon monoxide (a gasotransmitter) neuroprotective systems. Effects of carbon monoxide on L-lactate affect neuroprotection – interactions of the gasotransmitter with L-lactate are important to CNS stability, which will be reviewed in this article.

Differences between paediatric and adult suspected neuropsychiatric adverse drug reactions of Melatonin reported to the European Medicines Agency

Melatonin has been approved as a sleep medication in Europe since 2007. The pharmacological dosages of this substance are much higher than the physiological ones, so it is no surprise that it has potential for many adverse effects. In children melatonin has been used for many years off-label, but in 2018 the Committee for Medicinal Products for Human Use (CHMP) granted paediatric-use marketing authorization for melatonin. We used the European Medicines Agency (EMA) database to compare the distribution of melatonin adverse drug reaction (ADRs) between the pediatric and the adult population. The results will serve as a basis for future research involving melatonin use in specific populations. All ADR reports received in EMA up to 23.03.2019 were analyzed for overall numbers, age and gender. The nature of the ADRs and the most frequently reported drug substances and drug event combinations were evaluated using MedDRA 21.0. As of 27th March 2019, EudraVigilance contained 1061 spontaneous reports. After excluding all the cases with other suspected or concomitant drugs, we are left with 177 cases. In children ADRs were generally associated with central nervous system (CNS) excitability, whereas in adults there was mainly inhibition. The present study focused on the ADR reports of melatonin in one of the largest databases. Future research of melatonin in the pediatric population is needed, because the current SmPCs lack such information, and in the cases of melatonin use in children are increasing in recent years.