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Multimodality In Vivo ImagingSystems: Twice the Power orDouble the Trouble?

Simon R. Cherry

Department of Biomedical Engineering, Center for Molecular and Genomic Imaging, University ofCalifornia, Davis, California 95616; email: [email protected]

Annu. Rev. Biomed. Eng.2006. 8:3562

First published online as aReview in Advance onFebruary 28, 2006

The Annual Review ofBiomedical Engineeringisonline atbioeng.annualreviews.org

doi: 10.1146/annurev.bioeng.8.061505.095728

Copyright c 2006 byAnnual Reviews. All rightsreserved

1523-9829/06/0815-0035$20.00

Key Words

instrumentation, dual-modality, PET/CT, SPECT/CT,PET/MRI

Abstract

Many different types of radiation have been exploited to provide images of the stru

ture and function of tissues inside a living subject. Each imaging modality is charterized by differing resolutions on the spatial and temporal scales, and by a differ

sensitivity for measuring properties related to morphology or function. Combin

tions of imaging modalities that integrate the strengths of two modalities, and at same time eliminate one or more weaknesses of an individual modality, thus offer

prospect of improved diagnostics, therapeutic monitoring, and preclinical resear

using imaging approaches. This review discusses the advantages and challengesdeveloping multimodality imaging systems for in vivo use, highlights some successcombinations that are now routinely used in the clinic and in research, and discus

recent advances in multimodality instrumentation that may offer new opportunit

for imaging.

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Magnetic resonanceimaging (MRI): usesradiofrequency pulses toexcite protons between twoenergy states that are

created when a sample isplaced in a high magneticfield and employs magneticfield gradients to encodeposition and producecross-sectional imagesrelated to proton densityand tissue relaxationproperties

X-ray computedtomography (CT): alsoknown as CAT scans, in

which X-rays are

transmitted through thebody to form tomographicimages related to tissuedensity

Single photon emissioncomputed tomography(SPECT): a nuclearimaging technique thatutilizes a gamma cameraand a collimator to recordimages of the distribution ofradiolabeled molecules in

vivoPositron emissiontomography (PET): anuclear imaging techniquethat measures theconcentration of moleculeslabeled withpositron-emittingradionuclides in vivo

Ultrasound: real-timeimaging technique thatmeasures reflections ofhigh-frequency sound wavesat tissue iterfaces to providestructural information.Using the Doppler effect,ultrasound also can be usedto measure blood flow in

vessels

INTRODUCTION

Invivoimagingisoneoftheprimarytoolsusedtoevaluatestructureandfunctionnon-

invasively in a living subject. Electromagnetic radiation, including radiowaves [mag-netic resonance imaging (MRI)], visible and near-infrared light (optical imaging),

X-rays [X-ray computed tomography (CT)], gamma rays [single photon emission

computed tomography (SPECT)], annihilation photons [positron emission tomog-

raphy (PET)], and high-frequency sound waves, or ultrasound, are all successfullyemployed to interrogate the structure and/or function of tissues (1). In some cases,endogenous contrast may be intrinsic to the body tissues (electron density for CT,

proton density and tissue relaxation times for MRI, acoustic properties of tissue for

ultrasound, intrinsic optical properties of tissue for optical imaging). In many cases,contrast agents, designed to provide or augment the imaging signal, are introduced

into the body. Depending on the modality, these may be radiolabeled probes (PET,SPECT), molecules laden with high Z nuclei (CT), paramagnetic agents (MRI),

acoustically active microbubbles (ultrasound), or fluorescent molecules (optical imag-ing). By exploiting different types of radiation and using different contrast agents, an

enormous variety of parameters can be imaged in vivo, ranging from basic tissue den-

sity with X-rays to specific molecular targets, gene expression, and protein-proteininteractionsusing targeted contrast agents, and in some cases genetically manipulated

cells (24).The reason that several different imaging modalities exist is that they operate

within a defined parameter space that renders them well suited for some applications,while often very poorly suited for other applications. This parameter space generally

is characterized by factors such as spatial resolution, temporal resolution, detection

sensitivity, tissue penetration, signal-to-noise, and quantitative accuracy, with impor-tant considerations also related to issues such as radiation dosimetry (for modalities

employing ionizing radiation), cost and throughput, and contrast agent toxicity. Forexample, a common wish one hears is to have an imaging instrument with the spa-

tial resolution of MRI, the temporal resolution of ultrasound, and the sensitivity ofPET. Looking beyond these basic imaging parameters, it is also clear that each major

imaging modality measures fundamentally different information. Thus X-rays can

provide exquisite structural detail in bone, but optical imaging with fluorescentlylabeled proteins, and using the principles of fluorescent resonance energy transfer

(FRET), would likely be the way to look at protein-protein interactions in vivo. An-other consideration that tips the balance between different modalities is the volume

of the tissue under interrogation. For whole-body human imaging, the penetratingpower of radiofrequency radiation, X-rays and gamma rays, and ultrasound in the

range of 24 MHz is indicated. However, for imaging of isolated and accessible tis-

sues, such as skin, breast, and limbs, or preclinical imaging in small-animal modelssuch as mice and rats, higher frequency ultrasound and optical radiation also become

important players.Because no one imaging modality can provide information on all aspects of struc-

ture and function, an obvious approach is to interrogate a subject using multipleimaging modalities. This is not a new idea. For many decades, patients have been

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moved from one imaging machine to another to obtain data from different imaging

modalities. Initially, information would be analyzed by a simple visual synthesis ofthe image datasets by the physician or researcher. Quickly, powerful image registra-

tion techniques were developed that allowed tomographic data from one imaging

modality to be coregistered with data from the same patient obtained on a differentimaging system (5). This allowed direct overlay of the images and the ability to move

a linked cursor across two 3-D datasets that come from different scanners. These ap-proaches have important practical advantages. Existing equipment is used to capture

the image data, and the two scans can be scheduled at different times to maximize thethroughput on individual scanners. However, there are also clear limitations. First of

all, images are not perfectly registered. In some parts of the body, notably the brain,

misalignments can be very small. The fact that the brain is well approximated by arigid body contained within the skull often allows for accurate registration between

modalities using features in the images themselves, fiducial markers mounted on thebed, or multimodality headholders (5). However, in other parts of the body, organ

shape and location depends critically on how a subject is positioned in the scanner.Some organs can change shape over time (for example, the bladder filling with urine).

Thus, accurate registration becomes far more difficult. Although nonrigid registra-tion approaches have been developed, they are only robust across a certain set ofconditions. The other disadvantage of acquiring sequential scans on two different

scanners is that it is not possible to simultaneously measure two different parametersand correlate time-dependent changes in those parameters. Finally, if two modali-

ties are required, it would be more efficient from the patients perspective to acquirethem simultaneously or at least in rapid succession on a single instrument, rather

than moving a patient from system to system and all the scheduling challenges that

imposes.For these reasons, there has been considerable interest over the past 1015 years

in examining the possibility of building multimodality imaging systems in which two

or more imaging modalities are integrated to a greater or lesser extent into a sin-gle imaging unit. At one end of the spectrum is the concept of taking two imagingscanners and placing them side by side, with perhaps the only integration being a

common patient bed that moves through the system. At the other extreme would be

a fully integrated system with a single set of detectors or sensors that can detect theradiation from two different modalities. In the following sections, the early evolution

of multimodality systems is traced, with an emphasis on PET/CT and SPECT/CTas examples of multimodality systems that have become widely adopted. A selection

of other multimodality approaches will be reviewed, although this will not be a com-prehensive review of all the possible approaches being studied, rather a summary

of those that have particularly interesting or promising features. Finally, some of the

challenges of multimodality imaging are examined andfuture opportunities discussed.The review focuses on imaging systems that combine two or more modalities via a

hardware approach and does not discuss multimodality imaging that is achieved viaimage registration from two completely separate imaging systems, nor the integra-

tion of an imaging modality with other nonimaging instrumentation, such as depth

electrodes, stereotactic biopsies, or delivery of radiotherapy.

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STRUCTURAL-FUNCTIONAL IMAGING WITHPET/CT AND SPECT/CT

Imaging modalities can be divided very roughly into two groups: Those that ex-cel primarily at providing structural information (i.e., CT, MRI, and ultrasound) and

those that excel primarily at providing functional or molecular information (i.e., PET,

SPECT, and optical imaging). Therefore, it is not surprising that much of the effort

in multimodality imaging has been devoted toward integrating one technique fromeach group, thus enabling function and structure to be examined within the sameindividual and at the same time. There are many examples where having both struc-

tural and functional information is critical, for example, in localization of functional

abnormalities prior to localized treatment with surgery or radiation, or, in novel geneor cell-based therapies, determining the location within the body of therapeutic cells

or gene products.The most concerted efforts have been in integrating one of the nuclear medicine

techniques (PET or SPECT) with CT (6, 7). Both methods use high-energy electro-magneticphotons;inthecaseofCT,thesephotonsareusedintransmissionmodewith

an external source, in nuclear medicine a radioactive probe is injected into the patient

resulting in internal emission of the photons. PET/CT and SPECT/CT whole-bodyimaging systems arecommerciallyavailable andhave been widelyadopted,andsimilar

approaches are being developed for preclinical imaging in small-animal models andfor breast cancer imaging. The development of these systems was based on the mo-

tivation of providing anatomical localization of nuclear medicine radiotracer uptake,especially outside the brain, where the elastic transformations required to register

datasets from two separate scanners and imaging geometries are of limited accuracy.

Nowhere has this been more important than in oncologic applications (8), where thelocation (determined by CT) of suspicious lesions (determined by high radiotracer

uptake) is key to diagnosis and patient staging. In hindsight, it seems such an obviouscombination, yet it took roughly 30 years of development before the concept was

embraced. Some of the key developments and ideas are introduced below.

Emission/Transmission Imaging with Radionuclide Sources

Some form of transmission scanning has been incorporated into nuclear medicine

imaging for well over 35 years (9). Initially, the goal of transmission scanning was toprovide information on the body contours to help determine the location of radio-

tracer accumulation on 2-D projection images. Thus, approaches that utilized the

existing nuclear medicine detector system, usually a gamma camera, together with anexternal radionuclide transmission source, were implemented (1012). With the de-

velopment of the tomographic techniques of PET and SPECT in the 1970s, the roleof the transmission scan was extended to that of providing the information necessary

to correct the nuclear medicine images for the depth-dependent attenuation of theemission photons (1315). A range of different radionuclide sources and geometries

was investigated to optimize the overall quality and accuracy of the transmission scan

(9).

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Figure 1

Transmission image at level of thorax obtained with an external radionuclide source on agamma camera (left). Image courtesy of Dr. Freek Beekman, Utrecht University, The

Netherlands. X-ray CT scan of thorax (right). Image courtesy of G.E. Healthcare. Note betterspatial resolution, signal-to-noise ratio, and soft tissue contrast obtained with dedicated CTsystem.

The quality of the transmission or structural images that can be obtained with anexternal radionuclide source is relatively poor for a number of reasons (Figure 1).

Nuclear medicine imaging systems operate in pulse mode (i.e., each event is han-dled individually) because pulse-height information is important in rejecting scatter

radiation, and in PET, each photon must be analyzed to see if it meets the timecoincidence criterion. Thus the flux of radiation that can be handled by the elec-

tronics is relatively low, and hence the counting statistics are limited. Furthermore,the external radionuclide source usually is of an energy comparable to the emissionphoton energy (so that it can be used for photon attenuation correction), but at these

energies, soft tissue contrast is poor. Last, the resolution of most nuclear medicinedetector systems is on the order of several millimeters, thus limiting the resolution of

the transmission image to similar values. Therefore, despite a huge effort to optimize

transmission scanning with an external radionuclide source, the primary role of thetransmission data in recent times has been for attenuation correction and improved

quantification of nuclear medicine studies, and the transmission scan is rarely, if ever,used as a diagnostic tool on its own merits.

Early Combined X-Ray and Nuclear Medicine Imaging Systems

Hasegawa and his colleagues at the University of California, San Francisco, were thefirst group to develop a simultaneous emission/transmission system that incorporated

an X-ray tube for the transmission component and had the explicit goal of producing

high-quality structural information (7). In the early 1990s, they developed a system


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Figure 2

Images of the thorax and myocardium of a pig obtained from a high-purity germaniumdetector system developed at UCSF and capable of simultaneous SPECT and CT imaging.Reprinted with permission from Reference 18.

based on a linear array of high purity germanium detectors (HPGe) that were used tosimultaneously detect both the 100200 keV emission gamma rays from an injectedradiotracer, andthe transmitted X-raysfrom a low-power120 kVpX-raytube (16, 17).

Because the detector operated in pulse mode, processing the signal from each photon

interaction one at a time, only limited X-ray flux could be utilized. Nonetheless, theimage quality for anatomic imaging was dramatically improved, and this represents

the first true example of dual modality imaging (Figure 2). It is also one of the fewexamples of a truly integrated (rather than combined) imaging systemin which a single

detector system is used for both imaging modalities. The system was used primarily toperform highly quantitative studies in cardiovascular and oncology models in large-

animal models (18). It was never translated into clinical use, primarily owing to the

high cost of the large volume of HPGe or other semiconductor detectors that wouldbe required for human imaging.

Because of the difficulty of designing detector/electronic systems that can handlethe huge X-ray flux in pulse mode, the focus rapidly moved away from a single de-

tector system to the idea of integrating two separate detector systems, one optimizedfor X-ray imaging, the other for nuclear medicine imaging. In its simplest forms, this

involved placing a PETor SPECT scanner immediately adjacent to a CT scanner and

designing a common patient bed that could move through the two systems. This verypractical approach to dual-modality imaging does not permit simultaneous PET/CT

or SPECT/CT, but it involves absolutely no compromise in the image quality ob-tained from either system. Early prototype systems were developed by Hasegawa

and colleagues (SPECT/CT) (19) and by Townsend in collaboration with CTI, Inc.(PET/CT) (8), and they quickly demonstrated the combined power of these imag-

ing modalities for clinical cancer imaging (20, 21) and for improved quantification

of nuclear medicine research studies (2224). Commercial implementation rapidlyfollowed (2527), and at the present time, PET/CT and SPECT/CT are the fastest

growing areas in medical imaging instrumentation.

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Clinical Whole-Body PET/CT and SPECT/CT

All commercial systems today are based on the tandem approach described above

(28), where twoseparate imaging systems are combined in a single housing, andwherethe integration occurs at the level of the patient bed, with sophisticated software that

integrates data acquisition, image reconstruction, data correction, image quantifica-

tion, and image display between the two modalities. For example, one synergistic

application of the two modalities is the use of the CT data to correct for photonattenuation in the PET or SPECT study (29). Photons emitted from a radionuclidedeep inside the body are more likely to be absorbed or scattered prior to reaching an

external detector system than photons emitted at a shallower site, and therefore quan-

titative nuclear imaging requires correction for this depth-dependent attenuation ofphotons. The CT scan shows the attenuation properties of the tissue averaged over

the spectrum of X-ray energies used; however, the use of this data for attenuationcorrection of the PET or SPECT dataset is not as trivial as one might think. CT

data are inherently polyenergetic, whereas the photons emitted from radionuclidesin PET and SPECT are monoenergetic, and often are higher in energy than the

maximum X-ray energy generated by the X-ray tube. Thus, the linear attenuation

coefficients (values) of different tissues at the energies of the radionuclide photonscannot be simply derived from information in the CT scans. Simple segmentation

approaches have limitations because of the continuous nature of the-value distribu-tion in a patient (29). Approaches to map from CT-derived energy-averaged values

to values appropriate for attenuation correction of PET or SPECT data arising frommonoenergetic photons have therefore been developed (30, 31). These methods have

largely been successful; although, as discussed later, in the presence of CT contrast

agents and implanted metallic objects, problems may occur (29, 32). Dual-energyX-ray imaging can be used to unambiguously scale values across energies for low-

Z materials (33); however, this increases the complexity (and possibly the dose) ofthe CT imaging component. Whichever method is used, one must also take care to

match the spatial resolution of the CT-derived attenuation correction data to that of

the PET or SPECT emission data, otherwise artifacts may occur at tissue boundariesthat relate to differences in the spatial resolution of the two imaging techniques (34).

Once the appropriate values are computed, the CT data may also be used as theinput for modeling and correcting the distribution of Compton-scattered photons in

PET and SPECT.In addition to providing the anatomic context for radiotracer signals, and CT-

based attenuation and scatter correction of PET and SPECT images, there are

other, admittedly challenging, opportunities for synergistic use of PET/CT andSPECT/CT datasets. A major problem in the quantification of radiotracer uptake in

tissues of interest is the partial volume effect, which comes into play for structuressmaller than about three times the spatial resolution of the PET or SPECT images

(35). Radiotracer uptake can be severely underestimated in hot spots (for example,accumulation of a radiopharmaceutical in a small tumor) or overestimated in cold

spots (for example, a perfusion deficit in heart muscle) owing to this effect. Because

the CT images are obtained at considerably higher spatial resolution than the nuclearmedicine images (typically 1 mm or better versus >4 mm for PET or SPECT), the


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dimensions of organs, lesions, and other structures, assuming there is sufficient con-

trast, can be accurately determined from the CT images. With knowledge of the sizeand geometry of structures of interest, it may be possible to improve quantification of

radiotracer uptake within that structure (22, 36), especially in cases where the geom-

etry is quite simple and the background radiotracer distribution outside the structureof interest is low, or at least uniform. A secondopportunity that remains to be carefully

studied and exploited is the integrated reconstruction of the two datasets. Currently,the PET and CT datasets are each reconstructed independently. Thus, no prior in-

formation regarding possible correlation and colocation of structural and functionalinformation is taken into account. Because structure andfunctionoftenare correlated,

this association could be used to reconstruct one dataset based on information in the

other (e.g., use the CT image as a constraint for the PET or SPECT reconstruc-tion to encourage the reconstruction of the radiotracer distribution to correlate with

anatomical boundaries) (3743). An extension of this approach would be to recon-struct both datasets simultaneously with structure informing function and vice versa.

The obvious objection to these approaches is that there are cases where the relation-ship between structure and function either does not exist or it breaks down owing to

some pathological process. Therefore, the correlation between the two forms of datamust be achieved in a probabilistic fashion, with deviations permitted if the data donot support the anticipated correlation. Clearly, developing robust and generalizable

algorithms that incorporate these ideas is very challenging; nonetheless, there maybe very specific applications where robust approaches could be developed and where

integrated image reconstruction may improve diagnostic accuracy or quantificationof PET or SPECT data.

Whole-body PET/CT and SPECT/CT systems have revolutionized nuclear

medicine imaging, especially in oncology, where hot spots with suspiciously enhanceduptake of a tumor-seeking radiotracer can now be accurately localized and correlated

with anatomy. An example of a contemporary PET/CT scan is shown in Figure 3.

Despite the clear success of these multimodality systems, plentyof questionsandchal-lenges remain. One obvious difficulty is caused by various forms of patient motion.Because of the often lengthy duration of the PET or SPECT studies (typically tens of

minutes), it is quite possible that patients may move at some point during the study.

There are methods for detecting motion, but correction generally requires the use ofelastic software techniques that have their limitations, one of the reasons these mul-

timodality imaging systems were developed in the first place. Internal motion, suchas filling of the bladder and bowel motion that occur during the scanning period, is

particularly difficult to deal with and can lead to significant misregistration of imagesin these regions. The best way in which to reduce these problems is to speed up the

PET or SPECT study such that the entire study can be acquired in a few minutes.

The second form of motion is due to the cardiac and respiratory cycles. With fast CTscanners, the standard imaging protocol when imaging the thorax is to acquire data

while the patient holds their breath at maximum inspiration, thus effectively elim-inating respiratory motion. However, the PET or SPECT data are acquired over

many respiratory cycles, and therefore are blurred by the respiratory motion. Not

only does this cause problems in interpreting dual modality data in the region of the

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Figure 3

Whole-body PET and CT images from a multimodality PET/CT system. The center imageshows the 18F-fluorodeoxyglucose PET scan in which image intensity is reflective of glucosemetabolism. A large, metabolically active tumor is easily visualized. The right-hand imageshows a fusion of the PET and CT images allowing accurate localization of the tumor. Imagescourtesy of Dr. Cameron Foster and Dr. Ramsey Badawi, UC Davis Medical Center, Davis,California.

diaphragm but it also can cause significant artifacts in PET or SPECT images of the

heart, lungs, and liver owing to errors in the attenuation correction (32, 44, 45). Forexample, portions of the heart (especially the apex) in the respiration-averaged PET

or SPECT dataset appear to be located in the lung in the breath-hold CT image, andare therefore undercorrected for photon attenuation. This can lead to the appearance

of apical defects that could be mistaken for pathology. The best match of the CT and

PET/SPECT data appears to occur when the CT is acquired using a breath holdat end expiration (46, 47); however, this may not be possible for all patients because

it is considerably more difficult than a deep inspiration breath-hold protocol. Onepossible solution to respiratory motion is to gate the PET or SPECT studies to the

respiratory cycle (48); however, this results in a significant fraction of the data beingrejected and a significant increase in imaging time for the same signal-to-noise level.

Another approach is to acquire the CT data over the entire respiratory cycle so that

it is blurred to match the PET or SPECT data; however, this can obviously impactthe diagnostic quality of the CT scan. Clearly, motion correction at all levels remains

a critical area of research for multimodality PET/CT and SPECT/CT imaging.


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A second challenge relates to imaging when the attenuation values in the CT scan

are perturbed by a foreign entity. One class of such studies is in cardiac imaging ofpatients with implanted devices such as pacemakers and defibrillators (49). Another

problematic area is imaging in the presence of high-Z orthopedic and dental prosthe-

ses (50, 51). High-Z materials can cause beam hardening artifacts in the CT imagesthat can be propagated, via the attenuation correction, into the PET or SPECT im-

ages. They also create problems in the mapping ofvalues from CT energies (wherephotoelectric interactions are dominant in high-Z materials) to PET or SPECT en-

ergies (where Compton scatter is often the dominant mechanism). The magnitude ofthese effects vary depending on exactly how the attenuation correction is derived from

the CT data, but may be reduced by appropriate precorrection of the CT images. A

second, more common class of studies are those in which some form of CT contrastagent is employed. The contrast agent changes the attenuation coefficients in the CT

scan in a concentration and time-dependent fashion and dramatically complicatesthe mapping of attenuation values between different energies (5254). Once again,

the magnitude of these effects depends on the exact conditions of the study and themethod used to derive the PET/SPECT attenuation coefficients from the CT data

(5355).One final challenge relates to the relatively small transverse field of view found in

the CT components of most dual-modality imaging systems. A field of view diameter

is 50 cm, which in large patients, with their arms down (positioning typically usedfor lengthy dual modality studies) often leads to truncation of the arms, and occa-

sionally in the abdomen. For CT alone, there are methods for minimizing truncationartifacts in reconstructed images (56, 57). But when the CT is used for attenuation

correction of PET or SPECT data, it becomes a more difficult problem because the

truncated tissue needs to be accounted for. This can only be corrected by estimat-ing the missing tissue based on an extrapolation of the patient boundaries from the

available information (58).

Dual Modality Systems for Breast Cancer Imaging

Another area that hasreceived considerable attention, buthasyetto make a significant

clinical impact, is the combination of nuclear and X-ray imaging for the detectionand management of breast cancer. A variety of approaches are being investigated,

including incorporating gamma ray detectors into a mammography unit (5961), in-tegrating PET detectors into a biopsy unit (62), and combined emission/transmission

mammotomography systems (63). We are also involved in a project to develop a dedi-

cated breast PET/CT scanner building on the platform of existing breast CT scanner(64) and breast PET scanner (65) prototypes.

The general goal of these approaches is to utilize the uptake of tumor-avid ortumor-specific radiotracers to help improve the specificity of X-ray mammography

for classifying benign versus malignant lesions, and to base biopsy sites on bothfunctional and structural information. Figure 4 shows an example of a mammogram

and a positron emission mammography image taken from a combined system. A

further role for such technology might be in monitoring response to neoadjuvant

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Figure 5

Simultaneously acquiredPET and CT imagesshowing distribution of18F-fluoride ion in amouse. Reprinted withpermission from

Reference 72.

Scintillator: a material thatpromptly releases visiblelight when excited by

ionizing radiation such asX-rays and gamma rays

Lutetium oxyorthosilicate(LSO): a dense, fast, andrelatively bright scintillatorused in PET systems

X-ray photons and the nuclear medicine photons, especially for PET/CT imaging,

allowing them to be discriminated quite easily from each other. Furthermore, unlike

clinical CT with a rapidly rotating scanner and a high-powered X-ray tube, small-animal CT employs a relatively slow rotation and it often takes minutes to acquire a

complete dataset of a mouse. Therefore, acquisition times for PET and CT can bequite similar, and there may be advantages to simultaneously acquiring the PET and

CT datasets. This can be achieved relatively easily in a coplanar imaging system withsome minor shielding of the PET detectors to prevent X-rays from entering the PET

detectors (72). Simultaneously acquired PET and CT images of a mouse taken with

such a system are shown in Figure 5.Another advanced concept under development is a single detector and electronics

system that can be used for both X-ray and nuclear medicine imaging. High lumi-nosity scintillators, such as lutetium oxyorthosilicate (LSO), or stacks of different

scintillators (73), are combined with fast digitizers and digital electronics that canprocess up to 1 million X-rays per detector element per second in CT mode. Thus

CT and PET or SPECT data could be acquired in rapid succession using just a singledetection system (74).

The main reason that in vivo microCT systems predominantly use a low-power

X-ray tube and a slowly rotating gantry is one of practicality. It keeps the cost low.But there would be clear scientific advantages to having a high-powered X-ray tube

mounted on slip-ring technology for fast dynamic CT imaging. Such a system hasbeen developed (75), but its cost and size (even without dual-modality capability)

may limit its installation to large research institutions and companies. One important

challenge therefore is to find a way to build a fast, compact, and relatively low-cost PET/CT or SPECT/CT system that is consistent with the broader preclinical

research environment.

INTEGRATION OF PET AND MRI SYSTEMS

The idea of combining one of the nuclear medicine modalities with magnetic res-

onance imaging and spectroscopy is tantalizing in that this combination of modal-

ities might find ways to take advantage of the high spatial resolution and excellent

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Photomultiplier tube(PMT): a vacuum tube

with a photocathode thatconverts visible light into

electrons and amplifies thnumber of electrons by afactor of 106 to 107. Widused in PET and SPECTsystems

morphologic discrimination of MRI and the exquisite sensitivity of nuclear imaging,

in both preclinical and clinical imaging (6). Furthermore, one can consider the possi-bilities of integrating more advanced MR measurements, such as dynamic contrast-

enhanced MR, diffusion-tensor imaging,functional MRI,MR spectroscopic imaging,

neuronal tract tracing, cell trafficking, and paramagnetic contrast agents, with tracerkinetic experiments utilizing essentially massless radiolabeled probes that are targeted

to specific aspects of the biology of interest. Although clinical applications of suchtechnology are not immediately clear, especially when one considers that the cost

of a combined instrument is likely to be high, there are surely interesting researchquestions that could be addressed with a multimodality system, especially if the MR

and nuclear data can be acquired in a simultaneous or rapidly interleaved fashion,

allowing direct temporal correlation of the MR and nuclear signals during or follow-ing some form of therapeutic intervention. Such applications could not be addressed

using scans acquired at separate times on separate machines that are subsequentlyregistered by software.

The challenges in integrating nuclear and magnetic resonance imaging are fargreater than for the integration of nuclear imaging and X-ray imaging discussed

previously, as there are several ways in which the two imaging systems can interactand interfere with each other, causing major artifacts and a serious degradation inimage quality. Some of the primary issues to be considered are maintaining the ho-

mogeneity of the B0 field and the linearity of the gradient fields in the MR system,avoiding radiofrequency interference between the MR transmit/receive coils and the

electronics of the nuclear imaging system, susceptibility artifacts and eddy currentsrelated to the placement of materials inside the MR magnet, and the effect of the

magnetic field (both the static and switching gradient fields) on the nuclear imaging

system. Magnetic field effects are particularly problematic for detector systems basedon photomultiplier tubes (PMTs) that are highly sensitive to magnetic fields owing

to their impact on electron trajectories inside the vacuum of the PMT.

Despite these challenges, significant progress has been made over the past 15years. It is interesting to note that nobody has yet explored the simplest approach tothis problem, namely placing two separate imaging systems back to back with some

moderate shielding of the nuclear system to allow the PMTs to operate satisfactorily,

in analogy to the clinical PET-CT approaches. Instead, researchers have generallyfocused on methods to integrate the nuclear imaging system inside, or as part of,

the MR system. Because of the inherent need for a bulky, high-Z collimator andmoving parts to obtain SPECT images, the focus has been almost exclusively on the

combination of PET and MRI.The earliest motivation for combining PET with MRI was not driven by a desire

to make complementary measurements but rather to use the strong magnet of the

MRI system to help restrict the range of the positrons prior to annihilation (7679). Positrons are positively charged particles and therefore they will spiral around

the magnetic field lines, reducing their range (the distance traveled before they an-nihilate with an electron and produce the two back-to-back 511 keV photons that

are imaged) in two of the three spatial dimensions. Because positron range is one

factor that can limit the spatial resolution of PET imaging, especially when using


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Avalanche photodiode(APD): a silicon detectorthat converts visible lightinto charge carriers and

then amplifies them with again of 102103

radionuclides that emit relatively high-energy positrons (>1 MeV), this could lead to

improvements in spatial resolution. Simulations and measurements clearly demon-strated that field strengths in the range of 410 T could significantly reduce positron

range effects for several radionuclides of medical interest (76, 79). This would have

most impact for very high-resolutionsmall-animal studies usinghigh-energy positronemitters, such as 124Iand 15O,wherepositronrangestartstobecomeadominantfactor

(80). It is unusual in any clinical studies for positron range to be the limiting factor,rather, overall study statistics and photon noncolinearity tend to be the dominant

effects.In themid 1990s, interest grew in building systems that could acquire both MR and

PET images. In collaboration withMarsden andcolleagues at Kings College London,

we developed a series of simple MRI-compatible PET inserts to demonstrate thatsimultaneous PET and MR measurements were indeed possible (8183). The most

sophisticated of the prototypes (82) consisted of a ring of 72 small LSO scintillatorcrystals,coupled by 4-m-longoptical fibersto multichannel PMTs andelectronics that

were placed outside the magnet. This system was used for simultaneous FDG PETand spin echo MRI studies in vivo (Figure 6), simultaneous FDG PET and NMR

spectroscopy in an isolated, perfused rat heart preparation (84), and to assess artifactsin dual modality imaging at field strengths from 1.0 to 7.4 T (83). Although the systemproduced images, there were serious compromises in the PET performance owing

to the limited number of detectors that restricted the sensitivity to approximately0.03%.Scalingupthedesigntoreachthesensitivityofstate-of-the-artanimalimaging

systems, or to the size of a human imaging system, was deemed impractical owing tothe very large volume of optical fibers and the lack of space within the magnet bore

to accommodate those fibers.

There has been a series of recent developments in PET/MRI related to theavailability of improved semiconductor light sensors, namely avalanche photodiodes

(APDs). These sensors are very thin, and because of the high internal electric field

and the short transit distances of the charge carriers, they are quite immune to highmagnetic fields. This allows them to be placed inside a magnet and to operate quitenormally (85). A number of groups are now exploring the development of PET

inserts, both for animal and clinical imaging, that employ APD-based PET detec-

tors. The challenges related to interference of the systems outlined above still exist,and are actually harder given that the photodetector now resides inside the magnet;

nonetheless, by careful design of the detectors,electronics, andshielding, high-qualitypreliminary results have been obtained, as shown in Figure 7. At least three groups

(Siemens; University of Tubingen; and University of California, Davis) are currentlydeveloping APD-based PET inserts for MRI systems, so within the next 12 years,

the success or shortcomings of this approach should become clear.

A completely different approach is being taken at the University of Cambridge(86), where a novel split coil magnethasbeen designed in which a ring of conventional

PMT/fiber-optic-based detectors is placed in the gap of the MRI system (Figure 8).This allows a large number of PET detectors to be placed within the imaging field of

view, without the need to bring the fiber-optics out through the bore of the magnet.

This system is currently under construction.

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Figure 6

(a) Photograph of prototype MR-compatible PET system based on a small ring of scintillatorcrystals coupled via 4-m-long optical fibers to PMTs and electronics. (b) Close-up view ofscintillator ring. (c) Photograph of PET system inside clinical 1.5 T MRI system.(d) Simultaneous in vivo imaging with spin echo MRI and 18F-fluorodeoxyglucose (FDG)PET in a rat, showing registered cross-sectional images through the head. FDG uptake inmuscle and brain is particularly prominent.

Clearly, integrated PET/MRI imaging systems are at a very early stage of devel-

opment, yet there are encouraging signs that the new generation of systems will be

undergoing evaluation in the near future. The optimal design for PET/MRI systemsultimately will be dictated by the applications. Whether simultaneous PET and MR

imaging are required, whether PET is being performed in conjunction with advanced

MR techniques that have particularly stringent pulse-sequence and field homogene-ity requirements, and the compromise in performance one is able to accept in the

integrated system in comparison with two independent dedicated instruments willdrive future designs. For PET/MRI to become more than a scientific curiosity, and

to share in thesuccess of PET/CT or SPECT/CT, it will be critical to define scientificand clinical applications that uniquely require the integrated system.


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Figure 8

Schematic illustration of a 1 T split-coil MR magnet with a ring of PET scintillator detectors(blue), coupled by fiber-optics to photomultiplier tubes, inserted into the room temperaturegap. Image courtesy of Dr. Adrian Carpenter, Wolfson Brain Imaging Center, University ofCambridge, United Kingdom.

SELECTED OTHER MULTIMODALITY IMAGING SYSTEMS

Integrating Optical Imaging with Radiologic Imaging Modalities

Optical imaging is the most widely utilized modality for preclinical molecular imag-

ing, due in large part to easy accessibility of fluorescent probes and bioluminescentand fluorescent reporter proteins (87, 88). Until recently, optical imaging in small

animal models was largely confined to qualitative or semiquantitative 2-D imagingof the light distribution reaching the surface of the animal. Several groups have been

making excellent progress toward quantitative 3-D optical (89) fluorescence (90, 91)and bioluminescence tomography (92, 93). A related method, diffuse optical tomog-

raphy, is also being pursued for clinical applications, especially for breast imaging and

neonatal brain imaging (94).


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Owing to the limited anatomic information obtained from photons emitted at

depth inside tissue, there is interest in combining optical systems with other modali-ties, such as CT, MRI, and ultrasound, that provide high-resolution structural infor-

mation. An example of this is the work of Ntziachristos et al., in which a fiber-optically

coupled near-infrared imager was placed in the bore of a 1.5 T MR system for con-current MRI and optical imaging. The system was used for contrast-enhanced diffuse

optical tomography of thebreast(95) andto perform MR-guidedoptical spectroscopyin breast lesions (96). Anatomic information also is being used as a constraint in al-

gorithms for 3-D optical tomography (97, 98), and these approaches would benefitfrom dual modality optical/structural imaging systems.

Research is under way to couple optical imaging with PET and SPECT to allow

multimodal functional and molecular imaging. Chatziioannou et al. have been in-vestigating detector designs that are capable of detecting the faint bioluminescence

signals from luciferase reporter genes and can also efficiently convert the 511 keVannihilation photons emitted from PET radiotracers into light utilizing transparent

scintillators (99). The goal is to develop a single detector system that could be uti-lized for optical and PET imaging. This could allow, for example, the expression of

two reporter genes to be monitored at the same time, or other novel approaches todissecting molecular pathways and interactions.

While not strictly multimodality imaging, laser-induced photoacoustic tomogra-

phy shows promise as an in vivo imaging tool. It combines optical excitation of tissueusing a fast laser, with ultrasound detection of the photoacoustic waves produced by

laser-induced thermoelastic expansion of the tissue. Photoacoustic approaches canlead to large improvements in spatial resolution over conventional optical imaging

deep inside tissue, and improvements in contrast and a reduction in noise compared

with conventional ultrasound imaging. Both structural and functional in vivo imaginghave been accomplished with this technique (100).

Brain Mapping with Simultaneous fMRI and High-Density EEG

Functional MRI (fMRI) is widely used to study the hemodynamic consequences oftask or event-related neuronal activation, providing high spatial resolution localiza-

tion of these events, but on a relatively slow timescale (seconds). Monitoring the brainsurface with high-density electroencephalography (EEG) or magnetoencephalogra-

phy provides high temporal resolution (milliseconds); however, the electromagneticfields mapped at the surface of the brain cannot unambiguously be reconstructed to

provide the 3-D location of the sources of these fields within the brain without using

constraints or additional information (101). There is clearly value, therefore, in com-bining these techniques, and it is now possible to simultaneously and continuously

record EEG information within a magnet during the acquisition of fMRI data (102).Combining the high temporal but low spatial resolution EEG surface maps, with

the high spatial but low temporal resolution volumetric fMRI data, provide highlycomplementary data that is critical in understanding neural circuitry and pathways.

Although many of the technical challenges of combined fMRI/EEG imaging have

been solved, there still remain many questions regarding how best to design the study

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Sodium iodide [NaI(Tla bright scintillator widelused in gamma cameras aSPECT systems

protocols and analyze the resulting data to extract the maximum information possible

from these studies.

Combined PET/SPECT Systems

Although PET and SPECT provide similar functional and molecular imaging capa-

bilities, and would therefore perhaps not seem like good candidates for multimodalityimaging systems, they are both to a certain extent limited by the availability of ra-

diotracers, especially at sites that do not have extensive radiochemistry facilities. Forexample, SPECT does not have the equivalent of fluorodeoxyglucose, a widely appli-

cable metabolic marker, whereas PET does not have a high-quality perfusion agent

that can easily be distributed. Another problem for PET is that only one radiotracercan be imaged at a time. Dual tracer studies are not possible because the energy of the

photons emitted (511 keV) is independent of the radionuclide used. Thus, to maketwo measurements simultaneously requires that PET be combined with a second

modality.In small-animal molecular imaging and clinical imaging, one wants to take ad-

vantage of the entire complement of available radiotracers, whether they be labeledwith a positron-emitting or single gamma-emitting radionuclide, and hence a singleinstrument capable of PET and SPECT would be of value if the performance of the

individual systems is maintained and the cost of the multimodality instrument is lessthan the cost of the two individual instruments. For clinical imaging, there was a

trend in the 1990s of taking multiheaded gamma cameras designed for SPECT andadding coincidence circuitry between the two heads to permit PET imaging (103).

However, the quality of the PET datasets was limited by the count-rate performance

of the large-area gamma camera detectors, and the relatively low efficiency of thedetector heads for the high-energy 511 keV photon emissions of positron-emitting

radionuclides (104). More recently, a prototype PET/SPECT imaging system has

been developed with the goal of not compromising either PET or SPECT per-formance. The detectors are based on two layers of scintillator: a layer of NaI(Tl)scintillators, primarily to detect the lower-energy single photons from SPECT ra-

dionuclides, such as 201Tl and 99mTc, and a layer of LSO scintillator, primarily to

detect the higher-energy 511 keV annihilation photons for PET (105). For small-animal imaging, a multihead PET/SPECT system based on a scintillator known as

YAP has been developed and undergone initial evaluation (106). This system can beconfigured to acquire SPECT only, PET only, or both modalities simultaneously.

This system would be unique in allowing a PET radiotracer to be imaged at the same

time as a SPECT radiotracer, allowing two aspects of biologic function to be assessedsimultaneously.

CONCLUSIONS AND FUTURE DIRECTIONS

The goal of multimodality imaging systems, whether consisting of a simple combi-

nation of two separate imaging devices or the complete integration of two modalities

at the level of the detectors, electronics and software, should be to provide unique


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or enhanced information that impacts clinical diagnostics or scientific research. One

would like to avoid compromising the image quality obtained from either device,but when this is not possible, it becomes necessary that the multimodality system

provide some added value that is significant enough to overcome the deficiencies of

the combined system.Naturally, because of this requirement, a lot of the emphasis in multimodality

imaging research is on system design and data corrections that minimize any inter-ference or other undesirable consequences of bringing two systems together. From

the work cited in this article, it is evident that a great deal has been achieved in thisregard, although many challenges remain. As multimodality imaging systems start to

mature, the research focus will shift (and in some cases this has already happened) to

working out how to make the best use of the two complementary datasets to informthe user of the location, quantitative magnitude, and the time course of the signals of

interest.A development that will likely impact multimodality imaging instrumentation is

the rapid development in multimodality contrast agents (107, 108) and reporter genes(109). The ability to label molecules, cells, and targeted microbubbles or nanopar-

ticles in a generic and combinable fashion with radioactive, fluorescent, magnetic,or acoustic tags and the advent of multimodal reporter genes all auger well for thefuture of multimodality imaging systems. One can imagine powerful approaches to

understanding the distribution and kinetics of molecules, drugs, therapeutic cells, andgenes in vivo utilizing a combination of imaging modalities that are able to visualize

the same labeled entity with differing spatial, temporal, and sensitivity scales.Finally, there are two areas in which important developments are likely to occur.

In the clinical imaging arena, the integration of multimodality functional/structural

imaging with therapeutics (whether radiotherapy, cell or gene-based therapies, orconventional drug-based therapies) will continue to grow. If the dream of patient-

specific treatment is to become a reality, imaging will play a key role in predicting

which therapies to use (for example, by determining which molecular target or path-way is involved in a particular patient), in planning therapies (for example, definingtarget volumes for radiotherapy based on a functional measure coregistered with

anatomy), and in monitoring therapies (for example, determining the location and

number of functional therapeutic cells in the days, weeks, and months followingtreatment). At the other end of the spectrum, in the growing field of imaging ani-

mal models of disease and developing molecular imaging strategies, there is a criticalneed to correlate in vivo imaging with ex vivo imaging from histopathology, autora-

diography, and other high-resolution techniques. There is at present a paucity ofapproaches for registering excised biopsy or postmortem tissue with its exact location

in an in vivo imaging study, and such tools will be critical in correlating changes at the

cellular level with those observed at the more macroscopic tissue level using in vivowhole-body imaging approaches. An early attempt at bridging the divide between in

vivo and ex vivo imaging is the work of Humm et al. (110, 111).The field of multimodality imaging has clearly flourished over the past 15 years,

driven by the realization that different imaging modalities offer uniquely different

perspectives on their biological subjects, and by the development and increasing

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clinical relevance of physiologic, metabolic, and molecular imaging studies that de-

mand multimodality approaches to correlate function and structure. The field alsohas been enabled by a growing group of interdisciplinary imaging scientists who have

spurned a modality-centric ethos for an application-driven approach to imaging. Sig-

nificant improvements surely are ahead of us, but it is already clear that 1 + 1 can addup to more than 2 when it comes to multimodality imaging systems.

SUMMARY

1. Multimodality imaging systems should provide important scientific or di-agnostic information not readily attainable using two separate imaging sys-

tems, and where possible, the performance of each imaging system shouldbe preserved.

2. Multimodality imaging systems are being developed for clinical applications

(e.g., diagnostics and for clinical trials of new therapeutics) and for preclin-

ical applications (e.g., drug development, evaluating cell and gene-basedtherapies, and new molecular imaging assays).

3. The combination of structural and functional/molecular imaging tech-

niques, especially PET/CT and SPECT/CT, is the most successful exampleof multimodality imaging systems to date. The combination of PET and

MRI offers tantalizing opportunities, but also significant challenges.

4. There are relatively few examples of truly integrated multimodality imaging

systems in which a single system of detectors and electronics is used for twodifferent modalities. In most cases, two separate instruments are placed in

close proximity and integrated primarily through software.

5. Multimodality imaging systems are commercially available, and their range

of applications is growing rapidly. Numerous opportunities exist to improve

existing multimodalityimaging systems, and to develop new combinations ofmodalities. Opportunities also exist forbetter useof thedata being generatedby existing systems, especially in terms of the reconstruction of tomographic

images and quantitative evaluation of those images.

DISCLOSURE STATEMENT

S.C. is a paid consultant with CTI Concorde/Siemens.

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Annual Revie

of Biomedica

Engineering

Volume 8, 200

Contents

Fluorescence Molecular Imaging

Vasilis Ntziachristos p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 1

Multimodality In Vivo Imaging Systems: Twice the Power

or Double the Trouble?

Simon R. Cherry p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 35

Bioimpedance Tomography (Electrical Impedance Tomography)

R.H. Bayfordp p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p

63

Analysis of Inflammation

Geert W. Schmid-Schnbein p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 93

Drug-Eluting Bioresorbable Stents for Various Applications

Meital Zilberman and Robert C. Eberhart p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 153

Glycomics Approach to Structure-Function Relationships

of Glycosaminoglycans

Ram Sasisekharan, Rahul Raman, and Vikas Prabhakar p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 181

Mathematical Modeling of Tumor-Induced AngiogenesisM.A.J. Chaplain, S.R. McDougall, and A.R.A. Anderson p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 233

Mechanism and Dynamics of Cadherin Adhesion

Deborah Leckband and Anil Prakasam p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 259

Microvascular Perspective of Oxygen-Carrying and -Noncarrying

Blood Substitutes

Marcos Intaglietta, Pedro Cabrales, and Amy G. Tsai p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 289

Polymersomes

Dennis E. Discher and Fariyal Ahmed p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 323

Recent Approaches to Intracellular Delivery of Drugs and DNA

and Organelle Targeting

Vladimir P. Torchilin p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 343

Running Interference: Prospects and Obstacles to Using Small

Interfering RNAs as Small Molecule Drugs

Derek M. Dykxhoorn and Judy Lieberman p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 377

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