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Financed Projects

2015


Dual-ended Readout Innovative Method for Positron Emission Tomography
Positron Emission Tomography is among the best examples of the contribution of medical imaging systems to clinical research. The development of PET systems adequate for small animal imaging has been an active area of research in the last two decades, with important applications in drug development and imaging of gene expression. This allowed a better understanding of human diseases and the development of more effective ways for disease diagnosis and treatment, through the translation of pre-clinical molecular imaging discoveries in small animals, to medical practice. In the case of research-dedicated PET scanners for small animal imaging, size adequacy is essential. In fact, for instance, a rat’s heart is more than 100 times smaller than the human heart.
This work aims at developing a small PET scanner with improved spatial resolution using depth-of-interaction (DOI) information. The system combines scintillator-photodetector cells with a new DOI determination method, based on light guides (optical fibres) with silicon photomultiplier readout (SiPM).
The method requires a small number of components to obtain DOI; therefore, it allows producing a high-performance PET system at acceptable cost, presenting state-of-the-art characteristics.
The foreseen system comprises one ring of 128 1.5 x 1.5 x 20 mm3 LYSO crystals radially distributed. Each single LYSO crystal is read out on both ends by silicon photomultipliers (SiPMs), but using wavelength-shifting (WLS) fibers/bars and a reduced number of SiPMs on one end. The DRIM-PET can be modulated for axial capability by using several rings modules placed side-by-side.
Two different signal readout systems will be considered. A simpler one that uses only a few readout channels for readout of the entire 128 detector cells, being the position determination obtained by a resistive chain method. The more complex one, with improved capabilities in terms of reduction of false coincidences, sensitivity and position resolution, will use individual channels for each cell.
Experimental and simulation studies will be performed in order to optimize the system’s parameters the aim of building and characterizing a prototype for its interest as new PET scanner for pre-clinical research.
Dedicated image reconstruction methods and imaging software will be developed taking into account the characteristics of the system and in order to optimize the image quality as a function of produced signals.
Prototype characterization, using beta+ emitters, will be done, first with 22-Na calibration sources and after with phantoms filled with 18-F. Finally, in order to demonstrate the potential of the developed PET scanner, small animals with different pathologies of interest (e.g. oncologic) and radio-tracers will be used as final evaluation task.
Principal Investigator: João Veloso (UA)Descrição:


Period: June 2016 - May 2019
Team: Pedro Almeida; Nuno Matela
Partners:

Instituto de Nanoestruturas, Nanomodelação e Nanofabricação (Aveiro) (I3N) (http://www.i3n.org/)

CNC.IBILI (Coimbra) (http://www.uc.pt/en/fmuc/ibili)

IBEB – Instituto de Biofísica e Engenharia Biomédica (www.ibeb.fc.ul.pt)

Amount: 199.954,00€

Distress and regional brain metabolism: a correlational study in metastatic breast cancer patients
Distress screening in cancer patients is internationally recommend as good practice in quality cancer care, since high levels of cancer-related distress may negatively impact on their clinical outcomes, such as survival and quality of life.
Distress involves a range of feelings from vulnerability and sadness to depression, anxiety, adjustment disorders, panic and isolation. As have been shown in studies done by a researcher of our team, Michael Antoni negative affect in breast cancer patients has been associated with flattened diurnal cortisol rhythmicity and dysfunction of immune functioning, namely greater leukocyte inflammatory gene (IL-1, IL-6, TNF) expression which are related to hypothalamic pituitary adrenal axis dysregulation (HPA). HPA dysregulation is relevant in mBC patients since alterations in circulating cortisol interacts with immune cells to upregulate inflammatory signaling, which could promote disease progression. Distress in cancer patients may also
be correlated with objective measures of changes (increase or decrease) in brain glucose metabolism, in regions within the limbic cortical circuit of the brain.
Distress can be measured through simple self-report instruments completed by the patient, which assess patients’ subjective experience. However in many centers and countries this is not yet standard clinical practice and as a consequence most of the psychological suffering in cancer patients goes unrecognized by the clinical staff and untreated. The identification of distress in cancer patients is an important target in clinical care for optimizing patients’ well-being and their outcomes. As such it would be important to have alternative ways in the existing routine clinical practice to detect it and, more important, to have a measure/indicator of patient propensity for distress in response to illness challenges. This study may give a contribution in this
regard.
Studies using positron emission tomography (PET) with non-cancer subjects have demonstrated correlations between depression assessed by self-report measures and alterations in regional cerebral glucose metabolism (rCGM), as well as regional cerebral perfusion/blood flow in some specific brain regions. However, no studies correlating distress (which does not necessarily involve depression) with rCGM in cancer patients have been reported. However, FDG-PET exams are used in clinical practice to assess disease progression and response to treatment in metastatic breast cancer patients (mBC). With this research project we aim to fill in this gap since our primary objective is to examine associations among individual differences in reported depression, anxiety, cortisol levels and rCGM measures (FDG-PET) of baseline activity in specific regions within the limbic-cortical circuit of the brain such as in the amygdala, pulvinar nucleus, dorsolateral prefrontal cortex and subgenual anterior cingulate cortex in mBC patients. We expect to find that increasing levels of distress will be related with increasing or decreasing rCGM measures (FDG-PET) in these same specific regions of the brain. This may allow us to identify one or more specific regions within the limbic-cortical circuit of the brain, which are sensitive to levels of heightened distress and HPA axis alterations and as such could serve as an objective indicator of patient’s affective style. Individual differences in tonic alterations of activity level in specific brain regions could predict differences in propensity for distress in response to illness challenges and therefore will have impact on clinical management of cancer patients facilitating proper and early referral for an adequate psychosocial preventive intervention.
Using this ‘smooth’ way of screening for distress included in a routine clinical exam would benefit patients and professionals and be cost-effective, as it would avoid using additional resources and patients’ time. Having selective ways to target patients’ propensity for distress in the cancer setting is an important objective. The positive impact to have such a measure is significant because it will allow: (1) early screening of patients at higher risk for psychological morbidity (mainly depression); (2) early referral for psychosocial care to prevent and/or reduce distress and psychological morbidity (3) optimize patients’ selection for psychosocial care to those who may benefit more and therefore optimize and reduce healthcare costs; (4) optimize clinical outcomes (by reducing the potential adverse effects in immune function produced by psychological distress and/or morbidity in cancer patients); (5) open the door to future work that can test whether people who receive anti-depressants or Cognitive Behavioral Therapy-based interventions will show objective changes in brain activity and (5) promote cancer care for the whole patient.Descrição:


Period: Jan 2016 - Dec 2018
Team: Pedro Almeida
Amount: 158.710,00 €

2013


A novel approach for tumoral targeted phototherapy: focusing light through scattering
This proposal outlines a R&D programme aiming the study of new methodologies for concentrate light inside turbid biological media, one of the last frontiers in laser biomedical applications. The target: phototherapy by thermal activation and destruction of cancer cells.
The backbone of the proposed research is the development of a phase shaping method based on an iterative algorithm to create wavefronts inverting the diffusion of light. This algorithm will be developed, being the interrogation and phase partitioning strategies critical points to be considered when analysing its performance. Two main types of laser beams will be considered in the study (Gaussian and quasi-Bessel beams) and the potential of low coherence beams to improve the method will be analysed. The core scientific objectives to be pursued are:
- To produce and characterize multifunctional nanoparticles which phototherapeutic potential can be improved by their in-depth activation.
- To develop a new methodology based in phase shaping to concentrate light inside turbid biological media.
- To develop a simulator capable of predict the focusing capability of the methodology for a determined set of parameters.
- To demonstrate the technique by its experimental application under well controlled conditions.
- To demonstrate the technique in vitro and in vivo.
- To evaluate the potential, limitations and future developments of the technique.
Although light has long being used in biomedicine, scattering always limited its application. Superficial (tenths of micron for human epidermis) phototherapy is already a well established application, requiring intrusive methods to deliver light when the target is deeper inside the body. The latter solution removes the major advantage in using light: its non-intrusive potential. This motivates researchers to develop methods to concentrate light inside biological highly scattering media. However, only a few years ago phase shaping approaches have started to be developed for focusing light through turbid media, although not exactly directed to biological media. The idea: to use a phase modulator to produce wavefronts inverting the diffusion of light based on a close-loop approach. In biophysics, the research in this area as been mainly focused in increasing the depth light can propagate, with direct application in imaging techniques like microscopy and tomography. In these fields, scattered light is collected and its analysis allows imaging. In order to increase the observable path, several strategies have been envisaged. A recent one has been developed for optical coherence tomography by using quasi-Bessel beams. These beams have shown the capability of self-reconstruct along the turbid path thus allowing collect scattering at longer paths.
In this work we propose to further develop the phase-shaping principle with a dedicated approach to biomedical applications, in general, and photoactivation in particular. The preconditioning of the incident beam to a quasi-Bessel beam will increase the propagation of the beam, although scattered. Then, the developed phase shaping technique will act, concentrating the light where necessary. The use of these beams is expected to remove computational load of the iterative process and allow a better and faster convergence to a solution. The technique will be developed considering the parameters regarding a set of photosensitize substances identified as potentially relevant for the study.
A simulator will allow overcoming a limitation of the technique: its requirement of feedback information on the intensity distribution in the plane where light concentration is required. By using an optical design and scientific programming software, and by proper experimental validation, it will allow predicting the method’s performance in an open loop process (as in real applications).
A numerical model will be developed to predict the effects of a concentrated light beam on the considered substances and surrounding media.
The institutions proposing this candidature have a combined set of experiences that potentiate the development of this research. From FCUL, IBEB, CFA and LOLS joint forces will use they expertise in biomedical and light-matter interaction. FCTUNL has expertise in the application of optical techniques in the biomedical field, in particular but not exclusively in the area of ophthalmology, aiming the development of new techniques and methodologies for medical application. INL (BioPhotonics Group) will contribute with its expertise in the fields of phototherapy of cancer cells; photochemistry and biophotonics; synthesis, characterization and biofunctionalization of nanoparticles and bioimaging. COFAC, with its BioSciences Center (CBIOS), and INL will contribute with their expertise in the fields of multifunctional nanoparticles development and drug delivery for tumor therapy. In vivo tests will be performed at the Faculty of Pharmacy of the Univ. of Coimbra
Principal Investigator: João Miguel Pinto Coelho (IBEB and LOLS)Descrição:


Period: January 2013 - December 2014
Team: João Miguel Pinto Coelho; Hugo Ferreira
Partners:

IBEB – Instituto de Biofísica e Engenharia Biomédica
Centro de Física Atómica (FC/UL)
Laboratório de Óptica, Lasers e Sistemas, Departamento de Física da Faculdade de Ciências da Universidade de Lisboa (FCUL-DF-LOLS)
Laboratório Ibérico Internacional de Nanotecnologias (INL)
COFAC, Cooperativa de Formação e Animação Cultural, CRL (COFAC)
Fundação da Faculdade de Ciências e Tecnologia (FFCT/FCT/UNL)

Amount: 149 815€

Improvement of image quality and dose reduction in digital breast tomosynthesis using statistical image reconstruction algorithms
Tomosynthesis is an emerging radiological technique used for breast imaging. It produces a 3D image from a series of views, reducing the problem of overlapping structures in 2D mammography imaging. The clinical benefit of this technique for the diagnosis of breast cancer is still under evaluation. Recent studies show that Digital Breast Tomosynthesis (DBT) presents superior image quality and better cancer visibility, indicating a better sensitivity than digital mammography (DM). Some argue that DBT has not yet proven to result in better clinical performance than using DM, but others suggest that combining both techniques could lead to better overall performance. However, some authors go one step further and consider that DBT can be an alternative to DM in breast cancer screening, particularly for women with dense breasts. Despite these promising results, it is acknowledged that neither the acquisition nor the image reconstruction algorithms of DBT are fully optimized.

The majority of published clinical studies refers the use of analytical algorithms for image reconstruction. However, it is accepted that iterative methods can improve image quality relatively to analytical image reconstruction.

Iterative methods include statistical iterative reconstructions algorithms that incorporate a geometrical model for the transmission/detection process and take into account data statistics and a noise model. The inclusion of this statistical information enables better quantitation than Filtered Backprojection (FBP) in regions of low intensity / low count rates, as demonstrated for emission tomography.

In the proposed work, this characteristic is crucial since the number of photon counts in DBT projections is reduced as a consequence of low dose requirement. Therefore, we anticipate that statistical algorithms can not only lead to better DBT images, but can also play an important role on dose reduction if similar image quality can be obtained at a lower dose, increasing the clinical value of this technique.

Hospital da Luz has installed the first DBT scanner in Portugal and, being a research partner of this project, grants us access to the equipment. This is crucial not only for simulation validation and dosimetry purposes, but also for the development of image reconstruction algorithms, since the access to phantom and real data is mandatory along the way. In addition, radiologists from Hospital da Luz will contribute to the evaluation and optimisation of the new or redesigned algorithms.

In order to evaluate the potential reduction of patient doses, we will develop a Monte Carlo simulation platform, similar to the one that has already been validated for conventional digital mammography. This simulation tool will allow us to test different exposure configurations, for both dose and image quality purposes, without the need to irradiate patients. This simulation platform will be validated with dose measurements made with conventional dosimeters and with a new dosimeter that is currently being developed by LIP, one of the research partners.

Regarding image reconstruction, an important issue that hinders the use iterative image reconstruction algorithms is their computation time, which can amount up to several hours in a standard computer. To overcome this problem, we intend to take advantage of the modern graphic processor units (GPU) that are known to speed up image reconstruction by more than an order of magnitude. Some work has already been done within the IBEB group.

In recent years, this team has published several papers in image reconstruction and processing, Monte Carlo simulation and dosimetry. The two radiologists from Hospital da Luz have a long experience in mammography and are using DBT in clinical routine for more than two years. This background encourages us to address the problem from an integrated perspective. We do believe that there is work to be done in the improvement of image reconstruction algorithms for DBT and that this can have a significant repercussion on dose received by the patients. We also believe that simulation can provide additional information to radiologists and radiographers, so they can optimise on everyday routine each particular exam in respect to dose deliver to patients.

This project congregates academic and clinical expertise. The expected results are due to be fully available to the clinical partner, for the benefit of its patients. The global impact that DBT is expected to achieve in breast cancer diagnosis increases the potential value of the tools developed in this project. In the case of commercial valorisation of these tools, the institutions have already signed an agreement that includes the terms of the sharing of the intellectual property.

Principal Investigator: Pedro Almeida (IBEB)Descrição:


Period: June 2013 – December 2015
Team: Pedro Almeida; Nuno Matela; Ana Margarida Mota; Nuno Oliveira; Pedro Ferreira; Luís Janeiro
Partners:

IBEB – Instituto de Biofísica e Engenharia Biomédica (www.ibeb.fc.ul.pt)
Hospital da Luz, SA (http://www.hospitaldaluz.pt/)
LIP – Laboratório de Instrumentação e Física Experimental de Partículas (www.lip.pt)
C2TN – Centro de Ciências e Tecnologias Nucleares (http://c2tn.tecnico.ulisboa.pt/)

Amount: 150 532,00€

2008


Neuroimaging investigation of learning mechanisms in the human brain: new methodological approaches
The nervous system is constantly changing over the lifespan as a result of development and learning. Such plasticity-related changes occur at multiple levels of neural organization, from molecules and synapses to cortical maps and large-scale networks. Neuroimaging research over the past two decades has already contributed an extensive amount of information on how many sensory and cognitive functions are associated with particular brain structures. Increasing interest in the characterization of plasticity mechanisms in the human brain has posited new challenges to neuroimaging techniques, both of conceptual and methodological nature. In particular, it is thought that great insights will be possible through the conjoint analysis of activity within specific brain regions and functional connectivity between those regions.
In this Project, we propose to address this issue through the development and implementation of the following neuroimaging methodological approaches. Firstly, state-of-the-art acquisition methods for functional magnetic resonance imaging (fMRI) will be implemented in a 1.5 Tesla system in order to allow more quantitative and reliable assessment of learning-related brain activity changes. Secondly, different techniques for the analysis of brain connectivity will be developed and integrated, based on the combination of fMRI with electroencephalography (EEG) measurements for the assessment of both low and high frequency behavior.
Although conventional fMRI techniques using blood oxygenation level dependent (BOLD) contrast have already proved useful in the study of plasticity-related brain activity changes, they present severe constraints when the learning process of interest occurs over minutes or even hours, or when longitudinal designs are chosen to investigate effects over longer periods of time. Arterial spin labelling (ASL) perfusion imaging methods provide a more stable and quantitative measure of brain activity that constitutes an interesting complement to BOLD contrast. Moreover, a recently developed diffusion-weighted imaging (DWI) technique seems to provide an independent, quantitative measure of activation, therefore offering additional information. Protocols for the combined acquisition of BOLD, ASL and DWI fMRI will be implemented and validated using robust visual stimulation paradigms.
Synchronization of neural responses is thought to be modified as a function of learning and represents a possible plasticity mechanism. Functional connectivity investigations of fMRI data provide a way of assessing synchronization between brain regions. Protocols for both model- and data-driven analysis methods of connectivity will be implemented, in order to combine the complementary strengths of each strategy. Correlation-type exploratory approaches will be used to determine networks of functionally connected brain areas and specific causal models will then be tested, based on these networks and available neurophysiological information. Neural synchronization can also be assessed through coherence measures of EEG recordings. The high temporal resolution of this technique allows the investigation of functional connectivity at various frequency oscillation bands, which have previously been hypothesized to have differential cognitive significance. Time-series analysis methods will be implemented and validated for the measurement of phase coherence between EEG channels. Time-frequency decomposition techniques will be employed in order to explicitly access specific frequency bands of interest. Additionally, protocols for the simultaneous EEG and fMRI acquisition will be implemented and appropriate analysis methods developed for the integration of the multimodal data. By combining EEG with fMRI, we hope to enable the investigation of functional connectivity changes during learning over a broad range of frequencies.
Finally, the contextual cueing paradigm used for the study of implicit learning mechanisms will be investigated with the methods developed within this Project. Combined BOLD-ASL fMRI will first be used to determine brain activity changes related to the learning processes under study, testing hypotheses concerning the involvement of specific brain structures, namely the hippocampus and caudate nucleus. Functional connectivity analysis will also be conducted, in order to investigate the interactions between the participating brain regions. Finally, simultaneous EEG-fMRI measures will be used to investigate learning induced neuronal synchronization at different frequency bands.
In summary, with this Project we hope to contribute to the development and validation of valuable acquisition and analysis tools for the investigation of brain mechanisms of learning using neuroimaging techniques. Moreover, we expect that this Project will enable the cooperation between young scientists with expertise in the fields of Biomedical Engineering and Neuroscience, in the context of the National Network for Functional Brain Imaging recently approved by FCT.
Principal Investigator: Patrícia Figueiredo (IST)Descrição:


Period: January 2008 - December 2010
Team: Alexandre Andrade
Partners:

Instituto Superior Técnico (IST/UTL)

Siemens SA (Siemens)

Instituto Biomédico de Investigação de Luz e Imagem (IBILI/FM/UC)

IBEB – Instituto de Biofísica e Engenharia Biomédica

Amount: 172 158€