INSTITUTE OF PHYSICS PUBLISHING INVERSE PROBLEMS

Inverse Problems 19 (2003) 10311046 PII: S0266-5611(03)56256-6

Persistent angular structure: new insights from
diffusion magnetic resonance imaging data
Kalvis M Jansons
1
and Daniel C Alexander
2
1
Department of Mathematics, University College London, Gower Street,
London WC1E 6BT, UK
2
Department of Computer Science, University College London, Gower Street,
London WC1E 6BT, UK
E-mail: PASMRI@Kalvis.com
Received 14 November 2002, in nal form 13 June 2003
Published 22 August 2003
Online at stacks.iop.org/IP/19/1031
Abstract
We determine a statistic called the (radially) persistent angular structure (PAS)
from samples of the Fourier transform of a three-dimensional function. The
method has applications in diffusion magnetic resonance imaging (MRI), which
samples the Fourier transform of the probability density function of particle
displacements. The PAS is then a representation of the relative mobility of
particles in each direction. In PAS-MRI, we compute the PAS in each voxel
of an image. This technique has biomedical applications, where it reveals the
orientations of microstructural bres, such as white-matter bres in the brain.
Scanner time is a signicant factor in determining the amount of data
available in clinical brain scans. Here, we use measurements acquired for
diffusion-tensor MRI, which is a routine diffusion imaging technique, but
extract richer information. In particular, PAS-MRI can resolve the orientations
of crossing bres.
We test PAS-MRI on human brain data and on synthetic data. The human
brain data set comes from a standard acquisition scheme for diffusion-tensor
MRI in which the samples in each voxel lie on a sphere in Fourier space.
1. Introduction
Diffusion magnetic resonance imaging (MRI) measures the displacements of particles that are
subject to Brownian motion within a sample of material. The microstructure of the material
determines the mobility of these particles, which is normally directionally dependent. The
anisotropy of particle displacements gives information about the anisotropy, on a microscopic
scale, of the material in which the particles move. The probability density function p of particle
displacements (in three-dimensional space) reects the anisotropy of particle displacements.
0266-5611/03/051031+16$30.00 2003 IOP Publishing Ltd Printed in the UK 1031
1032 K M Jansons and D C Alexander
Diffusion MRI and, in particular, diffusion tensor magnetic resonance imaging (DT-
MRI) [1] is popular in biomedical imaging because of the insight it provides into the
microstructure of biological tissue [2, 3]. In biomedical applications, the particles are usually
water molecules. Water is a major constituent of many types of living tissue and water
molecules in tissue are subject to Brownian motion, i.e. the random motion driven by thermal
uctuations. The microstructure of the tissue determines the mobility of water molecules
within the tissue. Our primary interest is in using diffusion MRI to probe the microstructure of
brain tissue. However, the new approach we introduce here could be used much more widely.
For the following discussion, it is useful to have in mind the important lengthscales of the
brain tissue and the measuring process:
(i) The voxel volume is of order 10
9
m
3
.
(ii) The diffusion time is of order 10
2
s and, over this time, the root-mean-squared
displacement of water molecules is in the micrometre range.
(iii) The diameters of axon bres in human white matter can reach 2.50 10
5
m, but most
bres have diameter less than 10
6
m [35].
(iv) The packing density of axon bres in white matter is of order 10
11
m
2
[35].
White matter in the brain contains bundles of parallel axon bres. At the diffusion
lengthscale applicable in MRI, the average displacement of water molecules along the axis of
the bres is larger than in other directions. The function p has ridges in the bre directions in
a material consisting solely of parallel bres on a microscopic scale.
In diffusion MRI, an inverse problem is solved to determine from MRI measurements
features of the materials microstructure that affect the distribution of particle displacements.
One useful statistic is the root-mean-squared particle displacement
R =
__
R
3
|x|
2
p(x) dx
_1
2
. (1)
Statistics based on the root-mean-squared particle displacement (see section 2) highlight, for
example, regions of brain tissue damaged by stroke [6], head trauma [7], and neurodegenerative
diseases such as multiple sclerosis [8], in which the value of R often increases. This increase
is thought to occur because of cell loss, which reduces the hindrance to the movement of water
molecules.
Statistics that depend on the anisotropy of p provide information about the anisotropy
of the materials microstructure. Scalar statistics of this kind also highlight tissue that has
been affected by neurodegenerative diseases [8, 9]. The reduction in anisotropy observed in
affected areas is thought to result from microstructural changes, such as loss of axons and
gliosis (scarring due to axonal damage).
Diffusion-tensor MRI, which we discuss further in section 2, is a standard technique in
diffusion MRI. In DT-MRI, a Gaussian prole for p is assumed. However, this simple model
is often a poor approximation in material with complex microstructure, for example in areas
of the brain where white-matter bres cross. Here we introduce a technique called PAS-MRI.
In PAS-MRI, we determine a feature of p which we call the (radially) persistent angular
structure (PAS). The PAS represents the relative mobility of particles in each direction, which
can have many peaks. In brain imaging, these peaks can be used to determine the orientation
of white-matter bres. The new technique can resolve the directions of crossing bres, which
DT-MRI cannot. We demonstrate this in simulation and show results from white-matter bre-
crossings in the human brain. The human brain data were acquired originally for DT-MRI
using a clinical acquisition sequence.
Persistent angular structure 1033
A common application of diffusion MRI is bre tracking, or tractography [10, 11]. The
goal of tractography is to map the connectivity of a piece of brous material, such as a brain,
using MRI data that depends on the local bre orientations. Most tractography algorithms
use DT-MRI and are unreliable at bre-crossings. We expect similar algorithms based on
PAS-MRI to produce more detailed and reliable results.
In section 2, we provide some background on diffusion MRI. In section 3, we list the
parameters used to acquire the human brain data we use to test PAS-MRI and comment on
its properties. In section 4, we use an algorithm based on the maximum entropy method to
dene the PAS of p. We do not attempt a full maximum entropy reconstruction of p, but
focus instead on extracting just the PAS. In PAS-MRI, we determine the PAS by tting its
parameters to the MRI measurements in each image voxel. We discuss the implementation of
PAS-MRI in section 5. In section 6, we test PAS-MRI on synthetic data and then show results
from the human brain. We conclude in section 7 with some comparisons of PAS-MRI with
other diffusion MRI techniques and a discussion of areas for further work.
2. Background
In diffusion MRI, measurements are commonly made usingthe StejskalTanner pulsed gradient
spin echo (PGSE) method [12], which samples the Fourier transformof p. Two magnetic eld
gradient pulses of duration and separation are introduced to the simple spin-echo sequence.
Assuming rectangular pulse proles, the associated wavenumber is q = g, where g is the
component of the gradient in the direction of the xed eld B
0
and is the gyromagnetic
ratio [13, 14].
The MRI measurement A

(q; X, ) is dened at each location X of a nite regular image

grid in three-dimensional space and depends on the wavenumber, q, and the pulse separation,
. In PAS-MRI, we treat each voxel separately and use a xed . We therefore drop the
dependence of A

on and X from the notation.

The normalized MRI measurement A(q) is given by A(q) = (A

(0))
1
A

(q). When

1
is negligible [13, 14],
A(q) =
_
R
3
p(x) exp(iq x) dx. (2)
We ignore non-zero
1
effects [15], as even when
1
is not negligible, these effects will
not signicantly change the principal directions extracted by PAS-MRI.
The evolution of p is due to the combination of advection and diffusion. The main
contribution to advection is likely to come from movements of the sample with respect to the
MRI scanner, but there will be other contributions. In this study, however, we are interested
in the directional structure due to diffusion alone, and not the effects of advection. Assuming
the local advection velocity is zero, we expect that p(x) = p(x) is a good approximation,
so that (2) becomes
A(q) =
_
R
3
p(x) cos(q x) dx. (3)
One way to proceed is to measure A at each location on a regular grid of wavenumbers,
q, and then to use a fast Fourier transform (FFT) algorithm to obtain values of p on a discrete
set of displacements, x. This approach is called q-space imaging and is commonly used to
probe p in one dimension, as in [13, 16, 17]. Wedeen et al [18] succeed in acquiring data from
healthy volunteers for a direct FFT inversion in three dimensions. They measure A with 500
different wavenumbers in each scan. To acquire all the measurements in scanner time that is
1034 K M Jansons and D C Alexander
tolerable for conscious subjects, they increase the voxel size from the usual size in MRI (of
order 10
9
m
3
) to 64 10
9
m
3
.
We shall refer to the motion of particles by diffusion alone in a medium for which the
diffusion tensor is constant and homogeneous as simple diffusion. In simple diffusion, the
probability density function of particle displacements has a Gaussian prole [19] so that
p(x) = G(x; D, t ), where
G(x; D, t ) = ((4t )
3
det(D))

1
2
exp
_

x
T
D
1
x
4t
_
, (4)
D is the diffusion tensor and t is the diffusion time.
In DT-MRI, the apparent diffusion tensor is determined on the assumption of simple
diffusion. With the simple diffusion model, (2) gives
A(q) = exp(tq
T
Dq). (5)
Taking the logarithmof (5), we see that each A(q) provides a linear constraint on the elements
of D. To t the six free parameters of D, we need a minimum of six measurements of A(q)
with independent q. Because of the effects of noise, acquiring more than six A(q) provides
a better estimate of D. A common approach [20] is to acquire M measurements of A

(0)
together with measurements A

(q
j
), 1 j N, for which , , and |q| are xed, but each q
j
is unique. Then A(q
j
) = (

A

(0))
1
A

(q
j
), where

A

(0) is the geometric mean of the A

(0)
measurements. In the literature, 1 M 20 and N < 100. Fewer measurements of A

(q)
are required for DT-MRI than for the three-dimensional q-space technique of Wedeen et al
[18]. Thus, in DT-MRI, smaller voxel sizes can be used for images acquired in the same
scanner time. The q
j
are chosen so that they are well separated on the sphere and are not
directionally biased [21].
With the simple diffusion model, R = (2t Tr(D))
1
2
. Medical researchers often work with
Tr(D) directly rather than R to highlight damaged brain tissue, as in [68]. Scalar indices of
diffusion anisotropy can be derived from the diffusion tensor. A popular anisotropy index is
the fractional anisotropy [2], which is given by
=
_
3
2
3

i =1
(
i

1
3
Tr(D))
2
_1
2
_
3

i =1

2
i
_

1
2
, (6)
where
i
, i = 1, 2, 3, are the eigenvalues of D. Many tractographyalgorithms use the principal
eigenvector of D as an estimate of bre orientation [10, 11].
A drawback of DT-MRI is that the simple diffusion model is poor in many regions,
in particular those in which bres cross within a voxel. With more than six A(q) with
independent wavenumbers, some departures fromthe simple diffusion model may be detected
and observations of such departures are in the literature, e.g. [2224].
One alternative to the simple diffusion model has p as a mixture of Gaussian
densities [22, 25]:
p(x) = M
n
(x; D
1
, . . . , D
n
; a
1
, . . . , a
n
; t ), (7)
where
M
n
(x; D
1
, . . . , D
n
; a
1
, . . . , a
n
; t ) =
n

i =1
a
i
G(x; D
i
, t ), (8)
each a
i
[0, 1] and

i
a
i
= 1.
Equation (7) could, for example, model a macroscopically homogeneous system, which
consists of n interlocking subsystems on a microscopic scale, where we suppose that the rate
Persistent angular structure 1035
of exchange of particles between the different subsystems is negligible. In this case, the a
i
are the probabilities that a randomly chosen test particle is in subsystem i of the partitioned
medium, and the D
i
are the corresponding diffusion tensors. A simple extension to this model
would allow exchange of particles between subsystems.
3. Data
In this section, we give details of the data we use for testing PAS-MRI, acquired using a
standard DT-MRI sequence for human brain imaging.
The University College London Institute of Neurology provided data sets from healthy
volunteers together with details of their acquisition sequence [26]. All subjects were scanned
with the approval of the joint National Hospital and Institute of Neurology ethics committee
and gave informed written consent.
For these data sets, M = 6 and N = 54. Also = 0.04 s, = 0.034 s and
|g| = 0.022 T m
1
, which gives |q| = 2.0 10
5
m
1
. The 54 values of q
j
come from
an electrostatic spherical point set with equal and opposite pairs (see section 5.1) from which
we take a point from each equal and opposite pair.
The data sets contain 60 axial slices, with separation 2.310
3
m. Each rowof each slice
of the acquisition undergoes a linear phase correction step. In each slice, the 62 96 array of
measurements is padded with zeros to a 128 128 grid from which an image is created via a
FFT. After the Fourier transform, the phase is discarded by taking the modulus of the complex
value in each voxel, so phase errors are unimportant. In each slice, the voxels are 1.710
3
m
squares.
The total scan time is around 20 min. During this time subject motion can cause slight
misalignments among the 60 MRI volumes. Image distortion can also arise from magnetic
eld inhomogeneity. An image registration scheme based on automated image registration [27]
improves the alignment of each set of corresponding slices in the measurement volumes. One
of the measurement volumes for which q = 0 provides a reference set of slices. Automated
image registration computes two-dimensional afne transformations that minimize the sum of
square differences between each slice of the other volumes and the corresponding reference
slice.
4. Method
We do not know the probability density function, p, directly, but rather have a nite set of
values for the Fourier transformof p. In the test data that we use, all of the wavenumbers have
the same modulus and the same diffusion time, i.e. all the points lie on a sphere in Fourier
space.
We use a method based on the principle of maximumentropy [28] to obtain an expression
for the function that contains the least information subject to the constraints fromthe data. We
use S[ p], where S is the entropy [28], for the information content of a probability density
function p dened over a set . Thus the mathematical expression for the information content
of p is
I [ p] =
_

p(x) ln p(x) dx. (9)

Since we have only Fourier components of p for a small set of points, which may lie on
a sphere in Fourier space, we are unable to extract any useful information about the radial
structure of p and, in any case, the greatest interest is in the angular structure. To extract
1036 K M Jansons and D C Alexander
useful information about the angular structure in a computationally efcient way, we restrict
attention to determining a probability density function of the form
p(x) = p( x)r
2
(|x| r), (10)
where is the standard one-dimensional distribution, r is a constant and x is a unit vector
in the direction of x. In a sense, we are projecting the angular structure from all radii onto the
sphere of radius r, and ignoring any information about the radial structure in the data, which is
often very limited. The nal result is weakly dependent on the choice of r (as discussed later)
but the important features of the angular structure are not, provided we are inside the range of
r for which the method is reliable.
We determine a function of the above form that has minimum relative information with
respect to p
0
= (4r
2
)
1
(|x| r) and subject to the constraints of the data. We call p
the (radially) PAS. The domain of p is the unit sphere, as it represents only orientational
information.
The relative information of the probabilitydensity function pwith respect to the probability
density function p
0
is given by
I [ p; p
0
] =
_

p(x) ln
_
p(x)
p
0
(x)
_
dx. (11)
The constraints on p from the data, given by equation (2), can be incorporated into the
expression above using the method of Lagrange multipliers to yield
I [ p] =
_ _
p( x) ln p( x) p( x)
N

j =1
(
j
exp(iq
j
r x)) p( x)
_
d x, (12)
where q
j
, 1 j N, are the non-zero wavenumbers for the MRI measurements, the
j
are
Lagrange multipliers for the constraints from the data and the Lagrange multiplier controls
the normalization of p. The integral in (12) is taken over the unit sphere. Taking a variational
derivative I [ p] and solving I [ p] = 0, we nd that the information content, I [ p], has a
unique minimum at
p( x) = exp
_

0
+
N

j =1

j
exp(iq
j
r x)
_
, (13)
where
0
= 1.
We need to solve
_
p( x) exp(iq
j
r x) d x = A(q
j
) (14)
for the
j
, where the integral is taken over the unit sphere.
If we assume x x symmetry, which is typically justied, we can simplify the
expression for p by noting that
p( x) = exp
_

0
+
N

j =1

j
cos(q
j
r x)
_
(15)
and absorbing the factor of 2 into the denition of
j
, 1 j N. This also helps remove
some noise from the numerical analysis.
Note that this is not a maximum entropy reconstruction of p itself, but a method that
extracts the directional information from the MRI data set, which may be small and will often
be restricted to a sphere in Fourier space. The advantage of this approach, as shown later, is that
we obtain a robust statistic that corresponds well to the physiological structure of the human
brain. This technique will have applications in other areas where the directional structure on
a microscopic scale is of interest.
Persistent angular structure 1037
5. Implementation
In this section, we discuss the implementation of the tting procedure.
5.1. Spherical point sets
A spherical point set P is a nite set of points on the unit sphere in three-dimensional space.
The size of P is the number of elements it contains. In the implementation of PAS-MRI, we
use several different types of spherical point set, which we dene in this section.
5.1.1. Pseudo-randomspherical point sets. Pseudo-randomspherical point sets have pseudo-
randomelements taken from a uniformdistribution on the unit sphere. The spherical point set
U(n, s) is the pseudo-randomspherical point set with size n and seed s for the randomnumber
generator.
The spherical point set U
P
(n, s) is the pseudo-random spherical point set with equal and
opposite pairs. We dene
U
P
(2n, s) = U(n, s) {y : y U(n, s)}. (16)
5.1.2. Electrostatic spherical point sets. The spherical point set E
P
(n) is the electrostatic
spherical point set with equal and opposite pairs and size n. To choose E
P
(n), we nd local
minima of the electrostatic energy using a LevenbergMarquardt algorithmwhile maintaining
the constraint of equal and opposite pairs. We run the algorithmwith each starting conguration
U
P
(n, i ) for 1 i 500, and choose the nal conguration with the lowest energy for E
P
(n).
The spherical point sets E
P
(n) exist only for even n.
5.1.3. Covering spherical point sets. Covering spherical point sets have putatively minimal
covering radius. The covering radius C(P) of a spherical point set P is dened by
C(P) = max
|x|=1
_
min
yP
|x y|
_
. (17)
The spherical point set C
I
(n) is the covering spherical point set with icosahedral symmetry
and size n. These spherical point sets have putatively minimal covering radius subject to the
constraint of icosahedral symmetry. We choose C
I
(n) fromthe Hardin et al tables of spherical
codes with icosahedral symmetry [29] for values of n for which they are available.
5.1.4. Archimedean spherical point sets. We construct what we call Archimedean spherical
point sets using Archimedes well-known area-preserving mapping fromthe unit sphere to the
unit cylinder truncated to just contain the sphere. In the natural cylindrical coordinates, the
mapping takes a point on the sphere and projects it radially to the cylinder. To produce the
spherical point set, we place a point at the centre of each rectangle of a rectangular mesh on
the cylinder and map the points back onto the sphere.
The spherical point set A(k
2
) is the Archimedean spherical point set with size k
2
. The
spherical point set A(k
2
) comes from a regular n = k k rectangular mesh on the cylinder
that is aligned with the cylinder axis. Thus A(n) exists if and only if n is a perfect square.
5.2. Fitting procedure
In PAS-MRI, we use a LevenbergMarquardt algorithm [30] to nd the PAS, p, by tting the
(
j
)
N
j =0
in (13) to the data using (14). We model the distribution of the noise on the modulus
1038 K M Jansons and D C Alexander
of each MRI measurement by N(0,
2
) to construct the objective function for the algorithm.
We propagate these errors through
A(q
j
) = (

A

(0))
1
A

(q
j
)
to obtain

j
=
_
1 +
A(q
j
)
2
M
_1
2
, (18)
where
j
is the standard deviation of A(q
j
) and = (

A

(0))
1
.
The objective function for the LevenbergMarquardt algorithm is

2
((
i
)
N
i =0
) =
N

j =0
_
A(q
j
)

A(q
j
; (
i
)
N
i =0
)

j
_
2
, (19)
where q
0
= 0,

A(q
j
; (
i
)
N
i =0
) =
_
p( x) cos(q
j
r x) d x (20)
and p implicitly depends on the values of the (
i
)
N
i =0
. In (19), the j = 0 term imposes a soft
normalization constraint on p. We set A(q
0
) = 1 and choose the weighting
0
using (18).
The constant factor in (19) simplies the expression for the weightings of the terms without
affecting the locations of the minima of
2
.
We observe that reducing
0
has the effect of inating the PAS so that its peaks are less
sharp. This ination does remove some spurious principal directions that appear in p when p
is close to isotropic (see section 6.1), but can mask weak but genuine angular structure.
To start the minimization algorithm, we set
0
= ln(4) and
j
= 0, j = 1, . . . , N. We
terminate the algorithmafter an iteration in which the value of the objective function decreases,
but the decrease is less than 10
5
.
We compute the value of the objective function and its derivatives by numerical integration
at each iteration of the minimization algorithm. For a spherical point set P, we approximate
the integral of a function f over the unit sphere as follows:
_
f ( x) d x =
_
4
n
_

yP
f (y), (21)
where n is the size of P.
The size of the spherical point set required to approximate integrals using (21) to a given
level of accuracy depends on the integrand, f . We store a database of spherical point sets P
i
,
1 i L, in which the size of the spherical point set increases with the index, i . We rst run
the minimization algorithm using the smallest spherical point set, P
1
. After termination, we
compute the errors between numerical integrals computed using P
1
and those computed using
a larger test spherical point set Q. If any of these errors is above a preset threshold, we rerun
the minimization algorithmusing the next largest spherical point set. We repeat this procedure
until we nd a spherical point set large enough, or ag the failure to do so. We store six spherical
point sets in the database: P
1
= C
I
(1082), P
2
= C
I
(1922), P
3
= C
I
(4322), P
4
= C
I
(8672),
P
5
= C
I
(15872) and P
6
= C
I
(32672). The test spherical point set Q = A(350
2
).
5.3. Extraction of principal directions
Once we have found the PAS, p, from the data, one property of interest is its set of principal
directions, since we expect these to indicate the orientation of white-matter bres in the brain.
Persistent angular structure 1039
When we assume x x symmetry, as we do here, the peaks of p appear in equal and
opposite pairs. In this case, we do not distinguish x and x. Principal directions of p are then
non-directed lines in the directions of the pairs of peaks. In cases where we cannot assume
x x symmetry, we would work directly with peak directions of p.
To nd the principal directions of p, we compute p(s) for each point s in a spherical point
set S. We then nd the set
M =
_
x S : p(x) = max
sT (x)
p(s)
_
, (22)
where
T (x) = {s S : |s x| < } {s S : |s + x| < } (23)
and is a constant, which we set to 0.3. The spherical point set S is the union of 1000 random
rotations of a set containing a point from each equal and opposite pair of vertices of a regular
icosahedron with vertices on the unit sphere.
The set M contains estimates of the principal directions of p. We rene these estimates
by searching for local maxima of p using Powells method [30] starting at each element of M.
Finally, we discard tiny principal directions that occasionally appear for which the value of p
is less than the mean of p.
6. Experiments and results
In this section, we demonstrate PAS-MRI using the common DT-MRI scheme where the q
j
for the data are on a sphere. For convenience, we non-dimensionalize all lengths with |q|
1
,
which is a natural lengthscale. We also assume x x symmetry of p and equation (13)
thus becomes
p( x) = exp
_

0
+
N

j =1

j
cos( q
j
r x)
_
.
In a more general setting where the q
j
do not lie on a sphere, a typical or average wavenumber
would be used for the non-dimensionalization.
We test PAS-MRI on synthetic data and then show results from human brain data.
6.1. Synthetic data experiments
Given a function p with Fourier transform F, we generate a synthetic MRI measurement A

(q)
by setting
A

(q) = |F(q) + c|, (24)

where the real and imaginary parts of c C are independent identically distributed random
variables with distribution N(0,
2
). For a particular test function, we generate M synthetic
A

(0) measurements and a single A

(q
j
) for each j = 1, . . . , N. We then compute

A

(0)
and A(q
j
). Unless otherwise stated, we emulate the sequence used to acquire the human brain
data so that M = 6, N = 54, |q| = 2.0 10
5
m
1
, t = = 0.04 s. The q
j
are those used in
the brain data acquisition.
First, we test the algorithm on a range of simple test functions for p. We use the
simple diffusion model together with the statistical results of Pierpaoli et al [3] to simulate
measurements fromthe brain. To simulate measurements fromdense-white-matter regions we
use the diffusion tensor 10
10
diag(17, 2, 2) m
2
s
1
, where diag(X, Y, Z) is the diagonal matrix
with leading diagonal elements X, Y and Z. On average, the apparent diffusion tensor in grey
1040 K M Jansons and D C Alexander
Figure 1. Test functions p
i
, 0 i 4, plotted over the sphere of radius 2.4|q|
1
, together with
plots of each p
i
(; r) for r = 0.4, 1.4, 2.4. To plot a function f over the sphere of radius , we
plot f (x)x for each x P, where P is a spherical point set selected from P
i
, 1 i L (see
section 5.2).
matter is closer to isotropic than in white matter, but of the same order of magnitude [3]. We use
7 10
10
I m
2
s
1
to simulate measurements from grey matter. We simulate measurements
from white-matter bre-crossings using the mixture of Gaussian densities in (8). We use
rotations of 10
10
diag(17, 2, 2) m
2
s
1
for the diffusion tensor in each component.
We use the following ve test functions to test PAS-MRI:
p
0
(x) = M
1
(x; A
0
; 1; t ), p
1
(x) = M
1
(x; A
1
; 1; t ),
p
2
(x) = M
1
(x; A
4
; 1; t ), p
3
(x) = M
2
(x; A
1
, A
2
;
1
2
,
1
2
; t ),
p
4
(x) = M
3
(x; A
1
, A
2
, A
3
;
1
3
,
1
3
,
1
3
; t ),
where M
n
is dened in (8),
A
0
= 7 10
10
I m
2
s
1
, A
1
= 10
10
diag(17, 2, 2) m
2
s
1
,
A
2
= 10
10
diag(2, 17, 2) m
2
s
1
, A
3
= 10
10
diag(2, 2, 17) m
2
s
1
,
A
4
= 10
10
diag(9.5, 9.5, 2) m
2
s
1
.
We use p(; r) for the PAS found with parameter r from data synthesized from a test
function p. Figure 1 shows plots of each p
i
, 0 i 4, over the sphere of radius r|q|
1
for
r = 2.4 together with p
i
(; r) found from noise-free data for r = 0.4, 1.4, and 2.4.
We see from (15) that the PAS is the exponential of the sum of N + 1 waves (or basis
functions) over the sphere (including a constant term). The wavelength of the basis functions
of p decreases with increasing r. At low r, we have insufcient resolution to resolve the
Persistent angular structure 1041
Figure 2. Sixteen examples of p
i
(; 1.4), 0 i 4, found from synthetic data with increasing
noise level. To make each gure in the table, we scale each p
i
(; 1.4) to t exactly inside a
15 15 15 cube and project onto the xy-plane to form a 15 15 square. We pad these squares
to 16 16 squares and place them in the image array with no additional gaps.
interesting angular structure. At high r the resolution is too ne to be supported by the data.
As we can see in gure 1, when we set r too low, p(; r) has too few principal directions and
extra principal directions appear in p(; r) when r is set too high. At r = 1.4, the principal
directions of p
i
(; r), i = 1, 3, 4, match those of the test functions. We observe a range of
values of r over which the principal directions of p
i
(; r), i = 1,3,4, match those of p.
We say that spherical point sets X and Y are consistent if they satisfy all of the following
conditions:
X and Y have the same number of elements,
max
yY
(min
xX
(1 |x y|)) < T,
max
xX
(min
yY
(1 |x y|)) < T,
where T is the consistency threshold.
To test the PAS found from synthetic data, we compare the principal directions of p(
.
; r)
with the peaks of p at radius r|q|
1
. The spherical point set Y contains one point from each
equal and opposite pair of peaks of p at radius r|q|
1
, normalized to the unit sphere. The spher-
ical point set X is the set of the principal directions of p(; r) found using the method described
in section 5.3. We say that p(; r) is consistent if X and Y are consistent with T = 0.05.
We nd p
i
(; r), i = 1, 3, 4, from noise-free data with r at steps of 0.1 from 0.1 up to 2.9
and check the consistency of each p
i
(; r). We nd that p
1
(; r) is consistent for tested values
of r in [0.1, 1.6], p
3
(; r) is consistent for tested values of r in [0.6, 1.6] and p
4
(; r) for tested
values in [1.0, 2.4].
Figure 2 shows how noise in the simulated measurements affects the PAS. We dene
s =
1
F(0) and generate synthetic data for each test function with s {4, 8, 16, 32, 64}.
For i = 0, . . . , 4, we show 16 examples of p
i
(; 1.4) found from noisy data with different
seeds in the random number generator.
The PAS extracted from the data is determined by both the signal and the noise, though
the choice of r can be used to control the smoothness of the reconstruction to some extent.
We can consider the signal-to-noise ratio of the angular structure, which is distinct from the
notion of signal-to-noise ratio of the MRI measurements. When the angular structure is weak,
1042 K M Jansons and D C Alexander
as for p
0
and p
2
, its signal-to-noise ratio may be low even if the signal-to-noise ratio of the
MRI measurements is high. When the signal-to-noise ratio of the angular structure is low
the angular structure of the noise dominates the PAS, as we see in gure 2 where spurious
angular structure appears in p
0
(; 1.4) and p
2
(; 1.4). When the angular structure is strong, as
it is for p
1
, p
3
and p
4
, the noise has less effect. We note that published results from q-space
imaging appear to showa similar effect. For example, in the gures shown in chapter 8 of [31],
voxels in uid-lled and grey-matter regions of the brain contain functions with strong angular
structure, which is probably from noise in the MRI data.
To assess the performance on noisy data further, we compute the consistency fraction C,
which is the proportion of 256 trials in which p(; r) is consistent. With the noise model
in (24), we compute an estimate of from the human brain data using measurements in
background regions where the signal is practically zero. We also compute the mean value of
A

(0) over two white-matter regions of the human brain data set. In both regions, we nd
is approximately
1
16
of the mean A

(0). For the experiments on noisy synthetic data discussed

in the remainder of this section, we use s = 16 throughout.
We compute C for
r {0.2, 0.5, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 2.0, 2.3}. (25)
For r = 1.4, C > 99% for test functions p
1
, p
3
and p
4
, with similar results for r = 1.1, 1.2,
1.3, 1.5 where C > 95% for p
1
, p
3
and p
4
. For the other values of r given in (25), C < 90%
for at least one of p
1
, p
3
and p
4
. We thus use r = 1.4 for the experiments in the remainder of
this paper.
We investigate the dependence of C on the dimensionless quantity u = |q| R. We have
computed C for
u/u
0
{0.5, 0.7, 0.8, 1.0, 1.5, 2.0, 3.0, 4.0, 5.0, 7.0, 10.0}, (26)
where u
0
is the value of u for p
i
, i = 0, . . . , 4, with the value of |q| used in the brain data.
We nd that C > 99% for p
1
, p
3
and p
4
with u/u
0
= 1.0, 1.5, 2.0. For the values in (26)
outside this range, C decreases for all three test functions. This suggests that the choice of |q|
in the data is reasonable for the diffusion time, t . However, in applications where the signal
to noise ratio of the MRI measurements is higher, we expect increasing |q| to reveal more
detailed angular structure.
We also examine the dependence of C on the number, N, of measurements with non-zero
q. We run tests with
N {10, 12, 14, 16, 18, 20, 30, 40, 50, 60, 70}
and with M = 6. For the q
j
in each test, we take a point from each equal and opposite pair
in E
P
(2N). For p
1
, we nd that C > 99% for N 12. For p
3
, C > 99% for N 20. For
p
4
, C > 99% for only N > 50. To resolve the three orthogonal directions in p
4
consistently
the value of N in the human brain data (54) is just large enough. However, to resolve the two
orthogonal directions in p
3
, we could use fewer measurements and reduce scanning time or
increase image resolution.
We also investigate the effect of changing the mixing parameter in p
3
, as well as the
relative orientation of the two diffusion tensors. We use test functions
p
5
(x; a) = M
2
(x; A
1
, A
2
; a, 1 a; t ), (27)
where 0 a 1, and
p
6
(x; ) = M
2
(x; A
1
, R()
T
A
2
R();
1
2
,
1
2
; t ), (28)
where R() is a rotation matrix for a turn through angle about the z-axis. We show p
5
(; 1.4)
and p
6
(; 1.4) found fromdata synthesized with s = 16 in gures 3 and 4, respectively. We see
Persistent angular structure 1043
Figure 3. Examples of p
5
(; 1.4) found from noisy data synthesized with various values of a.
Figure 4. Examples of p
6
(; 1.4) from noisy data synthesized with various values of .
(a) (b)
Figure 5. Maps of (a) Tr(D) and (b) the fractional anisotropy over a coronal slice of a human brain
data set.
that PAS-MRI can still resolve the two principal directions when the weighting between the
components becomes less balanced or the principal directions become closer, but that the
consistency fraction decreases.
6.2. Human brain data experiments
In this section, we show results from PAS-MRI applied to a human brain data set. The
acquisition parameters for the data are given in section 3.
First we use DT-MRI to obtain an estimate Dof the diffusion tensor in each voxel. Figure 5
shows Tr(D) and the fractional anisotropy [2] over a coronal slice through the human brain data
set. The map of Tr(D) highlights uid-lled regions of the brain and the fractional anisotropy
highlights white-matter regions. We use a threshold of 6 on

A

(0) to remove background

regions of the image.
Figure 6 shows PAS-MRI results over the coronal slice used in gure 5. We have placed
boxes around two regions of interest in gures 5 and 6. The box nearer the bottomof the image
outlines a region of the pons and the box nearer the top includes part of the corpus callosum.
In the region of the pons outlined in gure 6, the transpontine tract (leftright orientation)
crosses the pyramidal tract (inferiorsuperior orientation). The PAS in this region picks out
the orientations of these crossing bres.
The bres of the corpus callosum are approximately parallel and run fromthe left to right
sides of the brain. We can see from gure 6 that, in most voxels within the corpus callosum,
the PAS has a single principal direction along the axis of the bres. The upper box in gure 6
1044 K M Jansons and D C Alexander
Figure 6. The PAS in each voxel of a coronal slice through a human brain data set. We scale each
p to t exactly inside a 15 15 15 cube and project onto the plane of the slice to form a 15 15
square. We pad these squares to 16 22 rectangles to reect the voxel dimensions and place them
in the image array with no additional gaps.
also contains some voxels fromareas of grey matter (the top rowin the box) and cerebro-spinal
uid (the bottom row in the box). In these regions, p is closer to isotropic and the principal
directions that appear in the PAS are noise dominated, as shown by the simulation results in
gure 2.
7. Discussion
We have introduced a newdiffusion MRI technique called PAS-MRI. In PAS-MRI, we nd the
PAS of the probability density function of particle displacements, p, fromMRI measurements
of the Fourier transformof p. We have demonstrated the technique using data acquired for DT-
MRI using a standard imaging sequence in which the measurements lie on a sphere in Fourier
space. However, PAS-MRI is not limited to data of this kind. In simulation, we nd that the
principal directions of the PAS reect the directional structure of several test functions. In
clinical applications, we aim to use the PAS to determine white-matter bre directions. Early
results for human brain data are promising.
The new technique has the advantage over existing techniques, such as DT-MRI and
three-dimensional q-space imaging, that it can resolve bre directions at crossings, but still
requires only a modest number of MRI measurements. In clinical applications, the data sets
are likely to remain small for practical use, as the time available for the MRI scan is usually
a signicant constraint. This is due not only to the cost, but also the time for which a patient
can be expected to remain in the scanner. In clinical applications, we thus expect tractography
results to improve by using PAS-MRI rather than DT-MRI or q-space imaging.
Persistent angular structure 1045
With DT-MRI, the images can have high resolution, since the method requires a relatively
small number of measurements. However, DT-MRI cannot resolve the directions of crossing
bres. The q-space imaging technique can resolve the directions of crossing bres, but
requires many more measurements so that images acquired in the same scanner time have
lower resolution. We note also that q-space imaging can provide information about the radial
structure of p, which PAS-MRI does not attempt to.
The spurious directions in the PAS for noisy data from isotropic regions also appear in
q-space imaging. In these circumstances, methods requiring fewer tted parameters, such as
DT-MRI, are less sensitive to noise.
Post-processing times are greater for PAS-MRI than for DT-MRI and q-space imaging.
One way to reduce computation times is to use PAS-MRI with a voxel classication algorithm,
such as that described in [24], to decide where the simple diffusion model is a poor
approximation. We can use DT-MRI in voxels in which the simple diffusion model is a
good approximation and PAS-MRI where it is not. However, with computer power rapidly
increasing year by year, computational issues will soon become unimportant.
We have restricted attention to the principal directions of the PAS, which is a robust feature.
Another useful statistic is the number of principal directions in the PAS. We expect this statistic
to help, for example, in identifying areas in which white-matter bres are destroyed by injury
or disease. Other features of the PAS, such as the relative heights and lengthscales of its peaks,
may also provide useful information about the material microstructure. It is not yet clear how
well such features correlate with p and further investigation is necessary. We hope others will
investigate the extent to which PAS-MRI can highlight the early signs of diseases, such as
multiple sclerosis.
In the current implementation, we t the PAS by searching for a minimum point of
2
from a single starting point to keep the computation time manageable. We have compared the
results to solutions closer to the global minimum of the objective function found by running
repeated trials fromdifferent starting points. Apart fromwhen the angular structure in the data
is weak, we nd that solutions from the single starting point are consistent with those closer
to the global minimum.
We plan to consider, elsewhere, extensions of PAS-MRI. We believe that one way in
which the current approach could be improved is to consider the optimal placement of the
observational points, i.e. the set of q
j
used in the MRI measurements. In particular, the results
are likely to improve for samples not restricted to a sphere in Fourier space.
Acknowledgments
We would like to thank Gareth Barker and Claudia Wheeler-Kingshott at the Institute of
Neurology, UCL, for providing the human brain data used in this work.
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