Lawrence Berkeley National Laboratory Positron Emission Tomography Instrumentation: Present Status and Future Directions William W. Moses Lawrence Berkeley National Laboratory October 11, 2016 Outline: Overview Present Status Future Directions

Well Established Clinical Technique 10 Million Studies Annually Nuclear Medicine Patient injected with small amount of radioactive drug. Drug localizes in patient according to metabolic properties of that drug. Radioactivity decays, emitting gamma rays. Gamma rays that exit the patient are imaged. Gamma Camera Well Established Clinical Technique 10 Million Studies Annually

Ideal Tracer Isotope • Interesting Chemistry Easily incorporated into biologically active compounds. • Appropriate Gamma Ray Energy Too low  absorbed in patient. Too high  passes through detector. • 1 Hour Half-Life Maximum study duration is 2 hours. Gives enough time to do the chemistry. • Easily Produced Short half life  local production.

Common Positron-Emitting Tracer Isotopes + 2 hour half-life. ± Chemically very good (replaces OH). – Cyclotron produced. + Chemically excellent. – 2 to 20 minute half-life. + Generator produced. – 2 minute half-life. – Chemically OK (acts like Na and K). 18F 15O, 11C, 13N 82Rb

Positron Emission Tomography (PET) Ring of Photon Detectors Radionuclide decays by emitting a positron (+ ). + annihilates with e– from tissue, forming back-to-back 511 keV photon pair. 511 keV photon pairs detected via time coincidence. Positron lies on line defined by detector pair. Detects Pairs of Back-to-Back 511 keV Photons Images a Slice of the Patient

Multi-Layer PET Cameras Scintillator Tungsten Septum Lead Shield Can image several slices simultaneously Can image cross-plane slices Can remove septa to increase efficiency (“3-D PET”) Planar Images “Stacked” to Form 3-D Image

“Standard” PET Detector Photodetector (light to electrical) Photomultiplier Tube 106 Gain 109 Hz Bandwidth Vacuum Device Electronics (electrical to digital) Analog ASIC Digitize Waveform Process in FPGA Scintillator Array (radiation to light) LSO Scintillator 30,000 photon/MeV 40 ns decay time 1 cm atten. length Measures Position, Energy, and Time Good Performance, Inexpensive, Easy to Pack

Separates Objects on Different Planes Computed Tomography Planar X-Ray Computed Tomography Separates Objects on Different Planes Images courtesy of Robert McGee, Ford Motor Company

Principle of Computed Tomography 2-Dimensional Object 1-Dimensional Horizontal Projection 1-Dimensional Vertical Projection By measuring all 1-dimensional projections of a 2-dimensional object, you can reconstruct the object

Commercial PET Cameras General Electric Siemens Cost ~$2 million. ~5 mm spatial resolution. Usually sold with x-ray CT attached.

Common Clinical Uses of PET Cancer / Oncology Heart Tissue Viability Brain Dysfunction Stroke Epilepsy Alzheimer’s Disease Images Function, Not Structure!

MRI & PET Images of Epilepsy • MRI “Sees” Structure with 0.5 mm Resolution • PET “Sees” Metabolism with 5.0 mm Resolution

Breast Cancer Determine Disease Extent / Plan Treatment Brain Heart Metastases Shown with Red Arrows Normal Uptake in Other Organs Shown in Blue Bladder Determine Disease Extent / Plan Treatment Measure Effectiveness of Therapy

Cardiac Disease Identify Areas with Low Blood Flow During Stress Rest Stress Identify Areas with Low Blood Flow During Stress Evaluate Whether Damaged Tissue Can Recover

“Recent” Advances in PET Instrumentation PET Today 8 mm Resolution 5 cm Axial Extent Cardiology / Neurology Academic Research 4 mm Resolution 15–25 cm Axial Extent Oncology Routine Clinical

Combine PET & CT (Oncology) CT Image PET Image Fused Image Post-Therapy Images courtesy of Stig Larsson, Karolinska Institute Anatomy from X-Ray CT, Function from PET Current “Standard of Care”

Combine PET & CT (Cardiac) Image courtesy of Gustav von Schulthess, University Hospital, Zurich Anatomy from X-Ray CT, Function from PET

Research Directions in PET Small Animal Organ Specific Cameras PET / MRI

Small Animal (Mouse) PET microPET II 17,640 LSO crystals (0.95x0.95x12.5 mm) 15 cm ring diameter 8 cm transverse FOV 4.9 cm axial FOV ~1.2 mm resolution ~2.5% sensitivity DEPARTMENT OF BIOMEDICAL ENGINEERING

Small Animal (Mouse) PET FDG Heart F– Bone Scan <1 mm Spatial Resolution Basic Biological Research Tumor Model Images courtesy of Simon Cherry, UC Davis

Small Animal (Mouse) PET / CT CT Image PET Image Fused Image Images courtesy of Simon Cherry, UC Davis

Positron Emission Mammography Image courtesy of M. Smith, D. Weisenberg, and S. Majewski, Jefferson National Lab. PET Cameras Optimized to Image Breast Cancer Reduced Field of View Lower Cost (10x) Higher Performance (2x – 30x)

Breast PET/CT Whole-body PET/CT Dedicated breast PET/CT Image courtesy of R. Badawi and S. Bowen, UC Davis

Combined PET/MRI Simultaneous Sequential Combine Anatomic Information from MRI (instead of CT) with Functional Information from PET Truly Simultaneous PET/MRI is Difficult: Need detectors that are insensitive to B Fields PET system cannot interfere with MRI system MRI system cannot interfere with PET system

Human & Animal PET/MRI Cameras Sold Commercially PET/MRI Images Rat PET Merged MRI Human Human & Animal PET/MRI Cameras Sold Commercially

What Can Be Improved in PET? Signal to Noise Ratio Dominated by Statistical Noise Spatial Resolution Near Fundamental Limit

PET: Impaired Image Quality in Larger Patients Slim Patient Large Patient For an equivalent data signal to noise ratio, a 120 kg person would have to be scanned 2.3 times longer than a 60 kg person 1) 1) Optimizing Injected Dose in Clinical PET by Accurately Modeling the Counting-Rate Response Functions Specific to Individual Patient Scans. Charles C. Watson, PhD et al Siemens Medical Solutions Molecular Imaging, Knoxville, Tennessee, JNM Vol. 46 No. 11, 1825-1834, 2005

Time-of-Flight in PET c = 30 cm/ns 500 ps timing resolution  7.5 cm localization Use time-of-flight to localize source along line of flight. Time of flight information reduces noise in images. Biggest improvement in large patients (where needed most). D Variance (Effective Sensitivity) Improved by 2D/ct Biggest Improvement in Large Patients 28

Statistical Noise in PET If there are N counts in the image, SNR = Signals from Different Voxels are Coupled  Statistical Noise Does Not Obey Counting Statistics 29

Commercial TOF PET w/ LSO ~550 ps Coincidence Timing Achieved Initially (2008) <400 ps Coincidence Timing Presently Achieved

TruFlight™: Enhanced Diagnostic Confidence Non-TOF Lymphoma within right iliopsoas muscle with central area of necrosis TOF improved delineation of lymphoma activity 116 kg; BMI = 31.2 14 mCi; 2 hr post-inj MIP Data courtesy of J. Karp, University of Pennsylvania

EXPLORER EXtreme Performance LOng REsearch scanneR Conventional PET (22 cm axial) EXPLORER (200 cm axial) Approach the Limits of PET Sensitivity

Image Better > 6-fold improvement in SNR Reconstruct at higher spatial resolution Detect smaller lesions Detect low-grade disease Better statistics for kinetic modeling Conventional PET EXPLORER

Image Longer 11C 18F 89Zr Major increase in dynamic range can image for 5 more half lives 11C > 3 hours 18F > 16 hours 89Zr > 30 days Conventional PET time EXPLORER

Image Faster Total-body PET in 15-30 seconds Image in a single breath hold Reduce effects of respiratory motion Total-body kinetic imaging with high temporal resolution Conventional PET 10-20 mins EXPLORER 15-30 secs

Image Gently (Low Dose) 40-fold reduction in dose Whole-body PET at ~0.15 mSv Annual natural background is ~2.4 mSv Return flight (SFO-LHR) is ~0.11 mSv PET can be used with minimal risk – new populations Conventional PET EXPLORER

Image More Often Conventional PET EXPLORER

Radial Elongation Penetration of 511 keV photons into crystal ring blurs measured position. Blurring worsens as detector’s attenuation length increases. Effect variously known as Radial Elongation, Parallax Error, or Radial Astigmatism. Can be removed (in theory) by measuring depth of interaction. Tangential Projection Radial Projection

Resolution Degrades Away From Center... Radial Elongation Point Source Images in 60 cm Ring Diameter Camera 1 cm Near Tomograph Center 14 cm from Tomograph Center Resolution Degrades Away From Center...

Silicon Photomultipliers SiPMs w/ Scintillator Crystals SiPM Array 24 mm 24 mm High Quantum Efficiency GHz Bandwidth w/ Reasonable Gain Individual Small Pixels Insensitive to Magnetic Fields Practical (compact, reliable, inexpensive…) SiPMs Can Improve Spatial Resolution & Timing

Theoretical Timing Resolution w/ SiPMs 10% 30% 50% 70% 90% 500 245 138 107 90 80 300 188 106 82 69 61 100 129 66 50 42 37 116 56 41 34 30 112 51 38 31 27 45 32 26 22 PDE (Quantum Eff.) (%) SPTR (Single Photon Timing Resol.) (ps rms) 3 mm Cube, 70% Collection Eff., 511 keV LSO (30k ph/MeV, 40 ns Decay, 30 ps Rise) 41

Much More Work To Be Done! Conclusion PET Instrumentation Has Improved Dramatically: Routine Clinical Use w/ Merged X-Ray CT Image Small Animal Current Trends: Multi-Modality (MRI, Ultrasound, Optical) Special Purpose (Disease-Specific) Cameras Time-of-Flight Future Improvements Require: New Scintillators, Photodetectors, & Electronics New Detector & Camera Designs New Reconstruction, Data Analysis, & Chemistry Much More Work To Be Done!

Detector for Human PET: “Block Detector Module” 4 PMTs (25 mm square) Saw cuts direct light toward PMTs. Depth of cut determines light spread at PMTs. Crystal of interaction found with Anger logic (i.e. PMT light ratio). 50 mm Scintillator Crystal Block 50 mm 30 mm Measures Position, Energy, and Time Good Performance, Inexpensive, Easy to Pack

Crystal Identification with Anger Logic Profile through Row 2 Uniformly illuminate block. For each event, compute X-Ratio and Y-Ratio, then plot 2-D position. Individual crystals show up as dark regions. Profile shows overlap (i.e. identification not perfect). Y-Ratio X-Ratio Can Decode ~200 Crystals with LSO Scintillator

Much More Work To Be Done! What Can Be Improved? Energy Resolution Reduce Scatter Background Spatial Resolution Reduce Penetration Effects Need Volumetric Detector Time Response Reduce Dead Time Improve TOF Performance Cost Array of Scintillator Crystals Photomultiplier Tubes Much More Work To Be Done!

Design Parameters Siemens mCT EXPLORER Axial FOV (cm) 21.8 200 Ring diameter (cm) 84.9 ~80 Scintillator LSO LYSO Spatial resolution (mm) 4.1 <4 TOF resolution (ps) 530 <400 Integrated CT unit? Yes

Sensitivity Improvement mCT EXPLORER Ratio Point Source in Air at FOV Center 24.9% 92.9% 3.7 Point Source w/ Attenuation (27 cm dia. x 200 cm long) 1.6% 3.9% 2.4 Whole Body NECR, 10 mCi (27 cm dia. x 200 cm long) 75.7 2,560 33.8 Pediatric NECR, 0.05 mCi (20 cm dia. x 70 cm long) 3.12 48.0 15.5 Brain VOXTISS 8 NECR, 10 mCi 6:1 activity 176 597 3.4 Cardiac VOXTISS 8 NECR, 20 mCi all activity in heart 613 1910 3.1 Non-TOF Values for NECR Given Multiply NECR by 1.4 – 2.8 to Obtain NECRTOF

Depth-Encoding PET Detector Module 24 mm 30 mm Image of Collimated Gamma Rays LSO Array (crystals 3x3x30 mm3) 64 Element PD Array 1” Square PMT Custom IC Flex Board PMT Provides Timing Pulse PD Array Identifies Crystal of Interaction PD+PMT Provides Energy Discrimination PD / (PD+PMT) Measures Depth of Interaction

Improvements In Scintillators Combine Best Properties of: LaBr3:30% Ce Timing resolution <100 ps Energy resolution <4% LuI3:Ce Light output >100,000 ph/MeV PbWO4 Density >8 g/cc High atomic number Inexpensive Image courtesy of Paul Lecoq, CERN PET Performance Determined by Scintillator

Improvements in Photodetectors Avalanche Photodiode Array Position-Sensitive APD 28 mm LSO Array Hamamatsu Photonics High Quantum Efficiency GHz Bandwidth w/ Reasonable Gain Individual Small Pixels Insensitive to Magnetic Fields Practical (compact, reliable, inexpensive…) RMD, Inc. Geiger Mode APDs (SiPMs) Show Great Promise…

Improvements In Electronics Timing Resolution Improve TOF Performance High-Performance CFD ASIC Multi-Channel Multi-Anode PMTs APD & SiPM Arrays Volumetric Detectors 100,000 Pixels in Camera! Cost Image courtesy of Jorgen Christianson, CERN Electronics Must Keep Pace w/ Detectors

Several Performance Measures Scintillator Light Yield Decay Time Attenuation Length Emission  Camera Spatial Resolution Sensitivity Scatter Fraction Field of View Medical False Pos/Neg Survival Rate Change in Care? Procedure Cost Link From Instrumentation to Medical is Difficult