Figure1. Aerial view of the Thomas Jefferson National Accelerator Facility electron accelerator and experimental halls.

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1 Applying Nuclear Physics Research Detector Technology to Biomedical Applications Drew Weisenberger, Brian Kross, James Proffitt, Stan Majewski, John McKisson, Alexander Stolin and Carl Zorn Thomas Jefferson National Accelerator Facility Newport News, VA Introduction Specialized cancer-finding tools to guide a life-saving decision for a woman with suspected breast cancer. New technology for answering basic questions on the nature of neurological disease. These are novel biomedical applications of technology originally developed to probe the physical nature of matter at the subatomic level. I will provide a brief background and describe two applications of nuclear physics detector technology to biomedical challenges that could have relevance to everyone. The United States Department of Energy s (DOE) Thomas Jefferson National Accelerator Facility (Jefferson Lab) is a nuclear physics research facility for scientists worldwide with the primary mission to explore the nature of the nucleus of the atom and its constituents. Figure1. Aerial view of the Thomas Jefferson National Accelerator Facility electron accelerator and experimental halls. Jefferson Lab scientists direct a 6 GeV continuous electron beam to a target. The collision between the electrons and the quarks that make up the protons and neutrons of the target s atoms results in the release of a splash of subatomic particles. Large, sophisticated detector systems detect the splash particles, measuring properties such as

2 energy, trajectory and charge. This data allows physicists to extract information on the nature of quarks, protons, neutrons and the nucleus itself. Figure 2: Photograph of the detector installed in experimental Hall B, one of the three experimental halls in operation at Jefferson Lab. Hall B is equipped with a unique largeacceptance detector that records the products of the electron beam-target collision in all directions. To better understand the nature of this interaction, a lot of basic research goes solely into the development of the detector technology that is used as the eyes for the nuclear physicist. This same technology has the potential to advance instrumentation development for nuclear medicine and biomedical applications. DOE (and its predecessors) has a 50+ year history of applying physics research to medical advances. The Office of Biological and Environmental Research (BER) of DOE has been leveraging biomedical knowledge connected to energy. The BER Medical Sciences program sponsors research at DOE facilities, universities and small businesses to enhance patient care through beneficial applications of nuclear physics research technologies. Most of the nuclear medicine imaging technologies used today was made possible by past BER-funded research. Nuclear Particle Detection As high-energy particles pass through matter, there is a probability that they will transfer energy into that material. Physicists have developed materials that will produce a signal

3 when a high-energy particle passes through. The particle could be a charged subatomic particle, such as a muon, or a high-energy photon, such as a gamma ray. For instance, one type of detector material is called a scintillator. A scintillator can be a gas, liquid or solid. The scintillator reacts to the passage of ionizing radiation such as high-energy photons (x-rays and gamma-rays) by emitting a very weak but very fast pulse of light. This pulse is then detected by a very sensitive light-measuring device called a photomultiplier tube. A photomultiplier tube converts the pulse into an amplified electrical signal that can then be measured and recorded. Scintillators coupled to photomultiplier tubes are the primary detector material used in clinical nuclear medicine imaging. Biomedical Application of Nuclear Physics Technology Nuclear medicine uses radioactive isotopes of familiar atoms such as carbon, oxygen and iodine and less heard of atoms such as technetium and fluorine to image biochemical processes deep within the body. The radioactive isotopes emit high-energy photons such as x-rays and gamma rays when they undergo radioactive nuclear decay. Such radioactive isotopes can be attached to pharmaceutical molecules that have a specific biochemical function in the body. Once injected into patients, many of the highenergy photons emitted by the isotopes can make their way out of the body without being scattered or absorbed and thus are detectable. The Detector and Imaging group at Jefferson Lab has used some of the same principles used in the large nuclear physics detectors to develop detectors than can image radioactive isotopes in the body. The group has developed detector systems for a wide range of medical uses, including breast cancer detection, cardiac imaging, brain cancer therapy and small animal imaging for biomedical research. The Jefferson Lab Detector and Imaging Group The Detector and Imaging Group is headed by Stan Majewski and is composed of seven individuals, including scientists and technical staff. The group s primary mission is to support the nuclear physics research program at Jefferson Lab. The group s biomedical instrumentation and imaging research efforts have evolved since 1995 as an adjunct to the group's primary mission. These efforts are based on the group's expertise in several areas: radiation detector development, including 1) component technologies of pixellated scintillators, position-sensitive photomultiplier tubes and light guides and 2) fast analog detector readout electronics and computer-controlled data acquisition; and also 3) Monte Carlo and analytic simulation and three dimensional image reconstruction for nuclear medicine imaging. Biomedical activities are focused in the area of nuclear medicine, in which imaging human or animal physiology is achieved with pharmaceuticals that are labeled with gamma or positron-emitting radionuclides. In collaboration with academia, other DOE national laboratories and industrial partners, the group has developed and evaluated compact, portable gamma and positron imaging devices as well as hand-held nonimaging intraoperative probes. The goals of the devices are to improve understanding of

4 human physiology and disease mechanisms and ultimately improve patient care. The group's work is currently concentrated in two main areas: 1) dedicated organ imaging for cancer, including breast (scintimammography also know as breast-specific gamma imaging (BSGI), positron emission mammography (PEM)), brain and heart imaging and 2) high resolution, high sensitivity gamma imaging of small animals. Nuclear Medicine Imaging Basics The main goal of medical imaging in terms of nuclear medicine is to generate images of the distribution of radioactively labeled molecules in the body. The objective is to image biological function through the use of a radioactively tagged molecule. The molecule has a specific function within the organism being imaged. Function can be contrasted with structure. Imaging function and structure are two different imaging modalities. We are all familiar with dental x-rays. The purpose of the dental x-ray is to get a structural image of teeth. The image generated in a dental x-ray is a two-dimensional representation of the density variation across the tooth. It is possible to take several x-ray pictures or projections at different angles about the object that when combined and analyzed via a computer results in a three-dimensional representation of the density variation throughout the volume of the structure being imaged, in this case, an x-ray computed tomograph. X-ray computed tomography (x-ray CT) can be used to produce images of a tooth, a limb or the entire body. In nuclear medicine, there are two primary functional imaging modalities. These are single-photon computed tomography (SPECT) and positron-emission tomography (PET). Cancer can be imaged by use of radioactively tagged molecules known as radiopharmaceuticals that accumulate in or around tumor cells. When the radioactive atoms in SPECT radiopharmaceuticals decay, they emit gamma rays. To form a three-dimensional picture of the distribution of SPECT radiopharmaceuticals, a scintillator-based gamma camera is used. A collimator made of lead or tungsten with many parallel channel openings is placed in front of the scintillator to only permit the detection of gamma rays coming from the patient in directions perpendicular to the scintillator s plane. The most commonly used radioisotope for SPECT imaging is technetium-99m. A typical clinical gamma camera is composed of a collimator and a scintillator slab coupled through a light guide to an array of standard photomultiplier

5 tubes. The camera is typically 36 inches in diameter. Figure 3. Schematic diagram of a typical clinical gamma-camera. In PET radiopharmaceuticals, radioactive decay results in the emission of a positron. The emitted positron is an example of a class of particles known as anti-matter. The positron is the anti-particle of an electron, with the same mass as an electron but opposite electric charge. When anti-matter and matter interact, the encounter results in the annihilation of the two with a resulting release of energy. When a positron and an electron collide, they result in a pair of gamma-ray photons of energy 511 kev traveling at nearly 180 opposite directions from the annihilation point. It is the coincident detection of the two oppositely directed 511 kev gamma-rays that is used to compute a three-dimensional image of the distribution of the radiopharmaceutical. The most common PET radiopharmaceutical used in medicine today is the isotope fluorine-18, from which fluorodeoxyglucose (FDG, a form of sugar) is made. Breast Cancer Detection The JLab Detector and Imaging Group has developed a compact application-specific gamma camera based on a matrix of low-profile position-sensitive photomultiplier tubes (PSPMTs) butted together and optically coupled to a scintillator crystal array. This combination allowed the group to construct ideal gamma camera systems for breast imaging which use the SPECT radiopharmaceutical technetium-99m or the PET radiopharmaceutical fluorine-18 FDG.

6 In the past, clinical gamma cameras used to image breasts were large and bulky. The group s experience with photomultiplier tubes and scintillators for nuclear physics research provide the basis for designing better breast-imaging tools. Although x-ray mammograms are still the recommended screening tool for breast cancer, in many cases, a mammogram is unable to give clinicians a clear indication of the presence and location of breast tumors. This is often the case for young women who have active breast tissue, for women with breasts that have a high amount of fibrosity and for women with breast implants. The group has developed systems that are being used in research applications to image breast cancer using the PET compound, fluorine-18 FDG. These systems use a pair of detectors in order to detect the coincident 511 kev gamma-ray radiation mentioned earlier. A detector the group built and tested in collaboration with Duke University has been used in patient studies involving over 200 patients. Another detector system was built and recently installed at the University of West Virginia onto a special gantry for researching the possibility of guiding breast cancer biopsies using PET-based radiopharmaceuticals. Both of these systems are used as research tools for researchers looking for better ways to detect and treat breast cancer. The group s designs for breast cancer detection using SPECT-based radiopharmaceuticals such as technitium-99m have been patented and licensed to a small high-tech company in Newport News, Virginia, Dilon Technologies. Over 25,000 patients nationwide have been imaged with the Dilon camera. The company has sold more than sixty units to clinical centers in the US and abroad. Figure 4. Dilon camera made with Jefferson Lab developed technology.

7 Small Animal Imaging Biomedical research into basic biological understanding, human disease and drug development depend heavily on investigations involving small animal models. Recent advances in nuclear medicine-based small animal imaging technology have enabled researchers to use live animals to study special protein molecules known as transporters and receptors. However, this type of research has been restricted by the necessity of using anesthetics or physical restraint during an imaging session. Both methods of restraint potentially alter the neurological and physiological processes that are of interest to researchers. For this reason, Jefferson Lab, Oak Ridge National Laboratory (ORNL), and Johns Hopkins University are developing and testing a detector system for imaging unrestrained animals. Tools and techniques are being developed to acquire high-resolution SPECT images of the head of unrestrained rodents and to match these image volumes with separately acquired x-ray microct images. The system is composed of a precision x-ray CT/SPECT gantry, two high-resolution 10 cm x 20 cm SPECT gamma cameras and an infrared-based tracking system. Three separate desktop computers control the gantry, acquire SPECT image projection data and determine via the infrared cameras the position and pose of the mouse s head. During the typically 120 SPECT image projections, the system uses three high-speed infrared cameras to track the head of the mouse being studied. This is done through realtime imaging of three infrared reflectors attached to the head of the mouse and illuminated by a series of infrared light-emitting diodes. The infrared camera system uses triangulation to determine the position and coordinates of the head. The gantry CPU acts as the master, with a clock to which the other two CPUs are synchronized. In this way, the separately stored and time-tagged data sets -- gantry projection angle, SPECT image data and mouse pose -- can later be combined and analyzed. From this data, tomographic images can be computed in which all effects of the animal s motion is removed, thus giving researchers the ability to study complicated brain chemistry without the obscuring influence of anesthesia. The system is installed at Johns Hopkins University where is being tested in preparation for animal studies.

8 Figure 5. Awake Animal System installed at Johns Hopkins University. Final Words Overcoming the challenges nuclear physicists face in exploring the structure of the nucleus of the atom and its constituents has led to not only better understanding of the universe but also new technology that directly benefits society through biological and medical applications. These new opportunities for advances in biomedical research have resulted from the Department of Energy bringing together scientists and engineers to explore the structure of matter. We have shown just two examples of how very valuable biomedical spin offs can result from purely nuclear physics basic research pursuits. References Brem RF, Schoonjans JM, Kieper DA, Majewski S, Goodman S, Civelek C. High resolution scintimammography: a pilot study. J Nucl Med 2002; 43: Raylman RR, Majewski S, Smith MF, Wojcik R, Weisenberger AG, Kross B, Popov V, Derakhshan JJ. Comparison of scintillators for positron emission mammography (PEM) systems. IEEE Trans Nucl Sci 2003; 50: Turkington TG, Majewski S, Weisenberger AG, Popov V, Smith MF, Sampson WH, Wojcik R, Kieper D. A large field of view positron emission mammography imager IEEE Nuclear Science Symposium Conference Record. Scott Metzler, Ed. Norfolk, Virginia, November 10-16, ISBN

9 Weisenberger, AG, Gleason SS, Goddard J, Kross B, Majewski S, Meikle SR, Paulus MJ, Pomper M, Popov V, Smith MF, Welch BL and Wojcik R, "A Restraint Free Small Animal SPECT Imaging System with Motion Tracking," IEEE Transactions on Nuclear Science, vol., 52, no. 3, June 2005.

Radioisotopes and PET

Radioisotopes and PET 1 Radioisotopes Elements are defined by their number of protons, but there is some variation in the number of neutrons. Atoms resulting from this variation are called isotopes. Consider