Validation of Nanosecond Pulse Cancellation Using a Quadrupole Exposure System

Nanosecond pulsed electric fields (nsPEFs) offer a plethora of opportunities for developing integrative technologies as complements or alternatives to traditional medicine. Studies on the biological effects of nsPEFs in vitro and in vivo have revealed unique characteristics that suggest the potential for minimized risk of complications in patients, such as the ability of unipolar nsEPs to create permanent or transient pores in cell membranes that trigger localized lethal or non-lethal outcomes without consequential heating. A more recent finding was that such responses could be diminished by applying a bipolar pulse instead, a phenomenon dubbed bipolar cancellation, paving the way for greater flexibility in nsPEF application design. Transitioning nsPEFs into practical use, however, has been hampered by both device design optimization and the intricacies of mammalian biology. Generating electric fields capable of beneficially manipulating human physiology requires high-voltage electrical pulses of nanosecond duration (nsEPs) with high repetition rates, but pulse generator and electrode design in addition to the complex electrical properties of biological fluids and tissues dictate the strength range and distribution of the resulting electric field. Faced with both promising and challenging aspects to producing a biomedically viable option for inducing a desired nsPEF response that is both focused and minimally invasive, the question becomes: how can the distinct features of unipolar and bipolar nsPEF bioeffects be exploited in a complex electrode exposure system to spatially modulate cell permeabilization? This dissertation presents a systematic study of an efficient coplanar quadrupole electrode nsPEF delivery system that exploits unique differences between unipolar and bipolar nsPEF effects to validate its ability to control cell responses to nsPEFs in space. Four specific aims were established to answer the research question, with specific attention to the roles played by pulse polarity, grounding configuration and electric field magnitude in influencing nsPEF stimulation of electropermeabilization in space. Using a prototype wire electrode applicator charged by a custom-built multimodal pulse generator, the aims were to spatially quantifyelectropermeabilization due (1) unipolar and (2) bipolar nsPEF exposure, to (3) apply synchronized pulses with a view to canceling bipolar cancellation (CANCAN) through superposition that could shift the effective nsPEF response, and to (4) evaluate the ability of the quadrupole system to facilitate remote nsPEF electropermeabilization. Numerical simulations were employed to approximate the nsPEF distribution for a two-dimensional (2-D) area resulting from unipolar, bipolar or CANCAN exposure in a varied-pulse quadrupole electrode configuration. For all experiments, the independent variables were fixed for pulse width (600 ns), pulse number (50) and repetition rate (10 Hz). Electropermeabilization served as the biological endpoint, with green fluorescence due to cell uptake of the nuclear dye YO-PRO-1® (YP1) tracer molecule serving the response variable. An agarose-based 3-D tissue model was used to acquire, quantify and compare fluorescence intensity data in vitro, which was measured by stereomicroscopy to enable macro versus micro level 2-D visualization. Results of this investigation showed that increasing the magnitude of the applied voltage shifts unipolar responses from localization at the anodal to cathodal electrode, and that adding a second proximal ground electrode increases the response area. Bipolar nsPEF responses were generally less intense than unipolar, but these depended on both the inter-electrode location measured and amplitude of the second phase. CANCAN preliminary indicated some ability to decrease strong uptake at electrodes, but evaluation across experimental and published data indicate that greater differences between unipolar and bipolar responses are needed to improve possibilities for distal stimulation. Overall, this work demonstrated the potential for more complex pulser-electrode configurations to successfully modulate nsPEF electropermeabilization in space by controlling unipolar and bipolar pulse delivery and contributed to a deeper understanding of bipolar cancellation. By providing a set of metrics for test and evaluation, the data provided herein may serve to inform model development to support prediction of nsPEF outcomes and help to more acutely define spatial-intensity relationships between nsPEFs and cell permeabilization as well as delineate requirements for future non-invasive nsPEF therapies

Brain and Human Body Modeling 2020

​This open access book describes modern applications of computational human modeling in an effort to advance neurology, cancer treatment, and radio-frequency studies including regulatory, safety, and wireless communication fields. Readers working on any application that may expose human subjects to electromagnetic radiation will benefit from this book’s coverage of the latest models and techniques available to assess a given technology’s safety and efficacy in a timely and efficient manner. Describes computational human body phantom construction and application; Explains new practices in computational human body modeling for electromagnetic safety and exposure evaluations; Includes a survey of modern applications for which computational human phantoms are critical

Modulation of neural oscillations and associated behaviour by transcranial Alternating Current Stimulation (tACS)

Transcranial alternating current stimulation (tACS) is a non-invasive brain stimulation method that involves the application of weak electric currents to the scalp. tACS has the potential to be an inexpensive, easily administrable, and well-tolerated multi-purpose tool for cognitive and clinical neuroscience as it could be applied to establish the functional role of rhythmic brain activity, and to treat neural disorders, in particular those where these rhythms have gone awry. However, the mechanisms by which tACS produces both "online" and "offline" effects (that is, those that manifest during stimulation and those that last beyond stimulation offset) are to date still poorly understood. If the potential of tACS is to be harnessed effectively to alter brain activity in a controlled manner, it is fundamental to have a good understanding of how tACS interacts with neuronal dynamics, and of the conditions that promote its effect. This thesis describes three experiments that were conducted to elucidate the mechanisms by which tACS interacts with underlying neural network activity. Experiments 1 and 2 investigated the mechanism by which tACS at alpha frequencies (8 12 Hz, α-tACS) over occipital cortex induces the lasting aftereffects on posterior α power that were previously described in the literature. Two mechanisms have been suggested to underlie alpha power enhancement after α tACS: entrainment of endogenous brain oscillations and/or changes in oscillatory neural networks through spike timing-dependent plasticity (STDP). In Experiment 1, we tested to what extent plasticity can account for tACS-aftereffects when controlling for entrainment characteristics. To this end, we used a novel, intermittent α-tACS protocol and investigated the strength of the aftereffect as a function of phase continuity between successive tACS episodes, as well as the match between stimulation frequency and individual alpha frequency (IAF). Alpha aftereffects were successfully replicated with enhanced α power after intermittent stimulation compared to sham. These aftereffects did not exhibit any of the expected characteristics of prolonged entrainment in that they were independent of tACS phase-continuity and did not show stable phase alignment or synchronisation to the stimulation frequency. These results indicate that prolonged entrainment is insufficient to explain the aftereffects and suggest that the latter emerge through some form of network plasticity. To clarify the nature of these plasticity mechanisms, we then aimed to assess whether STDP could explain the α power increase. We developed a conceptual STDP model that predicted bi-directional changes in α power depending on the relative mismatch between the tACS frequency and IAF. After observing in Experiment 1 that tACS at frequencies slightly lower than the IAF produced α enhancement, Experiment 2 used a similar intermittent protocol that manipulated tACS frequency to be either slightly lower or higher than IAF to respectively enhance or suppress α activity. In addition, a control condition with continuous stimulation aimed to replicate previous results from other groups. However, we did not observe a systematic α power change in any of the active conditions. The lack of consistency between the two experiments raises concerns regarding the reproducibility and effect size of tACS aftereffects. The third experiment investigated the mechanism of online effects and tested predictions that were based on the assumption that entrainment is the underlying process mediating behavioural changes during tACS. We capitalised on two well-described phenomena: firstly, the association between α power lateralisation and visuospatial attention, and secondly, the fluctuation of perceptual performance with α phase. Specifically, the experiment tested whether event-related α-tACS applied over right parieto-occipital cortex can induce a visuospatial bias in a peripheral dot detection task that would reflect α power lateralisation, and whether detection performance depends on the phase of the tACS waveform. In control trials either no tACS or 40 Hz-tACS (gamma) was applied to make use of the putative opposing roles of alpha and gamma oscillations in visual processing. As expected from lateralised enhancement of alpha oscillations, visual detection accuracy was weakly impaired for targets presented in the left visual field, contralateral to tACS. However, this effect was neither frequency specific nor waveform phase-dependent. Therefore, it is unlikely that the negative effect of tACS on visuospatial performance reflects entrainment. Overall, the results of these experiments only partially met our hypotheses. Experiment 1 produced the α enhancement that was expected based on the literature while the follow-up experiment failed to reproduce these results under similar conditions. This outcome demonstrates at best that tACS aftereffects on α activity are not robust, may vary widely across individuals, and might be extremely sensitive to small changes in experimental parameters and state variables. The results of the third experiment call into question the assumption of online entrainment as basis for the observed behavioural effect. These findings point to the need for improved methodology, for more systematic and exhaustive exploration of the relative effects of tACS across different parameter settings, tasks, and individuals; and for the replication of promising but thus far often anecdotal results. They also inspire guidelines for more informative experimental designs

New Training Strategies and Evaluation Methods for Improving Health and Physical Performance

The aim of this Special Issue was to propose, on the basis of the evidence that the current literature provides, new training techniques and specific evaluation methods for the different populations practicing physical activity

Applications of EMG in Clinical and Sports Medicine

This second of two volumes on EMG (Electromyography) covers a wide range of clinical applications, as a complement to the methods discussed in volume 1. Topics range from gait and vibration analysis, through posture and falls prevention, to biofeedback in the treatment of neurologic swallowing impairment. The volume includes sections on back care, sports and performance medicine, gynecology/urology and orofacial function. Authors describe the procedures for their experimental studies with detailed and clear illustrations and references to the literature. The limitations of SEMG measures and methods for careful analysis are discussed. This broad compilation of articles discussing the use of EMG in both clinical and research applications demonstrates the utility of the method as a tool in a wide variety of disciplines and clinical fields

Spatio-temporal evolution of interictal epileptic activity : a study with unaveraged multichannel MEG data in association with MRIs.

This thesis addresses issues relating to MEG modelling, analysis and interpretation of results. A source model employing current density distributions, namely Magnetic Field Tomography (MET), is used to obtain the MEG results. The first issue of concern refers to the registration of MEG data with structural MR images in an attempt to improve the localisation capability of MEG/MET. Simulations testing some spatial and tem poral aspects of the reconstruction capability of MET are also provided. A novel way of conducting MET studies in depth is suggested and implemented: the iterative use of a source space designed to cover deep situated structures on either side of the brain. The main bulk of this thesis is concerned with research into interictal epileptic activity as recorded by means of multichannel MEG system s and analysed using MET. The major aim is to investigate whether or not MET analysis of unaveraged MEG data (single epochs) is feasible in cases of pathophysiological signals and more specifically interictal signals from patients with epilepsy of a complex partial type. The investigation is undertaken against the "traditional" view of the impropriety and absurdity of using single epoch records in the MEG analysis due to noise dominance; we provide evidence that analysis of single, unaveraged epileptic spikes is actually feasible: we demonstrate spatio-temporal coherence in the MET results of the various single interictal events and show that activity extracted from the "averaged event" is made up of activity contributions which occur intermittently and at variable latencies. Our statements are drawn from the study of both superficial and deep activity