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Bacteria-infected wounds pose challenges to healing due to persistent infection and associated damage to nerves and vessels. Although sonodynamic therapy can help kill bacteria, it is limited by the residual oxidative stress, resulting in prolonged inflammation. To tackle these barriers, novel 4 octyl itaconate-coated Li-doped ZnO/PLLA piezoelectric composite microfibers are developed, offering a whole-course "targeted" treatment under ultrasound therapy. The inclusion of Li atoms causes the ZnO lattice distortion and increases the band gap, enhancing the piezoelectric and sonocatalytic properties of the composite microfibers, collaborated by an aligned PLLA conformation design. During the infection and inflammation stages, the piezoelectric microfibers exhibit spatiotemporal-dependent therapeutic effects, swiftly eliminating over 94.2 % of S. aureus within 15 min under sonodynamic therapy. Following this phase, the microfibers capture reactive oxygen species and aid macrophage reprogramming, restoring mitochondrial function, achieving homeostasis, and shortening inflammation cycles. As the wound progresses through the healing stages, bioactive Zn2+ and Li + ions are continuously released, improving cell recruitment, and the piezoelectrical stimulation enhances wound recovery with neuro-vascularization. Compared to commercially available dressings, our microfibers accelerate the closure of rat wounds (Φ = 15 mm) without scarring in 12 days. Overall, this "one stone, four birds" wound management strategy presents a promising avenue for infected wound therapy.

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The impact of electrical stimulation has been widely investigated on the wound healing process; however, its practicality is still challenging. This study explores the effect of electrical stimulation on fibroblasts in a culture medium containing different electrically-charged polysaccharide derivatives including alginate, hyaluronate, and chitosan derivatives. For this aim, an electrical stimulation, provided by a zigzag triboelectric nanogenerator (TENG), was exerted on fibroblasts in the presence of polysaccharides' solutions. The analyses showed a significant increase in cell proliferation and an improvement in wound closure (160 % and 90 %, respectively) for the hyaluronate-containing medium by a potential of 3 V after 48 h. In the next step, a photo-crosslinkable hydrogel was prepared based on hyaluronic acid methacrylate (HAMA). Then, the cells were cultured on HAMA hydrogel and treated by an electrical stimulation. Surprisingly, the results showed a remarkable increase in cell growth (280 %) and migration (82 %) after 24 h. Attributed to the electroosmosis phenomenon and an amplified transfer of soluble growth factors, a dramatic promotion was underscored in cell activities. These findings highlight the role of electroosmosis in wound healing, where TENG-based electrical stimulation is combined with bioactive polysaccharide-based hydrogels to promote wound healing.

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Definitions of human pain acknowledge at least two dimensions of pain, affective and sensory, described as separable and thus potentially differentially modifiable. Using electroencephalography, we investigated perceptual and neural changes of emotional pain modulation in healthy individuals. Painful electrical stimuli were applied after presentation of priming emotional pictures (negative, neutral, positive) and followed by pain intensity and unpleasantness ratings. We found that perceptual and neural event-related potential responses to painful stimulation were significantly modulated by emotional valence. Specifically, pain unpleasantness but not pain intensity ratings were increased when pain was preceded by negative compared to neutral or positive pictures. Amplitudes of N2 were higher when pain was preceded by neutral compared to negative and positive pictures, and P2 amplitudes were higher for negative compared to neutral and positive pictures. In addition, a hierarchical regression analysis revealed that P2 alone and not N2, predicted pain perception. Finally, source analysis showed the anterior cingulate cortex and the thalamus as main spatial clusters accounting for the neural changes in pain processing. These findings provide evidence for a separation of the sensory and affective dimensions of pain and open new perspectives for mechanisms of pain modulation.

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For patients with epilepsy, one of the biggest problems is the unpredictability of the time when the next seizure will occur. Interestingly, some epileptic patients experience a sensory sensation preceding seizures, called aura, which helps them move to safety before a seizure. Here, we describe the development of the first animal model of auras, which could allow for a more detailed study of this phenomenon. Specifically, in mice, we presented sensory stimuli (sound and light cues) a few seconds before kindling an animal to induce seizures. Animals were kindled by electrical stimulation in the basolateral amygdalar nucleus. Over the course of stimulation sessions, animals started showing progressively stronger freezing behavior to sensory cues preceding kindling. Interestingly, seizures are known to cause retrograde amnesia, thus it was surprising that the association between seizures and preceding sensory cues developed in all experimental animals. In summary, our experiments show that similarly to auras, a sensory sensation can be associated with incoming generalized seizures and is not erased by retrograde amnesia.

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Individuals with motor dysfunction caused by damage to the central nervous system are unable to transmit voluntary movement commands to their muscles, resulting in a reduced ability to control their limbs. However, traditional rehabilitation methods have problems such as long treatment cycles and high labor costs. Functional electrical stimulation (FES) based on brain-computer interface (BCI) connects the patient's intentions with muscle contraction, and helps to promote the reconstruction of nerve function by recognizing nerve signals and stimulating the moving muscle group with electrical impulses to produce muscle convulsions or limb movements. It is an effective treatment for sequelae of neurological diseases such as stroke and spinal cord injury. This article reviewed the current research status of BCI-based FES from three aspects: BCI paradigms, FES parameters and rehabilitation efficacy, and looked forward to the future development trend of this technology, in order to improve the understanding of BCI-based FES.

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Electrical stimulation is an important adjuvant therapy for spinal surgery, but whether receiving electrical stimulation can improve the fusion rate after spinal surgery is still controversial. The purpose of this study was to analyse and evaluate the effect of electrical stimulation on the fusion rate after spinal surgery. We systematically searched for related articles published in the PubMed, Embase and Cochrane Library databases on or before September 30, 2023. The odds ratio (OR) with 95% confidence interval (CI) and the fusion rates of the experimental group and the control group were calculated by a random-effects meta-analysis model. The analysis showed that receiving electrical stimulation significantly increased the probability of successful spinal fusion (OR 2.66 [95% CI 1.79-3.97]), and the average fusion rate of the electrical stimulation group (86.8%) was significantly greater than that of the control group (73.7%). The fusion rate in the direct current (DC) stimulation group was 2.33 times greater than that in the control group (OR 2.33 [95% CI 1.37-3.96]), and that in the pulsed electromagnetic field (PEMF) group was 2.60 times greater than that in the control group (OR 2.60 [95% CI 1.29-5.27]). Similarly, the fusion rate in the capacitive coupling (CC) electrical stimulation group was 3.44 times greater than that in the control group (OR 3.44 [95% CI 1.75-6.75]), indicating that regardless of the type of electrical stimulation, the fusion rate after spinal surgery improved to a certain extent. Electrical stimulation as an adjuvant therapy seems to improve the fusion rate after spinal surgery to a certain extent, but the specific effectiveness of this therapy needs to be further studied.

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Bioelectronic bone implants are being widely recognized as a promising technology for highly personalized bone/implant interface sensing and biophysical therapeutic stimulation. Such bioelectronic devices are based on an innovative concept with the ability to be applied to a wide range of implants, including in fixation and prosthetic systems. Recently, biointerface sensing using capacitive patterns was proposed to overcome the limitations of standard imaging technologies and other non-imaging technologies; moreover, electric stimulation using capacitive patterns was proposed to overcome the limitations of non-instrumented implants. We here provide an innovative low-power miniaturized electronic system with ability to provide both therapeutic stimulation and bone/implant interface monitoring using network-architectured capacitive interdigitated patterns. It comprises five modules: sensing, electric stimulation, processing, communication and power management. This technology was validated using in vitro tests: concerning the sensing system, its ability to detect biointerface changes ranging from tiny to severe bone-implant interface changes in target regions was validated; concerning the stimulation system, its ability to significantly enhance bone cells' full differentiation, including matrix maturation and mineralization, was also confirmed. This work provides an impactful contribution and paves the way for the development of the new generation of orthopaedic biodevices.

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Activity-regulated cytoskeleton-associated protein (Arc) plays a crucial role in synaptic plasticity, a process integral to learning and memory. Arc transcription is induced within a few minutes of stimulation, making it a useful marker for neuronal activity. However, the specific neuronal activity patterns that initiate Arc transcription have remained elusive due to the inability to observe mRNA transcription in live cells in real time. Using a genetically encoded RNA indicator (GERI) mouse model that expresses endogenous Arc mRNA tagged with multiple GFPs, we investigated Arc transcriptional activity in response to various electrical field stimulation patterns. The GERI mouse model was generated by crossing the Arc-PBS knock-in mouse, engineered with binding sites in the 3' untranslated region (UTR) of Arc mRNA, and the transgenic mouse expressing the cognate binding protein fused to GFP. In dissociated hippocampal neurons, we found that the pattern of stimulation significantly affects Arc transcription. Specifically, theta-burst stimulation consisting of high-frequency (100 Hz) bursts delivered at 10 Hz frequency induced the highest rate of Arc transcription. Concurrently, the amplitudes of nuclear calcium transients also reached their peak with 10 Hz burst stimulation, indicating a correlation between calcium concentration and transcription. However, our dual-color single-cell imaging revealed that there were no significant differences in calcium amplitudes between Arc-positive and Arc-negative neurons upon 10 Hz burst stimulation, suggesting the involvement of other factors in the induction of Arc transcription. Our live-cell RNA imaging provides a deeper insight into the complex regulation of transcription by activity patterns and calcium signaling pathways.

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Novel stimulation methods are needed to overcome the limitations of contemporary cochlear implants. Optogenetics is a technique that confers light sensitivity to neurons via the genetic introduction of light-sensitive ion channels. By controlling neural activity with light, auditory neurons can be activated with higher spatial precision. Understanding the behaviour of opsins at high stimulation rates is an important step towards their translation. To elucidate this, we compared the temporal characteristics of auditory nerve and inferior colliculus responses to optogenetic, electrical, and combined optogenetic-electrical stimulation in virally transduced mice expressing one of two channelrhodopsins, ChR2-H134R or ChIEF, at stimulation rates up to 400 pulses per second (pps). At 100 pps, optogenetic responses in ChIEF mice demonstrated higher fidelity, less change in latency, and greater response stability compared to responses in ChR2-H134R mice, but not at higher rates. Combined stimulation improved the response characteristics in both cohorts at 400 pps, although there was no consistent facilitation of electrical responses. Despite these results, day-long stimulation (up to 13 h) led to severe and non-recoverable deterioration of the optogenetic responses. The results of this study have significant implications for the translation of optogenetic-only and combined stimulation techniques for hearing loss.

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Peripheral neuromodulation has emerged as a powerful modality for controlling physiological functions and treating a variety of medical conditions including chronic pain and organ dysfunction. The underlying complexity of the nonlinear responses to electrical stimulation make it challenging to design precise and effective neuromodulation protocols. Computational models have thus become indispensable in advancing our understanding and control of neural responses to electrical stimulation. However, existing approaches suffer from computational bottlenecks, rendering them unsuitable for real-time applications, large-scale parameter sweeps, or sophisticated optimization. In this work, we introduce an approach for massively parallel estimation and optimization of neural fiber responses to electrical stimulation using machine learning techniques. By leveraging advances in high-performance computing and parallel programming, we present a surrogate fiber model that generates spatiotemporal responses to a wide variety of cuff-based electrical peripheral nerve stimulation protocols. We used our surrogate fiber model to design stimulation parameters for selective stimulation of pig and human vagus nerves. Our approach yields a several-orders-of-magnitude improvement in computational efficiency while retaining generality and high predictive accuracy, demonstrating its robustness and potential to enhance the design and optimization of peripheral neuromodulation therapies.

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The presence of mixed microplastics (MPs) in anaerobic wastewater treatment processes has been shown to impede fermentation performance by suppressing microbial activity. Microbial electrosynthesis (MES), with its extensive potential, offers a promising solution for refractory substances management and methane recovery, achieved through the enhancement of microbial metabolism and interspecies electron transfer. This study, therefore, delves into the functional impacts and the microbial response to MES in the remediation of wastewater contaminated with mixed-MPs. Results indicated that mixed-MPs could inhibit methane production (-52.38%) and substance removal (-26.59%), and MES could effectively mitigate this inhibitory effect (-22.86%, -19.01%). Concurrently, MES also boosts enzymatic activities pivotal for electron transfer, such as cytochrome c and nicotinamide adenine dinucleotide (NADH), as well as those linked to energy metabolism like adenosine triphosphate (ATP). Furthermore, MES bolsters microbial resistance to mixed-MPs, as evidenced by an increase in extracellular polymeric substances (EPS), albeit with a minor rise in reactive oxygen species (ROS) production and lactate dehydrogenase (LDH) release. Correspondingly, electric stimulation promoted the enrichment of functional microorganisms associated with fermentation, acetate production, electrogenesis, and methanogenesis, and stimulated elevated expression levels of genes related to methane metabolism. Notably, the Methanothrix-mediated acetoclastic pathway emerges as the predominant methanogenic route, succeeded by the Methanobacterium-driven hydrogenotrophic pathway. Lastly, the study underscores the supportive role of applied voltage and carriers in energy metabolism and substance transport, which are associated with methanogenesis. Overall, MES demonstrates efficacy in mitigating the biotoxicity induced by mixed-MPs exposure and in enhancing anaerobic wastewater treatment and methane recovery.

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PURPOSE: Rehabilitation technology can be used to provide intensive training in the early phases after stroke. The current study aims to assess the feasibility of combining robotics and functional electrical stimulation (FES), with an assist-as-needed approach to support actively-initiated leg movements in (sub-)acute stroke patients. METHOD: Nine subacute stroke patients performed repetitions of ankle dorsiflexion and/or knee extension movements, with and without assistance. The assist-as-needed algorithm determined the amount and type of support needed per repetition. The number of repetitions and range of motion with and without assistance were compared with descriptive statistics. Fatigue scores were obtained using the visual analogue scale (score 0-10). RESULTS: Support was required in 44 % of the repetitions for ankle dorsiflexion and in 5 % of the repetitions of knee extension, The median fatigue score was 2.0 (IQR: 0.2) and 4.0 (IQR: 1.5) for knee and ankle, respectively, indicating mild to moderate perceived fatigue. CONCLUSION: This study demonstrated the feasibility of assist-as-needed assistance through combined robotic and FES support of leg movements in stroke patients. It proved particularly useful for ankle dorsiflexion. Future research should focus on implementing this approach in a clinical setting, to assess clinical applicability and potential effects on leg function.

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BACKGROUND: Galvanic Vestibular Stimulation (GVS) is a non-invasive electrical stimulation technique that is typically used to probe the vestibular system. When using direct current or very low frequency sine, GVS causes postural sway or perception of illusory (virtual) motions. GVS is commonly delivered using two electrodes placed at the mastoids, however, placements involving additional electrodes / locations have been employed. Our objective was to systematically evaluate all known GVS electrode placements, compare induced current flow, and how it relates to the archetypal sway and virtual motions. The ultimate goal is to help users in having a better understanding of the effects of different placements. METHODS: We simulated seven GVS electrode placements with same total injected current using an ultra-high resolution model. Induced electric field (EF) patterns at the cortical and the level of vestibular organs (left and right) were determined. A range of current flow metrics including potential factors such as inter-electrode separation, percentage of current entering the cranial cavity, and symmetricity were calculated. Finally, we relate current flow to reported GVS motions. RESULTS: As expected, current flow patterns are electrode placement specific. Placements with two electrodes generally result in higher EF magnitude. Placements with four electrodes result in lower percentage of current entering the cranial cavity. Symmetric placements do not result in similar EF values in the left and the right organs respectively- highlighting inherent anatomical asymmetry of the human head. Asymmetric placements were found to induce as much as ~3-fold higher EF in one organ over the other. The percentage of current entering the cranial cavity varies between ~15% and ~40% depending on the placement. CONCLUSIONS: We expect our study to advance understanding of GVS and provide insight on probable mechanism of action of a certain electrode placement choice. The dataset generated across several metrics will support hypothesis testing relating empirical outcomes to current flow patterns. Further, the differences in current flow will guide stimulation strategy (what placement and how much scalp current to use) and facilitate a quantitatively informed rational / optimal decision.

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Neurofibromatosis Type 1 (NF1) is a complex genetic disorder characterized by the development of benign neurofibromas, which can cause significant morbidity in affected individuals. While the molecular mechanisms underlying NF1 pathogenesis have been extensively studied, the development of effective therapeutic strategies remains a challenge. This paper presents the development and validation of a novel biomaterial testing model to enhance our understanding of NF1 pathophysiology, disease mechanisms and evaluate potential therapeutic interventions. Our long-term goal is to develop an invitro model of NF1 to evaluate drug targets. We have developed an in vitro system to test the cellular behavior of NF1 patient derived cells on electroconductive aligned nanofibrous biomaterials with electrical stimulatory cues. We hypothesized that cells cultured on electroconductive biomaterial will undergo morphological changes and variations in cell proliferation that could be further enhanced with the combination of exogenous electrical stimulation (ES). In this study, we developed electrospun Hyaluronic Acid-Carbon Nanotube (HA-CNT) nanofiber scaffolds to mimic the axon's topographical and bioelectrical cues that influence neurofibroma growth and development. The cellular behavior was qualitatively and quantitively analyzed through immunofluorescent stains, Alamar blue assays and ELISA assays. Schwann cells from NF1 patients appear to have lost their ability to respond to electrical stimulation in the development and regeneration range, which was seen through changes in morphology, proliferation and NGF release. Without stimulation, the conductive material enhances NF1 SC behavior. Wild-type SC respond to electrical stimulation with increased cell proliferation and NGF release. Using this system, we can better understand the interaction between axons and SC that lead to tumor formation, homeostasis and regeneration.

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The closed-loop control of pathological brain activity is a challenging task. In this study, we investigated the sensitivity of continuous epileptiform short discharge generation to electrical stimulation applied at different phases between the discharges using an in vitro 4-AP-based model of epilepsy in rat hippocampal slices. As a measure of stimulation effectiveness, we introduced a sensitivity function, which we then measured in experiments and analyzed with different biophysical and abstract mathematical models, namely, (i) the two-order subsystem of our previous Epileptor-2 model, describing short discharge generation governed by synaptic resource dynamics; (ii) a similar model governed by shunting conductance dynamics (Epileptor-2B); (iii) the stochastic leaky integrate-and-fire (LIF)-like model applied for the network; (iv) the LIF model with potassium M-channels (LIF+KM), belonging to Class II of excitability; and (v) the Epileptor-2B model with after-spike depolarization. A semi-analytic method was proposed for calculating the interspike interval (ISI) distribution and the sensitivity function in LIF and LIF+KM models, which provided parametric analysis. Sensitivity was found to increase with phase for all models except the last one. The Epileptor-2B model is favored over other models for subthreshold oscillations in the presence of large noise, based on the comparison of ISI statistics and sensitivity functions with experimental data. This study also emphasizes the stochastic nature of epileptiform discharge generation and the greater effectiveness of closed-loop stimulation in later phases of ISIs.

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Ingestible electronics have the capacity to transform our ability to effectively diagnose and potentially treat a broad set of conditions. Current applications could be significantly enhanced by addressing poor electrode-tissue contact, lack of navigation, short dwell time, and limited battery life. Here we report the development of an ingestible, battery-free, and tissue-adhering robotic interface (IngRI) for non-invasive and chronic electrostimulation of the gut, which addresses challenges associated with contact, navigation, retention, and powering (C-N-R-P) faced by existing ingestibles. We show that near-field inductive coupling operating near 13.56 MHz was sufficient to power and modulate the IngRI to deliver therapeutically relevant electrostimulation, which can be further enhanced by a bio-inspired, hydrogel-enabled adhesive interface. In swine models, we demonstrated the electrical interaction of IngRI with the gastric mucosa by recording conductive signaling from the subcutaneous space. We further observed changes in plasma ghrelin levels, the "hunger hormone," while IngRI was activated in vivo, demonstrating its clinical potential in regulating appetite and treating other endocrine conditions. The results of this study suggest that concepts inspired by soft and wireless skin-interfacing electronic devices can be applied to ingestible electronics with potential clinical applications for evaluating and treating gastrointestinal conditions.

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PURPOSE OF REVIEW: Oscillopsia and unsteadiness are common and highly debilitating symptoms in individuals with bilateral vestibulopathy. A lack of adequate treatment options encouraged the investigation of vestibular implants, which aim to restore vestibular function with motion-modulated electrical stimulation. This review aims to outline the ocular and postural responses that can be evoked with electrical prosthetic stimulation of the semicircular canals and discuss potential approaches to further optimize evoked responses. Particular focus is given to the stimulation paradigm. RECENT FINDINGS: Feasibility studies in animals paved the way for vestibular implantation in human patients with bilateral vestibulopathy. Recent human trials demonstrated prosthetic electrical stimulation to partially restore vestibular reflexes, enhance dynamic visual acuity, and generate controlled postural responses. To further optimize prosthetic performance, studies predominantly targeted eye responses elicited by the vestibulo-ocular reflex, aiming to minimize misalignments and asymmetries while maximizing the response. Changes of stimulation parameters are shown to hold promise to increase prosthetic efficacy, together with surgical refinements and neuroplastic effects. SUMMARY: Optimization of the stimulation paradigm, in combination with a more precise electrode placement, holds great potential to enhance the clinical benefit of vestibular implants.

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Changes in performance caused by positive and negative expectations (i.e., placebo and nocebo responses) were found to play an important role in many aspects of motor performance. This study aimed to test the impact of placebo/nocebo responses and the assumed moderating role of dispositional optimism and anxiety on proprioceptive accuracy, an essential aspect of motor functions. 78 undergraduate university students completed questionnaires assessing dispositional optimism, state anxiety, and motivation to cooperate, then were randomly assigned to three experimental groups. A sham subliminal electric stimulation was applied with claimed positive (placebo group, n = 26), negative (nocebo group, n = 26) or neutral (control group, n = 26) impact on proprioceptive accuracy. Proprioceptive accuracy was measured with active and passive versions of the Joint Position Reproduction task before and after the intervention. Expected and perceived changes in performance were also assessed; changes in state anxiety, optimism, and motivation to cooperate were used as control variables (covariates). Mixed analyses of variance indicated that the experimental manipulation did not affect actual proprioceptive accuracy but impacted expected and perceived performance. Adding the covariates to the models did not substantially change the results. Further, no significant association emerged between actual and perceived change in performance in the active test, and only a weak correlation was found in the passive test. Expected performance did not predict actual performance but predicted perceived performance in both tasks. The results suggest that only perceived (subjective) aspects of proprioceptive accuracy are susceptible to placebo and nocebo interventions.

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The measurement of skeletal muscle fatigue in response to cycling exercise is commonly done in isometric conditions, potentially limiting its ecological validity, and creating challenges in monitoring the time course of muscle fatigue across an exercise bout. This study aimed to determine if muscle fatigue could be reliably assessed by measuring quadriceps twitch force evoked while pedaling, using instrumented pedals. Nine participants completed three laboratory visits: a step incremental test to determine power output at lactate threshold, and on separate occasions, two constant-intensity bouts at a power output 10% above lactate threshold. Femoral nerve electrical stimulation was applied to elicit quadriceps twitch force both while pedaling (dynamic) and at rest (isometric). The test-retest reliability of the dynamic twitch forces and the agreement between the dynamic and isometric twitch forces were evaluated. Dynamic twitch force was found to have excellent reliability in an unfatigued state (intraclass correlation coefficient (ICC) = 0.920 and mean coefficient of variation (CV) = 7.5%), and maintained good reliability at task failure (ICC = 0.846 and mean CV = 11.5%). When comparing dynamic to isometric twitch forces across the task, there was a greater relative decline in the dynamic condition (P = 0.001). However, when data were normalized to the 5 min timepoint when potentiation between conditions was presumed to be more similar, this difference disappeared (P = 0.207). The reliability of this method was shown to be commensurate with the gold standard method utilizing seated isometric dynamometers and offers a new avenue to monitor the kinetics of muscle fatigue during cycling in real time.

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