Hepatic arterial infusion enhances DOTATOC radiopeptide therapy in patients with neuroendocrine liver metastases

Intravenously administered radiolabeled peptides targeting somatostatin receptors are used for the treatment of unresectable gastroenteropancreatic neuroendocrine tumors (GEP-NETs). Recently, we demonstrated a high first-pass effect during intra-arterial (i.a.) administration of positron emission tomography (PET) labeled (68)Ga-DOTA(0)-d-Phe(1)-Tyr(3)-octreotide (DOTATOC). In this pilot study, we investigated the therapeutic effectiveness of arterial administered DOTATOC, labeled with the therapeutic β emitters (90)Y and (177)Lu. (90)Y- and/or (177)Lu-DOTATOC were infused into the hepatic artery of 15 patients with liver metastases arising from GEP-NETs. Response was assessed using DOTATOC-PET, multiphase contrast enhanced computed tomography, magnetic resonance imaging, and the serum tumor marker chromogranin A. Pharmacokinetic data of the arterial approach were assessed using (111)In-DOTATOC scans. With the treatment regime of this pilot study, complete remission was achieved in one (7%) patient and partial remission was observed in eight (53%) patients, six patients were classified as stable (40%; response evaluation criteria in solid tumors criteria). The concomitant decrease of elevated serum tumor marker confirmed the radiologic response. Median time to progression was not reached within a mean follow-up period of 20 months. Receptor saturation and redistribution effects were identified as limiting factors for i.a. DOTATOC therapy. The high rate of objective radiologic response in NET patients treated with arterial infusion of (90)Y-/(177)Lu-DOTATOC compares favorably with systemic chemotherapy and intravenous radiopeptide therapy. While i.a. DOTATOC therapy is only applicable to patients with tumors of limited anatomic distribution, the results of this pilot study are a promising development in the treatment of GEP-NET and warrants further investigation of this novel approach.

The Influence of Different Metal-Chelators on the Biological Profil of Nanoparticles for Gallium-68 Based Molecular Imaging

The use of metal chelators is becoming increasingly important in the development of new tracers for molecular imaging. With the rise of the field of nanotechnology, the fusion of both technologies has shown great potential for clinical applications. The pharmacokinetcs of nanoparticles can be monitored via positron emission tomography (PET) after surface modification and radiolabeling with positron emitting radionuclides. Different metal ion chelators can be used to facilitate labeling of the radionuclides and as a prerequisite, optimized radiolabeling procedure is necessary to prevent nanoparticle aggregation and degradation. However, the effects of chelator modification on nanoparticle pharmacokinetic properties have not been well studied and currently no studies to date have compared the biological effects of the use of different chelators in the surface modification of nanoparticles.

Lateralized and frequency-dependent effects of prefrontal rTMS on regional cerebral blood flow

Repetitive transcranial magnetic stimulation (rTMS) is a means to study the function and connectivity of brain areas. The present study addressed the question of hemispheric asymmetry of frontal regions and aimed to further understand the acute effects of high- and low-frequency rTMS on regional cerebral blood flow (rCBF). Sixteen healthy right-handed men were imaged using H(2)(15)O positron emission tomography (PET) immediately after stimulation. High (10 Hz)- and low (1 Hz)-frequency suprathreshold short-duration rTMS was applied over either the left or right dorsolateral prefrontal cortex (DLPFC). Slow and fast rTMS applied over the left DLPFC significantly increased CBF in the stimulated area. Compared to baseline, slow rTMS induced a significant increase in CBF contralateral to the stimulation site, in the right caudate body and in the anterior cingulum. Furthermore, slow rTMS decreased CBF in the orbitofrontal cortex (OFC, ipsilateral to stimulation side). Fast rTMS applied over the right DLPFC was associated with increased activity at the stimulation site, in the bilateral orbitofrontal cortex and in the left medial thalamus compared to 1-Hz rTMS. These results show that rCBF changes induced by prefrontal rTMS differ upon hemisphere stimulated and vary with stimulation frequency. These differential neurophysiological effects of short-train rTMS with respect to side and frequency suggest hemisphere-dependent functional circuits of frontal cortico-subcortical areas.

Identification of brain structures involved in micturition with functional magnetic resonance imaging (fMRI)

OBJECTIVE: The voluntary control of micturition is believed to be integrated by complex interactions among the brainstem, subcortical areas and cortical areas. Several brain imaging studies using positron emission tomography (PET) have demonstrated that frontal brain areas, the limbic system, the pons and the premotor cortical areas were involved. However, the cortical and subcortical brain areas have not yet been precisely identified and their exact function is not yet completely understood. MATERIALS AND METHODS: This study used functional magnetic resonance imaging (fMRI) to compare brain activity during passive filling and emptying of the bladder. A cathetherism of the bladder was performed in seven healthy subjects (one man and six right-handed women). During scanning, the bladder was alternatively filled and emptied at a constant rate with bladder rincing solution. RESULTS: Comparison between passive filling of the bladder and emptying of the bladder showed an increased brain activity in the right inferior frontal gyrus, cerebellum, symmetrically in the operculum and mesial frontal. Subcortical areas were not evaluated. CONCLUSIONS: Our results suggest that several cortical brain areas are involved in the regulation of micturition.

NOVEL AMINO ACID TRANSPORTER-TARGETED RADIOTRACERS FOR BREAST CANCER IMAGING

Breast cancer is the most common malignancy among women in the world. Its 5-year survival rate ranges from 23.4% in patients with stage IV to 98% in stage I disease, highlighting the importance of early detection and diagnosis. 18F-2-Fluoro-2-deoxy-glucose (18F-FDG), using positron emission tomography (PET), is the most common functional imaging tool for breast cancer diagnosis currently. Unfortunately, 18F-FDG-PET has several limitations such as poorly differentiating tumor tissues from inflammatory and normal brain tissues. Therefore, 18F-labeled amino acid-based radiotracers have been reported as an alternative, which is based on the fact that tumor cells uptake and consume more amino acids to sustain their uncontrolled growth. Among those radiotracers, 18F-labeled tyrosine and its derivatives have shown high tumor uptake and great ability to differentiate tumor tissue from inflammatory sites in brain tumors and squamous cell carcinoma. They enter the tumor cells via L-type amino acid transporters (LAT), which were reported to be highly expressed in many cancer cell lines and correlate positively with tumor growth. Nevertheless, the low radiosynthesis yield and demand of an on-site cyclotron limit the use of 18F-labeled tyrosine analogues. In this study, four Technetium-99m (99mTc) labeled tyrosine/ AMT (α-methyl tyrosine)-based radiotracers were successfully synthesized and evaluated for their potentials in breast cancer imaging. In order to radiolabel tyrosine and AMT, the chelators N,N’-ethylene-di-L-cysteine (EC) and 1,4,8,11-tetra-azacyclotetradecane (N4 cyclam) were selected to coordinate 99mTc. These chelators have been reported to provide stable chelation ability with 99mTc. By using the chelator technology, the same target ligand could be labeled with different radioisotopes for various imaging modalities for tumor diagnosis, or for internal radionuclide therapy in future. Based on the in vitro and in vivo evaluation using the rat mammary tumor models, 99mTc-EC-AMT is considered as the most suitable radiotracer for breast cancer imaging overall, however, 99mTc-EC-Tyrosine will be more preferred for differential diagnosis of tumor from inflammation.

Development of a specific tracer for metabolic imaging of alveolar echinococcosis: A preclinical study

Positron emission tomography (PET)-computed tomography (CT) using [18F]-fluorodeoxyglucose (FDG) (FDG-PET/CT) is a valuable method for initial staging and follow up of patients with alveolar echinococcosis (AE). However, the cells responsible for FDG uptake have not been clearly identified. The main goal of our study was to evaluate the uptake of PET tracers by the cells involved in the host-parasite reaction around AE lesions as the first step to develop a specific PET tracer that would allow direct assessment of parasite viability in AE. Candidate molecules ([18F]-fluorotyrosine (FET), [18F]-fluorothymidine (FLT), and [18F]-fluorometylcholine (FMC), were compared to FDG by in vitro studies on human leukocytes and parasite vesicles. Our results confirmed that FDG was mainly consumed by immune cells and showed that FLT was the best candidate tracer for parasite metabolism. Indeed, parasite cells exhibited high uptake of FLT. We also performed PET/CT scans in mice infected intraperitoneally with E. multilocularis metacestodes. PET images showed no FDG or FLT uptake in parasitic lesions. This preliminary study assessed the metabolic activity of human leukocytes and AE cells using radiolabeling. Future studies could develop a specific PET tracer for AE lesions to improve lesion detection and echinococcosis treatment in patients. Our results demonstrated that a new animal model is needed for preclinical PET imaging to better mimic human hepatic and/or periparasitic metabolism.

Dose-painting intensity-modulated proton therapy for intermediate- and high-risk meningioma.

BACKGROUND Newly diagnosed WHO grade II-III or any WHO grade recurrent meningioma exhibit an aggressive behavior and thus are considered as high- or intermediate risk tumors. Given the unsatisfactory rates of disease control and survival after primary or adjuvant radiation therapy, optimization of treatment strategies is needed. We investigated the potential of dose-painting intensity-modulated proton beam-therapy (IMPT) for intermediate- and high-risk meningioma. MATERIAL AND METHODS Imaging data from five patients undergoing proton beam-therapy were used. The dose-painting target was defined using [68]Ga-[1,4,7,10-tetraazacyclododecane tetraacetic acid]- d-Phe(1),Tyr(3)-octreotate ([68]Ga-DOTATATE)-positron emission tomography (PET) in target delineation. IMPT and photon intensity-modulated radiation therapy (IMRT) treatment plans were generated for each patient using an in-house developed treatment planning system (TPS) supporting spot-scanning technology and a commercial TPS, respectively. Doses of 66 Gy (2.2 Gy/fraction) and 54 Gy (1.8 Gy/fraction) were prescribed to the PET-based planning target volume (PTVPET) and the union of PET- and anatomical imaging-based PTV, respectively, in 30 fractions, using simultaneous integrated boost. RESULTS Dose coverage of the PTVsPET was equally good or slightly better in IMPT plans: dose inhomogeneity was 10 ± 3% in the IMPT plans vs. 13 ± 1% in the IMRT plans (p = 0.33). The brain Dmean and brainstem D50 were small in the IMPT plans: 26.5 ± 1.5 Gy(RBE) and 0.002 ± 0.0 Gy(RBE), respectively, vs. 29.5 ± 1.5 Gy (p = 0.001) and 7.5 ± 11.1 Gy (p = 0.02) for the IMRT plans, respectively. The doses delivered to the optic structures were also decreased with IMPT. CONCLUSIONS Dose-painting IMPT is technically feasible using currently available planning tools and resulted in dose conformity of the dose-painted target comparable to IMRT with a significant reduction of radiation dose delivered to the brain, brainstem and optic apparatus. Dose escalation with IMPT may improve tumor control and decrease radiation-induced toxicity.

External assessment of myocardial glucose metabolism with $\sp{18}$F-2 -deoxy-2 -fluoro-D-glucose

Despite the popularity of the positron emitting glucose analog, ($\sp{18}$F) -2-deoxy-2-fluoro-D-glucose (2FDG), for the noninvasive "metabolic imaging" of organs with positron emission tomography (PET), the physiological basis for the tracer has not been tested, and the potential of 2FDG for the rapid kinetic analysis of altered glucose metabolism in the intact heart has not been fully exploited. We, therefore, developed a quantitative method to characterize metabolic changes of myocardial glucose metabolism noninvasively and with high temporal resolution.^ The first objective of the work was to provide direct evidence that the initial steps in the metabolism of 2FDG are the same as for glucose and that 2FDG is retained by the tissue in proportion to the rate of glucose utilization. The second objective was to characterize the kinetic changes in myocardial glucose transport and phosphorylation in response to changes in work load, competing substrates, acute ischemia and reperfusion, and the addition of insulin. To assess changes in myocardial glucose metabolism isolated working rat hearts were perfused with glucose and 2FDG. Tissue uptake of 2FDG and the input function were measured on-line by external detection. The steady state rate of 2FDG phosphorylation was determined by graphical analysis of 2FDG time-activity curves.^ The rate of 2FDG uptake was linear with time and the tracer was retained in its phosphorylated form. Tissue accumulation of 2FDG decreased within seconds with a reduction in work load, in the presence of competing substrates, and during reperfusion after global ischemia. Thus, most interventions known to alter glucose metabolism induced rapid parallel changes in 2FDG uptake. By contrast, insulin caused a significant increase in 2FDG accumulation only in hearts from fasted animals when perfused at a sub-physiological work load. The mechanism for this phenomenon is not known but may be related to the existence of two different glucose transporter systems and/or glycogen metabolism in the myocardial cell.^ It is concluded that (1) 2FDG traces glucose uptake and phosphorylation in the isolated working rat heart; and (2) early and transient kinetic changes in glucose metabolism can be monitored with high temporal resolution with 2FDG and a simple positron coincidence counting system. The new method has revealed transients of myocardial glucose metabolism, which would have remained unnoticed with conventional methods. These transients are not only important for the interpretation of glucose metabolic PET scans, but also provide insights into mechanisms of glucose transport and phosphorylation in heart muscle. ^

Aspectos metodológicos para la evaluación de sistemas de tomografía por emisión de positrones empleando técnicas Montecarlo, protocolos estandarizados y diferentes trazadores

Esta tesis analiza los elementos que afectan a la evaluación del rendimiento dentro de la técnica de radiodiagnóstico mediante tomografía por emisión de positrones (PET), centrándose en escáneres preclínicos. Se exploran las posibilidades de los protocolos estándar de evaluación sobre los siguientes aspectos: su uso como herramienta para validar programas de simulación Montecarlo, como método para la comparación de escáneres y su validez en el estudio del efecto sobre la calidad de imagen al utilizar radioisótopos alternativos. Inicialmente se estudian los métodos de evaluación orientados a la validación de simulaciones PET, para ello se presenta el programa GAMOS como entorno de simulación y se muestran los resultados de su validación basada en el estándar NEMA NU 4-2008 para escáneres preclínicos. Esta validación se ha realizado mediante la comparación de los resultados simulados frente a adquisiciones reales en el equipo ClearPET, describiendo la metodología de evaluación y selección de los parámetros NEMA. En este apartado también se mencionan las aportaciones desarrolladas en GAMOS para aplicaciones PET, como la inclusión de herramientas para la reconstrucción de imágenes. Por otro lado, la evaluación NEMA del ClearPET es utilizada para comparar su rendimiento frente a otro escáner preclínico: el sistema rPET-1. Esto supone la primera caracterización NEMA NU 4 completa de ambos equipos; al mismo tiempo que se analiza cómo afectan las importantes diferencias de diseño entre ellos, especialmente el tamaño axial del campo de visión y la configuración de los detectores. El 68Ga es uno de los radioisótopos no convencionales en imagen PET que está experimentando un mayor desarrollo, sin embargo, presenta la desventaja del amplio rango o distancia recorrida por el positrón emitido. Además del rango del positrón, otra propiedad física característica de los radioisótopos PET que puede afectar a la imagen es la emisión de fotones gamma adicionales, tal como le ocurre al isótopo 48V. En esta tesis se evalúan dichos efectos mediante estudios de resolución espacial y calidad de imagen NEMA. Finalmente, se analiza el alcance del protocolo NEMA NU 4-2008 cuando se utiliza para este propósito, adaptándolo a tal fin y proponiendo posibles modificaciones. Abstract This thesis analyzes the factors affecting the performance evaluation in positron emission tomography (PET) imaging, focusing on preclinical scanners. It explores the possibilities of standard protocols of assessment on the following aspects: their use as tools to validate Monte Carlo simulation programs, their usefulness as a method for comparing scanners and their validity in the study of the effect of alternative radioisotopes on image quality. Initially we study the methods of performance evaluation oriented to validate PET simulations. For this we present the GAMOS program as a simulation framework and show the results of its validation based on the standard NEMA NU 4-2008 for preclinical PET scanners. This has been accomplished by comparing simulated results against experimental acquisitions in the ClearPET scanner, describing the methodology for the evaluation and selection of NEMA parameters. This section also mentions the contributions developed in GAMOS for PET applications, such as the inclusion of tools for image reconstruction. Furthermore, the evaluation of the ClearPET scanner is used to compare its performance against another preclinical scanner, specifically the rPET-1 system. This is the first complete NEMA NU 4 based characterization study of both systems. At the same time we analyze how do the significant design differences of these two systems, especially the size of the axial field of view and the detectors configuration affect their performance characteristics. 68Ga is one of the unconventional radioisotopes in PET imaging the use of which is currently significantly increasing; however, it presents the disadvantage of the long positron range (distance traveled by the emitted positron before annihilating with an electron). Besides the positron range, additional gamma photon emission is another physical property characteristic of PET radioisotopes that can affect the reconstructed image quality, as it happens to the isotope 48V. In this thesis we assess these effects through studies of spatial resolution and image quality. Finally, we analyze the scope of the NEMA NU 4-2008 to carry out such studies, adapting it and proposing possible modifications.

The default mode network is functionally and structurally disrupted in amnestic mild cognitive impairment — a bimodal MEG–DTI study

Over the past years, several studies on Mild Cognitive Impairment (MCI) and Alzheimer's disease (AD) have reported Default Mode Network (DMN) deficits. This network is attracting increasing interest in the AD community, as it seems to play an important role in cognitive functioning and in beta amyloid deposition. Attention has been particularly drawn to how different DMN regions are connected using functional or structural connectivity. To this end, most studies have used functional Magnetic Resonance Imaging (fMRI), Positron Emission Tomography (PET) or Diffusion Tensor Imaging (DTI). In this study we evaluated (1) functional connectivity from resting state magnetoencephalography (MEG) and (2) structural connectivity from DTI in 26 MCI patients and 31 age-matched controls. Compared to controls, the DMN in the MCI group was functionally disrupted in the alpha band, while no differences were found for delta, theta, beta and gamma frequency bands. In addition, structural disconnection could be assessed through a decreased fractional anisotropy along tracts connecting different DMN regions. This suggests that the DMN functional and anatomical disconnection could represent a core feature of MCI.

Detectores monolíticos y sensores compatibles con altos campos magnéticos para tomografía por emisión de positrones

Esta tesis recoje un trabajo experimental centrado en profundizar sobre el conocimiento de los bloques detectores monolíticos como alternativa a los detectores segmentados para tomografía por emisión de positrones (Positron Emission Tomography, PET). El trabajo llevado a cabo incluye el desarrollo, la caracterización, la puesta a punto y la evaluación de prototipos demostradores PET utilizando bloques monolíticos de ortosilicato de lutecio ytrio dopado con cerio (Cerium-Doped Lutetium Yttrium Orthosilicate, LYSO:Ce) usando sensores compatibles con altos campos magnéticos, tanto fotodiodos de avalancha (Avalanche Photodiodes, APDs) como fotomultiplicadores de silicio (Silicon Photomultipliers, SiPMs). Los prototipos implementados con APDs se construyeron para estudiar la viabilidad de un prototipo PET de alta sensibilidad previamente simulado, denominado BrainPET. En esta memoria se describe y caracteriza la electrónica frontal integrada utilizada en estos prototipos junto con la electrónica de lectura desarrollada específicamente para los mismos. Se muestran los montajes experimentales para la obtención de las imágenes tomográficas PET y para el entrenamiento de los algoritmos de red neuronal utilizados para la estimación de las posiciones de incidencia de los fotones γ sobre la superficie de los bloques monolíticos. Con el prototipo BrainPET se obtuvieron resultados satisfactorios de resolución energética (13 % FWHM), precisión espacial de los bloques monolíticos (~ 2 mm FWHM) y resolución espacial de la imagen PET de 1,5 - 1,7 mm FWHM. Además se demostró una capacidad resolutiva en la imagen PET de ~ 2 mm al adquirir simultáneamente imágenes de fuentes radiactivas separadas a distancias conocidas. Sin embargo, con este prototipo se detectaron también dos limitaciones importantes. En primer lugar, se constató una falta de flexibilidad a la hora de trabajar con un circuito integrado de aplicación específica (Application Specific Integrated Circuit, ASIC) cuyo diseño electrónico no era propio sino comercial, unido al elevado coste que requieren las modificaciones del diseño de un ASIC con tales características. Por otra parte, la caracterización final de la electrónica integrada del BrainPET mostró una resolución temporal con amplio margen de mejora (~ 13 ns FWHM). Tomando en cuenta estas limitaciones obtenidas con los prototipos BrainPET, junto con la evolución tecnológica hacia matrices de SiPM, el conocimiento adquirido con los bloques monolíticos se trasladó a la nueva tecnología de sensores disponible, los SiPMs. A su vez se inició una nueva estrategia para la electrónica frontal, con el ASIC FlexToT, un ASIC de diseño propio basado en un esquema de medida del tiempo sobre umbral (Time over Threshold, ToT), en donde la duración del pulso de salida es proporcional a la energía depositada. Una de las características más interesantes de este esquema es la posibilidad de manejar directamente señales de pulsos digitales, en lugar de procesar la amplitud de las señales analógicas. Con esta arquitectura electrónica se sustituyen los conversores analógicos digitales (Analog to Digital Converter, ADCs) por conversores de tiempo digitales (Time to Digital Converter, TDCs), pudiendo implementar éstos de forma sencilla en matrices de puertas programmable ‘in situ’ (Field Programmable Gate Array, FPGA), reduciendo con ello el consumo y la complejidad del diseño. Se construyó un nuevo prototipo demostrador FlexToT para validar dicho ASIC para bloques monolíticos o segmentados. Se ha llevado a cabo el diseño y caracterización de la electrónica frontal necesaria para la lectura del ASIC FlexToT, evaluando su linealidad y rango dinámico, el comportamiento frente a ruido así como la no linealidad diferencial obtenida con los TDCs implementados en la FPGA. Además, la electrónica presentada en este trabajo es capaz de trabajar con altas tasas de actividad y de discriminar diferentes centelleadores para aplicaciones phoswich. El ASIC FlexToT proporciona una excelente resolución temporal en coincidencia para los eventos correspondientes con el fotopico de 511 keV (128 ps FWHM), solventando las limitaciones de resolución temporal del prototipo BrainPET. Por otra parte, la resolución energética con bloques monolíticos leidos por ASICs FlexToT proporciona una resolución energética de 15,4 % FWHM a 511 keV. Finalmente, se obtuvieron buenos resultados en la calidad de la imagen PET y en la capacidad resolutiva del demostrador FlexToT, proporcionando resoluciones espaciales en el centro del FoV en torno a 1,4 mm FWHM. ABSTRACT This thesis is focused on the development of experimental activities used to deepen the knowledge of monolithic detector blocks as an alternative to segmented detectors for Positron Emission Tomography (PET). It includes the development, characterization, setting up, running and evaluation of PET demonstrator prototypes with monolithic detector blocks of Cerium-doped Lutetium Yttrium Orthosilicate (LYSO:Ce) using magnetically compatible sensors such as Avalanche Photodiodes (APDs) and Silicon Photomultipliers (SiPMs). The prototypes implemented with APDs were constructed to validate the viability of a high-sensitivity PET prototype that had previously been simulated, denominated BrainPET. This work describes and characterizes the integrated front-end electronics used in these prototypes, as well as the electronic readout system developed especially for them. It shows the experimental set-ups to obtain the tomographic PET images and to train neural networks algorithms used for position estimation of photons impinging on the surface of monolithic blocks. Using the BrainPET prototype, satisfactory energy resolution (13 % FWHM), spatial precision of monolithic blocks (~ 2 mm FWHM) and spatial resolution of the PET image (1.5 – 1.7 mm FWHM) in the center of the Field of View (FoV) were obtained. Moreover, we proved the imaging capabilities of this demonstrator with extended sources, considering the acquisition of two simultaneous sources of 1 mm diameter placed at known distances. However, some important limitations were also detected with the BrainPET prototype. In the first place, it was confirmed that there was a lack of flexibility working with an Application Specific Integrated Circuit (ASIC) whose electronic design was not own but commercial, along with the high cost required to modify an ASIC design with such features. Furthermore, the final characterization of the BrainPET ASIC showed a timing resolution with room for improvement (~ 13 ns FWHM). Taking into consideration the limitations obtained with the BrainPET prototype, along with the technological evolution in magnetically compatible devices, the knowledge acquired with the monolithic blocks were transferred to the new technology available, the SiPMs. Moreover, we opted for a new strategy in the front-end electronics, the FlexToT ASIC, an own design ASIC based on a Time over Threshold (ToT) scheme. One of the most interesting features underlying a ToT architecture is the encoding of the analog input signal amplitude information into the duration of the output signals, delivering directly digital pulses. The electronic architecture helps substitute the Analog to Digital Converters (ADCs) for Time to Digital Converters (TDCs), and they are easily implemented in Field Programmable Gate Arrays (FPGA), reducing the consumption and the complexity of the design. A new prototype demonstrator based on SiPMs was implemented to validate the FlexToT ASIC for monolithic or segmented blocks. The design and characterization of the necessary front-end electronic to read-out the signals from the ASIC was carried out by evaluating its linearity and dynamic range, its performance with an external noise signal, as well as the differential nonlinearity obtained with the TDCs implemented in the FPGA. Furthermore, the electronic presented in this work is capable of working at high count rates and discriminates different phoswich scintillators. The FlexToT ASIC provides an excellent coincidence time resolution for events that correspond to 511 keV photopeak (128 ps FWHM), resolving the limitations of the poor timing resolution of the BrainPET prototype. Furthermore, the energy resolution with monolithic blocks read by FlexToT ASICs provides an energy resolution of 15.4 % FWHM at 511 keV. Finally, good results were obtained in the quality of the PET image and the resolving power of the FlexToT demonstrator, providing spatial resolutions in the centre of the FoV at about 1.4 mm FWHM.

Vascular imprints of neuronal activity: Relationships between the dynamics of cortical blood flow, oxygenation, and volume changes following sensory stimulation

Modern functional neuroimaging methods, such as positron-emission tomography (PET), optical imaging of intrinsic signals, and functional MRI (fMRI) utilize activity-dependent hemodynamic changes to obtain indirect maps of the evoked electrical activity in the brain. Whereas PET and flow-sensitive MRI map cerebral blood flow (CBF) changes, optical imaging and blood oxygenation level-dependent MRI map areas with changes in the concentration of deoxygenated hemoglobin (HbR). However, the relationship between CBF and HbR during functional activation has never been tested experimentally. Therefore, we investigated this relationship by using imaging spectroscopy and laser-Doppler flowmetry techniques, simultaneously, in the visual cortex of anesthetized cats during sensory stimulation. We found that the earliest microcirculatory change was indeed an increase in HbR, whereas the CBF increase lagged by more than a second after the increase in HbR. The increased HbR was accompanied by a simultaneous increase in total hemoglobin concentration (Hbt), presumably reflecting an early blood volume increase. We found that the CBF changes lagged after Hbt changes by 1 to 2 sec throughout the response. These results support the notion of active neurovascular regulation of blood volume in the capillary bed and the existence of a delayed, passive process of capillary filling.

High-resolution microPET imaging of carcinoembryonic antigen-positive xenografts by using a copper-64-labeled engineered antibody fragment

Rapid imaging by antitumor antibodies has been limited by the prolonged targeting kinetics and clearance of labeled whole antibodies. Genetically engineered fragments with rapid access and high retention in tumor tissue combined with rapid blood clearance are suitable for labeling with short-lived radionuclides, including positron-emitting isotopes for positron-emission tomography (PET). An engineered fragment was developed from the high-affinity anticarcinoembryonic antigen (CEA) monoclonal antibody T84.66. This single-chain variable fragment (Fv)-CH3, or minibody, was produced as a bivalent 80 kDa dimer. The macrocyclic chelating agent 1,4,7,10-tetraazacyclododecane-N,N′,N′′, N′′′-tetraacetic acid (DOTA) was conjugated to the anti-CEA minibody for labeling with copper-64, a positron-emitting radionuclide (t1/2 = 12.7 h). In vivo distribution was evaluated in athymic mice bearing paired LS174T human colon carcinoma (CEA positive) and C6 rat glioma (CEA negative) xenografts. Five hours after injection with 64Cu-DOTA-minibody, microPET imaging showed high uptake in CEA-positive tumor (17.9% injected dose per gram ± 3.79) compared with control tumor (6.0% injected dose per gram ± 1.0). In addition, significant uptake was seen in liver, with low uptake in other tissues. Average target/background ratios relative to neighboring tissue were 3–4:1. Engineered antibody fragments labeled with positron-emitting isotopes such as copper-64 provide a new class of agents for PET imaging of tumors.

Cerebral cortical hyperactivation in response to mental stress in patients with coronary artery disease

The central nervous system (CNS) effects of mental stress in patients with coronary artery disease (CAD) are unexplored. The present study used positron emission tomography (PET) to measure brain correlates of mental stress induced by an arithmetic serial subtraction task in CAD and healthy subjects. Mental stress resulted in hyperactivation in CAD patients compared with healthy subjects in several brain areas including the left parietal cortex [angular gyrus/parallel sulcus (area 39)], left anterior cingulate (area 32), right visual association cortex (area 18), left fusiform gyrus, and cerebellum. These same regions were activated within the CAD patient group during mental stress versus control conditions. In the group of healthy subjects, activation was significant only in the left inferior frontal gyrus during mental stress compared with counting control. Decreases in blood flow also were produced by mental stress in CAD versus healthy subjects in right thalamus (lateral dorsal, lateral posterior), right superior frontal gyrus (areas 32, 24, and 10), and right middle temporal gyrus (area 21) (in the region of the auditory association cortex). Of particular interest, a subgroup of CAD patients that developed painless myocardial ischemia during mental stress had hyperactivation in the left hippocampus and inferior parietal lobule (area 40), left middle (area 10) and superior frontal gyrus (area 8), temporal pole, and visual association cortex (area 18), and a concomitant decrease in activation observed in the anterior cingulate bilaterally, right middle and superior frontal gyri, and right visual association cortex (area 18) compared with CAD patients without myocardial ischemia. These findings demonstrate an exaggerated cerebral cortical response and exaggerated asymmetry to mental stress in individuals with CAD.

Forebrain mechanisms of nociception and pain: Analysis through imaging

Pain is a unified experience composed of interacting discriminative, affective-motivational, and cognitive components, each of which is mediated and modulated through forebrain mechanisms acting at spinal, brainstem, and cerebral levels. The size of the human forebrain in relation to the spinal cord gives anatomical emphasis to forebrain control over nociceptive processing. Human forebrain pathology can cause pain without the activation of nociceptors. Functional imaging of the normal human brain with positron emission tomography (PET) shows synaptically induced increases in regional cerebral blood flow (rCBF) in several regions specifically during pain. We have examined the variables of gender, type of noxious stimulus, and the origin of nociceptive input as potential determinants of the pattern and intensity of rCBF responses. The structures most consistently activated across genders and during contact heat pain, cold pain, cutaneous laser pain or intramuscular pain were the contralateral insula and anterior cingulate cortex, the bilateral thalamus and premotor cortex, and the cerebellar vermis. These regions are commonly activated in PET studies of pain conducted by other investigators, and the intensity of the brain rCBF response correlates parametrically with perceived pain intensity. To complement the human studies, we developed an animal model for investigating stimulus-induced rCBF responses in the rat. In accord with behavioral measures and the results of human PET, there is a progressive and selective activation of somatosensory and limbic system structures in the brain and brainstem following the subcutaneous injection of formalin. The animal model and human PET studies should be mutually reinforcing and thus facilitate progress in understanding forebrain mechanisms of normal and pathological pain.