Functional MRI with active, fully implanted, deep brain stimulation systems: Safety and experimental confounds

We investigated safety issues and potential experimental confounds when performing functional magnetic resonance imaging (fMRI) investigations in human subjects with fully implanted, active, deep brain stimulation (DBS) systems. Measurements of temperature and induced voltage were performed in an in vitro arrangement simulating bilateral DBS during magnetic resonance imaging (MRI) using head transmit coils in both 1.5 and 3.0 T MRI systems. For MRI sequences typical of an fMRI study with coil-averaged specific absorption rates (SARs) less than 0.4 W/kg, no MRI-induced temperature change greater than the measurement sensitivity (0.1 °C) was detected at 1.5 T, and at 3 T temperature elevations were less than 0.5 °C, i.e. within safe limits. For the purposes of demonstration, MRI pulse sequences with SARs of 1.45 W/kg and 2.34 W/kg (at 1.5 T and 3 T, respectively) were prescribed and elicited temperature increases (> 1 °C) greater than those considered safe for human subjects. Temperature increases were independent of the presence or absence of active stimulator pulsing. At both field strengths during echo planar MRI, the perturbations of DBS equipment performance were sufficiently slight, and temperature increases sufficiently low to suggest that thermal or electromagnetically mediated experimental confounds to fMRI with DBS are unlikely. We conclude that fMRI studies performed in subjects with subcutaneously implanted DBS units can be both safe and free from DBS-specific experimental confounds. Furthermore, fMRI in subjects with fully implanted rather than externalised DBS stimulator units may offer a significant safety advantage. Further studies are required to determine the safety of MRI with DBS for other MRI systems, transmit coil configurations and DBS arrangements

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

Complex myograph allows the examination of complex muscle contractions for the assessment of muscle force, shortening, velocity, and work in vivo

<p>Abstract</p> <p>Background</p> <p>The devices used for <it>in vivo </it>examination of muscle contractions assess only pure force contractions and the so-called isokinetic contractions. In isokinetic experiments, the extremity and its muscle are artificially moved with constant velocity by the measuring device, while a tetanic contraction is induced in the muscle, either by electrical stimulation or by maximal voluntary activation. With these systems, experiments cannot be performed at pre-defined, constant muscle length, single contractions cannot be evaluated individually and the separate examination of the isometric and the isotonic components of single contractions is not possible.</p> <p>Methods</p> <p>The myograph presented in our study has two newly developed technical units, i.e. a). a counterforce unit which can load the muscle with an adjustable, but constant force and b). a length-adjusting unit which allows for both the stretching and the contraction length to be infinitely adjustable independently of one another. The two units support the examination of complex types of contraction and store the counterforce and length-adjusting settings, so that these conditions may be accurately reapplied in later sessions.</p> <p>Results</p> <p>The measurement examples presented show that the muscle can be brought to every possible pre-stretching length and that single isotonic or complex isometric-isotonic contractions may be performed at every length. The applied forces act during different phases of contraction, resulting into different pre- and after-loads that can be kept constant – uninfluenced by the contraction. Maximal values for force, shortening, velocity and work may be obtained for individual muscles. This offers the possibility to obtain information on the muscle status and to monitor its changes under non-invasive measurement conditions.</p> <p>Conclusion</p> <p>With the Complex Myograph, the whole spectrum of a muscle's mechanical characteristics may be assessed.</p

Cancer treatment: an overview of pulsed electric field utilization and generation

Patients diagnosed with cancer receive different types of treatments based on the type and the level of the tumour. An emerging treatment that differs from well-developed systematic therapies (i.e., Chemotherapy, Radiotherapy, and Immunotherapy) is Tumour Treating Field (TTF) treatment. Tumour behaviour under TTF treatment varies based on the electric field intensity; the process of exposing the tumour cells to an electric field is called electroporation. From the electrical perspective, the most efficient method for electroporation is to use a voltage pulse generator. Several pulse generator topologies have been introduced to overcome existing limitations, mitigate the drawbacks of classical generators, and provide more controllable, flexible, and portable solid-state voltage pulse generators. This paper provides a review of cancer treatment using TTF and highlights the key specifications required for efficient treatment. Additionally, potential voltage pulse generators are reviewed and compared in terms of their treatment efficacy and efficient use of electrical power

Modeling and design of an electromagnetic actuation system for the manipulation of microrobots in blood vessels

Tese de mestrado integrado em Física, apresentada à Universidade de Lisboa, através da Faculdade de Ciências, 2015A navegação de nano/microdispositivos apresenta um grande potencial para aplicações biomédicas, oferecendo meios de diagnóstico e procedimentos terapêuticos no interior do corpo humano. Dada a sua capacidade de penetrar quase todos os materiais, os campos magnéticos são naturalmente adequados para controlar nano/microdispositivos magnéticos em espaços inacessíveis. Uma abordagem recente é o uso de um aparelho personalizado, capaz de controlar campos magnéticos. Esta é uma área de pesquisa prometedora, mas mais simulações e experiências são necessárias para avaliar a viabilidade destes sistemas em aplicações clínicas. O objectivo deste projecto foi a simulação e desenho de um sistema de atuação eletromagnética para estudar a locomoção bidimensional de microdispositivos. O primeiro passo foi identificar, através da análise de elementos finitos, usando o software COMSOL, diferentes configurações de bobines que permitiriam o controlo de dispositivos magnéticos em diferentes escalas. Baseado nos resultados das simulações, um protótipo de um sistema de atuação magnética para controlar dispositivos com mais de 100 m foi desenhado e construído de raiz, tendo em conta restrições de custos. O sistema consistiu num par de bobines de Helmholtz e rotacionais e um par de bobines de Maxwell dispostas no mesmo eixo. Além disso, componentes adicionais tiveram de ser desenhados ou selecionados para preencher os requisitos do sistema. Para a avaliação do sistema fabricado, testes preliminares foram realizados. A locomoção do microrobot foi testada em diferentes direções no plano x-y. As simulações e experiências confirmaram que é possível controlar a força magnética e o momento da força que atuam num microdispositivo através do campos produzidos pelas bobines de Maxwell e Helmholtz, respectivamente. Assim, este tipo de atuação magnética parece ser uma forma adequada de transferência de energia para futuros microdispositivos biomédicos.Navigation of nano/microdevices has great potential for biomedical applications, offering a means for diagnosis and therapeutic procedures inside the human body. Due to their ability to penetrate most materials, magnetic fields are naturally suited to control magnetic nano/microdevices in inaccessible spaces. One recent approach is the use of custom-built apparatus capable of controlling magnetic devices. This is a promising area of research, but further simulation studies and experiments are needed to estimate the feasibility of these systems in clinical applications. The goal of this project was the simulation and design of an electromagnetic actuation system to study the two dimensional locomotion of microdevices. The first step was to identify, through finite element analysis using software COMSOL, different coil configurations that would allow the control of magnetic devices at different scales. Based on the simulation results, a prototype of a magnetic actuation system to control devices with more than 100 m was designed and built from the ground up, taking into account cost constraints. The system comprised one pair of rotational Helmholtz coils and one pair of rotational Maxwell coils placed along the same axis. Furthermore, additional components had to be designed or selected to fulfil the requirements of the system. For the evaluation of the fabricated system, preliminary tests were carried out. The locomotion of a microdevice was tested along different directions in the x-y plane. The simulations and experiments confirmed that it is possible to control the magnetic force and torque acting on a microdevice through the fields produced by Maxwell and Helmholtz coils, respectively. Thus, this type of magnetic actuation seems to provide a suitable means of energy transfer for future biomedical microdevices

High efficacy extremely low frequency (ELF) pulsed electromagnetic field (PEMF) device for wound healing promotion

This research project successfully presents and discusses the design and construction of an extremely low frequency (ELF) PEMF device built on the basis of a Two-Axis (2-Axis) Helmholtz coil system (HCS) that is capable of producing a uniform time varying magnetic field in the frequency range of 2-500Hz and magnetic induction (magnetic flux density) of 0.5mT - 2.5mT. A custom software program was written in order to systematically analyze the induced magnetic field distribution and its region of uniformity within 10%, 1% and 0.1% of the center field, prior to commencing experimentation with the selected biological model systems. The applications of the developed ELF PEMF exposure device have been investigated in terms of the experimental evaluation of ELF PEMF irradiation on protein, i.e. Collagenase enzyme, and gram-positive and gram- negative bacterial cultures of Staphylococcus aureus (S. aureus) and Escherichia coli (E. coli) respectively. Through this study it was experimentally proved that it is possible to optimize ELF PEMF parameters (frequency, f, and magnetic flux density, B) of the applied irradiation which can modulate (increase or decrease) the biological activity of the studied Collagenase enzyme. Important findings from the conducted experiments showed that the biological activity of Collagenase enzyme is increased by 7-15% and 4-15% upon irradiation at 3Hz and 8Hz for the magnetic flux densities of 0.5-2.5mT. The effects of the applied ELF PEMF exposure system on growth and proliferation of bacterial culture of S. aureus and E. coli have also been experimentally evaluated. All bacterial cultures exposed to ELF PEMF showed a decrease in their growth rate when compared to control samples. For S. aureus, a specific viability pattern “quadrature polynomial” was observed upon ELF PEMF irradiation. The occurrence of the frequency and magnetic flux density “windows” was observed at the higher end of the studied frequencies range and all magnetic flux densities except 1.5mT. Maximum relative decrease of 68.56% was observed at the frequency 300Hz and magnetic flux density 1.5mT. For E. coli, the overall observation is that E. coli bacteria were generally more responsive to the applied irradiation treatment, where the exponential relationship between the colony-forming unit (CFU) values (bacterial growth) and applied exposures was observed. The results obtained clearly demonstrate that the effects of irradiation on bacterial growth are frequency and magnetic flux density dependent. In general, the decrease in bacterial cell viability was achieved at all studied range of frequencies (2-500Hz) and every magnetic flux density (0.5mT, 1mT, 1.5mT, 1.5mT, 2mT and 2.5mT). Minimum and maximum changes in bacterial cells growth for the exposed samples were recorded at 3Hz and 0.5mT, and 500Hz and 2.5mT, respectively. The maximum effect observed at the 500Hz and 2.5mT corresponds to the relative decrease of 77.26 % in bacterial growth. The outcomes of this research project provides evidence based support to the hypothesis that optimal ELF PEMF parameters can induce therapeutic effects in proteins and cells and thereby, ELF PEMF therapies have a great potential for possible treatment of wounds and overall wound healing promotion

Wired, wireless and wearable bioinstrumentation for high-precision recording of bioelectrical signals in bidirectional neural interfaces

It is widely accepted by the scientific community that bioelectrical signals, which can be used for the identification of neurophysiological biomarkers indicative of a diseased or pathological state, could direct patient treatment towards more effective therapeutic strategies. However, the design and realisation of an instrument that can precisely record weak bioelectrical signals in the presence of strong interference stemming from a noisy clinical environment is one of the most difficult challenges associated with the strategy of monitoring bioelectrical signals for diagnostic purposes. Moreover, since patients often have to cope with the problem of limited mobility being connected to bulky and mains-powered instruments, there is a growing demand for small-sized, high-performance and ambulatory biopotential acquisition systems in the Intensive Care Unit (ICU) and in High-dependency wards. Furthermore, electrical stimulation of specific target brain regions has been shown to alleviate symptoms of neurological disorders, such as Parkinson’s disease, essential tremor, dystonia, epilepsy etc. In recent years, the traditional practice of continuously stimulating the brain using static stimulation parameters has shifted to the use of disease biomarkers to determine the intensity and timing of stimulation. The main motivation behind closed-loop stimulation is minimization of treatment side effects by providing only the necessary stimulation required within a certain period of time, as determined from a guiding biomarker. Hence, it is clear that high-quality recording of local field potentials (LFPs) or electrocorticographic (ECoG) signals during deep brain stimulation (DBS) is necessary to investigate the instantaneous brain response to stimulation, minimize time delays for closed-loop neurostimulation and maximise the available neural data. To our knowledge, there are no commercial, small, battery-powered, wearable and wireless recording-only instruments that claim the capability of recording ECoG signals, which are of particular importance in closed-loop DBS and epilepsy DBS. In addition, existing recording systems lack the ability to provide artefact-free high-frequency (> 100 Hz) LFP recordings during DBS in real time primarily because of the contamination of the neural signals of interest by the stimulation artefacts. To address the problem of limited mobility often encountered by patients in the clinic and to provide a wide variety of high-precision sensor data to a closed-loop neurostimulation platform, a low-noise (8 nV/√Hz), eight-channel, battery-powered, wearable and wireless multi-instrument (55 × 80 mm2) was designed and developed. The performance of the realised instrument was assessed by conducting both ex vivo and in vivo experiments. The combination of desirable features and capabilities of this instrument, namely its small size (~one business card), its enhanced recording capabilities, its increased processing capabilities, its manufacturability (since it was designed using discrete off-the-shelf components), the wide bandwidth it offers (0.5 – 500 Hz) and the plurality of bioelectrical signals it can precisely record, render it a versatile tool to be utilized in a wide range of applications and environments. Moreover, in order to offer the capability of sensing and stimulating via the same electrode, novel real-time artefact suppression methods that could be used in bidirectional (recording and stimulation) system architectures are proposed and validated. More specifically, a novel, low-noise and versatile analog front-end (AFE), which uses a high-order (8th) analog Chebyshev notch filter to suppress the artefacts originating from the stimulation frequency, is presented. After defining the system requirements for concurrent LFP recording and DBS artefact suppression, the performance of the realised AFE is assessed by conducting both in vitro and in vivo experiments using unipolar and bipolar DBS (monophasic pulses, amplitude ranging from 3 to 6 V peak-to-peak, frequency 140 Hz and pulse width 100 µs). Under both in vitro and in vivo experimental conditions, the proposed AFE provided real-time, low-noise and artefact-free LFP recordings (in the frequency range 0.5 – 250 Hz) during stimulation. Finally, a family of tunable hardware filter designs and a novel method for real-time artefact suppression that enables wide-bandwidth biosignal recordings during stimulation are also presented. This work paves the way for the development of miniaturized research tools for closed-loop neuromodulation that use a wide variety of bioelectrical signals as control signals.Open Acces