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

RatCAP: A Small, Head Mounted PET Tomograph for Imaging the

Brain of an Awake Rat

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, 3/15/04 2

The Collaboration The Collaboration

Part of a larger project for Imaging The Awake Animalalso involving motion tracking in both PET and MRI

SUNY

BNL


The PeopleThe 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


The Problem 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.


Neurotransmitter Activity in the Brain 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

DA

DA

DA DA

MAO A

DA

DA

signal

DA

DA

DA

DADADA DA

DA

DA DA

DA

DA

DA

11C-Cocaine


Effects of AnesthesiaEffects 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) 273-280

Reduction in glucose metabolism with isoflurane in humans

Similar effects are seen in the rat

D.B. Stout et al, UCLA 1998


RatCAP: Rat Concious Animal PETRatCAP: 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


Design RequirementsDesign 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


Freedom of MovementFreedom of Movement

Similar support structures are used in microdialysis experiments

“Ratturn Bowl”Tether support system allows reasonable freedom of movement


RatCAP Support SystemRatCAP Support System

Gimbal ring allows head movement

Weight is completely

counterbalanced(animal only feels inertia)


Tomograph RingTomograph Ring

Ring containing 12 block detectors of 2x2 mm2 x 5 mm deep LSO crystals with APDs and integrated readout electronics

Readout chip

APD

LSO

Socket LSO APD


SensitivitySensitivity

Comparison of sensitivity with other small animal PET scanners

BNL RatCAP4 cm Ø x 2 cm~ 150 cps/Ci

(0.41%)

Concord mPET R4 15 cm Ø x 8 cm

(1.86%)

UCLA mPET 17 cm Ø x 2 cm

• Intrinsic detector sensitivities are essentially the same• Coincidence sensitivities are proportional to axial acceptance


Parallax EffectsParallax Effects

Due to the small diameter of the ring, the parallax error is a major factor in determining the spatial resolution

2 cm


Spatial Resolution and Field of ViewSpatial Resolution and Field of View

Resolution at theedge of the rat brain

Single layer - 10 mm ~ 2.5 mmDouble layer - 5 mm ~ 2.0 mm

First prototype will be a single layer of 5 mm crystalsWill sacrifice sensitivity for improved spatial resolution

SimSet Simulation


LSO Crystal ArraysLSO 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


Optimization of Light CollectionOptimization of Light Collection

crystal length (mm)

0 5 10 15 20 25

pe/M

eV

500

1000

1500

2000

2500

3000

unwrapped air

unwrapped cookie

wrapped cookie

wrapped air

Dashed = Measured Solid = Opticad

OPTICAD

Ray Tracing Program

2x2 mm2 single crystals wrapped in 3M reflector and coupled with a silicone

cookie to a calibrated PMT

Npe/MeV = N/MeV x x QE

2400 = 25,000 x 0.4 x 0.24

10 mm crystal (wrapped with cookie)

0.2

0.25

0.3

0.35

0.4

0.45

0.5

0.55

0.6

0 1 2 3 4 5 6 7 8 9 10

Distance along crystal

Ligh

t Col

lect

ion

Effic

ienc

y


Comparison of Light Output and Energy Resolution of Different CrystalsComparison 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

manufacturer length note <pe/MeV> <resolution> CTI 8mm slotted block 2918 0.25

Proteus 5mm glued 1513 0.2010mm glued 2356 0.19

Proteus 5mm no glue 3113 0.1910mm no glue 2455 0.17

Proteus 5mm end glued - no mask 4491 0.165mm end glued - mask 2962 0.17

With Silicone cookie


Light Output and Uniformity of Crystal ArraysLight 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 %


Avalanche PhotodiodesAvalanche Photodiodes

4x8 array 1.6 x 1.6 mm2

active pixel area

Hamamatsu S8550Npe ~ 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

(CT~ 10 pF)

APDs (101-115)Average gains (32 ch each)

0 100 200 300 400

Ga

in

1

10

100

Reverse bias (volts)

Measured APD dark currents (each curve represents the summed dark current for all 32 channels)

Reverse bias (volts)

320 330 340 350 360 370 380 390 400 410 420

Dar

k cu

rren

t (n

A)

10

100

1000

apd 101 apd 102 apd 103 apd 104 apd 105 apd 106 apd 107 apd 109 apd 110 apd 111 apd 112 apd 113 apd 114 apd 115

G ~ 50


APD Gain and Quantum Efficiency VariationAPD Gain and Quantum Efficiency Variation

Measured with N2 laser + optical fiber

1.01 1.08 1.14 1.18

1.00 1.00 1.14 1.12

1.00 1.02 1.07 1.04

0.97 0.96 1.02 0.99

0.92 0.94 1.01 0.99

0.94 0.96 1.00 0.98

0.95 1.00 0.94 0.95

0.92 0.93 0.90 0.93

Gain + Quantum Efficiency variationTotal spread ~ ± 20 %

Channel to channel differences dominated by

quantum efficiency variation

ADC channels

5000 6000 7000 8000 9000 10000 11000 12000

Co

un

ts0

2

4

6

8

10

12

14

Sigma/mean = 6.4%Average gain = 50


Electronics & Readout SystemElectronics & 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


Electronics & Readout SystemElectronics & 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

DCMCM

PC

VME

Time Stamp

500 MHz

HVLV

DAC

Serial data 100 MHz

x12

8 bits


Custom Front End Readout ChipCustom 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


Custom Front End Readout ChipCustom Front End Readout Chip

A 0 A 1 A 2 A 3 A 4

A 0 A 1 A 2 A 3 A 4

C L O C K

C F D

T IMINGE D G E

C HA NA D D R E S S

E D G E +A D D R E S S

T se rial

T c lk

• 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


ASIC PerformanceASIC Performance

0

0.1

0.2

0.3

0.4

0.5

0.6

0 50000 100000 150000 200000 250000 300000

Input charge (electron)

Ou

tpu

t si

gn

al (

V)

Slope = 15.2 mV/fCENC = 902 29 e’s rms

Linearity Energy Resolution

Peaking Time Measurements

CinMeasurement Simulation

0 pF 73.2 ± 1.4 ns 74.0 ns

12 pF 80.4 ± 1.8 ns 80.0 ns

FWHM = 18%


ASIC PerformanceASIC Performance

Noise

ENCmin= 1117 @ 100 nsCintot = 20 pF

Timing (ZCD)

Noise is dominated by photostatistics contributionExpect ~ 2.4 ns rms total

ENC

elec

tr ons

( RM

S)


ASIC Performance - Timing ResolutionASIC Performance - Timing Resolution

3.54 ns FWHM

6.7 ns FWHM(2.4 ns rms)

LSO+APD vs BaF2+PMT

Electronic Timing Resolutionat 511 keV equivalent energy

Coupled to LSO/APD with 511 keV ’s timed against a BaF2 scintillator w/PMT

Time (ns)-8 -6 -4 -2 0 2 4 6 8

Cou

nts

0

1000

2000

3000

4000

5000

FWHM = 2.47 ns

Same with CFD

Preamp/Shaper + ZCD


Rotatable Stage for Obtaining Partial Tomographic DataRotatable Stage for Obtaining Partial Tomographic Data

Source phantoms mounted on rotatable stage to simulate full

tomographic ring


Point Source ResolutionPoint Source Resolution

1 mm dia 68Ge point sourceat R=1.6 mm in rotation stage

profile axis (mm)2 4 60

im ag e int

en sit

y (ar

b)

0

2

4FWHM = 2.1 mm

Intrinsic spatial resolution measured with 22Na point source (< 1 mm dia)

Average peak FWHM = 1.28 mmConcorde P4 MicroPET = 1.75 mm

UCLA MicroPET = 1.58 mm


Source ImagesSource Images

Single 1 mm dia. 68Ge point source 1.6 mm off axis

2 mm

Multiple 68Ge point sources (~ 2mm) spaced ~ 4 mm

4 mm

4 mm


Modeled Reconstructed ImagesModeled 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


Real Image Reconstruction Real Image Reconstruction

• Small but nearly completely filled field of view • Large parallax error (no DOI information)• Finite pixel size (2x2 mm2) 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) 113-122


Preliminary Studies using MLEM MethodPreliminary Studies using MLEM Method

• 221 voxels (1 mm3) over 17 mm dia image field• 552 sinograms (23 x 24 R)• 121,992 system matrix• 107 photons generated per voxel

Discrete approximations to the RatCAP used with SimSET

Spatial resolution already improved over FBP

1.05

1.1

0 0.2 0.4 0.6

point source distance from the center [cm]

rad

ial

reso

luti

on

[m

m]

Since RatCAP is small, can ultimately handle full system matrix

1.09 mm


Other ApplicationsOther 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 MonitorNon-Invasive Wrist Monitor


Wrist Monitor for Measuring the Arterial Input Function 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 68Ge line source

A.VillaneuvaWrist Phantom


Simulated Input Function Measurement Simulated Input Function Measurement

Measure activity as an aqueous solution of a 11C - labeled radioisotope passes between two block detectors

0

10

20

30

40

50

60

70

80

0 100 200 300 400 500 600 700 800

Scatter Evaluation

Time (seconds)

w/scatter w/o scatter

0

1

2

3

4

5

6

7

8

0 0.5 1 1.5 2 2.5

Measured Input Function

Time (minutes)

Expected input function resolution using Wrist Monitor


SummarySummary

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

Documents

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