Design study of a novel geometrical arrangement for an in-beam small animal positron emission tomography scanner.

Objective.We designed a geometrical solution for a small animal in-beam positron emission tomography (PET) scanner to be used in the project SIRMIO (Small animal proton irradiator for research in molecular image-guided radiation-oncology). The system is based on 56 scintillator blocks of pixelated LYSO crystals. The crystals are arranged providing a pyramidal-step shape to optimize the geometrical coverage in a spherical configuration.Approach.Different arrangements have been simulated and compared in terms of spatial resolution and sensitivity. The chosen setup enables us to reach a good trade-off between a solid angle coverage and sufficient available space for the integration of additional components of the first design prototype of the SIRMIO platform. The possibility of moving the mouse holder inside the PET scanner furthermore allows for achieving the optimum placement of the irradiation area for all the possible tumor positions in the body of the mouse. The work also includes a study of the scintillator material where LYSO and GAGG are compared with a focus on the random coincidence noise due to the natural radioactivity of Lutetium in LYSO, justifying the choice of LYSO for the development of the final system.Main results.The best imaging performance can be achieved with a sub-millimeter spatial resolution and sensitivity of 10% in the center of the scanner, as verified in thorough simulations of point sources. The simulation of realistic irradiation scenarios of proton beams in PMMA targets with/without air gaps indicates the ability of the proposed PET system to detect range shifts down to 0.2 mm.Significance.The presented results support the choice of the identified optimal design for a novel spherical in-beam PET scanner which is currently under commissioning for application to small animal proton and light ion irradiation, and which might find also application, e.g. for biological image-guidance in x-ray irradiation.

Observation of the radiative decay of the 229Th nuclear clock isomer.

The radionuclide thorium-229 features an isomer with an exceptionally low excitation energy that enables direct laser manipulation of nuclear states. It constitutes one of the leading candidates for use in next-generation optical clocks1-3. This nuclear clock will be a unique tool for precise tests of fundamental physics4-9. Whereas indirect experimental evidence for the existence of such an extraordinary nuclear state is substantially older10, the proof of existence has been delivered only recently by observing the isomer's electron conversion decay11. The isomer's excitation energy, nuclear spin and electromagnetic moments, the electron conversion lifetime and a refined energy of the isomer have been measured12-16. In spite of recent progress, the isomer's radiative decay, a key ingredient for the development of a nuclear clock, remained unobserved. Here, we report the detection of the radiative decay of this low-energy isomer in thorium-229 (229mTh). By performing vacuum-ultraviolet spectroscopy of 229mTh incorporated into large-bandgap CaF2 and MgF2 crystals at the ISOLDE facility at CERN, photons of 8.338(24) eV are measured, in agreement with recent measurements14-16 and the uncertainty is decreased by a factor of seven. The half-life of 229mTh embedded in MgF2 is determined to be 670(102) s. The observation of the radiative decay in a large-bandgap crystal has important consequences for the design of a future nuclear clock and the improved uncertainty of the energy eases the search for direct laser excitation of the atomic nucleus.

Radioactive Beams for Image-Guided Particle Therapy: The BARB Experiment at GSI.

Several techniques are under development for image-guidance in particle therapy. Positron (ß+) emission tomography (PET) is in use since many years, because accelerated ions generate positron-emitting isotopes by nuclear fragmentation in the human body. In heavy ion therapy, a major part of the PET signals is produced by ß+-emitters generated via projectile fragmentation. A much higher intensity for the PET signal can be obtained using ß+-radioactive beams directly for treatment. This idea has always been hampered by the low intensity of the secondary beams, produced by fragmentation of the primary, stable beams. With the intensity upgrade of the SIS-18 synchrotron and the isotopic separation with the fragment separator FRS in the FAIR-phase-0 in Darmstadt, it is now possible to reach radioactive ion beams with sufficient intensity to treat a tumor in small animals. This was the motivation of the BARB (Biomedical Applications of Radioactive ion Beams) experiment that is ongoing at GSI in Darmstadt. This paper will present the plans and instruments developed by the BARB collaboration for testing the use of radioactive beams in cancer therapy.

Performance evaluation of a staggered three-layer DOI PET detector using a 1 mm LYSO pitch with PETsys TOFPET2 ASIC: comparison of HAMAMATSU and KETEK SiPMs.

In this study, we propose a staggered three-layer depth-of-interaction (DOI) detector with a 1 mm crystal pitch and 19.8 mm total crystal thickness for a high-resolution and high-sensitivity small animal in-beam PET scanner. A three-layered stacked LYSO scintillation array (0.9 × 0.9 × 6.6 mm3crystals, 23 × 22 mm2surface area) read out by a SiPM array (8 × 8 channels, 3 × 3 mm2active area/channel and 50µm microcell size) with data acquisition, signal processing and digitization performed using the PETsys Electronics Evaluations kit (based on the TOFPET v2c ASIC) builds a DOI LYSO detector block. The performance of the DOI detector was evaluated in terms of crystal resolvability, energy resolution, and coincidence resolving time (CRT). A comparative performance evaluation of the staggered three-layer LYSO block was conducted with two different SiPM arrays from KETEK and HAMAMATSU. 100% (KETEK) and 99.8% (HAMAMATSU) of the crystals were identified, by using a flood irradiation the front- and back-side. The average energy resolutions for the 1st, 2nd, and 3rd layers were 16.5 (±2.3)%, 20.9(±4.0)%, and 32.7 (±21.0)% (KETEK) and 19.3 (±3.5)%, 21.2 (±4.1)%, and 26.6 (±10.3)% (HAMAMATSU) for the used SiPM arrays. The measured CRTs (FWHM) for the 1st, 2nd, and 3rd layers were 532 (±111) ps, 463 (±108) ps, and 447 (±111) ps (KETEK) and 402 (±46) ps, 392 (±54) ps, and 408 (±196) ps (HAMAMATSU). In conclusion, the performance of the staggered three-layer DOI detector with 1 mm LYSO pitch and 19.8 mm total crystal thickness was fully characterized. The feasibility of a highly performing readout of a high resolution DOI PET detector via SiPM arrays from KETEK and HAMAMATSU employing the PETsys TOFPET v2c ASIC could be demonstrated.

Radiation protection modelling for 2.5 Petawatt-laser production of ultrashort x-ray, proton and ion bunches: Monte Carlo model of the Munich CALA facility.

The 'Centre for Advanced Laser Applications' (CALA) is a new research institute for laser-based acceleration of electron beams for brilliant x-ray generation, laser-driven sub-nanosecond bunches of protons and heavy ions for biomedical applications like imaging and tumour therapy as well as for nuclear and high-field physics.The radiation sources emerging from experiments using the up to 2.5 petawatt laser pulses with 25 femtosecond duration will be mixed particle-species of high intensity, high energy and pulsed, thus posing new challenges compared to conventional radiation protection. Such worldwide pioneering laser experiments result in source characteristics that require careful a-priori radiation safety simulations.The FLUKA Monte-Carlo code was used to model the five CALA experimental caves, including the corridors, halls and air spaces surrounding the caves. Beams of electrons (<5 GeV), protons (<200 MeV),12C (<400MeV/u) and197Au (<10MeV/u) ions were simulated using spectra, divergences and bunch-charges based on expectations from recent scientific progress.Simulated dose rates locally can exceed 1.5 kSv h-1inside beam dumps. Vacuum pipes in the cave walls for laser transport and extraction channels for the generated x-rays result in small dose leakage to neighboring areas. Secondary neutrons contribute to most of the prompt dose rate outside caves into which the beam is delivered. This secondary radiation component causes non-negligible dose rates to occur behind walls to which large fluences of secondary particles are directed.By employing adequate beam dumps matched to beam-divergence, magnets, passive shielding and laser pulse repetition limits, average dose rates in- and outside the experimental building stay below design specifications (<0.5µSv h-1) for unclassified areas,<2.5µSv h-1for supervised areas,<7.5µSv h-1maximum local dose rate) and regulatory limits (<1mSv a-1for unclassified areas).

Electronic Bridge Excitation in Highly Charged

The excitation of the 8 eV ^{229m}Th isomer through the electronic bridge mechanism in highly charged ions is investigated theoretically. By exploiting the rich level scheme of open 4f orbitals and the robustness of highly charged ions against photoionization, a pulsed high-intensity optical laser can be used to efficiently drive the nuclear transition by coupling it to the electronic shell. We show how to implement a promising electronic bridge scheme in an electron beam ion trap starting from a metastable electronic state. This setup would avoid the need for a tunable vacuum ultraviolet laser. Based on our theoretical predictions, determining the isomer energy with an uncertainty of 10^{-5} eV could be achieved in one day of measurement time using realistic laser parameters.

Energy of the 229Th nuclear clock transition.

Owing to its low excitation energy and long radiative lifetime, the first excited isomeric state of thorium-229, 229mTh, can be optically controlled by a laser1,2 and is an ideal candidate for the creation of a nuclear optical clock3, which is expected to complement and outperform current electronic-shell-based atomic clocks4. A nuclear clock will have various applications-such as in relativistic geodesy5, dark matter research6 and the observation of potential temporal variations of fundamental constants7-but its development has so far been impeded by the imprecise knowledge of the energy of 229mTh. Here we report a direct measurement of the transition energy of this isomeric state to the ground state with an uncertainty of 0.17 electronvolts (one standard deviation) using spectroscopy of the internal conversion electrons emitted in flight during the decay of neutral 229mTh atoms. The energy of the transition between the ground state and the first excited state corresponds to a wavelength of 149.7 ± 3.1 nanometres, which is accessible by laser spectroscopy through high-harmonic generation. Our method combines nuclear and atomic physics measurements to advance precision metrology, and our findings are expected to facilitate the application of high-resolution laser spectroscopy on nuclei and to enable the development of a nuclear optical clock of unprecedented accuracy.

Towards a novel small animal proton irradiation platform: the SIRMIO project.

Background: Precision small animal radiotherapy research is a young emerging field aiming to provide new experimental insights into tumor and normal tissue models in different microenvironments, to unravel complex mechanisms of radiation damage in target and non-target tissues and assess efficacy of novel therapeutic strategies. For photon therapy, modern small animal radiotherapy research platforms have been developed over the last years and are meanwhile commercially available. Conversely, for proton therapy, which holds potential for an even superior outcome than photon therapy, no commercial system exists yet. Material and methods: The project SIRMIO (Small Animal Proton Irradiator for Research in Molecular Image-guided Radiation-Oncology) aims at realizing and demonstrating an innovative portable prototype system for precision image-guided small animal proton irradiation, suitable for installation at existing clinical treatment facilities. The proposed design combines precise dose application with in situ multi-modal anatomical image guidance and in vivo verification of the actual treatment delivery. Results and conclusions: This manuscript describes the status of the different components under development, featuring a dedicated beamline for degradation and focusing of clinical proton beams, along with novel detector systems for in situimaging and range verification. The foreseen workflow includes pre-treatment proton transmission imaging, complemented by ultrasonic tumor localization, for treatment planning and position verification, followed by image-guided delivery with on site range verification by means of ionoacoustics (for pulsed beams) and positron-emission-tomography (PET, for continuous beams). The proposed compact and cost-effective system promises to open a new era in small animal proton therapy research, contributing to the basic understanding of in vivo radiation action to identify areas of potential breakthroughs for future translation into innovative clinical strategies.

Preparing an Isotopically Pure 229Th Ion Beam for Studies of 229mTh.

A methodology is described to generate an isotopically pure 229Th ion beam in the 2+ and 3+ charge states. This ion beam enables one to investigate the low-lying isomeric first excited state of 229Th at an excitation energy of about 7.8(5) eV and a radiative lifetime of up to 104 seconds. The presented method allowed for a first direct identification of the decay of the thorium isomer, laying the foundations to study its decay properties as prerequisite for an optical control of this nuclear transition. High energy 229Th ions are produced in the α decay of a radioactive 233U source. The ions are thermalized in a buffer-gas stopping cell, extracted and subsequently an ion beam is formed. This ion beam is mass purified by a quadrupole-mass separator to generate a pure ion beam. In order to detect the isomeric decay, the ions are collected on the surface of a micro-channel plate detector, where electrons, as emitted in the internal conversion decay of the isomeric state, are observed.

Laser spectroscopic characterization of the nuclear-clock isomer 229mTh.

The isotope 229Th is the only nucleus known to possess an excited state 229mTh in the energy range of a few electronvolts-a transition energy typical for electrons in the valence shell of atoms, but about four orders of magnitude lower than typical nuclear excitation energies. Of the many applications that have been proposed for this nuclear system, which is accessible by optical methods, the most promising is a highly precise nuclear clock that outperforms existing atomic timekeepers. Here we present the laser spectroscopic investigation of the hyperfine structure of the doubly charged 229mTh ion and the determination of the fundamental nuclear properties of the isomer, namely, its magnetic dipole and electric quadrupole moments, as well as its nuclear charge radius. Following the recent direct detection of this long-sought isomer, we provide detailed insight into its nuclear structure and present a method for its non-destructive optical detection.

Submillimeter ionoacoustic range determination for protons in water at a clinical synchrocyclotron.

Proton ranges in water between 145 MeV to 227 MeV initial energy have been measured at a clinical superconducting synchrocyclotron using the acoustic signal induced by the ion dose deposition (ionoacoustic effect). Detection of ultrasound waves was performed by a very sensitive hydrophone and signals were stored in a digital oscilloscope triggered by secondary prompt gammas. The ionoacoustic range measurements were compared to existing range data from a calibrated range detector setup on-site and agreement of better than 1 mm was found at a Bragg peak dose of about 10 Gy for 220 MeV initial proton energy, compatible with the experimental errors. Ionoacoustics has thus the potential to measure the Bragg peak position with submillimeter accuracy during proton therapy, possibly correlated with ultrasound tissue imaging.

Lifetime Measurement of the

The first excited isomeric state of ^{229}Th possesses the lowest energy among all known excited nuclear states. The expected energy is accessible with today's laser technology and in principle allows for a direct optical laser excitation of the nucleus. The isomer decays via three channels to its ground state (internal conversion, γ decay, and bound internal conversion), whose strengths depend on the charge state of ^{229m}Th. We report on the measurement of the internal-conversion decay half-life of neutral ^{229m}Th. A half-life of 7±1 µs has been measured, which is in the range of theoretical predictions and, based on the theoretically expected lifetime of ≈10^{4} s of the photonic decay channel, gives further support for an internal conversion coefficient of ≈10^{9}, thus constraining the strength of a radiative branch in the presence of internal conversion.

A Laser Excitation Scheme for

Direct laser excitation of the lowest known nuclear excited state in ^{229}Th has been a long-standing objective. It is generally assumed that reaching this goal would require a considerably reduced uncertainty of the isomer's excitation energy compared to the presently adopted value of (7.8±0.5) eV. Here we present a direct laser excitation scheme for ^{229m}Th, which circumvents this requirement. The proposed excitation scheme makes use of already existing laser technology and therefore paves the way for nuclear laser spectroscopy. In this concept, the recently experimentally observed internal-conversion decay channel of the isomeric state is used for probing the isomeric population. A signal-to-background ratio of better than 10^{4} and a total measurement time of less than three days for laser scanning appear to be achievable.

Ionoacoustic tomography of the proton Bragg peak in combination with ultrasound and optoacoustic imaging.

Ions provide a more advantageous dose distribution than photons for external beam radiotherapy, due to their so-called inverse depth dose deposition and, in particular a characteristic dose maximum at their end-of-range (Bragg peak). The favorable physical interaction properties enable selective treatment of tumors while sparing surrounding healthy tissue, but optimal clinical use requires accurate monitoring of Bragg peak positioning inside tissue. We introduce ionoacoustic tomography based on detection of ion induced ultrasound waves as a technique to provide feedback on the ion beam profile. We demonstrate for 20 MeV protons that ion range imaging is possible with submillimeter accuracy and can be combined with clinical ultrasound and optoacoustic tomography of similar precision. Our results indicate a simple and direct possibility to correlate, in-vivo and in real-time, the conventional ultrasound echo of the tumor region with ionoacoustic tomography. Combined with optoacoustic tomography it offers a well suited pre-clinical imaging system.

Direct detection of the (229)Th nuclear clock transition.

Today's most precise time and frequency measurements are performed with optical atomic clocks. However, it has been proposed that they could potentially be outperformed by a nuclear clock, which employs a nuclear transition instead of an atomic shell transition. There is only one known nuclear state that could serve as a nuclear clock using currently available technology, namely, the isomeric first excited state of (229)Th (denoted (229m)Th). Here we report the direct detection of this nuclear state, which is further confirmation of the existence of the isomer and lays the foundation for precise studies of its decay parameters. On the basis of this direct detection, the isomeric energy is constrained to between 6.3 and 18.3 electronvolts, and the half-life is found to be longer than 60 seconds for (229m)Th(2+). More precise determinations appear to be within reach, and would pave the way to the development of a nuclear frequency standard.

Comparative Characterization Study of a LaBr3(Ce) Scintillation Crystal in Two Surface Wrapping Scenarios: Absorptive and Reflective.

The properties of a 50 mm × 50 mm × 30 mm monolithic LaBr3:Ce scintillator crystal coupled to a position-sensitive multi-anode photomultiplier (PMT, Hamamatsu H9500), representing the absorbing detector of a Compton camera under study for online ion (proton) beam range verification in hadron therapy, was evaluated in combination with either absorptive or reflective crystal surface coating. This study covered an assessment of the energy and position-dependent energy resolution, exhibiting a factor of 2.5-3.5 improvement for the reflectively wrapped crystal at 662 keV. The spatial dependency was investigated using a collimated (137)Cs source, showing a steep degradation of the energy resolution at the edges and corners of the absorptively wrapped crystal. Furthermore, the time resolution was determined to be 273 ps (FWHM) and 536 ps (FWHM) with reflective and absorptive coating, respectively, using a (60)Co source. In contrast, the light spread function (LSF) of the light amplitude distribution on the PMT segments improved for the absorptively wrapped detector. Both wrapping modalities showed almost no differences in the energy-dependent photopeak detection efficiency.