To investigate the impact of electrode structure on Electrical Stimulation Therapy (EST) for chronic wound healing, this study designed three variants of flexible microelectrodes (FMs) with Ag-Cu coverings (ACCs), each exhibiting distinct geometrical configurations: hexagonal, cross-shaped, and serpentine. These were integrated with PPY@PDA/PANI (3/6) hydrogel dressings. Comprehensive animal studies, coupled with detailed electrical and mechanical modeling and simulations, were conducted to assess their performance. Results indicated that the serpentine-shaped FM outperformed its counterparts in terms of flexibility and safety, exhibiting minimal thermal effects and a reduced risk of burns. Notably, FMs with metal coverings under 3% demonstrated promising potential for optoelectronic self-powering capabilities. Additionally, simulation data highlighted the significant influence of hydrogel non-uniformity on the distribution of electrical properties across the skin surface, providing critical insights for optimizing EST protocols when employing hydrogel dressings.

Abstract Introduction: In the last thirty years, brain neuromodulation techniques have been used as an alternative to pharmacological treatment of neurological disorders. Parkinson's disease (PD) is a neurodegenerative disorder leading to bradykinesia, rest tremor, postural changes, and non-motor symptoms such as depression, anxiety, sleep disorders, pain, and cognitive decline that compromises executive functions (EFs), responsible for the orderly execution of behaviors and tasks of daily life and intentional and directed actions. To this date, a few studies with transcranial direct current stimulation (tDCS) have shown beneficial effects in PD patients concerning specific motor and non-motor symptoms, targeting the motor cortex and/or prefrontal regions. Objective: The main objective of this study was to evaluate the effects of left prefrontal tDCS across a broad spectrum of motor and non-motor symptoms of PD using established validated scales. Method: Single-blind randomized clinical trial with 18 volunteers with PD, aged between 45 and 80 years (66.1 ± 9.65), who met inclusion and exclusion criteria. Participants were submitted to assessments of motor and non-motor functions employing psychometric scales and tests to evaluate EFs and were randomly divided into two groups: control (sham stimulation) and experimental (active stimulation). All participants were involved in three separate tDCS sessions. The anode was positioned over the left dorsolateral prefrontal cortex and the cathode over the right supraorbital region, with a direct current intensity of 2mA, lasting 20 minutes. At the end of the three sessions, all participants were reassessed. Results: Significant effects of tDCS on non-motor functions were observed for cognition (verbal fluency of actions, clock copy test, appointment by visual confrontation, and verbal memory with immediate free recall) and subjective assessment of sleep quality (overall restlessness and discomfort in the arms and legs at night, leg and arm cramps at night and distressing dreams). There was also an improvement in the rate of errors and successes for congruent and incongruent stimuli of the Stroop Test. The beneficial effects on motor function were decreased rigidity, improved gait, and greater agility in the finger-tapping test. Conclusion: Three tDCS sessions showed positive results for participants with PD, producing significant improvements in various motor and non-motor functions, including sleep quality, cognition, and EFs. Additionally, the present results indicate that tDCS neuromodulation of the left dorsolateral prefrontal cortex region is feasible, safe, and provides significant objective benefits for PD patients.

Shoulder tendinopathies produce pain and reduce functionality. The aim of this randomized clinical trial was to analyze the effects of Percutaneous electrolysis (PE), Percutaneous peripheral Nerve Stimulation (PNS) and eccentric exercise (EE), on pain (NPRS), strength, electromyographic activity, ultrasound characteristics of the tendon (echogenicity, thickness and hypervascularization) and functionality (DASH and SPADI) on individuals with supraspinatus tendinopathy. Participants (n=50) were divided into two groups, they received 4 treatment sessions, one per week, of PE and PNS (n=25) or 10 treatment sessions of TENS and US (n=25). Both groups performed EE program consisted of 3 sets of 10 repetitions of each of the 3 exercises, twice a day, during the 4 weeks. Follow-up was carried out at 4, 12 and 24 weeks after the start of the intervention. There are statistically significant differences in the analysis between groups (p<0.001) in the post-treatment and follow-up measurements favorable to the PE+PNS+EE treatment on pain (NPRS), strength, supraspinatus electromyographic amplitude, ultrasound characteristics of the tendon (echogenicity, thickness and hypervascularization) and DASH and SPADI questionnaires. The combined treatment PE, PNS and EE is an effective option in the clinical management of tendinopathies, with positive results in the short and long term on the variables studied.

Global stress is widespread in todays post-pandemic world of political and economic uncertainty. Vibroacoustic technology is a vibrotactile intervention with multiple uses, and its impact on stress lacks interpretation. This research assessed if the vibroacoustic technology of a Vibroacoustic Sound Massage (VSM) can reduce psychological, physiological and cognitive stress. The Perceived Stress Scale (PSS-10), and electrocardiogram (ECG) and electroencephalogram (EEG) biosignals were used to quantify results. Participants were divided into Low Stress and High Stress groups. ECG results show VSM increased parasympathetic activity for all participants, with the Low Stress group more effected. EEG results indicate increased concentration (TBR), reduced arousal and increased relaxation (BAR), and non-significant effects on participant well-being (FAA), though variability in this metric was homogenised after VSM. Together, these results validate VSM as an effective support tool for stress management and further research is required.

Plant growth promoting rhizobacteria (PGPR) are a diverse group of microorganisms including genera such as Pseudomonas, Bacillus, Serratia, Enterobacter and Klebsiella. These bacteria have the ability to colonize roots externally and internally, and to directly enhance plant growth employing various mechanisms like phytohormone production and nutrient mineralization. These microbes can also promote plant growth indirectly by secreting antimicrobial compounds (e.g., siderophores, hydrogen cyanide) to antagonize root pathogens or by inducing defensive responses in the plant. Interestingly, there are also cases where production of antibiotic compounds such as 2,4-Diacetylphloroglucinol have the direct effect of enhancing plant growth and yield, irrespective of their biocontrol effects. The objective of this paper is to review publications showcasing PGPRs that have the capacity to both control root pathogens and stimulate plant growth, and to discuss what mechanisms might be involved.

Neuromonitoring of the efferent nerve impulses transmission in the spinal cord tracts during surgical scoliosis treatment makes it possible to assess whether the functional status is deteriorating, affecting the procedure's safety. Is there any relationship between pre- and intraoperative motor evoked potentials recordings and does idiopathic scoliosis (IS) surgical correction improve directly the spinal efferent transmission? This study aimed to compare the results of surface recorded electromyography (EMG), electroneurography (ENG, M and F-waves), and especially motor evoked potentials (MEP) from tibialis anterior (TA) muscle bilaterally in 353 girls with the right idiopathic scoliosis (types 1A-4C according to Lenke classification). It has not yet been documented whether the results of MEPs recordings induced by transcranial single magnetic stimulus (TMS, pre – and postoperatively) and trains of electrical stimuli (TES; intraoperatively in T0-before surgery, T1 – after pedicle screws implantation, T2 – after scoliosis curvature distraction and derotation following two rods implantation) can be compared for diagnostic verification of improvement of the spinal neural transmission. The study also attempted to determine whether the constant level of optimal anesthesia during the certain surgical steps of scoliosis treatment affects the parameters of MEPs recorded during neuromonitoring procedures. No neurological deficits have been observed postoperatively. Values of amplitudes but not latencies in MEPs recordings evoked with TMS in IS patients compared before and after surgery indicated a slight improvement in the efferent transmission of neural impulses within the fibers of the spinal tracts postoperatively. Results of all neurophysiological studies in IS patients were significantly asymmetrical and recorded worse on the concave side, suggesting greater neurological motor deficits at p=0.04. This asymmetry had been significantly reduced following IS surgery. The surgeries in IS patients brought significant improvement (p=0.04) in parameters of amplitudes of sEMG recordings, however reflecting still the consequences of the neurogenic injury of TA muscle motor units. ENG studies results indicated the symptoms of the axonal type injury in peroneal motor fibers improved only on the concave side at p=0.04 in parallel with the significant improvement of F-waves parameters, which suggests that surgeries might result in the lumbar ventral roots decompression. There were not detected significant differences in amplitudes or latencies of MEPs induced with TMS or TES comparing the parameters recorded preoperatively (one day before surgery) and intraoperatively in T0. The amplitudes of TES evoked MEPs increased gradually at p=0.04 in the subsequent periods (T1 and T2) of observation. The significant reduction of MEPs latency at p=0.05 was observed only at the end of the IS surgery. Studies on the possible connections between the level of anesthesia fluctuations and the required TMS stimulus strength, as well as the MEPs amplitude changes measured in T0-T2 revealed lack of relationships. It is not likely that they could be the factors influencing the efferent transmission in spinal pathways beside the surgical procedures. Considering that MEPs amplitude parameter reflects the number of axons excited from the motor cortex and transmitting the efferent impulses via spinal descending tracts in the white matter, pre- (TMS evoked) and intraoperative (TES evoked) recordings are reliable for evaluating the patient’s neurological status before and during surgical scoliosis correction procedures. The results of this study indicate an agreement between preoperative and early-intraoperative evaluations with these both diagnostic methods. An increase of MEPs amplitude parameters recorded on both sides after scoliosis surgery proves immediate improvement of the total efferent spinal cord transmission. Considering comparative pre- and postoperative sEMG and ENG recordings it can be concluded that surgeries might directly result in the additional lumbar ventral roots decompression. Our results of the tests on the possible variability of the anesthesia level on the parameters of intraoperative recorded MEPs show no clear relationships. We can conclude that MEPs parameters changes are determined by the surgery procedures during neuromonitoring, not the anesthesia conditions if they are kept stable, which influences a decrease in the number of false-positive neuromonitoring warnings. Further studies on a larger population of patients with long-lasting observation postoperatively are required to confirm the presented conclusions on the direct influences of scoliosis surgery on improvement of the motor function in patients with IS.

Technological advances in DBS hardware and software represent a significant growth area in functional neurosurgery. These advancements have the potential to significantly enhance treatment outcomes and expand the scope of neurological disorders that can be effectively addressed through DBS interventions. The introduction of directional DBS marks a new phase in neuromodulation, offering extended benefits for patients with Parkinson's disease, more efficient optimization of clinical outcomes, and targeted treatment of refractory symptoms through data-driven approaches. Implementing a multimodal programming strategy, incorporating novel current fractionation technology and image-guided tools for lead localization and brain sensing, further reduces reliance on traditional trial-and-error programming methods, paving the way for a more predictive application of this therapy. These advancements are expected to drive the development of sophisticated closed-loop stimulation systems capable of integrating continuous data streams for improved patient care.

Background: In this investigation, we explored the effects of pharmacological cholinergic stimulation on cardiac function and renal inflammation following acute myocardial infarction (AMI) in spontaneously hypertensive rats (SHRs). Methods: Adult male SHRs were randomized into three experimental groups: sham-operated; AMI+Veh (infarcted, treated with vehicle); and AMI+PY (infarcted, treated with the cholinesterase inhibitor pyridostigmine bromide (PY) - 40 mg/kg, once daily for seven days). Rats were euthanized 7 or 30 days post-surgery. Clinical parameters were assessed on the day before euthanasia. Subsequent to euthanasia, blood samples were collected and renal tissues were harvested for histological and gene expression analyses aimed to evaluate inflammation and injury. Results: Seven days post-surgery, the AMI+PY group demonstrated improvements in left ventricular diastolic function and autonomic regulation, and a reduction in renal macrophage infiltration compared to the AMI+Veh group. Furthermore, there was a notable downregulation of pro-inflammatory gene expression and an upregulation of anti-inflammatory gene expression. Analysis 30 days post-surgery showed that PY treatment had a sustained positive effect on renal gene expression, correlated with a decrease in biomarkers indicative of subclinical kidney injury. Conclusion: Short-term cholinergic stimulation with PY provides both cardiac and renal protection by mitigating the inflammatory response after AMI.

This research presents a novel algorithmic implementation to improve the analysis of visually controlled interception and accompanying motor action through the computational application of harmonic ratios and stimulation invariants. Unlike traditional models that focus mainly on psychological aspects, our approach integrates the relevant constructs into a practical mathematical framework. This allows for dynamic prediction of interception points with improved accuracy and real-time perception-action capabilities, essential for applications in neurorehabilitation and virtual reality. Our methodology uses stimulation invariants as key parameters within a mathematical model to quantitatively predict and improve interception outcomes. The results demonstrate the superior performance of our algorithms over conventional methods, confirming their potential for ad-vancing robotic vision systems and adaptive virtual environments. By translating complex theo-ries of visual perception into algorithmic solutions, this study provides innovative ways to im-prove motion perception and interactive systems. This study aims to articulate the complex inter-play of geometry, perception, and technology in understanding and utilizing cross-ratios at infin-ity, emphasizing their practical applications in virtual and augmented reality settings.

A chronically stable electrode material with low impedance for recording neural activity and high charge-injection capacity for functional electro-stimulation is desirable for the fabrication of implantable microelectrode arrays that aims to restore impaired or lost neurological functions in humans. For this purpose, we have investigated the electrochemical properties of sputtered ruthenium oxide (RuOx) electrode coatings, deposited on planar microelectrode arrays, using an inorganic model of interstitial fluid (model-ISF) at 37o C as the electrolyte. Through a combination of cyclic voltammetry (CV) and electrochemical impedance spectroscopy (EIS) modelling study we have established the contribution of faradaic reaction as the major charge-injection contributor within the safe neural stimulation potential window of 0.6 V vs Ag|AgCl. We have also established the reversibility of the charge-injection process for sputtered RuOx film by applying constant charge-per-phase current stimulations at different pulse widths and by comparing the magnitudes of leading and trailing access voltages during voltage transient measurements. Finally, the impedance of the sputtered RuOx film was found to be reasonably comparable in both its oxidized and reduced states, although electronic contribution from capacitive double-layer was found to be slightly higher for the completely oxidized film around 0.6 V than its reduced counterpart around -0.6V.

Transcutaneous nerve stimulation has several neuromodulatory applications, including pain management, sensory restoration, and motor recovery. Transcutaneous stimulation delivered via electrode arrays offers ease of use and reconfigurability through non-invasive means. Also, employing electrode arrays allows regulation of the permeated electric fields for greater control over the stimulation performance. Field shaping involves the regulation of permeated electric fields and is a well-established practice for deep brain stimulation; however, its applicability to peripheral nerve stimulation still needs exploration. Adopting such techniques can help to overcome current limitations with transcutaneous stimulation, like poor targetability, early onset of fatigue, and perceived discomfort. This article provides a perspective on the applicability of field-shaping techniques in improving the overall stimulation outcome.

Emotional experiences are a part of our lives. The maladaptive functioning of an individual's emotional field can lead to emotional disturbances of various kinds, such as anxiety and depression. Currently, there is an increasing prevalence of emotional disorders that cause great human suffering and high socio-economic costs. Emotional processing has a biological basis. The major neuroscientific theories of emotion are based on biological functioning, and all of them take into account the anatomy and function of the tenth cranial nerve: the vagus nerve. The vagus nerve connects the subdiaphragmatic and supradiaphragmatic areas and modulates emotional processing as the basis of interoceptive functioning. Auricular vagus nerve stimulation is a new and innovative neuromodulation technique based on the function of the vagus nerve. Several interventions have shown that this new neurostimulation technique is a very promising resource for treating emotional disorders. In this paper, we summarise three neuroscientific theories of emotion, explain what transauricular vagus nerve stimulation is, and present arguments for its use and continued research.

Norepinephrine plays an important role in modulating memory consolidation and evocation through its beta-adrenergic receptors (Adrβ: β1, β2 and β3), which are expressed in the hippocampus (HC) and amygdala (AMY). Here we hypothesized that multisensory stimulation would reverse the memory impairment caused by the inactivation of the Adrβ3 with consequent inhibition of sustained glial-mediated inflammation and glutamatergic depuration. To test this, 21- and 86-day-old Adrβ3KO mice and respective controls underwent to (i) gustative and olfactive stimuli of positive and negative valence associated with (ii) intellectual challenges to reach the food in addition to (iii) objects in hidden places (iv) foraging for 8 weeks followed by (v) analysis of GFAP, Iba-1 and EAAT2 protein expression in the HC and AMY. While this protocol restored the memory impairment when applied to Adrβ3KO animals immediately after weaning, it had no effect when applied to adult animals. In fact, we observed that aging worsens the memory of Adrβ3KO mice. Although no significant expression of GFAP and Iba1 were observed in HC of young and old mice, Adrβ3KO increased EAAT2 expression HC of old mice, while MS didn’t change EAAT2 in young mice but enhanced it expression in older. Relative to AMY of old mice Adrβ3KO increased GFAP expression compared whit WT mice and MS sustained the GFAP expression and increased the EAAT2 expression compared with WT group. These results suggest that a richer and more diverse environment helps to correct memory impairment when applied right after weaning Adrβ3KO animals, also show that the changes in GFAP, Iba1 and EAAT2 expression levels in young and old mice indicate a functional significance in the process of learning and memory and that the control of neuroinflammation in limbic areas mediates this response. They also reinforce the idea that disruption of noradrenergic signaling could be involved in the cognitive impairment observed later in life.

Cannabis is the most widely cultivated, trafficked and abused illicit drug (“WHO | Cannabis,” n.d.; “World Drug Report 2020,” n.d.). In 2018, an estimated 192 million people aged 15-64 years used cannabis for nonmedical purposes globally (Degenhardt et al., 2013). The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2016 estimated that, across the globe, there were more than 22·1 million people with cannabis dependence (Degenhardt et al., 2018). Moreover, the same study calculated that cannabis dependence could be accounted for 646 thousand Disability Adjusted Life Years, globally. Importantly, cannabis dependence mostly affects young adults (20-24 years), and thus has significant negative impact on the growth and productivity of not only these individuals but also to the societies and nations (Degenhardt et al., 2013). In addition to the dependence syndrome, cannabis use is associated with increased risk of psychosis, cognitive dysfunction, academic problems, and road side accidents (Volkow et al., 2014). A review showed a fairly consistent associations between cannabis use and both lower educational attainment and increased reported use of other illicit drugs (Macleod et al., 2004). In the United States, Cannabis Use Disorder (CUD) is an escalating problem in young adults by legalization (Cerdá et al., 2020) where National Survey on Drug Use and Health reported increased prevalence from 5.1% in 2015 to 5.9% in 2018 in 18-25 year olds (“2019 NSDUH Detailed Tables | CBHSQ Data,” n.d.). The psychoactive effects are due to type 1 cannabinoid receptor (CB1), the cannabinoid binding protein, that are highly expressed in the cerebellar cortex (Marcaggi, 2015). CB1 is primarily found in the molecular layer at the most abundant synapse type in the cerebellum (Marcaggi, 2015) that can shape the spike activity of cerebellar Purkinje cell (Brown et al., 2019). Moreover, granule cell to Purkinje cell synaptic transmission can trigger endocannabinoid release (Alger and Kim, 2011), which may be important for information processing by cerebellar molecular layer interneurons (Dorgans et al., 2019). This suggests that endocannabinoids could be essential to neurocognitive aspects of cerebellar function (Di Marzo et al., 2015)^,(Marcaggi, 2015)^,(Alger and Kim, 2011). Accumulating evidence also suggests cerebellar modulation of the reward circuitry and social behaviour, via direct cerebellar innervation of the ventral tegmental area (VTA) including dopamine cell bodies (A1) in the VTA (Carta et al., 2019). The VTA-dopamine (DA) signalling in the nucleus accumbens (NAc) and the medial prefrontal cortex (mPFC) (Lohani et al., 2019) play a key role in motivatedbehaviours and cognition. Cerebellar neuropathological changes can result in aberrant dopaminergic activity in the NAc and mPFC (ROGERS et al., 2011)^,(Lohani et al., 2019). Therefore, there is a critical need to determine how cerebellum modulate limbic VTA-DA signalling. Cerebellar Non-Invasive Brain Stimulation (NIBS) is postulated to be most relevant in CUD since endocannabinoids are essential to cerebellar function that includes reward-related behaviours, information processing, and cognitive control. (Di Marzo et al., 2015)^,(Marcaggi, 2015)^,(Alger and Kim, 2011). Furthermore, cerebellar NIBS can facilitate training of cognitive control in CUD during a during visual cue reactivity paradigm using a mobile virtual reality (VR) interface that can also allow remote delivery of cerebellar NIBS in conjunction with VR-based cognitive training for home-based intervention. Specifically, transcranial electrical stimulation (tES) can be translatable to low-cost (<$150) mobile devices that can be used in a low resource home-based setting (Carvalho et al., 2018).

Tardive dyskinesia (TD) is a phenomenon predominantly observed as a result of the long-term use of dopamine receptor blockers (antipsychotics). TD is a group of involuntary, irregular hyperkinetic movements, mainly in the muscles of the face, eyelid muscles, lips, tongue, and cheeks, and less frequently in the limbs, neck, pelvis, and trunk. In some patients, TD takes on an extremely severe form, massively disrupting functioning, moreover, causing stigmatization and suffering. Deep brain stimulation (DBS), a method used, among others, in Parkinson's disease, is also an effective treatment for TD and often becomes a method of last resort, especially in severe, drug-resistant forms. The procedure is relatively new in TD, so the available reliable clinical studies are few and consist mainly of case reports. Unilateral and bilateral stimulation of two sites has proven efficacy in TD treatment. Most authors describe stimulation of the globus pallidus internus (GPi); less frequent descriptions involve the hypothalamic nucleus (STN). In the present paper, we provide up-to-date information on the stimulation of both mentioned brain areas. We also compare the efficacy of the two methods by comparing the two available studies, which included the largest groups of patients. Although GPi stimulation is more frequently used clinically, our initial analysis indicates comparable results (reduction of involuntary movements) with STN DBS.

Covalent DNA protein crosslinks (DPCs) are common lesions that block replication. We examine here the consequence of DPCs on mutagenesis involving replicational template-switch reactions in Escherichia coli. 5-azacytidine (5azaC) is a potent mutagen for template-switching, dependent on DNA cytosine methylase (Dcm), implicating the trapped Dcm-DNA covalent complex as the initiator for mutagenesis. The leading strand of replication is more mutable than the lagging strand, explained by blocks to the replicative helicase and/or fork regression. We find that template-switch mutagenesis induced by 5-azaC does not require DSB repair via RecABCD. The ability to induce the SOS response is anti-mutagenic by an unknown mechanism. Mutants in recB, but not recA, exhibit high constitutive rates of template-switching and we suggest that RecBCD-mediated DNA degradation prevents template-switching associated with fork regression. A mutation in the DnaB fork helicase also promotes high levels of template-switching. We also find that other DPC-inducers, formaldehyde (a non-specific crosslinker) and ciprofloxacin (a topoisomerase II poison) are also strong mutagens for template-switching. Induction of mutations and genetic rearrangements that occur by template-switching may constitute a previously unrecognized component of the genotoxicity and genetic instability promoted by DPCs.

We use Matlab 3D finite element fluid flow/transport modelling to simulate localized wellbore temperature events of order 0.05-0.1oC logged in Fennoscandia basement rock at ~ 1.5km depths. The temperature events are approximated as steady-state heat transport due to fluid draining from the crust into the wellbore via naturally occurring fracture-connectivity structures. Flow simulation is based on the empirics of spatially-correlated fracture-connectivity fluid flow widely attested by well-log, well-core, and well-production data. Matching model wellbore-centric radial temperature profiles to a 2D analytic expression for steady-state radial heat transport with Peclet number Pe ≡ r0φv0/D (r0 = wellbore radius, v0 = Darcy velocity at r0, φ = ambient porosity, D = rock-water thermal diffusivity), gives Pe ~ 10-15 for fracture-connectivity flow intersecting the well, and Pe ~ 0 for ambient crust. Darcy flow for model Pe ~ 10 at radius ~ 10 meters from the wellbore gives permeability estimate κ ~ 0.02Darcy for flow driven by differential fluid pressure between least principal crustal stress pore pressure and hydrostatic wellbore pressure. Model temperature event flow permeability κm ~ 0.02Darcy is related to well-core ambient permeability κ ~ 1µDarcy by empirical poroperm relation κm ~ κ exp(αmφ) for φ ~ 0.01 and αm ~ 1000. Our modelling of wellbore temperature events calibrates the concept of reactivating fossilized fracture-connectivity flow for EGS permeability stimulation of basement rock.

Background/Objectives: The aim of this study was to investigate feasibility and safety of neuromuscular electrical stimulation (NMES) in patients on extracorporeal membrane oxygenation (ECMO) and assess thoroughly any potential adverse events. Methods: We conducted a safety and feasibility study including 16 ICU patients on ECMO support who were admitted to the cardiac surgery ICU from January 2022 to December 2023. Patients underwent a 45-minute NMES session, still on ECMO support, that included a warm up phase of 5 minutes, a main phase of 35 minutes and a recovery phase of 5 minutes. NMES was implemented on vastus lateralis, vastus medialis, gastrocnemius and peroneus longus muscle of both lower extremities. Two stimulators delivered biphasic, symmetric impulses of 75 Hz, with 400 μsec pulse duration, 5 sec on (1,6 sec ramp up and 0,8 sec ramp down) and 21 sec off. The intensity levels aimed to cause visible contractions and be well tolerated. Primary outcomes of the study were feasibility and safety, evaluated by whether the NMES sessions were successfully achieved, and by any adverse events and complications. Secondary outcomes included indices of rhabdomyolysis from biochemical blood test, 24 hours after the application of NMES. Results: All patients successfully completed their 45-minute NMES session, without presenting hemodynamic deterioration, adverse events or signs of rhabdomyolysis. The majority of patients achieved type 4 and 5 quality of muscle contraction. Conclusions: NMES is a safe and feasible exercise methodology in patients supported with ECMO.

Background: The antimalarial drug chloroquine and antimicrobial drug azithromycin have received significant attention during the current COVID-19 pandemic. Both drugs can alter cardiac electrophysiology and have been associated with drug-induced arrhythmias. Meanwhile, sympathetic activation is commonly observed during systemic inflammation and oxidative stress (e.g., in SARS-CoV-2 infection), and may influence the electrophysiological effects of chloroquine and azithromycin. Here, we investigated the effect of beta-adrenergic stimulation on proarrhythmic properties of chloroquine and azithromycin using a detailed in silico model of ventricular electrophysiology. Methods: Concentration-dependent chloroquine and azithromycin-induced alterations in ion-channel function were incorporated into the Heijman canine ventricular cardiomyocyte model. Single and combined drug effects on action-potential (AP) properties were analyzed using a population of 592 models accommodating inter-individual variability. Sympathetic stimulation was simulated by an increase in pacing rate and experimentally validated isoproterenol-induced changes in ion-channel function. Results: At 1 Hz pacing, therapeutic doses of chloroquine and azithromycin (5 and 20 µM, respectively) individually prolonged AP duration (APD) by 33% and 13%. Their combination produced synergistic APD prolongation (+161%) with incidence of proarrhythmic early afterdepolarizations in 53.5% of models. Increasing the pacing frequency to 2 Hz shortened APD and together with 1 µM isoproterenol corrected the drug-induced APD prolongation. No afterdepolarizations occurred following increased rate and simulated application of 0.1-1 µM isoproterenol. Conclusion: Sympathetic stimulation limits chloroquine- and azithromycin-induced proarrhythmia by reducing their APD-prolonging effect, suggesting the importance of heart rate and autonomic status monitoring in particular conditions (e.g., COVID-19).

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) has become an effective and widely used tool in the treatment of Parkinson’s disease (PD). STN-DBS has varied effects on speech. Clinical speech ratings suggest worsening following STN-DBS, but quantitative intelligibility, perceptual, and acoustic studies have produced mixed and inconsistent results. Improvements in phonation and declines in articulation have frequently been reported during different speech tasks under different stimulation conditions. Questions remain about preferred STN-DBS stimulation settings. Seven right-handed, native speakers of English with PD treated with bilateral STN-DBS were studied off medication at three stimulation conditions: stimulators off, 60 Hz (low frequency stimulation - LFS), and the typical clinical setting of 185 Hz (High frequency - HFS). Spontaneous speech was recorded in each condition and excerpts were prepared for transcription (intelligibility) and difficulty judgements. Separate excerpts were prepared for listeners to rate abnormalities in voice, articulation, fluency, and rate. Intelligibility for spontaneous speech was reduced at both HFS and LFS when compared to STN-DBS off. Speech produced at HFS was more intelligible than that produced at LFS, but HFS made the intelligibility task (transcription) subjectively more difficult. Both voice quality and articulation were judged to be more abnormal with STN-DBS on. STN-DBS reduced the intelligibility of spontaneous speech at both LFS and HFS but lowering the frequency did not improve intelligibility. Voice quality ratings with STN-DBS were correlated with the ratings made without stimulation. This was not true for articulation ratings. STN-DBS exacerbated an existing voice disorder and may have introduced new articulatory abnormalities.

Background: Cervical myelopathy (CM) is a common cause of morbidity and disability in patients with mucopolysaccharidosis (MPS) and, therefore, early detection is crucial for best surgical intervention and follow-up. Transcranial Magnetic Stimulation (TMS) non-invasively evaluates the conductivity along the cortico-spinal tract, also allowing preclinical diagnosis and monitoring. Methods: motor evoked potentials (MEPs) to TMS were recorded in a group of 8 patients with MPS-related CM. Responses were obtained during mild tonic contraction through a circular coil applied over the “hot spot” of the first dorsal interosseous and tibialis anterior muscles, bilaterally. Central motor conduction time was estimated as the difference between MEP cortical latency and the peripheral motor conduction time by cervical or lumbar magnetic stimulation. Peak-to-peak MEP amplitude to cortical stimulation and right-to-left difference of each parameter were also measured. Results: TMS revealed abnormal findings from both upper and lower limbs compatible with axonal damage and demyelination in 6 of them. Notably, a subclinical cervical spinal disease was detected before the occurrence of an overt CM in two patients, whereas TMS signs compatible with a CM of variable degree persisted despite surgery in all treated subjects. Conclusions: TMS screening should be performed in MPS patients, before and after surgery.

This study aims to precisely characterize the use of magnetoelectric nanoparticles (MENPs) for stimulating peripheral nerves. Numerical methods were employed to quantify the interaction between MENPs and nervous tissue. The influence of MENPs orientation, concentration and distance was assessed in terms of the external potential distribution exerted by the MENPs, the amplification of the exerted MENPs stimulation required to excite the neural fibers and the current injected into the intracellular space. The results highlight the significance of MENPs concentration for stimulation accuracy and efficiency, the impact of MENPs orientation on the electric potential distribution sensed by the nervous tissue, as well as the importance of the MENPs distance over the fibers’ recruitment. Given the considerable variability in the interaction between MENPs and nerves, our research provides a crucial step towards understanding this interaction, offering quantitative support for the application of MENPs in nervous tissue stimulation.

Neuropathic pain is caused by a lesion or disease of the somatosensory system and is one of the most incapacitating pain types, representing a significant non met medical need. Due to the increase in research in the field and since innovative therapeutic strategies are required, namely in intractable neuropathic pain, neurostimulation has been used. Within this approaches, transcranial magnetic stimulation (TMS) that uses a transient magnetic field to produce electrical currents over the cortex emerges in the literature. Since this is an area in expansion and due to the putative role of TMS, we performed a bibliometric analysis in Scopus with the primary objective of identify the scientific production related to the use of TMS to manage neuropathic pain. The research had no restrictions and the analysis focused on the characteristics of the literature retrieved, scientific collaboration and main research topics from inception to July 6, 2023. A total of 474 articles were collected. A biggest co-occurrence between the terms “neuropathic pain” and “transcranial magnetic stimulation” was obtained. The journal “Clinical Neurophysiology” leads the Top 5 most productive sources. The United States is the most productive country with 50% of the documents being “review articles” followed by France with 56% of the documents being “original articles”. Lefaucheur, JP and Saitoh, Y are the two most influents authors. The most frequent type of documents was “original article”. This study allows to perform a general overview in the field of TMS application for neuropathic pain and is useful to establish future directions of research in this field.

Transcutaneous electrical stimulation of the spinal cord is used to restore locomotion and body weight support in patients with severe motor disorders. We studied effects of this non-invasive stimulation on postural control in healthy subjects. Stimulation at the L1-L2 vertebrae was performed to activate the extensor muscles of the lower limbs. Because postural regulation depends on the cognitive style, the effects of the stimulation were analyzed separately in field-dependent (FD) and field-independent (FI) participants. During the study young adults (N=16, half FD and half FI participants, all right dominant leg) stood on a force platform in a soundproof chamber with their eyes closed. Stimulation was applied in the midline between the L1-L2 vertebrae or over the left or right dorsal roots of the spinal cord; under control condition there was no stimulation. Stimulation destabilized posture in healthy subjects, whereas patients with movement disorders usually showed an improvement in postural control. In FD participants, left dorsal root and midline stimulation increased several postural parameters by up to 30%. Dorsal root stimulation on the side of the supporting leg reduced postural control, while stimulation on the side of the dominant leg did not. No significant changes were observed in the FI participants.

Heating has been recently used as an alternative application to electrical stimulation to modulate excitability and to induce neuritogenesis and the expression of neuronal markers, but a long-term functional differentiation has not been described so far. Here we present the results obtained by a new approach for scalable thermal stimulation on the behavior of a model of dorsal root ganglion neurons, the F-11 cell line. Initially, we performed experiments of bulk stimulation in incubator for different time intervals and temperatures, and significant differences in neurite elongation and in electrophysiological properties were observed in cultures exposed at 41,5°C for 30 minutes. Thus, we exposed the cultures to the same temperature increase by irradiating, with a near infrared laser, a disc of Prussian Blue nanoparticles and poly-vinyl alcohol, that we stuck on the outer surface of the petri dish. In irradiated cells neurites were significantly longer and the electrophysiological properties (action potential firing frequency and spontaneous activity) were significantly increased compared to the control. These results suggest that a targeted thermal stimulation could be a promising technique to induce differentiation and support the future application of this method as a strategy to modify neuronal behavior in vivo.

Aim: In a human pilot case, we used a root formed temporary prosthetical device (Intra-alveolar Device - IAD), to investigate the effect of mechanical stimulation on hard tissue clinically and radiographically. Background: The extraction of a tooth determines the resorption of the alveolar bone. This determines challenge to place an implant and to integrate the prosthesis in soft tissue. Mechanical stimulation is fundamental for bone tropism but is not understood the effect of mechanical stimulation on post-extraction site. Case presentation: A 24 years old woman was enrolled. The IAD’s were used as expected by protocol. Clinical healing was uneventfully. Vertical radiographical bone resorption measured on CBCT was -0,14mm (5,6%) while horizontal bone resorption was -0,21mm (12,36%). Conclusion: This study demonstrated the feasibility of the proposed model. We need clinical prospectical studies enrolling more patients

Due to its time effective, joint friendly and highly customizable character whole-body-electromyostimulation (WB-EMS) is regarded as a feasible solution for a large variety of training issues particularly in the area of non-athletic application. To identify gaps in research and summarize prevalent evidence we conducted an evidence map on outcomes addressed by WB-EMS trials in middle-aged to older, non-athletic adults. Based on a comprehensive systematic search in five databases and two study registers according to PRISMA, 54 projects published in 80 articles were included. More than 90% of the studies reported outcomes related to the physical fitness or function domain. Body composition parameters were addressed by two thirds of the projects. Health-related outcomes addressed by WB-EMS included cancer/neoplasm (n=7), endocrine regulation (n=8), glucose metabolism (15), nervous system diseases (n=2), cardiovascular system diseases (n=22), non-specific chronic low back pain (n=4), osteopenia (n=5) and diseases of the renal system (n=12). Outcomes related to inflammation were addressed 18 times. Of importance, no studies reported clinically relevant adverse effects related to the WB-EMS intervention. In summary, while considerable evidence on outcomes related to fitness/function and body composition is prevalent, evidence gaps of WB-EMS research were particular evident for diseases of the nervous and cerebrovascular system.

Pain is a multifaceted multisystem disorder that adversely affects neuro-psychological processes. This study compares the effectiveness of central-stimulation (tDCS) and peripheral-stimulation (TENS) in pain-inhibition during a cognitive-task in healthy volunteers and to observe potential neuro-cognitive improvements. Healthy eighty volunteers went through a complete experimental protocol comprising pain-induction (CPT), administration of tDCS/TENS, EEG-data acquisition, and cognitive assessments. The protocol for this study is categorized into 04-groups: G1(Control), G2(TENS), G3(Anodal-tDCS), and G4(Cathodal-tDCS). Paired t-tests (p

In the tissue regeneration field, stem cell transplantation and the control of their differentiation represent a promising therapeutic strategy. The second aspect can be achieved using electrical stimulation. This study aims to characterize the effect of a microsecond electrical stimulation on MSCs and iNSCs, in the context of the RISEUP FET-OPEN project (n. 964562) that seeks to control these cells differentiation for the spinal cord injury treatments. Here, the effect of a specific microsecond electric pulses stimulation, characterized by bipolar pulses of 100 µs + 100 µs, delivered for 30 minutes at an intensity of 250 V/cm, on i) cell proliferation, ii) cell cycle, iii) gene expression and iv) apoptosis was evaluated. Results show that the stimulation does not affect cell proliferation, cell cycle, and apoptosis, but induced some variations in gene expression, in particular in EGR1, FOS, and POU5F1. These ob-servations led us to deeply investigate the cell proliferation until 72h from the stimulation observing an increase in the iNSCs. The main outcome of this study is that the chosen stimulation protocol is safe and not toxic for MSCs and iNSCs. The observed variations in the gene expression need to be deeply investigated to assess the molecular mechanisms involved.

Prevention of obstetric trauma from damage to the pelvic floor is not always possible and sacral nerve stimulation (SNS) may be necessary later in life. Sacral nerve stimulation has been a promising innovation in the management of moderate to severe faecal incontinence and following sphincter repair failure. Although the indication spectrum for SNS is expanding, the success of neuromodulation for constipation is limited. Adverse events of SNS requiring re-intervention are not common but a long-term successful outcome may depend on interventions for maintenance of the device.

Background: In Transcranial Direct Current Stimulation (tDCS) the injected current gets distributed across the brain areas. The motive is to stimulate the target region-of-interest (ROI), while minimizing the current in non-target ROIs. For this purpose, determining the appropriate current-dose for an individual is difficult. Aim: To introduce Dose-Target-Determination-Index (DTDI) to quantify the focality of tDCS and examine the dose-focality relationship in three different populations. Method: Here, we extended our previous toolbox i-SATA to the MNI reference space. After a tDCS montage is simulated for a current-dose, the i-SATA(MNI) computes the average (over voxels) current density for every region in the brain. DTDI is the ratio of average current density at target ROI to the ROI with maximum value (peak region). Ideally target ROI should be the peak region, so DTDI shall range from 0 to 1. Higher the value, the better the dose. We estimated the variation of DTDI within and across individuals using T1-weighted brain images of 45 males and females distributed equally across three age groups- (a) Young adults (20 ≥ x ˂ 40 years), (b) Mid adults (40 ≥ x ˂ 60 years), and (c) Older adults (60 ≥ x ˂ 80 years). DTDI’s were evaluated for the frontal montage with electrodes at F3 and right supra-orbital for three current doses 1mA, 2mA, and 3mA with the target ROI at left middle frontal gyrus. Result: As the dose is incremented, DTDI may show (a) increase, (b) decrease, and (c) no change across the individuals. The focality decreases with age and the decline is stronger in males. Higher current dose at older age can enhance the focality of stimulation. Conclusion: DTDI provides information on which tDCS current dose will optimize the focality of stimulation. DTDI recommended dose should be prioritised based on the age (> 40 years) and sex (especially males) of an individual. The toolbox i-SATA(MNI) is freely available.

Brain-stimulation reward, also known as intracranial self-stimulation (ICSS), is a commonly used procedure for studying brain reward function and drug reward. In electrical ICSS, an electrode is surgically implanted into the medial forebrain bundle in the lateral hypothalamus or the ventral tegmental area in the midbrain. Operant lever responding leads to the delivery of electrical pulse stimulation. The alteration in the stimulation frequency-lever response curve is used to evaluate the impact of pharmacological agents on brain reward function. If a test drug induces a leftward or upward shift in the ICSS response curve, it implies a reward-enhancing or abuse-like effect. Conversely, if a drug causes a rightward or downward shift in the functional response curve, it suggests a reward-attenuating or aversive effect. A significant drawback of electrical ICSS is the lack of cellular selectivity in understanding the neural substrates underlying drug reward versus aversion. Excitingly, recent advancements in optical ICSS (oICSS) have facilitated the development of at least three cell type-specific oICSS models – dopamine-, glutamate-, and GABA-dependent oICSS. In these new models, a comparable frequency-rate response curve has been established and employed to study the substrate-specific mechanisms underlying brain reward function and a drug's rewarding versus aversive effects. In this review article, we summarize recent progress in this exciting research area. The findings in these new behavioral models have not only increased our understanding of the neural mechanisms underlying drug reward and addiction but have also introduced a novel experimental approach in preclinical medication development for treating substance use disorders.

Emotions play a vital role in understanding human behavior and interpersonal relationships. The ability to recognize emotions through Electroencephalogram (EEG) signals offers an alternative to traditional methods, such as questionnaires, enabling the identification of emotional states in a non-intrusive manner. Automatic emotion recognition holds great potential, eliminating the need for clinical examinations or physical visits, thereby contributing significantly to the advancement of Brain-Computer Interface (BCI) technology. However, one of the key challenges lies in effectively selecting and extracting relevant features from the EEG signal to establish meaningful distinctions between different emotional states. The process of feature selection is often time-consuming and demanding. In this research, we propose a groundbreaking approach for automatically identifying three emotional states (positive, negative, and neutral) by leveraging auditory stimulation of EEG signals. Our novel method directly applies the raw EEG signal to a Convolutional Neural Network-Long Short Term Memory (CNN-LSTM) architecture, bypassing the conventional feature extraction and selection steps. This unconventional approach offers a significant departure from existing literature. Our proposed network architecture comprises ten convolutional layers, followed by three LSTM layers and two fully connected layers. Through extensive simulations and evaluations on 12 active channels, our algorithm demonstrates exceptional performance, achieving an accuracy of 97.42\% and 95.23\% for the binary classification of negative and positive emotions, as well as a Cohen's Kappa coefficient of 0.96 and 0.93 for the three-class classification (negative, neutral, and positive), respectively. These promising results highlight the efficacy of our novel methodology and its potential implications in advancing emotion recognition using EEG signals.

Deep-Brain Stimulation (DBS) is a a highly effective and safe medical treatment that improves the lives of patients with a wide range of neurological and psychiatric deceases, and has been consolidated as a first-line tool in the treatment of these conditionsin the last two decades. Closed Loop Deep-Brain Stimulation (CLDBS) pushes this tool further by automatically adjusting the stimulation parameters to the brain response in real time. In this context, this paper presents a Low-Noise Amplifier (LNA) and a Neurostimulator circuits fabricated in the low-power/low-voltage 65 nm CMOS process from the TSMC, which were designed targeting implantable applications. To achieve the best trade-off between input-referred noise and power consuption, metaheuristic algorithms were employed to determine and optimizes the dimentions of the LNA devices during the design phase. The measurement results showed that the LNA had a gain of 40.6 dB, a 3 dB bandwidth spanning over three decades from 10 Hz to 8.6 kHz, and a power consumption of 6.19 uW. Simulations results indicated an input-referred noise of 4.86 uVrms for the LNA. The circuit of the Neurostimulator is a programmable Howland Current-Pump, whose measurements showed its ability to generate currents with arbitrary shapes ranging from between 325 uA to +318 uA. The simulations showed a quiescent power consumption of 0.13 W with a zero neurostimulation current. The LNA and the Neurostimulator circuits are supplied with 1.2 V voltage and occupy a microdevice area of 145 um x 311 um and 88 um x 89 um, respectively, making them suitable for implantation in applications involving Closed Loop Deep-Brain Stimulation.

ADHD, a neurodevelopmental condition, is distinguished by a triad of symptoms including inattention, hyperactivity, and impulsivity. It is frequently accompanied by comorbidities such as anxiety, depression, and learning disabilities. As a result, clinicians often face challenges in accurately diagnosing ADHD and differentiating it from other conditions. As a prospective remedy for ADHD, scientists have investigated Transcranial Direct Current Stimulation (tDCS), a non-invasive technique of stimulating the brain. It involves applying low-intensity electrical currents to specific regions of the brain to modulate neural activity. This review paper aims to provide an overview of the comorbidities associated with ADHD and the differential diagnosis of the condition. It also explores the potential of tDCS as a treatment option for ADHD, including its mechanisms of action and efficacy in improving ADHD symptoms. The comorbidities discussed in this review include anxiety disorders, mood disorders, and substance use disorders. These comorbidities are frequently seen in individuals with ADHD and can complicate the diagnosis and treatment of the condition. The paper also highlights the importance of considering comorbidities when assessing ADHD, as well as the potential impact of these conditions on treatment outcomes. The differential diagnosis section of the paper explores conditions that can present with symptoms similar to ADHD, such as anxiety disorders, mood disorders, and learning disabilities. It emphasizes the need for a thorough assessment and differential diagnosis to identify ADHD and differentiate it from other conditions accurately. The final section of the paper discusses the potential of tDCS as a treatment option for ADHD. It examines the mechanisms of action of tDCS and its efficacy in improving ADHD symptoms, including attention, hyperactivity, and impulsivity. It also explores the potential for tDCS to improve comorbid conditions associated with ADHD. Overall, this review provides a comprehensive overview of comorbidities and differential diagnoses in ADHD and the potential of tDCS as a treatment option. The paper highlights the importance of a thorough assessment and personalized treatment plan for individuals with ADHD, particularly those with comorbidities.

Background: Transcranial direct current stimulation (tDCS) is a neuromodulatory technique that delivers low levels of a constant current via scalp electrodes to specifically targeted areas of the brain. The effects of tDCS on whole-body exercise performance has been of interest in recent literature. The purpose of the current investigation was to investigate if tDCS, administered via Halo Sport, influences time trial performance in trained cyclists, and if changes in exercise performance are associated with prefrontal cortex (PFC) activation and/or muscle oxygenation (SmO2). Methods: Twelve recreationally trained cyclists volunteered to participate in two 10-kilometer time trials following 20 minutes of tDCS or a sham condition. Results: T-tests showed there was no significant difference in performance (time to completion) or physiological measures (BLa-, HR, SmO2, PFC oxygenation) between the Halo and sham conditions. Conclusions: These results indicate that the application of tDCS via Halo Sport does not induce changes in exercise performance or related physiological parameters during a 10-kilometer cycling time trial.

Background: Neuromuscular electrical stimulation (NMES) has beneficial effects on physical functions in Multiple Sclerosis (MS) patients. However, the neurophysiological mechanisms underlying these functional improvements are still unclear. This study aims at comparing acute responses in spinal excitability, as measured by soleus Hoffmann reflex (H-reflex), between MS patients and healthy individuals, following three experimental conditions involving the ankle planta flexor muscles: 1) passive NMES (pNMES); 2) NMES superimposed to isometric voluntary contraction (NMES+); and 3) isometric voluntary contraction (ISO). Methods: 20 MS patients (MSp) and 20 healthy individuals as control group (CG) took part in a single experimental session. During each condition, participants performed 15 repetitions of 6 seconds at 20% of maximal voluntary isometric contraction, with 6 seconds of recovery between repetitions. Before and after each condition, H-reflex amplitudes were recorded. Results: In MSp, H-reflex amplitude did not change following any experimental condition (ISO: p = 0.506; pNMES: p = 0.068; NMES+: p = 0.126). In CG, H-reflex amplitude significantly increased following NMES+ (p = 0.01), decreased after pNMES (p = 0.000) and was unaltered following ISO (p = 0.829). Conclusion: the different H-reflex responses between MS and CG might reflect a reduced ability of MS patients in modulating spinal excitability.

Although cardiac resynchronization therapy (CRT) reduces morbidity and mortality and reverses left ventricular (LV) remodeling in heart failure patients with LV electrical dyssynchrony, induced proarrhythmia has been reported. The mechanism of CRT-induced proarrhythmia remains under debate. In this case report, a description of how a LV pacing induced polymorphic ventricular tachycardia immediately after the initiation of CRT has been reported. Changing the pacing configuration using a multipoint pacing stimulation, we can assume that VTs induced are related to the reentry mechanism facilitated by the unidirectional block. As a result, MPP pacing configuration near the scar area avoid the onset of a unidirectional block with the establishment of the reentry phenomenon thus avoiding induced VTs.

As a stimulus signal, coded electrical signals can control the motion behavior of animals, which has been widely used in the field of animal robots. In current research, most of the stimulus signals used by researchers are traditional waveform, such as square waves. To enrich the stimulus waveform, a wireless animal robot stimulation system based on neuronal electrical signal characteristics is presented in this paper. The stimulator uses the CC1101 wireless module to control animal behavior through brain stimulation. The LabVIEW-based graphical user interface(GUI) can manipulate brain stimulation remotely while the stimulator powered by battery. Additionally, the spikes of animals have been simulated by this system through Direct Digital Synthesizer(DDS) algorithm. The GUI enable users to customize the combination of these analog spike signals. The recombined signals are sent to the stimulator through CC1101 as stimulus signals. In vivo experiments conducted on five pigeons verified the efficacy of the stimulation mechanism. The analog spike signal with an amplitude of 3-5V successfully caused the pigeon’s turning behavior. The feasibility of the analog spike signals as stimulus signals was successfully verified. Increased the diversity of stimulus waveform in the field of animal robots.

Deep brain stimulation (DBS) is an effective and safe medical treatment that improves the lives of patients with a wide range of neurological and psychiatric diseases, and has been consolidated as a first-line tool in the last two decades. Closed loop deep brain stimulation (CLDBS) pushes this tool further by automatically adjusting the stimulation parameters to the brain response in real-time. This paper presents a CLDBS with 2 stimulation channels and 2 acquisition channels. Each channel has a low-noise amplifier (LNA) buffer in differential configuration to eliminate the DC signal component of the input. Energy management is efficiently done by the control and communication unit. The battery supports almost 9 hours with both the acquisition and stimulation circuits active. If only the stimulation circuit is used as an Open Loop DBS (OLDBS), the battery can hold sufficient voltage for 24 hours of operation. The whole system is low-cost and portable and therefore it could be used as a wearable.

There is currently an interest in “active” implantable biomedical devices that include mechanical stimulation as an integral part of their design. This paper reports the experimental use of a porous scaffold made of interconnected networks of slender ferromagnetic fibres that can be actuated in vivo by an external magnetic field applying strains to in-growing cells. Such scaffolds have been previously characterized in terms of their mechanical and cellular responses. In this study, it is shown that the shape changes induced in the scaffolds can be used to promote osteogenesis in vitro. In particular, immunofluorescence, gene and protein analyses reveal that the actuated networks exhibit higher mineralization and extracellular matrix production, and express higher levels of osteocalcin, alkaline phosphatase, collagen type 1a1, runt-related transcription factor 2 and bone morphogenetic protein 2 than the static controls at the 3-week time point. The results suggest that the cells filling the inter-fibre spaces are able to sense and react to the magneto-mechanically induced strains facilitating osteogenic differentiation and maturation. This work provides evidence in support of using this approach to stimulate bone ingrowth around a device implanted in bone and can pave the way for further applications in bone tissue engineering.

Imperceptible vibratory noise stimulation has shown to be an effective means of improving stability for both whole body postural control and simple motor control tasks. While the physiological mechanism affording this improvement is uncertain, it is suspected that sensory noise stimulation may elicit a stochastic resonance-like effect within the somatosensory system. A stochastic resonance effect describes the phenomenon in which noise added to a non-linear system improves signal detection rather than degrading it. One hallmark of stochastic resonance is the existence of an optimal noise level which elicits the best system performance. There is disagreement in the literature regarding the presence of an optimal stimulation level for motor stability in humans. The goals of this study were to: 1) determine optimal stimulation level as a function of an individual’s sub-sensory threshold level, and 2) to determine whether performance of a force stability task was significantly better when subjects received stimulation at this identified optimal level compared to other sub-sensory threshold stimulation levels. Eighteen (18) participants completed an isometric finger flexion task with visual feedback while receiving noise stimulation scaled to varying percentages of their individual sub-sensory threshold level. Performance for this force stabilization task was quantified as the root-mean-square (RMS) error between the target force and the actual generated force values. Despite controlling all other signal properties and varying only amplitude, optimal noise stimulation values still varied widely across participants (10-100% sub-sensory threshold level). Statistical modeling revealed a significant improvement in task performance with optimal noise stimulation compared to other sub-sensory stimulation levels (p ≤ 0.019) with estimated marginal mean differences in force errors ranging from 0.13 to 0.23 N. Moderate significant Spearman correlations (r_s = 0.49 and r_s = 0.56, respectively) were found between finger flexion maximal voluntary contraction (MVC) and sub-sensory threshold level and MVC and optimal stimulation level. A strong, significant Spearman correlation (r_s = 0.65) was observed between sub-sensory threshold level and optimal stimulation level. Although these correlations do not provide a means to predict optimal stimulation level as a function of these other measures, optimal stimulation level appears to increase with sub-sensory threshold and MVC.

The capacity to externally control transcranial magnetic stimulation (TMS) devices is becoming increasingly important in brain stimulation research. Here we introduce MAGIC (MAGnetic stimulator Interface Controller), an open-source MATLAB toolbox for controlling Magstim and MagVenture stimulators. MAGIC includes a series of MATLAB functions which allow the user to arm/disarm the stimulator, send triggers, change stimulator settings such as amplitude, interpulse intervals, and frequency, and receive stimulator setting information via a serial port connection between a computer and the stimulator. By providing external control capability, MAGIC enables greater flexibility in designing research protocols which require trial-by-trial changes of device settings to realize a priori trial randomization or interactive ad hoc adjustment of parameters during an ongoing experiment. MAGIC thus helps to prevent experimental confounds related to the block-wise variation of parameters and facilitates the integration of TMS with cognitive/sensory tasks, and the development of more adaptive brain state-dependent brain stimulation protocols.

Background: biophysical stimulation therapy, and in particular Pulsed Electromagnetic Fields (PEMFs) and capacitively coupled electric fields (CCEFs) has significantly increased in the last twenty years. For this, it is necessary to have clear information regarding the efficacy, the therapeutic indication and the expected objectives. Methods: we conducted a narrative review taking into consideration different types of studies with different areas of application. The objective was to take into consideration and analyze the different fields of use and the relevant information present in the literature. Results: There is unanimous opinion regarding the usefulness of applying biophysical therapy on the bone compartment both in terms of the tissue healing process and the symptoms associated with this situation. Differently, but no less importantly, in the joint compartment positive opinions were observed mainly on the inflammatory and catabolic process, however, at present,we did not report evidence regarding cartilaginous tissue regeneration. Conclusion: the effectiveness of PEMFs and CCEFs on the bone healing process in the Orthopedic and Traumatology fields is consolidated evidence in the literature. We have also found positive results on symptoms and patient compliance with rehabilitation therapies. Therefore, notable application can be envisaged in the fields of Prosthetic Surgery and Sports Medicine.

This paper presents a thorough review of Electrical Muscle Stimulation (EMS) in the context of Augmented Reality (AR) and Virtual Reality (VR), specifically focusing on its application in providing kinesthetic feedback. Our systematic review of 17 studies reveals the growing interest and potential of EMS in this domain, as evidenced by the growing body of literature and citations. Key elements presented in our review encompass a catalog of the applications developed to date, specifics of the stimulation parameters used, the participant demographics of the studies, and the types of measures used in these research efforts. We discovered that EMS offers a versatile range of applications in AR/VR, from simulating physical interactions like touching virtual walls or objects, to replicating the sensation of weight and impact. Notably, EMS has shown effectiveness in areas such as object handling and musical rhythm learning, indicating its broader potential beyond conventional haptic feedback mechanisms. However, our review also highlights major challenges in the research, such as inconsistent reporting of EMS parameters and a lack of diversity in study participants. These issues underscore the need for improved reporting standards and more inclusive research approaches to ensure wider applicability and reproducibility of results.

BACKGROUND: Functional constipation can lead to painful defecations, fecal incontinence, and abdominal pain, significantly affecting a child's quality of life. Treatment options include non-pharmacological and pharmacological approaches, but some cases are intractable and require alternative interventions like neuromodulation. A subtype of neuromodulation, called Transcutaneous Posterior Tibial Nerve Stimulation (TPTNS), comprises electrical stimulation at the ankle level, by means of electrodes fixed to the skin. TPTNS is a minimally invasive, easy-to-apply technique that can potentially improve constipation symptoms in the pediatric population by stimulating the sacral nerves. AIM: To evaluate the clinical results and applicability of TPTNS as an adjuvant treatment for children and adolescents with functional constipation. METHODS: Between April 2019 and October 2021, 38 patients diagnosed with functional constipation according to the Rome IV Criteria were invited to participate in the study. The study followed a single-center, uncontrolled, prospective cohort design. Patients received TPTNS for 4 or 8 weeks, with assessments conducted immediately after the periods of TPTNS and 4 weeks after the end of the intervention period. The data normality distribution was determined by the Shapiro-Wilk test. Wilcoxon test and Student's t-test for paired samples were used to compare quantitative variables, and the McNemar test was used to compare categorical variables. RESULTS: Of the 38 enrolled patients, 28 children and adolescents with intractable function constipation completed the study, receiving TPTNS for 4 weeks. Sixteen patients (57.1%) extended the intervention period for 4 extra weeks, receiving 8 weeks of intervention. TPTNS led to significant improvements in stool consistency, frequency of defecation, and bowel function scores, with a reduction in abdominal pain. Quality of life across physical and psychosocial domains showed substantial enhancements. The quality of life-related to bowel habits also improved significantly, particularly in lifestyle, behavior, and embarrassment domains. The positive effects of this intervention are seen relatively early, detected after 4 weeks of intervention, and even 4 weeks after the end of the intervention. TPTNS was well-tolerated, with an adherence rate of approximately 78%, and no adverse effects were reported. CONCLUSION: TPTNS is an adjuvant treatment for intractable functional constipation, improving bowel function and quality of life. The effects of TPTNS were observed relatively early and sustained even after treatment cessation.

Injured peripheral nerves regenerate their axons in contrast to those in the central nervous system. However, functional recovery after surgical repair is often disappointing. The basis for the poor recovery is the progressive deterioration with time and distance, of the growth capacity of the neurons that lose their contact with targets (chronic axotomy) and the growth support of the chronically denervated Schwann cells (SC) in the distal nerve stumps. This is despite the retained capacity of chronically denervated and atrophic muscle to accept reinnervation. Progressive decline in regeneration associated genes in both axotomized neurons and denervated SCs accounts for the decline in regenerative success in association with silencing of neural activity in sensory neurons due to their disconnection from their sense organs and, in motoneurons due to loss of their synaptic contacts in the spinal cord. Whilst exogenous neurotrophic factors promote nerve regeneration, the profuse axonal outgrowth and difficulties in delivery are avoided by promoting their endogenous expression with brief (1 hour) low frequency (20Hz) electrical stimulation (ES) proximal to the injury site. ES accelerates axon outgrowth and in turn, target reinnervation in both animals and human subjects. Applying ES to intact nerve days prior to nerve injury, conditional ES (CES) increases axonal outgrowth and regeneration rate with the potential for application in nerve transfer surgeries and end-to-side neurorrhaphies. However, the additional surgery for applying CES electrodes may be a hurdle. ES is applicable in all surgeries with excellent outcomes.

Previous studies on the mechanisms underlying willed actions reported that the premotor cortex may be involved in the construction of motor awareness. However, its exact role is still under investigation. Here we investigated the role of the dorsal premotor cortex (PMd) in motor awareness by modulating its activity applying inhibitory rTMS to PMd, before a specific motor awareness task (under three conditions: without stimulation, after rTMS and after sham stimulation). During the task, subjects had to trace straight lines to a given target, receiving a visual feedback of the line trajectories on a computer screen. Crucially, in most trials the trajectories on the screen were deviated and to produce straight lines, subjects had to correct their movements towards the opposite direction. After each trial, participants were asked to judge whether the line seen on the computer screen corresponded to the line actually drawn. Results show that participants in the no stimulation condition did not recognize the perturbation until 14 degrees of deviation. Importantly, active, but not sham, rTMS significantly modulated motor awareness, decreasing the amplitude of the angle at which participants became aware of the trajectory correction. These results suggest that PMd plays a crucial role in action self- monitoring.

Paired associative stimulation (PAS) is a non-invasive brain stimulation technique that modulates synaptic plasticity in the human motor cortex (M1). Since previous studies have primarily used motor evoked potentials (MEPs) as outcome measure, cortical correlates of PAS-induced plasticity remain unknown. Therefore, the aim of this observational study was to investigate cortical correlates of a standard PAS induced plasticity in the primary motor cortex by using a combined TMS-EEG approach in a cohort of eighteen healthy subjects. In addition to the expected long-lasting facilitatory modulation of MEPs amplitude, PAS intervention also induced a significant increase in transcranial magnetic stimulation evoked potentials (TEPs) P30 and P60 amplitude. No significant correlation between the magnitude of PAS-induced changes in TEP components and MEP amplitude were observed. However, the linear regression analysis revealed that the combined changes in P30 and P60 component amplitudes significantly predicted the MEP facilitation after PAS. The findings of our study offer novel insight into the neurophysiological changes associated with PAS-induced plasticity at M1 cortical level and suggest a complex relationship between TEPs and MEPs changes following PAS.

Multiple sclerosis (MS) is an immune-mediated, chronic inflammatory disease of the central nervous system (CNS), characterized by demyelination, axonal degeneration, and cognitive impairment. It also has an important impact on the quality of life of patients and their family members. An estimated 2,500,000 people in the world have multiple sclerosis. Neurophysiological parameters, like sensitivity to demyelination and the strength of excitatory and inhibitory synaptic interactions in the cerebral cortex, can be identified through transcranial magnetic stimulation (TMS) in patients affected by multiple sclerosis (MS). These parameters can be valid and objective parameters that can be correlated with the progression of MS, and can provide reliable indices for the severity of illness and the efficacy of drugs used to treat it. The discovery of specific and detailed neurophysiological parameters as surrogate end points for disease activity could represent an important step in clinical trials. Changes in cortical connectivity have already been demonstrated in MS, but in clinical practice, other measures are usually used to evaluate disease activity. We speculate that TMS may be more effective in identifying disease progression that leads to long-term disability, compared to standard surrogate markers, due to the fact that it represents a direct measure of synaptic transmission(s) in MS.

Background: Aging impacts semantic abilities, therefore semantic exercises might be a valuable tool for cognitive stimulation in healthy older adults. However, programs in this area are limited. Methods: In the current paper, we adapted the BOX linguistic semantic program for online use via the CerUp platform. Our goal was to prepare the optimization future experience of CerUp users, including potential changes in task structure, level of difficulty and instructions, and participants’ adherence, engagement, performance accuracy, perceived difficulty, and adequacy ratings assigned to the instructions we provided that might guide future changes. Additionally, we created a map of hypothesized task-specific features that may guide tailor-made uses of the program. Results: To that end, we present preliminary results on the usability of CerUp. By analyzing task-specific usability data alongside the hypothesized map of task-specific features, we also tested the validity of the latter. Conclusions: These preliminary results on the usability of the CerUp platform highlight the potential of programs for semantic stimulation. Such findings can inform future optimizations of the program, tailored to users’ needs and effectively supporting overall language skills and general cognition.

Recent studies show that repetitive transcranial magnetic stimulation (rTMS) improves cognitive and motor functions in patients with Parkinson’s Disease (PD). Gamma rhythm low-field magnetic stimulation (LFMS) is a new non-invasive rTMS technique that generates diffused and low-intensity magnetic stimulation to deep cortical and subcortical areas. To investigate potential therapeutic effects of LFMS in PD, we subjected an experimental mouse model to LFMS (as early treatment). We examined the LFMS effect on motor functions as well as neuronal and glial activities in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induced male C57BL/6J mice. Mice received MPTP injection (30 mg/kg, i.p., once daily for 5 days) followed by LFMS treatment, 20 minutes each day for 7 days. LFMS treatment improved motor functions compared to the sham-treated MPTP mice. Further, LFMS significantly improved tyrosine hydroxylase (TH) and decreased glial fibrillary acidic protein (GFAP) levels, in substantia nigra pars compacta (SNpc) and non- significantly in striatal (ST) regions. LFMS treatment improved neuronal nuclei (NeuN) level in SNpc. Our findings suggest that early LFMS treatment improved the neuron survival and in turn, motor functions in MPTP intoxicated mice brain. Further investigation is required to clearly define the molecular mechanisms by which LFMS improves motor and cognitive function in PD patients.

Tremor is a prevalent symptom associated with multiple conditions, including Essential Tremor (ET), Parkinson’s disease (PD), multiple sclerosis (MS), stroke, and trauma. The surgical management of tremor evolved from stereotactic lesions to deep-brain stimulation (DBS), which allowed safe and reversible interference with specific neural networks. This paper reviews the current literature on DBS for tremor, starting with a detailed discussion of current tremor targets (Vim, Raprl, caudal Zi, Vo and STN) and continuing with a discussion of results obtained when performing DBS in the various aforementioned tremor syndromes. Future directions for DBS research are then briefly discussed.

In individuals with spinal cord injury (SCI), rapid skeletal muscle atrophy and metabolic dysfunction pose profound rehabilitation challenges, often resulting in substantial loss of muscle mass and function. This study evaluates the effect of combined neuromuscular electrical stimulation (Comb-NMES) on skeletal muscle cross-sectional area (CSA) and inflammatory signaling within the acute phase of SCI. We applied a novel Comb-NMES regimen, integrating both high-frequency resistance and low-frequency aerobic protocols on the vastus lateralis muscle, to participants early post-SCI. Muscle biopsies were analyzed for CSA and inflammatory markers pre-and post-intervention. The results revealed a preservation of muscle CSA in the Comb-NMES group compared to a control group receiving transcutaneous electrical nerve stimulation and passive movements. Inflammatory signaling proteins such as TLR4 and Atrogin-1 were downregulated, whereas markers associated with muscle repair and growth were modulated beneficially in the Comb-NMES group. The study's findings suggest that early application of Comb-NMES post-SCI can attenuate inflammatory pathways linked to muscle atrophy and potentially promote muscle repair, advocating for its inclusion in early rehabilitation efforts. However, the small sample size and variability in injury characteristics emphasize the need for further research to corroborate these results across a more diverse and extensive SCI population.

Chemoradiotherapy (CRT) is the standard treatment for locally advanced head and neck cancer; however, CRT may cause post-treatment dysphagia. Transcutaneous electrical sensory stimulation (TESS), developed in recent years for swallowing rehabilitation, has been used at many medical facilities. Although TESS has been used for dysphagia in several fields, its safety and efficacy in patients with head and neck cancer remain to be clarified. Therefore, this study evaluated the safety of TESS in ten patients with head and neck cancers undergoing CRT. Swallowing rehabilitation intervention and TESS implementation were performed for all patients during CRT. Non-blood toxicity adverse events (AEs), such as dermatitis and mucositis, occurred during CRT; however, the severity was less than Grade 3. No patient experienced pain due to TESS. As survival time analysis using the Kaplan–Meier method for interferential current device implementation rates revealed a feasibility of 100% for up to 60 Gy and a feasibility of 78% for up to 70 Gy, it concludes that TESS was feasible until 70 Gy. This study confirmed the feasibility and safety of TESS in the head and neck region, even during CRT. Although the precise mechanism of TESS on dysphagia is not yet clear, its continued use has great potential for improving sensory disturbance.

This study evaluated the anti-inflammatory effects, protection of gut barrier integrity, and stimulation of phagocytosis in peripheral cells of a nutritional supplement based on a synergistic combination of yeast-based ingredients with a unique 1,3/1,6-glucan complex and a consortium of postbiotic Saccharomyces cerevisiae rich in selenium and zinc. The anti-inflammatory effect in Caco-2 cells in the presence and absence of a pro-inflammatory challenge (tumour necrosis factor alpha [TNF-α]/interferon gamma [IFN-ɣ]) showed statistically significant reductions of IFN-ɣ induced protein-10 (IP-10), and monocyte chemoattractant protein-1 (MCP-1) levels vs. controls (p &lt; 0.001). Disruption of the gut integrity in the presence or absence of Escherichia coli (ETEC H10407) showed transepithelial electrical resistance (TEER) values higher in the ABB C1® group after 6 hours of testing. Spontaneous build-up of the gut epithelium monolayer over 22 days was also greater in the ABB C1® condition vs. a negative control. ABB C1® showed a significantly higher capacity to stimulate phagocytosis as compared with controls of algae β-1,3-glucan and yeast β-1,3/1,6 glucan (p &lt; 0.001). This study supports the mechanism of action by which ABB C1® may improve the immune response and be useful to prevent infection and allergy in clinical practice.

Background Posttraumatic stress disorder (PTSD) is a complex condition that represents a significant burden in terms of individual disability and societal costs. Despite decades of research investigating treatment options, PTSD remains a major cause of quality-of-life impairment. We hypothesized that patients with PTSD might benefit from peripheral somatosensory stimulation (PSS) therapy. Methods Six adult patients with clinically diagnosed PTSD were enrolled to undergo daily PSS therapy over a 4-week period. Patients completed two surveys evaluating satisfaction with treatment and overall well-being (Survey 1) and severity of PTSD symptoms (Survey 2). Survey 1 was completed weekly during the course of the study. Survey 2 was based on the 9-question National Stressful Events Survey PTSD Short Scale (NSESSS) and was completed as a baseline prior to initiation of therapy and then at the conclusion of the trial. All data were analyzed by an independent statistician. Results Six male patients were enrolled in the study; all completed the trial. All patients demonstrated a decrease in symptoms within one week of initiation of therapy. This benefit was sustained and appeared to further improve over the course of the trial. For Survey 1, the overall median scores demonstrated a significant time-dependent improvement across measurement times (p < 0.001). For Survey 2, patients had statistically significant improvements from baseline regarding feelings of being emotionally upset and being overly alert. Results from a cumulative link mixed model demonstrated that treatment yielded a 38.2-fold higher likelihood of transitioning from a higher PTSD score at baseline to a lower (improved) score at week 4. No adverse events were described by the patients. Conclusions PSS stimulation appeared to improve symptoms in all six patients with PTSD symptoms in this trial. Patients had unanimous and clinically meaningful improvement in overall PTSD symptoms with treatment. By week 4, all patients responded that they enjoyed the treatment and would like to keep their device. We suggest that further investigation into the potential usefulness of PSS therapy in patients with PTSD is warranted.

Background: This systematic review aimed to provide a comprehensive overview of the effects of Functional Electrical Stimulation (FES) on gait characteristics in healthy individuals. Methods: Six electronic databases (PubMed, Embase, Epistemonikos, PEDro, COCHRANE Library, Scopus) were searched for studies evaluating the effects of FES on spatiotemporal, kinematic and kinetic gait parameters in healthy individuals. Two examiners evaluated the eligibility and quality of included studies using the PEDro scale. Results: A total of 15 studies met the inclusion criteria. Findings from the literature reveal that FES can be used to modify lower-limb joint kinematics, i.e., to increase or reduce the range of motion of hip, knee and ankle joints. In addition, FES can be used to alter kinetics parameters, including ground reaction forces, center of pressure trajectory, or knee joint reaction force. As a consequence of these kinetics and kinematics changes, FES can lead to changes in spatiotemporal gait parameters, such as gait speed, step cadence, and stance duration. Conclusion: The findings of this review improve our understanding of the effects of FES on gait biomechanics in healthy individuals, and highlight the potential of this technology as a training or assistive solution for improving gait performance in this population.

Tarsal tunnel syndrome is a focal compressive neuropathy of the posterior tibial nerve or one of its associated branches. Brief mention is made in the literature of the use of corticosteroid injections for this condition. The basic technique of hydrodissection is used for other nerve entrapments and includes identifying the region of nerve compression, and the injection of a fluid medium to dissect between structures or fascial planes. We introduce our treatment protocol using a methylprednisolone/sterile water/ropivacaine hydrochloride injectate mix and peripheral nerve stimulation to a perform hydrodissection technique for tarsal tunnel syndrome.

Based on the geologic conditions of natural gas hydrate (NGH) accumulations in the Shenhu area, northern slope of the South China Sea, this paper used a method of combining reservoir stimulation technique (RST) with depressurization to investigate the conversion efficiency of marine NGH reservoirs in different intrinsic permeability and initial NGH saturation conditions, and analyze the influence of variably-stimulation effect on marine NGH conversion efficiency in different accumulation conditions, provided a reference scheme for improving the NGH conversion efficiency in the Shenhu area. In this work, we performed calculations for the variations in CH4 production rate and cumulative volume of CH4 in different initial NGH saturation, intrinsic permeability and stimulation effect conditions, variance analysis and range analysis methods were used to analyze the significance of these key factors and their interaction, and investigated the sensitivity of stimulation effect on NGH conversion efficiency, respectively. The simulation results showed that stimulation effect have a significant influence on NGH conversion efficiency, and the influence of interaction between these three factors were not obvious. Possibly most important, we clarified an optimum stimulation effect for higher NGH conversion efficiency under different accumulation conditions, especially in low-permeability and high-saturation, which corresponding stimulation effect were different.

The present study explored the expression of CD62L and CD44 by bovine peripheral blood mononuclear cells (PBMCs) and WC1.1+ γδ T cells under Staphylococcus aureus cell culture stimu-lation. In this study, peripheral blood cells were isolated from ten dairy cows and cocultured with S. aureus. Afterward, the γδ T cell subpopulation and the expression of CD44, CD62L and prolif-erative (Ki67+) cells were evaluated by flow cytometry. Our results showed that the percentages of proliferative PBMCs and WC1.1+ γδ T cells were higher when stimulated with S. aureus. The percentage of CD44+ cells increased in S. aureus-stimulated cultured PMBCs and WC1.1+ γδ T cells, as did the CD44 geometric mean fluorescence intensity (GMFI). The rate of CD62L cells did not differ among groups for either PBMCs or WC1.1+ γδ T cells. A higher GMFI of CD62L in prolif-erative PBMCs than nonproliferative PBMCs upon stimulation with S. aureus was detected, whereas no impact on the GMFI of CD62L was observed in WC1.1+ cells. In summary, our study identified that S. aureus was associated with high expression of CD44 in overall PBMCs and WC1.1+ γδ T cells, and they could generate memory WC1.1+ γδ T cells, preferably central memory cells.

Effects of pulsed electromagnetic fields (PEMF) on immunological factors in a 2,4-dinitrochlorobenzene (DNCB)-induced atopic dermatitis (AD) model were investigated. Hairless mice were randomly assigned to control, acetone and olive oil solution-treated (AOO), PEMF 15 Hz, PEMF 75 Hz, and sham groups (n=5 each). AOO solution was used to dissolve DNCB. Both PEMF and sham groups were exposed to similar DNCB doses, causing similar AD symptoms. After AD induction for five weeks, only the PEMF group was exposed to PEMF stimulations (15 Hz, 75 Hz, and 15 mT) for two weeks inside the solenoid coil. In both groups, splenomegaly was observed, as AD was induced by hyperimmune reactions caused by DNCB sensitization. However, splenomegaly did not occur in the PEMF-exposed groups, and spleen weight decreased similarly to that of the control. Hence, the total splenocytes in the PEMF group were similar to those in the control group, whereas the sham group showed thrice the number of splenocytes compared to the PEMF group. The serum immunoglobulin E levels did not significantly change in the PEMF group; however, they increased more than fourfold in the sham group. These results demonstrate that PEMF stimulation ameliorates the abnormal symptoms caused by hyperimmune reactions.

Image analysis is widely applied in plant science for phenotyping and monitoring botanic and agricultural species. Although a lot of software is available, tools integrating image analysis and statistical assessment of seedling growth in large groups of plants are limited or absent, and do not cover the needs of the researchers. In this study, we developed Morley, a free, open-source graphical user interface written in Python. Morley automates the following workflow: (1) group-wise analysis of a few thousand seedlings from multiple images; (2) recognition of seeds, shoots and roots in seedling images; (3) calculation of shoot and root lengths and surface areas, (4) evaluation of statistically significant differences between plant groups, (5) calculation of germination rates, (6) visualization and interpretation. Morley is designed for laboratory studies of biotic effects on seedling growth, when molecular mechanisms underlying morphometric changes are analyzed. Performance was tested using cultivars of T. aestivum, P. sativum on seedlings of up to 1 week old. Accuracy of the measured morphometric parameters was comparable with the ones obtained using ImageJ and manual measurements. Dose-dependent laboratory tests for germination affected by new bioactive compounds and fertilizers, assuming extraction of seedlings from a substrate and/or dissection are among the suggested applications.

MicroRNA-155 (miR-155) expression promotes inflammatory responses in macrophages. Activation of macrophages with lipopolysaccharide (LPS) elevates miR-155, while the anti-inflammatory cytokine interleukin-10 (IL10) reduces miR-155 levels. MiR-155 exists in two forms, miR-155-5p and miR-155-3p, produced from the precursor of miR-155 (pre-miR-155). MiR-155-5p is the most abundant strand in activated macrophages, but in response to LPS, the miR-155-3p level is upregulated first, followed by miR-155-5p later. We have previously identified CELF2 protein which interacts with pre-miR-155 and impairs miR-155-5p expression. We now show that CELF2 only regulates the miR-155-5p expression and that another protein FUBP1 controls miR-155-3p levels in response to LPS and IL10.

This study reports a correlation between EEG and structural brain changes in patients after severe traumatic brain injury in a coma. The novelty of our approach was based on the combination of structural visualization (MRI) and functional neuroimaging (EEG) during tactile stimulation. The structural morphometry indicated a decrease of whole-brain cortical thickness, the gray-matter volume of the cortex, and subcortical structures in comatose patients compared to healthy subjects. In resting-state EEG, coma patients had significantly higher power of the slow-wave activity of 2-6 Hz and significantly less power of the alpha and beta rhythm. Importantly, coma patients showed a significant decrease of theta-rhythm power in tactile stimulation compared to the resting state, and this EEG pattern was not found in the control group. The decrease of the theta-rhythm power significantly correlated with the better outcome from a coma. Spectral changes in EEG in response to tactile stimuli showed no association with brain morphometric measures in healthy controls. In patients, decreasing theta-rhythm power correlated positively with the volume of whole-brain gray matter, right putamen, and insula; and negatively with the volume of damaged brain tissue. Increasing beta-rhythm power, specific tactile EEG response for a healthy brain, correlated with the cortical thickness of the somatosensory Paracentral and Precentral area. The observed decrease of gray-matter volume indicates brain atrophy in coma patients, which could be associated with neurodegeneration induced by injury. Our results also demonstrate that slow-wave desynchronization, as a nonspecific response to tactile stimulation, can serve as a sensitive index of morphometric changes after brain injury and coma outcome.

Background: Objectives. The objective of this study was to compare the efficacy of direct current stimulation (DCS) applied at the transcranial, suboccipital and spinal level on experimental sensory modalities and pain outcome measures in healthy subjects. The hypothesis of this study was that systematic analysis of the efficacy of DCS on modulating evoked thermal and mechanical pain modalities and mechanisms such as endogenous pain modulation in healthy individuals would reveal sensitive outcome measures help develop this technique for the control of chronic pain. Materials and Methods. Database searches were conducted up to December 2019 for randomized controlled trials that performed sham-controlled DCS of experimental sensory modalities and pain outcomes following transcranial, suboccipital and spinal locations in healthy participants. Standardized mean differences with 95% confidence intervals were calculated for sensory modalities, including random-effect metanalysis. Results: Thirty-one studies were included for analysis (647 participants). A significant decrease in pain intensity for active vs sham transcranial stimulation was identified for pain intensity (n=158; SMD=0.79; 95% CI=0.56 to 1.02), a significant increase in heat pain threshold (n=222; SMD=1.16; 95% CI=0.95 to 1.37), and a significant increase in cold pain threshold (n = 155; SMD = 0.77, 95% CI 0.53 to 1.01). No significant modulation of pressure pain threshold was identified with DCS and only a limited number of studies focused on experimental pain modulation following neuromodulation at the suboccipital or spinal level. Conclusions: These results show significant transcranial DCS neuromodulation of pain intensity and on thermal pain modalities. Future studies should focus on endogenous pain and sensory modality modulation with sham-controlled DCS applied at transcranial, suboccipital and spinal locations.

Skeletal muscle contraction evokes numerous genetic and biochemical alterations that underpin the beneficial effects of exercise. The present study aimed to elucidate the mechanism and significance for contraction-evoked antioxidant adaptation in C2C12 myotubes using electrical pulse stimulation (EPS). As NQO1 and GSTA2 are the top antioxidants upregulated by Nrf2, dose-response and time-course experiments of EPS were performed to optimize the parameter at 10 volts for 4 days by evaluating their protein expression. Western blot analysis demonstrated that EPS-cells expressed significantly higher Nrf2 and a broad array of downstream antioxidant enzymes involved in multiple antioxidant systems. These effects were completely abolished by pretreatment with a ROS scavenger, N-acetylcysteine. MitoSOX-Red, CM-H2DCFDA, and EPR spectroscopy revealed a significantly higher ROS level in mitochondria and cytosol in EPS-cells compared to non-stimulated cells. Seahorse and Oroboros revealed that EPS significantly increased maximal mitochondrial oxygen consumption rate, along with upregulated protein expression of mitochondrial complexes I/V, mitofusin-1, and mitochondrial fission factor. A post-stimulation time-course experiment demonstrated that upregulated NQO1 and GSTA2 last at least 24 hours following the cessation of EPS, whereas elevated ROS declines immediately. These finding suggest an antioxidant preconditioning effect in the EPS-cells. A cell viability study using the CCK-8 assay suggested that EPS-cells displayed 11- and 36-fold higher survival rate compared to control-cells in response to 2 and 4 mM H₂O₂ treatment, respectively. In summary, we found that EPS upregulated a large group of antioxidant enzymes in C2C12 myotubes via a contraction-mitochondrial-ROS-Nrf2 pathway. This antioxidant adaptation protects cells against oxidative stress-associated cytotoxicity.

Background: A growing number of studies have reported Coronavirus disease (COVID-19)-related to both respiratory and central nervous system dysfunctions. This study evaluates the neuromodulatory effects of spinal cord transcutaneous stimulation (scTS) on the respiratory functional state in healthy controls and patients with post-COVID-19 respiratory deficits as a step toward the development of a rehabilitation strategy for these patients.; Methods: In this before-after, interventional, case-controlled clinical study, ten individuals with post-acute COVID-19 respiratory deficits and eight healthy controls received a single twenty-minute-long session of modulated monophasic scTS delivered over the T5 and T10 spinal cord segments. Forced Vital Capacity (FVC), Peak Forced Inspiratory Flow (PIF), Peak Expiratory Flow (PEF), Time-To-Peak of Inspiratory Flow (tPIF), and Time-To-Peak of Expiratory Flow (tPEF) were assessed before and after the intervention; Results: In COVID-19 group, the scTS intervention led to significantly increased PIF (p= .040) and PEF (p= .049) in association with significantly decreased tPIF (p= .035) and tPEF (p= .013). In the Control Group, the exposure to scTS also resulted in significantly increased PIF (p= .010) and significantly decreased tPIF (p= .031). Unlike the results in COVID-19 group, there was significantly decreased PEF (p= .028) in association with significantly increased tPEF (p= .036). There were no changes for FVC after scTS in both groups (p= .67 and p= .503); Conclusions: In post-COVID-19 patients scTS facilitates excitation of both inspiratory and expiratory spinal neural networks leading to an immediate improvement of respiratory functional performance. This neuromodulation approach could be utilized in rehabilitation programs for patients with COVID-19 respiratory deficits.

The circadian and stress-realizing systems are interconnected, and the balance of their interaction determines the state of human health. The objective of this study was to investigate the modulating effect of activating the circadian system on heart rate variability in female medical students with high anxiety while performing a cognitive task. After 20 minutes of adequate stimulation of circadian photoreceptors with a monochromatic blue light, the cognitive task performance resulted in a decrease in sympathetic impact. During the session of using Blue Sky Pro glasses, a trend of increasing heart rate variability was observed in a state of relative rest (especially in the first 5 minutes). A comparative analysis of the parameters of the letter cancellation test before and after light exposure revealed a statistically significant increase in the indexes reflecting mental productivity, work accuracy, and concentration of attention. The results suggest an essential physiological role of the human circadian system in modulating the autonomic and psycho-emotional conditions, as well as cognitive functions of individuals with high anxiety. Our findings indicate the possibility of quickly correcting the balance in human systemic regulatory mechanisms using the activation of retinal circadian photoreceptors by blue light.

Predictive processes and numerous cognitive, motor, and social skills depend heavily on sequence and statistical learning. The visuomotor Serial Reaction Time Task (SRTT) can measure these fundamental cognitive processes. In this review, we sought to answer whether repetitive transcranial magnetic stimulation (rTMS) is suitable for modulating visuomotor sequence learning and which factors mediate its efficacy. We systematically analyzed the eligible records (n = 17) that attempted to modulate the performance of the SRTT with rTMS. The purpose of the analysis was to determine how the following factors affected SRTT performance: (1) stimulated brain areas, (2) rTMS protocols, (3) stimulated hemisphere, (4) timing of the stimulation, (5) SRTT sequence properties, and (6) other methodological features. The primary motor cortex (M1) and the dorsolateral prefrontal cortex (DLPFC) were found to be the most promising stimulation targets. Low-frequency protocols over the M1 usually weaken performance, but the results are less consistent for the DLPFC. These inconsistencies (at least in part) may be due to the current frequency-based heuristics of rTMS effects developed for explaining local stimulation effects in the motor cortex. Although this review cannot provide an ultimate answer about the optimal stimulation and task parameters, it comprehensively discusses the behavioral effects of six factors that are crucial for designing future studies to modulate sequence learning with rTMS. Moreover, we conclude that synergistically combining functional neuroimaging with rTMS could adequately link the rTMS-induced network effects with the behavioral findings that are crucial to develop a unified cognitive model of visuomotor sequence learning.

Spinal Cord Stimulation (SCS) is an effective and validated treatment to address chronic refractory neuropathic pain in Persistent Spinal Pain Syndrome-Type 2 (PSPS-T2) patients. Surgical SCS lead placement is traditionally performed under general anesthesia due to its invasiveness. In parallel, recent works have suggested that Awake Anesthesia (AA), consisting in Target Controlled Intra-Veinous Anesthesia (TCIVA), could be an interesting tool to optimize lead anatomical placement using patient intra-operative feedback. We hypothesized that combining AA with Minimal Invasive Surgery (MIS) could improve SCS outcomes. The goal of this study was to evaluate SCS lead performance (defined by the area of pain adequately covered by paraesthesia generated via SCS), using an intraoperative objective quantitative mapping tool, and secondarily to assess pain relief, functional improvement and change in quality of life with a composite score. We analyzed data from a prospective multicenter study (ESTIMET) to compare the outcomes of 115 patients implanted with MIS under AA (MISAA group) or General Anesthesia (MISGA group), or by Laminectomy under General Anesthesia (LGA group). All in all, MISAA appears to show significantly better performance in terms of patient pain coverage, as well as improved secondary outcomes. One step further, our results suggest that MISAA combined with intra-operative hypnosis could potentialize patient intraoperative cooperation and could be proposed as a personalized package offered to PSPS-T2 patients eligible for SCS implantation in highly dedicated neuromodulation centers.

Impact of Nitrogen Foamed Stimulation Fluids Stabilized by Nanoadditives on Reservoir Rocks of Hydrocarbon Deposits

Herein, we evaluated the electrophoretic deposition of nanohydroxyapatite/superhydrophilic multiwalled carbon nanotube composites (nHAp/MWCNT) onto stainless steel biomedical alloys for applications in bone tissue engineering. First, nHAp/MWCNT composites were dispersed into 0.042 mol L⁻¹ of Ca(NO₃)₂·4H₂O + 0.025 mol L⁻¹ NH₄H₂PO₄ electrolytes (pH = 4.8) at two different concentrations. Next, a voltage of −2 V was applied using 316L stainless steel as a working electrode and (0.27 cm²), a high-purity platinum coil wire as the auxiliary electrode, and an Ag/AgCl(3 M) electrode was used as the reference electrode. The nHAp/MWCNT composites were characterized by transmission electron microscopy. The deposited nHAp and nHAp/MWCNT films were characterized by profilometry, scanning electron microscopy, X-Ray diffractometry and Raman spectroscopy. Human osteoblast cells were cultivated with the different materials, and in vitro cytotoxicity was evaluated using lactate dehydrogenase (LDH) assay. The osteogenesis process was evaluated by mRNA levels of the three genes that are directly related to bone repair: Alkaline Phosphatase, Osteopontin and Osteocalcin. We showed that rough, crystalline apatite thin films containing phases of nHAp were successfully deposited onto 316L stainless steel alloys. Also, we noticed that nHAp/MWCNT thin films deposited onto 316L stainless steel alloys upregulated the expression of important genes related to bone mineralization and maturation. Our results strongly support the possibility of this new alternative to modify the surface of metallic biomedical alloys to promote bone tissue regeneration.

Objective: to evaluate the effects of excitatory repetitive transcranial magnetic stimulation (rTMS) of the international 10-20 system P3 point (intraparietal sulcus region) in chronic patients with a frontal lesion and parietal sparing due to stroke on the impaired upper (UL) and lower limb (LL) as measured by Fugl-Meyer Assessment (FMA). Methods: three patients (C1: 49.83/2.75, C2: 53.17/3.83, C3: 63.33/3.08 years-old at stroke/ years post-stroke, respectively) received two weeks (five days/ week) of rTMS at 10 Hz of P3. A patient was treated in similar conditions with a sham coil (S1: 56.58/4.33). No complimentary therapy was delivered during the study. Patients were evaluated before, after- and two months post-treatment (A1, A2 and A3, respectively). Results: we found increased scores for LL in motor function subsection for C1 and C3 and in sensory function for C2 by A2 that remained at A3. We also found an increased score for UL motor function for C2 and C3, but the score decreased by A3 for C2. C3 score for UL range of motion increased by A3 compared to A1 and A2. Conclusion: In a variable way, P3 excitatory rTMS increased FMA scores in different upper and lower limb subsections of our three treated patients.

We previously found that chronic adenosine A1 receptor stimulation with N6-Cyclopentyladenosine increased α-synuclein misfolding and neurodegeneration in a novel α-synucleinopathy model, a hallmark of Parkinson’s disease. Here, we aimed to synthesize a dimer caffeine-indan linked by a 6-carbon chain to cross the blood-brain barrier and tested its ability to bind α-synuclein, reducing misfolding, behavioural abnormalities, and neurodegeneration in our rodent model. Behavioural tests and histological stains assessed neuroprotective effects of the dimer compound. A rapid synthesis of the 18F-labelled analogue enabled Positron Emission Tomography and Computed Tomography imaging for biodistribution measurement. Molecular docking analysis showed that the dimer binds to α-synuclein N- and C-termini and the non-amyloid-β-component (NAC) domain, similar to 1-aminoindan, and this binding promotes a neuroprotective α-synuclein “loop” conformation. The dimer also binds to the orthosteric binding site for adenosine within the adenosine A1 receptor. Immunohistochemistry and confocal imaging showed the dimer abolished α-synuclein upregulation and aggregation in the substantia nigra and hippocampus, and the dimer mitigated cognitive deficits, anxiety, despair, and motor abnormalities. The 18F-labelled dimer remained stable post-injection and distributed in various organs, notably in the brain, suggesting its potential as a Positron Emission Tomography tracer for α-synuclein and adenosine A1 receptor in Parkinson’s disease therapy.

Concurrent Optical and Magnetic Stimulation (COMS) combines extremely low frequency electromagnetic and light stimulation modalities for enhanced wound healing. In this report, we investigated the potential mechanistic synergism between magnetic and light components by comparing their individual and combined cellular responses. Although each individual stimulation mode was capable of stimulating cell proliferation, magnetic fields exposure alone produced greater proliferation enhancement than light alone, yet their combined effects of were supra-additive of the individual responses. Reactive oxygen species were incrementally reduced by exposure to light, magnetics fields and their combination, where statistical significance was ultimately achieved. On the other hand, ATP production was significantly enhanced in response to magnetic exposure alone or in combination with light. These results suggest that mitochondrial respiratory efficiency was preferentially improved by the combination of the two stimuli. Protein expression related to cell proliferation was preferentially enhanced by the combinatory COMS modality as were the protein levels of the TRPC1 cation channel previously implicated as part of a calcium-mitochondrial signaling axis invoked by electromagnetic exposure and involved in proliferation. These results corroborate that light facilitates functional synergism with magnetic fields that ultimately impinge on mitochondria-dependent developmental responses. The aminoglycoside antibiotics (AGAs) have been previously shown to antagonize TRPC1-mediated magnetotransduction. Streptomycin applied during the exposure to any of the stimulation modes reduced proliferation enhancement, whereas streptomycin added after the exposure did not. Notably, the COMS modality and magnetic field exposure were capable of partially overcoming streptomycin antagonism of proliferation, whereas light alone was not. Transductional antagonism of combinatorial photon-electromagnetic effects by streptomycin thus aligns with previous studies showing that the AGAs block TRPC1-mediated magnetotransduction when applied during exposure. The prophylactic usage of the AGAs (neomycin) should be avoided during COMS therapy to maintain clinical efficacy and would be a common concern with most other electromagnetic regenerative paradigms.

Postural instability (PI) in Parkinson’s disease (PD) exposes patients to increased risk of falls (RF). Although dopaminergic therapy and deep brain stimulation (DBS) improve motor performance in advanced PD patients, their effects on PI and RF are not clear. PI and RF were assessed by a stabilometric platform in 6 advanced PD patients. Patients were evaluated on and off dopaminergic medication and four DBS conditions: bilateral-DBS, DBS of the more- or less-affected side and DBS-off. Dopaminergic medication alone worsened PI and RF, DBS alone worsened RF, and no medication/DBS combination produced an improvement in postural control with respect to the OFF-medication/DBS-off condition. When ON-medication, PI and RF significantly improved after turning the DBS on, regardless of medication condition. Among DBS conditions, bilateral-DBS provided the maximal improvement of PI and RF when ON medication, and minimal worsening of PI and RF when OFF medication, whereas patients performed worse when in most-affected side DBS condition. These results can help in developing the best therapeutic strategy for postural disorders in patients with advanced PD.

The cough assessment is fundamental in the weaning process as it gives information on the possibility to expel food and secretion from the airways. The majority of persons suffering from severe acquired brain injury (ABI) are not able to cough voluntarily due to severe motor deficits. In the present study, we evaluated the cough reflex in ABI patients using a new method based on a capsaicin spray stimulation test. 100 Healthy controls demographically matched with 50 ABI patients were included in this study. Clinical observations demonstrated robust cough response in both healthy controls and ABI patients, as well as the safety and tolerability of capsaicin spray stimulation. ABI patients with dysphagia were characterized by slower and delayed cough responses. Further studies are needed to validate this feasible, less-invasive, and simple-to-comprehend technique in inducing cough reflex. According to this preliminary evidence, we believe that this test might be translated into a simple and effective treatment to improve cough strength training reflexive cough modulation in ABI patients.

In order to improve the adaptability of broilers to low-temperature environments and their ability to resist acute cold stress (ACS), 240 one-day-old broilers were selected and randomly divided into three groups. The control treatment (CC) was raised at the conventional feeding temperature from 1-43 days (d), the cold stimulation treatments (CS) were kept at 3 °C below the temperature of CC at 1-d intervals for 3 and 6 hours from 15 to 35 d, namely CS3 and CS6, respectively. Then all broilers were kept at 20 °C from 36 to 43 d. ACS was then carried out at 44 d, and the ambient temperature was dropped to 10 °C for 6 hours. The study investigated the production perfor-mance, as well as levels of intestinal barrier genes (including Claudin-1, E-cadherin, Occludin, ZO-1, ZO-2 and Mucin2), secretory IgA in duodenum and jejunum, and immunoglobulins (IgA and IgG) in serum. The results showed that IMCS could increase the daily weight gain and decrease the feed conversion ratio. During the IMCS, the expression levels of intestinal barrier genes were up-regulated and the content of secretory IgA was increased. When IMCS ceased for one week, the level of immunoglobulins in serum stabilized, and the expression levels of Occludin, ZO-2 and Mucin2 still maintained high levels. After ACS, broilers that received IMCS training maintained the high levels of intestinal barrier genes and secretory IgA.

Background: Demographic aging is a reality in developed countries, which poses a social challenge of great responsibility. Thus, numerous studies have been developed in an attempt to understand which factors best predict healthy aging. The aim of this study was to investigate and systematize literature on intervention programs that simultaneously include cognitive stimulation and physical activity, understand the importance of the use of new technology in these programs, and understand their impact on cognitive function in older adults, giving indications about their contribution to healthy aging. Methods: A narrative approach was used for extraction and synthesis of the data. Relevant studies were identified from electronic databases such as PubMed, Scopus, Web of Science and Academic Search Complete. Results: Thirty-two articles, involving 2815 participants, were identified. All selected studies were randomized controlled studies. The studies were published between 2011 and 2020. All studies included a combination of cognitive and physical interventions. Many of the studies used technology to administer the cognitive stimulation program. Conclusions: Most of the analyzed studies use new technologies in physical and cognitive interventions, demonstrating that this new form of intervention exerts lasting and stable benefits in cognition.

An ongoing EU Horizon 2020 Project called BionicVEST is investigating the effect of constant electrical stimulation (ES) of the inferior vestibular nerve in patients with bilateral vestibular dysfunction (BVD)[1]. The evidence is that constant ES results in improved postural stability and gait performance and so the question of central importance is how could constant ES of mainly saccular afferents in these BVD patients cause this improved performance? We suggest that the constant ES is substituting for the absent saccular neural input to the vestibular nuclei and the cerebellum in these BVD patients and indirectly via these structures to other structures which have been of great recent interest in motor control. One target area, the anterior midline cerebellum (the uvula) has recently been targeted as a location for deep brain stimulation in human patients to improve postural stability and gait. There are projections from midline cerebellum to basal ganglia including the striatum, structures involved in the initiation of gait. It may be that the effect of this activation of peripheral saccular afferent neurons is analogous to the effect of deep brain stimulation (DBS) by electrodes in basal ganglia acting to help alleviate the symptoms of patients with Parkinson's disease.

This review describes and discusses unusual axonal structural details and evidence for unmasking of sulfhydryl groups (-SH) in axoplasmic membranes resulting from electrical stimulation or asphyxia. Crayfish axons contain fenestrated septa (FS) that in phase contrast micrographs appear as repeated striations. In the electron microscope each septum is made of two cross-sectioned membranes containing ~550 Å pores, each occupied by a microtubule. Thin filaments, likely to be made of kinesin, bridge the microtubule to the edge of the pore. FS are believed to play a role in axoplasmic flow. The axons also display areas in which axon and sheath-glial cell plasma membranes are sharply curved and project into the axoplasm. In freeze-fractures, the protoplasmic leaflet (P-face) of the projections appears as elongated indentations containing parallel chains of particles. The sheath-glial cell plasma membrane also contains particles, but they are irregularly aggregated. The axons also display areas where axonal and glial plasma membranes fuse, creating intercellular pores. In axons fixed during electrical stimulation the plasma membrane, the outer membrane of mitochondria, membranes of other cytoplasmic organelles and gap junctions increase in electron opacity and thickness, resulting from unmasking of sulfhydryl groups (-SH). Similar changes occur in asphyxiated nerve cords.

This study aimed to investigate the effects of forearm postures and elbow joint angles on muscle torque and mechanomyography (MMG) signals. The torque about the elbow and MMG of the biceps brachii (BB) muscle were measured in 36 healthy subjects using an in-house elbow flexion testbed and Neuromuscular electrical stimulation (NMES) of the BB muscle. The BB muscle received stimulation intensity while the forearm was positioned in the neutral, pronation or supination. The elbow was flexed at angles 10°, 30°, 60° and 90°. (0° = full elbow extension). The study analyzed the impact of forearm posture(s) and elbow joint angle(s) on the root mean square value of torque (TQ_RMS). Subsequently, MMG parameters such as the root mean square value (MMG_RMS), the mean power frequency (MMG_MPF), and the median frequency (MMG_MDF), were analyzed in the longitudinal, lateral, and transverse axes of the BB muscle fibers. Forearm posture and elbow flexion angle were found to significantly influence TQ_RMS (P < 0.05). Similarly, MMG_RMS, MMG_MPF and MMG_MDF exhibited a significant difference for all postures and angles (P < 0.05). However, the combined main effect of forearm postures and elbow joint angles was insignificant in the longitudinal axis (P > 0.05). The study also found that MMG_RMS and TQ_RMS increased with the joint angle to 60° and decreased to the other angle(s). However, during this investigation,MMG_MPF and MMG_MDF exhibited a consistent decrease in response to joint angles. This finding suggests that the muscle contraction evoked by NMES may be influenced by the interplay between actin and myosin filaments, which are responsible for muscle contraction and are in turn influenced by muscle length. As restoring the function of limbs is a common goal in rehabilitation services, it becomes imperative to develop methods that may enable the real-time tracking of exact muscle dimensional changes and activation levels.

The yellow-legged Asian hornet (Vespa velutina Lepeletier 1836 (Hymenoptera: Vespidae)) is naturally distributed in China, Southeast Asia and India; however it has since detected outside of its native area, confirmed as being established in South Korea, Europe and Japan. Health risks and deaths caused by the invasive Vespa velutina stings have become a public health concern, being the most common cause of anaphylaxis due to hymenopterans in some European regions. This in turn has led to increased demand from medical practitioners and researchers for Vespa velutina venom for diagnostic and therapeutic purposes. In this study, a straightforward, quick and inexpensive method for obtaining Vespa velutina venom by electric stimulation is described. The venom extracts were analyzed by nuclear magnetic resonance spectroscopy (1H-NMR), confirming the composition of the obtained material. The availability of Vespa velutina venom will lead to improved diagnostic and therapeutic methods, mainly by venom immunotherapy (VIT), in patients allergic to this invasive species.

Fear extinction requires coordinated neural activity within the amygdala and medial prefrontal cortex (mPFC). Any behavior has a transcriptomic signature that is modified by environmental experiences, and specific genes are involved in functional plasticity and synaptic wiring during fear extinction. Here, we investigated the effects of optogenetic manipulations of prelimbic (PrL) pyramidal neurons on amygdala gene expression to analyze the specific transcriptional pathways involved in adaptive and maladaptive fear extinction. To this aim, transgenic mice were (or not) fear-conditioned and during the extinction phase they received optogenetic (or sham) stimulations over PrL pyramidal neurons. At the end of behavioral testing, electrophysiological (neural cellular excitability and Excitatory Post-Synaptic Currents) and morphological (spinogenesis) correlates were evaluated in the PrL pyramidal neurons. Furthermore, transcriptomic cell-specific RNA-analyses (differential gene expression profiling and functional enrichment analyses) were performed in amygdala pyramidal neurons. Our results show that the optogenetic activation of PrL pyramidal neurons in fear-conditioned mice induces fear extinction deficits, reflected in an increase of cellular excitability, excitatory neurotransmission, and spinogenesis of PrL pyramidal neurons, and in strong modifications of the transcriptome of amygdala pyramidal neurons. Understanding the electrophysiological, morphological and transcriptomic architecture of fear extinction may facilitate the comprehension of fear-related disorders.

Despite advances in the understanding of its molecular pathophysiology, prostate cancer remains largely incurable, highlighting the need for novel therapies. We developed a chimeric antigen receptor (CAR) specific for prostate specific membrane antigen (PSMA), a glycoprotein that is overexpressed in prostate cancer, which expression involves neovasculature of several tumor entities, thus envisaging an additional antiangiogenic effect. To optimize the CAR design, we compared two CARs with signaling domains containing one or two T cell costimulatory elements, in addition to CD3ζ. Conversely, what has been described for other CARs, a third-generation CAR (containing CD28 and 41BB co-signaling domains) induced a potent antitumor effect similar to a second-generation CAR (containing CD28 co-signaling domain), though we observed a detrimental effect of the additional costimulatory domain that was attributed to increased activation-induced cell death (AICD). This “super-stimulation” resulted in exhaustion of cells, higher frequencies of cell death and, more importantly, the impossibility of sufficiently expanding the CAR cells to obtain the minimum number of cells requested for in vivo therapies. While the superiority of 2nd and 3rd generation over 1st generation CAR T cells has been clearly shown in both preclinical and clinical studies, the optimal combination of costimulatory domains for 3rd generation CAR-T cells must still be defined and should be evaluated case-by-case in order to fine-tune immunotherapy approaches.

Purpose: Dysarthria, a neurological injury of the motor component of the speech circuitry, is of common consequences of traumatic brain injury (TBI). Palilalia is a speech disorder characterized by involuntary repetition of words, phrases, or sentences. Based on the evidence supporting the effectiveness of transcranial direct current stimulation (tDCS) in some speech and language disorders, we hypothesized that using tDCS would enhances the effectiveness of speech therapy in a client with chronic dysarthria following TBI. Method: We applied the constructs of the “Be Clear” protocol, a relatively new approach in speech therapy in dysarthria, together with tDCS on a chronic subject who affected by dysarthria and palilalia after TBI. Since there was no research on the use of tDCS in such cases, regions of interest (ROIs) were identified based on deviant brain electrophysiological patterns in speech tasks and resting state compared with normal expected patterns using the Quantitative Electroencephalography (QEEG) analysis. Results: Measures of perceptual assessments of intelligibility, an important index in the assessment of dysarthria, ​​were superior to the primary protocol results immediately and 4 months after intervention. We did not find any factor other than the use of tDCS to justify this superiority. The percentage of repeated words, an index in palilalia assessment, had a remarkable improvement immediately after intervention but fell somewhat after 4 months. We justified this case with subcortical origins of palilalia. Conclusion: Our present case-based findings suggested that applying tDCS together with speech therapy may improve intelligibility in similar case profiles as compared to traditional speech therapy. To reconfirm the effectiveness of the above approach in cases with dysarthria following TBI, more investigation need to be pursued.

Vascular endothelial growth factors (VEGFs) are regarded as the key vasculogenic mediators in the human body, of which VEGF-A is considered as one of the important types. It is the major growth factor possessing increasing vascular permeability as well as angiogenesis properties. This article provides intuition into the different effects of VEGF-A on vessels in ovarian hyper stimulation syndrome (OHSS) which is defined as a complication of in-vitro fertilization for infertility treatment, and obesity, a universally health problem. These are two dissimilar pathways outcomes for VEGF-A effects, thereby This article reviews updated information about the mentioned disorders and reveals that how this kind of growth factor yields different results on vasculature by activating distinct intracellular signaling in endothelial cells.

S-adenosylmethionine (SAM) is considered to be a useful therapeutic agent for degenerative cartilage diseases, although its mechanism is not clear. We previously found that polyamines stimulate expression of differentiated phenotype of chondrocytes. We also found that cellular communication network factor 2 (CCN2) played a huge role in the proliferation and differentiation of chondrocytes. Therefore, we hypothesized that polyamines and CCN2 could be involved in the chondroprotective action of SAM. In this study, we initially found that exogenous SAM enhanced proteoglycan production but not cell proliferation in human chondrocyte-like cell line-2/8 (HCS-2/8) cells. Moreover, SAM enhanced gene expression of cartilage-specific matrix (aggrecan and type II collagen), Sry-Box transcription factor 9 (SOX9), CCN2 and chondroitin sulfate biosynthetic enzymes. Blockade of the methionine adenosyltransferase 2A (MAT2A) enzyme catalyzing intracellular SAM biosynthesis restrained the effect of SAM on chondrocytes. The polyamine level in chondrocytes was higher in SAM-treated culture than control culture. Additionally, alcian blue staining and RT-qPCR indicated that the effects of SAM on the production and gene expression of aggrecan were reduced by the inhibition of polyamine synthesis. These results suggest that the stimulation of polyamine synthesis and gene expression of chondrogenic differentiation factors, such as CCN2, account for the mechanism underlying the action of SAM on chondrocytes.

Low-intensity noisy galvanic vestibular stimulation (nGVS) can improve static and dynamic postural deficits in patients with bilateral vestibular loss (BVL). In this study, we aimed to explore the neurophysiological and neuroanatomical substrates underlying nGVS treatment effects in a rat model of BVL. Regional brain activation patterns and behavioral responses to repeated 30-min nGVS treatment in comparison to sham stimulation were investigated by serial whole-brain [18F]-FDG-PET measurements and quantitative locomotor assessments before and at 9 consecutive time points up to 60 days after chemical bilateral labyrinthectomy (BL). [18F]-FDG-PET revealed a broad nGVS-induced modulation on regional brain activation patterns encompassing biologically plausible brain networks in the brainstem, cerebellum, multisensory cortex and basal ganglia during the entire observation period post-BL. nGVS broadly reversed brain activity adaptions occurring in the natural course post-BL. Parallel behavioral locomotor assessment demonstrated a beneficial treatment effect of nGVS on sensory-ataxic gait alterations, particularly in the early stage of post-BL recovery. Stimulation-induced locomotor improvements were finally linked to nGVS brain activity responses in the brainstem, hemispheric motor and limbic networks. In conclusion, combined [18F]-FDG-PET and locomotor analysis discloses the potential neurophysiological and neuroanatomical substrates that mediate previously observed therapeutic nGVS effects on postural deficits in patients with BVL.

The scope of this work was part of our previous research on Pulsed Power Plasma Stimulation Technique. Electromagnetic fields generated during a pulsed power plasma discharge were simulated using a finite element method in the COMSOL RF module. The field distributions were calculated during and after the pulse. The current paper takes advantage of prior work measuring and modeling the current distribution in the plasma arc. Agreement with laboratory experimental measurements provides support for extension of the model to reservoir scale. The validated model was used to quantify the signal attenuation level in different medium environment.

Age-related hearing loss (ARHL) is the most common sensory disorder in the elderly. It is associated with aging and hair cell death due to oxidative stress-induced mitochondrial dysfunction. Although transgenic mice and long-term cultures for induction of aging have been used to study ARHL, there are presently no ARHL animal models stimulated by intermittent environmental change for aging. In this study, an ARHL animal model was established by inducing continuous oxidative stress to promote short-term aging of cells, determined based on the expression of the hearing loss-induced phenotype and aging related factors in the short term. The incidence of hearing loss was significantly different among the groups subjected to intermittent hypoxic environment, high-fat diet (HFD), and injection with D-galactose. Continuous oxidative stress and HFD were factors that accelerated cellular aging. Increase in UCP2 affected oxidative stress and mitochondrial dysfunction. CDH23, SLC26A4, KCNQ4, Myo7a, and Myo6, which are ARHL-related factors, were modified by oxidative stress in cells of the hearing organ. We found that intermittent hypoxic, HFD, and galactose injection accelerated cellular aging in the short term. Thus, we anticipate that the development of this hearing loss animal model, which reflects intermittent environmental changes, will benefit future research on ARHL.

A pattern of NK cell heterogeneity in each individual determines proliferative and functional responses of NK cells to activating stimuli. Obtaining the progeny of a single cell by cloning original population is one of the ways to study the NK cell heterogeneity. In this work, we used single cell sorting into a plate and stimulation by IL-2 and gene-modified K562 feeder cells expressing membrane-bound IL-21 (K562-mbIL21) that led to generation of phenotypically confirmed and functionally active NK cell clones. We applied two models of clone cultivation, which differently affected their phenotype, lifespan and functional activity. The first model, which included weekly restimulation of clones with K562-mbIL21 and IL-2, resulted in the generation of relatively short-lived (5-7 weeks) clones of highly activated NK cells. HLA-DR expression in the expanded NK cells correlated strongly with IFN-γ production. The second model, in which NK cells were restimulated mainly with IL-2 alone, produced long-lived clones (8-14 weeks) that expanded up to 10⁷ cells with lower ability to produce IFN-γ. Our method is applicable for studying variability in phenotype, proliferative and functional activity of the certain NK cell progeny in response to the stimulation, which may help in selecting NK cells best suited for clinical use.

Background: Although autophagy is a pro-survival process of tumor cells, in particular conditions and when differently regulated by specific signals it can stimulate cell death. We previously demonstrated that the selective stimulation of the M2 muscarinic receptor subtype (M2 mAChR) negatively controls cell proliferation and survival and causes oxidative stress and cytotoxic and genotoxic effects in both GBM cell lines and GBM stem cells (GSCs). In this work, we have evaluated whether autophagy was induced as a downstream mechanism of the observed cytotoxic processes induced by M2 mAChR activation by the orthosteric agonist APE or the dualsteric agonist N-8-Iper. Methods: To assess the activation of autophagy, we analyzed the expression of LC3B by Western blot analysis and in LC3B-EGFP transfected cell lines. Apoptosis was assessed by Caspases 3 and 9 protein expression. Results: Our data indicate that activation of M2 mAChR by N-8-Iper promotes autophagy in both U251 and GB7 cells lines as suggested by the LC3B-II expression level and analysis of the transfected cells by fluorescence microscopy. Autophagy induction by M2 mAChRs is regulated by the decreased activity of the PI3K/AKT/mTORC1 pathway and upregulated by the pAMPK expression. Downstream autophagy activation, the increase of apoptosis was also observed in both cell lines after treatment with the two M2 agonists. Conclusions: N-8-Iper treatment causes autophagy via pAMPK upregulation, followed by apoptosis in both investigated cell lines. In contrast, the absence of autophagy in APE-treated GSC cells seems to indicate that cell death could be triggered by mechanisms alternative to those observed for N-8-Iper.

Abstract: A biomaterial is proposed for closing extensive bone defects in the maxillofacial region. The composition of the biomaterial includes high-molecular chitosan, chondroitin sulfate, hyaluronate, heparin, alginate and inorganic nanostructured hydroxyapatite. The purpose of the study is to demonstrate morphological and histological early signs of reconstruction of a bone cavity of critical size. The studies were carried out on 84 white female rats weighing 200-250 g. The study group consisted of 84 subjects in total, 40 in the experimental group and 44 in the control group. In all animals, three-walled bone defects measuring 0.5 x 04 x 05 cm were applied subperiosteally in the region of the angle of the lower jaw and filled in experimental group using lyophilized gel mass of chitosan-alginate-hydroxyapatite (CH-SA-HA). In control animals, the bone cavities were filled with an auto-blood clot after bone trepanation and bleeding. The observation periods are 3.5.7 days, 2.3.4.6.8 and 10 weeks. The control of bone regeneration was carried out using multiple morphological and histological analyses. Results showed that following implantation the chitosan construct actively replaced early-stage defects with the formation of a full-fledged new bone tissue as compared to the control group. Already, by the 7th day morphological analysis showed that formation of spongy bone tissue could be seen. After 2 weeks there was a pronounced increase in bone volume (P<0.01), and at 6 weeks after surgical intervention the closure of the defect was 70-80%, after 8 weeks - 100% without violation of bone morphology with a high degree of mineralization. Thus, the use of modified chitosan after filling eliminates bone defects of a critical size in the maxillofacial region, reveals early signs of bone regeneration, and serves as a promising material in reconstructive dentistry.

The introduction of ventricular shunts dramatically changed the outcome and quality of life of hydrocephalic patients. However, shunt surgery continues to be associated with numerous adverse events. Headache is one of the most common complications after shunt operation. It is often over a prolonged duration, the symptoms resemble migraine, and pain does not respond to medication. We propose invasive peripheral nerve stimulation as a possible solution in the treatment of patients suffering from chronic headache associated with shunted hydrocephalus. A young woman with daily holocephalic headache with diffuse pain exacerbated by lying down. Imaging revealed panventricular enlargement and possible stenosis of the aqueduct. When a ventriculoperitoneal shunt was placed, clinical symptoms resolved. Nevertheless, she gradually exacerbated after a second valve replacement due to wound infection. Imaging revealed decompressed ventricles and appropriate shunt placement. The diagnosis of chronic post-intracranial disorder headache was set. Therefore, occipital nerve stimulation was applied and considering that the patient had not a total response, bilateral parietal stimulation was added. Three months after the combined PNS she experienced total remission of headache. Combined PNS eases refractory headaches much more than occipital nerve stimulation alone and could be considered as a solution for shunted hydrocephalus associated headache.

Individual differences in the responsiveness of the brain to transcranial electrical stimulation (tES) is increasingly demonstrated in large variability in the tES effects. Anatomically detailed computational brain models have been developed to address this variability; however, static brain models are not ‘realistic’ in accounting for the dynamic state of the brain. Therefore, human-in-the-loop optimization is proposed in this perspective article based on an extensive systems analysis of the tES neurovascular effects. First, modal analysis was conducted using a physiologically detailed neurovascular model that found stable modes in the 0 Hz to 0.05 Hz range for the pathway for vessel response through the smooth muscle cells, measured with functional near-infrared spectroscopy (fNIRS). tES effects in the 0 Hz to 0.05 Hz range can also be measured with functional magnetic resonance imaging (fMRI)-tDCS data with a maximum TR=10sec. Therefore, we investigated an open-source fMRI-tDCS dataset that used a TR=3.36sec. We found that both the anodal tDCS condition and sham tDCS condition had similar Finite Impulse Response at the region of interest underlying the anode and a remote location, which indicated a global hemodynamic effect of sham tDCS beyond the intended transient sensations. Here, transient sensations can have arousal effects on the hemodynamics so we conducted a healthy case series for black box modeling of fNIRS-pupillometry of short-duration tDCS effects. The block exogeneity test rejected the claim that tDCS is not a 1-step Granger-cause of the fNIRS total hemoglobin changes (HbT) and pupil dilation changes (p<0.05). Also, grey-box modeling using fNIRS of the tDCS effects in chronic stroke showed HbT response to be significantly different (paired-sample t-test, p<0.05) between the ipsilesional and the contralesional hemisphere for primary motor cortex tDCS and cerebellar tDCS which was subserved by the smooth muscle cells. Here, our perspective is that various physiological pathways subserving tES effects can lead to state-trait variability that can be challenging for clinical translation. Therefore, we conducted a case study on human-in-the-loop optimization using our reduced dimension model and a stochastic, derivative-free Covariance Matrix Adaptation Evolution Strategy. Future studies need to investigate human-in-the-loop optimization of tES for reducing inter-subject and intra-subject variability in tES effects.

Background: Maladaptive neuroplasticity related learned response in substance use disorder (SUD) can be ameliorated using non-invasive brain stimulation (NIBS); however, inter-individual variability needs to be addressed for clinical translation. Objective: Our first objective was to develop a hypothesis for NIBS for learned response in SUD based on competing neurobehavioral decision systems model. Next objective was to conduct computational simulation of NIBS of cortico-cerebello-thalamo-cortical (CCTC) loop in cannabis use disorder (CUD) related dysfunctional “cue-reactivity” – a closely related construct of “craving” that is a core symptom. Our third objective was to test the feasibility of our neuroimaging guided rational NIBS approach in healthy humans. Methods: “Cue-reactivity” can be measured using behavioral paradigms and portable neuroimaging, including functional near-infrared spectroscopy (fNIRS) and electroencephalogram (EEG), metrics of sensorimotor gating. Therefore, we conducted computational simulation of NIBS, including transcranial direct current stimulation(tDCS) and transcranial alternating current stimulation(tACS) of the cerebellar cortex and deep cerebellar nuclei(DCN), of the CCTC loop for its postulated effects on fNIRS and EEG metrics. We also developed a rational neuroimaging guided NIBS approach for cerebellar lobule (VII) and prefrontal cortex based on healthy human study. Results: Simulation study of cerebellar tDCS induced gamma oscillations in the cerebral cortex while tTIS induced gamma-to-beta frequency shift. Experimental fNIRS study found that 2mA cerebellar tDCS evoked similar oxyhemoglobin(HbO) response in-the-range of 5x10-6M across cerebellum and PFC brain regions (=0.01); however, infra-slow (0.01–0.10 Hz) prefrontal cortex HbO driven(phase-amplitude-coupling, PAC) 4Hz, ±2mA (max.) cerebellar tACS evoked HbO in-the-range of 10-7M that was statistically different (=0.01) across those brain regions. Conclusion: Our healthy human study showed the feasibility of fNIRS of cerebellum and PFC as well as fNIRS-driven ctACS at 4Hz that may facilitate cerebellar cognitive function via the frontoparietal network. Future work needs to combine fNIRS with EEG for multi-modal imaging.

Spinal muscular atrophy (SMA) is an orphan disease characterized by progressive degeneration of spinal alpha motor neurons. In recent years, nusinersen and several other drugs have been approved for the treatment of this disease. Transcutaneous spinal cord stimulation (tSCS) modulates spinal neuronal networks, resulting in changes in locomotion and posture in patients with severe spinal cord injury and stroke. We hypothesize that tSCS can activate motor neurons that are intact and restored by medication, slow the decline in motor activity, and contribute to the development of motor skills in SMA patients. Thirty-seven children and adults with SMA types 2 and 3 participated in the study. The median duration of drug treatment was over 20 months. Application of tSCS was performed during physical therapy for 20-40 minutes per day for ~12 days. Outcome measures were specific SMA motor scales, goniometry of contractured joints, forced vital capacity. Significant increases in motor function, improved respiratory function, and decreased contracture were observed in both types 2 and 3 SMA participants. The magnitude of functional changes was not associated with participants age. Further studies are needed to elucidate the reasons for the beneficial effects of spinal cord electrical stimulation in SMA.

Transcranial direct current stimulation (tDCS) is acknowledged for its non-invasive modulation of neuronal activity in psychiatric disorders. However, its application in insomnia research yields varied outcomes depending on different tDCS types and patient conditions. Our primary objective is to elucidate its efficiency and uncover the underlying mechanisms in insomnia treatment. We hypothesized that anodal prefrontal cortex stimulation activates glutaminergic projections from the infralimbic cortex (IL) to ventrolateral preoptic area (VLPO) to promote sleep. After administering 0.06 mA of electrical currents for 8 minutes, our results indicate significant non-rapid eye movement (NREM) enhancement in naïve mice within the initial 3 hours post-stimulation, persisting up to 16-24 hours. In the insomnia group, tDCS enhanced NREM sleep bout numbers during acute stress response and improved NREM and REM sleep duration in subsequent acute insomnia. Sleep quality, assessed through NREM delta powers, remains unaffected. Interference of the IL-VLPO pathway, utilizing designer receptors exclusively activated by designer drugs (DREADDs) with the cre-DIO system, partially blocked tDCS's sleep improvement in stress-induced insomnia. This study elucidated that the activation of the IL-VLPO pathway mediates tDCS's effect on stress-induced insomnia. These findings support the understanding of tDCS effects on sleep disturbances, providing valuable insights for future research and clinical applications in sleep therapy.