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Multimodality Imaging
Introduction
Michael Moseley, PhD; Geoffrey Donnan, MD
N
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functional imaging for primary-to-metastatic cancer
screening of the body,3– 4 neuroassessment of gliomas,5
integrated stroke imaging exams,6 and functional neuroimaging exams.7
Newer tools seen in integrated neuroimaging methodologies that possess potential multimodal utility include
near-infrared spectroscopy (NIRS) or optical imaging for
real-time assessment of wavelength-specific absorption of
photons by oxygenated and deoxygenated tissues.8 –9 NIRS
is promising in that the contrast mechanism for the signals
is closely related to that of intrinsic optical imaging of
exposed cortex using visible light. Because of this, NIRS is
an inexpensive means of assessing the newborn or the
ischemic brain oxygenation. As such, it is ideal for
combination studies in the MR scanner, for example. NIRS
has only recently been used to investigate functional
activation of the human cerebral cortex, although effort has
begun to use imaging systems that allow the generation of
images of a larger area of the subject’s head and, thereby,
the production of maps of cortical oxygenation changes.10
A second new field with multimodal potential is the
incorporation of two-dimensional electroencephalography
(EEG) and magnetoencephalography (MEG) techniques.
The clear utility of EEG/MEG lies in the fact that the
observed signals are directly coupled to neuronal electrical
activity. That is, EEG and MEG reflect the electric
potential and magnetic fields resulting from synaptic
transmembrane currents in neurons. Importantly, the EEG
and MEG scans can be rapidly and noninvasively acquired
as the neuronal activity is being monitored, as in epilepsy,
for example. Because of this, many new reports of the
untidy of acquiring the EEG signal together with and
within the functional MRI (fMRI) examination have appeared to shed new light on the high-speed dynamics of
neuronal activation and activation center communication
and processing.11–12
In contrast to many of the imaging modalities mentioned, fMRI provides good spatial localization (0.5 to
2 mm, limited only by the signal-to-noise ratio) of an
increased blood oxygenation activity with a relatively
good temporal resolution (0.1 to 10 seconds) by measuring
the blood oxygenation level– dependent change in image
oninvasive “multimodal” in vivo imaging is not just
becoming standard practice in the clinic, but is
rapidly changing the evolving field of experimental imaging of genetic expression (“molecular imaging”). The
development of multimodality methodology based on nuclear medicine (NM), positron emission tomography (PET)
imaging, magnetic resonance imaging (MRI), and optical
imaging is the single biggest focus in many imaging and
cancer centers worldwide and is bringing together researchers and engineers from the far-ranging fields of
molecular pharmacology to nanotechnology engineering.
The rapid growth of in vivo multimodality imaging arises
from the convergence of established fields of in vivo
imaging technologies with molecular and cell biology. The
cross-pollination of these disciplines has been accelerated
in part by the establishment of the National Institutes of
Health NCI P20 and P50 awards, for example, and by the
sheer potential of the technology.
Multimodality imaging is widely considered to involve the
incorporation of two or more imaging modalities, usually
within the setting of a single examination using, for example,
dual- or triple-labeled optical or nuclear medicine “reporter”
agents or by performing ultrasound or optical studies within
the MR, single-photon emission computed tomography
(SPECT), or x-ray computed tomography (CT) environment.
Clinically, the best example of multimodality imaging is seen
in the rapid evolution of PET-SPECT and PET-CT scanner
hybrids. The PET modality has developed into perhaps the
most used “multimodal” imaging method. The incorporation
of PET into single, hybrid, and multimodality units to provide
functional (typically from injected F-18DG studies) and
anatomic information is becoming extremely popular,1–2 so
much so that, for example, PET/CT hybrids can be found in
outpatient screening centers located in shopping malls.
The role of any multimodal imaging approach ideally
should provide the exact localization, extent, and metabolic activity of the target tissue, yield the tissue flow and
function or functional changes within the surrounding
tissues, and in the topic of imaging or screening, highlight
any pathognomonic changes leading to eventual disease.
Multimodal clinical NM, PET, and MRI techniques have to
date fallen into the growing fields of molecular and
Received July 20, 2004; accepted August 5, 2004.
From the Department of Radiology (M.M.), Stanford University, Stanford, Calif; and the University of Melbourne and National Stroke Research
Institute (G.D.), Victoria, Australia.
Correspondence to Dr Michael Moseley, 1291 Welch Road, Lucas Center, P286, Stanford, CA 94305. Email [email protected]
(Stroke. 2004;35[suppl I]:2632-2634.)
© 2004 American Heart Association, Inc.
Stroke is available at http://www.strokeaha.org
DOI: 10.1161/01.STR.0000143214.22567.cb
2632
Moseley and Donnan
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intensity response.13 This change in signal depends on a
number of physiological features, such as the concentration of deoxygenated hemoglobin, blood flow, regional
proton density, and blood volume. Like many modalities,
however, inferences about neuronal activity made from the
fMRI examination is limited by our real understanding of
the coupling between the observed blood flow– dependent
signals and the real neuronal electrical activity within the
region of the signal change. Nonetheless, fMRI is becoming a potentially exciting area for multimodality imaging.
Functional neuroimaging using EEG together with fMRI,
with its insight into blood oxygenation level– dependent
dynamics and relationship to the evoked neuronal magnetic fields, has become the new event horizon in functional neuroimaging. This is also true for a number of
novel approaches using information from the NIRS signals
acquired during the fMRI examination.14 –15 The correlation of the observed electric/magnetic, optical, and MRI
signals to biophysical models of neuronal circuitry is
state-of-the-art in fMRI research. Notwithstanding, it is
noted that in that most tomographic imaging methods have
a relatively course resolution, the observed effects reflect
the averaged activity of thousands or millions of neurons.
This will require new modeling approaches, in which local
populations of neurons are treated as statistical ensembles,
for example.
A great deal of emphasis has been seen in the development
of new and novel MR contrast agents, largely because MR
has the superior spatial and temporal resolution in the
volumetric 2-D and 3-D tomographic imaging technologies.
Emerging imaging-based assays of vascular status beyond the
conventional knowledge of the microvascular permeability to
a blood-borne MR-visible tracer extend to receptor ligands
bound to gadolinium taking advantage of binding to bloodborne molecules such as albumin or thrombin. More recently,
we have seen transgene expression (␤-galactosidase, tyrosinase, engineered transferrin receptor) being visualized using
T1-shortening contrast MRI.16 In addition, macrophages can
be marked with certain iron-containing contrast agents which,
through accumulation at the margins of glioblastomas, ameliorate the visual demarcation in MRI. Finally, the field of
labeling exogenous “stem” cells with MR-sensitive ion nanoparticles has emerged to a near-clinical reality in which
implanted or injected cell trafficking and assimilation can be
monitored by MR.17
Beyond the clinics, there is also a growing interest in
building and designing dedicated devices for specific
applications, such as high-resolution scanners for imaging
small animals of use in the many new molecular imaging
centers appearing worldwide for reporter gene-expression
imaging studies in small animals.18 –20 The coupling of
nuclear and optical reporter genes represents only the
beginning of far wider applications of this research.
Initially, fluorescence and bioluminescence optical imaging, in providing a cheaper alternative to the more intricate
microPET, microSPECT, and microMRI scanners, have
gathered the most focus to date. In the end, however, as
animal models develop in complexity and size, the volumetric tomographic technologies, which offer deep tissue
Multimodality Imaging
2633
penetration and high spatial resolution, will be married
with noninvasive small animal optical imaging.
The presentations at the 2004 Princeton Conference in
Baltimore, Md, that highlighted the development and new
topics in multimodality imaging deal with the efforts to
bring NM, encephalography, MRI, and optical techniques
into a clinical and human neuroimaging reality. Much of
the attention within this session deals with the major
challenge to all attempts to integrate multimodality approaches arising from the realization that distinct physiological mechanisms underlie the signal generation for
different imaging modalities. As was made clear during
this multimodality imaging session, much of the work to
be done in the near future will focus on several topics.
First, we need an understanding of the coupling between
the measured signals and the underlying neuronal or
metabolic activity of a tissue to relate the observed
electric/magnetic, optical, and MRI signals to biophysical
models of neuronal circuitry or genetic expression.21
Second, we need to move beyond our understanding of the
expression of upregulated endogenous genes, coding for
simple transporters and hexokinase/thymidine kinase
genes. Third, we should explore the molecular behaviors of
tissues or tumors that would serve as specific targets for
patient-tailored therapies. We feel that the field of multimodal imaging is clearly directed to providing noninvasive
analyses of both endogenous and exogenous gene expression in the “molecular imaging” animal models that are
effectively translating new treatment and therapy strategies
from experimental into clinical applications that are poised
to make clear clinical impacts.
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Multimodality Imaging: Introduction
Michael Moseley and Geoffrey Donnan
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Stroke. 2004;35:2632-2634; originally published online September 30, 2004;
doi: 10.1161/01.STR.0000143214.22567.cb
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