Materials 2012, 5, 590-616; doi:10.

3390/ma5040590
OPEN ACCESS

materials
ISSN 1996-1944
www.mdpi.com/journal/materials
Review

Magnetic Resonance Characterization of Porous Media Using

Diffusion through Internal Magnetic Fields
Hyung Joon Cho 1,*, Eric E. Sigmund 2 and Yiqiao Song 3,4
1
School of Nano-Bioscience and Chemical Engineering, Ulsan National Institute of Science and
Technology, Ulsan 689-798, Korea
2
Department of Radiology, New York University, 660 First Avenue, New York, NY 10016, USA;
E-Mail: [email protected]
3
Schlumberger-Doll Research, One Hampshire Street, Cambridge, MA 02139, USA;
E-Mail: [email protected]
4
Athinoula A Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts
General Hospital, Charlestown, MA 02215, USA

* Author to whom correspondence should be addressed; E-Mail: [email protected];

Tel.: +82-052-217-2520; Fax: +82-052-217-2509.

Received: 16 March 2012; in revised form: 27 March 2012 / Accepted: 28 March 2012 /
Published: 12 April 2012

Abstract: When a porous material is inserted into a uniform magnetic field, spatially
varying fields typically arise inside the pore space due to susceptibility contrast between
the solid matrix and the surrounding fluid. As a result, direct measurement of the field
variation may provide a unique opportunity to characterize the pore geometry. The
sensitivity of nuclear magnetic resonance (NMR) to inhomogeneous field variations
through their dephasing effects on diffusing spins is unique and powerful. Recent theoretical
and experimental research sheds new light on how to utilize susceptibility-induced internal
field gradients to quantitatively probe the microstructure of porous materials. This article
reviews ongoing developments based on the stimulated echo-pulse sequence to extend
the characterization of porous media using both spatially resolved and unresolved
susceptibility-induced internal gradients that operate on a diffusing-spin ensemble.

Keywords: gradients; susceptibility; diffusion; decay due to diffusion in the internal field
(DDIF); porous media; trabecular bone
Materials 2012, 5 591

1. Introduction

Magnetic susceptibility contrast-induced inhomogeneous magnetic fields show a fingerprint of the

underlying pore geometry when porous media are subjected to an external, uniform magnetic field.
Nuclear magnetic resonance (NMR) provides a unique opportunity for nondestructively detecting such
internal field variations, and susceptibility contrast-based NMR methods hold great promise for
investigating the structural and functional properties of porous media.
For example, fluid-filled rocks, soils, or tissues (e.g., bones), which are comprised of at least
two phases with different magnetic susceptibilities, give rise to an inhomogeneous internal magnetic
field across their pores when embedded inside a uniform magnetic field. The presence of a nonuniform
field often influences NMR-relaxation experiments and diffusion measurements. This effect was first
recognized by Brown [1]. Since then, a large amount of effort has gone into understanding the effects
of internal gradients on various grain-packing geometries and designing pulse sequences that minimize
their effects [2–6]. Recent theoretical and experimental research [7–9] sheds light onto utilizing
susceptibility-induced internal gradients to probe the detailed structures of porous materials, such as
the pore size of oil-bearing rocks and the surface-to-volume ratio of trabecular bones [8–12].
In the context of biological tissues, when a superparamagnetic contrast agent, such as iron-oxide
particles [13–16], is confined to a vascular or blood-bearing space, inhomogeneous and localized fields
develop around the capillary vessels due to susceptibility differences between the vessel space,
interstitium, and the outside tissue in the uniformly applied magnetic field. The presence of these
induced fields may accelerate conventional T2*- and T2-relaxation rates. As a result, Dennies et al.
reported that the size of tumor microvessels can be determined by measuring the in vivo ratio between
susceptibility contrast-induced T2* and T2 in the presence of an iron-oxide intravascular contrast
agent [17], a technique known as vessel-size imaging. Because the vessel geometry is a significant
determinant of susceptibility contrast, in-depth characterization of the internal gradients in the
microvessel structure may provide important information about the morphology of abnormal tumor
vessels [18–20].
The sensitivity of NMR for measuring internal field variations led to the development of several
pulse sequences to characterize them. Traditionally, the signal of the gradient echo is reduced below
the spin-spin relaxation limit due to dephasing of the magnetization from the inhomogeneous field,
which is known as relaxation. Therefore, asymmetric spin-echo sequences, which sample the
magnetization away from the point of maximum spin coherence, are sensitive to effects of
susceptibility contrast [21,22]. The decay due to diffusion in the internal field (DDIF) method uses a
stimulated echo sequence and the fact that the internal field, which is modulated by spatial variations
in susceptibility, causes signal decay when sampled by a diffusing spin ensemble. DDIF essentially
monitors the time-dependent evolution of magnetization in the internal magnetic field and determines
the distribution of its decay constants in order to obtain quantitative information on the pore structure.
The structural parameters of a fluid-filled porous medium, such as the pore size of oil-bearing rocks
and the surface-to-volume ratio of a network of trabecular bones, can be estimated by the decay
characteristics of magnetization in the presence of internal gradients using bulk DDIF contrast [7–9].
In this paper, we will review several recent extensions of the DDIF method that use microimaging
to verify that the strength and orientation of the susceptibility-induced internal gradients can be
Materials 2012, 5 592

faithfully mapped using stimulated echo-based NMR relaxometry [8,23–25]. When the pore size is
larger or comparable to the image voxel, spatially resolved DDIF contrast provides detailed
information about the strength and orientation of the internal gradients by measuring susceptibility
contrast across the pores. For smaller pores, the variation in the internal gradient may be unresolved
because the signals from multiple pores are averaged across a single image voxel. However, even in
this case, DDIF-encoded relaxation data still contains salient structural information that can be inferred
using proper analytical techniques, such as Laplace inversion or spectrum heterogeneity [9,26].
An alternative quantitative description of the internal field can be obtained through self-correlation
of the field. This approach is useful when the pore size of the underlying microstructure is significantly
smaller than the size of the magnetic resonance imaging (MRI) voxel, which is the case for fine-grain
rocks and tissue microvessels. In these cases, the statistical properties of the internal field may be used
to determine relevant structural parameters. For example, Audoly et al. showed that the structural factor
(i.e., 2-point density correlation function) of porous media can be approximated using the
self-correlation function of the internal magnetic field [27]. They further argued that this correlation is
closely related to the fluid transport properties of the material. Cho et al. demonstrated that a
pulsed-field gradient (PFG) method involving both applied and internal field gradients, can be used to
obtain spatial magnetic correlation functions that are in good agreement with theoretical
simulations [28]. For biological applications, such as brain imaging, Jensen et al. showed that temporal
magnetic field correlation (MFC) functions can be measured using the asymmetric spin-echo sequence
with a range of asymmetric time shifts followed by Gaussian fitting. They further argued that MFC is a
more specific metric of the microscopic field inhomogeneities compared with conventional relaxation
parameters, such as T2 or T2* [21,22]. Thus, a range of techniques and applications exist that use
internal fields to increase their microstructural sensitivities.
This article is organized as follows: first, the basic concept of stimulated echo-based internal field
contrast will be introduced along with its extension to an imaging module, followed by the basic
data-analysis method used for bulk (i.e., spatially unresolved) and imaging experiments. DDIF
imaging experiments that use a 2-dimensional (2D) cylindrical phantom will be discussed to show the
direct correlation between spatially resolved DDIF contrast and the strength of a local
susceptibility-induced internal gradient [23]. Furthermore, the feasibility of measuring the local axis of
orientation of the cylindrical microstructure from directional measurements of its internal gradient
distribution will be discussed. Illumination of the origin and the contrast mechanism that were
previously reported for porous media, such as trabecular bone and which complement the interpretation
of the bulk DDIF technique, will be reviewed along with spatially resolved DDIF. Finally, a
pulsed-field gradient-NMR (PFG-NMR) method that utilizes an asymmetric, stimulated echo sequence
to extract the magnetic field correlation function will be discussed, describing the connections between
the statistical properties of the internal field and a porous material’s structural 2-point correlation
function. Representative examples in a system of randomly packed beads will be described using a pair
of symmetric and asymmetric stimulated echoes [28]. Finally, these examples will be discussed in the
broader context of microstructurally sensitive MR techniques, and future applications will be considered.
Materials 2012, 5 593

2. Utilization of the Internal Magnetic Field for Studying Porous Media

2.1. Diffusion in the Presence of Internal Field Gradients

NMR measurements of the apparent diffusion coefficients (ADC) of molecules have provided
unique structural details on porous media since the advent of PFG-NMR [29,30]. Once spatially
encoded with a magnetic field gradient, diffusing molecules give rise to an effective signal reduction
of the NMR spin echoes, which enables an accurate estimation of ADC with given known field
gradients. In addition to their absolute values, directional anisotropy of ADC values has been observed
and provides useful structural contrast in porous and biological media [31,32]. It has also been
theoretically and experimentally shown that the time-dependent diffusion coefficient of porous media
contains information about the surface-to-volume ratio [33,34].
The influence of the internal magnetic field gradients generated by variations in magnetic
susceptibility on NMR-diffusion measurements has also been recognized. If the internal gradient
significantly interferes with the external PFG gradients, the apparent extracted diffusivity can be
altered. Various methods have been suggested as ways to overcome this interference [3–5]. On the
other hand, susceptibility-induced internal gradients contain the fingerprint of the underlying structures,
and thus several techniques that focus on quantifying the effects of diffusion within internal gradients
alone have been developed to extract such properties as the pore size or the surface-to-volume ratio
from porous media [9,35–37]. In this review, we focus on describing the decay of the echo signal
through diffusing molecules in the presence of internal gradients (and in some cases external gradients)
using stimulated echo-based pulse sequences. As we will discuss below, the translational motion of the
spins is a vital component of these techniques, although the diffusivity itself is sometimes an implicit
parameter rather than an explicitly measured quantity.
DDIF is a stimulated echo-based relaxation measurement that utilizes susceptibility-induced
internal magnetic field gradients and molecular diffusion to probe the structures of porous media [7,9].
Imagine that the magnetic field, is higher in one part of the pore and lower in another due to the
susceptibility contrast of the medium. The first step of DDIF is to establish a spatial magnetization
profile that represents the inhomogeneous local magnetic field across the pore. A schematic DDIF
pulse sequence is shown in Figure 1a. Transverse spin magnetization after the first -pulse develops a
spatially dependent phase due to variations in the local internal magnetic field during the encoding
period ( ). At the end of the encoding period, the encoded transverse magnetization is flipped to the
longitudinal direction and the spins diffuse during the diffusion period ( ). This movement of
diffusing spins across different regions of the internal magnetic field causes a reduction in the
magnetization profile. This reduction in the magnetization can be detected using a third -pulse, which
produces a stimulated echo. The decay of these amplitudes typically demonstrates multi-exponential
decay behavior for variable diffusion times ( ) due to the distribution of field gradients in the sample.
When the molecules diffuse a distance ( 2 ) equal to the pore size, the spatial nonuniformity
of the magnetization diminishes, and the magnetization decay is dominated by spin-lattice relaxation
(T1). Figure 1b shows the pulse sequence used to measure the spin-lattice relaxation times as a
reference experiment to DDIF contrast. The -pulse in the middle of the encoding period unwraps the
spatially dependent phase acquired during due to the inhomogeneous magnetic field and
Materials 2012, 5 594

re-establishes a uniform magnetization. This suppresses the effect of the inhomogeneous field on the
variable , while retaining the same spin-spin (T2) relaxation present in the DDIF-encoded sequence
for convenient normalization. The combination of DDIF and reference scans allows a stronger
distillation of the internal field contrast from the total magnetization.

Figure 1. (a) Decay due to diffusion in the internal field (DDIF) and (b) reference pulse
sequences. and are the encoding and diffusion time periods, respectively. Stimulated
echoes were detected by DDIF and free induction decay for the reference scan. Reproduced
from Reference [12] with permission.

Extensions of DDIF contrast, including its use in imaging modules, can be implemented in order to
obtain spatially resolved information regarding the distribution of the internal field gradient. In this
article, we review its extension to 2D spin-warp imaging, as shown in Figure 2, but the basic DDIF
pulse sequence can be attached as a precursor to other imaging modules. In such a sequence, the DDIF
pulse sequence encodes the magnetization contrast and an imaging technique is applied to observe its
spatial distribution. The concept of DDIF imaging is thus similar to that of Т1-, Т2-, and
diffusion-weighted imaging. In particular, the stimulated echo sequence can precede any fast imaging
modality, such as RARE or BURST, to accelerate the acquisition of spatially resolved DDIF
contrast [38]. In the case of spin-warp imaging, as shown in Figure 2, field gradients are applied during
soft -pulses for slice selection. The use of pulsed spoiler gradients during ensures the selection of
the stimulated echo pathway. Read and phase gradients are applied just before the stimulated echo
formation to minimize unwanted diffusion-weighting from these gradients.
Because applied field gradients also cause signal decay, one needs to be cautious during the design
of pulse sequences to minimize any encoding gradients before because they will interfere with
internal field encoding. Read and phase gradients can occur after , and they induce, at most,
-independent diffusion-weighting. However, an unfocused slice gradient during the second -pulse
or a crusher gradient before the second -pulse can induce -dependent diffusion-weighting and
interfere with the internal gradient during . For example, the effective decay rate of the
slice-selective gradient of the second -pulse (see Figure 2) can be estimated according to the equation,
, where, τp , Gs and D correspond to the pulse length, slice-gradient strength, and
diffusivity, respectively. is the gyromagnetic ratio. When τp = 2 ms and Gs = 4 G/cm, this estimation
Materials 2012, 5 595

produces an additional decay rate of 0.3 (1/s). The total background decay rate of the DDIF imaging
sequence in Figure 2 can be estimated as 0.7 (1/s), assuming the T1 relaxation of free
(unrestricted) water molecules. This correction is one example of the need to separate internal and
external field effects when interpreting DDIF data. Future examples in this review will carry this
idea further and illustrate the constructive and destructive interference patterns of the internal and
external gradients.

Figure 2. Slice-selective 2-dimensional (2D) spin-warp DDIF imaging sequence. The

spoiler gradient was applied during to remove the unwanted coherence pathway signal.
The readout gradient was applied just before stimulated echo acquisition to reduce signal
decay due to the external field gradients at different diffusion times. A pulsed-field
gradient can be applied during to extract cross-terms between the internal and external
gradients. Reproduced from Reference [23] with permission.

2.2. Data Analysis

Before explaining the appropriate data-analysis techniques used to analyze bulk and imaging DDIF
contrast, it is worthwhile to introduce the length scales relevant to the DDIF experiment: imaging
voxel size (∆x), structural scale (ls), and diffusion length (lD). The structural scale (ls) refers to the
average pore size of the medium, and the diffusion length (lD) is defined as, 2 where D is
the diffusion constant and is the diffusion time, respectively [39,40].
For bulk DDIF measurements, when ∆x ls, lD, the decay of the echo amplitudes typically shows
multi-exponential behavior for short , reflecting the internal gradient distribution in the sample. In
these cases, the DDIF signal is essentially a sum of weighted exponential functions
(i.e., a Laplace transformation), as given by Equation (1).
S (t ) =  f (τ )e−t / τ dτ (1)
Materials 2012, 5 596

As grows longer, the echo amplitude eventually follows regular spin-lattice relaxation as the
spatial nonuniformity of magnetization disappears. To illustrate this behavior, representative DDIF and
reference (T1) data on 3 different bovine trabecular bone samples are shown in the bottom panel of
Figure 3a. The difference in magnetic susceptibility between the solid and liquid phase of a
water-filled trabecular bone gives rise to field variations and contributes to DDIF signal decay over
short . The corresponding trabecular structure of each sample is shown in the top panel, obtained
from high-resolution microscopic computed tomography (μCT). Qualitatively, a faster initial decay
rate is apparent in the time domains of the DDIF echo amplitudes of sample B with respect to samples
A and C. In the bottom panel of Figure 3b, the corresponding DDIF spectra are shown for each
sample [12].
To obtain the DDIF spectra, Laplace inversions are performed on the echo amplitudes that are
acquired at logarithmically spaced . Reference data (R) are subtracted from the DDIF data ( ) to
remove the relaxation contribution, as shown in Equation (2).
Es = E0 − a0 R (2)
The Laplace inversion procedure is then applied to the subtracted amplitudes ( ) to obtain the
spectra of the decay times. Since an individual inversion can be numerically ill-conditioned, proper
consideration of noise sensitivity is helpful. The uncertainty of the DDIF spectrum can be verified
using a number of Laplace inversions of the original data combined with different simulations of the
Gaussian-distributed noise, whose amplitude matches the measured echo amplitudes standard
deviation. Inversion consistency can be maintained by using a constant regularization parameter for
each data set. As shown in the bottom panel of Figure 3b, the DDIF spectra clearly show larger
weights for the short, fast decay times of sample B, which is consistent with the faster decay of its
time-domain DDIF decay signal shown in Figure 3a [12].
Conversely, when the voxel size of interest is much smaller than the relevant structural length scale
(∆x ls), a constant gradient within each high-resolution voxel may be assumed and the decay of the
echo amplitude of each imaging voxel can be fit to a single exponential model. Consequently, the echo
decay rate of each voxel can be modeled as shown in Equation (3) [41,42].
1 1
= + γ 2 G int 2 te 2 D (3)
TDDIF Tback
Equation (3), Tback is the background relaxation time, including T1 and diffusion-weighting of the
slice gradient, γ is the gyromagnetic ratio, Gint is the strength of the internal gradient, is the
encoding time, and D is the diffusion constant. Note that this formula omits directionally dependent
cross-terms between the internal and external gradients; this effect will be discussed in upcoming
sections. In order to experimentally extract the DDIF decay rates affected by the internal gradients,
these background rates can be subtracted after fitting a single exponential function to the individual
pixels of the image. It is worthwhile to estimate the noise level of the signal-free region of the image
and include only data points with amplitudes larger than the noise level. In the DDIF-imaging
experiment, it was also observed that the signal decay that was obtained at low resolution, in some
cases, demonstrated multi-exponential behavior when there was a significant gradient distribution
within each voxel. Ideally, Laplace inversions could be applied to the data in each voxel; however,
Materials 2012, 5 597

voxel-wise data sets may not be sufficiently sampled in time ( ) or possess insufficient signal-to-noise
ratio (SNR) to support Laplace inversions. In these cases, reasonable comparisons can be made by
limiting the fit to a shorter diffusion time over which most of the voxels display single exponential
behavior. This initial rate represents the overall average rate of the entire voxel.

Figure 3. In the top panel, high-resolution microscopic computed tomography (μCT)

images of 3 trabecular bone samples with different yield stresses are shown. Transverse
and longitudinal slices are shown in the first and second rows, respectively. A 3D
rendering of a cubical subvolume is shown in the third row. Images were acquired at an
isotropic spatial resolution of 34 µm. In the bottom panel, section (a) shows the
corresponding decay in the raw echo amplitudes as a function of the diffusion time of each
sample. Section (b) shows the corresponding DDIF spectra obtained from Laplace
inversions. Reproduced from Reference [12] with permission.
Materials 2012, 5 598

2.3. DDIF Microimaging with a 2D Cylindrical Phantom

Some varieties of porous media (e.g., vascular capillary bundles, axonal nerve fibers, myofibers)
possess some degree of symmetry and collective anisotropy, which are closely related to their
integrities and functions. In some cases, DDIF may be employed to sensitize MR to microstructural
anisotropy via its influence on the internal field pattern. Furthermore, in the simplest case, the
cylindrical symmetry of a bundle of capillary tubes (i.e., “fibers”) makes it essentially a 2D object, so
that exact comparisons with theoretical calculations can be performed. When intrinsic or extrinsic
susceptibility contrast exists between the fiber and the surrounding medium, internal gradients arise at
the interface around the fiber. Quantitative characterization of these gradients may provide important
tools to infer the fibrous microstructure, such as the directions of the nerve pathways in brain, cardiac
or skeletal muscle architecture, or the tortuosity of cancerous microvasculature. To that end,
techniques can be employed to offset the internal and external gradients and maximally sensitize DDIF
to anisotropy.
The susceptibility-induced internal gradient profile of a single capillary tube in the presence of a
magnetic field, Bz , along the axial direction (z) of the cylinder offers insights into the anisotropy of the
internal field (Figure 4). The difference in susceptibility ( Δ χ ) between the wall of the cylinder and the
rest of the medium is the source of the internal gradient and can be analytically described as shown in
Equation (4).
x2 − 3 y 2
G int x ≈ B0Δχ (a 2 − b2 ) x ,
( x 2 + y 2 )3
y 2 − 3x 2 (4)
G int y ≈ B0Δχ (a 2 − b2 ) y
( x 2 + y 2 )3
G int z ≈ 0

Figure 4. (a) Capillary cylinder in the presence of B0 (diameter: 1.55 mm; wall thickness:
0.2 mm); (b) Calculated susceptibility-induced internal gradients along the x, y and z
directions. Reproduced from Reference [43] with permission.
Materials 2012, 5 599

Figure 4b plots the profiles of the corresponding susceptibility-induced gradients along the x, y and
z-axes, respectively. Note that no internal gradients exist when the field is applied along
the z-axis of the cylinder. Also, for a transversely applied field, the internal gradient is oppositely
oriented on either side of the cylinder and is absent within it.
In order to experimentally obtain spatially resolved information on the susceptibility-induced
internal gradients, a DDIF-imaging experiment was performed. Figure 5 shows an expanded
spin-density image of a randomly packed water-filled glass capillary phantom (inner radius: 0.58 mm,
outer radius: 0.77 mm), and Figure 5b shows the corresponding DDIF signal decay of the individual
voxels denoted in Figure 5a. The details of this acquisition have been previously described [43]. The
susceptibility-induced internal field is approximately constant inside the cylinders, and DDIF decay
rates of 0.76 (1/s) for point 1 inside the cylinder is in good agreement with the sum of background
contributions from T1 (0.4 (1/s)) and the uncompensated slice gradients (0.3 (1/s)).

Figure 5. (a) Spin-density image of the pore space in packed cylindrical capillary tubes;
(b) Signal decay rates of each point labeled in (a). Reproduced from Reference [23]
with permission.

Figure 6 shows a direct comparison between spatially resolved DDIF rates and theoretically
calculated internal gradient values at corresponding positions in the randomly packed capillary tubes.
The signal decay rate is slower at the center of the cylinder and at the extracylindrical pore center and
faster near the walls, indicating higher internal gradients near the walls of the cylinder. Agreement
between the theoretical calculations of the internal gradients and the DDIF measurements is excellent.
This work demonstrates the sensitivity of DDIF imaging is sufficient to directly characterize
susceptibility-induced internal gradients.
Materials 2012, 5 600

Figure 6. (a) Measured DDIF decay rates in packed cylindrical capillary tubes;
(b) Calculated strength of the internal gradients in the corresponding pore space;
(c) Experimental measurements of DDIF decay rates along the lines across the pores
denoted in (a). (d) Theoretical calculation of the squared internal gradient across the lines
in the same pore space denoted in (b). Reproduced from Reference [23] with permission.

It is worthwhile to note that the DDIF-imaging method essentially measures the squared value of
the local internal gradient (Gint2), as shown in Equation (3). As a result, any directional information
regarding the internal gradient is lost. In general, the gradient of the magnetic field vector is a
second-rank tensor. In the presence of a strong magnetic field along the z-axis, only 3 partial
i i i
∂Bz ∂Bz ∂Bz
derivatives ( , , ) of the z -component of the susceptibility-induced magnetic field ( Bzi )
∂z ∂x ∂y
i
∂Bx ∂B y
i

are of interest because the others ( , , …) correspond to fields in the rotating frame and do not
∂z ∂z
affect the long-term spin dynamics. As a result, three partial derivatives characterize the relevant
internal gradient for NMR measurements of an isotropic-susceptibility constant ( χ ) . Because the
Materials 2012, 5 601

internal magnetic field gradient is a vector quantity, not only the strength but also the orientation of the
internal gradient should provide the maximum amount of information about the underlying structural
geometry. Conventional DDIF measurement, as illustrated thus far, only reflects the magnitude of the
gradient, not the orientation.
To determine the orientation of the internal gradient, an external field gradient can be applied to
generate a cross-term between the external and internal gradients. Let us imagine that a pulsed-field
gradient of arbitrary direction is applied during encoding period ( ) of the pulse sequence, as shown in
Figure 2. The spins experience both internal and external gradients during the encoding period and,
1
thus, magnetization decays following a new, effective decay rate ( ) as the diffusion time ( )
Tcross
increases.
1 1
= + γ 2 Gtotal 2 te 2 D
Tcross Tback
2 2 2
 
G total = Gint + Gext + 2Gint ⋅ Gext (5)
2
The squared magnitude of this gradient ( Gtotal ) contains a cross-term (vector dot product) of the
internal and external gradients, as shown in Equation (5). The orientation of the internal gradient in an

image voxel can be estimated by varying the interference effects of the internal (Gint ) and external

(Gext ) gradients on the magnetization decay as the direction of the external gradient is changed. In
fact, three measurements with independent, external field gradient directions, and one without an

external gradient, are sufficient for determining the local Gint vector within an imaging voxel
according to Equation (5).
Figure 7 illustrates the significant changes that occur in the spatially resolved DDIF rates as the
direction of the applied field gradient (5 mT/m; which is on the order of the internal gradient used in
this experiment) is changed from an axial to a transverse orientation relative to the cylindrical axis.
When the external gradient is applied perpendicularly to the cylindrical axis (a), the fastest decay rates
are observed in the regions where the internal and external gradients have the same direction. When
the external gradient is applied parallel to the cylindrical axis (c), no apparent effect on the cross-term
is observed because no internal gradient is present along the direction of the cylindrical axis. In the
bottom panel, comparisons between the experimental and theoretical calculations and histogram
analyses of the decay rates for both cases are shown to illustrate the differences in the distributions of
the decay rates when the direction of the external gradient is varied. The absence of an axial
component in the internal gradient suggests the feasibility of determining the direction of the
cylindrical capillaries using the cross-term between the external and internal gradients, similar to
recent findings [43].
Materials 2012, 5 602

Figure 7. In the top panel, sections (a–c) show spatial maps of the DDIF cross-term rates,
respectively, when external pulsed-field gradient (PFG) is applied along different
directions. In the bottom panel, sections (d) and (e) compare the internal gradient strength
across the pore denoted in (c) determined from experimental DDIF rates with that derived
from theoretical calculations. (f) Histogram distribution of the measured internal gradient
strengths along the [100] and [001] directions, respectively. Reproduced from Reference [43]
with permission.

It is worthwhile to note that internal gradients may contribute to non-Gaussian diffusion-weighted

behavior. For example, in the case of a 2D cylindrical phantom, the diffusion-weighted signal follows
a single exponential temporal decay when the external gradient is applied along the z-direction.
On the other hand, a clear deviation from single exponential behavior is observed when the external
gradient is applied along either the x- or y-direction, where broad distributions of internal gradients
exist, as shown in Figure 8 [43]. Capuani et al. also recently reported spatiotemporal anomalous
diffusion in heterogeneous porous media and hypothesized that the internal gradients act as
contributing factors [44]. While different control variables (diffusion time, applied diffusion weighting)
may have been applied in these examples, the underlying mechanism of internal gradients inducing
apparent non-Gaussian diffusion is a potential common theme.
Materials 2012, 5 603

Figure 8. (a) Calculated decay characteristics of the unresolved DDIF signal when the
external gradient is applied along the x, y and z directions, respectively; (b) Corresponding
experimental measurements of the DDIF-signal decay. Reproduced from Reference [43]
with permission.

2.4. Comparison between Bulk and Resolved DDIF Contrast in Trabecular Bone

Spatially resolved internal gradient profiles of porous media provide rich information regarding the
underlying structures and complement conventional DDIF-relaxation measurements. For example, in
this review, we compared bulk and spatially resolved DDIF contrast in trabecular bone.
Bone tissue is a solid mineral matrix, filled with soft bone marrow that is comprised of a mixture of
liquid and adipose (fatty) tissue. Human bone is normally classified as cortical or trabecular. Cortical
bone, which usually comprises the shaft of a long bone, is very dense with low porosity. Trabecular
bone (spongy bone) is a complex network of plates and rods with a typical thickness of the order of
100 µm that occurs for example in vertebral bodies, and femoral, or tibial joints. These load-bearing
zones are often at high risk of fracture in patients with abnormal bone remodeling, such as those with
osteoporosis. Total bone density is commonly accessed with dual X-ray absorptiometry (DEXA),
which senses the amount of bone without regard to its microscopic arrangement. The bone
microstructure of trabeculae can be characterized using X-ray-based μCT; however, the high dose of
radiation necessary for current X-ray technology, limits its clinical application. Because MRI provides
superior soft tissue contrast without ionizing radiation, there is a great deal of interest in developing
clinical MRI methods that can be used to probe the trabecular bone structure in vivo; in that spirit,
methods that employ the internal field signature via its effect on free induction decay, as well as direct
microimaging of the trabecular bone structure in certain anatomical zones, are gaining
prominence [45–56].
Because the susceptibility difference between the solid bone matrix and the intervening
composition of fluid, marrow, and fat gives rise to magnetic field variations in trabecular bone, several
MRI methods were developed to characterize the relationship between the strength and linewidth
( 1 / T2 ' ) of bone tissue. Several studies consistently show a prolonged T2 ' value in osteoporosis patients
that increases as the intertrabecular space reduces the surface area where the susceptibility-induced
field exists.
Materials 2012, 5 604

Research on bulk-DDIF measurement of bovine trabecular samples [12] (Figures 3 and 9) shows
higher spectral weights in short-decay regions of bone samples with high surface-to-volume ratios. For
the full range of samples examined in that study, it was shown that the integrated weight of the
short-decay region (20 ms < TDDIF < 500 ms) of the DDIF spectra of each sample correlates well with
the projected surface-to-volume ratio (PSVR) that was determined using both independent PFG-NMR
measurements as well as the mean intercept length (MIL) of the trabecular bone samples obtained
using μCT image analysis, as shown in Figure 9. MIL was found by averaging the lengths of the line
segments between trabeculae across the whole structure. MIL and other related metrics, such as
trabecular density, are well-known measures of the integrity of trabecular bone structures.

Figure 9. (a) DDIF results and PFG-PSVR measurements as a function of yield stress for
17 trabecular bone samples; (b) Calculated mean intercept lengths of the corresponding
samples. (c) Calculated projected surface-to-volume ratio (PSVR) values of the μCT
images. (d) Calculated trabecular number for corresponding sample. Reproduced from
Reference [12] with permission.
Materials 2012, 5 605

The concept of PSVR is similar to that of ADC in an anisotropic medium along the direction of the
applied gradient. The leading order behavior of the time-dependent diffusion coefficient in an
D (t ) 4 S S
anisotropic medium ( D (t ) ) is described by ≈ 1− ( ) p D0 t , where ( ) p corresponds to
D0 3 π V V
PSVR along the direction of the applied external gradient [33].
To independently measure PSVR using NMR, in comparison with DDIF measurements, the
time-dependent diffusion coefficient ( D (t ) ) was measured using PFG-NMR on the same trabecular
bone samples along different directions of the applied external gradient. PSVR was obtained from the
slope of the D (t ) data, as suggested by Mitra et al. [33]. The MIL values of each sample were found
by drawing a line in the proposed direction through the 3D image volume and averaging the distances
between trabecular plates along the line of that orientation through the whole sample volume.
In Figure 9a, PSVR measurements of the time-dependent diffusion measurements and the
corresponding DDIF weight for short-decay times are plotted against the mechanical yield stress for
the full range of samples. DDIF weight is seen to closely resemble PSVR measurements along the
Bz-direction. In Figure 9b, 9c and 9d, calculated PSVR, inverse MIL and trabecular number from high-
resolution (34 µm) μCT images of the same bone samples are plotted to show the close correlation
between DDIF measurements and PFG-NMR measurements. Direct calculation of the internal
magnetic field of the trabecular bone samples also sheds some light on the origin of DDIF contrast. We
noted that deviations in the internal magnetic field from the applied field mainly occurred near plates
that were oriented perpendicular to the applied field (Bz) direction.
Spatially resolved DDIF experiments with high (125 µm) and low (1.2 mm) resolution images of
the trabecular bone samples also provide direct insight into DDIF contrast [24]. Figure 10 shows the
experimental micro-imaging results of trabecular bone samples B and C [24]. Three different types of
images—a spin-density image, a 1 / T1 rate map, and a DDIF rate map—of four different cases are
plotted: two axial images of two samples, one coronal image intercepting both samples, and one
low-resolution coronal image. One-dimensional profiles of spin density and DDIF decay rates were
extracted for quantitative comparison, as shown in Figure 10. For both samples and orientations, clear
DDIF decay rates maxima and spin-density minima were observed near the trabecular surfaces.
Spatially resolved 1 / T1 maps were found to be quite uniform for both samples B and C in both slice
orientations. On the other hand, the DDIF rate maps show striking contrast between the two samples.
Overall, higher DDIF rates were observed in both the high- and low-resolution image experiments with
sample B, which has a higher surface-to-volume ratio than sample C.
Figure 11 shows the theoretically calculated DDIF decay map of coronal images of both samples
based on high-resolution μCT images. These results include binarized high-resolution images and
downsampled, partial-volume averaged, low-resolution images. Again, high-resolution DDIF rate
maps show pronounced maxima near the surfaces that are transverse to the applied field direction. The
coarsening of resolution appears to spread contrast throughout the structure. A qualitative resemblance
is clearly observed between the calculated low-resolution DDIF maps and the corresponding
experimental DDIF maps, shown in Figure 10.
Materials 2012, 5 606

Figure 10. Experimental DDIF microimaging. Spin-density images are shown in the first
column. The second column shows a map of the spin-lattice relaxation rate. The third
column shows a map of DDIF decay rates. The fourth column shows 1D profiles through
the centers of each image, as indicated by the vertical lines. The first and second rows
show axial images of samples C and B, respectively. The third row shows high-resolution
coronal images of both samples B and C together, and the fourth row shows low-resolution
coronal images of samples B and C. Reproduced from Reference [24] with permission.
Materials 2012, 5 607

Figure 11. Calculated local DDIF contrast (internal gradient map) of samples B and C. For
each sample, the upper left is the binarized high-resolution μCT image. The upper right is
the high-resolution calculated DDIF map. The lower left is the downsampled
low-resolution image, and the lower right is the calculated low-resolution DDIF map.
Reproduced from Reference [24] with permission.

The in vitro studies performed on water-saturated trabecular bone highlight the presence and
information content of DDIF contrast in particular biological structures. However, depending on the
composition and skeletal location, bone marrow-water diffusion is restricted by adipose cells
(which also have low rates of diffusion), which may reduce the achievable DDIF contrast [57–60].
However, preliminary in vivo studies have demonstrated DDIF contrast in human trabecular bone, and
studies exploring the influence of marrow composition and/or distribution in the pore space have shed
promising light on the in vivo source of DDIF contrast [61,62]. Recently, it has been also shown that
DDIF contrast is apparent in fresh bone specimens with intact bone marrow [63]. Future work may
build upon these results to determine the optimal clinical role of internal field diffusion-weighting in
trabecular bone and its potential to infer structural markers of mechanical strength in arbitrary
skeletal locations.

2.5. Measurement of Magnetic Field Correlation Functions

When the pore size is much smaller than the spatial resolution, statistical description and
characterization of the internal magnetic field are compelling alternatives to microimaging. Signal
decay due to diffusing spins in the presence of an internal field provide statistical measurements of
internal field variation at the microscopic level. Correspondingly, important structural parameters, such
as the structural factors of the porous medium, may be approximated by bulk, low-resolution NMR
measurements. Audoly et al. first calculated the field correlation function of the internal magnetic field
of a sample of randomly packed spheres and demonstrated a similarity between the field correlation
function and the structural correlation function [27]. This work shows that the statistical features of
Materials 2012, 5 608

internal magnetic fields are closely and quantitatively related to the corresponding features of the
underlying geometry.
It was recently shown that a pair of symmetric and asymmetric stimulated echo PFG-NMR
experiments can be used to directly measure the correlation function of the internal magnetic field [28].
First, we used PFG-NMR to select spins by their translational diffusion displacements without effects
from the internal field. Then, a similar experiment was performed that included the effects of the
internal field. For a group of spins with specific diffusion displacements, the magnetic field difference
across this displacement resulted in additional decay in the second experiment.
Let us consider a conventional internal field-compensated stimulated echo sequence,
π π
- τ - π - τ ' - - t d - π - τ - π - τ ' -echo, as shown in Figure 12a. Bipolar external field gradient pulses
2 2 2

of length δ are applied during the periods. The π -pulse in the middle of the first and second
-pulses refocuses the phase evolution of the spins due to field inhomogeneities when τ = τ ' . The
echo signal of the ensemble of diffusing spins at the echo time is then given by Equation (6).
   
E(q, Δ) =  P(r , Δ)eiq⋅r dr (6)

Figure 12. Pulse sequences used to measure the pair correlation function of the internal
magnetic field. (a) Balanced sequences used to nullify the effect of the internal field;
(b) Imbalanced sequence used to introduce the effect of the internal field. Reproduced from
Reference [28] with permission.

 
In Equation (5), q = γG ext t is the wave vector due to the external field gradient. Δ is the diffusion

time. A Fourier transform of the echo signal, with respect to q , will produce the average propagator

P ( r , Δ ). In the second experiment, the timing of the π -pulse is adjusted so that τ − τ ' = t is nonzero;
we call this sequence unbalanced, as shown in Figure 12b. In this case, the spins experience the
internal field during the unbalanced encoding periods ( τ ≠ τ ' ) causing a net phase accumulation due
to the internal field. The echo signal will be further weighted by the internal field effects of the
diffusing spins. In this case, the echo signal can be written as shown in Equation (7), within the
average propagator formalism.
Materials 2012, 5 609

   i     
E' (q, Δ) =  P(r , Δ)eiq⋅r eiγt ( Bz ( r )−Bz (0)) dr ≡  P' (r , Δ)eiq⋅r dr
i

(7)
When the full q-space is mapped, followed by 3D Fourier transformation, the ratio between the
unbalanced and balanced measurements will yield the following.
P'
C (r ) = ≈ 1 − γ 2 t 2 < ( Bzi ) 2 > +γ 2t 2 < Bzi (r ) Bzi (0) > (8)
P
The second moment ( < ( Bzi ) 2 > ) and the field correlation function ( < Bzi (r ) Bzi (0) > ) of the
susceptibility-induced internal magnetic field ( Bzi ) can then be obtained along arbitrary directions of
the diffusing spins in the porous medium. The bracket refers to an ensemble average.
For an isotropic sample, a single gradient-direction experiment may be sufficient to measure the
propagator because the 3D isotropic propagator can be written as a product of the propagator in each
direction. Then, the ratio of the 1D Fourier transformation data between the balanced and unbalanced
sequences will yield the following.
P'   
C1( r ||) ≡ ≈ b + γ 2 t 2 <  P (r⊥ , Δ ) B zi ( r ) B zi (0) dr⊥ > (9)
P

where b ≈ 1 − γ 2 t 2 < ( Bzi ) 2 > , and the bracket refers to an ensemble average. Since r has two

components, parallel to ( r || ) and perpendicular ( r ) to the applied gradient direction, the integration of
⊥

 
r means that C1 is only a function of r || .
⊥

For comparison with this type of measurement, numerical evaluation of the internal magnetic field
of a densely packed hard sphere model can be performed by the superposition of the magnetic fields
from the dipoles located at the center of the each sphere. When a single sphere of radius R0 and
permeability μ1 is embedded into a medium with permeability μ 2 in the presence of an external
 
magnetic field ( B z ), the magnetic dipole moment ( m ) of the sphere due to susceptibility mismatch is
given by Equation (9) [64–67].
 μ − μ1 3

m= 2 R0 Bz (10)
μ 2 + 2μ1

If we only consider small and isotropic susceptibilities, then the dipole moment along the direction
 
of Bz can be approximated as m = 4π / 3 R Δ χ B z , where the susceptibility difference between the
0
3


grain and the medium is 4πΔ χ = ( μ 2 − μ1 ) . The internal magnetic field at position R is given by the
superposition of the dipole fields of each sphere and can be calculated as show in Equation (11).
i         
3m( R − Ri )( R − Ri ) − ( R − Ri ) 2 m
B ( R) =    (11)
i ( R − Ri ) 5

In Equation (11), Ri is the center of each sphere. As before, if we take the B0 -field along
the z-direction, the z-component of the internal field is the only relevant component of the
NMR experiment.
Now, the correlation function of the internal magnetic field is analogous in form to that derived
from a single PFG direction experiment. Specifically, the magnetic field correlation function, derived
from the calculated internal field distribution is described by Equation (12).
Materials 2012, 5 610

  
 B ( R )B ( R ) P(r
i, j
i
z i
i
z j ⊥ )
κ (r ||) = , (12)
n'
K = κ (r ||) / κ (0)
 
In Equation (12), Ri − R j = r || ( r || is the direction of the applied field gradient), n ' is the number
  
of coordinate pairs with distance r || , and r⊥ is the component of Ri − R j that is perpendicular to the

direction of applied gradient. P( r⊥ ) is the probability function that weights each contribution to the
sum by the number of coordinate pairs whose projected separation perpendicular to the field gradient

direction is r⊥ . In that sense P is similar to an experimentally measured propagator but in this
expression is evaluated purely numerically.
Figure 13a shows the numerically calculated internal field correlations ( K ( r ||) , r || // z),
where z is the direction of the main magnetic field) as a function of the porosity of a random packing
of spheres. The porosity of the bead pack is changed by randomly removing beads from the pack. The
initial slope decreases as the porosity increases, which also reduces the surface-to-volume ratio.
Figure 13b shows a linear relationship between the initial slope of the calculated field correlation
function and the surface-to-volume ratio of the system of packed spheres, which is consistent with
previously reported findings ( K ' ( r ||) = A / 4 * SVR ) [27]. On the other hand, strong anisotropy was
observed when the direction of r || was changed in the calculation. The slope A was found to be 1.5,
1.1, and 1.1 along r || = z , x , and y, respectively. Audoly et al., reported A = 1.28 when r ||= r
(i.e., the average of the 3D ensemble), which corresponds to the average value of the three orthogonal
A values in the internal field correlation function.

Figure 13. (a) Numerically evaluated pair correlation functions of the internal fields with
varying porosity; (b) Linear relationship between the initial slope of the pair correlation
function and surface-to-volume ratio obtained by the porosity of the pack [68]. Reproduced
from Reference [28] with permission.

Figure 14a shows experimental measurements of the field correlation function of a sample of
randomly packed glass beads using the unbalanced stimulated echo technique. Three independent
measurements along the r || = z , x , y directions of the external gradient are shown. The reduction in
Materials 2012, 5 611

[ C1(0) − C1( ∞ ) ] was strongest along the z -direction (the direction of the main magnetic field), and
this reduction was similarly smaller along the x - and y -directions in the gradient. The anisotropy
ratio of the reduction in the experimental measurements (2.2:0.92:1) was also in good agreement with
the theoretical calculations of κ ( 0 ) (1.8:0.97:1) along z, x and y directions.

Figure 14. (a) Experimental measurements of the field correlation functions of a randomly
packed sample of glass beads. Three independent measurements along the r || = z , x , y
directions of external gradient are shown. The reduction in [ C1(0) − C1( ∞ ) ] was strongest
along the z-direction. (b) Comparisons of the experimental measurements with the
numerical calculations. Reproduced from Reference [28] with permission.

Comparison between the numerically and experimentally measured field correlation functions
( K = [C1(r ||) − b] /[C1(0) − b] ) for different bead sizes and gradient directions are shown in Figure 14b.
The surface-to-volume ratios extracted from the initial slopes of the field correlation function
measurements were in generally good agreement with the surface-to-volume ratios calculated in
separate porosity measurements. Full 3D q-space mapping is expected to yield a complete description
of the correlation function of internal magnetic fields along arbitrary directions and resolve the residual
discrepancies between theory and experiment in Figure 14. Because the area of comprehensive 3D
susceptibility mapping is becoming quite important to the in vivo clinical realm [65–67], the proposed
correlation function mapping may have diagnostic potential.

3. Conclusions

Susceptibility contrast is ubiquitous in materials, and MR is uniquely sensitive to magnetic field

variations caused by susceptibility contrast. Characterization of the internal magnetic field properties
of porous media and the development of new, relevant MR pulse sequences have the potential to provide
important structural and functional information regarding porous media via nondestructive techniques.
This paper reviews the basic concept of DDIF contrast and its extension to imaging. Appropriate
data-analysis methods for bulk- and DDIF-imaging experiments have been discussed. DDIF-imaging
experiments with 2D cylindrical phantoms show the direct correlation between DDIF contrast and the
strength of the local internal gradients due to susceptibility differences. Interpretation of bulk-DDIF
Materials 2012, 5 612

contrast in trabecular bone samples was confirmed using both micro-imaging experiments and internal
field calculations of the same samples. A new PFG-NMR method for measuring magnetic field
correlations was presented, and representative experiments and theoretical calculations are described
for a randomly packed system of spheres, showing the potential for utilizing the statistical features of
internal fields to obtain structural information. Potential applications of this method for use in in vivo
trabecular bone and microvasculature imaging are in progress.

Acknowledgments

This work was supported in part by a grant from the National Research Foundation of Korea, which
is funded by the Korean government (Nos. 2011-0000886 and 2011-0005711).

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