RatCAP: A Small, Head Mounted PET Tomograph for Imaging the Brain of an Awake Rat Craig Woody Brookhaven National Lab Sherbrooke University Seminar March 15, 2004

C.Woody, Sherbrooke University Seminar, 3/15/042 The Collaboration Part of a larger project for Imaging The Awake Animal also involving motion tracking in both PET and MRI SUNY BNL

C.Woody, Sherbrooke University Seminar, 3/15/043 The People BNL Physics: C. Woody, S. Stoll, M. Purschke, W.Lenz, M. Lenz, S.Boose Chemistry: D. Schlyer, A. Villanueva, J. Fowler Medical: P. Vaska, N. Volkow* (now at NIH) Instrumentation: P. O’Connor, V. Radeka, J.-F. Pratte*, S. Junnakar, G. DeGeronimo, B.Yu, A.Kandasamy, K.Wolniewicz, S. Rescia Stony Brook S. Shokouhi, A. Kriplani, S.Krishnamoorthy, S.Southekal (BME students) I. Rampil, C.Page, A.Bell (Dept. of Anesthesiology) Sherbrooke* R.Lecomte, R.Fontaine, S. Robert

C.Woody, Sherbrooke University Seminar, 3/15/044 The Problem Anesthesia can greatly depress brain functions and affect the neurochemistry that one is trying to study Cannot study animal behavior while under anesthesia One wants to use PET to study the neurophysiological activity and behavior in laboratory animals in order to understand and treat these effects in humans. However, animals currently need to be anesthetized during PET imaging.

C.Woody, Sherbrooke University Seminar, 3/15/045 Neurotransmitter Activity in the Brain Drugs like cocaine can block the re-uptake sites for neurotransmitters like dopamine which upsets the normal equilibrium and can cause effects of addiction DA MAO A DA signal DA 11 C-Cocaine

C.Woody, Sherbrooke University Seminar, 3/15/046 Effects of Anesthesia The effect of anesthesia on the uptake of β-CFT on dopamine transporters in the monkey brain. H.Hideo et.al., Synapse 42 (2001) Reduction in glucose metabolism with isoflurane in humans Similar effects are seen in the rat D.B. Stout et al, UCLA 1998

C.Woody, Sherbrooke University Seminar, 3/15/047 RatCAP: Rat Concious Animal PET Mockup of the portable ring on the head of a rat A septa-less, full-ring tomograph with a diameter of 4 cm and an axial extent of 2 cm, suspended by a tether, which will allow nearly free movement of the awake animal Harderian gland (at eye position) microPET images RatCAP mounting position superimposed on Concorde R4 MicroPET image of a rat brain

C.Woody, Sherbrooke University Seminar, 3/15/048 Design Requirements The tomograph ring must be light enough to be supported by the rat and allow reasonable freedom of movement Light weight detectors (~ 150 g total weight) Light weight electronics with low power dissipation  New custom ASIC High data rates and large singles background Small field of view and large parallax effects Limited sampling due to space and weight requirements Must be rugged enough withstand activity of the rat

C.Woody, Sherbrooke University Seminar, 3/15/049 Freedom of Movement Similar support structures are used in microdialysis experiments “Ratturn Bowl” Tether support system allows reasonable freedom of movement

C.Woody, Sherbrooke University Seminar, 3/15/0410 RatCAP Support System Gimbal ring allows head movement Weight is completely counterbalanced (animal only feels inertia)

C.Woody, Sherbrooke University Seminar, 3/15/0411 Tomograph Ring Ring containing 12 block detectors of 2x2 mm 2 x 5 mm deep LSO crystals with APDs and integrated readout electronics Readout chip APD LSO Socket LSOAPD

C.Woody, Sherbrooke University Seminar, 3/15/0412 Sensitivity Comparison of sensitivity with other small animal PET scanners BNL RatCAP 4 cm Ø x 2 cm ~ 150 cps/  Ci (0.41%) Concord m PET R4 15 cm Ø x 8 cm (1.86%) UCLA m PET 17 cm Ø x 2 cm Intrinsic detector sensitivities are essentially the same Coincidence sensitivities are proportional to axial acceptance

C.Woody, Sherbrooke University Seminar, 3/15/0413 Parallax Effects Due to the small diameter of the ring, the parallax error is a major factor in determining the spatial resolution 2 cm

C.Woody, Sherbrooke University Seminar, 3/15/0414 Spatial Resolution and Field of View Resolution at the edge of the rat brain Single layer - 10 mm ~ 2.5 mm Double layer - 5 mm ~ 2.0 mm First prototype will be a single layer of 5 mm crystals Will sacrifice sensitivity for improved spatial resolution SimSet Simulation

C.Woody, Sherbrooke University Seminar, 3/15/0415 LSO Crystal Arrays Studying different types of crystal arrays to optimize light output and energy resolution CTI white powder reflector Proteus unbonded 3M reflector Proteus single crystals

C.Woody, Sherbrooke University Seminar, 3/15/0416 Optimization of Light Collection unwrapped air unwrapped cookie wrapped cookie wrapped air Dashed = Measured Solid = Opticad OPTICAD Ray Tracing Program 2x2 mm 2 single crystals wrapped in 3M reflector and coupled with a silicone cookie to a calibrated PMT N pe /MeV = N  /MeV x  x QE 2400 = 25,000 x 0.4 x 0.24

C.Woody, Sherbrooke University Seminar, 3/15/0417 Comparison of Light Output and Energy Resolution of Different Crystals Prototype LSO arrays measured with Hamamatsu 4x8 APD Conclusion: Crystals wrapped with 3M reflector and air gap give the highest light output and best energy resolution

C.Woody, Sherbrooke University Seminar, 3/15/0418 Light Output and Uniformity of Crystal Arrays Proteus cutting, polishing and assembly process Average light yield ~ 5300 p.e./MeV (~ 18% higher than prototype) Spread of average from array to array  ~ 5 % Average spread within an array  ~ 18% Total spread within an array up to ± 50 %

C.Woody, Sherbrooke University Seminar, 3/15/0419 Avalanche Photodiodes 4x8 array 1.6 x 1.6 mm 2 active pixel area Hamamatsu S8550 N pe ~ 2700 Typical G ~ 50  ~ 135K signal e’s Common voltage for each 16 channels Dark current < 40 nA (~ 1.2 nA/ch) Expected noise in final ASIC ~ 1100 e’s (C T ~ 10 pF) G ~ 50

C.Woody, Sherbrooke University Seminar, 3/15/0420 APD Gain and Quantum Efficiency Variation Measured with N 2 laser + optical fiber Gain + Quantum Efficiency variation Total spread ~ ± 20 % Channel to channel differences dominated by quantum efficiency variation

C.Woody, Sherbrooke University Seminar, 3/15/0421 Electronics & Readout System  Tomograph ring with detectors and front end readout electronics are mounted to the head of the rat  Tether carries signals, high and low voltage power to a Control Module Data collection module Control Module  CM communicates with a VME based Data Collection Module that adds time stamp information and reads out the data

C.Woody, Sherbrooke University Seminar, 3/15/0422 Electronics & Readout System  No analog information  Pixel address is encoded and data is transmitted by individual serial line for each block to the Data Collection Module  Single ZCD per channel generates time information  DCM adds time stamp to each event and does coincidence timing or list mode processing of singles data Singles rates up to 100 kHz/block 1 byte/block  1.2 MB/sec off ring DCM produces 64 bits (43 bit time stamp)  ~ 10 MB/sec to PC Block 1 Block 2 Block … Block 12 DCM CM PC VME Time Stamp 500 MHz HV LV DAC Serial data 100 MHz x12 8 bits

C.Woody, Sherbrooke University Seminar, 3/15/0423 Custom Front End Readout Chip Custom ASIC in 0.18 μm CMOS 4 mW per channel 32 channels  125 mW per chip ~ 1.5 W total on ring Final size: 4.2 x 1.7 mm Prototype 2 J.-F. Pratte

C.Woody, Sherbrooke University Seminar, 3/15/0424 Custom Front End Readout Chip Discriminator pulse is encoded to give 5 bit address Leading edge of encoded serial pulse train gives time information 100 MHz clock Maximum 100 KHz/block  0.7% deadtime CSP gain 3.3 mV/fC Overall gain 15 mV/fC Digital Output (P.O’Connor) Preamp/Shaper/ZCD

C.Woody, Sherbrooke University Seminar, 3/15/0425 ASIC Performance Slope = 15.2 mV/fC ENC = 902  29 e’s rms LinearityEnergy Resolution Peaking Time Measurements C in MeasurementSimulation 0 pF73.2 ± 1.4 ns74.0 ns 12 pF80.4 ± 1.8 ns80.0 ns FWHM = 18%

C.Woody, Sherbrooke University Seminar, 3/15/0426 ASIC Performance Noise ENC min = 100 ns Cin tot = 20 pF Timing (ZCD) Noise is dominated by photostatistics contribution Expect ~ 2.4 ns rms total ENC electrons (RMS)

C.Woody, Sherbrooke University Seminar, 3/15/0427 ASIC Performance - Timing Resolution 3.54 ns FWHM6.7 ns FWHM (2.4 ns rms) LSO+APD vs BaF2+PMT Electronic Timing Resolution at 511 keV equivalent energy Coupled to LSO/APD with 511 keV  ’s timed against a BaF 2 scintillator w/PMT Same with CFD Preamp/Shaper + ZCD

C.Woody, Sherbrooke University Seminar, 3/15/0428 Rotatable Stage for Obtaining Partial Tomographic Data Source phantoms mounted on rotatable stage to simulate full tomographic ring

C.Woody, Sherbrooke University Seminar, 3/15/0429 Point Source Resolution 1 mm dia 68 Ge point source at R=1.6 mm in rotation stage profile axis (mm) im ag e int en sit y (ar b) FWHM = 2.1 mm Intrinsic spatial resolution measured with 22 Na point source (< 1 mm dia) Average peak FWHM = 1.28 mm Concorde P4 MicroPET = 1.75 mm UCLA MicroPET = 1.58 mm

C.Woody, Sherbrooke University Seminar, 3/15/0430 Source Images Single 1 mm dia. 68 Ge point source 1.6 mm off axis 2 mm Multiple 68 Ge point sources (~ 2mm) spaced ~ 4 mm 4 mm

C.Woody, Sherbrooke University Seminar, 3/15/0431 Modeled Reconstructed Images Monte Carlo simulations using SimSet Reconstruction using Filtered Back Projection Fully sampled image of four phantom sources Image reconstructed using incomplete data set with interpolation Image reconstructed using incomplete data set Test Phantom S.Shokouhi

C.Woody, Sherbrooke University Seminar, 3/15/0432 Real Image Reconstruction Small but nearly completely filled field of view Large parallax error (no DOI information) Finite pixel size (2x2 mm 2 ) at small radius Incomplete azimuthal sampling Will use a 3D statistical image reconstruction method (Maximum Likelihood Expectation Maximization) to include effects of: Unique features of the RatCAP: Arc correction Rebinning Detector gaps Normalization Scatter and attenuation Shepp & Vardi, IEEE Trans. Med. Imaging (1982)

C.Woody, Sherbrooke University Seminar, 3/15/0433 Preliminary Studies using MLEM Method 221 voxels (1 mm 3 ) over 17 mm dia image field 552 sinograms (23  x 24 R) 121,992 system matrix 10 7 photons generated per voxel Discrete approximations to the RatCAP used with SimSET Spatial resolution already improved over FBP Since RatCAP is small, can ultimately handle full system matrix 1.09 mm

C.Woody, Sherbrooke University Seminar, 3/15/0434 Other Applications A wide range of quantitative PET studies using tracer kinetic modeling demand accurately measured radiotracer concentration in arterial blood as a function of time after injection (Arterial Input Function). The common method of measuring the input function is the invasive withdrawal of blood from a wrist artery. However, because of its health risks for both patients and hospital personnel, it is not compatible with clinical studies. A small ring tomograph similar to the RatCAP can be used to image the artery and measure the input function Non-Invasive Wrist Monitor

C.Woody, Sherbrooke University Seminar, 3/15/0435 Wrist Monitor for Measuring the Arterial Input Function For human studies, the input function is taken from the radial artery in the wrist. Activity in the surrounding veins produce a significant background which can be rejected using the good spatial resolution of the wrist monitor. Planar image of a 1 mm diameter 68 Ge line source A.Villaneuva Wrist Phantom

C.Woody, Sherbrooke University Seminar, 3/15/0436 Simulated Input Function Measurement Measure activity as an aqueous solution of a 11 C - labeled radioisotope passes between two block detectors w/scatterw/o scatter Expected input function resolution using Wrist Monitor

C.Woody, Sherbrooke University Seminar, 3/15/0437 Summary The ability to carry out PET imaging studies in live, awake animals would provide valuable new information on the neurophysiological behavior in both animals and humans The RatCAP will provide a new tool for carrying out these studies in laboratory rats. Preliminary studies have shown that the design parameters of the RatCAP have been met and we are proceeding to complete the design and construct the actual detector. A small imaging tomograph such as this may have other useful applications in nuclear medicine