Vol.2, No.6, 445-457 (2009)
SciRes Copyright © 2009 Openly accessible at http://www.scirp.org/journal/JBISE/
Contrast enhancement methods in sodium MR imaging: a
new emerging technique
Rakesh Sharma1, Avdhesh Sharma2, Soonjo Kwon3, Ross Booth3
1Department of Medicine, Columbia University, New York, USA; 2Image Processing Lab, Department of Electrical Engineering,
Maharana Pratap A&T University, Udaipur Rajasthan, India; 3Biological Engineering, Utah State University, Logan, USA.
Email: rs2010@columbia.edu; soonjo.kwon@usu.edu
Received 23 August 2008; revised 20 July 2009; accepted 25 July 2009.
Background: In the last decade, sodium mag-
netic resonance imaging was investigated for its
potential as a functional cardiac imaging tool for
ischemia. Later interest was developed in con-
trast enhancement for intracellular sodium. Lit-
tle success was reported to suppress extracel-
lular sodium resulting in the intracellular so-
dium MRI image acquisition using quantum fil-
ters or sodium transition states as contrast
properties. Now its clinical application is ex-
panding as a new challenge in brain and other
cancer tumors. Contrast enhancement: We
highlight the physical principles of sodium MRI
in three different pulse sequences using filters
(single quantum, multiple quantum, and triple
quantum) meant for sodium contrast enhance-
ment. The optimization of scan parameters, i.e.
times of echo delay (TE), inversion recovery (TI)
periods, and utility of Dysprosium (DyPPP) shift
contrast agents, enhances contrast in sodium
MRI images. Inversion recovery pulse sequence
without any shift reagent measures the intra-
cellular sodium concentration to evaluate ische-
mia, apoptosis and membrane integrity. Mem-
brane integrity loss, apoptosis and malignancy
are results of growth factor loss and poor
epithelial capability related with MRI visible in-
tracellular sodium concentration. Applications
and limitations: The sodium MR imaging tech-
nical advances reduced scan time to distinguish
intracellular and extracellular sodium signals in
malignant tumors by use of quantum filter tech-
niques to generate 3D sodium images without
shift regents. We observed the association of
malignancy with increased TSC, and reduced
apoptosis and epithelial growth factor in breast
cancer cells. The validity is still in question.
Conclusion: Different modified sodium MRI
pulse sequences are research tools of sodium
contrast enhancement in brain, cardiac and
tumor imaging. The optimized MRI scan pa-
rameters in quantum filter techniques generate
contrast in intracellular sodium MR images
without using invasive contrast shift agents.
Still, validity and clinical utility are in question.
Keywords: Sodium MRI; Double Quantum; Inver-
sion Recovery; Contrast Enhancement; Cancer
Sodium-23 (Na-23) nuclei are in abundance in the body
but exhibit poor magnetic resonance sensitivity and
serve as sodium MRI clinical imaging modalities. The
sodium Na-23 nucleus is detectable by MRI due to its
3/2 spin existing as -3/2, -1/2, 0, ½, 3/2 (5 states).
Physical nature of sodium-23 with spin = 3/2 is suitable
to have a nonvanishing magnetic moment and Larmor
frequency = 11.26 MHz and exhibits four transition
states with five different energy levels in the static mag-
netic field. MR detection sensitivity is very low (9.3 %)
at in vivo concentration (approximately 0.05 %).
Sodium is abundant (100 %) in living body tissue in
3/2 spin state. The sodium ion is the predominent cation
in the extracellular fluid (139 mmol/L), while its intra-
cellular concentration is very low (in the order of 8-10
mmol/L), mainly bound with glycosides and proteins.
The role of increased intracellular sodium due to con-
certed efflux through Na+/K+ ATP-ase intrinsic action,
angiogenesis, and cell proliferation was described in
ischemia, hypoxia, arrhythmia, myocardial edema, and
tumors [1]. The sodium concentration is sensitive to
disease as an indicator of cellular and metabolic integrity.
Na-23 concentration in tissues is present in the order of
tens of millimoles. The low sodium concentration results
in low signal-to-noise ratio of 23Na MR imaging in long
imaging times and/or poor spatial resolution. Therefore,
it needs the use of shift reagents or pulse sequences with
R. Sharma et al. / J. Biomedical Science and Engineering 2 (2009) 445-457
SciRes Copyright © 2009 Openly accessible at http://www.scirp.org/journal/JBISE/
filters such as single-, double-, triple-, and multiple
quantum (SQ, DQ, TQ and MQ) filters to enhance the
sodium contrast [2].
Evidence of sodium transfer rates across the blood-
brain barrier dates back to its use in MRI [3] followed by
the use of spin echo pulse sequence for experimental
sodium imaging with first surface coil [4]. Soon after it,
in vivo clinical sodium imaging at clinical 1.5 T scan-
ners was first described using multislice spin echo pulse
sequences [5]. Later developments were made at high
magnetic field MRI scanners using ultrashort echo time
sequences and hardware improvements that permitted
better spatial resolution with shorter imaging times and
better quantitative measurements of tissue sodium con-
centration without use of shift reagents [6].
This paper describes the phases and roles of quantum
filters in pulse sequence design to generate intracellu-
lar/extracellular sodium contrast, high signal-to-noise
ratio, and high resolution in magnetic resonance sodium
images by triple-quantum filter and double inversion
recovery pulse sequence without using paramagnetic
shift reagents. Triple quantum filter was evaluated as a
superior method for high signal-to-noise ratio but needs
a long acquisition time [7]. Other available multiple-
quantum, single-, and double quantum filter tomographic
magnetic resonance pulse sequences generate intracellu-
lar sodium images with high signal-to-noise ratio but
need paramagnetic shift reagents as contrast agents.
1.1. Nature of Sodium MR Signal
At high field magnetic resonance application, the applied
phase-cycled radio frequency pulses at set time intervals
cause an alignment of nuclei populations within the
sample, resulting in a measurable signal in the transverse
plane. Optimized times of echo delay (TE) in single-,
double-, triple quantum filters; optimized times of inver-
sion times (TI) for inversion recovery pulse sequence;
and application of a multiple quantum filter after injec-
tion of paramagnetic shift contrast reagents detected the
distinct intracellular sodium signal to obtain a sodium
weighted image. As a result, two sodium MRI signals
are achieved with distinct MRI signal intensities to
measure sodium intracellular and extracellular concen-
trations in the tissue. The MR signal intensity is related
with tissue sodium content as follows: The MR signal
intensity of Na-23 is:
MR sensitivity = % Na-23/H-1. C (Na-23). A.γ. S2+S,
where % Na-23/H-1 is sodium abundance, C (Na-23) is
tissue concentration, A is MR scanner intrinsic parameter,
γ is Gyromagnetic Ratio and S is nuclear spin.
Due to the Gyromagnetic Ratio of Na-23 = 11.25
MHz/T relative MR sensitivity is lesser. Moreover, sen-
sitivity is further decreased due to less sodium content in
the tissue: about 1/1000th MR sensitivity of proton, so it
needs use of high magnetic field imaging scanner and
data acquisition techniques with contrast enhancement
mechanisms, such as MQ, SQ, DQ and TQ. Sodium
concentration is higher in blood than that in myocardium
and other tissues. This high sodium density in blood
contributes to tissue contrast in sodium MR imaging.
However, a very small amount of Na-23 is MR visible in
free ionic extracellular form due to poor sensitivity.
Other intracellular forms of invisible sodium are mainly
bound to proteins and phospholipids in the tissue, so
intracellular sodium MRI visualization needs quantum
1.2. Quadruple Interactions and Sodium MR
Sodium signal is conventionally represented as quadru-
ple interactions between Na-23 and its molecular envi-
ronment. In sodium nuclei, magnetic resonance excita-
tion and subsequent transition of electrons to different
energy levels of nuclear spins produce single-, double-,
triple-, and multiple quantum sodium transition MR sig-
nals as said earlier. These different quantum transitions
can be filtered by use of specific SQ, DQ, TQ and MQ
pulse sequence techniques by use of selective phases in
pulse sequence design as described later. These tech-
niques also produce spectral patterns reflecting the per-
centage of invisible intracellular sodium. These sodium
spectra are iterated superimposed positions of different
spectra and represent simulated signals from intracellular
sodium in the cytoplasm including interstitium, mito-
chondria, intravascular space, and so on. However, this
invisible “intracellular” Na-23 results from the presence
of a broad frequency peak (T2, very short component). It
masks the corresponding frequency peak. Another con-
tributory factor to intracellular Na-23 MR invisibility is
long correlation times for short and long T2 components.
For the heart, the correlation time is in the range of 10-12
to 10-9 seconds. As a result, intracellular sodium is in-
visible. The double quantum pulse technique (instead of
single quantum pulse technique) selects only double
quantum transitions of sodium. These double quantum
transitions allow sodium to be more ordered with long
correlation time. These pulse sequence techniques visu-
alize the intracellular sodium.
1.3. Nature of Sodium Nuclei and MRI
The Larmor frequencies of sodium in extracellular and
intracellular sodium populations are the same because
they have the same resonant frequencies. Therefore,
three different approaches are used in distinguishing
these two types of sodium nuclei. These include different
relaxation times between intracellular and extracellular
sodium, the use of paramagnetic shift reagents, and the
use of special multi-quantum pulse sequences.
R. Sharma et al. / J. Biomedical Science and Engineering 2 (2009) 445-457
SciRes Copyright © 2009 Openly accessible at http://www.scirp.org/journal/JBISE/
1.4. Sodium Relaxation Times
Based on the observation that tissue transverse relaxa-
tion time for the intracellular space is smaller than that
of extracellular space, intracellular space can be imaged
by shortening the spin-echo time. Intracellular sodium
signal intensity proportionally increases due to intracel-
lular space. Sodium transverse relaxation time (T2) is
biexponential in nature, while sodium is bound with
negatively charged macromolecules – mainly proteins or
metabolites. Perhaps the longitudinal relaxation time (T1)
also behaves as biexponential.
1.4.1. Paramagnetic Shift Reagents
Paramagnetic shift reagents are chelates of paramagnetic
lanthanide ions with anionic complexes. These sub-
stances don’t cross the intact cell membranes. These
reagents interact with extracellular sodium and introduce
a frequency shift in the resonance frequency of extracel-
lular sodium. This shift allows the advantage of produc-
ing two separate spectral peaks arising from intracellular
and extracellular sodium. Common lanthanide ions used
as paramagnetic shift reagents are Dy3+ (Dysprosium),
Tm3+ (Thulium), Gd3+ (Gadolinium), PPP5- (Tripoly-
phosphate), and TTHA6- (Tetraethylene Triaminehexa
acetic acid). These reagents bind with intracellular cal-
cium and cause physiological disturbances and, in some
cases, toxicity, so their use is limited. To overcome such
problems, several approaches were recently developed
based on the modification of pulse sequences and hard-
ware improvements as described in the following sec-
1.5. Quantum Filters
These are MR pulse sequences that allow direct observa-
tion of multiple quantum transitions. These filters usu-
ally are constructed by phase cycling manipulations. The
general pulse sequence scheme is 90°-t/2-180°-t/2-90°
-π-90°-acquire, where t is creation time and π is evolu-
tion time by use of pulsed field gradients. Characteristi-
cally, these filters are sensitive to variations in phase
cycles up to 5° and magnetic field inhomogeneity. The
filter can be single-, double-, triple-, or multiple quan-
tum and allow single, double-, triple-, and multiple
quantum transitions. In the following sections, we intro-
duce readers to our strategy of quantum filters used in
sodium MRI pulse sequence design.
1.5.1. Single Quantum Pulse Sequence
Due to its multiple spin state transitions, an alternative
MR single quantum approach is used to measure intra-
cellular Na content based on the interaction of Na poly-
anions and their resultant effects on nuclear spin transi-
tions. Spin 3/2 nuclei (such as Na-23) have a nonvan-
ishing quadrupole moment, allowing interaction with
electrostatic field gradients. The pulse sequence is a spin
echo sequence.
1.6. Multiple Quantum Pulse Sequence for
Origin of Double- and Triple Quantum
For intracellular sodium, using only multiple-quantum
(MQ) NMR requires paramagnetic shift reagents (SRs)
that have distinct disadvantages including: toxicity, pos-
sible drug interaction, expanded space, and imperme-
ability to the blood brain barrier. It is known that the
correlation time, tc of the time variations of the electro-
static field gradients in spin 3/2 nuclei satisfies the rela-
tion if wLtc >> 1, where wL is the Larmor frequency.
These nuclei can display biexponential relaxation and
MQ spin transitions do occur in the nuclei and these
transitions are detected by specific pulse sequences
called multiple- quantum filters.
A phase-cycled RF pulse sequence applied over a
slice-select axis selects both echo and anti-echo signals
of spin undergoing multiple-quantum spin transitions at
resonating Larmor frequency. The RF pulse has both a
flip angle and a phase angle. The phase angles are cycled
using multiple-quantum transition filter and simultane-
ously produce an output signal proportional to the sum
of echo and anti-echo signals of MQ coherence. It in-
cludes the evolution period with a flip angle of 180° to
refocus the RF pulse to avoid inhomogeneity-induced
amplitude deterioration. This output signal is measured
by induction current in the RF coil during the realign-
ment process and is used in tomographic MQ transition
23Na MRI images.
The pulse sequence comprises: a preparation period of
length tP extending from time t0, an evolution period of
length te and a detection period of length td. The RF
pulse sequence manipulates the selected nuclei to exhibit
them with single quantum coherence. During the evolu-
tion period, the pulse sequence implements a MQ filter
which isolates the coherence (e.g. double- or triple
quantum) and simultaneously selects both echo and anti-
echo signals corresponding to the coherence by; a) an
evolution period first flip angle RF pulse timewise cen-
tered at tP which converts the selected nuclei from sin-
gle-quantum coherence to the selected multiple- quan-
tum coherence; b) an evolution period of second 90° flip
angle RF timewise centered at tP+te, converts the se-
lected nuclei from multi-quantum to single-quantum
coherence. Therefore, during the detection period, se-
lected nuclei exhibit single quantum coherence to gener-
ate a single quantum signal.
The resultant collective phase angle of evolution pe-
riod RF pulse= ΦE=Φ3-2Φ4+Φ5, wheree ΦE is collective
radio frequency phase during evolution time, and Φ4 &
Φ5 are phases of 90° RF pulses. A further preparation
period of 90° flip angle radio frequency slice-selecting
pulse, a preparation 180° flip angle refocusing pulse, and
a detection period 180° flip angle radio frequency are
applied – centered at t0, ½ tP and tP+te+1/2 td, respec-
tively. The preparatory 90° flip angle RF pulse selects a
R. Sharma et al. / J. Biomedical Science and Engineering 2 (2009) 445-457
SciRes Copyright © 2009 Openly accessible at http://www.scirp.org/journal/JBISE/
slab of sample perpendicular to a slice-selection axis as
shown in Figure 1. The preparatory 90° flip angle
slice-selection RF pulse has phase angle Φ1, the pre-
paratory 180° Rf refocusing pulse has Φ2, and detection
period 180° flip angle RF pulse has phase angle ΦP of
the RF pulses during preparation time (evolution period
90° flip angle RF phase Φ3) as described earlier(8). The
phase angle is ΦP= Φ1-2Φ2+Φ3 and the output signal will
be Φ= ΦP-m ΦE+ Φ5+2 Φ6+ ΦR, where m is the integer of
magnetization, Φ is the phase of detected signal, and ΦR
is the phase of receiver.
For double quantum filtered images, m=+2, and for
triple quantum filtered images, m=+3. The phases will
be Φ1= (n/2)π, Φ2=[n/2+int(n/4)] π, Φ3=(n/2)π,
Φ4=Φ5=Φ6=0 and ΦR =nπ for double quantum filter; and
phases will be Φ1= (n/3)π, Φ2=[n/3+int(n/6)] π,
Φ3=(n/3+1/2)π, Φ4=0, Φ5=(1/6) π, Φ6=0 and ΦR
=[n+int(n/6)]π for triple quantum filter, where n/6 is
integer part of the variable n/6. The variable n is positive
integer of 0…N-1. N is a multiple of 8 and 12 for dou-
ble- and triple quantum filters respectively.
The magnetic gradient pulse sequence is also applied
along with the RF pulse sequence for positional infor-
mation in the data. A slice-select gradient pulse, first and
second phase encoding gradient pulse, and read-out gra-
dient pulse are applied along read-axis after detection
period 180° RF refocusing pulse during output signal
observed as shown in Figure 1. The read-out pulse area
before time tP+te+td is equal to the area of read-out gra-
dient pulse. These gradient pulses exhibit simultaneous
synchrony with RF pulses.
1.6.1. Inversion Recovery Pulse Sequence
The inversion recovery technique can suppress the ex-
tracellular sodium nuclei with specific ranges of the lon-
Figure 1. The figure illustrates a series of radiofrequency
pulses and a synchronized series of magnetic gradient pulses
for phase cycled evolution period 180° flip angle refocusing
Figure 2. A scheme of inversion recovery pulse sequence is
presented. On top, one cycle of IR with two recovery curves is
shown for a single slice. First, 180˚ pulse is flipping the
magnetization Mz for first recovery followed by 90˚ pulse for
FID and second recovery within TR period. At bottom, the
application of two inversion pulses πA and πB is shown for
slices A and B with simultaneous application of RF and gradi-
ent pulses.
gitudinal relaxation time, T1 using fast spin-echo pulse
sequence. The sequence has two sets of slice selective
inversion pulse trains (long recovery period TI1 for ex-
tracellular sodium and short recovery period TI2 for in-
tracellular sodium nuclei). The first inversion pulse is
played during a long recovery period TI1, during which
extracellular sodium magnetization recovers just past its
null point while longitudinal magnetizations of intracel-
lular sodium nuclei are almost fully restored. The second
set of inversion pulse is played during short recovery
period TI2, when intracellular Na nuclei magnetizations
reach their null points following TI2 interval and become
180° out-of-phase. After inversion pulses, a fast spin-
echo acquisition sequence is applied to achieve mag-
netization in z-direction (Mz) as following:
Mz=M0 [(1-2e-TIe/T1e + e-TR/T1e)(1-2e-TIi/T1i) (1)
where ‘e’ represents extracellular sodium nuclei and ‘i’
represents intracellular sodium nuclei. M0 is initial lon-
gitudinal magnetization, TI1 & TI2 are long and short
inversion times, and T1e & T1i are longitudinal relaxation
times of extracellular and intracellular sodium nuclei,
The relaxation time for intracellular Na nuclei varies
from 5-10 milliseconds (for Na bound to large molecules
or dispersed in highly order environment) to 51 milli-
seconds (for extracellular sodium nuclei in free solution).
Based on 3D projection reconstruction imaging pulse
sequence, echo time TE as short as 0.1 ms can be
R. Sharma et al. / J. Biomedical Science and Engineering 2 (2009) 445-457
SciRes Copyright © 2009 Openly accessible at http://www.scirp.org/journal/JBISE/
achieved. This captures the more rapid decay of short T2
sodium components in the NMR signal so as to further
improve the signal to noise (SNR).
As shown in Figure 2, radio frequency pulse at 180˚
is followed by a 90˚ pulse for slice excitation utilizing
echo-train length with any option of selective or nonse-
lective, single or composite, sinc, sech or tyco pulse as
needed. So, inversion pulses are played out during in-
version TI1 and TI2 periods for both types of sodium
nuclei. Data acquired includes projection reconstruction
with slice selection or without slice selection using
spin-echo or gradient echo. Thus, inversion/acquisition
periods are played out for several slices per repetition of
fast spin echo (FSE) sequence exhibiting two distinct
null points for both sodium nuclei populations.
After first 180° RF pulse flips the magnetization from
M-z Mz’, the two different inversion times (TI1 and TI2)
for two sodium populations exhibit two null points and
growth of longitudinal magnetizations. In this sequence,
soon after TI, a 90˚ RF pulse is applied to flip the longi-
tudinal magnetization into the x-y plane for the T1
growth curve within repetition time TR. At this point,
frequency induction decay (FID) is measured when the
longitudinal magnetization is flipped into the x-y plane.
Thereafter 180˚ RF pulses are repeatedly applied. The
magnetization signal ‘S’ may be measured as: [S] α
M0(1-2e-TI/T1)(1-eTR/T1), as T1 recovery curves for both
180˚ and 90˚ degree pulses applied.
The intracellular and extracellular populations of nu-
clei have different longitudinal relaxation times, so they
generate intracellular/extracellular sodium contrast. To
set the IR pulse sequence to suppress the contribution of
sodium nuclei with specific ranges of T1, the inversion
time TI1 or TI2 is set as (ln 2)(T1ex), where T1ex is the
composite longitudinal relaxation time. This inversion
time then determines the time between the 180o and 90o
pulses in the IR pulse sequence.
2.1. Projection Reconstruction Methods
First, projection reconstruction was proposed based upon
Fourier transformation of the FID (free induction decay)
signals [9].
Now, these FID signals are obtained by rotating a
magnetic field gradient with back-projection to deter-
mine the spin-density function or enhanced contrast. So
far, this technique has been used only for animal hearts.
These signals can be gated to heart rate to reduce the
motion artifact. Signals are reconstructed from 12 pro-
jections. Each projection is obtained from an average of
320 FID signals. For image matrix 64 x 64 total data
acquisition, time is approximately 15 minutes.
2.2. Three-Dimensional Fourier Techniques
In this technique, phase-encoding is made in two or-
thogonal directions, and a fixed gradient is applied in a
third direction of read-out gradient [10]. The pulse- en-
coding steps are applied, typically 40 steps along each
phase-encoding direction. As a result two echo signals
with different spin-echo times are generated and added
in a coherent manner to enhance contrast. This phe-
nomenon also improves the signal-to-noise ratio. This
technique is used for the human brain. In cardiac sodium
imaging the utility of this technique is limited to animal
heart experiments. Typically short TR = 100 ms is used
to get data in 3 hours, including different spin echoes
summation. The application of greater sodium signal in
the left anterior descending artery was observed in oc-
clusion, followed by re-perfusion of circumflex in the
coronary artery after ischemia.
2.3. Hybrid Spin Echo Techniques
The spin-spin T2 relaxation time of intracellular sodium
is shorter than that of the extracellular sodium compart-
ment, so it is difficult to observe it to create contrast, and
it needs a hybrid spin-echo pulse sequence. In the hybrid
approach, both projection-reconstruction and Fourier
encoding schemes are used at the same time. Fourier
analysis does slice selection in one direction while an-
other projection-reconstruction is performed in two other
orthogonal directions. This technique is good for clinical
MR scanners with gradient refocused sequence with
modified head coil to generate echo time as short as 2.8
msec [11].
2.4. Surface Coil Techniques and Coil
Sodium imaging at short T2 relaxation times can be per-
formed by use of a customized radio-frequency coil fo-
cused on the region-of-interest to improve the signal-to-
noise ratio. The pulse sequence is applied with optimiz-
ing the minimum saturation time of preamplifier and
duration of 90-degree RF pulse. This effect minimizes
the magnetic homogeneity influence over the free in-
duction image and the short T2 can be imaged. This
technique is relatively better than others for human
cardiac sodium imaging on clinical scanners. First,
using different transmitter gains optimizes the gain for
90° pulse, and different transmitter gains at increased
and decreased gain values yields 23Na images at different
flip angles of 45°, 90°, and 135° with matrix sizes 32 x
32 x 32 points. Nonlinear least squares fit of the pixels
intensities in all three images determines the B1 field
strength (for 5% maximum intensity on image) as a
function of the related [Na]i image intensities in re-
sponse to the local RF coils for receive and transmit sen-
sitivities [13].
R. Sharma et al. / J. Biomedical Science and Engineering 2 (2009) 445-457
SciRes Copyright © 2009 Openly accessible at http://www.scirp.org/journal/JBISE/
The image signal intensity depends on coil transmit
and coil receive sensitivity as:
0kkkk MRI  (2)
where Ik is the signal intensity of the kth pixel, Rk is a
sensitivity at the coil center, and M0k is the equilibrium
magnetization. The flip angle Φk is a function of the
transmitter gain setting (TG) as:
)10)( TG
kk CR (3)
(C · Rk) and M0k were each fitted with a single parameter
for each pixel. The constant ‘C’ is independent of spatial
position and receives sensitivity. It is also directly pro-
portional to the transmit field distribution for the coil
[13]. After normalization, the product (C · Rk) yields the
relative sensitivity Rk for the kth pixel. The B1 (expressed
as B1/2 ) depends on reference transmit power, TGref:
where tp is the pulse duration.
Local field B1 and longitudinal relaxation time T1
determine the correction factors for saturation for each
pixel k, SFk as follows:
where B1k is the B1 field in the respective ROI and is the
gyromagnetic ratio for [Na]i using the pulse time tp=0.4
msec, and the TR=120 msec [13].
2.5. Rotating Frame Techniques
Conventionally, sodium imaging can be done using the
rotating frame technique based on superimposing a
magnetic field gradient on the excitation field B1. As a
result, during this excitation period, spatial localization
and spatial encoding may be performed very fast to gen-
erate sodium contrast. In this process, loss of MR signal
intensities is also minimized. In an isolated perfused
rabbit heart, sodium-rotating frame imaging experiment
was completed in 12 msecs in a 128 x 128-image matrix
with a clinical 1.5 T scanner [12].
2.5.1. Use of Contrast Agents
Different shift agents such as dysprosium or Tm (DOTP)
contrast agents increase the sensitivity and specificity of
sodium MRI by shifting intracellular sodium magnetiza-
tion away from extracellular sodium magnetization (ex-
hibited well as shifted peaks). Dextran-magnetite in-
creases the contrast between tumor and surrounding soft
tissue sodium images. Normal reticulo-endothelial cells
take up a greater amount of magnetic particles than tu-
mor cells do, which supports the potential for tumor so-
dium imaging by contrast agents. However, a major role
of sodium imaging seems to distinguish myocardial
Techniques used for sodium in vivo MRI: Several
approaches have been used. Despite little success, these
techniques are gaining interest in physiological MR im-
aging using intracellular sodium. Some landmark tech-
niques have been described for image generation.
2.5.2. Spectrally Weighted Twisted Projection
The 3D sodium MRI imaging can be made faster by
reducing the T2 signal attenuation effects. This is im-
plemented by 3D twisted projection imaging. At high
spatial frequencies, the sample density is reduced, and as
a result the reduced readout time is achieved. This leads
to decreased T2 signal attenuation, which translates into
improved signal-to-noise ratio (SNR) without a loss of
resolution [14].
2.5.3. Biexponential Relaxation Effect and
Sodium Concentration Mapping
Dual-frequency RF coils with identical B1 field distribu-
tions at the two different observation frequencies pro-
vide sodium and proton mapping. These optimize both
dual frequencies in dual quadrature RF coils. Sodium
and proton channels are decoupled to make dual-quad-
rature birdcage configurations. The fourth harmonic of
sodium frequency happens to be very close to proton
frequency. This is suitable for echo-planar imaging and
metabolite quantification [15].
2.5.4. 3-D Triple Quantum-Filtered Twisted
Projection Na-23 Imaging
A new approach was developed based on a three pulse,
six-step, coherence transfer filter (with fast twisted pro-
jection imaging sequence) to generate spatial maps of
the TQ signal. In principle, three pulse coherence filter
leads to TQ sodium images. In these images, the image
intensity depends on the spatial variation of the flip an-
gle. This image intensity is lesser than the flip angle
chosen in the four pulse TQ filter. This technique allows
the generation of RF inhomogeneity corrected TQ so-
dium images after TQ signal variation. The pulse se-
quence of TQ filtering is based on spherical tensor op-
erators or a density matrix. It consists of three non-se-
lective RF pulses, and sometimes a fourth RF pulse be-
tween the three first and the second pulses, to refocus the
main magnetic field inhomogeneities [16]. In this pulse
sequence, RF induces different flip angles as θ30, 2θ30,
θ150, θ0…. flip angles where the phase stepped up through
the values 30°, 90°, 150°, and so on. The second pulse is
intended for the B inhomogeneities refocusing and is
absent in the case referred to as “three pulse”. The
preparation time is the period between two phases and
evolution time is the period between θ150 and θ0.
R. Sharma et al. / J. Biomedical Science and Engineering 2 (2009) 445-457
SciRes Copyright © 2009 Openly accessible at http://www.scirp.org/journal/JBISE/
2.6. Simultaneous Quadruple and Double
Quantum Na-23 MR Imaging
Na-23 is a quadruple nucleus with biexponential relaxa-
tion or non-vanishing quadruple coupling. Both proper-
ties contribute to generate Na-23 multiple-quantum (MQ)
coherence [17]. The Multiple Quantum Filter pulse se-
quence can be represented as Eq.6:
(θ1,φ1)-tP/2-(θ2,φ2)-tP/2(θ3,φ3)-tE-(θ4,φ4)-Acq(T,φR), (6)
where refocused preparation time, φP and non-refocused
evolution time, φE may be represented as Eq.7:
43321 ;2
 EP (7)
where φ1-4 denote the phase of each RF pulse with flip
angle θ1-4, φR is receiver phase, and T is acquisition time,
each θ1=π/2 and θ2=π.
This sequence is good for detecting well-defined and
ordered structures in biological tissues. Both quadru-
ple-order and double-quantum signals can be generated
simultaneously by the same RF sequence without any
loss in signal amplitude. In addition, the acquired MQ
signals can be readily decomposed into their second –
and third – rank components, i.e. into quadruple order
and biexponential relaxation components. This allows
reduction of the scan time to acquire MQ signals of dif-
ferent coherence orders and ranks, which should prove
useful for in vivo studies.
2.7. Double Spin-Echo Imaging and
Transverse Relaxation Time
This approach of imaging is good for myocardial water
content analysis based upon the calculation of transverse
relaxation time from dual-quantum spin-echo MRI [18].
Right and left ventricles can be assessed for quantifica-
tion of myocardial edema. The transverse relaxation
times (T2) of ventricles can be calculated from the signal
intensities within multiple regions of interest over myo-
cardium as shown in Eq.8:
T2 =[(TE2-TE1)/ln(I1/I2)], (8)
where TE1 is first echo time, TE2 is second echo time,
and I1 & I2 are image amplitudes of first & second spin
2.8. Double-Quantum-Filtered Na-23 MR
The extracellular EC-Na and intracellular IC-Na con-
tents are better visualized by multiple-quantum-filter
spectra acquired in the absence of chemical shift or re-
laxation reagents. The intracellular IC-Na sensitivity can
be enhanced by double-quantum-filter (DQF) Na-23
NMR to measure the detection of Na+ motion anisotropy
with the presence of residual quadruple splitting (19).
However, the application of this technique is limited to
the experimental heart studies using the pulse sequence:
90°-τ/2- 180° -τ/2 -θ-t1-θ-t(Acq), where τ denotes the crea-
tion time and t1 is evolution time, θ is RF flip angle.
The magnetization M (τ, t, θ) for the MQF Na-23
NMR signal, when the quadruple splitting factor (ωQ) is
zero, is given by Eq.9:
M(τ, t, θ)=αM0[exp(-τ/T2s) - exp ( -τ/T2f )]
x [exp(-t/T*2s )-exp(-t/T*2f)] (9)
x sin2θ(1 - 3 cos2θ)
where α is a factor which depends on the degree of
quantum coherence , M0 is equilibrium magnetization,
T2f & T2s are fast & slow transverse relaxation times, and
T*2f & T*2s are the corresponding inhomogeneity-
broadened times. An important implication for this tech-
nique is the possibility of measuring intracellular sodium
concentration in animal hearts with the DQF spectrum in
the absence of shift or relaxation reagents. Significant
attenuation of the DQF spectrum derived from extracel-
lular Na+ allows to differentiate the NMR spectrum from
intracellular Na+.
2.9. Double Quantum Filtering and
Spin-Quantum Coherence
Conventionally, the double-quantum filtering method for
sodium imaging is completed in a four-step phase-cy-
cling scheme. In this process, the radio-frequency pulses
generate single-quantum coherence. Its phase appears
similar to the phase of a double-quantum coherence sig-
nal in the pulse sequence. Consequently, the interse-
quence stimulated echo passes through the double-
quantum filtration in the phase cycling scheme and gra-
dient pulses in the DQ pulse sequence, so the sin-
gle-quantum coherence is an unwanted component in
this pulse sequence. It is eliminated by the use of spoil-
ing RF pulses followed by dephasing gradient pulses
incorporated into the DQ filtering pulse sequence. These
spoiling pulses disperse the pulse transition and elimi-
nate the magnetization components of the intersequence
stimulated echo in the DQ pulse sequence [20]. Another
good way to eliminate single quantum coherence is to
increase the repitition time TR. Moreover, a low signal
level of DQ coherence also demands many signal aver-
aging at short TR to keep short scan time and not a
longer TR.
2.10. Chemical Shift Selective Acquisition
of Multiple Quantum-Filtered Na-23
In cardiac imaging, MQ signals over a wide off-reso-
nance bandwidth is a problem which causes interference
between echo and anti-echo. It is due to a resonance off-
set insensitive to the flip angle of the creation RF pulse;
usually the second π/2 pulse. Off-resonance effects are
applied to eliminate the MQ signal in the presence of a
chemical shift. It suppresses the MQ signal over a wide
range of off-resonance bandwidth [21]. Existing tech-
R. Sharma et al. / J. Biomedical Science and Engineering 2 (2009) 445-457
SciRes Copyright © 2009 Openly accessible at http://www.scirp.org/journal/JBISE/
niques for chemical-shift-selective acquisition of SQ
signals can be combined with MQ off-resonance effects
to enhance the selectivity of chemical shift.
2.11. Double Quantum Filtering and
Elimination of Intersequence
Stimulated Echo
In cardiac sodium imaging the ‘intersequence stimulated
echo’ is an unwanted component because the phase of
this echo has the same properties as that of the dou-
ble-quantum (DQ) signal. Using a partition method and
computer simulation can eliminate the magnetization
components of the intersequence stimulated echo [22].
The DQ filter pulse sequence with non-refocused prepa-
ration time (τP) and evolution time (τE) may be ex-
pressed as: (θ1,φ1)-τP- (θ2, φ2)-τE-(θ3φ3)-Acq (t2 ,φR),
where φn denotes the phase angle of each RF pulse
with the flip angle φn; t2 is acquisition or detection time
and φR is receiver phase.
2.12. Multiple Quantum Filters of Arbitrary
Phases of Na-23 Nuclei
These Triple Quantum filtered data acquisition, uses the
pulse sequence with arbitrary phase values: 90°(θ1)- t/2
-180°(θ2) - t/2 -90°(θ3) -δ - 90°(θ4) - acq(θ5) (T), where δ is
evolution time, t is the acquisition time, θ1, θ2, θ3, θ4,
and θ5 are the phase values. Multiple-quantum-filtered
(MQF) Na-23 NMR spectroscopy may provide increased
sensitivity in detecting IC Na and thus offers the possi-
bility of monitoring changes in IC Na content without
SR. The amplitude of the MQF spectrum is determined
by several factors such as transverse relaxation times,
creation times, and the amount of Na that exhibits MQ
coherence. By the behavior of relaxation and greater
IC-Na MQ coherence, it is possible to have MQF spec-
trum with intracellular sodium to measure IC-Na content
2.13. Spiral Cardiac Respiratory Gate
Multi-Shot Functional MRI as
Physiological fluctuations (possibly by sodium) are
known to be a major contribution to noise in fMRI data.
Cardiac noise adds noise to both the magnitude and
phase of the image in regions localized near vessels and
ventricles. Another factor, respiratory motion, has both
global changes in the phase of image and localized
variations in the image magnitude, particularly near ven-
tricles. Recently, an empirical model was used to capture
the observed features of physiological noise in fMRI
data to reduce intracellular ionic noise in fMRI data us-
ing a 3-D cylindrical-stack spiral pulse sequence [24].
Briefly, spiral waveforms of sequence were applied on
the x and y gradients. The waveforms were designed get
low slew rate limited except for the first few points, and
their maximum amplitude was 0.75 G/cm to give a 3.8 x
3.8 mm nominal in-plane resolution. Six interleaves
were measured by adjusting the spiral waveforms (mul-
tiplying the x and y gradients by coefficients of a rota-
tion matrix) to effectively rotate the k-space trajectory in
the kx - ky plane. At the end of each TR interval, crusher
gradients were used to minimize spillover of the FID
signal into subsequent intervals. Their amplitudes were
set to generate about 3π dephasing over each voxel di-
mension of covered volume of interest. It results in a
“stacked spirals” k-space acquisition scheme. With the
spiral acquisition, all gradient moments, Mn(t), can be
shown as Eq.10:
G(t)tndt (10)
with t = 0 at the center of the RF pulse, are zero at the
center of k-space (t = tc).
The zeroth [M0(t)] and first [M1(t)] order moments of
the slab select null at gradient at t = tc by using two addi-
tional gradient phases after the slice selection lobe. Fur-
thermore, the magnetization were nulled at t =TR i.e.,
M0(t) for the phase encode gradient and M0(t) and M1(t)
for the spiral waveforms. These spiral waveforms are
made of trapezoid waveforms at amplitude with mini-
mum gradient moments. In addition, a phase encoding
scheme is inverted and quadratic RF phase modulation is
performed to minimize stimulated echoes. Additional
gradient pulses can minimize stimulated echoes after
acquisition. Another good practice to decrease the scan
time is inserting extra ‘dummy views’ to avoid extra
acquisitions when the physiological phase corresponds
to the view far away from the actual view to acquire,
although these ‘dummy views’ reduce fMRI temporal
resolution and lead to improper assessment of functional
activity & physiological variance. Cardiac ordering
shows greater utility due to shorter cardiac periods. It
can reduce inter-image variance by using k-space post-
processing techniques and may enhance sodium contrast.
This technique is very promising but longer scan times
are required.
Sodium MRI can be used in anatomical imaging appli-
cations in brain, tumors and cardiac cycle (25-29). Spe-
cial attention was focused on achieving intracellular so-
dium images. Triple Quantum filter in spin echo acquisi-
tion mode and inversion recovery methods are consid-
ered useful for it without using shift contrast agents.
However, the triple-quantum filtered technique requires
a very long repetition time. Inversion recovery technique
suffers from poor nulling and poor suppression of ex-
tracellular or intracellular sodium population (30-31).
Moreover, for imaging applications with the resolutions
of 64 or 128 pixels, physiological noise corrupt even
better regions without variation. These are referred to as
‘ghosts’, and may be shifted away from the area of in-
R. Sharma et al. / J. Biomedical Science and Engineering 2 (2009) 445-457
SciRes Copyright © 2009 http://www.scirp.org/journal/JBISE/
terest or avoided by using the ‘view ordering’ technique.
It was done by sorting the views for which physiological
period T = T0 (α =1) ‘low frequency sort mode’ or T = T0
x N/2 ‘high frequency sort mode’, where α =N/2,
N=total number of views). For cardiac sodium MRI data
acquisition in real time, the physiological phase and
corresponding view are obtained again and again till all
views are expended. Physiological ghosts, phase varia-
tion is cause of further inter-image fluctuations in car-
diac MRI time course and affect activation related
changes in the acquired signal.
The sodium concentration may be measured by plac-
ing a phantom next to tumor or animal during MR im-
aging. The mean sodium concentration per kilogram wet
body weight in the region of interest will be:
Na kk
][ (13)
The coefficients a and b were calculated from the so-
dium concentrations C1 and C2 and signal intensities I1
and I2 of the two phantoms as
Intracellular sodium concentration measurement: Sev-
eral attempts to measure the intracellular sodium con-
centration including sodium flame photometry and ion
electrodes in serum; ratiometric, electrom beam CT,
atomic force (AFM) spectroscopy in tumors; and sodium
MRS in myocardium suggested the role of ATP energy
and Na+/K+ pump in ischemia & tumor apoptosis.
Therapies that alter tumor ion homeostasis or affect/
destroy tumor cell membrane integrity are likely to gen-
erate changes that are observable with 23Na MR imaging
and sodium concentration measurements [29,31]. For
different methods, the concentration of intracellular so-
dium can be measured based on NMR peak areas by
subtraction or magnetization ratio and intracellular/ex-
tracellular volumes as following:
b (15)
where R1 and R2 are sensitivity factors.
In the following section, we describe our experiments
in support of increased sodium in malignancy and asso-
ciation with apoptosis in breast tumors and epithelial
growth factor in breast isolated cancer cells. For simplic-
ity, we introduce readers to the biochemical basis of in-
creased sodium in tumor cells. The low sodium-hydro-
For MQ method, gen exchange kinetics by slow sodium-hydrogen trans-
porter is center point. In malignant tumor cells, acidic
pH enhances the intracellular sodium that impairs both
the sodium-hydrogen transporter ability and Na+/K +
pump resulting in reduced [Na+/K+] ATPase enzyme to
release sodium (high intracellular sodium concentration
inside cells) from mitochondrial oxidation which also
triggers cells to slow down apoptosis or other associated
epithelial growth factors [high intracellular Na with low
apoptosis and EGF]. The low concentration of intracel-
lular sodium is sensitive to any malignancy change and
serves as a diagnostic rapid MRI imaging assay to test
1][ xvMRinR
where [x] and [y] denote the corresponding tissue and
standard phantom intracellular sodium concentrations. K
is a constant equal to MM0,v (y) /[y]. VR/Vin is the ratio of
reference and intracellular volumes in tissue.
For DQ method,
[Nai+]DQ= {(Ain/Aref)-(intercept)}/(slope) (12)
where Ain and Aref represent areas under tissue and
phantom intracellular sodium peaks. 3.1. Chemosensitivity Rapid Assays Using
Sodium MRI
For SQ method,
IC[Na] = {Ain/Aout}{Vout/Vin}{EC[Na]} (13) Very limited studies reported the value of intracellular
sodium in a chemosensitivity assessment by cell prolif-
eration and apoptosis in prostate and breast tumors.
However, its applications are expanding to glioma, car-
tilage, and liver [32,33]. A technical advance was re-
ported using an inversion recovery pulse sequence and
optimization of inversion times to achieve intracellular
sodium images in less time. Its application was applied
in texotere chemosensitivity response to PC 3-induced
mouse prostate and MCF 7-induced rat breast tumors as
shown in Figure 3. The enhanced contrast of increased
intracellular sodium MRI signal was correlated with
histopathology characterization of tumor tissues [34,35,
Ain and Aout are areas of the SQ 23Na NMR peaks for IC
and EC spaces; EC [Na] is extracellular Na concentration.
With these measurements, changes can be observed
much earlier than with the effects of anatomic remodel-
ing. 1H MR imaging FLAIR sequence, use of MR con-
trast agents, and T2-weighted imaging along with 23Na
MR imaging may improve tumor visualization of a ne-
crotic core or proliferating zones by multiparametric
analysis methods. Other approaches of enhancement of
3D 23Na images signal-to noise ratio depend on receivers
and coils and the twisted-projection imaging pulse se-
quence [32].
Openly accessible at
R. Sharma et al. / J. Biomedical Science and Engineering 2 (2009) 445-457
SciRes Copyright © 2009 Openly accessible at http://www.scirp.org/journal/JBISE/
Figure 3. Inversion recovery pulse sequence using optimized inversion
time generated high resolution intracellular sodium images of tumor (right
on the phantom image) in each panel. On right, a tumor image is enlarged
to show regional heterogeneity of MCF 7 induced breast tumor in rat. P
represents image of agarose-sodium phantom and alphabets at different
points indicate different stages of tumor growing cells to correlate with
histology as shown in table to highlight the accuracy of sodium MR signal
intensity and tumor pathology staging [36].
Figure 4. A Comparison between normal and malignant hu-
man breast epithelial cells (grown in a 2D monolayer and 3D
culture matrix) shows a role of EGF in luminal structure for-
mation. Normal human breast epithelial (NHBE) cells (grown
in the 3D culture matrix) form a luminal structure of normal
phenotype. (a) Normal human breast epithelial cells in
monolayer without rBME (2D monolayer) with normal EGF,
(b) NHBE cells in rBME (3D matrix) with reduced EGF, (c)
NHBE cells in rBME (3D) with normal EGF, (d) Malignant
human breast epithelial cells (HTB-132 obtained from ATCC)
in rBME (3D) with reduced EGF. Notice the role of FGF and
the rBME matrix used in association with malignant character-
istic of cells.
36]. However, the exact cause of increased TSC is not
known. In another set of breast cancer culture cells, we
observed the reduced EGF in tissues sensitive to sodium
ion homeostasis and metabolic integrity.
3.2. Correlation between Intracellular
Sodium Signal and Malignancy
Elevated TSC in breast lesions measured by non-inva-
sive 23Na MRI appears to be an indicator at the cellular
level associated with malignancy. This Na-23 MRI
method may have potential to improve the specificity of
breast MRI with only a modest increase in scan time per
patient [37]. Several physiological and biochemical
changes associated with proliferating malignant tumors
may cause an increase in total tissue sodium concentra-
tion (TSC) as a result of impaired sodium-hydrogen
transporter and [Na/K] pump activity resulting in re-
duced EGF (Figure 5).
Normal and malignant epithelial ductal cells were
grown on a reconstituted basement membrane extract
(rBME). In the event of the correct signaling from
growth factor and extra-cellular matrix proteins, isolated
human breast epithelial (HBE) cells formed their origi-
nal phenotype in vivo. HBE cells in the absence of re-
constituted basement membrane extract (rBME) failed to
assemble organized structures, and arrested growth when
R. Sharma et al. / J. Biomedical Science and Engineering 2 (2009) 445-457
SciRes Copyright © 2009 Openly accessible at http://www.scirp.org/journal/JBISE/
EGF+ECMproteins  
NullPoints (A)and(B)(TQ,DQandMQfiltersshowdifference)
Freeextr a ce l l u l a r Na
(A) LongT
(B) LongT
(outer) (inner)
Figure 5. This schematic description represents the origin of in-
tracellular sodium across the membrane and different null points
of sodium inside and outside generate contrast due to different
longitudinal relaxation constants as basis of sodium MRI. The in-
creased intracellular sodium leakage out of cells is associated with
hypoxia and apoptosis in cancer. EGF: Epidermal Growth Factor,
ECM: Extracellular matrix, and ETS: Electron Transfort System.
they reached confluence. HBE cells on-top of rBME
could display an acinar structure with a dead luminal
space in the absence of epidermal growth factors (EGF)
(Figure 4(b)). This simulated the ductal structures of
breast epithelial cells found in vivo. Under the same
condition, carcinoma cells exhibited colony overgrowth,
luminal filling, and loss of intracellular sodium (Figure
4(d)). These changes eventually reduce the resistance
against apoptosis and enhance the cell proliferation re-
sulting in severe morphological deformities visible by
microscopy and imaging as earlier reported elsewhere
[37]. It was observed that EGF disrupted the formation
of luminal structures of HBE either in monolayer or in 3
dimensional cell cultures with rBME. It may be attrib-
uted with the possibility if luminal structures bound with
sodium get free by the disruption after adding EGF.
When EGF was reduced or removed from the cultures,
normal phenotypes (e.g. luminal structure and uniformed
size) of human breast epithelial cell were obtained. With
the variation of the time to reduce EGF, we could gener-
ate different sizes of luminal structure of HBE
3.3. Limitations of Sodium Contrast and
Due to high concentrations of extracellular sodium, its
suppression by using inversion recovery pulses makes it
difficult to get absolute intracellular sodium images.
However, intracellular sodium images may be indicators
of edema, interstitial space, cell proliferation, malig-
nancy, and hypoxia as criteria to divide tumor dormancy,
slow-growing, and fast growing regions. Newer tech-
niques without the use of shift reagents using high reso-
lution RF coils generate 3D23Na images with high sig-
nal-to noise ratio in less than 15 minutes, permitting use
of combined 23Na and 1H MR imaging protocols with
total examination times of about 45 minutes. Moreover,
sodium imaging in myocardium and cardiac ischemia is
well investigated as a clinical tool.
A present state-of-art for sodium MR imaging is pre-
sented with a focus on quantum filters in pulse se-
quences and their variants in order to acquire intracellu-
lar sodium images with hands-on software pulse se-
quence design and MRI physics principles. Triple quan-
tum filtering scheme and non-invasive inversion recov-
ery fast spin-echo pulse sequences are described for dis-
tinct intracellular sodium MR images. Our experiments
on breast tumors and isolated culture cells indicated the
association of malignancy with increased intracellular
sodium and reduced apoptosis and reduced EGF in cells
with possibility of other growth factors involved.
The present work was supported by the grant GIA 0086 funded by
Aventis Pharmaceutical Company Inc. for design and development of
sodium MRI technique. Partly the work was presented at workshop
ISMRM: Minimization of data acquisition with maximum outcome in
2002. The study for the normal and malignant breast epithelial cell
culture was supported by NIH (1 R21 CA 131798-01A1).
[1] I. L. Cameron, N. K. Smith, T. B. Pool, and R. L. Sparks,
R. Sharma et al. / J. Biomedical Science and Engineering 2 (2009) 445-457
SciRes Copyright © 2009 Openly accessible at http://www.scirp.org/journal/JBISE/
(1980) Intracellular concentration of sodium and other
elements as related to mutagenesis and oncogenesis in
vivo, Cancer Res., 40(5), 1493–500.
[2] A. Amidsen and M. Schou, (1968) Lithium and the trans-
fer rate of sodium across the blood-brain barrier, Psy-
chopharmacologia, 12(3), 236–238.
[3] B. J. Carroll, L. Steven, R. A. Pope, and B. Davies, (1969)
Sodium transfer from plasma to CSF in severe depressive
illness, Arch. Gen. Psychiatry, 21(1), 77–81.
[4] M. E. Moseley, W. M. Chew, M. C. Nishimura, T. L.
Richards, J. Murphy-Boesch, G. B. Young, T. M. Mar-
schner, L. H. Pitts, and T. L. James, (1985) In vivo so-
dium-23 magnetic resonance surface coil imaging: Ob-
serving experimental cerebral ischemia in the rat, Magn.
Reson. Imaging, 3(4), 383–387.
[5] W. H. Perman, P. A. Turski, L. W., Houston, G. H. Glover,
and C. E. Hayes, (1986) Methodology of in vivo human
sodium MR imaging at 1.5 T, Radiology, 160(3),
[6] S. S. Winkler, D. M. Thomasson, K. Sherwood, and W. H.
Perman, (1989) Regional T2 and sodium concentration
estimates in the normal human brain by sodium-23 MR
imaging at 1.5 T, J. Comput. Assist. Tomogr., 13(4), 561–
[7] J. M. Dizon, J. S. Tauskela, D. Wise, D. Burkhoff, P. J.
Cannon, and J. Katz, (1996) Evaluation of triplequan-
tum-filtered 23Na NMR in monitoring of Intracellular Na
content in the perfused rat heart: comparison of intra- and
extracellular transverse relaxation and spectral ampli-
tudes, Magn. Reson. Med., 35(3), 336–345.
[8] K. J. Jung and J. Katz, (1996) Chemical-shift-selective
acquisition of multiple-quantum-filtered 23Na signal, J.
Magn. Reson. B., 112(3), 214–227.
[9] P. G. Morris, (1986) Nuclear magnetic resonance imaging
in medicine and biology, Clarendon Press, Oxford, Eng-
land, 123.
[10] S. W. Lee, S. K. Hilal, and Z. H. Cho, (1986) A multinu-
clear magnetic resonance imaging technique-simultane-
ous proton and sodium imaging, Magn. Reson. Imaging,
4(4), 343–350.
[11] P. J. Cannon, A. A. Maudsley, S. K. Hilal, H. E. Simon,
and F. Cassidy, (1986) Sodium nuclear magnetic reso-
nance imaging of myocardial tissue of dogs after coro-
nary artery occlusion and reperfusion, J. Am. Coll. Car-
diol., 7(3), 573–579.
[12] C. T. Moonen, S. E. Anderson, and S. Unger, (1987)
23Na rotating frame imaging in the perfused rabbit heart
using separate transmitter and receiver coils, Magn.
Reson. Med., 5(3), 296–301.
[13] R. Ouwerkerk, K. B. Bleich, J. S. Gillen, M. G. Pomper,
and P. A. Bottomley, (2003) Tissue sodium concentration
in human brain tumors as measured with 23Na MR im-
aging. Radiology, 227(2), 529–3.
[14] F. E. Boada, G. X. Shen, S. Y. Chang, and K. R. Thulborn,
(1997) Spectrally weighted twisted projection imaging:
reducing T2 signal attenuation effects in fast three-di-
mensional sodium imaging, Magn. Reson. Med., 38(6),
[15] I. Hancu, F. E. Boada, and G. X. Shen, (1999) Three-
dimensional triple-quantum-filtered (23)Na imaging of in
vivo human brain, Magn. Reson. Med., 42(6), 1146–
[16] A. Borthakur, I. Hancu, F. E. Boada, G. X. Shen, E. M.
Shapiro, and R. Reddy, (1999) In vivo triple quantum
filtered twisted projection sodium MRI of human articu-
lar cartilage, J. Magn. Reson., 141(2), 286–290.
[17] K. J. Jung, P. J. Cannon, and J. Katz, (1997) Simultane-
ous acquisition of quadrupolar order and doublequantum
23Na signals, J. Magn. Reson., 129(2), 130–133.
[18] L. M. Boxt, D. Hsu, J. Katz, P. Detweiler, S. McLaughlin,
T. J. Kolb, and H. M. Spotnitz, (1993) Estimation of
myocardial water content using transverse relaxation
time from dual spin-echo magnetic resonance imaging,
Magn. Reson. Imaging, 11(3), 375–383.
[19] G. X. Shen, J. F. Wu, F. E. Boada, and K. R. Thulborn,
(1999) Experimentally verified, theoretical design of
dual-tuned, low-pass birdcage radiofrequency resonators
for magnetic resonance imaging and magnetic resonance
spectroscopy of human brain at 3.0 Tesla, Magn. Reson.
Med., 41(2), 68–275.
[20] K. J. Jung, J. Katz, L. M. Box, S. K. Hilal, and Z. H. Cho,
(1995) Breakthrough of single-quantum coherence and
its elimination in double-quantum filtering, J. Magn.
Reson. B., 107(3), 235–241.
[21] K. J. Jung, J. S. Tauskela, and J. Katz, (1996) New dou-
ble-quantum filtering schemes, J. Magn. Reson. B.,
112(2), 103–110.
[22] K. J. Jung and J. Katz, (1997) Mathematical analysis of
generation and elimination of intersequence stimulated
echo in double-quantum filtering, J. Magn. Reson., 124
(1), 232–236.
[23] J. S. Tauskela, J. M. Dizon, J. Whang, and J. Katz, (1997)
Evaluation of multiple-quantum-filtered 23Na NMR in
monitoring intracellular Na content in the isolated per-
fused rat heart in the absence of a hemical-shift reagent, J.
Magn. Reson., 127(1), 115–127.
[24] V. A. Stenger, S. Peltier, F. E. Boada, and D. C. Noll,
(1999) 3D spiral cardiac/respiratory ordered fMRI data
acquisition at 3 Tesla, Magn. Reson. Med., 41(5), 983–
[25] H. Serrai, A. Borthakur, L. Senhadji, and R. Reddy,
(2000) Bansal, N. Time-domain quantification of multi-
ple-quantum-filtered (23)Na signal using continuous
wavelet transform analysis, J. Magn. Reson. 142(2),
[26] J. B. Ra, S. K. Hilal, C. H. Oh, and I. K. Mun, (1988) In
vivo magnetic resonance imaging of sodium in the hu-
man body. Magn Reson Med., 7(1), 11–22.
[27] S. K. Hilal, A. A. Maudsley, J. B. Ra, H. E. Simon, P.
Roschmann, S. Wittekoek, Z. H. Cho, and S. K. Mun,
(1985) In vivo NMR imaging of sodium-23 in the human
head, J Comput Assist Tomogr, 9 (1), 1–7.
[28] T. Hashimoto, H. Ikehira, H. Fukuda, A. Yamaura, O.
Watanabe, Y. Tateno, R. Tanaka, and H. E. Simon, (1991)
In vivo sodium-23 MRI in brain tumors: Evaluation of
preliminary clinical experience, Am J Physiol Imaging,
6(2), 74–80.
[29] K. L. Allen, A. L. Busza, S. R. Williams, and S. C. Wil-
liams (1994) Early changes in cerebral sodium distribu-
tion following ischaemia monitored by 23Na magnetic
resonance imaging, Magn Reson Imaging, 12(6), 895–
[30] R. Sharma and R. P. Kline, (2004) Chemosensitivity
assay in mice prostate tumor: Preliminary report of flow
R. Sharma et al. / J. Biomedical Science and Engineering 2 (2009) 445-457
SciRes Copyright © 2009 http://www.scirp.org/journal/JBISE/Openly accessible at
cytometry, DNA fragmentation, ion ratiometric methods
of anti-neoplastic drug monitoring. Cancer Cell Interna-
tional Cancer Cell International, 4(3).
[31] R. P. Kline, E. X. Wu, D. P. Petrylak, M. Szabolcs, P. O.
Alderson, M. L. Weisfeldt, P. Cannon, and J. Katz, (2000)
Rapid in vivo monitoring of chemotherapeutic response
using weighted sodium magnetic resonance imaging,
Clin Cancer Res., 6(6), 2146–56.
[32] P. M. Winter, V. Seshan, J. D. Makos, A. D. Sherry, C. R.
Malloy, and N. Bansal, (1998) Quantitation of intracellu-
lar [Na+] in vivo by using TmDOTP5-as an NMR shift
reagent and extracellular marker, J Appl Physiol. 85(5),
[33] P. M. Winter, H. Poptani, and N. Bansal, (2001) Effects
of chemotherapy by 1,3-bis(2-chloroethyl)-1-nitrosourea
on single-quantum- and triple-quantum-filtered 23Na and
31P nuclear magnetic resonance of the subcutaneously
implanted 9L glioma, Cancer Res., 61(5).
[34] J. M. Colet, N. Bansal, C. R. Malloy, and A. D. Sherry,
(1999) Multiple quantum filtered 23Na NMR spectros-
copy of the isolated, perfused rat liver, Magn Reson Med.
41(6), 1127–35.
[35] R. Sharma, R. P. Kline, E. X. Wu, and J. K. Katz, (2005)
Rapid in vivo Taxotere quantitative chemosensitivity re-
sponse by 4.23 Tesla sodium MRI and histo-immu-
nostaining features in N-Methyl-N-Nitrosourea induced
breast tumors in rats, Cancer Cell International, 5, 26.
[36] R. Sharma, (2008) Extended expression for transverse
magnetization using four pulse sequence to construct
double quantum filter of arbitrary phases for spin 3/2 so-
dium nuclei, International J. Computer Research, 16(4),
[37] R. Ouwerkerk, M. A. Jacobs, K. J. Macura, A. C. Wolff,
V. Stearns, and S. D. Mezban, N. F. Khouri, D. A.
Bluemke, and P. A. Bottomley, (2007) Elevated tissue
sodium concentration in malignant breast lesions de-
tected with non-invasive 23Na MRI, Breast Cancer Re-
search and Treatment, 106(2), 151–60.