Validation of the simulation code PRIMO for external radiotherapy

Cancer is one of the leading causes of death around the world and the number of patients is expected to increase in the next years. Most of the cancer patients are treated with radiotherapy for at least a part of their treatment. The success of a radiation therapy treatment lies on its correct planning and the accurate prediction of dose distribution in the patient. These dose distributions are generated using treatment planning systems. Analytical algorithms are commonly used despite more accurate results can be achieved using Monte Carlo based algorithms due to the long calculation times required by them. In 2013 a new Monte Carlo based algorithm, PRIMO, was developed. In this program, based on PENELOPE, several variance reduction techniques have been included in order to speed up the calculations as well as a graphical user interface has been designed to make it user friendly. This work will help to validate the simulation code PRIMO. The validation of a treatment planning algorithm involves many different tests, among them, a basic validation of computed doses compared to measurements in water, as well as the verification of its dosimetric accuracy in complex situations. The aim of this work is to investigate the performance of the PRIMO code, in particular to study its dosimetric accuracy in complex situations such as the presence of materials different than water (lung and bone) and when computing the dose within the first millimeters of the patient. This aim was translated into a set of computational experiments performed on simple geometrical phantoms as well as on computerized tomography images. Results showed that the algorithm allows to obtain accurate results in water phantoms, as well as in regions susceptible to errors like the build up region and regions with material heterogeneities

Electroporation and peripheral nerve stimulation

This thesis aimed at addressing questions within the fields of electroporation and peripheral nerve stimulation and, in particular, those that arise from the interaction between the two phenomenona. On the one hand, electroporation can have various direct and indirect effects in the neuronal functions. This thesis investigates the possible role of electroporation in pulsed radiofrequency treatments for chronic pain. On the other hand, during electroporation based treatments, electrical stimulation of peripheral nerves appears as an unwanted effect causing muscle contractions and acute pain. This thesis analyzes the rationale behind the use of bipolar pulses to mitigate this effect and the implications of such approach in irreversible electroporation treatments. In addition, this thesis provides a theoretical framework to explain a series of results that were in apparent contradiction with the common knowledge of the electroporation phenomenon. Finally, this thesis presents a neuromuscular model to study the recruitment patterns in intramuscular electrical stimulation.Aquesta tesi té com a objectiu resoldre qüestions en els camps de l’electroporació i l’estimulació dels nervis perifèrics, i sobretot, aquelles que es deriven de l’interacció entre els dos fenòmens. L’electroporació pot tenir diversos efectes directes o indirectes en les funcions neuronals. En aquesta tesi s’investiga el possible paper de l’electroporació en els tractaments de radiofreqüència polsada. D’altra banda, durant els tractaments basats en l’electroporació, l’estimulació elèctrica dels nervis perifèrics apareix com a efecte secundari causant contraccions musculars i dolor. En aquesta tesi s’analitza com l’ús de polsos bipolar pot mitigar aquests efectes i quines implicacions té aquesta estratègia en els tractaments d’electroporació irreversible. En aquesta tesi també es presenta un marc teòric per explicar una sèrie de resultats que entren en aparent contradicció amb els nostres coneixements sobre l’electroporació. Finalment, es presenta un model neuromuscular que permet estudiar la resposta d’un múscul quan és estimulat mitjançant elèctrodes intramusculars

Validation of the simulation code PRIMO for external radiotherapy

Cancer is one of the leading causes of death around the world and the number of patients is expected to increase in the next years. Most of the cancer patients are treated with radiotherapy for at least a part of their treatment. The success of a radiation therapy treatment lies on its correct planning and the accurate prediction of dose distribution in the patient. These dose distributions are generated using treatment planning systems. Analytical algorithms are commonly used despite more accurate results can be achieved using Monte Carlo based algorithms due to the long calculation times required by them. In 2013 a new Monte Carlo based algorithm, PRIMO, was developed. In this program, based on PENELOPE, several variance reduction techniques have been included in order to speed up the calculations as well as a graphical user interface has been designed to make it user friendly. This work will help to validate the simulation code PRIMO. The validation of a treatment planning algorithm involves many different tests, among them, a basic validation of computed doses compared to measurements in water, as well as the verification of its dosimetric accuracy in complex situations. The aim of this work is to investigate the performance of the PRIMO code, in particular to study its dosimetric accuracy in complex situations such as the presence of materials different than water (lung and bone) and when computing the dose within the first millimeters of the patient. This aim was translated into a set of computational experiments performed on simple geometrical phantoms as well as on computerized tomography images. Results showed that the algorithm allows to obtain accurate results in water phantoms, as well as in regions susceptible to errors like the build up region and regions with material heterogeneities

Modeling implanted metals in electrical stimulation applications

International audienceOBJECTIVE: Metal implants impact the dosimetry assessment in electrical stimulation techniques. Therefore, they need to be included in numerical models. While currents in the body are ionic, metals only allow electron transport. In fact, charge transfer between tissues and metals requires electric fields to drive electrochemical reactions at the interface. Thus, metal implants may act as insulators or as conductors depending on the scenario. The aim of this paper is to provide a theoretical argument that guides the choice of the correct representation of metal implants in electrical models while considering the electrochemical nature of the problem Approach: We built a simple model of a metal implant exposed to a homogeneous electric field of various magnitudes. The same geometry was solved using two different models: a purely electric one (with different conductivities for the implant), and an electrochemical one. As an example of application, we also modeled a transcranial electrical stimulation (tES) treatment in a realistic head model with a skull plate using a high and low conductivity value for the plate. MAIN RESULTS: Metal implants generally act as electric insulators when exposed to electric fields up to around 100 V/m and they only resemble a perfect conductor for fields in the order of 1000 V/m and above. The results are independent of the implant’s metal, but they depend on its geometry. tES modeling with implants incorrectly treated as conductors can lead to errors of 50% or more in the estimation of the induced fields Significance: Metal implants can be accurately represented by a simple electrical model of constant conductivity, but an incorrect model choice can lead to large errors in the dosimetry assessment. Our results can be used to guide the selection of the most appropriate model in each scenario

Biophysical modeling of the electric field magnitude and distribution induced by electrical stimulation with intracerebral electrodes

International audienceIntracranial electrodes are used clinically for diagnostic or therapeutic purposes, notably in drug-refractory epilepsy (DRE) among others. Visualization and quantification of the energy delivered through such electrodes is key to understanding how the resulting electric fields modulate neuronal excitability, i.e. the ratio between excitation and inhibition. Quantifying the electric field induced by electrical stimulation in a patient-specific manner is challenging, because these electric fields depend on a number of factors: electrode trajectory with respect to folded brain anatomy, biophysical (electrical conductivity / permittivity) properties of brain tissue and stimulation parameters such as electrode contacts position and intensity. Here, we aimed to evaluate various biophysical models for characterizing the electric fields induced by electrical stimulation in DRE patients undergoing stereoelectroencephalography (SEEG) recordings in the context of pre-surgical evaluation. This stimulation was performed with multiple-contact intracranial electrodes used in routine clinical practice. We introduced realistic 3D models of electrode geometry and trajectory in the neocortex. For the electrodes, we compared point (0D) and line (1D) sources approximations. For brain tissue, we considered three configurations of increasing complexity: a 6-layer spherical model, a toy model with a sulcus representation, replicating results from previous approaches; and went beyond the state-of-the-art by using a realistic head model geometry. Electrode geometry influenced the electric field distribution at close distances (∼3 mm) from the electrode axis. For larger distances, the volume conductor geometry and electrical conductivity dominated electric field distribution. These results are the first step towards accurate and computationally tractable patient-specific models of electric fields induced by neuromodulation and neurostimulation procedures. © 2023 IOP Publishing Ltd

Avoiding nerve stimulation in irreversible electroporation: a numerical modeling study

Electroporation based treatments consist in applying one or multiple high voltage pulses to the tissues to be treated. As an undesired side effect, these pulses cause electrical stimulation of excitable tissues such as nerves and muscles. This increases the complexity of the treatments and may pose a risk to the patient. To minimize electrical stimulation during electroporation based treatments, it has been proposed to replace the commonly used monopolar pulses by bursts of short bipolar pulses. In the present study, we have numerically analyzed the rationale for such approach. We have compared different pulsing protocols in terms of their electroporation efficacy and their capability to trigger action potentials in nerves. For that, we have developed a modeling framework that combines numerical models of nerve fibers and experimental data on irreversible electroporation. Our results indicate that, by replacing the conventional relatively long monopolar pulses by bursts of short bipolar pulses, it is possible to ablate a large tissue region without triggering action potentials in a nearby nerve. Our models indicate that this is possible because, as the pulse length of these bipolar pulses is reduced, the stimulation thresholds raise faster than the irreversible electroporation thresholds. We propose that this different dependence on the pulse length is due to the fact that transmembrane charging for nerve fibers is much slower than that of cells treated by electroporation because of their geometrical differences.This work was supported by the Ministry of Economy and Competitiveness of Spain through the grant TEC2014-52383-C3-2-R. RVD’s research is supported by the National Institutes of Health under award number NIH 1R21 CA192041-01

High-voltage pulsed electric field laboratory device with asymmetric voltage multiplier for marine macroalgae electroporation

Optimization of protocols is required for each specific type of biomass processed by electroporation of the cell membrane with high voltage pulsed electric fields (PEF). Such optimization requires convenient and adaptable laboratory systems, which will enable determination of both electrical and mechanical parameters for successful electroporation and fractionation. In this work, we report on a laboratory PEF system consisting of a high voltage generator with a novel asymmetric voltage multiplying architecture and a treatment chamber with sliding electrodes. The system allows applying pulses of up to 4 kV and 1 kA with a pulse duration between 1 μs and 100 μs. The allowable energy dissipated per pulse on electroporated biomass is determined by the conditions for cooling the biomass in the electroporation cell. The device was tested on highly conductive green macroalgae from Ulva sp., a promising but challenging feedstock for the biorefinery. Successful electroporation was confirmed with bioimpedance measurements

Evaluating optimal strategies for electric field dosimetry from intracranial electrodes

International audienceIntracranial electrodes are used clinically for diagnostic (e.g. in drug-refractory epilepsy) or therapeutic (deep brain stimulation, e.g. epilepsy) purposes. Electrical stimulation delivered through such electrodes is key to understand how the resulting electric fields modulate neuronal (hyper)excitability. However, quantifying such fields in a patient-specific way is challenging, since etiology impacts brain anatomy (morphology) and biophysical properties (e.g., conductivity). Here, we evaluate how to approximate the electric fields from intracranial electrodes used clinically. Those results are the first step towards computationally tractable, patient-specific models of electric fields generated during neuromodulation protocols

Dynamics of cell death after conventional IRE and H-FIRE treatments

High-frequency irreversible electroporation (H-FIRE) has emerged as an alternative to conventional irreversible electroporation (IRE) to overcome the issues associated with neuromuscular electrical stimulation that appear in IRE treatments. In H-FIRE, the monopolar pulses typically used in IRE are replaced with bursts of short bipolar pulses. Currently, very little is known regarding how the use of a different waveform affects the cell death dynamics and mechanisms. In this study, human pancreatic adenocarcinoma cells were treated with a typical IRE protocol and various H-FIRE schemes with the same energized time. Cell viability, membrane integrity and Caspase 3/7 activity were assessed at different times after the treatment. In both treatments, we identified two different death dynamics (immediate and delayed) and we quantified the electric field ranges that lead to each of them. While in the typical IRE protocol, the electric field range leading to a delayed cell death is very narrow, this range is wider in H-FIRE and can be increased by reducing the pulse length. Membrane integrity in cells suffering a delayed cell death shows a similar time evolution in all treatments, however, Caspase 3/7 expression was only observed in cells treated with H-FIRE.This work was supported by the Ministry of Economy and Competitiveness of Spain (Grant No. TEC2014-52383-C3-2-R), the Pancreatic Cancer Action Network (Grant No. 16-65-IANN) and Cures Within Reach (Grant No. PUJFSANY). Antoni Ivorra gratefully acknowledges financial support by ICREA under the ICREA Academia programme

Interleaved intramuscular stimulation with minimally overlapping electrodes evokes smooth and fatigue resistant forces

Objective. It is known that multi-site interleaved stimulation generates less muscle fatigue compared to single-site synchronous stimulation. However, in the limited number of studies in which intramuscular electrodes were used, the fatigue reduction associated with interleaved stimulation could not consistently be achieved. We hypothesize that this could be due to the inability to place the intramuscular electrodes used in interleaved stimulation in locations that minimize overlap amongst the motor units activated by the electrodes. Our objective in the present study was to use independent intramuscular electrodes to compare fatigue induced by interleaved stimulation with that generated by synchronous stimulation at the same initial force and ripple. Approach. In the medial gastrocnemius muscle of an anesthetized rabbit (n = 3), ten intramuscular hook wire electrodes were inserted at different distances from the nerve entry. Overlap was measured using the refractory technique and only three electrodes were found to be highly independent. After ensuring that forces obtained by both stimulation modalities had the same ripple and magnitude, fatigue induced during interleaved stimulation across three independent distal electrodes was compared to that obtained by synchronously delivering pulses to a single proximal electrode. Main results. Contractions evoked by interleaved stimulation exhibited less fatigue than those evoked by synchronous stimulation. Twitch force recruitment curves collected from each of the ten intramuscular electrodes showed frequent intermediate plateaus and the force value at these plateaus decreased as the distance between the electrode and nerve entry increased. Significance. The results indicate that interleaved intramuscular stimulation is preferred over synchronous intramuscular stimulation when fatigue-resistant and smooth forces are desired. In addition, the results suggest that the large muscle compartments innervated by the primary intramuscular nerve branches give rise to progressively smaller independent compartments in subsequent nerve divisions.This project has received funding from the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation programme (grant agreement No. 724244). AI gratefully acknowledges the financial support by ICREA under the ICREA Academia programme. JdV and XN were supported by project GRAFIN PCI2018-093029, funded by Ministerio de Ciencia, Innovación y Universidades and European Union ERDF/ESF