1. 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

2. 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

3. 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.

4. 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

5. 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

6. 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

7. “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

8. 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

9. 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

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

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

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

13. 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

14. 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

15. “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

16. 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”

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

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

19. 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

20. 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

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

22. 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)

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

24. 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

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

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

27. 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, , 2005

28. 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

29. 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

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

31. 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

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

33. 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

34. 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

35. 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

36. 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

37. Image More Often
Conventional PET
EXPLORER

38. 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

39. 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...

40. 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

41. 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

42. 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!

43. 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

44. 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

45. 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!

46. 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

47. 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

48. 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

49. 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

50. 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…

51. 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

52. 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