The RatCAP Conscious Small Animal PET Tomograph Craig Woody Brookhaven National Lab EuroMedIm 2006 Marseille, France May 10, 2006

C.Woody,EuroMedIm 2006, 5/10/062 Imaging The Awake Animal Animals need to be anesthetized during PET imaging due to their inability to lie motionless in the scanner 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 study neurophysiological activity and behavior in laboratory animals using PET in order to better understand these effects in humans.

C.Woody,EuroMedIm 2006, 5/10/063 RatCAP: Rat Conscious Animal PET A miniature, complete full-ring tomograph mounted to the head of an awake rat. Compact, light weight (< 200 g), low power detector Small field of view (38 mm dia. x 18 mm axial) Attached to the head of the rat and supported by a tether which allows reasonable freedom of movement for the animal

C.Woody,EuroMedIm 2006, 5/10/064 Tomograph Ring Readout chip APD LSO Socket LSO array Ring containing 12 block detectors of 2x2 mm 2 x 5 mm deep LSO crystals with APDs and integrated readout electronics APD (Hamamastu S8550) Actual RatCAP Ring

C.Woody,EuroMedIm 2006, 5/10/065 Readout Electronics Totally Digital Output 5 bit address Leading edge gives timing No ADC’s Minimizes cabling ZCD Bare chip Packaged chip Custom ASIC ( 0.18  m CMOS) 32 channels preamp, shaper, discriminator ~ 1W total power

C.Woody,EuroMedIm 2006, 5/10/066 Energy resolution is used primarily for scatter rejection Presently have common threshold for all channels Measure count rate as a function of threshold for all channels and differentiate spectra Requires setting threshold low enough for good efficiency for lowest channel (~ 146 keV)  poor timing resolution for others Next version of chip will have independent gain and threshold settings for each channel Differential pulse height spectrum Threshold scan Threshold (mV) Energy Resolution FWHM ~ 23% Thresh

C.Woody,EuroMedIm 2006, 5/10/067 Large background from activity in the rat’s body High singles rate (~ 50 KHz/block) Not possible to shield background due to added weight Next version of chip will use a leading edge discriminator and time-over-threshold measurement (  energy) for time walk correction and improved timing resolution Timing Resolution Timing resolution is used to reject randoms background Coincidence window 2  ~ 2 FWHM 2  ~28 ns

C.Woody,EuroMedIm 2006, 5/10/068 Position Resolution Rat Brain Striatum Phantom FWHM (mm) R4 MicroPET RatCAP 7 mm 15 mm Point Source Resolution Intrinsic Spatial Resolution 1.28 mm FWHM Concorde P4 MicroPET = 1.75 mm UCLA MicroPET = 1.58 mm 3.4:1 activity ratio (striatum to background)

C.Woody,EuroMedIm 2006, 5/10/069 Sensitivity RatCAP Point Source Sensitivities 150 kev 400 keV Small Animal PET Sensitivities (Threshold = 250 keV) microPET (original) 0.56% ATLAS 1.8% microPET R4 4.4% microPET P4 2.3% microPET II (proto)2.3% microPET Focus % microPET Focus % microPET R4 = 45 6 uCi/cc Count Rate (kcps) 4  Ci 2  = 40 ns

C.Woody,EuroMedIm 2006, 5/10/0610 RatCAP Support System Weight is completely counterbalanced (animal feels only inertia) Gimbal ring allows head movement Inner ring attaches to head which mounts to tomograph

C.Woody,EuroMedIm 2006, 5/10/0611 Adaptation to Wearing the Ring Corticosteroid Levels in Untrained rats wearing the RatCAP Animal training and conditioning should reduce stress levels significantly

C.Woody,EuroMedIm 2006, 5/10/0612 Animal Training

C.Woody,EuroMedIm 2006, 5/10/0613 Mounting the RatCAP to the Head

C.Woody,EuroMedIm 2006, 5/10/0614 Rat wearing the RatCAP

C.Woody,EuroMedIm 2006, 5/10/0615 First Images MicroPET R4 Overlay RatCAP 517 g rat, 802 uCi 18 F-FDG i.p. injection 45 min awake uptake, then chloral hydrate euthanasia MicroPET R4 scan 10 min, LLD = 250 keV, 2  = 10 ns 3D MLEM (20 iterations) RatCAP scan 33 minutes livetime over 150 min scan –equivalent to 1.9 X decays of R4 scan Monte Carlo-based 3D MLEM –200 iterations –Randoms correction –No efficiency correction (yet) RatCAP FOV

C.Woody,EuroMedIm 2006, 5/10/0616 Methamphetamine Images Using the RatCAP RatCAP The resolution of the RatCAP is slightly better than the commercial MicroPET scanner MicroPET RatCAP vs MicroPET Time Activity Curve Time in seconds ROI Activity in nCi/cc RatCAP MicroPET

C.Woody,EuroMedIm 2006, 5/10/0617 Fluoride Scan 3 mCi 18 F Injection Uptake mainly in the bone Brain Skull Artifact ( due to randoms correction)

C.Woody,EuroMedIm 2006, 5/10/0618 Summary The ability to image the awake animal will open up many new possibilities in neurophysiology and neurochemistry The RatCAP is a fully functional miniature 3D tomograph that can be used for PET imaging of live, unanesthesized rats, and will provide one of the first opportunities to perform detailed studies on awake animals The device can also be used as a standard small animal tomograph for anesthesized animals, and can be used for other applications using the same detector components The first preliminary studies using the RatCAP have been completed, and we are now looking forward to the first real awake animal images and to improving its design in the future.

C.Woody,EuroMedIm 2006, 5/10/0619 The Team P. Vaska, C. Woody, D. Schlyer, J.-F. Pratte, P. O’Connor, V. Radeka, S. Shokouhi, S. Stoll, S. Junnarkar, M. Purschke, S.-J. Park, S. Southekal, V. Dzhordzhadze, W. Schiffer, D. Marsteller, D. Lee, S.Dewey, A. Villanueva, S. Boose, A. Kandasamy, B. Yu, A. Kriplani, S. Krishnamoorthy, S. Maramraju Brookhaven National Laboratory J. Neill, M. Murphy, T. Aubele, R. Kristiansen Long Island University R. Lecomte and R. Fontaine University of Sherbrooke

C.Woody,EuroMedIm 2006, 5/10/0620 Backup slides

C.Woody,EuroMedIm 2006, 5/10/0621 Effects of Anesthesia Blood flow and metabolism depend on type and dose of anesthesia Global and regional cerebral blood flow is affected by anesthesia Cerebrovascular reactivity to CO 2 is perturbed Neural activity is suppressed Effects are different for different animals and species M.Pomper, Johns Hopkins The effect of anesthesia on the uptake of β-CFT on dopamine transporters in the monkey brain. From the 9th International Conference: Peace Through Mind/Brain Science, Hamamatsu, Japan, Jan , 2002

C.Woody,EuroMedIm 2006, 5/10/0622 Effects of Anesthesia Blood flow and metabolism depend on type and dose of anesthesia Global and regional cerebral blood flow is affected by anesthesia Cerebrovascular reactivity to CO 2 is perturbed Neural activity is suppressed Effects are different for different animals and species M.Pomper, Johns Hopkins Reduction in glucose metabolism with isoflurane in humans Similar effects are seen in the rat D.B. Stout et al, UCLA 1998

C.Woody,EuroMedIm 2006, 5/10/0623 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,EuroMedIm 2006, 5/10/0624 Readout System n Time Signal Processing Module FPGA time stamps and packages singles events into 64 bit words 1.3 ns bit resolution n VME data acquisition VxWorks running PDAQ Up to 40 MB/s to Linux box n Online monitoring Singles & coincidence rates n Offline processing Time and energy calibrations Coincidence sorting Randoms estimation Efficiency normalization Sinogram sorting FPGA

C.Woody,EuroMedIm 2006, 5/10/0625 Rat wearing the RatCAP

C.Woody,EuroMedIm 2006, 5/10/0626 Wrist Scanner for Measuring the Arterial Input Function Obective: to perform non-invasive quantification of the Arterial Input Function using PET Imaging. Activity in the surrounding veins produce a significant background which can be rejected using the good spatial resolution from PET

C.Woody,EuroMedIm 2006, 5/10/0627 Wrist Phantom Studies Radial arteryUlnar artery Wrist Phantom ArteryVein Planar Image obtained with Wrist Phantom 1 cm