Transcranial Direct Current Stimulation in the Treatment of Gait Disturbance in Post-Stroke Patients: An Overview of Systematic Reviews.

INTRODUCTION: Transcranial direct current stimulation (tDCS) is a promising technique for brain modulation after a cerebrovascular accident (CVA). This treatment modality has been previously studied in the recovery of patients. The aim of this review is to analyse the evidence for the application of tDCS in the recovery of gait disturbance in stroke patients. METHODS: This review was conducted according to the recommendations of the PRISMA statement. Three different electronic databases were searched for relevant results: PubMed, Scopus, and Cochrane, from 2015 to January 2022. We included reviews and meta-analyses that only considered randomised controlled trials (RCTs) that investigated the effects of transcranial direct current stimulation, in combination or not with other physiotherapy treatments, compared to no treatment, usual care, or alternative treatment on gait recovery. Our primary outcomes of interest were walking speed, mobility, and endurance; secondary outcomes included motor function. RESULTS: Thirteen studies with a total of 195 RCTs were included. Data on population, outcome measures, protocols, and outcomes were extracted. The Amstar-2 scale and the GRADE system of certainty of evidence were used. Only one study received high certainty of evidence, 5 received low certainty of evidence, and 7 received critically low certainty of evidence. Moderate to low-quality evidence showed a beneficial effect of tDCS on gait parameters, but not significantly. CONCLUSIONS: Although the tDCS produces positive changes in gait recovery in spatio-temporal parameters such as mobility, endurance, strength, and motor function, there is insufficient evidence to recommend this treatment. Higher-quality studies with larger sample sizes are needed for stronger conclusions.

The Role of the Posterior Cerebellum in Dysfunctional Social Sequencing.

Recent advances in social neuroscience have highlighted the critical role of the cerebellum in social cognition, and especially the posterior cerebellum. Studies have supported the view that the posterior cerebellum builds internal action models of our social interactions to predict how other people's actions will be executed and what our most likely responses are to these actions. This mechanism allows to better anticipate action sequences during social interactions in an automatic and intuitive way and to fine-tune these anticipations, making it easier to understand other's social behaviors and mental states (e.g., beliefs, intentions, traits). In this paper, we argue that the central role of the posterior cerebellum in identifying and automatizing social action sequencing provides a fruitful starting point for investigating social dysfunctions in a variety of clinical pathologies, such as autism, obsessive-compulsive and bipolar disorder, depression, and addiction. Our key hypothesis is that dysfunctions of the posterior cerebellum lead to under- or overuse of inflexible social routines and lack of plasticity for learning new, more adaptive, social automatisms. We briefly review past research supporting this view and propose a program of research to test our hypothesis. This approach might alleviate a variety of mental problems of individuals who suffer from inflexible automatizations that stand in the way of adjustable and intuitive social behavior, by increasing posterior cerebellar plasticity using noninvasive neurostimulation or neuro-guided training programs.

Electrotactile Feedback for the Discrimination of Different Surface Textures Using a Microphone.

Most commercial prosthetic hands lack closed-loop feedback, thus, a lot of research has been focusing on implementing sensory feedback systems to provide the user with sensory information during activities of daily living. This study evaluates the possibilities of using a microphone and electrotactile feedback to identify different textures. A condenser microphone was used as a sensor to detect the friction sound generated from the contact between different textures and the microphone. The generated signal was processed to provide a characteristic electrical stimulation presented to the participants. The main goal of the processing was to derive a continuous and intuitive transfer function between the microphone signal and stimulation frequency. Twelve able-bodied volunteers participated in the study, in which they were asked to identify the stroked texture (among four used in this study: Felt, sponge, silicone rubber, and string mesh) using only electrotactile feedback. The experiments were done in three phases: (1) Training, (2) with-feedback, (3) without-feedback. Each texture was stroked 20 times each during all three phases. The results show that the participants were able to differentiate between different textures, with a median accuracy of 85%, by using only electrotactile feedback with the stimulation frequency being the only variable parameter.

No efficacy of transcranial direct current stimulation on chronic migraine with medication overuse: A double blind, randomised clinical trial.

BACKGROUND: Transcranial direct current stimulation was suggested to provide beneficial effects in chronic migraine, a condition often associated with medication overuse for which no long-term therapy is available. METHODS: We conducted a randomised controlled trial to assess long-term efficacy of transcranial direct current stimulation. Adults diagnosed with chronic migraine and medication overuse were assigned to receive in a 1:1:1 ratio anodal, cathodal, or sham transcranial direct current stimulation daily for five consecutive days, along with standardised drug withdrawal protocol. Primary outcome was 50% reduction of days of headache per month at 12 months. Co-secondary outcomes were 50% reduction of days of headache per month at 6 months, reduction of analgesic intake per month, and change in disability and quality of life, catastrophising, depression, state and trait anxiety, dependence attitude and allodynia intensity. Patients were not allowed to take any migraine prophylaxis drug for the entire study period. RESULTS: We randomly allocated 135 patients to anodal (44), cathodal (45), and sham (46) transcranial direct current stimulation. At 6 and 12 months, the percentage of reduction of days of headache and number of analgesics per month ranged between 48.5% and 64.7%, without differences between transcranial direct current stimulation (cathodal, anodal, or the results obtained from the two arms of treatment, anodal plus cathodal) and sham. Catastrophising attitude significantly reduced at 12 months in all groups. There was no difference for the other secondary outcomes. CONCLUSIONS: Transcranial direct current stimulation did not influence the short and long-term course of chronic migraine with medication overuse after acute drug withdrawal. Behavioral and educational measures and support for patients' pain management could provide long-term improvement and low relapse rate.Trial registration number NCT04228809.

Neural changes associated with cerebellar tDCS studied using MR spectroscopy.

Anodal cerebellar transcranial direct current stimulation (tDCS) is known to enhance motor learning, and therefore, has been suggested to hold promise as a therapeutic intervention. However, the neural mechanisms underpinning the effects of cerebellar tDCS are currently unknown. We investigated the neural changes associated with cerebellar tDCS using magnetic resonance spectroscopy (MRS). 34 healthy participants were divided into two groups which received either concurrent anodal or sham cerebellar tDCS during a visuomotor adaptation task. The anodal group underwent an additional session involving MRS in which the main inhibitory and excitatory neurotransmitters: GABA and glutamate (Glu) were measured pre-, during, and post anodal cerebellar tDCS, but without the behavioural task. We found no significant group-level changes in GABA or glutamate during- or post-tDCS compared to pre-tDCS levels, however, there was large degree of variability across participants. Although cerebellar tDCS did not affect visuomotor adaptation, surprisingly cerebellar tDCS increased motor memory retention with this being strongly correlated with a decrease in cerebellar glutamate levels during tDCS across participants. This work provides novel insights regarding the neural mechanisms which may underlie cerebellar tDCS, but also reveals limitations in the ability to produce robust effects across participants and between studies.

Non-Invasive Brain Stimulation in Dementia: A Complex Network Story.

Non-invasive brain stimulation (NIBS) is emerging as a promising rehabilitation tool for a number of neurodegenerative diseases. However, the therapeutic mechanisms of NIBS are not completely understood. In this review, we will summarize NIBS results in the context of brain imaging studies of functional connectivity and metabolites to gain insight into the possible mechanisms underlying recovery. We will briefly discuss how the clinical manifestations of common neurodegenerative disorders may be related with aberrant connectivity within large-scale neural networks. We will then focus on recent studies combining resting-state functional magnetic resonance imaging with NIBS to delineate how stimulation of different brain regions induce complex network modifications, both at the local and distal level. Moreover, we will review studies combining magnetic resonance spectroscopy and NIBS to investigate how microscale changes are related to modifications of large-scale networks. Finally, we will re-examine previous NIBS studies in dementia in light of this network perspective. A better understanding of NIBS impact on the functionality of large-scale brain networks may be useful to design beneficial treatments for neurodegenerative disorders.

Activation of primate frontal eye fields with a CMUT phased array system.

BACKGROUND: There are pushes toward non-invasive stimulation of neural tissues to prevent issues that arise from invasive brain recordings and stimulation. Transcranial Focused Ultrasound (TFUS) has been examined as a way to stimulate non-invasively, but previous studies have limitations in the application of TFUS. As a result, refinement is needed to improve stimulation results. NEW METHOD: We utilized a custom-built capacitive micromachined ultrasonic transducer (CMUT) that would send ultrasonic waves through skin and skull to targets located in the Frontal Eye Fields (FEF) region triangulated from co-registered MRI and CT scans while a non-human primate subject was performing a discrimination behavioral task. RESULTS: We observed that the stimulation immediately caused changes in the local field potential (LFP) signal that continued until stimulation ended, at which point there was higher voltage upon the cue for the animal to saccade. This co-incided with increases in activity in the alpha band during stimulation. The activity rebounded mid-way through our electrode-shank, indicating a specific point of stimulation along the shank. We observed different LFP signals for different stimulation targets, indicating the ability to"steer" the stimulation through the transducer. We also observed a bias in first saccades towards the opposite direction. CONCLUSIONS: In conclusion, we provide a new approach for non-invasive stimulation during performance of a behavioral task. With the ability to steer stimulation patterns and target using a large amount of transducers, the ability to provide non-invasive stimulation will be greatly improved for future clinical and research applications.

Interfering with sleep apnea.

The effects of electromagnetic interference have been hiding in plain sight for millennia and are now being applied to the non-invasive stimulation of deep tissues. In the article by Missey et al., the effect of non-invasive stimulation of the hypoglossal nerve by an interference envelope of interfering carrier waves is examined in mice and participants with sleep apnea. This stimulation is capable of activating the nerve and reducing apnea-hypopnea events. Temporally interfering electric fields have potential applications far beyond hypoglossal stimulation and may represent a revolutionary new approach to treating illness and understanding the functional organization of the nervous system.

Choosing the optimal target area for repeated transcranial magnetic stimulation in treating neuropathic pain in spinal cord injury patients: a comparative analysis.

Objective: The specific target area of repeated transcranial magnetic stimulation (rTMS) in treating neuropathic pain resulting from spinal cord injury (SCI-NP) remains uncertain. Methods: Thirty-four participants with SCI-NP were allocated into three groups, namely, the motor cortex (M1, A) group, the left dorsolateral prefrontal cortex (LDLPFC, B) group, and the control (sham stimulation, C) group. The intervention was administered totally 10 times. Outcome measures assessed pre-(T0) and post-(T1)intervention, including Numerical Rating scale (NRS), anxiety (SAS), depression (SDS), sleep quality (PSQI), brief pain inventory (BPI), and impression of change. Results: All outcomes in groups A and B significantly changed after intervention (p < 0.05), and the delta value (T1-T0) also significantly changed than group C (p < 0.05). The delta value of SDS in the group B was better than the group A, and the change of pain degree in the group B was moderately correlated with the change in PSQI (r = 0.575, p < 0.05). Both patients in the groups A and B showed significant impression of change about their received therapy (p < 0.05). Conclusion: Both targets are effective, but LDLPFC is more effective in reducing depression in SCI-NP. Healthcare providers might select the suitable area according to the specific attributes of their patients.

Cathodal high-definition transcranial direct current stimulation (HD-tDCS) of the left ventral prefrontal cortex (vPFC) interferes with conscious error correction.

Precise motor timing requires the ability to flexibly adapt one's own movements with respect to changes in the environment. Previous studies suggest that the correction of perceived as compared to non-perceived timing errors involves at least partially distinct brain networks. The dorsolateral prefrontal cortex (dPFC) has been linked to the correction of perceived timing errors and evidence for a contribution of the ventrolateral PFC (vPFC) specifically to the correction of non-perceived errors exists. The present study aimed at clarifying the functional contribution of the left vPFC for the correction of timing errors by adopting high-definition transcranial direct current stimulation (HD-tDCS). Twenty-one young healthy volunteers synchronized their right index finger taps with respect to an isochronous auditory pacing signal. Perceivable and non-perceivable step-changes of the metronome were interspersed, and error correction was analyzed by means of the phase-correction response (PCR). In subsequent sessions anodal and cathodal HD-tDCS was applied to the left vPFC to establish a brain-behavior relationship. Sham stimulation served as control condition. Synchronization accuracy as well as error correction were determined immediately prior to and after HD-tDCS. The analysis suggests a detrimental effect of cathodal HD-tDCS distinctively on error correction in trials with perceived timing errors. The data support the significance of the left vPFC for error correction in the temporal domain but contradicts the view of a role in the correction of non-perceived errors.

Better Fields or Currents? A Head-to-Head Comparison of Transcranial Magnetic (rTMS) Versus Direct Current Stimulation (tDCS) for Neuropathic Pain.

While high-frequency transcranial magnetic stimulation (HF-rTMS) is now included in the armamentarium to treat chronic neuropathic pain (NP), direct-current anodal stimulation (a-tDCS) to the same cortical targets may represent a valuable alternative in terms of feasibility and cost. Here we performed a head-to-head, randomized, single-blinded, cross-over comparison of HF-rTMS versus a-tDCS over the motor cortex in 56 patients with drug-resistant NP, who received 5 daily sessions of each procedure, with a washout of at least 4 weeks. Daily scores of pain, sleep, and fatigue were obtained during 5 consecutive weeks, and functional magnetic resonance imaging (fMRI) to a motor task was performed in a subgroup of 31 patients. The percentage of responders, defined by a reduction in pain scores of > 2 SDs from pre-stimulus levels, was similar to both techniques (42.0% vs. 42.3%), while the magnitude of "best pain relief" was significantly skewed towards rTMS. Mean pain ratings in responders decreased by 32.6% (rTMS) and 29.6% (tDCS), with half of them being sensitive to only one technique. Movement-related fMRI showed significant activations in motor and premotor areas, which did not change after 5 days of stimulation, and did not discriminate responders from non-responders. Both HF-rTMS and a-tDCS showed efficacy at 1 month in drug-resistant NP, with magnitude of relief slightly favoring rTMS. Since a significant proportion of patients responded to one procedure only, both modalities should be tested before declaring a patient as unresponsive.

New trends in non-pharmacological approaches for cardiovascular disease: Therapeutic ultrasound.

Significant advances in application of therapeutic ultrasound have been reported in the past decades. Therapeutic ultrasound is an emerging non-invasive stimulation technique. This approach has shown high potential for treatment of various disease including cardiovascular disease. In this review, application principle and significance of the basic parameters of therapeutic ultrasound are summarized. The effects of therapeutic ultrasound in myocardial ischemia, heart failure, myocarditis, arrhythmias, and hypertension are explored, with key focus on the underlying mechanism. Further, the limitations and challenges of ultrasound therapy on clinical translation are evaluated to promote application of the novel strategy in cardiovascular diseases.

Next generation CANCAN focusing for remote stimulation by nanosecond electric pulses.

Focusing electric pulse effects away from electrodes is a challenge because the electric field weakens with distance. Previously we introduced a remote focusing method based on bipolar cancellation, a phenomenon of low efficiency of bipolar nanosecond electric pulses (nsEP). Superpositioning two bipolar nsEP into a unipolar pulse canceled bipolar cancellation ("CANCAN" effect), enhancing bioeffects at a distance despite the electric field weakening. Here, we introduce the next generation (NG) CANCAN focusing with unipolar nsEP packets designed to produce bipolar waveforms near electrodes (suppressing electroporation) but not at the remote target. NG-CANCAN was tested in CHO cell monolayers using a quadrupole electrode array and labeling electroporated cells with YO-PRO-1 dye. We routinely achieved 1.5-2 times stronger electroporation in the center of the quadrupole than near electrodes, despite a 3-4-fold field attenuation. With the array lifted 1-2 mm above the monolayer (imitating a 3D treatment), the remote effect was enhanced up to 6-fold. We analyzed the role of nsEP number, amplitude, rotation, and inter-pulse delay, and showed how remote focusing is enhanced when re-created bipolar waveforms exhibit stronger cancellation. Advantages of NG-CANCAN include the exceptional versatility of designing pulse packets and easy remote focusing using an off-the-shelf 4-channel nsEP generator.

Advances in Spinal Cord Neuromodulation: The Integration of Neuroengineering, Computational Approaches, and Innovative Conceptual Frameworks.

Spinal cord stimulation (SCS) is an approved treatment for intractable pain and has recently emerged as a promising area of research for restoring function after spinal cord lesion. This review will focus on the historical evolution of this transition and the path that remains to be taken for these methods to be rigorously evaluated for application in clinical practice. New developments in SCS are being driven by advances in the understanding of spinal cord lesions at the molecular, cellular, and neuronal levels, as well as the understanding of compensatory mechanisms. Advances in neuroengineering and the computational neurosciences have enabled the development of new conceptual SCS strategies, such as spatiotemporal neuromodulation, which allows spatially selective stimulation at precise time points during anticipated movement. It has also become increasingly clear that these methods are only effective when combined with intensive rehabilitation techniques, such as new task-oriented methods and robotic aids. The emergence of innovative approaches to spinal cord neuromodulation has sparked significant enthusiasm among patients and in the media. Non-invasive methods are perceived to offer improved safety, patient acceptance, and cost-effectiveness. There is an immediate need for well-designed clinical trials involving consumer or advocacy groups to evaluate and compare the effectiveness of various treatment modalities, assess safety considerations, and establish outcome priorities.

Effects of different transcranial magnetic stimulations on neuropathic pain after spinal cord injury.

Introduction: Repetitive transcranial magnetic stimulation (rTMS) is an effective non-invasive cortical stimulation technique in the treatment of neuropathic pain. As a new rTMS technique, intermittent theta burst stimulation (iTBS) is also effective at relieving pain. We aimed to establish the pain-relieving effectiveness of different modalities on neuropathic pain. The study was conducted in individuals with spinal cord injury (SCI) and different modalities of rTMS. Methods: Thirty-seven individuals with SCI were randomly allocated to three groups, in which the "iTBS" group received iTBS, the "rTMS" group received 10 Hz rTMS, and the "iTBS + rTMS" group received iTBS and 10 Hz rTMS successively of the primary motor cortex 5 days a week for 4 weeks, and they all underwent the full procedures. The primary outcome measure was change in the visual analog scale (VAS), and the secondary outcomes were measured using the Hamilton Rating Scale for Depression (HAM-D) and the Pittsburgh Sleep Quality Index (PSQI). All the outcomes were evaluated at 1 day before stimulation (baseline), 1 day after the first week of stimulation (S1), and 1 day after the last stimulation (S2). Results: The VAS scores showed significant pain improvement after 4 weeks of stimulation (p = 0.0396, p = 0.0396, and p = 0.0309, respectively) but not after 1 week of stimulation. HAM-D scores declined, but the decreases were not significant until 4 weeks later (p = 0.0444, p = 0.0315, and p = 0.0447, respectively). PSQI scores were also significantly decreased after 4 weeks of stimulation (p = 0.0446, p = 0.0244, and p = 0.0088, respectively). Comparing the three modalities, VAS, HAM-D, and PSQI scores at S1 showed no differences, and, at S2, VAS scores showed significant differences (p = 0.0120; multiple comparisons showed significant differences between iTBS and iTBS + rTMS, p = 0.0091), while the HAM-D and PSQI scores showed no differences. Discussion: The primary and secondary outcomes all showed significant improvement, indicating that the three different modalities were all effective at relieving the pain. However, not all the three stimulations were of same effectiveness after treatment; there were statistical differences in the treatment of neuropathic pain between iTBS as a priming stimulus and as a single procedure.

Translational approaches to influence sleep and arousal.

Sleep disorders are widespread in society and are prevalent in military personnel and in Veterans. Disturbances of sleep and arousal mechanisms are common in neuropsychiatric disorders such as schizophrenia, post-traumatic stress disorder, anxiety and affective disorders, traumatic brain injury, dementia, and substance use disorders. Sleep disturbances exacerbate suicidal ideation, a major concern for Veterans and in the general population. These disturbances impair quality of life, affect interpersonal relationships, reduce work productivity, exacerbate clinical features of other disorders, and impair recovery. Thus, approaches to improve sleep and modulate arousal are needed. Basic science research on the brain circuitry controlling sleep and arousal led to the recent approval of new drugs targeting the orexin/hypocretin and histamine systems, complementing existing drugs which affect GABAA receptors and monoaminergic systems. Non-invasive brain stimulation techniques to modulate sleep and arousal are safe and show potential but require further development to be widely applicable. Invasive viral vector and deep brain stimulation approaches are also in their infancy but may be used to modulate sleep and arousal in severe neurological and psychiatric conditions. Behavioral, pharmacological, non-invasive brain stimulation and cell-specific invasive approaches covered here suggest the potential to selectively influence arousal, sleep initiation, sleep maintenance or sleep-stage specific phenomena such as sleep spindles or slow wave activity. These manipulations can positively impact the treatment of a wide range of neurological and psychiatric disorders by promoting the restorative effects of sleep on memory consolidation, clearance of toxic metabolites, metabolism, and immune function and by decreasing hyperarousal.

Focal non-invasive deep-brain stimulation with temporal interference for the suppression of epileptic biomarkers.

Introduction: Neurostimulation applied from deep brain stimulation (DBS) electrodes is an effective therapeutic intervention in patients suffering from intractable drug-resistant epilepsy when resective surgery is contraindicated or failed. Inhibitory DBS to suppress seizures and associated epileptogenic biomarkers could be performed with high-frequency stimulation (HFS), typically between 100 and 165 Hz, to various deep-seated targets, such as the Mesio-temporal lobe (MTL), which leads to changes in brain rhythms, specifically in the hippocampus. The most prominent alterations concern high-frequency oscillations (HFOs), namely an increase in ripples, a reduction in pathological Fast Ripples (FRs), and a decrease in pathological interictal epileptiform discharges (IEDs). Materials and methods: In the current study, we use Temporal Interference (TI) stimulation to provide a non-invasive DBS (130 Hz) of the MTL, specifically the hippocampus, in both mouse models of epilepsy, and scale the method using human cadavers to demonstrate the potential efficacy in human patients. Simulations for both mice and human heads were performed to calculate the best coordinates to reach the hippocampus. Results: This non-invasive DBS increases physiological ripples, and decreases the number of FRs and IEDs in a mouse model of epilepsy. Similarly, we show the inability of 130 Hz transcranial current stimulation (TCS) to achieve similar results. We therefore further demonstrate the translatability to human subjects via measurements of the TI stimulation vs. TCS in human cadavers. Results show a better penetration of TI fields into the human hippocampus as compared with TCS. Significance: These results constitute the first proof of the feasibility and efficiency of TI to stimulate at depth an area without impacting the surrounding tissue. The data tend to show the sufficiently focal character of the induced effects and suggest promising therapeutic applications in epilepsy.

Measuring brain response to transcutaneous vagus nerve stimulation (tVNS) using simultaneous magnetoencephalography (MEG).

Objective.Transcutaneous vagus nerve stimulation (tVNS) is a form of non-invasive brain stimulation that delivers a sequence of electrical pulses to the auricular branch of the vagus nerve and is used increasingly in the treatment of a number of health conditions such as epilepsy and depression. Recent research has focused on the efficacy of tVNS to treat different medical conditions, but there is little conclusive evidence concerning the optimal stimulation parameters. There are relatively few studies that have combined tVNS with a neuroimaging modality, and none that have attempted simultaneous magnetoencephalography (MEG) and tVNS due to the presence of large stimulation artifacts produced by the electrical stimulation which are many orders of magnitude larger than underlying brain activity.Approach.The aim of this study is to investigate the utility of MEG to gain insight into the regions of the brain most strongly influenced by tVNS and how variation of the stimulation parameters can affect this response in healthy participants.Main results.We have successfully demonstrated that MEG can be used to measure brain response to tVNS. We have also shown that varying the stimulation frequency can lead to a difference in brain response, with the brain also responding in different anatomical regions depending on the frequency.Significance.The main contribution of this paper is to demonstrate the feasibility of simultaneous pulsed tVNS and MEG recording, allowing direct investigation of the changes in brain activity that result from different stimulation parameters. This may lead to the development of customised therapeutic approaches for the targeted treatment of different conditions.

Analyzing the Effects of Parameters for Tremor Modulation via Phase-Locked Electrical Stimulation on a Peripheral Nerve.

(1) Background: Non-invasive neuromodulation is a promising alternative to medication or deep-brain stimulation treatment for Parkinson's Disease or essential tremor. In previous work, we developed and tested a wearable system that modulates tremor via the non-invasive, electrical stimulation of peripheral nerves. In this article, we examine the proper range and the effects of various stimulation parameters for phase-locked stimulation. (2) Methods: We recruited nine participants with essential tremor. The subjects performed a bean-transfer task that mimics an eating activity to elicit kinetic tremor while using the wearable stimulation system. We examined the effects of stimulation with a fixed duty cycle, at different stimulation amplitudes and frequencies. The epochs of stimulation were locked to one of four phase positions of ongoing tremor, as measured with an accelerometer. We analyzed stimulation-evoked changes of the frequency and amplitude of tremor. (3) Results: We found that the higher tremor amplitude group experienced a higher rate of tremor power reduction (up to 65%) with a higher amplitude of stimulation when the stimulation was applied at the ±peak of tremor phase. (4) Conclusions: The stimulation parameter can be adjusted to optimize tremor reduction, and this study lays the foundation for future large-scale parameter optimization experiments for personalized peripheral nerve stimulation.

Interference targeting of bipolar nanosecond electric pulses for spatially focused electroporation, electrostimulation, and tissue ablation.

Stimulation and electroporation by nanosecond electric pulses (nsEP) are distinguished by a phenomenon of bipolar cancellation, which stands for a reduced efficiency of bipolar pulses compared to unipolar ones. When two pairs of stimulating electrodes are arrayed in a quadrupole, bipolar cancellation inhibits nsEP effects near the electrodes, where the electric field is the strongest. Two properly shaped and synchronized bipolar nsEP overlay into a unipolar pulse towards the center of the electrode array, thus canceling the bipolar cancellation (a "CANCAN effect"). High efficiency of the re-created unipolar nsEP outweighs the weakening of the electric field with distance and focuses nsEP effects to the center. In monolayers of CHO, BPAE, and HEK cells, CANCAN effect achieved by the interference of two bipolar nsEP enhanced electroporation up to tenfold, with a peak at the quadrupole center. Introducing a time interval between bipolar nsEP prevented the formation of a unipolar pulse and eliminated the CANCAN effect. Strong electroporation by CANCAN stimuli killed cells over the entire area encompassed by the electrodes, whereas the time-separated pulses caused ablation only in the strongest electric field near the electrodes. The CANCAN approach is promising for uniform tumor ablation and stimulation targeting away from electrodes.