Craig Levin - US grants

DESCRIPTION (provided by applicant): We request funding for a biennial "Workshop on the Nuclear Radiology of Breast Cancer". This proposed workshop immediately follows the annual IEEE Nuclear Science Symposium & Medical Imaging Conference in years 2004, 2006, and 2008. In 2002 a similar Workshop was co-funded by NCI and NIBIB. As in 2002 the overall goals of the proposed events are to convene imaging physicists and engineers as well as chemists, biologists, physicians and students from around the world to discuss important issues related to breast cancer evaluation using functional imaging techniques involving nuclear radiotracers. Key issues to address are the recent successes and limitations of nuclear imaging approaches [positron emission tomography (PET) and single photon emission computed tomography (SPECT)] and what steps are required to continue to increase their role in breast cancer management. Thus in addition to having educational goals the meeting serves as a venue to understand and perhaps suggest solutions to important problems associated with breast cancer detection, diagnosis, and staging. The outline of the two-day program is as follows: (1) Review of the biology, biochemistry, and markers of breast cancer; (2) Review of the clinical state-of-the-art in breast cancer radiology using standard approaches; (3) Overview of promising new technologies for breast cancer imaging; (4) Review of current clinical perspectives on the role of nuclear medicine breast imaging; (5) Discussion of the cost-effectiveness of nuclear breast imaging; (6) Overview of breast cancer treatment and role of nuclear medicine in chemo-resistance determination; (7) Review of existing and promising breast cancer radiotracers; (8) Clinical trial results with commercial dedicated nuclear emission cameras; (9) International review of research groups specifically working on improving gamma ray and positron emission cameras dedicated to breast cancer imaging; (7) International commercialization and long term industrial outlook of dedicated breast imaging modalities; and (8) Research funding opportunities. While there is a logically progressive and structured format, the setting is meant to be informal, with a larger portion of the workshop devoted to discussion and interaction between the audience members and presenters compared to standard didactic scientific meetings. To encourage an intimate environment for information exchange and problem solving the workshop will be limited to 100 participants with strong interest in this field. Two members per research group will be invited to participate. There will be appropriate involvement of women and minorities. There will also be a competition for up to 10 student travel awards to promote education/training in this field. This workshop will provide the latest research information and lively interaction and discussions. The resulting information will be made available to the public.

Specialized Resource 3-Small Animal Imaging Resource (Dr. Levin/Moseley Co-Pi's): This resource provides access to all the small animal imaging instruments used by all current and future ICMIC at Stanford investigators. The ability to use a multimodality imaging approach to solve a biological problem of interest with bioluminescene and fluorescence optical imaging, small animal computed tomography (microCT), micro positron emission tomography (microPET), micro single photon emission computed tomography (microSPECT), digital whole body autoradiography (DWBA), small animal high-resolution ultrasound, and small animal magnetic resonance imaging (MRI) are all key components of this resource. The ability to utilize multimodality small animal imaging instruments and to have expertise available to evolve these technologies and their uses are a key feature of this important resource. All Research and Developmental Projects will utilize this resource.

DESCRIPTION (provided by applicant): We propose to build an advanced positron emission tomography (PET) system dedicated to breast cancer imaging. The system uses a novel position sensitive photon detector concept that has been developed under grant R21 CA098691 that we propose to translate into the clinic. This new sensor will help to push the performance limits of PET for cancer imaging. The design uses scintillation crystals coupled in an innovative manner to new, highly compact semiconductor photodetector arrays. This development allows us to achieve 1 mm spatial resolution with direct photon interaction depth measurement, high 511 keV photon detection efficiency, and a scintillation detector configuration that promotes >95% scintillation light collection efficiency for exceptional energy and coincident time resolution. Although this new photon sensor concept could in principle be utilized in any high resolution PET cancer imaging application, we are focusing on breast cancer because there is particular potential for high impact. PET has shown promise for breast cancer imaging, but has not been incorporated into standard practice due to inadequate breast cancer specificity and sensitivity, relatively long scan times, and high cost. If successful, our developments will have impact on increasing the role of PET in breast cancer management by addressing all of these issues. The proposed system will have 1 mm reconstructed spatial resolution in order to better visualize <2.5 mm structures of high focal uptake as indication of early breast cancer. This camera will use 2 cm thick, closely packed crystals, and close proximity breast imaging for up to 15% coincidence efficiency to help realize the desired spatial resolution proposed and rapidly (in 10 seconds) generate images. PET breast imaging poses particular challenges due to background activity in the thorax producing high random and Compton scatter coincident photon rates that result in lower lesion to background contrast. The excellent energy and temporal resolutions and flexible orientation achieved with the new design will help to reduce background photon scatter and random effects on lesion contrast. This system will also help breast cancer researchers to evaluate more specific breast cancer tracers and monitor potential treatments. For this five-year project we will integrate the novel detector modules into a gantry, develop a data acquisition system, implement data correction, calibration, and image reconstruction algorithms, and test the system with point source measurements.

DESCRIPTION (provided by applicant): We propose to study novel imaging sensors composed of a semiconducor material known as Cadmium Zinc Telluride (CZT), and incorporate these sensors into an innovative configuration for an advanced Positron Emission Tomography (PET) system designed for imaging small laboratory animal cancer models. The next generation of discoveries in molecular cancer imaging assay research require PET instruments with an order of magnitude higher sensitivity for visualizing and quantifying very low concentrations of molecular probe targeting subtle molecular-based cancer processes. In order to realize this goal, new PET instruments must provide enhanced 511 keV photon coincidence detection efficiency, spatial, energy, and coincident time resolutions, and count rate performance all at once. The most sensitive high resolution PET systems use photon detectors comprising scintillation crystals coupled to photomultiplier tubes. However, these systems still have relatively low (~3%) coincidence photon detection efficiency and the scintillation detectors have relatively inefficient conversion of the 511 keV energy into an electronic signal, especially for high resolution designs that utilize miniscule (<2 mm wide) scintillation crystal elements and fiber optic coupling. Low 511 keV photon detection efficiency and weak crystal light signals degrade many of the crucial performance parameters in PET, such as spatial and contrast resolution and quantitative accuracy that are important for molecular probe sensitivity. The proposed compact CZT detector configuration together with the 3- dimensional (3D) interaction localization capabilities yield an order of magnitude better coincidence detection efficiency (~20%), which will enable sufficient counts collected to reconstruct images at the desired 1 mm3 spatial resolution with a relatively short data acquisition time. The proposed superior energy resolution (<3% at 511 keV) allows efficient rejection of random and scatter background to achieve high contrast and quantitative accuracy without compromising photopeak window counts. Finally, 3D event positioning in the proposed CZT detectors is set electronically by an electrode pattern, rather than by cutting miniscule crystals, significantly simplifying construction. If successful, the capabilities of PET to detect, visualize and quantify low concentrations of molecular cancer probe will be enhanced substantially, which would impact the development of new cancer imaging assays and help to guide discovery of novel treatments for cancer.

Specialized Resource 2 (SR2) provides access to all small animal imaging instruments required by the ICMIC@Stanford research community, with emphasis on the four Research Projects and four Developmental Projects. The facility is part of the Stanford School of Medicine "core program", providing access to all the imaging systems available to the research community at the University;the Molecular Imaging Program at Stanford (MIPS;http://mips.stanford.edu/) oversees its operation. SR2 is central to the entire ICMIC@Stanford proposed research and to the overall MIPS. This resource is closely supported by the Imaging Quantitation and Analysis Resource (Specialized Resource 3, or SR3), that provides assistance and support for data analysis acquired on instruments in this facility. The Imaging Facility was initially developed as a part of a Small Animal Imaging Resource Program (SAIRP), and was called the Stanford Center for Innovation in In Vivo Imaging (SCP). A previous SAIRP grant provided the funds to establish the core, and allow it to offer free imaging to all users. Significant funds from the Stanford BioX program and the Departments of Radiology &Pediatrics were also provided to help purchase certain imaging instruments for the facility. However the core transitioned as of September 2005 to a for-fee facility.

DESCRIPTION (provided by applicant): We propose to greatly advance the signal detection limits of positron emission tomography (PET) by developing a next-generation pre-clinical PET system capable of substantial improvements in visualization and quantification of cellular and molecular signatures of disease. We will build upon advances made in previous work that explored and developed an innovative concept for a 3-D position sensitive photon scintillation detector technology for small animal PET. The proposed project will first greatly improve upon this promising detector technology, substantially (not incrementally) advancing its performance, while also making it even more practical to implement. We will then translate that advanced technology into a small prototype of a box- shaped, small animal PET system with adjustable FOV that we will build from a novel multi-layer detector module. In those detector layers, we will incorporate scintillation crystal arrays with 0.5 mm pixels in order to substantially advance the spatial resolution of small animal PET. This goal is facilitated by the new scintillation detection concept, where the scintillation light collection aspect ratio in each crystal element is very high, even for 0.5 mm width elements. The 0.5 mm resolution goal in reconstructed images is also facilitated by the significantly improved 511 keV photon sensitivity enabled by the box-shaped system design, for reasons that we will clarify in this application. The scintillation crystal arrays are coupled to novel, extremely thin, high gain position sensitive photodetectors arranged in an innovative edge-on configuration that enables directly measured 511 keV photon interaction depth (DOI) within any crystal, and promotes >90% scintillation light collection efficiency, independent of DOI. The resulting robust, non-varying light signal facilitates superior photon energy and temporal resolutions, which, together with 0.5 mm intrinsic spatial resolution, help to enhance PET signal detection and quantification in the presence of background activity. In this detector module's edge-on, layered arrangement, incoming photons traverse a minimum of ~2 cm thick crystal with a crystal packing fraction of 70% in order to promote high 511 keV photon detection efficiency, while the 0.5 mm DOI resolution helps to preserve spatial resolution uniformity throughout the sensitive volume of the resulting PET system. In addition this detector configuration is able to localize individual 511 keV photon interactions occurring in distinct crystal array layers. This is an unusual capability for a PET detector, which we refer to as 3-D positioning. This capability is important for achieving the desired 0.5 mm reconstructed resolution since incoming photons will often interact in multiple crystal elements of the ultra-high resolution detectors. If successful, the proposed 0.5 mm resolution, high sensitivity, 3-D positioning detectors, in conjunction with new event processing algorithms our group is investigating, enable substantial improvements in resolution, contrast, and reconstructed image signal-to-noise ratio. Impact: If successful, this research will advance the ability of PET to detect, visualize and quantify low concentrations of PET tracer accumulating in cells of interest, thus increasing signal detection capabilities for applications in translational cardiovascular, neurological, and cancer research.

DESCRIPTION (provided by applicant): We propose to advance time-of-flight (ToF) positron emission tomography (PET) detector instrumentation that, if successful, will further enhance abilities to visualize and quantify molecular signatures of disease in the clinic. ToF PET uses the arrival time difference of detected coincidence photons to better estimate the position of the positron annihilation along the response line between any two detector elements in the PET system. Accurate ToF event positioning requires sub- nanosecond coincidence time resolution to reduce the uncertainty in annihilation photon emission location along a response line. For state-of-the-art clinical ToF PET systems, which achieve ~600-900 ps full-width-at-half-maximum (FWHM) coincidence time resolution [using photomultiplier tubes (PMTs)], the photon depth of interaction (DoI) uncertainty within the e2 cm length detector crystals does not significantly affect ToF position uncertainty. For the proposed d300 ps coincidence time resolution, the ToF uncertainty due to photon DoI within e2 cm length crystals cannot be ignored. Thus, our goal in this proposal is to create a PET detector with d300 ps FWHM coincidence time resolution that also measures photon DoI within the scintillation crystal. In addition to enhancing photon arrival time information, the capability for photon DoI resolution also promotes spatial resolution uniformity across the field of view (FoV). Furthermore, the proposed design has the unique capability to measure the 3D position and energy of each individual interaction of multi-interaction photon events, which can be exploited to further improve spatial resolution and contrast resolution. To achieve these design goals, we propose to explore a new detector design based on single ended readout of e2 cm length scintillation crystals coupled one-to-one to arrays of fast, high-gain silicon photomultiplier (SiPM) photodetectors. The full detector signal waveforms will be digitized by novel, commercially available sampling architectures, and DoI (and 3D positioning) information is determined by correlation with various parameters of the digitized detector pulse shape for each event, such as pulse height, rise and falling edge frequency patterns. In a PET system, DoI information leads to more accurate ToF event positioning along a response line that can impact reconstructed image performance, but in this work we focus on studying dependence of photon arrival time and coincidence time resolution on photon DoI. If the proposed design does not meet the time and DoI resolution specifications, as a backup plan, an alternative detector architecture based on layers of short scintillation detectors will be studied. Impact: If successful, a PET system built with the proposed detectors will increase image signal-to-noise ratio (SNR) three-fold compared to a non-ToF system for a 40 cm diameter patient, and provide enhancement of spatial resolution and contrast resolution that together will substantially enhance the ability to visualiz and quantify molecular signatures of disease residing in diffuse background activity. Alternatively the substantial SNR boost can be exploited to reduce injected dose or scan time.

DESCRIPTION (provided by applicant): The Stanford Molecular Imaging Scholars (SMIS) program is an integrated, cross-disciplinary postdoctoral training program at Stanford University that brings together 45 faculty mentors from 15 departments in the Schools of Medicine, Engineering, and Humanities and Sciences. Molecular imaging, the non-invasive monitoring of specific molecular and biochemical processes in living organisms, continues to expand its applications in the detection and management of cancer. We train, on average, ~7 postdoctoral trainees per year. SMIS faculty mentors provide a diverse training environment spanning biology, physics, mathematics/biocomputation/ biomedical informatics, engineering, chemistry, biochemistry, cancer biology, immunology, and medical sciences. The centerpiece of the SMIS program is the opportunity for trainees (PhD or MD with an emphasis on PhD) to conduct innovative molecular imaging research that is co-mentored by faculty in complementary disciplines. SMIS trainees also engage in specialized coursework, seminars, national conferences, clinical rounds, including ethics training and the responsible conduct of research. The three-year program culminates with the preparation and review of a mock grant, in support of trainee transition to an independent career in cancer molecular imaging. During this initial 3.7 year period, 14 trainees have entered the SMIS program; 8 are currently enrolled and 6 have completed the program as of this writing. Two additional trainees will complete in August, 2010, bringing the total number of SMIS graduates to 8. Those who have moved on are either in faculty positions, other academic positions, or working in biotechnology. Demand for the SMIS training is high; we now receive, on average, more than 20 applications per year from qualified candidates seeking placement in our program, which can accommodate only 2-4 new trainees per year. For the upcoming cycle, we propose an enriched SMIS program that achieves the following: expands our recently added Program Area in Nanotechnology; strategically selects additional faculty mentors; presents improvement in all other training and career development components; expands leadership for our mock grant program and our clinical exposure component; and pursues rigorous recruitment of underrepresented minority candidates. The goal of the SMIS program is to continue to provide talented young investigators with the scientific and professional education/career development opportunities to become leaders in the field of molecular imaging of cancer.

DESCRIPTION (provided by applicant): Funding is requested to support graduate student and postdoctoral trainees currently working at US institutions to attend the 2013 IEEE Medical Imaging Conference, which is held jointly with the IEEE Nuclear Science Symposium every October. This annual international conference is the largest and most important meeting dedicated to radiotracer based medical imaging methods, particularly positron emission tomography (PET) and single photon emission computed tomography (SPECT). Additional topics of interest include multimodality imaging such as PET/CT and PET/MR. The emphasis is on detectors, imaging systems and algorithms for image reconstruction and image quantization. At the most recent meeting in 2011 in Valencia, Spain, 684 papers were presented within the Medical Image Conference and total attendance was 2260 with at least half of the attendees declaring the Medical Imaging Conference to be their primary interest. This grant will provide twenty graduate students and post-doctoral trainees with $500 to partially support conference registration and short course fees.

DESCRIPTION (provided by applicant): We propose to explore new non-linear photonic materials to enable time-of-flight (ToF) positron emission tomography (PET) detectors with <30 pico-second (ps) time resolution, as opposed to 500-900 picoseconds achieved by state-of-the-art PET systems that use scintillation crystals. PET is currently the standard-of-care for cancer management and an important tool in basic research. A PET system comprises a ring of position sensitive scintillation detectors. A PET scan collects millions of events comprising pairs of oppositely-directed 511 kilo-electron- volt (keV) photons that are emitted from the patient after injection of a radioactive contrast agent. The measured distribution of these two-photon hits recorded by the system detectors is used to reconstruct a 3-D image volume that represents the tracer biodistribution, which is used to characterize and quantify cellular and molecular disease states before and after treatment. If successful, the proposed <30 ps time resolution will enable an order of magnitude more accurate and precise localization of a positron decay event along the response line formed between any two 511 keV annihilation photon detector elements in a PET system. This disruptive technology would represent a tremendous paradigm shift for PET as it would drastically change the way a PET system operates. The fact that many more events would be accurately positioned along a response line through the patient enables substantial signal amplification for unprecedented ability to visualize and quantify disease signatures. The resulting huge image signal-to-noise (SNR) boost could also be exploited to reduce patient injected radioactive dose or scan time by a factor of 100, amazing features that would both continue to increase PET's widespread use as the standard-of-care for disease management, as well as open up new roles for the imaging modality in the clinic as well as in animal research into molecular mechanisms of disease. To achieve our goal of <30ps time resolution, we will explore non-linear photonic materials where picosecond changes in optical parameters are common and measured using modern optics methods, rather than using scintillation detectors which at best achieve hundreds of ps time resolution through spontaneous light emission processes and photodetection. The project will require the investigators to research and obtain several candidate high Z, high-density photonic materials; create an optical test bed for exploring fast temporal properties of photonic materials; measure ionization-induced modulation of optical properties in these materials; and investigate scaling up issues relevant to building a practical PET detector from these novel material and methods. This is an exciting multi-disciplinary project that involves concepts in fields such as physics, photonics, optics, electrical engineering, radiology, computer science, materials science, nano-science, and applied mathematics with a goal of enabling substantial improvements in ToF PET performance to drive important advances in the study and clinical management of cancer, cardiovascular disease and neurological disorders. The following contains confidential information that should not be used except for purpose of review and evaluation of this proposal.

? DESCRIPTION (provided by applicant): We propose to create and explore a radio-frequency (RF)-penetrable positron emission tomography (PET) system technology that can be inserted into a magnetic resonance imaging (MRI) system for acquiring simultaneous PET/MRI data. Integrated PET/MRI has risen to the cutting edge of medical imaging technology, showing promise to be a powerful tool in disease characterization as it enables the simultaneous measurement of molecular, functional, and anatomical information in soft tissues of the body. Because of this promise, companies such as Siemens, GE, and Philips have developed and are now offering combined PET/MR systems. However, one of the challenges affecting the long-term impact of this technology is the current cost ($5-6M) due to the huge investment required by a company to develop an integrated product, and the need for the user to purchase both PET and MRI sub-systems. Our lab is addressing these issues by creating the world's first RF-penetrable PET ring, which can in principle be inserted into any existing MR system, while still allowing use of the built-in MR RF transmit coil. This would avoid the expensive integration of the two modalities, which, up to now, in order to achieve whole-body PET/MR, has required substantial modifications to the MR system, including re-engineering the body transmit coil sub-system to reside inside the PET ring. Thus, the proposed technology would substantially lower the cost barrier for an existing MR site to upgrade to PET/MR capability since they would just need to purchase the RF-transmissive PET insert, and it also would reduce the industry investment to achieve integrated PET/MRI. Hypothesis: Using the novel electro-optical signal transmission scheme proposed, we can create a PET insert that is penetrable to a RF field and thus can achieve simultaneous ToF-PET/MR using the built in body transmit coil of an MR system. The basic idea to enable the PET ring insert to be RF-penetrable (i.e. for the RF field to leak inside of the PET ring) is to have it electrically floating with respect to the MR system, and to have small gaps between PET detector modules where the field lines can leak in. This floating PET ring is made possible via the concept of electro-optical signal transmission, which draws from the field of telecommunications; in our formulation, the fast scintillation detector signals are coupled to tiny lasers, converted to near infrared light, and transmitted down long telecommunications-grade optical fibers, thus enabling electrical isolation from the MR system. In addition, since the electro-optical approach uses optical fibers, it substantially reduces the electrical footprint within the MR system compared to a PET system design that uses long electrical cables, while achieving excellent spatial, energy, and temporal resolutions required for PET. In this project, we will develop a full proof-of-principle of this RF-penetrable concept via a brain-size PET insert, and test its RF transmissivity in a 3T MRI system. In order to achieve these goals, we explore many innovative concepts.

Project Summary/Abstract We propose to study a promising candidate for the next generation time-of-flight (TOF)-positron emission tomography (PET) annihilation photon detector. By enabling significant increases in the reconstructed image signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR), TOF-PET has demonstrated substantial clinical impact on the visualization and quantification of molecular signatures of cancer in patients. In particular it has been shown to improve image quality and accuracy in count starved and contrast limited lesion detection scenarios. The effective photon sensitivity boost provided by TOF can also be exploited to significantly reduce injected dose to the patient and/or study duration, factors that would make PET more practical, cost-effective, and safe for a variety of clinical cancer imaging applications. Thus, studies that further advance the TOF-PET technique, and photon sensitivity in general, are highly worthwhile. The key to better TOF-PET performance is to improve the annihilation photon pair coincidence time resolution (CTR) measured between any two detection elements in the system, which has been a focus of research for the past two decades. Current commercially available PET systems achieve a CTR of roughly 350 to 800 ps full-width-at-half-maximum (FWHM). A goal of this proposal is to employ a novel scintillation detection configuration in order to achieve 100 ps FWHM CTR, without compromising other important performance parameters. This novel configuration also enables another capability not possible with the conventional PET detector: The ability to measure the energy and three-dimensional (3D) position of one or more annihilation photon interactions in the detector. Owing to the fact that most incoming 511 keV photons undergo inter-crystal Compton scatter in the detectors, we can exploit the kinematics of that process to estimate the photon angle-of-incidence. If successful, that capability enables us to accurately position the first interaction of such multi-crystal events, but also offers the potential to retain a high fraction of photon events that are normally rejected by a conventional PET system, such as single (unpaired) photons, random coincidences, tissue-scatter coincidences, and multiple (>2) photon coincidences. Since these normally-discarded events are over 10-fold more probable than true coincidence events in a standard PET study, this 3D position sensitive detector shows promise as another method to greatly boost photon sensitivity. If successful, this resulting substantial photon sensitivity increase, along with the substantial image SNR enhancement possible with 100 ps CTR would enable PET to be more sensitive, accurate, and practical for cancer imaging. In this project we will design and develop these next-generation detectors, integrate these modules into a prototype partial-ring PET system, and compare image quality and accuracy available with this partial-ring system to a state-of-the-art whole body TOF-PET system currently installed in our imaging clinic.

PROJECT SUMMARY/ABSTRACT We propose to explore a new mechanism of ionizing radiation detection for positron emission tomography (PET) using the modulation of optical properties instead of scintillation, with the ultimate goal to achieve less than 10 picosecond (ps) annihilation photon pair coincidence time resolution, which is an order of magnitude better than possible with state-of-the-art scintillation based PET detectors. PET is a non-invasive imaging technology used every day throughout the world that enables visualization and quantification of the molecular signatures of disease in living subjects in the clinic as well as in biological research. A PET study comprises the collection of millions of annihilation photon pairs emitted from a positron-emitting radionuclide-labeled contrast agent injected into the patient. The two-photon hits are recorded by the system detectors and used to reconstruct a 3D image volume that represents the tracer biodistribution. If successful, the proposed < 10 ps coincidence time resolution would represent a tremendous paradigm shift for PET as it would drastically change the way a PET system operates. The resulting remarkable time-of-flight (ToF) capability will bring substantial signal amplification over existing systems. The enormous image signal-to-noise ratio (SNR) boost can be exploited to greatly enhance lesion detection, for example, for lesions with low contrast-to-background ratio; significantly reduce both patient injected dose and patient scan duration, potentially opening new clinical and research roles for which PET currently has no involvement at all; or pave the way for completely new PET system designs with greatly improved spatial resolution. In previous studies performed, we have shown that ionizing radiation can modulate optical properties, for example, the refractive index, of a detector material. We have found that the modulation signal amplitude is linearly dependent on both the event detection rate and average photon energy. In this project, we will work on further exploring mechanisms of optical property modulation to detect individual 511 keV photon interactions, and study the timing properties of this proposed detection concept with the goal to achieve < 10 ps coincidence time resolution. We first propose to achieve the detection of individual 511 keV photons using the mechanism of optical property modulation by developing novel methods to amplify the modulation signal and detection systems with significantly improved sensitivity. Then we plan to study the intrinsic timing properties of the optical property modulation process and explore methods to achieve < 10 ps coincidence time resolution for coincident 511 keV photon interactions. For the final aim, we will learn how to use this new mechanism of ionizing radiation detection to build a practical, ?tileable? ToF-PET detection element. This is an exciting multi-disciplinary project that borrows ideas from the field of modern optics with a goal of enabling substantial improvements in ToF-PET performance to drive important advances in the study and clinical management of disease.

Project Summary/Abstract According to the BRAIN 2025 working group report, there is a need to drastically improve the spatiotemporal resolution of positron emission tomography (PET), in order to facilitate the translation of new tracers that target neuroreceptor function and dynamic PET imaging on the milliseconds timescale. To address this challenge, we propose to demonstrate feasibility of a next generation annihilation photon detector module that, if successful, will serve as the fundamental building block of an advanced brain-dedicated PET system to be developed in follow-on work after this feasibility stage. This next-generation system design shows promise to transform the capabilities of PET in human neuroimaging through substantial (>10-fold) boosts in reconstructed image signal-to-noise ratio (SNR) and contrast-to-noise ration (CNR). Besides employing a smaller system diameter (e.g. 32 cm diameter) compared to the standard whole body PET system, this proposed enhancement is enabled by two unique features proposed (1) 100 picosecond (ps) coincidence time resolution (CTR), and (2) the ability to measure the energy and three-dimensional (3D) position of one or more annihilation photon interactions in the detector. These two new capabilities are achieved through a highly innovative scintillation detector configuration described in detail in the proposal. By precisely measuring the flight time of annihilation photons from their emission point within the patient to the detectors, the time-of-flight (TOF) PET technique enables a significant image SNR and CNR boost because it allows more events to be placed closer to their true point of emission along detector response lines of the system during the image reconstruction process. The key to better TOF-PET performance is to improve the annihilation photon pair CTR measured between any two detection elements in the system. Current commercially available PET systems achieve a CTR of roughly 350 to 800 ps full-width-at-half-maximum (FWHM). The proposed goal of 100 ps FWHM CTR alone represents a significant PET technology advance. But the novel detector configuration proposed also enables another capability not possible with the conventional PET detector. Owing to the fact that most incoming 511 keV photons undergo inter-crystal Compton scatter in the detectors, we can exploit the kinematics of that process to estimate the photon angle-of-incidence. If successful, that capability enables us to accurately position the first interaction of such multi-crystal events, but also offers the possibility to retain a high fraction of photon events that are normally rejected by a conventional PET system, such as single (unpaired) photons, random coincidences, tissue-scatter coincidences, and multiple (>2) photon coincidences. Since these normally-discarded events are over 10-fold more probable than true coincidence events in a standard PET study, this 3D position sensitive detector technology shows promise as another method to greatly boost photon sensitivity, and thus reconstructed image SNR. In this project we will design and develop two next-generation PET detectors and integrate them into MRI-compatible detector modules. The performance of these modules will be characterized outside and inside a 3 Tesla clinical MRI system to demonstrate feasibility of this concept.