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Planned actions can be triggered involuntarily by a startling acoustic stimulus (SAS), resulting in very short reaction times (RT). This phenomenon, known as the StartReact effect, is thought to result from the startle-related activation of reticular structures. However, other sensory modalities also can elicit a reflexive startle response. Here, we assessed the effectiveness of an intense startling electric stimulus (SES) in eliciting the StartReact effect as compared to a SAS. We tested SES intensities at 15 and 25 times the perceptual threshold of each participant, as well as SAS intensities of 114 dB and 120 dB. The electrical stimulation electrodes were placed over short head of the biceps brachii on the arm not involved in the task. Intense electric and acoustic stimuli were presented on 20% of the trials in a simple RT paradigm requiring a targeted ballistic wrist extension movement. The proportion of trials showing short latency (≤ 120 ms) startle reflex-related activation in sternocleidomastoid was significantly lower on intense electrical stimulus trials compared to intense acoustic trials, and the startle response onset occurred significantly later on SES trials compared to SAS. However, when a startle reflex was observed, RTs related to the prepared movement were facilitated to a similar extent for both SES and SAS conditions, suggesting that the accelerated response latency associated with the StartReact effect is independent of stimulus type.

Due to the natural barrier of skin structure, traditional topical drug utilization for skin disease management has been severely constrained by low bioavailability. While current microneedle (MN)-based systems confront challenges related to therapeutic efficacy, penetration depth, and delivery precision, they offer considerable promise as minimally invasive platforms. To address these limitations, electric stimulus (ES) has been strategically integrated as a programmable external trigger within microneedle patches, enabling spatiotemporal control over drug release kinetics. This review systematically delineates recent advancements in ES-assisted microneedle systems for managing dermatological conditions, highlighting their dual capacity to enhance transdermal permeability while minimizing systemic toxicity through localized delivery, in alignment with emerging trends in functional integration and device miniaturization. This encompasses a comprehensive analysis of the regulatory role of ES, strategic selection of power supply modules, and the rational design of microneedles in conjunction with their corresponding drug-loading strategies. Guided by the Three I Principles (Integrated-Intelligent-Individualized), future developments should focus on creating closed-loop systems with embedded biosensors for real-time biomarker monitoring, implementing AI-driven adaptive dosing algorithms, and developing modular microneedle arrays. This paradigm shift towards patient-centered care will require cross-disciplinary convergence of flexible electronics, biocompatible energy harvesters, and precision medicine approaches to accommodate personalized treatment regimens. Graphical abstract

Vision loss after optic neuropathy is considered irreversible. Here, repetitive transorbital alternating current stimulation (rtACS) was applied in partially blind patients with the goal of activating their residual vision. We conducted a multicenter, prospective, randomized, double-blind, sham-controlled trial in an ambulatory setting with daily application of rtACS (n = 45) or sham-stimulation (n = 37) for 50 min for a duration of 10 week days. A volunteer sample of patients with optic nerve damage (mean age 59.1 yrs) was recruited. The primary outcome measure for efficacy was super-threshold visual fields with 48 hrs after the last treatment day and at 2-months follow-up. Secondary outcome measures were near-threshold visual fields, reaction time, visual acuity, and resting-state EEGs to assess changes in brain physiology. The rtACS-treated group had a mean improvement in visual field of 24.0% which was significantly greater than after sham-stimulation (2.5%). This improvement persisted for at least 2 months in terms of both within- and between-group comparisons. Secondary analyses revealed improvements of near-threshold visual fields in the central 5° and increased thresholds in static perimetry after rtACS and improved reaction times, but visual acuity did not change compared to shams. Visual field improvement induced by rtACS was associated with EEG power-spectra and coherence alterations in visual cortical networks which are interpreted as signs of neuromodulation. Current flow simulation indicates current in the frontal cortex, eye, and optic nerve and in the subcortical but not in the cortical regions. rtACS treatment is a safe and effective means to partially restore vision after optic nerve damage probably by modulating brain plasticity. This class 1 evidence suggests that visual fields can be improved in a clinically meaningful way. ClinicalTrials.gov NCT01280877.

Diffusion tensor magnetic resonance electrical impedance tomography (DT-MREIT) is a newly developed technique that combines MR-based measurements of magnetic flux density with diffusion tensor MRI (DT-MRI) data to reconstruct electrical conductivity tensor distributions. DT-MREIT techniques normally require injection of two independent current patterns for unique reconstruction of conductivity characteristics. In this paper, we demonstrate an algorithm that can be used to reconstruct the position dependent scale factor relating conductivity and diffusion tensors, using flux density data measured from only one current injection. We demonstrate how these images can also be used to reconstruct electric field and current density distributions. Reconstructions were performed using a mimetic algorithm and simulations of magnetic flux density from complementary electrode montages, combined with a small-scale machine learning approach. In a biological tissue phantom, we found that the method reduced relative errors between single-current and two-current DT-MREIT results to around 10%. For in vivo human experimental data the error was about 15%. These results suggest that incorporation of machine learning may make it easier to recover electrical conductivity tensors and electric field images during neuromodulation therapy without the need for multiple current administrations.

Low-intensity transcranial focused ultrasound (tFUS) offers new functional neuromodulation opportunities, enabling stimulation of cortical as well as deep brain areas with high spatial resolution. Brain stimulation of awake sheep, in the absence of the confounding effects of anesthesia on brain function, provides translational insight into potential human applications with safety information supplemented by histological analyses. We examined the effects of tFUS pulsing parameters, particularly regarding pulse durations (PDs), on stimulating the cortical motor area (M1) and its thalamic projection in unanesthetized, awake sheep ( n = 8). A wearable tFUS headgear, custom-made for individual sheep, enabled experiments to be conducted without using anesthesia. FUS stimuli, each 200 ms long, were delivered to the M1 and the thalamus using three different PDs (0.5, 1, and 2 ms) with the pulse repetition frequency (PRF) adjusted to maintain a 70% duty cycle at a derated in situ spatial-peak temporal-average intensity (I spta ) of 3.6 W/cm 2 . Efferent electromyography (EMG) responses to stimulation were quantified from both hind limbs. Group-averaged EMG responses from each of the hind limbs across the experimental conditions revealed selective responses from the hind limb contralateral to sonication. The use of 0.5 and 1 ms PDs generated higher EMG signal amplitudes compared to those obtained using a 2 ms PD. Faster efferent response was also observed from thalamic stimulation than that from stimulating the M1. Post-sonication behavioral observation and histological assessment performed 24 h and 1 month after sonication were not indicative of any abnormalities. The results suggest the presence of pulsing scheme-dependent effects of tFUS on brain stimulation and attest its safety in awake large animals.

This work addresses a facile and broadly applicable method of fabricating a new thermoplastic shape memory polymer (SMP) composite by blending three biopolymers such as polyvinyl alcohol, polyvinyl pyrrolidone and polyethylene glycol. Reduced Graphene (rGO) is used as electrical conductive fillers. Iron Oxide (Fe 3 O 4 ) and rGO-Fe 3 O 4 combination provides thermo-electric stimulus. Under the thermal stimulus, shape recovery rate of the SMP with hybrid fillers was faster, having quick response time (28 s) compared to electrical stimulus response time (75 s). The conductivity of the SMP matrices increased by 7, 10 and 15 orders of magnitude by incorporating Fe 3 O 4 , rGO and rGO- Fe 3 O 4 fillers, respectively. Moreover, the proposed shape memory polymer containing rGO-Fe 3 O 4 filler exhibits a higher Young’s modulus (> 80%) compared to neat polymer (1.75 GPa at room temperature and 0.6 GPa at glass transition temperature, T g). A maximum stress of 2.5 MPa and 4% recoverable strain was achieved in the SMP with 10 and 15 wt% of hybrid fillers and interestingly no stored strain evolves, upon cooling below T g . The developed SMP may be applied in morphing wing and other smart actuator applications.

Desynchronizing stimulation techniques were developed to specifically counteract abnormal neuronal synchronization relevant to several neurological and psychiatric disorders. The goal of our approach is to achieve an anti-kindling, where the affected neural networks unlearn abnormal synaptic connectivity and, hence, abnormal neuronal synchrony, by means of desynchronizing stimulation, in particular, Coordinated Reset (CR) stimulation. As known from neuroscience, psychology and education, learning effects can be enhanced by means of the spacing principle, i.e. by delivering repeated stimuli spaced by pauses as opposed to delivering a massed stimulus (in a single long stimulation session). To illustrate that the spacing principle may boost the anti-kindling effect of CR neuromodulation, in this computational study we carry this approach to extremes. To this end, we deliver spaced CR neuromodulation at particularly weak intensities which render permanently delivered CR neuromodulation ineffective. Intriguingly, spaced CR neuromodulation at these particularly weak intensities effectively induces an anti-kindling. In fact, the spacing principle enables the neuronal population to successively hop from one attractor to another one, finally approaching attractors characterized by down-regulated synaptic connectivity and synchrony. Our computational results might open up novel opportunities to effectively induce sustained desynchronization at particularly weak stimulation intensities, thereby avoiding side effects, e.g., in the case of deep brain stimulation.

Sharp-wave ripples (SWRs) are spontaneous neuronal population events that occur in the hippocampus during sleep and quiet restfulness, and are thought to play a critical role in the consolidation of episodic memory. SWRs occur at a rate of 30-200 events per minute. Their overall abundance may, however, be reduced with aging and neurodegenerative disease. Here we report that the abundance of SWR within murine hippocampal slices can be increased by paced administration of a weak electrical stimulus, especially when the spontaneously occurring rate is low or compromised. Resultant SWRs have large variations in amplitude and ripple patterns, which are morphologically indistinguishable from those of spontaneous SWRs, despite identical stimulus parameters which presumably activate the same CA3 neurons surrounding the electrode. The stimulus intensity for reliably pacing SWRs is weaker than that required for inducing detectable evoked field potentials in CA1. Moreover, repetitive ~1 Hz stimuli with low intensity can reliably evoke thousands of SWRs without detectable LTD or \"habituation.\" Our results suggest that weak stimuli may facilitate the spontaneous emergence of SWRs without significantly altering their characteristics. Pacing SWRs with weak electric stimuli could potentially be useful for restoring their abundance in the damaged hippocampus.

This study investigated the welfare consequences of training dogs in the field with manually operated electronic devices (e-collars). Following a preliminary study on 9 dogs, 63 pet dogs referred for recall related problems were assigned to one of three Groups: Treatment Group A were trained by industry approved trainers using e-collars; Control Group B trained by the same trainers but without use of e-collars; and Group C trained by members of the Association of Pet Dog Trainers, UK again without e-collar stimulation (n = 21 for each Group). Dogs received two 15 minute training sessions per day for 4-5 days. Training sessions were recorded on video for behavioural analysis. Saliva and urine were collected to assay for cortisol over the training period. During preliminary studies there were negative changes in dogs' behaviour on application of electric stimuli, and elevated cortisol post-stimulation. These dogs had generally experienced high intensity stimuli without pre-warning cues during training. In contrast, in the subsequent larger, controlled study, trainers used lower settings with a pre-warning function and behavioural responses were less marked. Nevertheless, Group A dogs spent significantly more time tense, yawned more often and engaged in less environmental interaction than Group C dogs. There was no difference in urinary corticosteroids between Groups. Salivary cortisol in Group A dogs was not significantly different from that in Group B or Group C, though Group C dogs showed higher measures than Group B throughout sampling. Following training 92% of owners reported improvements in their dog's referred behaviour, and there was no significant difference in reported efficacy across Groups. Owners of dogs trained using e-collars were less confident of applying the training approach demonstrated. These findings suggest that there is no consistent benefit to be gained from e-collar training but greater welfare concerns compared with positive reward based training.