The formation of the Earth remains an epoch with mysterious puzzles extending to our still incomplete understanding of the planet's potential origin and bulk composition. Direct confirmation of the Earth's internal heat engine was accomplished by the successful observation of geoneutrinos originating from uranium (U) and thorium (Th) progenies, manifestations of the planet's natural radioactivity dominated by potassium (40K) and the decay chains of uranium (238U) and thorium (232Th). This radiogenic energy output is critical to planetary dynamics and must be accurately measured for a complete understanding of the overall heat budget and thermal history of the Earth. Detecting geoneutrinos remains the only direct probe to do so and constitutes a challenging objective in modern neutrino physics. In particular, the intriguing potassium geoneutrinos have never been observed and thus far have been considered impractical to measure. We propose here a novel approach for potassium geoneutrino detection using the unique antimatter signature of antineutrinos to reduce the otherwise overwhelming backgrounds to observing this rarest signal. The proposed detection framework relies on the innovative LiquidO detection technique to enable positron (e+) identification and antineutrino interactions with ideal isotope targets identified here for the first time. We also provide the complete experimental methodology to yield the first potassium geoneutrino discovery.

The correlation of molecular neuroimaging and behavior studies in preclinical PET imaging is of major interest to unlock progress in the understanding of brain processes and assess the validity of preclinical studies in drug development. However, fully achieving this ambition requires performing molecular images of awake and freely moving animals, whereas most of the preclinical imaging procedures are currently performed under anesthesia. To overcome this issue, the MAPSSIC project aims to develop a pixelated intracerebral probe to be implanted into awake and freely moving rats. The aforementioned probe relies on IMIC (Imageur Moléculaire Intra Cérébral), a Monolithic Active Pixel Sensor (MAPS) prototype set to directly detect positrons. The IMIC sensors were produced in 5 different configurations. Measurements using a 204Tl source showed that the sensor parameters can be optimized to boost its performance allowing to increase the sensitivity and reduce the average cluster size. In addition, comparisons between sensor configurations show a clear gain provided by the introduction of CMOS process modifications. Finally, the choice of the optimal sensor configuration will depend on the expected in vivo conditions.

The correlation of molecular neuroimaging and behavior studies in the preclinical field is of major interest to unlock progress in the understanding of brain processes and assess the validity of preclinical studies in drug development. However, fully achieving this ambition requires to perform molecular images of awake and freely moving animals, whereas most of the preclinical imaging procedures are currently performed under anesthesia. To achieve such a combination, the MAPSSIC project aims to develop a pixelated intracerebral probe based on the MAPS technology to be implanted on awake freely moving rats. Thanks to its in situ position, the probe is able to directly detect short range positrons of β + radioisotopes whereas micro-PET devices use the coincident γ-rays from annihilation as a relevant signal. In this paper, we discuss the first characterization of the new probe’s sensors and present the results from Monte Carlo simulations of a typical animal experiment using a commonly used β + radiotracer to confirm the relevance of this imaging device. First measurements show an energy threshold lower than 1 keV allowing the detection of β + particles as well as a background sensitivity of 1.7 × 10 −3 cps. Simulations confirm the ability of the probe to record a local information, with more than 93 % of the detected particles being emitted within the first 2 mm surrounding the probe, that allows to perform kinetic studies on brain structures such as the striatum.

Radioisotope imaging is a powerful tool to understand the biological mechanisms in-vivo, especially in the brain of small animals, providing a significant model to study the human brain. In this context, we have developed and built a pixelated intracerebral positron probe to be embedded on awake and freely moving small animals, typically rats. This pixelated probe will represent a key instrument for neuroscientists to study neural mechanisms and correlate them to behavioral experiments. We describe in this paper the simulations carried out to design the intracerebral sensor, its architecture, and the detection of positrons in a volume with a couple of sensors assembled back-to-back. We also depict the architecture of the wireless acquisition system. Finally, we present the first measurements performed in real-time by this miniaturized probe with sealed radioactive sources and a 18F solution.

Preclinical behavior neuroimaging gathers simultaneous assessment of behavior and functional brain imaging. It is a potential key breakthrough to improve the understanding of brain processes and assess the validity of preclinical studies in drug development. Achieving such a combination is difficult, anesthesia or restraints inherent to conventional nuclear imaging preclude its use for behavior studies. In that context, we have proposed an original strategy using submillimetric probes to directly measures positrons inside the rat brain. This paper gives the results of Monte Carlo simulations of a new generation of intracerebral positron probe based on a complementary metal oxide semi-conductor monolithic active pixel sensor. We present the results obtained for a probe into a large homogeneous volume of radioactive water (F-18) leading to a sensitivity of 0.88 cps.Bq(-1).mm(3) and a mean energy deposition by positrons of 15.1 keV. Simulation in simplified brain-shaped sources modeling a C-11-raclopride experiment shows that the implanted volume modeling the left putamen contribute to 92.4% of the signal from positrons. We also investigate the effects of the thickness of the sensitive layer, the energy threshold and pixel dimensions on the detection capacities of the sensor. We demonstrate that an increase in the sensitive thickness from 18 to 190 mu m would lead to an increase of positrons sensitivity by a factor of 1.74, but to a decrease of the direct (positrons) to indirect (gamma-rays and electrons) sensitivity ratio by a factor of 1.59. Finally, we show that for a threshold lower than about 5 keV the effect of the pixel dimensions is negligible.

IMIC is a Monolithic Active Pixel Sensor prototype designed for the MAPSSIC project, which aims at developing wireless intracerebral probes dedicated to image positron-emitting source activity in the brain of awake and freely moving rats. Former experiments with the PIXSIC positron probe based on a passive sensor have validated the proof of concept, but have also shown limitations with regards to the probe robustness and to its transparency to annihilation photons. The IMIC circuit features a matrix of 16 x 128 active pixels of 30 x 50 mu m(2) size and targets to overcome the PIXSIC probe drawbacks by exploiting a thin sensitive layer of 18 mu m, still featuring an overall thickness close to 300 mu m. Additionally, by using a low power (55 nW/pixel) in-pixel front-end architecture providing binary output, IMIC solves the challenge of implanting an active sensor in tissues where overheating is forbidden. The needle-shaped sensor 610 mu m x 12000 mu m was fabricated and tested in laboratory. The whole sensor dissipates 160 mu W and its imaging capabilities were asserted with various sources: Fe-55, Sr-90 and F-18. These tests also demonstrated robust count-rate measurement with IMIC in the range 10-1000 counts/matrix/s. Finally, a dedicated setup qualitatively confirmed excellent in-sensitivity to 511 keV gamma-rays. In this paper, we present the sensor requirements and its detailed design. We also discuss the first characterisation results and the outlook for the integration of IMIC into an implantable probe.

IMIC is a Monolithic Active Pixel Sensor prototype for the MAPSSIC project dedicated to direct detection of low energy β+ rays in the brain of awake and freely-moving rats using CMOS technology. Former experiments using a β+ Si probe developed within the PIXSIC project validated a methodological proof of concept. However, conducting routinely such measurements would require improvements with respect to the passive pixel sensors employed in PIXSIC. The new IMIC circuit is fabricated in a 180 nm CMOS Image Sensor Technology and features a matrix of 16 × 128 pixels, which are 30 × 50 μm 2 large. The sensor has a needle-like aspect ratio (610 μm × 12 000 μm). The chip is produced on a 18 μm high-resistivity epitaxial layer substrate. The foreseen application requires high sensitivity to β-rays while being immune to background γ-rays. Another severe constraint is the limited power dissipation in order to minimize the thermal impact on the brain. IMIC is a fully-programmable digital sensor. The pixel design is based on the front-end architecture of the ALPIDE chip. However modifications have been made to store the information inside fired pixels between two readouts allowing low data throughput. The circuit is controlled through the SPI protocol, which allows for setting all the necessary polarization signals. The results of post-layout simulations show a high signal to noise ratio (>40) and low power dissipation of 115 μW/matrix. Laboratory characterization using β-rays validate these predictions and demonstrated that the slow readout can cope with the expected low activity (≈ 120 hits/matrix/s).

The aim of this study was to demonstrate the potential of a wireless pixelated β+-sensitive intracerebral probe (PIXSIC) for in vivo positron emission tomographic (PET) radiopharmacology in awake and freely moving rodents. The binding of [(11)C]raclopride to D2 dopamine receptors was measured in anesthetized and awake rats following injection of the radiotracer. Competitive binding was assessed with a cold raclopride injection 20 minutes later. The device can accurately monitor binding of PET ligands in freely moving rodents with a high spatiotemporal resolution. Reproducible time-activity curves were obtained for pixels throughout the striatum and cerebellum. A significantly lower [(11)C]raclopride tracer-specific binding was observed in awake animals. These first results pave the way for PET tracer pharmacokinetics measurements in freely moving rodents.

Topographic representation of the outside world is a key feature of sensory systems, but so far it has been difficult to define how the activity pattern of the olfactory information is distributed at successive stages in the olfactory system. We studied odor-evoked activation patterns in the main olfactory bulb and the anterior piriform cortex of rats using functional ultrasound (fUS) imaging. fUS imaging is based on the use of ultrafast ultrasound scanners and detects variations in the local blood volume during brain activation. It makes deep brain imaging of ventral structures, such as the piriform cortex, possible. Stimulation with two different odors (hexanal and pentylacetate) induced the activation of odor-specific zones that were spatially segregated in the main olfactory bulb. Interestingly, the same odorants triggered the activation of the entire anterior piriform cortex, in all layers, with no distinguishable odor-specific areas detected in the power Doppler images. These fUS imaging results confirm the spatial distribution of odor-evoked activity in the main olfactory bulb, and furthermore, they reveal the absence of such a distribution in the anterior piriform cortex at the macroscopic scale in vivo.

The aim of this work was to demonstrate the pharmacokinetic potential of a wireless pixelated β+-sensitive probe (PIXSIC).

The investigation of neurophysiological mechanisms underlying the functional specificity of brain regions requires the development of technologies that are well adjusted to in vivo studies in small animals. An exciting challenge remains the combination of brain imaging and behavioural studies, which associates molecular processes of neuronal communications to their related actions. A pixelated intracerebral probe (PIXSIC) presents a novel strategy using a submillimetric probe for beta(+) radiotracer detection based on a pixelated silicon diode that can be stereotaxically implanted in the brain region of interest. This fully autonomous detection system permits time-resolved high sensitivity measurements of radiotracers with additional imaging features in freely moving rats. An application-specific integrated circuit (ASIC) allows for parallel signal processing of each pixel and enables the wireless operation. All components of the detector were tested and characterized. The beta(+) sensitivity of the system was determined with the probe dipped into radiotracer solutions. Monte Carlo simulations served to validate the experimental values and assess the contribution of gamma noise. Preliminary implantation tests on anaesthetized rats proved PIXSIC's functionality in brain tissue. High spatial resolution allows for the visualization of radiotracer concentration in different brain regions with high temporal resolution.

In neuroscience, functional with positron emission tomography (PET) and behavioural assays in rodents are complementary approaches, despite the fact that they are rarely associated simultaneously because general anaesthesia inherent to PET precludes behavioural studies. To address this methodological limit, we have developped a radiosensitive pixelated intracerebral probe named PIXSIC that provides access to the combination of simultaneous observations of molecular and behavioural parameters on rodents. PIXSIC proposes a novel strategy for in vivo recording of the local time-activity curves of PET radiopharmaceuticals. It relies on a sub-millimetre pixelated probe of Si (200 µm thick, 690 µm wide and 17 mm long hosting 10 pixels with dimension 200 µm x 500 µm) implanted into the brain region of interest by stereotaxic surgery. Positrons resulting from decays of a PET radiotracer are detected by reverse-biased, high-resistivity silicon diodes. The system aims at time-resolved high sensitivity measurements in a volume of a few mm3 defined similarly as for the Beta-Microprobe by the positron range within tissues. The pixelated detection scheme adds imaging features as it allows recording of the time-activity curves in different brain regions along the probe position. PIXSIC has a compact and autonomous design based on a radiofrequency data exchange link that allows for full freedom in the animals motion and behavioural activity while limiting stress during acquisition. The first biological validations were performed on anaesthetized rats implanted with two probes, one in the region of interest (hippocampus or striatum, according to the radiotracer) and the other one in a control region (cerebellum). We used [11C]-raclopride for dopamine D2 receptors and [18F]-MPPF for serotonin 5HT1A receptors. According to our previous studies with the Beta-Microprobe (J Nucl Med 2002, 43(2):227-33; Eur J Nucl Med 2002 29(9) 1237-47), the radioactive signals measured with the PIXSIC pixels are reproducible and well-correlated with the distributions of the targeted receptors. The simultaneous measurement of implanted rats in a small animal PET camera confirmed the similarity between PIXSIC and microPET time-activity curves. Moreover, the binding curves highlighted the possibility for PIXSIC to distinguish different tracer kinetics within the structure of interest (cortex/striatum or cortex/hippocampus) in accordance to the stereotaxic location of the pixels. In addition, PIXSIC allowed us to perform the first kinetic measurements of [11C]-raclopride and [18F]-MPPF on awake and freely moving rats. In conclusion, PIXSIC constitutes an unprecedented instrumental methodology for connecting PET molecular and behavioral measurements with freely-moving rodents.

An exciting challenge for neuro-physiological investigations remains the combination of brain imaging and behavioral studies, which associates molecular processes of neuronal communications to their related actions. PIXSIC presents novel strategy using a submillimeter pixellated probe for β+ radiotracer detection based on a reverse-biased, high-resistivity silicon diode; This fully autonomous detection system permits local, time resolved measurements of radiotracers in a volume of a few mm3 with the probe dipped into aqueous solutions of [18F] and [11C]. Preliminary implantation tests on a anaesthetized rats proved functionality of the PIXSIC probe in brain tissues. High spatial resolution allows for the visualization of radiotracer concentration in different brain regions with a temporal resolution of less than 2 seconds

A new beta+ radiosensitive microprobe implantable in rodent brain dedicated to in vivo and autonomous measurements of local time activity curves of beta radiotracers in a volume of brain tissue of a few mm3 has been developed recently. This project expands the concept of the previously designed beta microprobe, which has been validated extensively in neurobiological experiments performed on anesthetized animals. Due to its limitations considering recordings on awake and freely moving animals, we have proposed to develop a wireless setup that can be worn by an animal without constraining its movements. To that aim, we have chosen a highly beta sensitive Silicon-based detector to devise a compact pixellated probe. Miniaturized wireless electronics is used to read-out and transfer the measurement data. Initial Monte-Carlo simulations showed that high resistive Silicon pixels are appropriate for this purpose, with their dimensions to be adapted to our specific signals. More precisely, we demonstrated that 200μm thick pixels with an area of 200μm×500μm are optimized in terms of beta+sensitivity versus relative transparency to the gamma background. Based on this theoretical study, we now present the development of the novel sensor, including the system simulations with technology computer-assisted design (TCAD) to investigate specific configurations of guard rings and their potential to increase the electrical isolation and stabilization of the pixel, as well as the corresponding physical tests to validate the particular geometries of this new sensor.

We present a design study of PIXSIC, a new beta(+) radiosensitive microprobe implantable in rodent brain dedicated to in vivo and autonomous measurements of local time activity curves of beta radiotracers in a small (a few mm(3)) volume of brain tissue. This project follows the initial beta microprobe previously developed at IMNC, which has been validated in several neurobiological experiments. This first prototype has been extensively used on anesthetized animals, but presents some critical limits for utilization on awake and freely moving animals. Consequently, we propose to develop a wireless setup that can be worn by an animal without constraints upon its movements. To that aim, we have chosen a Silicon-based detector, highly beta sensitive, which allows for the development of a compact pixellated probe (typically 600 x 200 x 1000 mu m(3)), read out with miniaturized wireless electronics. Using Monte-Carlo simulations, we show that high resistive Silicon pixels are appropriate for this purpose, assuming that the pixel dimensions are adapted to our specific signals. More precisely, a tradeoff has to be found between the sensitivity to beta(+) particles and to the 511 keV gamma background resulting from annihilations of beta(+) with electrons. We demonstrate that pixels with maximized surface and minimized thickness can lead to an optimization of their beta(+) sensitivity with a relative transparency to the annihilation background

The beta-microprobe is a simple and versatile technique complementary to small animal positron emission tomography (PET). It relies on local measurements of the concentration of positron-labeled molecules. So far, it has been successfully used in anesthetized rats for pharmacokinetics experiments and for the study of brain energetic metabolism. However, the ability of the technique to provide accurate quantitative measurements using (18)F, (11)C and (15)O tracers is likely to suffer from the contribution of 511 keV gamma rays background to the signal and from the contribution of positrons from brain loci surrounding the locus of interest. The aim of the present paper is to provide a method of evaluating several parameters, which are supposed to affect the quantification of recordings performed in vivo with this methodology. We have developed realistic voxelized phantoms of the rat whole body and brain, and used them as input geometries for Monte Carlo simulations of previous beta-microprobe reports. In the context of realistic experiments (binding of (11)C-Raclopride to D2 dopaminergic receptors in the striatum; local glucose metabolic rate measurement with (18)F-FDG and H(2)O(15) blood flow measurements in the somatosensory cortex), we have calculated the detection efficiencies and corresponding contribution of 511 keV gammas from peripheral organs accumulation. We confirmed that the 511 keV gammas background does not impair quantification. To evaluate the contribution of positrons from adjacent structures, we have developed beta-Assistant, a program based on a rat brain voxelized atlas and matrices of local detection efficiencies calculated by Monte Carlo simulations for several probe geometries. This program was used to

As mouse imaging has become more challenging in preclinical research, efforts have been made to develop dedicated PET systems. Although these systems are currently used for the study of physiopathologic murine models, they present some drawbacks for brain studies, including a low temporal resolution that limits the pharmacokinetic study of radiotracers. The aim of this study was to demonstrate the ability of a radiosensitive intracerebral probe to measure the binding of a radiotracer in the mouse brain in vivo. Methods: The potential of a probe 0.25 mm in diameter for pharmacokinetic studies was assessed. First, Monte Carlo simulations followed by experimental studies were used to evaluate the detection volume and sensitivity of the probe and its adequacy for the size of loci in the mouse brain. Second, ex vivo autoradiography of 5-hydroxytryptamine receptor 1A (5-HT1A) receptors in the mouse brain was performed with the PET radiotracer 2'-methoxyphenyl-(N-2'-pyridinyl)-p-F-18-fluorobenzamidoethylpiperazine (F-18-MPPF). Finally, the binding kinetics Of F-18-MPPF were measured in vivo in both the hippocampus and the cerebellum of mice. Results: Both the simulations and the experimental studies demonstrated the feasibility of using small probes to measure radioactive concentrations in specific regions of the mouse brain. Ex vivo autoradiography showed a heterogeneous distribution of F-18-MPPF consistent with the known distribution of 5-HT1A in the mouse brain. Finally, the time-activity curves obtained in vivo were reproducible and validated the capacity of the new probe to accurately measure F-18-MPPF kinetics in the mouse hippocampus. Conclusion: Our results demonstrate the ability of the tested radiosensitive intracerebral probe to monitor binding of PET radiotracers in anesthetized mice in vivo, with high temporal resolution suited for compartmental modeling.

Multimodal instrumentation is a new technical approach allowing simultaneous and complementary in vivo recordings of complementary biological parameters. To elucidate further the physiopathological mechanisms in intact small animal models, especially for brain studies, a challenging issue is the actual coupling of magnetic resonance imaging (MRI) techniques with positron emission tomography (PET): it has been shown that running the technology for radioactive imaging in a magnet alters the spatiotemporal performance of both modalities. Thus, we propose an alternative coupling of techniques that uses the β-MicroProbe instead of PET for local measurements of radioactivity coupled with MRI.

Understanding the cellular mechanisms of energy supply to neurons following physiological activation is still challenging and has strong implications to the interpretation of clinical functional images based on metabolic signals such as Blood Oxygen Level Dependent Magnetic Resonance Imaging or 18F-Fluorodexoy-Glucose Positron Emission Tomography. Intrinsic Optical Signal Imaging provides with high spatio temporal resolution in vivo imaging in the anaesthetized rat. In that context, intrinsic signals are mainly related to changes in the optical absorption of haemoglobin depending on its oxygenation state. This technique has been validated for imaging of the rat olfactory bulb, providing with maps of the actived olfactory glomeruli, the functional modules involved in the first step of olfactory coding. A complementary approach would be autofluorescence imaging relying on the fluorescence properties of endogenous Flavin Adenine Dinucleotide (FAD) or Nicotinamide Adenine Dinucleotide (NADH) both involved in intracellular metabolic pathways.The purpose of the present study was to investigate the feasibility of in vivo autofluorescence imaging in the rat olfactory bulb. We performed standard Monte Carlo simulations of photons scattering and absorption at the excitation and emission wavelengths of FAD and NADH fluorescence. Characterization of the fluorescence distribution in the glomerulus, effect of hemoglobin absorption at the excitation and absorption wavelengths as well as the effect of the blurring due to photon scattering and the depth of focus of the optical apparatus have been studied. Finally, optimal experimental parameters are proposed to achieve in vivo validation of the technique in the rat olfactory bulb.