The "Functional Imaging and Instrumentation" group of the Department of Physics and INFN Pisa is from years working on the development of new tools for molecular imaging, with focus on the pre-clinical applications of Positron Emission Tomography (PET) and its combination with the X-ray Computed Tomography (PET / CT), and applications preclinical and clinical imaging and spectroscopy in nuclear magnetic resonance imaging (MRI and MRS).
Our laboratory serves as an incubator for technologies of molecular imaging. The detectors are designed, developed and, when the technology is mature enough, are integrated into tools for specific applications. The development of data acquisition systems and software acquisition and image reconstruction is an integral part of the process of prototyping the imaging systems.
Among the research and development undertaken by our group, one is the development and application of a new medical imaging photodetector, the Silicon Photomultipliers (SiPM). The SiPM is a device in silicon consists of a matrix of small avalanche photodiodes (microcells) operated in Geiger mode. The micro-cells are connected in parallel so that the signal provided by the SiPM is the sum of the signals of the microcells (see figure 1).
The high gain (about 10^6) attainable at low supply voltages (order of 50 V), the compactness and versatility in design make these devices particularly suitable for their use in medical imaging systems such as PET and SPECT scanners, probes Intraoperative probes and, due to their insensitivity to magnetic fields, even in modern hybrid PET/MR systems. Since 2006, the group led the project INFN DASIPM which aimed to develop and apply the SiPM in various fields of research, spanning from astrophysics, calorimetry for high energy physics to medical imaging. As part of this project it was produced the first Italian SiPM in collaboration with the research institute FBK-irst that at present is among the world's leading manufacturers of this device. Appropriately tailored versions of these detectors will be used in a PET/MR scanner dedicated to investigations of psychiatric diseases (EU FP7 project TRIMAGE) and a system for verifying the quality of cancer treatments in hadrontherapy (Ministry project PRIN INSIDE) to be installed at the National Center of Oncology Hadrontherapy (CNAO) in Pavia (see figure 2).
Working in close collaboration with our colleagues at the Institute of Clinical Physiology (IFC-CNR Pisa), where physicists, biologists, radiochemical created the "Micro Imaging Lab" laboratory dedicated to pre-clinical investigations, we are now taking our technology from our laboratory in real systems ready to be used in routine practice.

Figure 1. Sketch of the Silicon photomultiplier.

Figure 1. Silicon photomultiplier matrix.

Several areas of Medical Physics require the development of dedicated software. In particular, we are involved in the automatic analysis of diagnostic digital images, eg Pulmonary CT (a), magnetic resonance images (MRI) of the brain (b) and of the muscoloskeletal system (c), in order to create software tools that provide useful information for the quantitative analysis and interpretation of the images.

1. A Lung CAD (Computer Aided Detection) able to automatically detect suspect nodules in Pulmonary CT examinations has been already developed and validated with excellent results. It is now available for radiologists as a web service on demand. Research activities as nodule volumetric evaluation, images coregistration to evaluate the temporal evolution of nodule volume growth and automatic research of Ground Glass opacities are still active.
2. Numerical analysis, segmentation tools and different classification approaches based on SVM (Support Vector Machines) are developed and applied to structural Magnetic Resonance Images of brain for different applications. For example, in the case of Alzheimer's Disease, the application of these analysis methods to subjects affected by Alzheimer's disease (AD) and healthy controls (CTRL) can allow the prediction of the outcome of subjects with Mild Cognitive Impairment (MCI). Instead, in the case of Autism Spectrum Disorders (ASD), the goal is the identification of areas that mostly contribute to separate classes of healthy and sick and localize the brain regions altered by the disease.
3. An analysis method able to make a quantitative evaluation of the fat infiltration and to relate it to the grade of muscle impairment has been developed and is currently applied to structural Magnetic Resonance Images of lower limbs of patients affected by neuromuscular disorders (NMD).

a) GUI of the lung CAD web service (left) and visualization of CAD findings with a dedicated plugin of OsiriX DICOM viewer (right).

b) Examples of discrimination maps overlaid to a representative structural MR image, obtained from SVM-RFE analysis.

c) Automatic muscle segmentation and intensity hystograms for healthy subject (left) and NMD patients with mild (middle) and severe (right) muscle involvment.

The research activity of the Laboratory of Medical Physics and MR technologies of IRCCS Stella Maris and IMAGO7 research foundation has been developing around two Magnetic Resonance (MR) scanners. The first is a clinical scanner at 1.5 Tesla (Signa Horizon LX General Electric HealthCare), optimized for neurological applications and operative at IRCCS Stella Maris from 1996. Since two years ago, an Ultra-High Field MR (UHF_MR) scanner at 7 Tesla for human application (Signa7T MR950 General Electric HealthCare) is active at IMAGO7. It is committed only for research purposes, being the first UHF-MR system in Italy. The long experience on clinical MR scanners allowed to execute and optimize: i) neurometabolic exams by Magnetic Resonance Spectroscopy (MRS) of hydrogen (1H) and phosphorous (31P); ii) functional imaging (fMRI); iii) metabolism studies as the perfusion weighted imaging by the measurement of the Cerebral Blood Flow (CBF) and iv) the study of cerebral microstructure by using diffusion techniques such as the Diffusion Tensor Imaging (DTI) and the Fiber Tracking. Principal focus of research activity is the application of all these MR methods to the field of neuroscience and in the neurological and psychiatric disease of developmental age. Thanks to the use of UHF-MR, many and new potentialities are opened in terms of increment of Signal to Noise Ratio (SNR), increment of spatial, temporal and spectral resolutions, as well as in the exploitation of new contrast mechanisms, able to depict the brain structure at sub-millimeter level, such as the techniques of Susceptibility Weighted Imaging, (SWI). However, at UHF-MR, there are also many technical challenges in the application of standard sequences,both in terms of safety (as the monitoring and the control of energy deposition on the patient) and in terms of distortions of the images and in-homogeneities of the signal. Furthermore, to take full advantage from UHF-MR, pulse sequences have to be optimized and hardware components such as dedicated and new designed RF coils have to be developed for specific MR applications. Thus, a specific R&D activity in collaboration with INFN and GE HealthCare is on-going.
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A promising technique for cancer treatment is using charged particles like protons and carbon ions, rather than photons, and several facilities operate in this field since many years (more information at: http://www.ptcog.ch). This growing interest in charged particle therapy is based on the highly improved dose conformation to the target volume potentially resulting in an improved sparing of organs-at-risk. Treatments with charged particles are, however, much more sensitive to uncertainties than photon treatments: an active research area in particle therapy is therefore how to monitor the dose delivery. Positron Emission Tomography (PET) is a non-invasive way of in-vivo verification of the dose delivered to the patient. During ion beam irradiation, various Beta+ emitting isotopes (15O, 11C, 13N etc) are generated in the patient. Although dose and activity are indirectly related, it is possible to obtain useful information about the proton range and delivered dose from beta+ activity measurements. By comparing the measured PET activity distributions with a pre-calculated Monte Carlo distribution, it is possible to check whether the delivered dose differs from the planned dose, i.e. to perform quality assurance of the treatment.
In this context, in Pisa (University of Pisa and INFN: National Institute of Nuclear Physics), a group of researchers has developed two different systems for this purpose: DoPET and INSIDE.
DoPET is a compact planar PET system, that can be installed in the beam delivery system, and was developed in the framework of the project RDH (Research and Development in Hadrontherapy) funded by INFN-Italy. This system is capable of acquiring data during the treatment as was demonstrated for proton irradiation with the CATANA cyclotron and with the CNAO synchrotron. DoPET, consisted of two planar 16 x 16 cm2 detector heads each composed of nine independent modules. Each module consisted of an H8500 PMT coupled to a 23x23 LYSO crystal matrix (2 mm pitch) with the readout performed by custom developed electronics. The Data Acquisition was designed to keep the acquisition dead time low and to have a relatively narrow coincidence window (few ns). DoPET has a sensitivity and spatial resolution so as to reconstruct the Bragg peak position to 1 mm in less than few minutes after the dose delivery for proton irradiations, limiting the biological washout problems.
INSIDE combine an in-beam PET scanner and a particle tracking system in a unique imaging device to measure on-line the particle range with high precision. This bi-modal monitoring system is being developed in the framework of the project INSIDE (Innovative Solutions For Dosimetry In Hadrontherapy) funded by MIUR, the Italian Minister for University and Research) under the PRIN program (Research Projects of National Relevance). The PET scanner, an evolution of the DoPET system, is tailored for the imaging of head and neck tumours. It is composed of two planar detectors, 10 cm wide (transaxially) x 25 cm long (axially, along the beam direction). The PET heads are composed of 2x5 detection units, each made of arrays of 256 LSF pixel crystals, 3x3x20 mm3 each, coupled one to one to analog solid state photodetectors called Silicon PhotoMultipliers (SiPM). A custom designed electronics system is being developed to cope with the prompt particle rates typical of a therapeutic beam (~10 MHz/cm2).
The PET activity map created in the target is complemented by the beam profile, obtained by tracking the secondary particles (protons) coming from the interaction of the primary beam with the target nuclei and from projectile fragmentation in case of carbon beams. The tracking system is composed of 6 planes of orthogonal squared scintillating fibers (each plane has 384 fibers) coupled to 1 mm2 SiPMs. The sensitive area is 19.2 x 19,2 cm2. An electromagnetic calorimeter made of LFS crystal arrays coupled to Position Sensitive PMTs is placed downstream the tracker and provides the residual energy of the charged particles.
The INSIDE system is designed to fit in the treatment room of the Centro Nazionale di Adroterapia Oncologica (CNAO, Pavia, Italy), at the moment the only dual ion (protons and Carbons) PT therapy facility in operation in Italy.

Left: DoPET during a data taking at Protontherapy Centre in Trento. Right: DoPET prototype as a whole.