Hybrid Imaging Instrumentation and Data Processing

REVIEW
published: 18 May 2018

doi: 10.3389/fphy.2018.00047
Hybrid Imaging: Instrumentation and

Data Processing
Jacobo Cal-Gonzalez 1*, Ivo Rausch 1 , Lalith K. Shiyam Sundar 1 , Martin L. Lassen 1 ,
Otto Muzik 2 , Ewald Moser 1,3 , Laszlo Papp 1 and Thomas Beyer 1
1
QIMP Team, Center for Medical Physics and Biomedical Engineering, Medical University Vienna, Vienna, Austria,
2
Department of Radiology, Children’s Hospital of Michigan, The Detroit Medical Center, Wayne State University School of
Medicine, Detroit, MI, United States, 3 MR Center of Excellence, Medical University of Vienna, Vienna, Austria
State-of-the-art patient management frequently requires the use of non-invasive imaging

methods to assess the anatomy, function or molecular-biological conditions of patients
or study subjects. Such imaging methods can be singular, providing either anatomical
or molecular information, or they can be combined, thus, providing “anato-metabolic”
information. Hybrid imaging denotes image acquisitions on systems that physically
combine complementary imaging modalities for an improved diagnostic accuracy and
confidence as well as for increased patient comfort. The physical combination of formerly
independent imaging modalities was driven by leading innovators in the field of clinical
Edited by:
research and benefited from technological advances that permitted the operation of
Claudia Kuntner, PET and MR in close physical proximity, for example. This review covers milestones
Austrian Institute of Technology, of the development of various hybrid imaging systems for use in clinical practice and
Austria
small-animal research. Special attention is given to technological advances that helped
Reviewed by:
Jose M. Perez, the adoption of hybrid imaging, as well as to introducing methodological concepts that
Centro de Investigaciones benefit from the availability of complementary anatomical and biological information, such
Energéticas, Medioambientales y
Tecnológicas, Spain
as new types of image reconstruction and data correction schemes. The ultimate goal of
Marc Huisman, hybrid imaging is to provide useful, complementary and quantitative information during
Medical Center, VU University patient work-up. Hybrid imaging also opens the door to multi-parametric assessment
Amsterdam, Netherlands
of diseases, which will help us better understand the causes of various diseases that
*Correspondence:
Jacobo Cal-Gonzalez currently contribute to a large fraction of healthcare costs.
[email protected]
Keywords: hybrid imaging, combined imaging, instrumentation, nuclear medicine, data processing, data
corrections
Specialty section:
This article was submitted to
Biomedical Physics,
a section of the journal
INTRODUCTION
Frontiers in Physics
Since the discovery of X-rays by Wilhelm Conrad Roentgen in 1895 [1], non-invasive medical
Received: 28 December 2017 imaging has become a standard tool for the diagnosis and staging of numerous diseases. X-ray
Accepted: 30 April 2018
Computed Tomography (CT) and Magnetic Resonance (MR), first introduced in the early [1]
Published: 18 May 2018
and late 1970s [2, 3], respectively, are the most widely used tomographic imaging techniques
Citation: for depicting morphological changes of the human anatomy [4–6]. Metabolic or functional
Cal-Gonzalez J, Rausch I, Shiyam
changes, which may occur without a corresponding change of anatomy, can be depicted by
Sundar LK, Lassen ML, Muzik O,
Moser E, Papp L and Beyer T (2018)
functional imaging, which has proven to provide essential information for the diagnosis and staging
Hybrid Imaging: Instrumentation and of many diseases. The first tomographic functional imaging modality was Single Photon Emission
Data Processing. Front. Phys. 6:47. Tomography (SPECT), introduced in the early 1960s [7], followed be the first Positron Emission
doi: 10.3389/fphy.2018.00047 Tomography (PET) system in 1972 [8] and the first MR system in 1977 [3].
Frontiers in Physics | www.frontiersin.org 1 May 2018 | Volume 6 | Article 47

Cal-Gonzalez et al. Hybrid Imaging: Instrumentation and Data Processing
By combining anatomical and functional imaging within Clinical SPECT/CT, PET/CT and PET/MR
a single, hybrid imaging system, complementary diagnostic Systems
information can be obtained in order to gather a comprehensive Figure 1 shows representative designs for SPECT/CT, PET/CT,
picture of the disease. First attempts for obtaining such “anato- and PET/MR systems available on the market today, and Table 1
metabolic images” [9] were based on sophisticated software summarizes their most important technical specifications.
techniques to co-register structural and functional information
[10, 11]. In the late 1990s, imaging systems that combine two SPECT/CT
complementary imaging techniques within the same gantry (e.g., The first combined SPECT/CT design was proposed by
PET/CT, SPECT/CT) became available [12, 13]. This approach is Mirshanov in 1987 [31]; however, it took a decade until
known as “hardware fusion”, in contrast to the software fusion SPECT/CT became commercially available following some key
approaches mentioned above. contributions by Blankespoor et al. [12]. Since then, SPECT/CT
This review briefly describes the developmental paths of has advanced rapidly and several commercial system designs are
hardware fusion systems and discusses their future in clinical available today.
routine and research. In section Basic Concepts of Hybrid Two facets of the design of the integrated CT components
Imaging we describe the basic concepts of clinical and preclinical can be identified: first, SPECT/CT systems include fully-
hybrid imaging systems. Section Hybrid Imaging Technology diagnostic CT systems with fast-rotation detectors that permit
highlights technological advances, such as novel detectors for the simultaneous acquisition of 16 or 64 detector rows, while
PET, SPECT, and CT, time-of-flight PET and organ-specific the X-ray tubes provide sufficient tube voltages together with
or total-body PET systems. In section Data handling we high tube current and automatic exposure control (General
discuss the data handling in hybrid imaging systems, including Electric Discovery NM/CT 670 and the Siemens Symbia [32]).
data acquisition, data storage, image reconstruction and data These systems also support advanced CT capabilities such as
correction techniques. Section Joint Data Exploration focuses cardiac gating, calcium scoring and iterative reconstruction [18,
on the potential of joint data exploration, and section Multi- 33].
Center Standardization summarizes ongoing efforts regarding On the other hand, SPECT/CT systems include rotating
the standardization of hybrid imaging systems. Finally, a SPECT components that come with adapted rotation times
summary of the state-of-art and an outlook on future trends and dose-optimized acquisition modes, while employing CT-
in hybrid imaging is presented in section Outlook and Future type components with limited acquisition flexibility, such as
Trends. lower tube voltages and currents (General Electric Hawkeye,
Philips Brightview-XCT [32]). The Hungarian company Mediso,
for example, offers a triple-modality SPECT/CT/PET system
BASIC CONCEPTS OF HYBRID IMAGING (Mediso AnyScan), which combines all three modalities within
a single device (Figure 1).
Among the range of existing functional imaging techniques Most clinical SPECT systems are based on planar detectors
(functional magnetic resonance imaging—fMRI, perfusion consisting of two-dimensional (2D) array of photomultiplier
MR imaging, magnetic particle imaging—MPI, Near-infrared tubes (PMTs) attached to the back of the scintillation crystal
spectroscopy—NIRS, etc.), PET and SPECT present as very with en-face collimators. The location of a photon interaction
sensitive methods for the non-invasive and quantitative site is computed as the center-of-gravity of the position-
investigation of physiological processes at a molecular level. dependent energy signals from the PMTs according to the so-
Nevertheless, PET and SPECT provide mostly functional called Anger logic [34]. In recent years, alternatives to the Anger
information that may not always be directly associated with logic have been proposed (see section Detector Technology
well-defined anatomical structures. The lack of high-contrast for CT, SPECT, and PET). However, the comparably high
anatomical information in either SPECT or PET image data costs involved, mainly from the use of solid state detectors,
(independent of the radiotracer) is a major limitation of these restricts adoption in smaller systems designed for special
imaging techniques. In order to maximize the potential of applications, such as cardiac [35], brain [36] or pre-clinical
PET or SPECT, it has been recognized that either nuclear imaging [37].
medicine modality could be combined with a high-resolution The benefit of SPECT/CT has been proven for a wide
anatomical imaging modality. In that regard, PET/CT and range of clinical applications [38–41]. The main advantages
PET/MR were developed with the aim of aligning functional of SPECT/CT include improved attenuation correction and
and anatomical information to improve the clinical outcome accurate anatomical allocation of the SPECT/CT findings, both
of these studies, while SPECT/CT was conceived primarily resulting in better diagnostic performance. Moreover, combined
for the purpose of providing routinely CT-based attenuation SPECT/CT imaging has demonstrated its value particularly in the
and scatter correction of SPECT data [14–16]. Nonetheless, clinical management of patients with cardiovascular disease [35].
the adoption of CT-based attenuation and scatter correction
has proven to yield similar benefits for SPECT and PET PET/CT
alike; these include shorter transmission times as well as The very first PET/CT prototype was proposed in 1984 at Gunma
higher-quality data for post-injection transmission imaging University in Japan [5]. The two tomographs were situated next
[17]. to each other with the patient table moving sideways between the

TABLE 1 | PET, SPECT, CT, and MR specifications of selected dual and triple modality clinical systems commercially available.
SPECT/CT PET/CT PET/SPECT/ PET/MR

CT
Cal-Gonzalez et al.
Company Siemens GE Philips Siemens Philips GE Toshiba Kindsway United imaging Mediso Siemens Philips GE
biotech
System name Intevo Discovery BrightView mCT and Ingenuity Vereos Discovery Discovery Celestion PoleStar uMI 510 uMI 780 Anyscan mMR Ingenuity Signa
NM/CT 670 XCT mCT flow PET/CT 690 IQ m660 PET/MR
References [18] [19, 20] [21] [22] [23] [24] [25] [26] [27] Vendor Vendor [28] [29] [30]
webpage
Frontiers in Physics | www.frontiersin.org

PET Scintillator – – – LSO LYSO LYSO LYSO BGO LYSO LYSO LYSO LYSO LYSO LSO LYSO LBS
specifications
Crystal size (mm3 ) – – – 4 × 4 × 20 4 × 4 × 22 4 × 4 × 19 4.2 × 6.3 × 6.3 × 6.3 × 4 × 4 × 12 3.63 × 3.63 2.35 × 2.35 × 15 2.76 × 2.59 × 18 3.9 × 3.9 × 20 4 × 4 × 20 4 × 4 × 22 4.2 × 5.3 × 25
25 30 × 20
Total detector elements – – – 32 448 28 336 23 040 13 824 11 520 30 720 37 632 110 592 101 920 39 672 28 672 28 336 20 160
Photo-detector – – – PMT PMT dSiPM PMT PMT PMT PMT PMT SiPM PMT APD PMT SiPM
ToF capability – – – Yes Yes Yes Yes No Yes Yes Yes Yes No No Yes Yes
Patient bore (cm) 78.0 71.7 70.0 70.0 74.0 88.0 N.A. 70.0 70.0 70.0 60.0 70.7 60.0
Transaxial FOV (cm) – – – 81.5 67.6 N.A. 70.0 70.0 70.0 N.A. 70.0 70.0 55.0 59.4 N.A. 60.0
Axial FOV (cm) – – – 21.8 18.0 16.4 15.7 26.0 19.6 N.A. 23.6 30.0 23.0 25.8 18.0 25.0
Energy window (keV) – – – 435–650 440–665 N.A. 425–650 425–650 425–650 425–650 N.A. LLD, 430 N.A. 430–610 460–665 425–650
Energy resolution (%) – – – 11.5 11.1 11.1 12.4 N.A. 12.4 N.A. N.A. N.A. N.A. 14.5 11.6 11.0
Time coincidence – – – 4.1 4.5 4.0 4.9 9.5 1.6–3.2 4.1 N.A. N.A. 5.0 5.9 6.0 4.6
window (ns)
Time resolution (ns) – – – 0.5 0.5 0.3 0.5 N.A. 0.4 0.43 0.485 N.A. N.A. 2.9 0.5 0.4
Transaxial resolution 1 – – – 4.4/4.9 4.8/5.1 4.1/4.5 4.7/5.0 4.5/5.4 5.1/5.1 3.76/4.56 2.85/3.07 Max resol. 2.9 4.1/4.9 4.3/5.0 4.7/5.1 4.2/5.2
cm/10 cm (mm)
3
Axial resolution 1 – – – 4.4/5.9 4.7/5.2 4.0/4.3 4.7/5.6 4.8/4.8 5.0 /5.4 3.64/5.29 3.01/2.97 4.2/5.1 4.3/6.6 4.6/5.0 5.8/7.1
cm/10 cm (mm)
Sensitivity (kcps/kBq) – – – 9.7 7.3 5.7 7.4 22.8 3.8 10.9 8.3 16 8.1 15.0 7.0 21.0
Scatter Fraction (%) – – – 33.2 36.7 30.0 37.0 36.2 37.3 N.A. 38.4 40.0 N.A. 37.9 at peak 26.0 43.6 at peak
NECR NECR
Peak NEC (kcps @ – – – 180 @ 28 124 @ 20.3 171 @ 50 139 @ 29 124 @ 9.1 70 @ 29.6 224.6 @ 109 @ 21.5 170 @ 16.0 150 @ N.A. 184 @ 23.1 89 @ 13.7 210 @ 17.5
kBq/mL) 29.0
SPECT Detector type 3.8 in. NaI 3.8 in. NaI 3.8 in. NaI – – – – – – – – – NaI – – –
specifications
Photo-detector PMT PMT PMT – – – – – – – – – 60(48) PMT – – –
Detector size (cm) 38.7 × 53.3 40.6 × 54.0 40.0 × 54.0 – – – – – – – – – 58.5(55.8) × – – –
47.0(41.8)
CT specifications Max CT slices 2,6,16 16 Cone beam 128 128 128 64 16 16 64 16 128 16 – – –
CT tube max voltage 130 140 120 140 140 140 140 140 135 140 140 140 140 – – –
(kVp)
CT tube max current 345 440 80 800 665 665 800 440 600 667 420 833 500 – – –
(mA)
Max CT rotation (s) 0.5 0.5 12 0.3 0.4 0.4 0.35 0.5 0.5 0.39 0.5 0.3 0.4 – – –
MR specifications PET/MR integration – – – – – – – – – – – – – Fully integrated Sequential Fully integrated

Magnet – – – – – – – – – – – – – Superconductor Superconductor Superconductor
Magnetic field – – – – – – – – – – – – – 3T 3T 3T
Magnet length (cm) – – – – – – – – – – – – – 163 157 N.A.
Magnet bore (cm) – – – – – – – – – – – – – 60 60 60
Maximum FOV (cm3 ) – – – – – – – – – – – – – 60 50 × 50 × 45 50 × 50× 50
N.A., data not available.

Hybrid Imaging: Instrumentation and Data Processing
May 2018 | Volume 6 | Article 47

FIGURE 1 | Images of commercially available hybrid imaging systems for clinical use. The figure shows three SPECT/CT, five PET/CT, three PET/MR and one triple
modality SPECT/PET/CT systems. Systems include the first CTM-PET(/CT) system (Siemens mCT Flow, see section Organ-Specific System Design and Total-Body
Systems); two SiPM-based PET systems (GE Signa, uMI 780), the first digital SiPM based PET system (Philips Vereos); a BGO-based system (GE Discovery IQ) and
the first commercially available fully-integrated PET/MR (Siemens mMR). Images taken from vendor’s web pages and published with the permission of the copyright
holders (the respective vendors).
two units. The first whole-body PET/CT prototype was proposed vendors have been presented following the advances in CT and
by Townsend and colleagues in the late 1990’s [13, 42]. Over PET instrumentation. To date, several vendors worldwide offer a
the years, PET/CT designs from various medical imaging system broad range of PET/CT designs.

The success of PET/CT imaging is based on several factors: Quantification in PET and SPECT
first, an anatomical and functional whole-body survey in a One of the most important advantages of tomographic nuclear
single session is logistically efficient for both the patient imaging techniques is the ability to accurately quantify the
and the healthcare provider. Second, due to the interplay of amount of radio-labeled biomolecules (radiotracers) in vivo. In
complementing data streams, the diagnostic information of a PET, this ability is based on the properties of the positron
PET/CT scan is superior to that of PET or CT alone [43, 44]. A emission coincidence detection, which allows for correction of
third advantage is the possibility to use CT information to correct photon attenuation in the emission signal by using information
PET data for photon attenuation and scatter or utilize it to correct gained from a separate transmission measurement [66]. As a
for partial volume effects [16]. result, emission images represent tracer concentration in units
of Bq/mL. However, for the assessment of functional processes,
PET/MR the sole knowledge of tracer concentration is not sufficient. The
An interesting alternative to PET/CT is to combine PET with tracer concentration in, for example, an organ depends on the
Magnetic Resonance Imaging (MR), since the range of MR amount of available radiotracer, which has led to the introduction
examinations is complementary to that of PET. MR imaging of the standardized uptake value (SUV) in the clinical reports.
reveals structural, functional and metabolic information through The SUV is a semi-quantitative measure that normalizes the
the interaction of three different magnetic fields (static, gradient, measured tracer concentration in tissue to a surrogate of the
dynamic) with the protons present in the tissues [2, 3]. The available tracer concentration in arterial blood / plasma. The
wide variety of imaging sequences, along with better soft-tissue most commonly used surrogate is the ratio of injected radiotracer
contrast compared to CT, renders MR an efficient diagnostic tool. to patient weight. The basic expression for SUV is [67]:
The potential of reducing patient dose by employing MR in lieu of
CT can be also considered an advantage compared to CT, mainly AMeasured
SUV = (1)
for pediatric examinations and cardiac imaging. AInjected /BW
However, the physical combination of PET and MR represents
a major technological challenge [45–48]. Conventional PET where AMeasured is the measured activity decay corrected to the
systems use PMTs to detect the scintillation light. These PMTs time of injection (kBq/mL). AInjected is the activity injected into
are highly sensitive to magnetic fields and, therefore, cannot the patient (kBq/mL) and BW is the body weight of the patient
be operated inside an MR magnet. One possible approach to (kg).
overcome this issue is to spatially separate the PET and the MR As of today, SUV remains a standard metric for PET-
system in combination with an active shielding of the PMTs based diagnosis and therapy response assessment in oncology
against the magnetic field from the MR. This design was proposed [68, 69]. However, the SUV represents only a simplified
in 2010 for the first whole-body PET/MR, the Philips Ingenuity measure to describe a physiological process. For absolute
TF PET/MR system [29]. Alternative approaches make use of quantification, i.e., the determination of physiological parameters
the potential of solid state photo-detectors, such as APDs or (such as metabolic rate of glucose consumption in mmol/g/min),
SiPMs [49–52], see section Detector Technology for CT, SPECT, pharmaco-kinetic modeling is required [68]; this entails the
and PET for details. This technology enables the design of knowledge of the time course of tracer concentration in arterial
fully integrated PET/MR systems that permit the simultaneous blood as well as in the tissue. From that, the pharmaco-kinetic
acquisition of PET and MR data within the same axial field-of- parameters can be derived from a temporal relationship between
view (aka co-planar FOV). Today, two integrated systems are these functions [70]. However, both the requirement of invasive
available commercially: the Siemens Biograph mMR [28] and the arterial blood sampling and the complexity of kinetic modeling
GE Signa PET/MR [30]. are significant limitations for the routine adoption of absolute
quantification in clinical routine so far [71].
Preclinical Hybrid Imaging In contrast to PET imaging, and given the more challenging
Animal models of human disease are the basis of many approaches toward attenuation and scatter correction, SPECT
research efforts to understand disease processes and the has not been considered a quantitative modality until recently.
development of new pharmaceuticals [53]. Similar to human However, methodological advances have led to an increase in
imaging, the combination of molecular imaging techniques the number of papers reporting high quantitative accuracy with
and CT or MR has been proven beneficial for small-animal SPECT [18, 72].
imaging [54]. Therefore, a large variety of dedicated small-
animal hybrid systems, has been developed since the 1990s, HYBRID IMAGING TECHNOLOGY
with all hybrid combinations (PET/CT, PET/MR, SPECT/CT,
SPECT/MR, and PET/SPECT/MR) commercially available. This section reviews the basic constituent technologies for
Figure 2 shows a number of dual- and triple-modality systems hybrid imaging systems. We start with a discussion on radiation
for small animal imaging that are available from several vendors. detectors used in CT, SPECT, and PET systems (section
Table 2 summarizes the main system specifications. A complete Detector Technology for CT, SPECT, and PET). Time-of-flight
description of all the available preclinical hybrid systems is and continuous table motion PET are discussed in sections
outside the focus of this review paper, please see [46, 61–65] for Time-of-Flight PET and Spiral PET, Continuous Table Motion,
details. respectively, while in section Organ-Specific System Design and

TABLE 2 | PET, SPECT, CT and MR specifications of selected dual and triple modality preclinical systems.
PET/CT SPECT/PET/CT SPECT /MR PET/MR
Company Sofie Sedecal MI Labs Mediso Siemens Bruker FLEXTM Mediso Mediso Bruker MR solutions
Cal-Gonzalez et al.
biosciences
System name GNEXT SuperArgus VECTor5 NanoScan Inveon Albira Si Triumph NanoScan NanoScan Bruker PET MRS-PETTM
PET/CT 4R SPECT/PET/CT SPECT/PET/CT SPECT/PET/CT SPECT/PET/CT SPECT/MR PET/MR /MR
References Vendor [55] [56–58] Vendor [59] Vendor [60] Vendor webpage Vendor Vendor
webpage webpage webpage webpage webpage

PET Detector type Pixelated Pixelated Uses the same Pixelated LYSO Pixelated LSO Continuous Pixelated - Pixelated LYSO Continuous Dual-layer
specifications LYSO/BGO LYSO/GSO detector (122S/82S) block detector LYSO/LGSO (122S/82S) block detector LYSO matrix
system than coupled to a 12 coupled to a 12 with 1/2 pixel
SPECT, with a × 12 SiPM × 12 SiPM offset
clustered- array array
pinhole
collimator
designed for
high-energy
photons, which
makes the
coincidence
detection not
needed.
Crystal size 1.01 × 1.01 × 1.45 × 1.45 × 1.12 × 1.12 × 1.5 × 1.5 × 10 N.A. 2.0 × 2.0 × – 1.12 × 1.12 × N.A. N.A.
(mm3 ) 6.1 mm3 LYSO (7+8) 13/1.51 × 1.51 (12+14) 13/1.51 × 1.51
6
1.55 × 1.55 × × 10 × 10
8.9 mm3 BGO
Total #detector 23 040/10 240 32 448 36 504/13 456 25 600 24 6 144 – 36 504/13 456 24 N.A.
elements
Photo-detector PMT PMT N.A. PMT SiPM PMT – N.A. SiPM N.A.
Depth-of- 2 layers 2 layers Yes (Monte No Yes 2 layers – Yes (Monte Yes Yes
interaction LYSO/BGO LYSO/GSO Carlo - based) LYSO/LGSO Carlo - based)
(DOI)
Transaxial FOV 13.0 12.0 1.2 central 12.0/8.0 10.0 8.0 11.0 – 12.0/8.0 8.0 7.0
(cm) (hourglass-
shaped)
Axial FOV (cm) 10.4 10.0 0.9 central 10.0 12.7 14.8 (3 rings 10.0 – 10.0 14.8 (3 rings 13.5 (3 rings
system) system) system)
Energy window N.A. 250–700 409–613 N.A. 350–625 350–650 N.A. – N.A. 350–650 N.A.
(keV)
Max spatial ? 1.0 0.8 (OSEM3D) 0.6 0.9 (OSEM3D) 1.4 (FBP) 0.7 (OSEM3D) 0.9 (MLEM) – 0.9 (OSEM3D) 0.7 (OSEM3D) ?0.9 (OSEM3D)
resolution (mm)
Sensitivity (%) N.A. 8.9 0.3 8.0/7.0 3.2 12 (3 rings N.A. – 8.0/7.0 12 (3 rings N.A.
system) system)
Scatter fraction N.A. N. A. N.A. N.A. 13.6/19.2 N.A. N.A. – N.A. N.A. N.A.
(%): mouse/rat
Peak NEC: N.A. N.A. N.A. 850 @ N.A. and 1394 @ 146 560 @ 35 and N.A. – 850 @ N.A. and 560 @ 35 and N.A.
mouse and rat 230 @N.A./460 and 560 @ 97 330 @ 43 230 @N.A./460 330 @ 43
(kcps @ MBq) @ N.A. and 130 @ N.A. and 130
@ N.A. @ N.A.
(Continued)

TABLE 2 | Continued
PET/CT SPECT/PET/CT SPECT /MR PET/MR
Company Sofie Sedecal MI Labs Mediso Siemens Bruker FLEXTM Mediso Mediso Bruker MR solutions
Cal-Gonzalez et al.
biosciences
System name GNEXT SuperArgus VECTor5 NanoScan Inveon Albira Si Triumph NanoScan NanoScan Bruker PET MRS-PETTM
PET/CT 4R SPECT/PET/CT SPECT/PET/CT SPECT/PET/CT SPECT/PET/CT SPECT/MR PET/MR /MR
References Vendor [55] [56–58] Vendor [59] Vendor [60] Vendor webpage Vendor Vendor
webpage webpage webpage webpage webpage

SPECT Detector type – – 3 head NaI(Tl) 4-head 2-head – 5-by-5 CZT Continuous NaI – – –
specifications continuous NaI pixelated NaI modules
Photo-detector – – 55 PMT per PMT PMT – – PMT – – –
detector
Detector size – – 50.8 × 38.1 28 × 28 15.0 × 15.0 – 12.7 × 12.7 28 × 28 – – –
(cm)
CT CT voxel size 20 20 80 10 20 90 50 – – – –
specifications (µm)
CT tube max N.A. 110 65 70 80 50 N.A. – – – –
voltage (kVp)
CT tube max N.A. N.A. 615 N.A. 500 1,000 N.A. – – – –
current (µA)
Max CT ? 60 15 40 36 N.A. N.A. N.A. – – – –
7
rotation (s)
MR PET/MR – – – – – – – Sequential Integrated and Sequential

specifications integration PET insert
Magnet – – – – – – – Superconductor Superconductor Superconductor
Magnetic field – – – – – – – 1.5/3T 3T 3 or 7 T
Magnet bore – – – – – – – N.A. 18 17 /24
(cm)
Maximum – – – – – – – 100 N.A. N.A.
resolution (µm)
Maximum FOV – – – – – – – N.A. N.A. Eliptical 10 ×
(cm3 ) 7/13.5 × 9.8
(3T) 11 ×
7/15.4 × 9.8
(7T)
Of note, the MI Labs, Mediso and Bruker companies also offer SPECT/CT and PET/CT systems with the same sub-system characteristics than the ones shown in the SPECT/PET/CT configurations. The Inveon SPECT/PET/CT system
was discontinued and it is not commercially available anymore. MR solutions also offer and SPECT/MR system with multi-pinhole SPECT technology and similar MR capabilities than the ones shown in their PET/MR. N.A., data not
available.

FIGURE 2 | Selected commercially available, dual- and triple-modality preclinical systems. Images taken from vendor’s web pages and published with the permission
of the copyright holders (the respective vendors).
Total-Body Systems we discuss organ-specific and total body also characterized by the highest light output (i.e., number of
hybrid imaging systems. Finally, in section MR Technology we photons emitted per unit of deposited energy), which is directly
provide a brief overview of the technology used in MR systems. related to the energy resolution. Most PET and SPECT systems
are composed of pixelated scintillators to assign the interaction
Detector Technology for CT, SPECT, and position of the gamma photon [74], although blocks made of
PET continuous crystal have been proposed as well [75, 76]. Table 3
The most commonly used radiation detectors for CT, SPECT, and lists some of the scintillators commonly used in CT, SPECT and
PET imaging systems are based on scintillator crystals, because PET detector systems together with their key properties [77–
they are fast, they provide a high stopping power for photons 81]. New scintillator materials are being developed continuously.
across a range of emission energies and their cost-per-volume Some examples include scintillators based on cerium doping
rate is far superior to other detector materials. A scintillation of lanthanide and transition metal elements, such as LuAP:Ce,
detector consist of a crystal that produces scintillation light after CeBr3, LuBO3:Ce, and others based on lead (Pb), tungsten (W),
the interaction with radiation and a photo-detector that converts and gadolinium (Gd) [82].
the scintillation light into an electrical signal [73], which is then Photomultiplier tubes (PMTs) represent the most common
processed by the electronic system. mean to measure and detect the scintillation light emitted by the
There are several scintillating materials that are currently scintillator crystal. They consist of a vacuum enclosure within
being used. They can be classified into organic or inorganic a thin photocathode layer at the entrance window and several
scintillators that come in solid, liquid or gaseous state. For electrodes, called dynodes, which amplify the electrical signal
medical imaging applications, solid inorganic scintillators are created in the photocathode by means of secondary electron
preferred, due to their higher density (i.e., stopping power), emissions. A PMT produces an electric pulse with amplitude
which is required for high sensitivity imaging systems. They are proportional to the number of scintillation photons that reach

TABLE 3 | Physical properties of some scintillators used in medical imaging applications (adapted from Lewellen [77]).
NaI BGO GSO LSO LYSO LaBr3 BaF2 LuAP
Composition NaI:Tl Bi4 Ge3 O12 Gd2 SiO5 :Ce Lu2 SiO5 :Ce (LuY)2 SiO5 :Ce LaBr3 :Ce BaF2 LuAP:Ce
Density (g/cm3 ) 6.7 7.1 6.7 7.4 7.1 5.3 4.9 8.3
Effective atomic number 51 74 59 66 60 47 54 65
Attenuation coefficient (cm−1 ) 0.34 0.92 0.62 0.87 0.86 0.47 0.44 0.90
Refractive index 1.85 2.15 1.85 1.82 1.81 1.88 – 1.95
Light yield (%NaI) 100 15 41 75 80 160 5 16
Wavelenght for max. Emission (nm) 410 480 430 420 420 370 220 365
Decay constant (ns) 230 300 56 40 41 25 0.8 18
Hygroscopic Yes No No No No No Slight No
TABLE 4 | Characteristics of photo-detectors used in medical imaging matrix of small APD cells biased to be operated above avalanche
applications (adapted from Lecomte [79]). breakdown in the so-called Geiger mode. Since the Geiger-mode
PMT APD SiPM
operation yields a high gain (105 –106 ), a multi-cell structure
can provide a proportional output for moderate photon flux by
Active area (mm2 ) 1–2,000 cm2 1–2,000 cm2 1–10 mm2 summing the signal of all cells that have been activated. In 2009,
Gain 105 –106 102 105 -106 Philips Healthcare introduced the digital SiPMs, also known as
Dynamic range 106 104 103 Digital Photon Counter (DPC), which combines a conventional
Excess noise factor 0.1–0.2 >2 1.1–1.2 array of Geiger-mode photodiodes with a fully-digital electronic
Rise time (ns) <1 2–3 1 readout system, thus, allowing timing resolutions of up to 60 ps
Time jitter (ns FWHM) 0.3 >1 0.1 Full Width Half Maximum (FWHM) [84–87].
Dark current <0.1 nA/cm2 1–10 nA/mm2 0.1–1 MHz/mm2 Semiconductor detectors represent the main alternative
Photon detection efficiency 25 60–80 <40 to scintillator-based detectors in CT and SPECT imaging
@ 420 nm systems. In comparison to scintillators the main advantage of
Bias-voltage (V) 1,000–2,000 100–1,500 >100 semiconductor detectors is the direct conversion from radiation
Power consumption 100 mW/ch 10 µW/mm2 <50 µW/mm2 to an electric pulse, which avoids the degrading effects associated
Gain dependence with <1%/◦ C 2–3%/◦ C 3–5%/◦ C with scintillation light production, propagation and conversion
temperature to an electrical signal in the photodetector. Their use in PET
Gain dependence with <1%/V 10%/V 100%/V systems is much less frequent, due to their lower stopping power
voltage for the high-energy 511 keV annihilation photons and their
Magnetic susceptibility Very high (mT) No (up to 9.4 T) No (up to 15 T) higher costs.
To date, the most widely investigated semiconductors for
nuclear medicine and CT imaging are CdTe and CdZnTe (CZT).
Both offer a relatively high stopping power (similar to the one
the photocathode, which, in turn, is proportional to the deposited offered by NaI:Tl scintillator crystals) and they can be operated
energy. at room temperature. Furthermore, with the use of highly
The main advantage of PMTs as scintillation light detector granulated detectors high spatial, energy and time resolution
is its high amplification capability (in the order to 106 –107 ). can be achieved [88]. Table 5 summarizes important properties
On the other hand, their most significant drawback of PMTs of some semiconductor materials used for medical imaging
is their sensitivity to magnetic fields, which makes them not applications [80].
suitable for use in combined PET/MR or SPECT/MR systems
[83]. A valid alternative to PMTs are solid-state detectors such Time-of-Flight PET
as Avalanche Photodiodes (APDs) or Silicon Photomultipliers Another important technological advance for PET systems,
(SiPMs). Solid-state detectors have several inherent advantages referred to as Time-of-Flight (ToF) PET, was made possible
over PMTs (Table 4), such as high quantum efficiency, compact with the introduction of very fast detectors. The concept of ToF
and flexible shape, ruggedness, demonstrated insensitivity to assumes that the annihilation point of two photons originating
magnetic fields up to 9.4 T and potentially inexpensive mass from a single positron annihilation can be calculated from their
production [49–51]. Solid-state detectors are semiconductor travel time differences [89–91].
devices with a low-field depleted region where visible or near- State-of-the-art PET systems achieve time resolutions of
UV photons can create electron-hole pairs by photoelectric effect. about 500 ps FWHM (using photo multiplier tubes) [19,
APDs exist as small discrete devices or as monolithic arrays, 29], down to about 300 ps FWHM (using SiPMs) [22,
which can be used for individual or multiplexed crystal readouts. 30], which corresponds to an uncertainty of determining
Silicon Photomultipliers (SiPMs) consists of a densely packed the origin of the annihilation along the Line Of Response

TABLE 5 | Physical properties of some semiconductor detectors used in medical technologies were made in recent years. For example, Siemens
imaging applications (adapted from Peterson and Furenlid [80]). Healthcare did propose a “Brain PET” system that was based on
Si Ge CdTe CdZnTe
a PET ring insert for a 3 T MR system [104]. More recently, a
SiPM-based PET insert has been developed for integration with
Density (g cm−3 ) 2.33 5.32 5.85 5.82 any MR scanner [105]. Alternative efforts aim at developing MR-
Attenuation @ 140 keV (cm−1 ) 0.02 0.72 3.22 3.07 compatible PET inserts for breast imaging. Initial prototypes
Energy e-h pair (eV) 3.61 2.98 4.43 5 have been proposed [106] with promising results, and a breast
Electron mobility lifetime (cm2 V−1 ) 0.42 0.72 0.003 0.003 hybrid PET/RF insert is being developed based on digital SiPMs
Hole mobility lifetime (cm2 V−1 ) 0.22 0.84 0.0005 0.00005 (dSiPMs) for enhanced diagnosis of breast cancer (HYPMED
2016: http://www.hypmed.eu/). Similar approaches have been
proposed for the diagnosis of prostate and pancreatic cancer,
whereby PET and Ultrasound (US) components are combined in
(LOR) of about 15 and 9 cm, respectively. With this additional an endoscope device [107].
information, the SNR in the reconstructed PET images can be The concept of a large axial FOV (aFOV) whole-body PET
improved significantly [92]. Thanks to recent improvements in was introduced by Crosetto in the 1990’s [108]. Following the
detector technology, new scintillator materials and fast digital introduction of this concept and after several simulation studies,
SiPMs photodetectors [93], ToF resolution can be significantly the EXPLORER (Extreme Performance Long Research scanner)
improved; the latest developments in PET detector technology consortium was set up with the task of building the world’s first
aim at timing resolutions of 100 ps FWHM, or less [92, total-body PET/CT system—the EXPLORER PET/CT [109, 110].
94]. The EXPLORER has a 200 cm aFOV based on mainstream PET
detector technology. It will consist of a total of 400,000 crystals,
Spiral PET, Continuous Table Motion thus, yielding about 100 times more LORs than a state-of-the-art
Commercially available whole-body PET systems offer fixed whole-body PET(/CT) system.
axial FOVs between 15 cm and 25 cm. To cover larger axial The elongated axial coverage of the EXPLORER type system
areas, multiple bed positions are acquired in a step-and- is expected to yield a 30–40 times increase in sensitivity
shoot protocol [95]. An alternative to the traditional step- over current generation PET systems. This translates to
and-shoot approach is a continuous table motion (CTM) detecting over 40% of the counts emitted from a point
during the acquisition. This technique was first proposed source in air located at the center of the FOV [111]. This
in 1992 by Dahlbom et al. [95] aiming to increase the impressive increase in sensitivity provides a number of key
uniformity of the sensitivity across the examined axial area. advantages: imaging at very low radioactivity levels (∼10 MBq)
First attempts to implement CTM in a clinical PET only [112], increased throughput from shorter examination times
system were made as early as 2001 [96] and followed by and whole-body imaging that can be performed within a
several implementations of CTM techniques in PET/CT systems single breath hold. With the total-body coverage provided
a few years later [97, 98]. However, it took until 2013 by the EXPLORER, it is also possible to perform whole-
to implement CTM into a commercially available system body dynamic PET imaging, thus, avoiding temporal gaps,
[19]. which are present in current multi-bed, multi-pass imaging
CTM offers two main advantages in comparison to step- protocols [113, 114]. However, efficient image reconstruction
and-shoot acquisitions: a uniform sensitivity across the entire and data handling schemes are required for the EXPLORER
axial FOV and the possibility to customize the axial scan range. system. Zhang et al. [112] proposed a quantitative image
While in step-and shoot acquisitions uniform sensitivity can reconstruction method that demonstrated a 7-fold increase
also be achieved by an appropriate selection of bed overlap, in the signal-to-noise ratio in comparison to current PET
the axial scan range is restricted to a discrete number of systems.
bed positions. Another advantage of CTM acquisitions is the Independent to the EXPLORER, a high-resolution 100
possibility of new acquisition protocols that support whole- cm-aFOV PET system, called “PET20.0,” is currently being
body parametric imaging [99]. Given the above benefits, CTM configured in cooperation between Ghent University and
can be regarded a particular asset in combined PET/CT Vrije Universiteit Brussels [115]. In comparison to the PET
imaging. EXPLORER, PET20.0 has a shorter aFOV of 100 cm. However,
with monolithic detector crystals and improved positioning
Organ-Specific System Design and methods, the spatial resolution of PET20.0 (2.0 mm) is expected
Total-Body Systems to be better than the spatial resolution of the EXPLORER
The development of state-of-the-art detectors allows the design (3.5 mm).
of high-resolution organ-specific hybrid systems, as well as high- In contrast to the aforementioned PET systems, a lower-cost
sensitivity total body PET/CT with extended axial field-of-view alternative based on resistive plate chamber (RPC) detectors has
(aFOV). been proposed also. In addition to being economic and reliable,
Although most attempts toward organ-specific imaging were RPC-PET detectors offer good spatial-temporal resolution, high
based on stand-alone PET or SPECT systems [100–103], time-of-flight resolution and high energy sensitivity. Further,
significant efforts in fully-integrated, organ-specific imaging the RPC detectors allow for the accurate measurement of

Depth-of-interaction (DOI), which renders RPC-PET parallax- There are two main categories for Image Reconstruction (IR)
error free. These properties make RPC-detectors an excellent algorithms in CT, SPECT and PET: analytical reconstructions and
option for an extended aFOV PET system [116]. iterative reconstructions [124–126]. Analytical approaches are
based on a closed-form equation that directly yields one solution
MR Technology based on the input (Figure 3A), while iterative techniques are
Currently over 60% of clinical MR systems operate at 1.5 Tesla based on a more accurate description of the imaging process,
for cost and safety reasons [3, 117]. To date, the conventional thereby resulting in a more complicated mathematical solution
upper limit for the field strength of clinical MR is 3 Tesla. The that requires multiple steps to achieve an image. Iterative
growing adoption of MR systems with 7 Tesla (over 80 units methods model the data collection process in a tomographic
installed worldwide) could be seen to represent the new frontier system and search for the image that is most consistent with the
of MR imaging1 . Of note, singular testing of MR systems with measured data (Figure 3B).
10.5 T (University of Minnesota, USA) and 11.7 T (CEA, Saclay,
France) is work-in-progress [3], but it is unlikely that these Analytical IR
ultra-high-field MR systems will soon be employed in hybrid The filtered-backprojection (FBP) reconstruction [127] method
imaging. is the standard method for image reconstruction of CT data.
For hybrid imaging of human subjects and patients, i.e., The FBP method combines a back-projection operation, which
combined PET and MR, actively shielded 3 T magnets have been describes the propagation of the measured projection data into
chosen by all manufacturers. In addition to the wide bore magnet, the image domain, with a filter component that compensates
fast gradient coils (slew rate 200 mT/m/ms) and dedicated RF for the low-pass blurring inherent to the back-projection
coils (proton frequency at 128 MHz) are required [3, 118]. approach. With the advances in CT technology, different
Recently, maximum gradient strength of up to 300 mT/m were adaptations of the FBP algorithm (interpolation methods, 3D-
realized at 3 T [119], although state-of-the-art clinical systems reconstruction methods: Feldkamp algorithm, etc. [128–132])
operate with a gradient strength of 70 mT/m, which is sufficient have been proposed to compensate for fan-beam and cone-beam
for most routine pulse sequences prescribed. Dedicated RF- geometries. Likewise, exact [128, 133] and approximate [134]
coil arrays are being developed to further improve sensitivity 3D reconstruction methods have been proposed for helical cone
and speed and to avoid costly ultra-high field magnets, thus, beam reconstruction, which are being used in most commercial
rendering a suitable option for combined PET/MR systems [120] CT systems due to their flexibility and computational efficiency
as well as for various parallel imaging techniques [121–123]. [125].
Parallel imaging enables more efficient data sampling to either
increase acquisition speed or the amount of information collected Iterative IR
per time interval. Iterative methods offer improvements over the analytical
approach because they allow the noise structure of the data to be
DATA HANDLING accounted for, thus, incorporating a more realistic model of the
system. All iterative reconstruction methods consist of three steps
This section provides an overview of standard data acquisition that are iterated until a convergence condition is met (Figure 3B).
and image reconstruction techniques for functional (SPECT, First, an estimated raw data set is created from an estimated initial
PET) and anatomical (MR, CT) imaging modalities (section image using a realistic model of the tomographic system. Second,
Image Acquisition and Reconstruction in CT, PET, and SPECT the artificial raw data is compared with the real data acquired by
to Quantitative Data Corrections in PET and SPECT). Advanced the system in order to obtain a correction term for each bin in the
data processing methods are described in sections Anatomically- projected data. Finally, these correction terms are back-projected
Driven PET/SPECT Image Reconstruction to Outlook and and used to update the image estimate.
Future Trends, which make use of the anatomical information Iterative reconstruction methods can be classified in
provided by the CT or MR images to improve the PET-SPECT deterministic and statistical approaches [135]. The most
quantification). frequently used deterministic approaches are the Algebraic
Reconstruction Technique (ART) [136], the simultaneous ART
Image Acquisition and Reconstruction in (SART) [137], and the ordered-subsets Simultaneous Iterative
CT, PET, and SPECT Reconstruction technique (OS-SIRT) [138]. Statistical methods
A CT image represents the tissue-dependent attenuation of incorporate counting statistics of the detected photons into
X-rays of the investigated object, thereby making use of an the reconstruction process. The most well-known methods are
X-ray source of known source strength and an opposite detector the Maximum likelihood expectation-maximization (ML-EM)
array, both of which rotate at a fixed speed around the center [139], its accelerated version by means of the ordered-subsets
of the FOV. Alternatively, SPECT and PET images represent expectation-maximization (OSEM) [140], and the model-
the distribution of activity concentrations (per voxel) of a single based iterative reconstruction (MBIR) [141], which is used
photon (SPECT) or a positron (PET) emitter. predominantly in multi-slice helical CT.
Image reconstruction methods in SPECT and PET are similar
1 Siemens Healthineers (Erlangen, Germany) obtained both, CE labeling and FDA to the methods employed in CT although the physical nature of
approval for their 7 T Terra system in 2017. the acquired data is different. These differences relate mainly to

FIGURE 3 | (A) Simplified view of the direct FBP image reconstruction technique: the projected data is filtered using different filter kernels and back-projected into the
image domain. Multiple projections are required to obtain the final CT image. (B) Schematic view of the iterative reconstruction process: first, a forward projection of
the initial estimated image is used to create the estimated projected data; then the estimated data is compared to the acquired raw data and a set of correction
factors is derived. These correction factors are back-projected and used to update the initial estimated image. All three steps describe an iterative loop, which is
repeated until a predefined condition is satisfied and the final image is generated. Similar reconstruction processes apply for SPECT and PET data.

the geometrical model (e.g., CT—fan-beam, cone-beam or helical to 16-bit digital resolution) and visualized on a computer screen
vs. PET—cylindrical rings of detectors vs. SPECT—rotating flat as gray scale values/images of tissue specific image contrast.
detector panels plus collimators), and, thus, to the level of In a mathematical framework, a Fourier transformation of the
mandatory a priori data corrections. detected signal is stored in k-space (2D-space consisting of all
Statistical IRs have been used extensively in SPECT and frequencies and phases detected in the measured RF signal) and
PET due to their benefits with regards to noise reduction and then transformed into image space (x,y) via the inverse Fourier
improved accuracy in the reconstructed images [124]. However, transformation. The result is a spatially resolved magnetization
these approaches are not yet widely adopted in clinical CT. This is vector M(r).
due to the numerous pre-processing and calibration steps in CT,
which change the statistical properties of the measured data; the Quantitative Data Corrections in PET and
high spatial resolution in CT, which requires the application of SPECT
edge-preserving regularization techniques; and the large amount In order to obtain quantitative and artifact-free PET or SPECT
of data that requires long reconstruction times. Nonetheless, images, several corrections must be applied to the acquired data,
the exponential growth of computer technology and the recent which include, for example: decay correction, photon attenuation
introduction of IR methods that can be implemented on a correction (AC), scatter correction, normalization, dead time
Graphic Processing Unit (GPU, [142]) render the use of iterative correction and randoms subtraction (only in PET). Here we
reconstruction in CT more and more a clinical commodity. will discuss the most widely methods used for quantitative data
corrections in PET and SPECT images, and their application in
PET/CT and SPECT/CT systems. In PET/MR, as the MR image
information is not related to the attenuation properties of the
Image Acquisition and Reconstruction in material, novel methodologies for AC need to be developed, and
MR are discussed in detail in section Novel MR-Based Attenuation
MR imaging is a non-invasive tomographic imaging technique Correction (AC) Methods for PET/MR. For a general overview
that acquires data from the inside of an object using on the quantitative correction methods for PET we refer the
radio-frequency (RF) excitation of protons that subsequently reader to Zaidi [144], while for SPECT we suggest [72, 145].
retransmit the absorbed energy, depending on the biological
environment. Nuclear induction of RFs is performed using coils Attenuation and Scatter Corrections in PET/CT
or coil arrays, with a wavelength larger or similar to the object The emitted photons in PET and SPECT are subject to
dimensions (at 3 T/128 MHz the proton wavelength in biological attenuation as they travel through the patient. As consequence,
tissue is about 30–50 cm). In order to allow spatial encoding of the number of detected photons in each LOR will be reduced.
RF emission from bulk tissue, gradient coils need to be used that The most widely used method for AC in PET/CT was proposed
limit the resonance frequency to a small portion of image space. by Kinahan et al. [17, 146] and it is known as “bilinear”
This is commonly performed using three independent linear segmentation-scaling method. Here, the PET attenuation image
gradient fields, although other approaches, using, e.g., radial or is estimated by first using a threshold to separate the bone
spiral gradients, exist. Following a combination of excitations and component from the soft tissues of the CT image, and then using
measurements, imaging and contrast modules can be selected separate scaling factors for the bone and non-bone component.
independently, thus, making MR a highly versatile and flexible Alternatively, the emitted photons may be scattered in the patient
imaging technique with excellent soft tissue contrast [143]. The body or in the detector itself, suffering a deviation of its trajectory.
imaging module defines the details (i.e., matrix size, 2D/3D) of As a consequence, the LOR of a scattered event will not be
the data collection from an object of a given size in a given longer aligned with the emission point. The most extensively used
time (i.e., measurement time). Anatomical MR data acquisition method for scatter correction in PET/CT (and PET/MR) is the
is performed for the purpose of high-resolution imaging (i.e., Single Scatter Simulation (SSS) method [147, 148], where only a
matrix size 256 × 256 up to 512 × 512) in a matter of a single scatter event is considered and multiple or out of the FoV
few minutes. For functional data, reduced spatial resolution is scatter contributions are included as scaling factors.
acceptable (i.e., 64 × 64 up to 128 × 128) in view of acquiring
3D frames within 10–50 ms and with short repetition times, TR, Attenuation and Scatter Corrections in SPECT/CT
of 100–2,000 ms over the course of several minutes. Similar to in PET/CT, the bilinear method proposed for CT-based
Given the variety of pulse sequences and sequence parameters AC can be used in combined SPECT/CT systems [18, 149].
(e.g., TR, TE, MA, FOV, etc.) data processing and analysis On the other hand, the most common approach for estimating
pipelines, particularly in research, can be rather complex. In scatter events in SPECT/CT is the measure of counts in
addition, differences in pulse sequences and processing software additional energy windows adjacent to the photopeak window.
can be observed between manufacturers [118], often depending The most common examples are the Dual Energy Window
on hardware performance or Intellectual Property (IP) issues. By (DEW) approach that neglects upper scatter or the Triple Energy
combining short (ms) magnetic pulses produced by an RF-coil Window (TEW) [150–152]. More complex solutions, based on
with orthogonal magnetic gradients in x, y, z; voxel localization Monte Carlo estimations of the scattered events, have been also
in 2D or 3D is enabled and the voltage induced in the receive coil proposed [153, 154] and are expected to be widely used in the
can be detected. This voltage is converted into numbers (12-bit near future.

Randoms Subtraction in PET correction [168] and the geometric transfer-matrix (GTM)
Random events occur when two uncorrelated photons, from two method [169]. Other post-reconstruction corrections consist of
different decays, are detected in coincidence within the timing voxel-based methods, such as the popular Mueller-Gaertner
window. The randoms events can be estimated by using a delayed method (MGM) [170], image deconvolution [171], and the
coincidence window [155]. “region-based voxel-wise correction” (RBV) [172]. Alternative
approaches for PVC operate in sinogram space, where statistical
Normalization in PET and SPECT noise is spatially uncorrelated and easier to incorporate in
Because of variations in the gain of PMTs, inaccuracies/tolerances the PVC procedure [173–176]. Reconstruction-based methods
in detector block building, physical variation of scintillator enhance the spatial resolution by using the implicit PVC
efficiency, etc., the detection sensitivity varies from detector compensation through system-response modeling [177]. More
to detector. Information on these variations, often known as advanced PVC methods make use of anatomical priors during the
normalization [145, 156], is required for the reconstruction of reconstruction process [159, 161], as described in the previous
quantitative and artifact-free images. section.
Despite the large number of PVC methodologies proposed
Anatomically-Driven PET/SPECT Image in the literature, explicit corrections for PVE are still far from
Reconstruction being fully utilized in clinical routine [178]. This is due to several
Iterative IR methods for PET and SPECT are challenged in challenges associated with their automated implementation.
two ways. First, PET, and SPECT images have an inherently First, the accurate delineation of the tissues of interest from the
limited spatial resolution due to the physical process that morphological images is a challenging task, especially in cases
leads to the image formation. And, second, noisy images are where the metabolic tissue boundaries do not correspond well to
obtained from over-iterated reconstructions, given the lack of the morphologic boundaries. Second, some of the PVC methods
an objective stopping rule in the iterative reconstruction. The require segmentation of tissues into different VOIs that span
latter problem is addressed in clinical routine by using a Gaussian the entire cross-sectional extent of the subject, which can be
post-reconstruction filter, which further degrades the perceived computationally intensive.
resolution and contrast of the images in return for lower noise
levels. Motion Compensation
Bayesian methods attempt to improve the quality of the The hybrid imaging protocols for SPECT/CT, PET/CT, and
reconstructed image by taking advantage of prior knowledge PET/MR systems often span acquisition times of several minutes
[157], that can be obtained, for example, from a co-registered and, thus, cover multiple breath-holds or cardiac contractions.
anatomical image (CT or MR). This information is known a Therefore, these hybrid images are subject to involuntary patient
priori and is often incorporated into a maximum a posteriori motion during the acquisition [179]. The induced respiratory
(MAP) objective function [158]. These reconstruction methods motion as well as cardiac contraction introduce motion blur in
lead to improvements of contrast and noise properties of the the acquired images (Figure 5), which may affect the clinical
reconstructed SPECT and PET images [159–161]. This a-priori interpretation of the acquired images [182].
known anatomical information can be introduced into the Patient motion has traditionally been detected through the use
reconstruction algorithm by using probabilistic image models of external markers, such as ECG-electrodes for cardiac motion
[162] or similarity measures between the anatomical and the or respiratory belts [183] as well as infrared/optical systems [184]
functional images [163]. for respiration-induced motion. Recently, the use of data-driven
methods has gained substantial interest for both stand-alone
Partial Volume Correction in PET and and multi-modality imaging systems [185–188]. Continuous
SPECT motion tracking can be used for motion compensation of PET
The partial volume effect (PVE) is related to the limited and MR images [189, 190]. In thoracic PET imaging, several
spatial resolution of the nuclear imaging system and affects the motion detection techniques have been proposed, through built-
quantitative accuracy of the images, particularly for small lesions in readout of the respiratory position and special radial-self
and brain structures (Figure 4). PVEs are caused by two different gating sequences, respectively [186, 187, 191]. Cardiac motion is
phenomena: the limited spatial resolution of the imaging system most commonly estimated by using cine-MR imaging and tagged
(Figure 4A) and the discrete image sampling of a continuous 3D MR imaging [192].
activity distribution (Figure 4B). PVE results in smearing of the Approaches toward respiratory and/or cardiac gating are
reconstructed activity levels and, thus, has a significant impact on commonly used to reduce motion-induced blurring in PET
their qualitative and quantitative assessment. and SPECT images, whereby the emission data is divided
A wide variety of partial volume correction (PVC) methods into gates that correspond to different respiratory or cardiac
have been developed in the past, most of them employing high- phases [185]. However, a more preferable solution is to
resolution anatomical information from a co-registered CT or perform motion compensation (MoCo) using the full data-
MR image as reference [164–167]. PVC methods can be grouped acquisition, both to reduce acquisition times and to improve
into two main categories: post-reconstruction and during- the signal-to-noise ratios in the PET or SPECT images.
reconstruction methods. Post-reconstruction methods include Therefore, different MoCo techniques have been proposed:
the region-based methods, such as the recovery-coefficient MoCo before image reconstruction (projection-based methods)

FIGURE 4 | Illustration of the partial volume effect (PVE) in medical imaging. (A) A circular source of uniform activity in a warm background region yields a measured
image in which part of signal emanating from the source is observed outside (spill-out) while part of the background signal is observed within the lesion (spill-in).
(B) The tracer distribution is sampled on a voxel grid and the contours of the voxels do not match the actual contours of the tracer distribution (Tissue-fraction).
FIGURE 5 | Effect of respiratory and cardiac motion on PET image quality. (A) Blurring effect due to cardiac motion in a patient scanned with 13N-NH3.
(B) Misalignment artifact between the PET-emission data and the corresponding MR-AC map. Misalignment artifacts like these are common in cardiac PET-imaging,
where they are known to cause false-positive findings in up to 40% of all studies [180]. Reprinted from Rausch et al. [181] with permission from Elsevier.
[193], during PET-image reconstruction—motion compensation (RTA). Recent studies have been performed to evaluate the
during image reconstruction (MCIR) [194], and after PET- performance of these three methodologies [196, 197]. More
image reconstruction [195]—Reconstruction Transform Average advanced methods, that use the synergistic information derived

from the simultaneous PET and MR data acquisition, have been [225, 226], such as body truncation, metal and respiratory
proposed to estimate [198] and to correct for motion in both artifacts, MR coils attenuation, etc. Some promising solutions
PET and MR images [189]. Other attempts focused on the for whole-body AC are currently under development, for further
implementation of joint MoCo and PVC approaches to further details we refer the reader to Leynes et al. [223], Mehranian et al.
improve the PET quantification of small lesions in regions that [225], Heußer et a. [227].
are susceptible to motion [199, 200].
In addition to respiratory and cardiac motion, non-periodic
and unpredictable motion can also occur during the scan. JOINT DATA EXPLORATION
Organ specific motion detection techniques have been developed
This section describes main efforts toward a fully-synergistic
for head and neck examinations, through the use of frequent
use of the anatomical and functional information available from
3D-MR navigators, which can be employed to apply motion
hybrid imaging examinations. In section Kinetic Modeling and
compensation (MoCo) to the PET images [201].
Image Derived Input Function (IDIF) we discuss the use of
While most of the aforementioned references were related to
image-derived input functions in the context of kinetic modeling,
PET/CT and PET/MR imaging, it is important to note that most
in section Multi-Parametric Imaging (MPI) we provide an
of these techniques are applicable also to SPECT [202], while
overview of the multi-parametric imaging studies performed
standard data-driven motion detection techniques for PET do
using SPECT/CT, PET/CT, and PET/MR systems. Finally, in
not work well for SPECT [203]. Nevertheless, the more advanced
sections In Vivo Disease Characterization and Image-Derived
Principal Component Analysis (PCA) and Laplacian Eigenmaps
Prediction Models we explore recent efforts in obtaining
(LE) methods for data-driven respiratory motion detection have
in vivo disease characterization and image-derived prediction
demonstrated good results for both PET and SPECT imaging
models.
[203, 204].
Kinetic Modeling and Image Derived Input

Novel MR-Based Attenuation Correction Function (IDIF)
(AC) Methods for PET/MR As discussed in section Quantification in PET and SPECT,
In PET/MR examinations the anatomical information used for absolute PET quantification requires the measurement
attenuation correction (AC) originates from the complementary of an input function, which is typically done by means
MR image information, which is not related to the attenuation of an arterial blood sampling. The measurement of an
properties of the material [205]. Moreover, the imaging of cortical arterial input function (AIF) is invasive, laborious and
bone is a challenge in MR given the fast relaxation times of stressful for the patient. Obtaining an image-derived input
solid materials [206]. As a consequence, it is not possible to function (IDIF) is a non-invasive alternative, whereby
distinguish between cortical bone and air in most MR sequences the input function (IF) can be directly obtained by
[207]. To address this issue, new AC methods had to be defining a volume-of-interest (VOI) in the PET images
developed, that can be categorized into three basic concepts [181] and using anatomical information from the MR or CT
(Figure 6): (i) segmentation-based methods, which are based on images to segment the tissue of interest to obtain the IDIF
a segmentation of MR images into different tissue classes; (ii) (Figure 7A).
atlas- or model-based approaches, which incorporate a-priory The concept of an IDIF has been successfully implemented
knowledge of attenuation properties of the investigated subject in clinical routine examinations for cardiovascular studies, due
from data bases; and (iii) reconstruction-based methods, which to the availability of large blood pools (i.e., left ventricle)
are based on a direct reconstruction of the attenuation and in the PET FOV [229, 230]. However in PET studies of
activity values from the emission data. the brain, calculation of the IDIF is challenged by two factors:
At present, standard AC approaches for whole-body imaging PVE [231, 232] due to the small size of the blood pools,
in clinical systems rely on segmentation-based methods [218, and subject motion [232, 233]. Various approaches have been
219], recently also in combination with atlas-based approaches proposed to extract an accurate IDIF that can be classified
incorporating the major bone structures into the AC [220, 221]. into PET-only based methods [232, 234–244], stand-alone PET
In general, these approaches perform reasonably well, although and MR-based methods [228, 245, 246], and fully-integrated
for specific application their accuracy may not be sufficient PET/MR-based methods [247–249]. Combined PET/MR can
[222]. Thus, several advanced AC methods have been explored potentially allow researchers to address the aforementioned
in conjunction with various types of PET/MR examinations challenges (PVE and subject motion) in an automatic way [228,
[217, 223, 224]. Most of the developed AC methods are tailored 248, 249], in addition to bearing a logistic advantage. It should
to brain examinations and provide acceptable accuracies (with be noted that various corrections (delay, dispersion, metabolite
deviations below 5% respect to CT-based AC) [217]. A selection correction) may be required to convert the measured blood IDIF
of available MRI based AC methods for the head is given to plasma IDIF.
in Figure 6. A detailed comparison of these methods can be An IF can be employed together with a physiological model
found in Ladefoged et al. [217]. However, for AC of body parts in order to calculate physiological parameters, such as metabolic
other than the brain as well as for AC of non-rigid hardware rate of glucose (umol/100 g/min) or blood flow (ml/100 g/min)
components (e.g., flexible surface coils), challenges still persist [250]. The creation of such parametric images can be divided into

FIGURE 6 | Illustration of popular MR-based AC methods using the same axial slice of AC maps of a patient processed with different AC methods: (A) Reference
CT-based AC; Standard methods: (B) standard DIXON-based MR-AC implemented in the Siemens mMR system (SW v. VB20), (C) UTE-based standard MR-AC for
brain examinations implemented in the Siemens mMR system (SW v. VB20); Template-based methods: (D) Koesters et al. [208], (E) Anazodo et al. [209],
(F) Izquierdo-Garcia et al. [210], (G) Burgos et al. [211], (H) Merida et al. [212]; MLAA-based methods: (I) Benoit et al. [213]; Segmentation-based methods: (J)
Cabello et al. [214], (K) Juttukonda et al [215], (L) Ladefoged et al. [216]. Figure adapted from Ladefoged et al. [217] (Courtesy of Claes N. Ladefoged, Rigshospitalet
Copenhagen, Denmark; Modified from the original image published under the creative commons license http://creativecommons.org/licenses/by-nc-nd/4.0/). Figure
published with the permission of the copyright holders (Claes N. Ladefoged).
three different methods: (i) graphical analysis, (ii) compartment where the cerebellum or the pons is often used as reference
model, and (iii) reference tissue model. The first two methods tissues.
require information on the non-bound tracer-activity available in
the blood.
Graphical analyses methods include the Gjedde-Patlak Multi-Parametric Imaging (MPI)
equation [251, 252], which describes irreversibly bound tracers, Multi-parametric imaging (MPI) has been of interest since
such as [18 F]FDG and the Logan-plot, which can be used to the adoption of standalone PET, CT, and MR imaging, but
describe the reversibly bound tracers [253]. Tissue-compartment gained further attention following the availability of combined
models have been proposed by Kety and Smith in 1948 for the imaging systems [257]. Combined, or dual-modality imaging
calculation of the blood-flow in the brain using nitric oxide systems facilitate multi-faceted and complex evaluations of
[254, 255]. Figure 7B represents a 2-tissue compartment model, tumor phenotypes, thus, promising an improved characterization
which is the most appropriate to evaluate the tracer dynamics of lesions and pathophysiology [258].
of FDG. Here, K1 is the influx-constant (amount of tracer In addition to the anatomical information provided by CT-
moving from the blood to the tissue), k2 the efflux-rate (amount images, quantitative assessment of physiological parameters
of tracer that returns to blood), CP the blood activity and extracted from CT-images in combination with functional PET-
CT the tissue concentration over time t. Compartment 1 (C1 ) images increase the diagnostic value [259]. For example, texture
represents the un-metabolized tracer and compartment 2 (C2 ) analyses (TA) of the tumor heterogeneity obtained from CT-
the metabolized tracer (where k3 represents phosphorylation images is frequently used in combination with functional PET
by hexokinase and k4 dephosphorylation) [256]. Reference data [259]. However, the TA varies significantly with the quality
tissue models are primarily employed for neurological studies of the underlying image data, thus, limiting the reproducibility

FIGURE 7 | Schematic view of the IDIF concept. (A) 1- PET coronal view showing the carotid arteries, 2- T1-MPRAGE image, 3- TOF MR angiography image of neck
region used to segment the carotid arteries, 4- PET coronal view co-registered with the segmented carotid arteries. (B) Illustration of the 2-tissue compartment model
commonly used for FDG tracer kinetics. Here, CP represents the blood activity and C1 , C2 the activity concentration of each tissue over time t. K1, k2, etc., are the rate
constants that define the rate of tracer movement between compartments. This figure was adapted from Sari et al. [228], with permission of SAGE Publications, Ltd.
of the procedure, particularly in the context of PET imaging PET/MR systems can help to shed new light on the mechanisms
[260]. that underlie structural changes in the brain through the
Fully-integrated PET/MR systems permit the quasi- use of targeted radio-labeled tracers in combination with
simultaneous acquisition and evaluation of functional and gadolinium-based contrast enhancement of MR [262]. Likewise,
structural information of patients, and, thus, support the the combination of PET and MR images has proven to add
multi-parametric assessment of these subjects, as shown for prognostic value for assessments of myocardial examinations
the patients with neurological disorders [261]. Specifically, [189, 263, 264], while the value of the multi-parametric images
the use of parametric imaging [section Kinetic Modeling obtained for oncological studies is still under evaluation
and Image Derived Input Function (IDIF)] of data from [265].

In Vivo Disease Characterization examination. Quantification in nuclear medicine examinations

Hybrid imaging plays an important role in the characterization of is not only a matter of proper imaging system performance.
several diseases [4]. Thanks to hybrid imaging lesion detection, The outcome of a study is influenced also by various factors
tissue delineation and therapy monitoring have become more related to imaging technology, biology and imaging physics
accurate [266]. Hybrid imaging has been key to cancer patient [290]. In PET/CT operations, for example, a significant variability
management [267], thanks also to its ability to depict tumor of system performance, examination protocols, and quantitative
heterogeneity in a morphological and functional context [260]. reporting across different centers has been described [291]. A
Given that conventional indices, such as standard uptake value similar variability in workflow has been observed in SPECT/CT
(SUV), maximum or metabolic tumor volume (MTV) are operations [292]. Although in SPECT/CT most readings are
insufficient to characterize malignancies [268], several groups based on a qualitative assessment of the tracer distribution,
have started to investigate the feasibility of in vivo tumor significant variation in quantitative evaluations of SPECT/CT
characterization in the context of textural evaluation [269]. examination can be expected from the use of CT-AC.
As a result of this initiative, first reports have appeared that This variability in quantification between systems and across
point at promising results of a quantitative assessment of sites is a major barrier to the utilization of quantitative nuclear
tumor heterogeneity in light of therapy response prediction medicine and hybrid imaging in larger cohort and multi-
[270, 271], disease-specific survival [272] as well as prognostic center studies [293]. To gain reproducible and statistically
stratification [273]. Meanwhile, challenges using textural features significant results, e.g., for the evaluation of a new drug
remain, since such calculations are highly sensitive to acquisition, or the usability of an imaging modality to assess treatment
reconstruction and sample size variations [274–276]. Overall, the response, a sufficient number of examinations has to be collected.
need of reproducibility evaluation as well as standardization of Since this is usually not possible within a single institution,
textural features is being acknowledged in the field [274]. data from several centers need to be pooled following the
The approach that considers medical images as data mining harmonization of imaging protocols [293]. Several guidelines
sources for large-scale in vivo feature evaluations is called have been put forward [294–296] and specific programs, namely
radiomics [277]. It is expected that with the introduction the accreditation programs of the EANM or the ACR, have been
of hybrid imaging, radiomics holds the potential to lead to launched to sensitize the imaging community and to help address
automated tumor characterization [278–280] and personalized this challenge toward pooled data evaluation.
treatment regiments in the future [281]. For more details, we In general, most of the factors influencing simple quantitative
refer to the companion review by Papp et al.2 in this journal issue. readings, as SUV, are understood and—in many cases—
corrections and workarounds exist [290]. However, with the
Image-Derived Prediction Models availability of more advanced image evaluation techniques,
Machine learning (ML) algorithms have the ability to identify such as ML-based approaches employing textural parameters,
key patterns and characteristics of large scale datasets [282]. new challenges for a standardized evaluation arise. Textural
While the concept of ML is not new, it has only recently parameters are strongly influenced by the choice of image
become popular thanks to recent advances in computational reconstruction, voxel size and post processing steps (e.g.,
power and capacities that made it feasible to handle large Gaussian filtering). Furthermore, the choice and definitions of
datasets. ML holds also a great potential for dealing with “big the textural analysis metrics vary widely and the evaluation
data” generated by hybrid imaging methods [280]. For example, techniques differ substantially, thus, rendering a comparison
ML has been successfully applied in hybrid imaging to predict between studies almost impossible [260, 297]. The need for
survival [283], treatment outcome [284], and tumor grading standardization efforts in the field of textural analyses has been
[285]. Furthermore, unsupervised ML allows the identification highlighted previously [260, 298, 299], and efforts are currently
of breast cancer subtypes [286]. For more details, we refer to the under way to address this challenge [260, 300–302].
companion review by Papp et al.4 in this journal issue.
OUTLOOK AND FUTURE TRENDS
MULTI-CENTRE STANDARDIZATION
Open Research Data, Sharing Knowledge
The performance of a SPECT or PET system is related to factors Clinical research is an essential building block for the concept
as detector type and geometry, the properties of the built in of efficient patient management. Research studies are generally
electronics and the implemented data processing. To characterize complex and the resulting data are valuable, not only to the
the system performance, standardized procedures are published principal investigator but to society as a whole [303]. Although
by the National Electrical Manufacturers Association (NEMA) today’s ubiquitous multi-modality imaging protocols produce an
[287–289]. While these standards are a good example how to abundance of qualitatively diverse data sets, there is a lack of
set up a basic set of measurements for the purpose of system genuinely integrative analysis schemes that could provide added
characterization and comparison, their results are generally value to a pure additive analysis.
not suitable to predict the quantitative accuracy of a clinical Moreover, many researchers remain reluctant to share their
data with an expert audience [304, 305] beyond describing
2 Papp et al. Personalizing medicine through hybrid imaging and medical big data them as part of peer-reviewed publications. In contrast, sharing
analysis. research data in a structured and tangible way has been shown

to yield benefits for both, the principal investigators of the study disentangle the coincidences originating from each tracer [317,
who generated the data as well as other experts [306] in the field 318].
who may re-use the data with alternative evaluation algorithms
to extract new information that may subsequently benefit patient Dual-Modality Tracers/Contrasts
management [303]. Obviously, a reliable anonymization or even Contrast-enhanced CT data as part of a combined PET/CT
pseudo-anonymization of the relevant data must precede any examination provides additional, helpful information in
type of data accrual and accessibility as part of public data comparison to non-enhanced PET/CT studies [319–321]. Here,
repositories. Frequently, the challenges associated with prior data the main benefit relates to a more precise anatomical localization
handling alone render such repositories a mighty wish rather of pathologies by differentiating lesions from surrounding
than a useful reality. structures. On the other hand, MR provides highly-detailed
Still, after data are properly anonymized and made available non-invasive anatomical image information and excellent soft
under an open data policy, the quality of such public tissue contrast [322], even in comparison to contrast-enhanced
Supplementary Material collections of published studies, at least, CT.
is frequently variable, and many times the re-use of these data Efforts are under way to develop dual-modality contrast in
is not possible [307]. The same holds true for the quality of PET/MR based on nanoparticle-based probes. Currently, super
alternative public data archives that were shown to contain paramagnetic iron oxide nanoparticles (SPIONs) are used that
incomplete data and data archived only partially in over 56% incorporate positron emitters (e.g., 52-Mn, 59-Fe, and 124-I) and
cases that prevented re-use [305]. contain small surface molecules (peptides, organic molecules)
Nevertheless, future trends in multi-modality imaging point that bind to tumor tissue [323, 324]. Although the physiological
toward the emergence of advanced database structures that functionality of the PET probe is limited by its attachment
include interactive 3D visualization tools and powerful data to a large nanoparticle, the combination provides high spatial
mining applications. The leading candidate for generating resolution (MR) with high sensitivity (PET).
such flexible database structures is the XML (eXtensible With the advent of hybrid microPET/SPECT/CT systems,
Markup Language) model [308] due to its flexibility and efforts to develop multi-tracer PET-SPECT studies have been
scalability. The flexibility of XML database structures allows made. Although the scattered photons from PET preclude to
the combination of patient data with similar disease within a obtain useful information in SPECT with simultaneously injected
common reference frame, allowing meta-analysis of data patterns PET/SPECT tracers [325, 326], sequential studies where the
distributed over many modalities. An example of such an SPECT radiotracer is injected and imaged first and the PET
overarching effort is the National Database for Autism Research radiotracer is injected and imaged in the presence of the SPECT
(NDAR, http://data-archive.nimh.nih.gov/#NDAR-anchor), an tracer have shown promising results [326].
NIH-funded data repository that aims to accelerate progress in
autism spectrum disorder (ASD) research through data sharing, Hybrid Imaging and Therapy (Planning,
data harmonization, and the reporting of research results. Follow-Up)
One of the major developments in radiotherapy in the coming
Multi-Tracer PET and SPECT Imaging years is the use of hybrid imaging for individualized biology-
Another interesting application is the multi-tracer SPECT or guided radiation therapy (RT) [327]. Given the information
PET imaging, which aims to image two or more tracers in a on the tumors provided by PET/CT and PET/MR imaging,
single scan, simultaneously characterizing multiple aspects of dual-modality PET-based imaging represents an optimal
physiology and function without the need for repeat imaging basis for RT individualization, especially in the context of
visits [309]. Tracer separation in multi-tracer SPECT takes intensity-modulated radiotherapy (IMRT). The combination of
advantage of the differences in the spectro-temporal properties IMRT and hybrid imaging enables the modulation of radiation
(differences in the gamma emission energies and dynamic dose distribution according to local phenotypic or micro-
behavior) of the radionuclides to identify the tracer distributions environmental variations in an individual tumor (aka “dose
[310, 311]. painting”) [328, 329]. The goal of the dose painting process is to
Multi-tracer PET must rely on differences in the kinetics select and delineate target volumes (and organs at risk) on the
and/or spatial distributions of the tracers, because the energy basis of complementary diagnostic information, thus, aiding in
of annihilation photons of all tracers is 511 keV. The different heterogeneous delivery of radiation within the tumor volume
techniques to separate multiple-tracer PET may be based by targeting radio-resistant areas. This approach is particularly
on the analysis of the different radioactive half-lives of the promising in treatment monitoring, by taking into account
radionuclides [312, 313], multi-tracer compartment models [314] the individual patient response and dynamically adjusting the
or generalized methods that make use of PCA to separate the treatment plan based on current outcome. Given the broad
tracers [315]. A recent development in multi-tracer PET is the selection of established PET tracers, hybrid imaging provides
combination of a pure and a non-pure positron emitter [316]. RT planning with patho-physiological information pertaining to
This technique relies upon detecting the auxiliary prompt gamma various molecular pathways of the tumor, including metabolism,
in coincidence with an annihilation event in order to measure proliferation, oxygen delivery and consumption as well as
triple-coincidence events originating from only one of the tracers, receptor or gene expression. Examples are [18 F]FDG [330] and
and use the spatial distribution of the triple coincidences to [18 F]/[11 C]choline [331–333] as surrogates for tumor burden,

[18 F]FLT as a surrogate for proliferation (or cellular growth Hybrid imaging is supported by continuous cross-specialty
fraction) [334], and hypoxia sensitive tracers such as [18 F]FMISO efforts on integrating hardware components and leveraging
[335] and [64 Cu]ATSM [336] as surrogates of cellular complementary signals for improved image quality and
hypoxia. quantitative accuracy of non-invasive assessments of the patients
On other hand, PET monitoring is a popular method for and subjects.
range verification of particle therapy: proton or hadron therapy To date, multiple evidence exists for the benefits of hybrid
[337]. Positron emitters are generated inside the patient during imaging that extend from increased diagnostic accuracy, faster
treatment, and therefore, by using PET imaging the delivered examinations to cross-fertilization of know-how from formerly
dose can be indirectly measured [338, 339]. This can be done distinct professional groups.
during the irradiation (on-line or in-beam PET), which is Hybrid imaging is able to provide unique information on
beneficial when imaging short-lived emitters [340], or after the diseases that—when pooled in larger-scale studies—can be
treatment in an off-site system (off-line), which can provide utilized in a “big data” approach to design automated, computer-
better counting statistics for relatively long-lived radionuclides based models for disease and therapy response prediction,
[341]. In on-line systems, the integration of PET imaging both of which benefit also from ongoing technological and
into the treatment environment poses geometric constraints, methodological improvements of hybrid imaging systems.
conditioning the imaging performance. In off-line imaging, full- Hybrid imaging invites stakeholders from a variety of
ring scanners are used, offering higher detection efficiency. scientific disciplines in an effort to provide diagnostic means that
However, transferring the patient to a separate system may cause help us understand the complex biological processes involved in
alignment errors or isotope washout [337]. a disease better and, thus, help patients today and in the years to
come.
Future Trends
In our opinion, future trends in the field of hybrid imaging relate
AUTHOR CONTRIBUTIONS
to:
1. The development of new advanced imaging technologies that JC-G collected the data and wrote sections Introduction,
allow for more precise and accurate information, such as the Basic Concepts of Hybrid Imaging, Detector Technology for
use of faster ToF detectors, the design of total-body systems CT, SPECT and PET, Image Acquisition and Reconstruction
with very high sensitivity, the introduction of organ-specific in CT, PET, and SPECT; Quantitative Data Corrections in
systems with very high spatial resolution and new probes for PET and SPECT; Anatomically-Driven PET/SPECT Image
contrast-enhanced PET/CT and PET/MR. Reconstruction; Partial Volume Correction in PET and SPECT;
2. The development of advanced quantitative corrections for and Multi-Tracer PET and SPECT Imaging. He also merged
hybrid imaging data. This encloses accurate techniques for and revised all the individual contributions from the other
attenuation and scatter correction of PET and SPECT data in authors and prepared the full version of the manuscript
hybrid systems, more efficient multi-modality techniques for with all figures and tables. IR wrote sections Time-of-Flight
patient motion correction, as well as advanced and efficient PET; Spiral PET, Continuous Table Motion; Novel MR-Based
methodologies for PVC of the lower resolution functional Attenuation Correction (AC) Methods for PET/MR; and Multi-
images. Center Standardization. LS wrote sections Organ-Specific System
3. The development of efficient and clinically viable multi- Design and Total-Body Systems; Kinetic Modeling and Image
modality protocols and computational frameworks that Derived Input Function (IDIF); and prepared all the figures of
can handle various large data cohorts. An essential feature the manuscript. ML wrote sections Motion Compensation and
of such integration efforts is the quantitative description Multi- Parametric Imaging (MPI). OM wrote section Outlook
of data properties, so that relationships in anatomical and and Future Trends. EM wrote sections MR Technology, Image
functional domains between complementing modalities Acquisition and Reconstruction in MR, and contributed to
can be expressed in a mathematically concise way. Thus, others. LP wrote sections In vivo Disease Characterization
taking advantage of high-level integration schemes, and Image-Derived Prediction Models. TB conceived the topic,
quantitative results are combined into data structures prepared the abstract and conclusions from the full version of
that provide a consistent framework for the application the manuscript and revised all the individual contributions. All
of both machine learning and advanced data mining authors participated in manuscript review.
techniques.
ACKNOWLEDGMENTS
CONCLUSION
The authors would like to thank Miklos Kovacs for the useful
Hybrid imaging is the physical combination of complementary discussions about SPECT systems and configurations, Claes
anato-metabolic imaging modalities, and, to date, relates mainly N. Ladefoged for kindly providing us with the image data
to combined SPECT/CT, PET/CT, and PET/MR imaging, for Figure 6 and Jun Bao for providing us with the technical
which are available for clinical use and small-animal research. specifications of the uMI PET/CT systems.

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published: 18 May 2018

Hybrid Imaging: Instrumentation and

State-of-the-art patient management frequently requires the use of non-invasive imaging

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SPECT/CT PET/CT PET/SPECT/ PET/MR

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MR specifications PET/MR integration – – – – – – – – – – – – – Fully integrated Sequential Fully integrated

N.A., data not available.

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PET/CT SPECT/PET/CT SPECT /MR PET/MR

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PET/CT SPECT/PET/CT SPECT /MR PET/MR

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MR PET/MR – – – – – – – Sequential Integrated and Sequential

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NaI BGO GSO LSO LYSO LaBr3 BaF2 LuAP

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Kinetic Modeling and Image Derived Input

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In Vivo Disease Characterization examination. Quantification in nuclear medicine examinations

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REFERENCES 23. Bettinardi V, Presotto L, Rapisarda E, Picchio M, Gianolli L, Gilardi MC.

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