Ionization Detail Parameters for DNA Damage Evaluation in Charged Particle Radiotherapy: Simulation Study Based on Cell Survival Database.

Details of excitation and ionization acts hide a description of the biological effects of charged particle traversal through living tissue. Nanodosimetry enables the introduction of novel quantities that characterize and quantify the particle track structure while also serving as a foundation for assessing biological effects based on this quantification. This presents an opportunity to enhance the planning of charged particle radiotherapy by taking into account the ionization detail. This work uses Monte Carlo simulations with Geant4-DNA code for a wide variety of charged particles and their radiation qualities to analyze the distribution of ionization cluster sizes within nanometer-scale volumes, similar to DNA diameter. By correlating these results with biological parameters extracted from the PIDE database for the V79 cell line, a novel parameter R2 based on ionization details is proposed for the evaluation of radiation quality in terms of biological consequences, i.e., radiobiological cross section for inactivation. By incorporating the probability p of sub-lethal damage caused by a single ionization, we address limitations associated with the usually proposed nanodosimetric parameter Fk for characterizing the biological effects of radiation. We show that the new parameter R2 correlates well with radiobiological data and can be used to predict biological outcomes.

Modeling of dose and linear energy transfer homogeneity in cell nuclei exposed to alpha particles under various setup conditions.

PURPOSE: Different alpha exposure setups are often used to study the relation between biological responses and LET. This study aimed to estimate the dose heterogeneity and uncertainty in four exposure setups using Geant4 and PARTRAC codes. The importance of the irradiation system characteristics was shown in the context of reporting experimental results, especially in radiobiological studies at the molecular level. MATERIALS AND METHODS: Geant4 was used to estimate the dose distributions in cells grown on a disk exposed to alpha particles penetrating from above and below. The latter setup was simulated without and with a collimator. PARTRAC was used for the validation of Geant4 simulations based on distributions of the number of alpha particles penetrating a round nucleus and the deposited energy. RESULTS: The LET distributions obtained for simulated setups excluding the collimator were wide and non-Gaussian. Using a collimator resulted in a Gaussian LET distribution, but strongly reduced dose rate and dose homogeneity. Comparison between PARTRAC and Geant4 calculations for the cell nucleus exposed to alpha radiation showed an excellent agreement. CONCLUSIONS: The interpretation of results from radiobiological experiments with alpha particles should always cover the characteristics of the experimental setup, which can be done precisely with computational methods.

Intercomparison of nanodosimetric distributions in nitrogen simulated with Geant4 and PTra track structure codes.

To facilitate the use of Geant4-DNA for radiation transport simulations in micro- and nanodosimeters, which are physically operated with tissue-equivalent gases such as nitrogen (and propane), this work aims to extend the cross section data available in Geant4-DNA to include those of nitrogen for electron energies ranging from 1 MeV down to the ionisation threshold. To achieve this, interaction cross section data for nitrogen that have been used with the in-house PTB PTra track structure code have been implemented in the current state-of-the-art Geant4-DNA simulation toolkit. An intercomparison has been performed between the two codes to validate this implementation. To quantify the agreement between the cross section models for nitrogen adopted in PTra and those implemented in Geant4-DNA, the simulation results of both codes were analysed using three physical parameters describing the ionisation cluster size distribution (ICSD): mean ionisation cluster size, variance of the cluster size and the probability to obtain a single ionisation within the target. Statistical analysis of the results indicates that the interaction cross section models for nitrogen used in PTra (elastic scattering, impact ionisations and electronic excitations) have been successfully implemented in Geant4-DNA. In addition, simulated ICSDs were compared to those measured with the Jet Counter nanodosimeter for energies between 100 and 2000 eV. For greater energies, the ICRP data for LET and particle range were used as a reference. The modified Geant4-DNA code and data successfully passed all these benchmarks fulfilling the requirement for their public release in the next version of the Geant4 toolkit.

Geant4-DNA modeling of nanodosimetric quantities in the Jet Counter for alpha particles.

The purpose of this work was to validate the calculation accuracy of nanodosimetric quantities in Geant4-DNA track structure simulation code. We implemented the Jet Counter (JC) nanodosimeter geometry in the simulation platform and quantified the impact of the Geant4-DNA physics models and JC detector performance on the ionization cluster size distributions (ICSD). ICSD parameters characterize the quality of radiation field and are supposed to be correlated to the complexity of the initial DNA damage in nanoscale and eventually the response of biological systems to radiation. We compared Monte Carlo simulations of ICSD in JC geometry performed using Geant4-DNA and PTra codes with experimental data collected for alpha particles at 3.8 MeV. We investigated the impact of simulation and experimental settings, i.e., three Geant4-DNA physics models, three sizes of a nanometer sensitive volume, gas to water density scaling procedure, JC ion extraction efficiency and the presence of passive components of the detector on the ICSD and their parameters. We found that ICSD in JC geometry obtained from Geant4-DNA simulations in water correspond well to ICSD measurements in nitrogen gas for all investigated settings, while the best agreement is for Geant4-DNA physics option 4. This work also discusses the accuracy and robustness of ICSD parameters in the context of the application of track structure simulation methods for treatment planning in particle therapy.

Event-related potentials in the odd-ball paradigm and behavioral scales for the assessment of children and adolescents with disorders of consciousness: A proof of concept study.

OBJECTIVE: Quantification of signatures of conscious processing in children with disorders of consciousness (DoC) using odd-ball paradigms in multiple modalities. METHOD: We review the diagnostic approaches available in the field, from clinical scales to neuroimaging methods, and concentrate upon measures derived from electroencephalographic event related potentials. RESULTS: Evoked potentials were recorded in five procedures, encompassing visual, auditory and tactile modalities, from ten pediatric DoC patients-six in a minimally conscious state (MCS), three in unresponsive wakefulness syndrome (UWS) and one who emerged from MCS (eMCS)-and the control group of 10 healthy children. In almost all the eMCS and MCS patients, higher amplitude of P300 was observed and the effect was statistically significant in at least one out of the five performed procedures. Additionally, signs of conscious information processing were detected in one UWS patient. CONCLUSION: The presented results provide a proof of concept for the possibility of applying ERP-derived electrophysiological measures as an aid in the assessment of children and adolescents in DoC.

Parametric Description of EEG Profiles for Assessment of Sleep Architecture in Disorders of Consciousness.

We propose a fully parametric approach to the assessment of sleep architecture, based upon the classical electroencephalographic criteria, applicable also to the recordings of patients with disorders of consciousness (DOC). Sleep spindles and slow waves are automatically detected from the matching pursuit decomposition of overnight EEG recordings. Their evolution can be presented in the form of EEG profiles, yielding a continuous description of sleep architecture, compatible with the classical criteria used in sleep staging. We propose assessment of these EEG profiles by five parameters, which can be combined by a linear classifier, assessing the quality of sleep architecture. Proposed methodology is evaluated on 59 overnight EEG recordings from 19 patients from a hospital for children with severe brain damage, in relation to their behavioral diagnosis according to the Coma Recovery Scale-Revised. Presented results indicate robustness of the proposed approach, which may serve as a valuable aid in diagnosis of DOC patients. Complete software environment for computing and presentation of EEG profiles is freely available from http://svarog.pl .

Assessment of Statistically Significant Command-Following in Pediatric Patients with Disorders of Consciousness, Based on Visual, Auditory and Tactile Event-Related Potentials.

Disorders of consciousness (DOC) are among the major challenges of contemporary medicine, mostly due to the high rates of misdiagnoses in clinical assessment, based on behavioral scales. This turns our attention to potentially objective neuroimaging methods. Paradigms based on electroencephalography (EEG) are most suited for bedside applications, but sensitive to artifacts. These problems are especially pronounced in pediatric patients. We present the first study on the assessment of pediatric DOC patients by means of command-following procedures and involving long-latency cognitive event-related potentials. To deal with the above mentioned challenges, we construct a specialized signal processing scheme including artifact correction and rejection, parametrization, classification and final assessment of the statistical significance. To compensate for the possible bias of the tests involved in the final diagnosis, we propose the Monte Carlo evaluation of the processing pipeline. To compensate for possible sensory impairments of DOC patients, for each subject we check command-following responses to the stimuli in the major modalities: visual, tactile, and audio (words and sounds). We test the scheme on 20 healthy volunteers and present results for 15 patients from a hospital for children with severe brain damage, in relation to their behavioral diagnosis on the Coma Recovery Scale-Revised (CRS-R).

ON THE TWO MODES OF NANODOSIMETRIC EXPERIMENT.

A method of estimation of the ionisation cluster-size distribution for single primary particle from experimental data obtained in setup without primary particle detector is presented. The Jet Counter nanodosemeter was used in two kinds of experiments with alpha particles to validate the method. Possible application of the method is to perform measurements with previously precluded types of radiation like photons, neutrons and electrons. Details and limitations of the proposed approach are discussed.

MEASUREMENTS OF SPATIAL CORRELATIONS OF IONISATION CLUSTERS IN THE TRACK OF CARBON IONS-FIRST RESULTS.

An attempt towards an experimental set up which could provide the experimental data on correlation processes occurred simultaneously in two distanced DNA targets within a charged particle track is presented. A modified Jet Counter nanodosemeter was used in two experiments with carbon ions with mean energies of 52 and 23 MeV. The probability distributions of the correlated pairs of ionisation clusters produced in two neighbouring sensitive volumes are presented. A question of potential new descriptors of radiation quality is raised.

Status report: Nanodosimetry of carbon ion beam at HIL.

We present preliminary data for measured distributions of ionization cluster size produced by carbon ions in tissue equivalent media. The experiments were carried out with a beam of 92 MeV carbon ions from the U200p cyclotron at the Heavy Ion Laboratory (HIL), University of Warsaw, and nitrogen targets using the so-called Jet Counter set-up.