Comparison Between Echo Contrast AgentSpecific Imaging

Modes and Perfusion-Weighted Magnetic Resonance

Imaging for the Assessment of Brain Perfusion
Saskia H. Meves, MD; Wilko Wilkening, MSc; Tammo Thies, BA; Jens Eyding, MD;
Thilo Hlscher, MD; Michael Finger, PhD; Gebhard Schmid, MD; Helmut Ermert, PhD;
Thomas Postert, MD; for the Ruhr Center of Competence for Medical Engineering

Background and PurposeContrast burst imaging (CBI) and time variance imaging (TVI) are new ultrasonic imaging
modes enabling the visualization of intravenously injected echo contrast agents in brain parenchyma. The aim of this
study was to compare the quantitative ultrasonic data with corresponding perfusion-weighted MRI data (p-MRI) with
respect to the assessment of brain perfusion.
MethodsTwelve individuals with no vascular abnormalities were examined by CBI and TVI after an intravenous bolus
injection of 4 g galactose-based microbubble suspension (Levovist) in a concentration of 400 mg/mL. Complementary,
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a dynamic susceptibility contrast MRI, ie, p-MRI, of each individual was obtained. In both ultrasound (US) methods and
p-MRI, time-intensity curves were calculated offline, and absolute time to peak intensities (TPI), peak intensities (PI),
and peak width (PW) of US investigations and TPI, relative cerebral blood flow (CBF) and relative cerebral blood
volume (CBV) of p-MRI examinations were determined in the following regions of interest (ROIs): lentiform nucleus
(LN), white matter (WM), posterior (PT), and anterior thalamus (AT). In addition, the M2 segment of the middle cerebral
artery (MCA) was evaluated in the US, and the precentral gyrus (PG) was examined in the p-MRI examinations. In
relation to a reference parenchymal ROI (AT), relative TPIs were compared between the US and p-MRI methods and
relative PI of US investigations with the ratio of CBF (rCBF) of p-MRI examinations in identical ROIs.
ResultsMean TPIs varied from 18.35.0 (AT) to 20.15.8 (WM) to 17.24.9 (MCA) seconds in CBI examinations and
from 19.45.3 (AT) to 20.44.3 (WM) to 17.34.0 (MCA) seconds in TVI examinations. Mean PIs were found to vary
from 581.9342.4 (WM) to 1522.9574.2 (LN) to 3400.9621.7 arbitrary units (MCA) in CBI mode and from
7.54.6 (WM) to 17.54.9 (LN) to 46.37.1 (MCA) arbitrary units in TVI mode. PW ranged from 7.34.5 (AT) to
9.14.0 (LN) to 24.312.8 (MCA) seconds in CBI examinations and from 7.13.9 (AT) to 8.73.5 (LN) to
26.718.2 (MCA) seconds in TVI examinations. Mean TPI was significantly shorter and mean PI and mean PW were
significantly higher in the MCA compared with all other ROIs (P0.05). Mean TPI of the p-MRI examinations ranged
from 22.06.9 (LN) to 23.06.8 (WM) seconds; mean CBF ranged from 0.00930.0041 (LN) to 0.00430.0021
(WM). There was no significant difference in rTPI in any ROI between US and p-MRI measurements (P0.2), whereas
relative PIs were significantly higher in areas with lower insonation depth such as the LN compared with rCBF.
ConclusionsIn contrast to PI, TPI and rTPI in US techniques are robust parameters for the evaluation of cerebral
perfusion and may help to differentiate physiological and pathological perfusion in different parenchymal regions of the
brain. (Stroke. 2002;33:2433-2437.)
Key Words: contrast media magnetic resonance imaging, perfusion-weighted perfusion
ultrasonography, Doppler, transcranial

I n recent years, there have been advances in ultrasound

(US) technology enabling the identification of perfusion in
a variety of parenchymal organs.1,2 The discovery that con-
trast microbubbles resonate and create backscatter signals not
only at the fundamental (transmitted) frequency but also at
multiples (harmonics) of this frequency is used in harmonic
imaging because tissue produces a smaller harmonic signal
than contrast microspheres.3,4 Various studies have shown
that transcranial harmonic imaging enables identification of
parenchymal cerebral echo contrast enhancement under phys-
iological and pathological conditions.510 More recently, it
has been observed that diagnostic US transmitted at high

Received February 25, 2002; final revision received May 30, 2002; accepted May 31, 2002.
From the Departments of Neurology (S.H.M., T.T., J.E., M.F., T.P.), Electrical Engineering (W.W., H.E.), and Radiology (G.S.), Ruhr University,
Bochum, and Department of Neurology, University Regensburg, Regensburg (T.H.), Germany.
Correspondence to Dr T. Postert, MD, Department of Neurology, St. Vincenz-Krankenhaus, Kiesau 14, D-33098 Paderborn, Germany. E-mail
t.postert@vincenz.de
2002 American Heart Association, Inc.
Stroke is available at http://www.strokeaha.org DOI: 10.1161/01.STR.0000032246.85531.8E

2433
 2434 Stroke October 2002
energy levels may destroy or modify the morphology of
microbubbles. These changes in microbubble shape and size
are reflected in the amplitude and spectral energy distribution
of the ultrasonic echoes so that short sequences of 6 to 10
pulses per line can reveal the presence of microbubbles. The
changes are then detected as broadband noise in the Doppler
spectrum (contrast-burst imaging [CBI]) or as characteristic
features of microbubbles using dedicated algorithms (time
variance imaging [TVI]). The result of the detection is
preferably displayed in color-coded US images.11 In 2 pilot
studies, it has been shown that echo contrastspecific imaging
modes exploiting this phenomenon, like CBI and TVI, are
sensitive techniques for the identification of parenchymal
microbubble distribution in the brain.12,13 A major disadvan-
tage that all US techniques have in common is the fact that
physical properties like nonlinear relationship between mi-
crobubble concentration and optic intensities14 and the depth-
dependent attenuation of the received harmonic signals make
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absolute quantification of peak intensities (PIs) impossible.
Furthermore, the diagnostic value of different US param-
eters is unknown because there has been no comparative
study between US techniques and reference methods. Vali-
dated indicators of absolute quantification of cerebral blood
flow (CBF) and cerebral blood volume (CBV) are PET15 and
xenon CT.16 Perfusion-weighted MRI (p-MRI) provides
semiquantitative information of brain perfusion that can be
easily compared with recently developed US perfusion meth-
ods. The present study was designed to evaluate the reliability
of quantitative parameters of US brain perfusion examina-
tions compared with corresponding p-MRI data.
Material and Methods
Subjects
Twelve patients (8 women, 4 men; mean age, 38.3 years; range, 26
to 50 years) without history of cerebrovascular or cardiovascular
disease with adequate acoustic temporal bone window were included
in the present study after informed consent was obtained. Exclusion
criteria were pregnancy, galactosemia, abnormal extracranial and
transcranial color-coded real-time sonography, abnormalities in T1-
and T2-weighted MRI examinations, and pathological blood pres-
sure or pulse rates. The study was approved by the local ethics
committee.
Ultrasound Examinations
Routine Color-Coded Duplex Examination of the
Extracranial and Intracranial Brain-Supplying Vessels
and CBV Measurements
We performed all examinations using a Siemens Sonoline Elegra US
system (Siemens Medical Systems, Inc, Ultrasound Group) equipped
with a 7.5-MHz linear-array transducer for the extracranial arteries
and a 2.5-MHz phased-array transducer for the intracranial vessels.
For diagnosis of an occlusion or a high-grade stenosis, criteria
identical to those in previously published studies were used.17,18 In
all patients, CBF volume was calculated according to Schning and
Scheel.19 CBF volume was determined as the sum of the flow
volumes of the internal carotid and vertebral arteries of both sides.
Physical Principle of CBI and TVI
CBI and TVI have been introduced in a recently published article.13
Briefly, both US techniques exploit the fact that microbubbles
undergo partial or complete destruction or splitting when exposed to
a high-energy ultrasound field. CBI, which is derived from power
Doppler, uses short sequences of typically 6 broadband pulses with
an elevated output power level to minimize acquisition time, im-
prove axial resolution, and optimize microbubble destruction. Pro-
cesses associated with the destruction of microbubbles produce
broadband noise in the Doppler spectrum that partially passes the
wall filter and can be displayed color coded as in conventional power
Doppler. These signals can be obtained even from nonmoving or
very slowly moving microbubbles and are consequently associated
with perfusion. TVI uses a different processing of the echo data. This
technique extracts the amplitude and spectral slope from 10 echoes
acquired per beam line. The spectral slope is a parameter describing
the symmetry of the power spectrum with respect to the center
frequency. Both parameters, amplitude and spectral slope, will vary
over time if the multiple insonifications alter the structure of the
microbubbles. TVI identifies characteristic variation using a stochas-
tic model for bubble destruction and then quantifies these variations.
Protocol of the Examination With Echo ContrastSpecific
Imaging Modes
US examinations were performed unilaterally with the transtemporal
approach. An axial diencephalic plane was adjusted by slightly
tilting the transducer toward the parietal lobe. The third ventricle,
adjacent hypoechogenic thalamus, and frontal horns of the lateral
ventricles were orientation landmarks. Complementarily, visualiza-
tion of the M2 segment of the middle cerebral artery (MCA) after
echo contrast agent injection ensured the correct position in the
diencephalic plane. Mechanical indexes were 1.5 and 1.0 for
CBI and TVI examinations, respectively. After application of the
echo contrast agent, series of 50 to 70 images were acquired at a
frame rate of 0.5 Hz. The field of view was set to an imaging depth
of 10 cm; the sector angle was 90. CBI and TVI examinations of the
ipsilateral brain hemisphere were performed; the time interval
between both investigations was at least 30 minutes to ensure that all
microbubbles were removed from the circulation. All examinations
were performed with the left-sided temporal approach and were
digitally recorded and evaluated offline.
Physical Properties and Application Mode of the Echo
Contrast Agent
In all examinations, 4 g of a galactose-based microbubble suspension
(Levovist, Schering AG) in a concentration of 400 mg/mL was
injected into a venous access with a standardized size (18 to 20
gauge) and localization (antecubital vein) by means of an US power
injector (Medrad Inc) at a rate of 8 mL/s. Levovist consists of air
bubbles surrounded by a galactose shell and stabilized by palmitic
acid. Mean particle size is 2.0 to 4.5 m; 97% of the microbubbles
are 10 m.
Evaluation of Quantitative Parameters
Regional cerebral echo contrast enhancement was quantified using
time-intensity curves (TIC). Peak intensities (PIs), time to peak
intensities (TPIs), and peak widths (PW, or the width of the TIC at
a 90% value of the PI) were calculated from a model function that
was fitted to the measured curve in at least mean square sense. The
model function has been described earlier.13 Unlike filter ap-
proaches, it does not disregard any of the information in the
measurements but incorporates knowledge on the expected signal.
Quantitative data were calculated for the following manually placed
regions of interest (ROIs): in the ipsilateral hemisphere, posterior
parts of the thalamus (ROIa), anterior parts of the thalamus (ROIb),
lentiform nucleus (ROIc), white matter (ROId), and MCA (M2
segment; ROIe) (see Figure 1). Finally, parameter images for TPI,
PI, and PW were formed by dividing each image within a series into
11-mm regions. Extracted data from corresponding regions were
displayed in a color-coded parameter image for each individual.
Mean values and SD of TPI, PI, and PW were calculated.
MRI Examinations
Protocol
Dynamic susceptibility contrast MRI, ie, p-MRI, based on the
acquisition of the signal time course after bolus administration of
contrast medium was performed on a 1.5-T whole-body Magnetom
 Meves et al Brain Perfusion: Comparison Between Ultrasound and MRI Methods 2435

TABLE 1. Mean Values and SD of Quantitative Parameters in

12 CBI Examinations
TPI, s PI, AU PW, s
ROIa 18.54.7 862.8661.3 7.84.6
ROIb 18.35.0 810.5618.8 7.34.5
ROIc 19.25.1 1522.9574.2 9.14.0
ROId 20.15.8 581.9342.4 8.34.4
ROIe 17.24.9* 3400.9621.7* 24.312.8*
AU indicates arbitrary units.
*Values of ROIe differ significantly from all other ROIs (P0.05).

time curves to a -variate function22 and then integrating the fitted

Figure 1. Basic gray-scale image in axial diencephalic plane
with visualization of the third ventricle (black arrow) and frontal
horns of the lateral ventricle (yellow arrow) as orientation land-
marks. Projection of the ROIs: posterior parts of the thalamus
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curve.
ROI analyses of TPI, CBF, and CBV were performed unilaterally
according to the US examinations in the following manually placed
regions: posterior parts of the thalamus (ROIa), anterior parts of the
thalamus (ROIb), lentiform nucleus (ROIc), white matter adjacent to

(a), anterior parts of the thalamus (b), lentiform nucleus (c), white
matter (d), and M2 segment of the MCA (e).
Symphony Quantum (Siemens AG) scanner equipped with a gradient
overdrive using the standard head coil. After conventional T1- and
T2-weighted imaging, a gradient-echo echoplanar imaging sequence
(echo time, 45 ms; repetition time, 1500 ms; slice thickness, 6 mm;
field of view, 250 mm; acquisition matrix, 128128) was chosen for
perfusion imaging. Then, 0.2 mmol Gd-DTPA/kg body weight was
injected through an 18-gauge venous access into an antecubital vein
by means of a MRI power injector (Medrad Inc) at a rate of 10 mL/s.
Data aquisition (acquisition time, 75 seconds) of the 50 images for
each of the 9 slices (image frequency, 0.67 Hz) started simulta-
neously with the contrast injection.
Postprocessing and Image Analysis
All data were transferred to a 3-dimensional Virtuoso CT/MR
Workstation (Siemens AG) and postprocessed with MEDx 3.3
software (Sensor Systems Inc). All raw p-MRI data were processed
on a pixel-by-pixel basis to generate maps of the TPI, relative CBF,
and relative CBV. To avoid confusion about terminology and to
guarantee the distinction to the ratios (see below), the relative CBF
will be referred to as CBF and the relative CBV as CBV in the
following text. Model-independent deconvolution of the tissue
curves with an automatic arterial input function20 to yield the residue
function via singular value decomposition21 was used to calculate
CBF. CBV maps were created by fitting the first-pass concentration-
the lentiform nucleus (ROId), and precentral gyrus (ROIf). Mean
values and SD of these parameters were calculated.
All data of the US and p-MRI examinations were obtained by the
same investigator (S.M.) to achieve identical localized ROIs in the
examinations.
Comparison Between US and p-MRI Examinations
For comparison of the TPI in US and p-MRI examinations, the TPI
of ROIb (thalamus anterior) was subtracted from the TPI in each
other ROI to obtain relative TPI (rTPI). This procedure was chosen
to reduce the variance of data induced by different US and p-MRI
examinations settings; eg, noisy p-MRI examinations under claus-
trophobic conditions are more likely to produce tachycardia and
elevated blood pressure, hence influencing blood circulation times.
The anterior thalamus was selected as reference region because of its
favorable insonation angle in mid parts of the ultrasonic beam and its
clearly depicted neighboring anatomical structures such as the third
ventricle in transcranial B-mode images.
A t test for paired samples was used to compare rTPI of US with
p-MRI measurements.
PIs of the US studies were compared with CBFs of the p-MRI
studies. US-PI represents the maximal intensity increase in gray-
scale images caused by the echo contrast agent in a defined sample
volume and is related to the maximum amount of contrast agent
bubbles but also to, for example, insonation depth.5 CBF is a
measure of the volume of blood delivered to the tissue in a given
amount of time, and regional CBF, known as tissue perfusion, is
proportional to the height of the tissue concentration-versus-time
curve after a bolus23; therefore, regional CBF is related to PI. The
ratios of the relative PI (rPI) and CBF (rCBF) of each ROI and the
reference region ROIb, respectively, were calculated, and a t test for
paired samples was applied to compare the US methods with the
p-MRI examinations.

TABLE 2. Mean Values and SD of Quantitative Parameters in

12 TVI Examinations
TPI, s PI, AU PW, s
ROIa 19.24.3 11.96.0 8.75.2
ROIb 19.45.3 12.25.3 7.13.9
ROIc 19.85.1 17.54.9 8.73.5
ROId 20.44.3 7.54.6 7.44.6
ROIe 17.34.0* 46.37.1* 26.718.2*
Figure 2. Parameter image of PIs in TVI mode. Red indicates
high PIs; blue, low PIs. Highest signal increase was in the M2 AU indicates arbitrary units.
segment of the MCA (white arrow). *Values of ROIe differ significantly from all other ROIs (P0.05).
 2436 Stroke October 2002

TABLE 3. Mean Values and SD of Quantitative Parameters in The rPI and rCBF of ROIa demonstrated no significant
12 p-MRI Examinations difference between the US and p-MRI modes. However, rPIs
TPI, s CBF CBV of ROIc and ROId were significantly higher in US compared
with rCBF in p-MRI-examinations (Table 5).
ROIa 22.86.9 0.00740.0031 0.160.05
ROIb 22.46.9 0.00810.0036 0.180.05 Discussion
ROIc 22.06.9 0.00930.0041 0.230.07 In various studies, p-MRI has been shown to visualize
ROId 23.06.8 0.00430.0021 0.090.04 ischemic brain parenchyma in acute stroke patients.26 How-
ROIf 22.56.2 0.01250.0056 0.300.08 ever MRI is intolerable in critical ill patients because it is time
consuming and is not generally available in the community
and its running costs are high. In contrast, US is an easily
Results available bedside method. Various US studies exploiting
In all individuals, US and p-MRI examinations were success- harmonic signals or signals resulting from destruction of
ful, and no side effects occurred. microbubbles were able to demonstrate physiological and
pathological brain tissue perfusion.510 Standard parameters,
US Examinations
however, for the analysis of TICs of US perfusion studies
Mean bilateral blood flow volumes were 58188 mL/min in the
such as PI and area under the curve could be evaluated only
internal carotid arteries and 14298 mL/min in the vertebral
qualitatively13,27,28 because of specific physical properties
arteries. Mean global CBF volume was 722114 mL/min.
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such as depth-dependent attenuation of the ultrasound signals,

These results were in accordance with previously published data
on cerebral blood volumes in young and healthy individuals.24
Parameter images of TPI and PI based on TICs were success-
fully calculated in all patients. In these color-coded single
images, it was possible to identify the different parenchymal
regions and the MCA by the echo contrast agent distribution
(Figure 2). All results of the CBI and TVI examinations are
given in Tables 1 and 2. Briefly, in CBI and TVI examinations,
mean TPIs were significantly lower (P0.05) in the MCA than
in the parenchymal regions, and mean PI and mean PW were
significantly higher (P0.05) in the MCA than in the parenchy-
mal regions.
rTPI of ROIa was 0.260.70 and of ROId was 1.361.55 in
CBI examinations; those values were 0.161.62 and 1.561.38
in TVI examinations (see Table 4). rPI of ROIa was 1.080.49
in CBI and 0.970.37 in TVI; rPI of ROIc was 2.070.81 in
CBI mode and 1.650.72 in TVI mode (see Table 5).
p-MRI Examinations
Mean TPI of p-MRI -examinations ranged between 22.06.9
(ROIc) and 23.06.8 (ROId) seconds, and mean CBF ranged
between 0.00430.0021 (ROId) and 0.01250.0056 (ROIf)
(see Table 3).
rTPI varied between 0.471.01 (rROIc) and 1.050.99
(rROId); rCBF ranged between 1.130.24 (rROIc) and
0.530.13 (rROId). The CBF ratio of gray matter to white
matter for ROIc and ROId was 2.230.57 and for ROIb and
1.970.55 ROId, which is in accordance with previous p-MRI
and PET studies.15,23,25
Comparison Between US and p-MRI Examinations
No significant difference in rTPI of ROIa, ROIc, and ROId of
the US and p-MRI-examinations could be shown (Table 4).
inhomogeneous temporal bone window, and nonlinear rela-
tion between echo contrast concentration and video intensi-
ty.13,14,2729 From an in vitro study,29 it is known that TPI in
US perfusion examinations may provide a more robust
parameter. In only 1 previously published study,13 TPI was
examined in different brain regions and revealed intraindi-
vidual homogeneous values in different brain regions consis-
tent with our present findings. In accordance with all previ-
ously published US studies, we observed a marked depth-
dependent decrease in PI in TVI and CBI examinations,
whereas TPI was not influenced by the insonation depth,
which supports an in vivo study by Bos et al.30 Hereby, a
quantitative comparison of ROIs is possible. The character-
istic time delay between a branch of a major artery and
parenchyma found in our study is a further criterion that helps
to characterize physiological brain perfusion.
Even though TPI is influenced by various factors such as heart
rate, heart ejection fraction, and position of the venous canula, its
potential to demonstrate hemodynamic impairment of cerebral
perfusion in conditions of acute stroke has been shown in
p-MRI.31 This is the first study to compare p-MRI with US
perfusion studies. We found no significant differences between
rTPI in US and MRI examinations in any ROI, thus supporting
the robustness and reliability of this parameter.
In contrast, rPIs were highly depth dependent and had a high
interindividual variability in all ROIs compared with corre-
sponding rCBF in p-MRI examinations. This finding is in
accordance with all previously published studies on the ultra-
sonic assessment of brain perfusion and confirms that this
parameter is not suitable for quantification of perfusion.
In return, PW as another diagnostic parameter has not been
regarded in previous ultrasonic studies. The PW was signifi-

TABLE 4. Comparison of rTPI in 12 CBI Versus p-MRI Examinations and in TVI

Versus p-MRI Examinations
p-MRI CBI P TVI P
rROIa (ROIa-ROIb) 0.400.96 0.260.70 0.75 0.161.62 0.70
rROIc (ROIc-ROIb) 0.471.01 0.151.16 0.33 0.082.02 0.59
rROId (ROId-ROIb) 1.050.99 1.361.55 0.60 1.561.38 0.27
 Meves et al Brain Perfusion: Comparison Between Ultrasound and MRI Methods
TABLE 5. Comparison of rPI in 12 CBI Versus rCBF in p-MRI Examinations and
of rPI in TVI Versus rCBF in p-MRI Examinations
p-MRI
rROIa (ROIa/ROIb) 0.910.07
rROIc (ROIc/ROIb) 1.130.24
rROId (ROId/ROIb) 0.530.13
cantly higher in the M2 segment than in the parenchymal ROIs
because destroyed microbubbles in large vessels are rapidly
replaced. These characteristic features of TICs allow the differ-
entiation of vessels and brain parenchyma. In future US perfu-
sion studies on acute stroke patients, shortened PW might be a
hint for the diagnosis of impaired perfusion.
In conclusion, our study demonstrates that TPI provides a
reliable parameter in US perfusion examinations because it is not
as depth dependent as other parameters like PI. Previously
published p-MRI studies in acute stroke patients demonstrated
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the diagnostic value of TPI maps for differentiation between
unaffected parenchyma, penumbra, and ischemic core area.
From the results of this study, future US studies should include
TPI maps in stroke patients to investigate the potential for a
semiquantitative differentiation between affected and unaffected
tissue. Additionally, these studies should be compared with other
quantitative techniques that assess brain perfusion like p-MRI.
Acknowledgments
This study was done for KMR (Kompetenzzentrum Medizintechnik
Ruhr) and supported by FoRUM (Forschungszentrum der Ruhr-
Universitt Medizinische Fakultt). W.W. was supported by BMBF
(Bundesministerium fr Bildung und Forschung).
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 Comparison Between Echo Contrast Agent-Specific Imaging Modes and
Perfusion-Weighted Magnetic Resonance Imaging for the Assessment of Brain Perfusion
Saskia H. Meves, Wilko Wilkening, Tammo Thies, Jens Eyding, Thilo Hlscher, Michael
Finger, Gebhard Schmid, Helmut Ermert and Thomas Postert
for the Ruhr Center of Competence for Medical Engineering
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Stroke. 2002;33:2433-2437
doi: 10.1161/01.STR.0000032246.85531.8E
Stroke is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright 2002 American Heart Association, Inc. All rights reserved.
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