Advanced magnetic resonance imaging (MRI) techniques, such as spectroscopy, perfusion, and functional imaging, have improved the imaging of brain tumors. In addition to the anatomic or structural information available with conventional MRI, advanced MRI techniques also provide physiologic information about tumor metabolism and hemodynamics. The authors review the physiology, techniques, and clinical applications of perfusion MRI, spectroscopy, functional MRI, and diffusion tensor imaging in the setting of neuro-oncology.
is an Assistant Professor, Department of Radiology,
is the Senior Neurodiagnostic fMRI Specialist, Department of
is an Instructor, and
is an Assistant Attending Physician, Department of Medical
is a Professor, Department of Radiology, Memorial Sloan-Kettering
Cancer Center, New York, NY.
The imaging of brain tumors has significantly improved with the
use of advanced magnetic resonance (MR) techniques, such as
spectroscopy, perfusion, and functional imaging. Conventional MR
imaging (MRI) provides mainly anatomic or structural information
about the brain. Unlike conventional imaging, advanced MR
techniques also provide physiological information concerning
metabolism and hemodynamics. These techniques not only aid in the
imaging diagnosis of brain tumors, they may also play a role in
clinical management of patients with brain tumors. A concise
compendium of the physiology, techniques, and clinical applications
of MR perfusion imaging, spectroscopy, functional MR imaging
(fMRI), and diffusion tensor imaging (DTI) in the setting of
neuro-oncology is reviewed in this article.
Brain tumors can induce angiogenesis or the formation of new
blood vessels. Hypoxia, which occurs as a tumor outgrows its blood
supply, can produce angiogenic cytokines; these cytokines are
responsible for angiogenesis.
Tumor vessels that are produced in this manner are histologically
abnormal and more permeable than normal. They are also disorganized
These vascular abnormalities and altered flow dynamics lead to
changes in blood volume and flow, which are exploited in MR
perfusion imaging. The most frequently used measure of perfusion in
neuro-oncology is the cerebral blood volume (CBV). The cerebral
blood volume (or the volume of blood passing through a portion of
the brain) is measured in milliliters of blood per 100 grams of
brain tissue (mL/100 g).
The most common perfusion technique is T2* dynamic
susceptibility imaging. The T2* effects of gadolinium result in
decreased signal intensity during the passage of gadolinium. The
change in signal intensity is plotted against time to form a signal
intensity time curve (Figure 1). The CBV is estimated from the area
encompassed by the curve, which is inverted in this case, since
there is signal loss. Repetitive imaging is performed shortly
before, during, and after the passage of gadolinium. Generally, 0.2
mmol/Kg of gadolinium is injected at a high rate using a power
injector. The CBV is normalized to uninvolved portions of the
brain. In cases in which an arterial input function is not
determined, only a relative CBV (rCBV) can be calculated. Dynamic
susceptibility perfusion imaging is based on the premise that
contrast material remains within the intravascular compartment.
High permeability or leakiness in regions of marked breakdown of
the blood-brain barrier (BBB) results in intravascular gadolinium
extravasating into the interstitial space. Extravasation can
significantly affect calculations and alter CBV values. Several
methods have been used to correct-or, more appropriately,
compensate for-the unwanted effect of extravasation on rCBV
calculations, including excluding portions of the signal intensity
time curve from the calculations. This corrective method still
leads to underestimation of the rCBV. Another method, sloping
baseline, leads to artifactually high rCBV. Using T1-weighted
dynamic perfusion imaging can eliminate the problem with the
breakdown of the BBB and permeability. In this technique, tumor
enhancement or permeability itself is used to calculate the rCBV,
so it does not need to be corrected.
In general, high-grade brain tumors have greater rCBV than
low-grade lesions (Figure 2).
MR perfusion can help identify and localize higher grade components
of tumors in guiding stereotactic biopsy and can also provide a
noninvasive estimate of tumor grade (Figure
Since the enhancing or even the T2 borders of gliomas do not
represent the true margins of the tumor, MR perfusion can be more
sensitive in defining the true extent of gliomas than can anatomic
Better delineation of tumor borders can help in radiation and
surgical planning. In the future, MR perfusion imaging will
probably play a role in better defining tumor margins for radiation
and surgical planning.
Differentiating tumor recurrence from radiation necrosis is a
problem that clinicians and radiologists face frequently. It should
be noted that cases of pure tumor recurrence and radiation necrosis
occur in only a minority of cases. The majority of cases fall
within a spectrum containing a mixture of both tumor and necrosis.
This adds further complexity to reaching a correct diagnosis.
Unlike tumors, which have elevated rCBV, radiation necrosis has
been shown to have diminished rCBV (Figure 4).
Since a significant number of patients fall within the spectrum,
perfusion imaging is of limited value in differentiating between
the two. The advantage of MR perfusion CBV data is its high
positive predictive value for the presence of high-grade
malignancy. In other words, if the CBV maps reveal elevated
perfusion, there is tumor present. The specificity of the
diagnostic task can be increased when perfusion imaging is combined
with MR spectroscopy.
Measurements of rCBV have been shown to be more useful in
assessing response to radiotherapy in patients treated with
stereotactic radiosurgery (SRS).
The vascularity of metastases can decrease within a few weeks of
treatment; however, the volume of enhancement might not change for
several months. MR perfusion imaging seems promising in the
follow-up of patients with brain metastasis, but more research is
necessary to evaluate its potential.
Clinical applications of proton magnetic resonance spectroscopy
(1H-MRS) are increasing as the techniques and hardware have become
more robust and user-friendly. Proton MRS provides biochemical and
metabolic information about tumors and normal brain.
The information obtained from 1H-MRS is unique and independent of
that obtained from other MRI techniques. In their study of
pediatric brain tumors, Tzika et al
showed that there is no correlation between the metabolic profile
of tumors and other imaging parameters, such as enhancement,
diffusion, and rCBV.
Spectroscopy can be done in single- or multivoxel (MRS imaging)
forms. The 2 most commonly used methods for volume
selection/excitation are stimulated echo acquisition mode (STEAM)
and point-resolved spectroscopy sequence (PRESS). In general,
shorter echo times are better achieved with STEAM; however, it is
more sensitive to motion.
In theory, for the same total echo time, the signal of PRESS is
twice as great as that of STEAM; PRESS is also less sensitive to
motion. With improving software, PRESS seems to be the most
commonly used method of volume selection in clinical practice at
The advantage of single-voxel 1H-MRS is its short acquisition
time (approximately 5 minutes). The down side is that it lacks
spatial resolution and cannot be used to better define the true
extent of a glioma. Histologically, gliomas are heterogeneous, and,
therefore, single-voxel spectroscopy cannot be used to map regional
metabolic variation. In other words, single-voxel spectroscopy
alone cannot reliably define the highest-grade components of the
tumor. It may also suffer from significant averaging with adjacent
normal brain tissues.
In the spectroscopy literature, the most commonly used echo
times are 144 msec and 270 msec. At these long echo times, the
spectrum is dominated by 5 different metabolite peaks. These are
the choline (Cho)-containing compounds, creatine (Cr),
N-acetylaspartate (NAA), lactate, and lipid (Figure 5). The choline
peak reflects cell membrane turnover. Creatine is a good surrogate
for energy synthesis, and NAA is a marker that is exclusive to
neuronal cells. Lactate results from anaerobic metabolism and is
detected in necrotic tumors and infarcted tissue. Cellular and
myelin breakdown products result in prominent lipid peaks. In
tumors, choline-containing compounds are increased, and NAA is
decreased relative to uninvolved or normal brain tissue.
This pattern of metabolic change is the spectroscopic hallmark of
Combined with MRI, MRS can aid in the evaluation of tumor type
and grade. The higher-grade gliomas tend to exhibit higher Cho/Cr
and Cho/NAA ratios. The high-grade gliomas also tend to have lipid
and lactate as the result of necrosis (Figure 6).
MR spectroscopy can help differentiate enhancing tumor from other
causes of enhancement (mainly necrosis) and is more specific in
differentiating nonenhancing tumor from edema and other causes of
T2 prolongation. These qualities have been exploited in order to
better define the true extent and morphology of gliomas. This
information has the potential to significantly alter target volumes
and doses in radiation therapy of brain gliomas when compared with
conventional radiotherapy. Although this is an attractive concept,
there are no studies to show benefits, changes in failure patterns,
or improved survival. MR spectroscopy is utilized more and more by
different groups in assessing response to therapy in patients with
primary brain tumors or metastases.
MR spectroscopy can noninvasively enable the distinction between
a solitary metastasis and high-grade gliomas, particularly when
combined with perfusion MR imaging. In their study, Law et al
showed that measurements of Cho and mean rCBV in the perienhancing
region are useful in differentiating solitary metastases from
high-grade gliomas. In the perienhancing region, T2 prolongation is
partly due to tumor infiltration (nonenhancing tumor) in patients
with high-grade gliomas. Whereas in the case of metastases, the
hyperintensity surrounding the region of enhancement is due to
vasogenic edema or nonspecific treatment effects rather than
infiltrating tumor. Therefore, elevated levels of choline and/ or
rCBV surrounding a peripherally enhancing mass reflect tumor
infiltration in a high-grade glioma (Figure 7).
As with perfusion MRI, MRS is also useful in estimating tumor
grade. It is commonly observed that the Cho/Cr ratio increases with
However, because of the innate heterogeneity of brain tumors, there
is a significant overlap between Cho/Cr levels and tumor grade.
Following treatment, MRS has a limited role in the assessment of
patients. Frequently, there is a mixture of tumor and necrosis
after therapy. This limits the utility of MRS in differentiating
residual/recurrent tumor from radiation necrosis, as is the case
with MR perfusion. As a tumor responds to treatment, the choline
decreases and lactate and/or lipids may increase.
MR spectroscopy can play a useful role after treatment in assessing
the therapeutic response. This is particularly important for early
detection of treatment failure so that an ineffective treatment can
be modified prior to a significant progression of disease.
Functional MRI is used for the purpose of neurosurgical planning
and neurologic risk assessment in the treatment of brain tumors.
It localizes the eloquent cortices controlling language, motor, and
memory functions. The results of an fMRI study can alter a
neurosurgical approach to a tumor, suggest that surgery is a safe
option in cases in which it might not otherwise have been offered,
or steer a clinician away from neurosurgery and toward other
treatment options when the risk of damage to the eloquent cortex is
Functional MRI is commonly used to map language function.
It is used to localize the areas of the cortex working to support
speech and to determine hemispheric dominance for language (Figure
8). Because fMRI is based on a noninvasive, endogenous signal, it
has the potential to replace the invasive Wada test (also known as
the intracarotid amytal test), which is the current gold standard
in language and memory lateralization.
Functional MRI has revealed unexpected hemispheric language
dominance in both adults and children.
In a case described by our group,
a 62-year-old right-handed man with a mostly nonenhancing left
temporoparietal glioma in the expected anatomic location of
Wenicke's area presented without language impairment. The fMRI
revealed split hemispheric dominance for language, with Broca's
area localizing to the left hemisphere and Wernicke's to the right
hemisphere. Intraoperative electrocortical stimulation confirmed
the fMRI results, and the patient underwent gross-total resection.
This patient might not otherwise have been offered an operation had
the fMRI not suggested atypical language localization.
Language paradigms vary with the location of the tumor.
Typically, for frontal lesions, the patient will perform tasks such
as generating words to a presented letter or verbs to visually
presented nouns, punctuated by periods of rest. For posterior
language localization, patients can be asked to name pictures or
fill in the appropriate missing word in a sentence. While targeted
testing is preferable, often both Broca's and Wernicke's areas are
activated during both productive and receptive language tasks,
making it not essential to tailor the language task to the lesion
location. However, it should be noted that posterior language
function (Wernicke's area), like many cognitive tasks, can be
difficult to measure in patients.
A targeted approach may help lessen the variability in capturing
this sometimes elusive language area.
The Wada test produces information about both language and
memory function. As a result, the ability to use fMRI to
noninvasively measure both language and memory function may further
displace the Wada test. There is as yet no commonly accepted set of
memory tasks for the purpose of neurosurgical planning. Golby et al
use a "novel versus repeated" protocol through which verbal memory
and spatial memory can be measured. In this protocol, the patient
is presented with novel and repeated images of faces, patterns,
scenes, and word pairs (in separate trials). The analysis yields
those areas that are active during the novel trials in which the
patient encodes the new stimuli. As noninvasive, repeatable
techniques, such as fMRI, improve in the measurement of hemispheric
dominance for memory and language, invasive tests, with their
associated morbidity (such as the Wada test), will be replaced.
Motor mapping, by contrast, is relatively easy for cognitively
impaired patients to perform and produces consistent and reliable
Often, patients perform cued movements of the fingers, feet, and/or
tongue, depending on the location of the lesion (Figure 9).
Localizing the motor strip and coregistering the results to a
surgical scan prior to a neurosurgical intervention can help guide
the direct cortical stimulation during an awake craniotomy and
possibly shorten operation time. In some cases, using fMRI to
confirm the expected location of the motor strip may avoid awake
Diffusion tensor imaging: A way to see beyond the gray
Although blood-oxygen-level-dependent (BOLD) fMRI is able to
directly visualize the exact location of a functional area of the
brain adjacent to a brain tumor,
there is a limitation in that the technique can depict activation
only in the cortical gray matter. Therefore, the information
provided to the operating neurosurgeon is limited to the cortex.
Brain tumors also invade the white matter,
however, BOLD fMRI is not able to provide accurate information
about the location of major white matter tracts. Accidental
resection or transection of a major white matter tract can lead to
There are 2 main reasons why preoperative identification of
white matter tracts is important. First, accurate localization of
important white matter tracts can affect the decision of whether or
not to operate. For example, if the main mass of the tumor
straddles the corticospinal tract, a neurosurgeon may be averse to
even at-tempting a gross total resection. Clearly, knowledge of the
location of the corticospinal tract in such a case would be
advantageous, since the neurosurgeon would not have to perform a
craniotomy, operate on the brain, and perform direct white matter
stimulation only to discover that the tumor is inoperable.
Secondly, preoperative localization of important white matter
tracts is essential in surgical planning. For example, in a tumor
that involves the corona radiata, it is often very difficult, if
not impossible, to determine the relationship of the tumor to the
corticospinal tract or the thalamocortical tract. This task becomes
even more difficult with the inevitable presence of mass effect and
infiltration of normal structures by tumor. Consequently, the
neurosurgeon may assume that the majority of the tumor to be
resected is anterior to the corticospinal tract, only to discover
during the operation that in reality, the corticospinal tract is
posterior to the tumor and that the initial approach taken has been
Diffusion tensor imaging
is a new MRI technique that is sensitive to directional movements
of water molecules and that allows the identification of functional
white matter tracts in vivo. Diffusion tensor imaging has the
potential to establish spatial relationships between eloquent white
matter and tumor borders and provide clinically valuable
information to assess the progression and regression of white
matter tracts as a result of tumor growth or resection.
In gray matter, it is usually sufficient to characterize the
diffusion characteristics with a single apparent diffusion
co-efficient (ADC), because measured water diffusivity is largely
independent of the orientation of the tissue. However, in an
anisotropic area, such as white matter, where the measured
diffusivity is known to depend upon the orientation of the tissue,
a single ADC is not able to describe the orientation-dependent
water mobility in the tissue. Diffusion tensor imaging, which is
based on the orientation-dependent water diffusion, can be achieved
using a single-shot diffusion-weighted (DW) spin-echo echo-planar
imaging (EPI) pulse sequence, in which 2 symmetric trapezoidal
gradient pulses are added around a 180° refocusing pulse in the
required gradient channel. Sets of DW-EPI images are collected with
diffusion gradients applied sequentially along at least 6
predetermined directions. From the DTI data, the 6 independent
elements of the diffusion tensor can be calculated for each pixel.
In tensor theory,
the directions of the main axes represent the so-called
eigenvectors and their length the so-called eigenvalues of the
tensor. Diagonalization of the tensor can be used to calculate the
) and the eigenvector. The vector corresponding to the largest
eigenvalue represents the direction in which water diffusion is
greatest and is assumed to correspond to the predominant fiber
orientation within each voxel. The elements of the tensor are used
to yield a mean diffusivity map (D) and the fractional anisotropy
is an indicator of free water fraction.
is used to measure the fraction of the total magnitude of
that is anisotropic and has a value of 0 for isotropic diffusion (λ
) and 1 for complete anisotropic diffusion (λ
=0). Therefore, it describes deviation from isotropic diffusion.
have shown that neoplasms and surrounding edematous brain have an
increase of free water fraction (high
value) and loss of structural organization (reduced
A number of recent developments have led to a new application of
. This application uses diffusion tensor data to identify specific
white matter tracts as opposed to white matter tracts in general
(Figure 10). For example, one can determine the location of the
corticospinal tract or the thalamocortical tract and differentiate
these tracts from all other white matter tracts in the corona
radiata. The ability to exactly define specific tracts traversing
the corona radiata and other nebulous white matter structures has
already had an impact on the treatment of brain lesions. A number
of recent publications have shown re-markable images of specific
white matter tracts in normal subjects using diffusion
However, this technology has just made its appearance and will no
doubt expand even further.
The integration of advanced imaging techniques (such as fMRI,
spectroscopy, DTI, and perfusion imaging) will offer increasingly
detailed information about pathologic processes. Furthermore, it is
hoped that such detailed information will aid in the development of
new treatments and will improve our understanding of the mechanism
underlying neurological disorders.