ELSEVIER Progress in Nuclear Magnetic Resonance Spectroscopy 28 (1995) 87-135

From NMR diffraction and zeugmatography to modern imaging

and beyond
Felix W. Wehrli
Department of Radiology. University of PennsylvaniaMedical Center, 3400 Spruce Street, PA 19104, USA
Received 29 April 1995

1. Introduction line narrowing techniques in solids, cross polariza-

It is a great honor for me to have been asked to
contribute to this special issue of ‘Progress in NMR
Spectroscopy’, commemorating the fiftieth anni-
versary of the inception of NMR. While my con-
tributions to the progress of this fascinating and
fruitful area of science have been utterly modest,
my fascination for NMR, ever since my first expo-
sure to it 30 years ago, is undiminished up to the
present day. I had the good fortune to witness an
evolution from what was then an already fairly
sophisticated spectroscopic technique, to the most
advanced medical imaging modality today. Surely
not even in their wildest dreams would those we
honor this year, Edward Purcell, and the late
Felix Bloch, and their colleagues, have predicted
that one day medical diagnoses would be made
on the basis of NMR images. I was among the
non-believers, but I was in good company. NMR
pioneers Anatole Abragam and Erwin Hahn
openly admit their skepticism [l].
I remember Paul Lauterbur presenting what he
celled ‘NMR zeugmatography’ at an otherwise
very uneventful ENC, at Boulder, Colorado, in
April 1973. This was the period just preceding the
2D NMR revolution. Pulse Fourier transform
NMR was already invented and carbon- 13 spectro-
scopy was in full swing. And so were many other
innovations, such as the superconducting magnet,
0079-6565/95/$29.00 0 1995 Elsevier Science B.V. All rights reserved
SSDI 0079-6565(95)01021-l
tion, and much more. To many of us it therefore
appeared that NMR was in a phase of maturation
and that perhaps it had already reached most of its
ultimate potential. How wrong one can be!
Nevertheless, Lauterbur’s discovery (the publica-
tion of which was not without hurdles) did not
immediately evoke great enthusiasm, in that for sev-
eral years only very few laboratories practised
research on spatially resolved NMR. In fact, much
of the early work was done by essentially two labora-
tories, Paul Lauterbur’s at New York State Univer-
sity at Stonybrook and the University of Nottingham
Physics Department with Peter Mansfield, Raymond
Andrew and Waldo Hinshaw. NMR imaging, or
MRI, as it is later became referred to by the medi-
cal community, soon began to capture broader
interest and during the late seventies industrial
companies became involved in its development.
MRI is, without question, the most significant
innovation in diagnostic imaging since the discov-
ery of X-rays. It is a curious coincidence that
NMR’s fiftieth anniversary can be celebrated
along with Roentgen’s discovery of X-rays a half
century earlier. Both principles led to tomographic
imaging and the beginnings of these developments
were almost simultaneous. However, X-ray com-
puted tomography (CT) matured much more
quickly than MRI, presumably because the tech-
nology was more readily available and X-ray
88 F. W. Wehrli/Progress in Nuclear Magnetic Resonance Spectroscopy 28 (1995) 87-135
projection imaging was already firmly implanted in
thousands of hospitals around the globe.
This article intends to highlight the major
milestones during NMR’s evolution from an
experimental technique, to the pre-eminent role it
currently plays as a diagnostic imaging modality in
medicine. I will deliberately omit reference to non-
imaging related developments (which will be cov-
ered in the two companion articles by Raymond
Andrew and Jim Shoolery), unless they have
obvious implications for MRI. Finally, the field is
so developed and the literature so abundant that
any attempt toward comprehensiveness would be
doomed to fail.
Some of the early history was drawn from
Mansfield’s erudite article in Contemporary Physics
[2] which delineates the evolution of the first four
years of NMR imaging. Hoult describes state-of-
the-art and prior history of imaging methods and
technology up to about 1979 in a book chapter in
Magnetic Resonance in Biology [3]. A most valu-
able resource also was Mansfield and Morris’ 1982
monograph “NMR in Biomedicine” [4] which is
perhaps the most complete and rigorous text on
the physics and technology of NMR imaging cov-
ering the field up to the end of 198 1.
2. Early history
Most spectroscopists, laboring with the magnet’s
shim controls, are well aware that the beat pattern
modulating the wiggles of the fast-passage signal is
due to magnetic field inhomogeneity. Gabillard
[5,6], in 1951, was the first to explain the mod-
ulation in terms of the distribution of the magnetic
field across the sample. In 1954, Carr and
Purcell [7] showed in a pulsed experiment that
the y-component of the transverse magnetization
in an off-resonance field AH, caused by a linear
field gradient across the sample, evolves as
sin(yAH,t)/yAH,t. This, of course, is the cosine
transform of the rectangular probability density
function of the field. It would clearly be far-fetched
to call Gabillard’s and Carr and Purcell’s experi-
ments precursors of spatially localized NMR.
Rather, these findings were by-products of experi-
ments designed to measure T2 in inhomogeneous
fields. Nevertheless, these early investigators had a
clear understanding of the effects of field gradients
on the NMR signal.
In their 1973 paper entitlted “NMR diffraction
in solids?” [S], Mansfield and Grannell explored the
potential of NMR for mapping the spatial struc-
ture of solids analogous to X-ray crystallography.
Specifically, they sought to evaluate the conditions
under which it might be possible to observe dif-
fraction in the FID resulting from interference
of the signals emanating from different lattice
sites in the presence of a linear field gradient
applied to the sample. They compared the phe-
nomenon to the intensity distribution resulting
from the diffraction of monochromatic light at
a grating. In the latter experiment the phase dif-
ference is the result of the different path lengths
to the various grating slits. By analogy, the point
sources at the lattice sites accumulate differential
phases by virtue of the different frequencies at
which the spins resonate in the gradient field.
Mansfield and Grannell came to the conclusion
that in the case of solids, such an experiment
would be exceedingly difficult to realize. Even
if dipolar broadening effects could be suppressed
by line narrowing techniques (which were already
known at that time), the gradient requirements of
about lo8 G cm-’ would be prohibitive. For a
hypothetical three-dimensional lattice they obtained
for the signal at each lattice point:
p(r)eip”du
where P(Y) represents the spin density within the
range Ax, Ay, AZ over which integration occurs.
The quantity p = yGt, in modern parlance, is the
spatial frequency vector where G is the field gradi-
ent. The total signal for a plurality of lattice points,
they reasoned, then is the discrete sum of the signal
from all lattice points.
Mansfield and Grannell recognized that given
the short lifetime of the signal and very large gra-
dients required, NMR crystallography was “some
way off”. However, they performed a model
experiment on a one-dimensional ‘lattice’ formed
by flat, equally spaced slabs of solid camphor. In
conjunction with a line narrowing technique, they
succeeded in observing the predicted diffraction
 F. W. WehrlijProgress in Nuclear Magnetic Resonance Spectroscop?, 28 (1995) 87-135 a9

signals (Figs. l(a)-(c)). They further showed the

Av=36B kHr
Fourier transform of the transient response to
yield a well-resolved series of equally spaced lines
which represent a one-dimensional projection
image of the camphor slabs (Figs. l(d)-(f)).
Mansfield and Grannell did not immediately
0 f0 20 30 40 50 60 iYO generalize their result which is valid for any con-
r(ms) tinuous or discontinuous spin distribution and
does not require translational symmetry. After
3 layers, G,=O77 C cm-’
Lauterbur’s fundamental imaging paper, they
Isl-order dlffraclion peak pointed out the more general nature of their
experiment [9].
Perhaps NMR had been discounted as a poten-
III
tial for imaging since the attainable resolution
20. 40 60 80 100 I20 140 seemed unappealing, given the magnitude of the
p,hll’ 1 radiation’s wavelength. At 60 MHz, for example,
5 layers, G,zO.77 G cm-1 the wavelength is 5 m, which would all but preclude
NMR. In experiments conducted in 1972 and
reported in 1973 [lo], Lauterbur showed that the
lst-ordrr dffraction notion of the interacting radiation field having to
possess a wave length comparable to the smallest
features to be resolved, is removed under certain
0 20 40 60 60 100 I20 140 conditions. This is the case, he reasoned, if local
pa (cm3 interactions are induced through a second field
which restricts those with the first field to a limited
region. The second field Lauterbur referred to in
his seminal paper, of course, is the gradient mag-
netic field, superimposed on the main field. Most
significantly, Lauterbur recognized that the
absorption signal recorded in the presence of a
static magnetic field gradient, represents the one-
0 IO
v hnscaltd) (kth) dimensional projection of the object’s spin density
(el, perpendicular to the gradient direction. He showed
further, in distinction to Mansfield and Grannell,
that by rotating the gradient in small angular incre-
ments (or rather the object in a constant amplitude,
constant direction gradient), a plurality of different
projections of the object can be obtained (Fig. Z(a)).
“-5 0 5
I (mm)
IO Subjecting these profiles, analogous to the proces-
sing of ray sums in CT, to a back-projection

Fig. 1. Transient proton NMR signal from layers of camphor

obtained with a line-narrowing pulse NMR technique: (a) three
layers; (b) same conditions as in (a) except that a field gradient
was applied orthogonal to the orientation of the layers, showing
diffraction peak; (c) experiment analogous to (b), for five-layer
sample; (d)-(f) Fourier transforms of transient responses of
(a)-(c). Three and five-line patterns in (e) and (f) represent spin
density projections (from Ref. [8], with permission).
 F. W. Wehrli/Progress in Nuclear Magnetic Resonance Spectroscopy 28 (1995) 87-135
...’.
,.’
Fig. 2. (a) Principle of Lauterbur’s zeugmatographic experi-
ment, schematically showing four angular projections of the
object, perpendicular to the direction of the magnetic field gra-
dients, represented by arrows. (b) Proton NMR zeugmatogram
of two water-containing tubes, arranged as in (a) (from Ref. [IO],
with permission).
algorithm (see, for example, Hounsfield [I l]), a
two-dimensional map of the object’s spin density,
can be obtained (Fig. 2(b)). It is remarkable that
the first two-dimensional NMR images were
generated without any specialized hardware, on a
routine Varian A-60 continuous-wave spec-
trometer, operating at 60 MHz, with the z-shim
coils as the source of the field gradients. Because
the interaction may be regarded as a coupling of
the two fields (polarizing and gradient), Lauterbur
dubbed the technique ‘zeugmatography’, derived
from the Greek word <evy~cu, ‘that which is used
for joining’.
Already at the time of his fundamental article,
Lauterbur seemed to have a clear vision of zeug-
matography’s enormous potential for medical
imaging. This is evident from an experiment he
describes, in which he shortened the spin-lattice
relaxation times in one of the water samples by
adding Mn2+ ions. By varying the r.f. power, he
showed that in this manner image contrast could
be selectively enhanced to emphasize local differ-
ences in relaxation times. As a possible application
of interest he mentioned the in vivo study of tumors
which were known to have prolonged relaxation
times relative to normal tissue [12]. The possibility
of imaging live objects was explored and zeugma-
tograms of biological objects, including a pecan
nut, cherrystone clam and a picture of the chest
cavity of a live mouse were published [13]. The
methodology used was analogous to the original
zeugmatographic experiment, except for the use
of a larger gap magnet operating at a field of
about 0.2 T.
It is clear that Lauterbur’s and Mansfield and
coworkers’ early work was independent. However,
following Lauterbur’s publication Manfield’s sub-
sequent investigations led him to the recognition
that his observations for discrete structures were
equally applicable to continuous spin distributions
[9] and that the spatial spin density could in general
be obtained as the inverse transform of Eqn (1). It
was less clear, however, at that stage, how p-space
could be scanned to obtain an array of data from
which an image could be reconstructed by discrete
Fourier transformation of the S(p) data. It is inter-
esting that the 2D image shown by Mansfield and
Grannell [9] still used projection-reconstruction
techniques analogous to Lauterbur’s. We will
return to Eq. (1) in conjunction with a discussion
of the k-space concept of imaging and evaluate its
implications in more detail.
In 1975 Mansfield and Grannell[9] published an
extensive paper in which they showed projection
images of small objects, including one of the
human finger. The latter presumably amounts to
 F. W. WehrlijProgress in Nuclear Magnetic Resonance Spectroscopy 28 11995) 87-135
(4
lsochromatic Plane
t into a gradient coil, the magnetic isocenter of this
I
20
(b)
Fig. 3. (a) Principle of Hinshaw’s sensitive point spatial localiz-
ation experiment. By periodically reversing the gradient, an iso-
chromatic plane is defined at location q where the signal
becomes time-invariant (adapted from Ref. 121). (b) Two-
dimensional proton spin density image from two concentric
water-filled tubes obtained at 60 MHz in 2 h by means of the
sensitive point technique (from Ref. [14], with permission).
the first ‘image’ of live human anatomy. They also
realized that achieving microscopic resolution
would require very high gradient strengths which,
even if technically achievable, would be limited by
translational self-diffusion. Reasoning that the
average distance that molecules diffuse during
gradient exposure cannot exceed the desired
resolution, they inferred that in a typical biological
specimen with a diffusion constant D = 1.85x
lo- 5 cm2 SC’ and G = 100 G cm-’ the resolution
limit would be about 6 pm. We will see later that
diffusion can indeed be significant at high gradient
strength, though a more severe impediment to very
high resolution is sensitivity.
In 1974 Hinshaw [14] proposed a technique
which circumvents the reconstruction problem
altogether. The idea was to isolate the signal from
91
a small region by oscillating gradient fields. It is
readily seen that by feeding an alternating current
coil defines a plane of constant field perpendicular
to the gradient direction (Fig. 3). Three time-
dependent gradients applied simultaneously, then
define a single ‘point’ where the field is time-
invariant. By subjecting the spins to regularly
spaced r.f. pulses, a signal is obtained which has a
time-dependent and a d.c. component. The latter
b
can be isolated by low-pass filtering and the sensi-
z tive point displaced across the object in small incre-
ments. In this manner, the entire object can be
sampled, point by point, thus obviating the need
for computer reconstruction.
A logical extension of this method is the multiple
sensitive point technique [ 151.Again, an alternating
gradient is set up, in say, y direction, in the presence
of a static gradient G,Y.Periodic excitation with a
train of 90 pulses at a frequency meeting the reso-
nance conditions for the null plane of the time-
varying gradient Gv as well as for location
x = w/yG, produces a signal for spins along a
line &,x). The Fourier transform of this signal
provides a map of spin density along the chosen
line. The line then can be displaced by moving
the isochromatic plane. It is clear that for an n*
matrix of image points the per-unit-time efficiency
of the experiment is improved n-fold.
In 1976 Damadian and coworkers [16,17] pre-
sented another idea of point localization relying
on an inhomogeneous field which produces a
saddle-shaped profile. They termed the technique
‘field focusing NMR’, abbreviated FONAR. By
selectively exciting the spins at a frequency match-
ing the Larmor frequency in the magnet’s ‘hot spot’
one point of the object is mapped. The object is
scanned by its being physically moved across the
hot spot. The method is obviously impractical and
was soon abandoned. Damadian’s work, which up
to the present day remains controversial [ 181 is
described in detail in Ref. [19].
3. Selective excitation for spatial localization
In its initial embodiment Lauterbur’s zeugmato-
graphy technique produced two-dimensional
92 F. W. Wehrli/Progress in Nuclear Magnetic Resonance Spectroscopy 28 (1995) 87-135
projection images. An obvious extension of the
method to generate images from a well-defined
slab of material would require one to spatially
confine excitation. The resulting image would
then be tomographic (derived from Greek
ropou = section), i.e. representing a map of the
spin density within the slab chosen.
This problem was addressed by a number of
workers in the field [20-231. Two approaches
were pursued: the first entails saturation of the
spins outside the slab of interest, achieved by
exciting the spins with an r.f. pulse of appropriate
frequency spectrum and a field gradient orthogonal
to the slab. Saturation would then be followed
immediately by a non-selective pulse, exciting the
spins in the slab [24]. Because of the difficulty in
achieving complete saturation, this method was
largely abandoned in its early stages. The alterna-
tive method, practiced in present-day two dimen-
sional imaging, relies on targeting excitation to the
slab of interest, by means of a shaped r.f. pulse such
as a gaussian [23] or sine-modulated pulse [25] in
the presence of a field gradient perpendicular to the
plane. Shaping the radiofrequency field as
sin(rrAvt)/rAvt results in a rectangular frequency
spectrum of bandwidth AU = l/r, with r repre-
senting the time of the first null point of the sine
function. Of course, in reality, the sine will have to
be truncated, which distorts the slice profile. There
is another reason why excitation across the slab is
not uniform. Hoult recognized this problem early
as a manifestation of the non-linearity of the Bloch
equations [25]. This problem is readily understood
by considering the effective field Beg that the spins
experience in a slab of thickness AZ at some loca-
tion z away from the center. Befr is the vector sum
of the off-resonance field AB = zG, and the applied
r.f. field B1, i.e. Beff = dm Hence, for an
r.f. pulse in the x direction of the rotating frame
of reference, for example, the spins at the edge of the
slab will be nutated by a much larger angle, and
around an axis tilted by 0 = atan(Bi /zGZ) relative
to the B, field. Whereas for small tlip angles (say
less than SO’), the problem is minimal, it becomes
severe for larger nutation angles. Joseph et al. pointed
out that by using this approach it is virtually impos-
sible to achieve effective uniform inversion across the
slice [26]. What these investigators described, of
course, was a problem of which spectroscopists
were well aware long before the advent of imaging
(see, for example Ref. [27]). It is merely a different
way of saying that with increasing offset from
resonance the signal decreases in amplitude and
experiences a phase shift.
Hoult [22] showed that the response to an r.f.
pulse is the Fourier transform of the product of
the pulse’s spectral density C(w) and a transfer
function G(w), the latter representing the line
shape. For a sine-modulated r.f. pulse C(w) is
square and for a flat spin distribution (such as a
profile across a slab of tissue), when relaxation is
ignored, the spectral line shape is also square.
Hence, the Fourier transform of the product of
the two functions is a sine. There is a problem
though, which has no counterpart in spectroscopy,
and which is crucial to effective slice-selective exci-
tation, i.e. the phase dispersion caused by the
sequential nutation of the spins. The signal is
created while the transmitter is on and at the end
of the pulse, when the receiver could be opened,
there is very little signal left. Hoult [22] showed
that, at least in the linear regime (i.e. low nutation
angle) reversal of the gradient after termination of
the r.f. pulse, produces an echo-like signal. Fig. 4
schematically shows the transient echo from a sinc-
modulated r.f. pulse detected upon gradient rever-
sal. The response is a sine itself whose Fourier
transform reproduces the square-like spin distribu-
tion. If, on the other hand, excitation were effected
with a square pulse, the echo would have a flat
amplitude distribution whose Fourier transform
is a sine and thus would be a poor representation
of the true spin density. In practice, the slice-
selection gradient is terminated at echo maximum.
The signal may then be received in the presence of a
further spatial encoding gradient, allowing collec-
tion of an FID to afford a projection profile for
projection-reconstruction imaging or, in the case
of application of an orthogonal gradient, Fourier
reconstruction as in Fourier zeugmatography.
Lai and Lauterbur [28,29] developed an
ingenious extension of the original zeugmato-
graphic experiment which circumvents slice selec-
tion altogether. By stepping both polar and
azimuthal angle for the orientation of the projec-
tion gradient, an array of projections is obtained
 F. W. WehrlijProgress in Nuclear Magnetic Resonance Spectroscopy 28 (1995) 87-135
Fig. 4. A shaped r.f. pulse such as is obtained with sine modula-
tion, applied in the presence of a linear field gradient, produces a
signal that has the same shape as the pulse. Since it is produced
while the transmitter is on, it cannot be received. However,
reversal of the sign of the gradient produces an echo-like signal.
If the gradient is terminated at the maximum of rephasing, there
will be no further phase evolution (redrawn from Ref. [3], p. 80).
(b)
Fig. 5. (a) Principle of 3D projection-reconstruction imaging: the imaging gradient G is rotated in a plane. From the resulting
projections, an image can be reconstructed which is a 2D projection of the object onto the plane. This process is repeated by rotating
plane in small angular increments. (b) The 2D projections are back-projected
shown for clarity (adapted from Lai and Lauterbur [28]).
93
from which a true 3D image data set can be recon-
structed. A two-step reconstruction technique first
generates an array of 2D projection images from a
series of 1D projections generated by rotating the
gradient in a particular plane. The resulting set of
2D projections than are back-projected to yield the
true 3D array of intensities. Images in any desired
plane can then be obtained by suitably rearranging
the data. The principle is outlined in Fig. 5.
4. Fourier zeugmatography and spin warp imaging
In 1975 Mtiller et al. at the Swiss Federal Insti-
tute of Technology introduced a new class of NMR
experiments which they denoted ‘two-dimensional
NMR spectroscopy’ [30]. The significance of this
development, which laid the groundwork for struc-
ture and conformational analysis of large biologi-
cal macromolecules, is highlighted by Ernst’s 1991
Nobel prize. Whether Fourier zeugmatography
[31] was inspired by this class of experiments is
not clear, but its kinship to 2D NMR spectroscopy
with which the majority of readers are familiar,
may be helpful to understand this crucial milestone
in the evolution of NMR imaging.
1D
the
to yield the 3D image data set. Only two 2D projections are
94 F. W. WehrlilProgress in Nuclear Magnetic Resonance Speclroscopy 28 (1995) 87-135
Unlike the projection-based techniques (where
it does not matter whether the projections are
obtained by continuous-wave scanning or as the
Fourier transform of the FID recorded in the
presence of a gradient), Fourier zeugmatography
is based on the successive application of orthogo-
nal pulsed field gradients prior to and during
sampling of the FID. The method can be under-
stood by reference to Fig. 6(a). Following excita-
tion by an r.f. pulse, the spins in the sample are
subjected to variable periods of field gradients G,
and GY. While these gradients are active, spins
at locations x and y resonate at frequencies
W(X)= yG,x and w(y) = yG,y. Their relative
phase at time t, + ty then is given as w(x)& +
w( y)ty. Hence, the phase of the resultant FID,
recorded in the presence of a third gradient G, is
modulated, with the modulation being a function
of the spins’ location. By stepping time periods t,
and tY in equal increments, a three-dimensional
array of time domain data is obtained whose
Fourier transform yields a three- dimensional spec-
trum. Ernst and colleagues showed the spectrum to
be given as the spatial spin density convolved with
a line shape function. The latter results from the
unequal weighting of individual signals by spin-
spin relaxation.
The 2D implementation of Fourier zeugma-
tography reported in the original work is parti-
cularly instructive to the spectroscopist, as it
illuminates the close relationship of the experiment
with 2D-resolved spectroscopy. Fig. 6(b) shows a
series of FIDs obtained from two small water con-
taining capillaries, oriented with their long axes
perpendicular to the z axis of the main field and
their centers along z. During the initial period
while gradient is G, active, a single-frequency
FID is obtained. During readout, a gradient G, is
switched on, producing two FIDs containing two
frequencies, given by the gradient amplitude and
the samples’ location on the z axis. The Fourier
transform with respect to t, affords a two-line
‘spectrum’ reflecting the two samples, with the
phase modulation being caused by the spins’ evolu-
tion during the time period t,. The second Fourier
transformation with respect to t, then yields the 2D
zeugmatogram.
In 1979 Hoult reported a related technique
which he called “rotating frame zeugmatography”
1321.Rather than imparting a phase shift onto the
FID prior to its collection by a static field gradient
he proposed using a gradient in the B1 field. Spins
located at different positions along, for example,
the x-axis are then nutated by flip angles yB,(x)~,
where T represents the duration of the pulse. The
signals are collected in the presence of a second
orthogonal static field gradient along y. It is then
recognized that by stepping r through a series of
values, an array of time-domain data is collected
analogous to conventional zeugmatography, and an
image is obtained by successive Fourier transforms
along the rows and columns of the data matrix.
While Fourier zeugmatography undoubtedly is
the parent of most modern imaging methods, the
basic experiment as described by Kumar et al. [31]
is not practical for medical imaging of large objects
and humans. As noticed by Ernst, the zeugmato-
gram is a filtered spin density function. The filtra-
tion is due to convolution of the signal with
exp( -t/ r;) which leads to progressive damping
of the later FIDs, as is evident in the spectral traces
of Fig. 6(b). More importantly, however, static
field inhomogeneities (resulting from imperfections
in the main field, or intrinsic gradients due to sus-
ceptibility variations within the object) can cause
large phase errors which increase with each incre-
ment in time. These phase errors lead to image
distortions and smearing of the spin density maps.
In 1980, Edelstein et al. from the University of
Aberdeen in Scotland, reported a new technique,
building on Fourier zeugmatography they called
‘spin warp NMR imaging’, which remedies some
of the above problems [33]. Rather than stepping
the time period during which the gradients are
applied as a means of modulating the phase of
the transient signal, they proposed to step the
amplitude of the first of the two orthogonal encod-
ing gradients (Fig. 7). Therefore, signal read-out
commences at precisely the same time for each of
an array of N signals. The benefit of this modifica-
tion, of course, is that it gives equal weighting of
the array of N signals. Most importantly, however,
phase shifts from static field inhomogeneity equally
affect all signals, i.e. spurious phase increments are
constant and thus do not distort the linearity of the
scale.
 95
F. W. Wehrli/Progress in Nuclear Magnetic Resonance Spectroscopy 28 (1995) 87-135

Fig. 6. (a) Principle of Fourier zeugmatography: following excitation by a 90” r.f.pulse gradients are applied along the three orthogonal
directions. By stepping gradient on-times 1, and t,,, while reading out the signal in the presence of the gradient gZ, and Fourier
transformation along the three time axes, a 3D zeugmatogram is obtained. (b) Sample data from 2D Fourier zeugmatography experi-
ment, showing an array of selected FIDs from a set of 64 signals obtained by applying pulsed linear field gradients along x and z axes for
two water-filled tubes, along with Fourier transforms (right). Tubes are arranged along the z axis. Broken vertical lines represent time
points of gradient switching from x to z (from Ref. [31], with permission).

The technique of Edelstein et al. contributed denoted a ‘gradient echo’, achieved by balancing
another element of novelty and significance to the the readout gradient in such a manner that the
further of NMR imaging. Rather than
evolution phase is zero at the center of the readout window,
sampling an FID, they collected what is now a condition which demands that J G( t)dt = 0. This
96 F. W. WehrlilProgress in Nuclear Magnetic Resonance Spectroscopy 28 (1995) 87-13.5

Adiabatic
RF field

Gradient G,

.Gradient G,

Gradient G,
-- - -. Signal
, I I I I
J I I 2 l3lLl 5 16
Interval number
(4

(b)
Fig. 7. (a) Spin warp NMR imaging pulse sequence: a 90” r.f. pulse, applied in the presence of a slice-selection gradient G,,, leads to an
echo produced by the gradient G,. The programmable-amplitude gradient G, causes a phase ‘warp’ and thus encodes spatial position
into the phase of the transient signal. The adiabatic fast-passage excitation prior to the slice-selective r.f. pulse is not mandatory but
many serve as a means of inverting spin populations prior to slice-selective excitation for generating Tl dependence of the signal. (b) Spin
warp image of the heart, showing right and left ventricle and interventricular septum. The blood appears bright due to inflow of fully
polarized spins between excitations (from Ref. [33], with permission).
 F. W. Wehrli/Progress in Nuclear Magnetic Resonance Spectrosropy 28 (1995) 87-135
t-*-+---B+
I 1 r
Fig. 8. (a) Timing diagram for a two-dimensional echo-planar
imaging experiment. Following slice-selective excitation, a gra-
dient G, whose polarity is alternately reversed is applied to form
a series of echoes (bottom trace). At the same time a weak gra-
dient is applied in the z direction. (b) Projection from an object
in the shape of an annulus (dotted line, top), obtained as the
Fourier transform of the echo signal, becomes discrete as a con-
sequence of the modulation of G,.. If, in addition, a gradient G;
is applied, as shown in (a), the projections are broadened (bot-
tom) and the signal at each frequency can be uniquely assigned
to a location in the object (from Ref. [109], with permission).
approach is analogous to the reversal of the slice
selection gradient following selective excitation.
Finally, the pulse sequence technique incorporates
selective r.f. pulses - in this case a gaussian shaped
pulse [23].
The ‘spin warp’ imaging technique - so named
because of the phase twist (or ‘warp’) to which the
spins are subjected in the direction of the gradient -
would later become the workhorse of clinical ima-
ging, and continues to be the standard imaging tech-
nique. It generates a rectilinear grid of data from
which it is straightforward to reconstruct images by
inverse Fourier transform, without the need for any
preprocessing of the raw data. Another advantage,
recognized immediately by the Aberdeen group, is
that magnetic field inhomogeneity causes spatial dis-
tortion only, rather than image blurring, observed
with projection-reconstruction. The latter advantage
was particularly valuable since the construction of
magnets providing a large-volume homogeneous
91
L
Ax
f
G, and G,
(b)
Fig. 8. (b)
field suited for whole-body studies, was difficult in
those days.
Prior to spin warp imaging Mansfield [34] and
Mansfield and Pykett [35] devised another ingenious
spin mapping technique which, as will become evi-
dent later, set an important milestone on the path to
modern high-speed imaging. The method is based on
the recognition that the transient signal recorded in
the presence of a gradient, can be recalled by rever-
sing the sign of the gradient, analogous to the prin-
ciple used for slice selection. However, in distinction
to the latter, a gradient G,”is applied after creation of
transverse magnetization (which could be confined
to a slab by means of some form of selective excita-
tion using a gradient G,, for example). This signal
decays rapidly due to phase dispersion, but rephases
upon reversal of the gradient polarity, as shown in
Fig. 8(a). The process can be repeated for a time on
the order of T;, the spins’ effective transverse relaxa-
tion time. The Fourier transform of each echo
affords a projection of the object onto the .v-axis.
98 F. W. WehrlilProgress in Nuclear Magnetic Resonance Spectroscopy 28 (1995) 87-135
Fig. 9. Time domain NMR signal from a volume element dxdydz in an object of magnetization density Mxy(r, I) in the presence of
a spatial encoding gradient G. The spins in the volume element dxdydz sense a field B(r) = G.r and thus evolve as
exp[-iy(G,x + G,y + G,z)t].
Further, the sinusoidal modulation produces discre-
teness in the projection profile (analogous to the
spectrum of a repetitive train of rectangular pulses).
The third dimension is obtained by applying an addi-
tional gradient G, of constant amplitude. The effect
of this gradient is a broadening of the profiles, the
extent of which is determined by the dimensions of
the object along the z-coordinate. Critical to the
experiment, as described in Ref. [35], is the choice
of G, which has to be set such that the resulting
broadened lines do not overlap each other. It is
then recognized that the spin density at each location
( y, z) is uniquely determined from the amplitudes at
each frequency and an image can be obtained by
simple rearrangement of the data. While this experi-
ment is undoubtedly the parent of modern echo-pla-
nar imaging, the method in the form described, is not
practical and has not been practiced outside
Mansfield’s laboratory.
5. Fourier relationship between object and data space
At this stage we shall digress briefly from a depic-
tion of the historic development of MRI and pro-
vide the proof that the object’s spin density and the
+
GYY + G,z)tl dxdydz
NMR signal are the Fourier inverses of one
another. We have seen that the fundamental
element in MRI is the spatial dependence of
the spins’ precession frequency and thus their
phase in the presence of a magnetic field
gradient G = (dH,,/&, aHs/dy, dH,Jdz) super-
imposed onto the static polarizing field Ho = Hz.
We shall now derive the general imaging equation
and introduce the concept of reciprocal space, first
conceived by Mansfield [2,8,9] and generalized
later by Twieg [36] and Ljunggren [37].
In the presence of a magnetic field gradient the
resonance frequency LJ becomes a function of
spatial position Y,according to
W(Y)= y(Ho + G-r) (2)
In Eq. (2) the scalar product G. r = G,x+
G,y + G,z represents the incremental field at loca-
tion Y,resulting from the superimposed field gradi-
ent G. In the rotating frame of reference in which
we ignore precession due to the polarizing field
(first term in Eq. (2)), it is readily seen that the
complex time-dependent NMR signal evolves as
exp(iywt) = exp(iyG. rt). In a volume element
dxdydz the signal dS(t) then becomes (Fig. 9)
 F. W. WehrlijProgress
x dxdydz
where MY,.(r) f) represents the magnetization den-
sity at location r. The total signal then is obtained
by spatial integration across the object. Unless the
gradients have constant amplitude, products G,t,
etc., of course, are integrals over time. We can then
define the wave vector (also denoted ‘spatial fre-
quency vector’) as follows:
k(t) = (27r)‘y ’ G(t’)dr’
10
where G( t’) is the time-dependent spatial encoding
gradient. From Eq. (4) it is evident that k(t) has
units of cm-’ or m-l (it thus measures ‘reciprocal
space’). Rather than expressing the NMR signal in
terms of the magnetization, which is modulated by
the relaxation terms in a manner specific to the
excitation scheme used, it is customary to express
it as a function of the spin density which is equiva-
lent to ignoring relaxation. We can then rewrite
Eq. (3) in spatial frequency format. For an object
of spin density p(r) the spatial frequency signal
S(k) is thus given by
S(k) = p(r)e’2~~t’)“dr
.IIs object
We now recognize that Eq. (6), except for the sym-
bols, is identical to Mansfield’s equation (Eq. (1)).
Pictorially, the spatial frequency may be regarded
as the phase rotation per unit length of the object
the magnetization experiences after being exposed
to a gradient G(t’) for some period t.
It is further seen from Eq. (5) that S(k) and p(r)
are Fourier transform pairs and thus
p(r) = I, ,paceS(k)e--i2”k(‘)“dk
sss 5
holds. Hence, the spatial spin density at any one
location can be obtained as the inverse Fourier
transform of the spatial frequency signal. The
path the spatial frequency vector follows during
execution of the pulse sequence is, of course,
determined by the time-dependent gradient
wave forms.
We may now examine the special case of 2D spin
warp imaging. For the sake of simplicity, we
in Nuclear Magnetic Resonance Speciroscopj, 28 (1995) 87-135 99
assume the gradients to have constant amplitude,
as illustrated in Fig. 10, and follow the trajectory of
(3) the spatial frequency vector as we execute one cycle
of the pulse sequence. The k-coordinate at time
point t is easily obtained from the areas under the
gradient-time curve. Immediately following the r.f.
pulse, k = 0 which is followed by subjecting the
magnetization to the two negative gradients,
hence bringing us to the third quadrant of k-space.
Application of the positive frequency-encoding
(also called ‘readout gradient’) during which
(4) sampling occurs, increases k, at constant k,..
At the center of the readout window, the spins
have maximum phase coherence, i.e. an echo is
formed for k, = 0. It is then easy to see that by
stepping GY incrementally during successive pulse
sequence cycles, the k-vector traces a rectilinear
raster and the data can be subjected to a discrete
2D Fourier transform to yield the spatial spin
density map.
The discrete sampling of k-space, of course,
requires compliance with the Nyquist criterion
which demands that two or more samples be
taken per phase cycle, i.e. the highest spatial fre-
quency ki,,,, (i = .Y,y) sampled has to obey the
relationship
(5) ki,,max*L; = Ni
(7)
where L; and Ni represent the field of view and
number of data samples, respectively. It thus fol-
lows for the sampling interval, Ak, that
A,+kimax=~_ ’
Ni 4 Ni. ALi
with AL, representing the image pixel size. From
Eqn (8) we infer that the resolution (crudely
approximated as pixel size) is given as the recipro-
(6) cal of the maximum spatial frequency.
The implications of Eq. (8) are illustrated in
Fig. 11 in which the k-space data were low-pass
filtered in order to lower their high spatial fre-
quency content. The resultant image, while still
showing the coarse features of the brain anatomy,
clearly lacks spatial detail.
Let us now briefly examine the signal-to-noise
ratio (SNR) implications of data sampling. Since
the image volume element AzAyAz (denoted
‘voxel’ in imaging jargon) is the smallest signal
100 F. W. Wehrli/Progress in Nuclear Magnetic Resonance Specfroscopy 28 (1995) 87-135

Phase
Encoding

Fig. 10. (a) Generic 2D spin warp pulse sequence, showing arbitrary cycle where the phase-encoding gradient GJ is negative. (b) The
location of the spatial frequency vector at time point 1 is obtained from integration of G(t). The solid line shows the path of the spatial
freauencv
. . vector k and the dot represents the locus of k at time point t. Sampling occurs during execution of the frequency-encoding
gradient, resulting in a raster of rectilinear k-space samples.

producing element, the signal amplitude S is acquisition system, we obtain

proportional to voxel size, AxAyAz, i.e.

S o( AxAyAz = NN
W+
X Y
where N, and NYdenote the number of samples k,
and ky; L, and L, represent the field of view in x
and y directions and AZ is the slice thickness.
Further, we obtain from the noise-reducing effect
of sampling
SNRoc 4-X
NNn
where n represents the number of signal averages.
Combining Eqs. (10) and (11) and considering
further that the noise is proportional to the square
root of the bandwidth 5f set by the data
(11)
the master equation for SNR in 2D Fourier
imaging. Extension of Eq. (11) to a third spatial
dimension is straightforward. Of course, relaxa-
tion terms need be included as well, though for a
given imaging technique such as 2D or 3D spin
warp, these merely act as scaling parameters and
(10) the signal can easily be calculated from the
Bloch equations.
The total data acquisition time is determined
by the time required to fill the matrix of NXNY
k-space samples, which for NY phase encodings
is nN,.TR.
 F. W. WehrlijProgress in Nuclear Magnetic Resonance Spectroscopy 28 (199.5) 87-135 101

(c) (d)
Fig. 11. (a) Image obtained from collecting 256 x 256 data samples; (b) its inverse 2D Fourier transform; (c) k-space map obtained by
subjecting the data of(b) to a low-pass filter in such a manner that the center sixteenth is retained. (d) Image reconstructed as the 2D
Fourier transform of the data of(c), showing significant blurring. The greyscale in (b) and (c) was inverted with darker shades of grey
corresponding to higher signal amplitudes. Note that image (d), while still showing the coarse features, fails to reveal finer details of the
brain’s anatomy, due to suppression of high spatial frequencies.
102 F. W. WehriijProgress in Nuclear Magnetic Resonance Spectroscopy 28 (1995) 87-135
6. Sensitivity and imaging efficiency
A question of significant practical importance is
the efficiency of an imaging method in terms of the
overall minimum data acquisition time and sensi-
tivity. Brunner and Ernst [38] addressed this ques-
tion by comparing the efficiency of all imaging
techniques known by early 1978 (thus excluding
spin warp), for imaging a volume consisting of a
3D array of voxels. They came to the intuitively
obvious conclusion that the sensitivity, i.e. the
SNR per unit time, is optimal for techniques in
which (i) data are gathered simultaneously from
the entire object; (ii) the dead dime during which
no sampling can occur, is minimized. These con-
ditions, they concluded, are best satisfied for 3D
projection-reconstruction techniques, and to a les-
ser degree, 3D Fourier imaging (meaning Fourier
zeugmatography). The latter, they found, was
somewhat impaired by T2 losses resulting from
the variable encoding period (a handicap not atten-
dant to spin warp imaging). They also concluded
that 3D Fourier and projection-reconstruction
techniques demanded excessively long intrinsic
scan times, and further that it was questionable
whether true 3D imaging requiring high resolution
in all three spatial dimensions, was realizable and
practical. The recognition that a 1003 array would
require 10 000 pulse sequence cycles, appearing to
require hours of scan time, was a daunting
prospect.
Besides impractical scan times, Brunner and
Ernst thought that NMR’s inherently low sensi-
tivity would be an impediment for imaging of
biological systems. In one of their concluding sen-
tences they state: “It is certain, however, that sen-
sitivity will remain one of the insurmountable
limitations of NMR techniques for biological
imaging”. We, of course, wonder, in hindsight,
how it was possible to defeat this gloomy predic-
tion, in particular given that no fundamental
breakthroughs in NMR signal detection occurred.
As we will see, the NMR signal in biological tissue
is even weaker than expected on the basis of what
was known at the time of Brunner and Ernst’s con-
clusions since the noise is usually dominated by the
sample rather than the circuit resistance [39]. We
shall return to this issue in the next section when
reviewing the evolution to large-scale imaging in
humans.
7. Scaling to human dimensions
Toward the end of the 197Os, the imaging
methodology had reached a level of sophistication
that made its application to the study of live bio-
logical systems, including animals and humans,
appear feasible. However, it became soon evident
that scaling of the zeugmatographic experiment
was not just straightforward engineering.
First, magnets had to be developed that provide
a volume of magnetization sufficient to accommo-
date the human body. We shall not dwell on the
different possible designs of magnets. It suffices to
mention that resistive, permanent and supercon-
ductive designs were being considered early on. It
was obvious that each of these designs had
advantages and drawbacks, either in terms of
cost, magnetic field stability, maximally achievable
field strength, stray field, etc., a discussion of which
is beyond the scope of this article. Initially, field
strength did not seem to be much of an issue
since it appeared that physical constraints did not
leave much latitude.
In 1978 Hoult projected that for a head-sized
solenoidal coil the maximum frequency would be
about 6 MHz. Hence, a field of about 0.1-0.2 T,
easily achievable with conventional resistive tech-
nology, seemed to be sufficient. He predicted a
SNR of about 1000: 1 for 1 ml of water at this
field strength, which would amount to about
30: 1 SNR for voxels corresponding to a linear
resolution of 2.3 mm and 5 mm slice thickness.
This resolution and SNR could be achieved from
a single FID, if the spatial encoding could be done
during the signal’s lifetime, he reasoned. If true,
Hoult’s optimistic projection (which did not
materialize) would permit single-shot echo-planar
imaging at these field strengths and there would be
little incentive to develop the much more expensive
superconductive magnets.
The question of field strength remained con-
troversial for some time. Hoult and Lauterbur
[39] showed that for a spherical, electrically lossy
sample, such as mammalian tissue, the sample
 F.W. WehrlilProgress in Nuclear Magnetic Resonance Spectroscopy 28 (1995) 87-135
Fig. 12. NMR head scan, obtained at 4 MHz on an experimen-
tal NMR machine constructed by Thorn-EMI. The imaging
time was 6 min and the slice thickness 1 cm.
resistance Y, increases as the fifth power of its
radius b and as w2, in contrast to coil resistance rc
which increases as w‘I* . Considering further that
the signal scales as w*, and that the total noise is
proportional to ,/x, the SNR can be written
as [49]
&I2
SNR oc (12)
aa2w112 + /3b5w2
where a and b are coil and sample radii, and cr and
p are constants. It is evident from Eq. (12) that with
increasing sample diameter and frequency, sample
resistance will eventually dominate, in which case
SNR 0: wb”* should hold, i.e. SNR would be
expected to scale linearly with frequency. This
result was later corroborated experimentally for
whole-body imaging [41]. Hence, contrary to
small-sample laboratory NMR where SNR is
well known to increase as w7’4, increasing field
strength as a means of enhancing sensitivity
appeared less rewarding for imaging. Radiofre-
quency penetration was another perceived hurdle
to the use of higher field strengths. In cylindrical
tissue models and using experimental values for
103
resistivity and permittivity, Bottomley and Andrew
showed that significant amplitude attentuation of
the r.f. field and phase shifts of up to 70” occur at
frequencies of 30 MHz and a depth of 20 cm [42].
Similar results were also obtained by Mansfield (see,
for example, Ref. [4], pp. 18 1-191). This, together
with the difficulty in designing r.f. coils which oper-
ate at the elevated frequencies, and the increased
r.f. power requirements to overcome inductive
losses, significantly determined the choice of field
strength in first-generation imagers. Another diffi-
culty which is exacerbated at higher fields, was the
relatively low field homogeneity achievable initially
in whole-body magnets. While Fourier imaging is
relatively forgiving in this respect, the field homo-
geneity requirements in projection-reconstruction
imaging are more stringent [43,44]. The latter
demands for the relative inhomogeneity across
the object, AB, that the inequality
AB<LG (13)
be satisfied, with L representing the field of view
and G the gradient amplitude. Assuming ABIB, to
be approximately field invariant, it was clear that
satisfying Eq. (13) would be challenging, given that
for early whole-body magnets AB/B, was no less
than about 50 ppm. With the above engineering
and perceived physics constraints, it is therefore
not surprising that the target fields for early
whole-body imaging systems were quite low,
ranging from about 400- 1500 Gauss.
8. Imaging of humans and the commercialization of
MRI
Between the mid and late 197Os, several groups
began construction of experimental whole-body
scanners [17,45-481, despite the many unresolved
engineering issues concerning magnet, gradient and
r.f. system. The prospects of visualizing and dif-
ferentiating diseased tissue on the basis of the
known differences in relaxation times was particu-
larly promising since X-ray images in general pro-
vide poor soft-tissue contrast without the use of
iodinated contrast agents.
Perhaps the earliest two-dimensional image of
human anatomy is one published by Hinshaw et al.
 F. W. Wehrli/Progress in Nuclear Magnetic Resonance Spectroscopy 28 (1995) 87-135

(a) (b)

Fig. 13. (a) Axial; (b) coronal; (c) sagittal images of the brain, first reported by Holland et al. in 1980. The images were obtained by the
projection-reconstruction method at 4.26 MHz (0.1 T field strength) in about 2 min per image at a pixel size on the order of 2 mm. Plane
selection was achieved by means of orthogonal oscillating gradients at the intersection of which the field is static. (From Holland et al.
[53], with permission.)

[49] who produced a high-quality image of the
human wrist at 30 MHz. The image had the
remarkable spatial resolution of 0.4 mm and a sec-
tion thickness of 3 mm, obtained by means of the
line scan technique developed by the authors. This
performance, though, was not representative for
other parts of the anatomy since the image was
taken in a small-bore magnet at a field strength
not yet amenable to whole-body imaging. In 1978
Damadian et al. [SO] reported an NMR image
through the human chest, obtained by means of
their field focusing technique. The resolution was
on the order of 6 mm and the scan time was 4.5 h.
While presented by their originators as the first
whole-body NMR image of a live human subject,
the work remains shrouded in controversy. Since
the technique used was impractical in several
respects, this work, even as a ‘first’, had little
impact on the later evolution of MRI.
The first commercial company with an
R&D program directed toward the development
of a tomographic medical imaging machine was
ThornEM who, a few years before, had pio-
neered X-ray CT. Unfortunately, much of this
early work is not documented in the open litera-
ture. Early testimony of EMI’s research efforts,
headed by Ian Young, is what may be the first
head image, obtained by projection-reconstruction
techniques, at a field strength of 0.1 T (Fig. 12).
Once it became evident that MRI was likely to
stay for good, a number of companies embarked
on engineering programs aimed at the development
of clinical imagers. Among these were Technicare
(a subsidiary of the pharmaceutical company John-
son &Johnson), Philips, Siemens, Pfizer (who sub-
sequently divested their medical imaging business
to Diasonics), General Electric and several
Japanese companies.
 F. W. WehrlilProgress in Nuclear Magnetic Resonance Spectroscop_v 28 (1995) 87- 135
Fig. 13
At the time of their pioneering work on spin
warp imaging, Hutchison and Mallard and
colleagues [48,51] at the University of Aberdeen,
constructed their own version of a whole-body
scanner, which was based on an electromagnet,
operating at 400 G, producing a transverse field
rather than the more conventional longitudinal
field obtained from four-coil magnets. The trans-
verse field was viewed as advantageous since it was
considered to provide a sensitivity superior by a
factor of 334 over a corresponding saddle coil.
Besides using the spin warp technique that they
had pioneered, they generated images which are
true maps of T, and proton density. They
reasoned that in this manner they would best
exploit the image contrast’s sensitivity to varia-
tions in the spin-lattice relaxation times of tissue
protons.
By 1980, there were several reports of NMR
head scans 152-541. Among these were the first
images in other than the traditional transaxial
plane’ [53] which highlighted one of MRI’s salient
features, i.e. its ability to generate images in
all three orthogonal planes, obviating the need
for changing the subject’s physical orientation
105
(Fig. 13). The latter, of course, is possible since
the three sets of orthogonal encoding gradients, if
properly designed, can be interchanged freely by
electronic means.
Within two years following construction of the
first whole-body NMR imaging machines there
were dramatic improvements in image quality
[54-561. While the superior image quality of the
Thorn-EM1 imager at that time was likely the
result of numerous incremental improvements in
hardware and imaging methodology, the single
most important advance was the replacement of
the resistive magnet by a 0.15 T superconductive
magnet, manufactured by Oxford Instruments.
Electromagnets were notoriously unstable and
short-term jitter in the field led to additional
noise in the images. In their 1982 book [4]
Mansfield and Morris write under ‘Notes added
in Proof: “The recent improvements in NMR
image quality have surpassed all earlier expect-
ations and could soon lead to a reassessment of
the role of NMR as a diagnostic imaging
modality”.
It was not clear at this stage which imaging tech-
nique would be most suited for clinical imaging.
EM1 practiced 2D projection-reconstruction (see,
for example, Refs. [54,57] and so did initially
Technicare (see, for example, Ref. [58]). Although
recognized as potentially powerful because of its
ability to allow reconstruction of images in any
desired plane, 3D projection-reconstruction appeared
only sporadically in whole-body imaging [59,60]
and was later abandoned (except in NMR micros-
copy). The ease of Fourier reconstruction offered
by rectilinear scanning and its relative insensitivity
to magnetic field inhomogeneity and gradient non-
linearity (except for spatial distortion which can
easily be corrected by postprocessing), a variant
of spin warp imaging was soon adopted by all
equipment manufacturers.
In Edelstein et al.‘s original spin warp technique
the echo was formed by reversal of the read gradi-
ent, evolving with exp(-t/T;), and thus is suscep-
tible to magnetic field inhomogeneity. While less
’ Orthogonal planes: axial, perpendicular to body axis;
coronal. plane dividing body into anterior and posterior parts:
sagittal, plane dividing body into left and right parts.
106 F. W. WehrlilProgress in Nuclear Magnetic Resonance Spectroscopy 28 (1995) 87-13.5
problematic at the 400 G field strength of the
Aberdeen imager, it was anticipated to be a
major problem at field strengths above 0.1 T. For
this reason, a 180” r.f. pulse was inserted after the
phase-encoding portion of the pulse sequence (cf.
Fig. 7) [43]. The modification required the polarity
of the pre-encoding portion of the read gradient to
be reversed since the 180” pulse, of course, has the
effect of reversing the spin phase.
Another important element critical to achieving
scan times competitive with alternative imaging
modalities was the introduction of multi-slice ima-
ging by Crooks et al. [61], i.e. the idea of using the
Tt relaxation recovery period following acquisition
of the echo to selectively excite the spins in other
slices within the imaging volume. Brunner and
Ernst [38] had already recognized this possibility
in their 1979 paper when discussing multiplanar
2D Fourier imaging, pointing out that sequentially
exciting multiple planes could enhance efficiency,
provided that T, > T2 holds, a condition which
is usually satisfied for tissue water protons.
9. Clinical image contrast
9.1. Tissue relaxation times
The early clinical images almost immediately
captured the medical community’s attention
because of their exquisite contrast, not only
among the various normal tissue types (e.g. grey
and white matter in the brain) but, more
importantly, their ability to differentiate normal
from diseased tissue. These findings were not
entirely unexpected since it was well known that
different tissues varied greatly in their relaxation
times (see, for example, Ref. [62]). Well before the
advent of imaging, Zimmerman and Brittin [63]
had proposed a model for relaxation in which
they treated relaxation as a two-site fast exchange
process involving exchange between protein-bound
and free water. Since l/Tt,,r,,, < 1/T1,2bound,the
fraction of bound, motionally hindered water,
determines the observed relaxation rate. This
view has more recently been challenged in that it
was shown that free water is relaxed by an
exchange-mediated cross-relaxation process [64,65].
Since the bound water has a correlation time sev-
eral orders of magnitude longer than free water, the
spectral densities are frequency-dependent. As a
result, tissue relaxation times, themselves, are sig-
nificantly frequency-dependent [66,67]. Damadian
found in excised tissues from implanted tumors in
rats a prolongation in T1 relative to both benign
tumors and normal tissue [ 121.He, incorrectly, as it
turned out, believed this phenomenon to be specific
to cancer. Hollis et al. [68] who studied human
cancer relaxation times showed the effect to be
non-specific and a hallmark of most pathologies.
A more detailed discussion of this topic is
obviously outside the scope of this review, but the
interested reader may consult the extensive reviews
by Bottomley et al. on the subject [67,69].
9.2. MRI contrast manipulation
As pointed out previously, Lauterbur, in his
1973 paper, first showed that by increasing r.f.
power images could be obtained that emphasize
differences in T, relaxation times [lo]. In 1975,
Mansfield and Grannell [9] pointed to the possi-
bility of perturbing the local spin populations
from equilibrium. The Aberdeen group advocated
the use of computed images in the form of a map of
T, relaxation times [33,70). Young et al. [54] and
Doyle et al. [56] showed that by preceding the
spatial encoding pulse sequence by an inversion
pulse, brain images could be obtained which
exhibit a degree of differentiation between white
and grey matter. One of the most intriguing early
papers showed that this method of contrast
enhancement was able to demonstrate multiple
sclerosis lesions with far better contrast than CT
[71] (Fig. 14).
A different type of image, which turned out to be
the most clinically sensitive, is obtained when the
signal is read out in the form of a spin-echo
[55,72]. In this case, the image signal evolves as
exp(-TE/T2) where TE represents the echo delay,
i.e. the time interval between the excitation pulse
and the appearance of the echo. While the
inversion-recovery images cause a relative suppres-
sion of tissues with prolonged T,, the spin-echo
images highlight regions with prolonged T2,
making them appear hyperintense relative to
 F. W. WehrlijProgress in Nuclear Magnetic Resonance Spectroscopy 28 (1995) 87-135
Fig. 14. A, CT; B, NMR scan of a patient with multiple
se& in the CT image (from Ref. [71] with permission).
other tissues. Unfortunately, however, T1 and T,
are often correlated, i.e. if T2 is prolonged, so is T,.
This conspiracy of nature can cause an abnormal-
ity to appear hyperintense even though the tissue
has prolonged relaxation times. It is readily seen
from the solution to the Bloch equation for a spin
echo that the magnetization is given by
where T, is the pulse sequence repetition time, and
p(H) is the proton spin density. Since TR > T,,
Eq. (14) simplifies to
M, cx p(H)(l - eeTR’T1)ePTE’TL
Hence, if an abnormality such as a lesion were to
have longer T, and T2 values relative to the sur-
rounding tissue, then at short echo time (TE < T,)
it would appear hypointense due to the dominance
of the first term in Eq. (15). However, at long TE,
the signal from the lesion would be dominated
by the second term and the lesion would be
hyperintense. There is thus a particular value at
which the relative suppressing and signal-
enhancing effect of the two terms cancel and the
107
sclerosis. The NMR scan reveals multiple periventricular lesions (arrows), not
abnormality would be isointense relative to the
normal tissue [73,74]. The phenomenon is illus-
trated in Fig. 15. The problem can be circumvented
by minimizing the degree of saturation, in which
case the first term in Eq. (15) vanishes, which
avoids contrast inversion.
Of course, if the relaxation times were known a
priori, the pulse sequence parameters that afford
(14) optimum contrast, could easily be computed (see,
for example, Refs. [74,75]). Unfortunately, patients
present with symptoms covering a wide variety of
pathologies and such an approach is therefore
impractical. A heuristic strategy seeking parameter
combinations that are most likely to reveal pathol-
ogy thus seemed to be more appropriate. Riederer
and co-workers suggested an alternative strategy
by what they called ‘image synthesis’ [76,77]. The
underlying idea is to optimize contrast retrospec-
tively by means of a user-interactive system consist-
ing of computation of three basis (i.e. pulse
sequence parameter independent) images, each
displaying either T,, T2 or proton density which
can be obtained from three sets of acquired images.
Once the basis images exist, images can be com-
puted retrospectively from Eq. (15) ideally in real
108 F. W. WehrlilProgress in Nuclear Magnetic Resonance Spectroscopy 28 (1995) 87-135

Fig. 15. Spin-echo images obtained from a four-echo Carr-Purcell pulse sequence at a repetition time of 1 s, corresponding to echo
s of 25,50,75 and 100 ms, as annotated. The core of the tumor in the right temporal lobe (on the left side in the image) is se:en as a
: of slight hypointensity at rE = 25 ms, while edema is nearly isointense to normal brain. As TE increases both edema and tumor
become hyperintense (from Ref. [75], with permission)

time with interactive control of TR and TE. This
approach, though appealing in principle, was
never accepted, perhaps because of the difficulty
to achieve perfect registration of the three data
sets, but also because radiologists prefer acquiring
images with different contrast characteristics in
different anatomic planes.
Obtaining pure T1, T, and p images was thought
by many to be the strategy of choice as it was
widely hypothesized that relaxation times would
be pathology-specific, as claimed by Damadian
[12]. Even if T1, T2 or proton density, separately,
did not provide sufficient discrimination, then
perhaps, it was argued by many, the combination
of the three parameters, would provide specificity.
None of these expectations have been fulfilled, in
that prolongation of relaxation times and increase
in spin density, turned out to be rather non-specific
phenomena.
In 1982 Crooks et al. introduced a general
imaging protocol which, with only small modi-
fications, became the workhorse of clinical
imaging [61,72]. It is based on the empirical find-
ing that T2 is the parameter that is most sus-
ceptible to pathologic changes. Since, except at
very low field strengths T2 < T, holds, T2 has
the potential to vary over a much greater
range (by several hundred percent), in contrast
to T1, which changes by no more than 50% in
pathologic tissue.
 F. W. WehrlijProgress in Nuclear Magnetic Resonance Spectroscopy 28 (1995) 87 135
9.3. TheJield strength debate
In 1982 Crooks et al. [61] demonstrated the
feasibility of head and whole-body imaging at
0.35 T field strength, which is more than twice the
upper limit predicted earlier based on the perceived
difficulty to tune a large diameter coil to fre-
quencies above 6 MHz (see, for example, Ref. [3],
p. 82). While the initial images (see also Ref. [72])
were not superior to those obtained by Young et al.
at 0.15 T [54,71,78,79], image quality improved
rapidly thereafter and was by many regarded as
superior to that achievable at lower field.
The critical importance attributed to SNR as
the single most significant factor limiting spatial
resolution, and the anticipation of intrinsically
higher SNR according to Eq. (12), created a strong
impetus for attempting imaging at even higher field
strengths. However, there was an additional
motivation to raise the field strength for imaging.
The conjecture that imaging and in vivo spectros-
copy would require systems operating at different
field strengths, provided a disincentive to industry
for developing in vivo medical spectroscopy (which
was much further from clinical practicality than
anatomical imaging). Clearly, if a compromise
field strength existed, that would provide sufficient
chemical shift dispersion while allowing high-
quality imaging, spectroscopy in humans could be
realized at little extra cost.
In 1982 a team of scientists at General Electric’s
Corporate Research & Development Center in
Schenectady, New York, under the direction of
Rowland Redington, set out to construct an experi-
mental whole-body NMR system, based on a 1.5 T
one-meter bore magnet, built by Oxford Instru-
ments. This system produced the first head images
and surface coil spectra the same year (see, Refs.
[40] and [SO] for details). The head images were
obtained with a slotted tube resonator r.f. coil
based on the Alderman-Grant design and the spec-
tra with a simple surface coil placed on the
anatomy of interest (Fig. 16).
GE’s stakes were high. Both anticipated
development and manufacturing cost (and thus
projected system price) would far exceed the cost
of a system operating around 0.5 T, the target field
chosen by most of GE’s competitors. The cost of
109
the magnet alone was on the order of a half million
US dollars. These magnets had tremendous stray
fields, with a 5 Gauss line (safety limit for cardiac
pacemakers) more than 10 m from the magnet cen-
ter. Many hospital sites therefore would require
magnetic shielding to be able to accommodate a
1.5 T system at all. The system would require
higher-strength gradients, and more powerful r.f.
amplifiers. Other potential hurdles were the
unknown biological effects, notably the possibility
of radiofrequency-induced tissue heating from
inductive losses, which scale as the square of the
resonance frequency. In particular, in the body, it
would be a challenge to comply with the Food and
Drug Administration’s (FDA) safety guidelines of
0.4 W kg-’ r.f. power deposition. Finally, the first
images were not of a sufficient quality to make their
clinical benefit immediately obvious. Another
argument advanced by adversaries of high-field
imaging was the predicted decreased contrast due
to the convergence of T1 as field strength increases,
as well as signal attenuation due to increased
saturation [81]. Or that, in order to keep the che-
mical shift artifact (a registration artifact resulting
from the chemical shift difference between fat and
water [82]), one would have to increase the read
gradient strength, with a concomitant increase in
bandwidth, and thus a loss in SNR [83].
None of the above arguments, some of them
aggressively defended in heated debates, such as
those at the 1984 Society of Magnetic Resonance
Annual Meeting in New York, were false. How-
ever, they did not alter the bottom-line observation
that SNR increases with field strength, even in the
large-object limit of dielectrically lossy samples (i.e.
the human body). The proof was given in a land-
mark paper by Edelstein et al. [41] who showed that
the intrinsic SNR scales linearly with field strength.
They defined the intrinsic signal-to-noise ratio q1
as the SNR per unit bandwidth measured from one
milliliter of water (in HZ-‘/~ ml-‘), as it would be
obtained from an ideal loss-less coil (i.e. the entire
noise is assumed to arise from the sample, rather
than the coil, and no losses from cables,
preamplifiers, etc. are included). Of course, in rea-
lity, there are coil and preamplifier losses. How-
ever, these can easily be measured from the
loaded and unloaded Q (QL and Qn) by inserting
 F. W. Wehrli/Progress in Nuclear Magnetic Resonance Spectroscopy 2R (1995) 87-135

(b)

-12 -8 -4 0 4 8 12 16 20
mm

Fig. 16. (a) Early 1.5T images of the head, obtained by means of a 2D spin-echo spin warp pulse sequence with a repetition time of 0.2 s
in a total scan time of 102 s. Only five of the nine images are shown. Voxel size was 1 x I x 5 mm3. (b) Phosphorus-31 from the temporal
lobe (left) and proton-coupled carbon-l 3 spectra from the thigh, obtained with the same instrument which produced the proton images
(from Ref. [40], with permission).
 F. W. WehrlilProgress in Nuclear Magnetic Resonance Specrroscopy 28 (1995) 87-135 111

y! (HEAD)
y? IAEDOYEN. 74 kG MAN)
dY *
25000 2 = 1.37 + .14 X 10’ ml-’ Hz”’ T -’ dy ’
de0
6000 - 2 = 3.7 f .4X 10’ml~’ Hz’ ’ 1 .’
r de0 l
I .

0
(4 0.00 0 25 0.50 0.75 1.00 1.25 1.50 (b) 000 o.z5 0.50 ;o ‘00 ‘z5 150
w

Fig. 17. Intrinsic SNR UT,as a function of static magnetic field strength for a linearly polarized r.f. field: (a) head: (b) abdomen (from
Ref. [41], with permission).

the subject’s head or body into the coil, as can the
preamplifier noise figure N. The intrinsic SNR
Qi for a particular tissue and loading condition
can then be obtained from the experimental SNR
Fig. 18. Acute hemorrhagic lesion in the left hemisphere of the
brain (right side in image) in 67 year old woman appears hypo-
intense due to shortened Tl, caused by diffusion of tissue water
in gradients set up by the paramagnetic deoxyhemoglobin
intact red blood cells (from Ref. [84], with permission).
Q as [41]
1@‘I20
@‘r= q (16)
(1 - QL/QE)“~
Edelstein et al. determined Qr at four field strengths
for both the head and abdomen and found them to
increase linearly (Fig. 17).
Of course, whether or not the gain in SNR with
increasing field strength is realizable, depends on a
number of factors. If, in order to keep the chemical
shift misregistration artifact (which scales linearly
with field strength), constant, on would have to
increase field gradient amplitudes linearly as well.
The resulting increase in sampling frequency band-
width then would entail a relative penalty of Bili2.
The effect of increased Ti is more difficult to quan-
tify since it is tissue dependent. For most tissues
longitudinal relaxation obeys a power law,
Ti x a@ [67], with b z 0.2-0.4, thus resulting in
a 25550% increase from 0.5 to 1.5 T.
Besides General Electric’s marketing ability and
the eventual recognition by the radiological com-
munity that enhanced SNR equates to superior
image quality, there was a clinical observation
with significant impact, which gave high-field
MRI a boost. It was the finding that at 1.5 T sub-
acute hemorrhage in T2-weighted images shows up
in as a zone of hypointensity suggesting greatly
reduced T2, a behavior opposite to the one
112 F. W. Wehrli/Progress in Nuclear Magnetic Resonance Spectroscopy 28 (1995) 87-135
exhibited by most pathologies. Gomori et al. [84]
showed that the phenomenon was due to a
relaxation mechanism previously described by
Thulborn et al. [85] for water relaxation in red
blood cells containing paramagnetic deoxyhemo-
globin (Fig. 18). The difference in magnetic sus-
ceptibility between the intra- and extracellular
environments causes strong local field gradients
that scale with field strength. Self-diffusion in
these gradients is a powerful T, relaxation
mechanism which has a square field dependence,
thus being more prominent at increased field
strength.
The question of optimum field strength for MRI
was not debated for much longer. It became clear
that the question itself was simplistic in that exact
criteria would have to be specified to define its
meaning. Is an optimum being sought for the per-
unit-time image quality in either head or body
imaging, or rather a compromise of the two?
Should the system be compatible with spectro-
scopic imaging? Or is it the break-even cost, defined
as the number of patients being scanned per day to
recover the cost, which is to be optimized? If cryo-
gen availability is a constraint this would immedi-
ately exclude field strengths above 0.3 T. As a result
of the varying boundary conditions imposed by
different economies, it is not surprising that today
a wide range of whole-body clinical instruments are
being offered, ranging in field strength from less
than0.1 Tto4T.
10. Increasing imaging speed
10.1. Extensions of spin warp imaging
We have seen that in spin warp imaging, data
space is sampled line by line, each data line being
separated in time by one pulse repetition period
TR. Hence, sampling NY rows takes the equivalent
of NYpulse repetition periods and the critical ques-
tion thus is how short TR can be chosen without
excessive signal attenuation from spin saturation.
Early critics of MRI pointed out that the tech-
nique would be inherently slower than its X-ray
counterparts. The duration of spin-lattice
relaxation times, being on the order of hundreds
of milliseconds up to seconds, appears to be a
major physical barrier to reaching data acquisition
rates anywhere comparable to those in CT. Of
course, as long as a 90”-180” spin echo is collected,
there is no easy way around this problem. At a
pulse repetition time of 0.1 s and T, x 1 s, we
would recover only 10% of the equilibrium magne-
tization. Of course, we have known since Ernst and
Anderson’s fundamental paper on pulse Fourier
NMR [86], that there is an optimal nutation
angle 0: for any value of TR/ TI , given by the relation
cos oopt = exp(- TR/ T, ). As we recall, oopt is
also the flip angle at which, in the event where
TR > T2, the signal is independent of the preces-
sion angle of the residual transverse magnetization.
The saturation problem can thus be alleviated if an
FID is collected. However, if we wish to acquire
an echo (to sample both halves of k-space), the
solution seems to be less straightforward. The
residual longitudinal magnetization following
the o pulse, of course, is inverted by the subse-
quent 180” pulse and we are therefore farther
from equilibrium than we would be if a 90”
pulse were chosen. One possibility of a low
flip-angle version of the spin warp sequence is
to reinvert the negative i&f, following the 180”
pulse by a second 180” pulse. The same effect
is achieved if an excitation flip angle
180” - c+,r, followed by a single 180” pulse, is
chosen [87]. These methods, unfortunately, were
difficult to implement because of the poor slice
profile of selective inversion pulses [26].
Reduced r.f. pulse flip angle excitation, of
course, can readily be reconciled with projection-
reconstruction imaging where an FID can be
sampled. It is also, as shown by Haase et al. [88],
compatible with the original embodiment of the
spin warp method [33] in which an echo is formed
by gradient reversal (subsequently termed ‘gradi-
ent echo’). In their paper Haase and colleagues
showed 64 x 128 and 256 x 256 images obtained
at 2.3 T in scan times of 1 and 6s respectively. In
an extension to a second phase-encoding dimen-
sion, Matthaei et al. later reported 3D images
from 1283 arrays acquired in 8 min scan time
[89]. These results clearly contradicted earlier pre-
dictions implying that 3D imaging would be
impractical [38].
 F. W. WehrlijProgress in Nuclear Magnetic Resonance Spectroscopy 28 (1995) 87-135 113

Fig. 19. Effect of pulse flip angle on contrast in gradient-echo images, obtained at a pulse repetition time of 300 ms and varying pulse flip
angle. Lowering the pulse flip angle emphasizes structures with long T, and high proton density such as grey matter and cerebrosp inal
fluid (F.W. Wehrli, unpublished).

The above work had a significant impact for
several reasons. First, it dispelled the notion that
MR imaging would be inherently slower than CT.
Second, the technique could be practiced on
standard imaging systems obviating the need for
high-speed gradients. Third, the potential benefit,
increased clinical efficiency, was immediately
obvious. Fourth, the technique provides significant
latitude as far as contrast is concerned, without the
need to alter the pulse timing parameters, merely
by adjusting the pulse flip angle. This latter aspect
is shown in Fig. 19 for a series of brain scans,
collected at constant pulse repetition and echo
time, but varying pulse flip angle. The contrast
behavior at low flip angle is predicted on the
basis of Eq. (17) which follows from the Bloch
equations for a train of r.f. pulses, assuming neg-
ligible transverse magnetization at the beginning of
each pulse sequence cycle:
1 - exp(-T,/Ti)
S(TR,a) c1: N(H)
I - cosoexp(-&/Ti) ‘lna
(17)
In Eq. (17) N(H) represents the proton spin den-
sity. It is readily seen that for o << 7r/2. the signal
becomes independent of T,, thus emphasizing
structures differing in proton density.
The FLASH technique as originally described is
subject to coherence artifacts when run under con-
ditions where T, < T2 applies. This, of course, is a
consequence of residual transverse magnetization,
Ernst and Anderson calculated the steady-state
transverse magnetization as a function of reso-
nance offset 0 = AwTn [86]. In the rotating frame
the resonance offset is a function of the gradient
amplitude (AU = yGiri) with i = x,y,z. This is
 F. W. WehrlijProgress in Nuclear Magnetic Resonance Spectroscopy 28 (1995) 87-135
0 I
0 10 20 30
R2' (Ilsec)
Fig. 20. Young’s modulus of elasticity obtained from compres-
sion of human lumbar vertebrae in inferior-superior direction,
plotted as a function of R;, the contribution to the effective
transverse relaxation rate of the water protons in the inter-
trabecular spaces (from Ref. [103], with permission).
not detrimental as long as the gradients are
constant from cycle to cycle. However, the phase-
encoding gradient is incremented and thus the pre-
cession angle varies as well. The solution to the
problem was found to be a phase-unwinding gra-
dient applied at the end of the pulse sequence cycle
[90]. This variant of the generic FLASH pulse
sequence has been denoted GRASS (gradient-
recalled acquisition in the steady state) or FISP
(fast imaging with steady-state precession).
In addition to its obvious benefits, gradient-echo
imaging led to a number of new applications, which
include the study of dynamic processes [91], such as
the passage of a bolus of contrast material through
liver and kidneys [92]. A particularly powerful
application of gradient-echo imaging is what
became known as cardiac ‘tine’ imaging [93] which
permits acquisition of images of the heart at multi-
ple cardiac phases. When a series of images pertain-
ing to successive cardiac phases are displayed
sequentially, a movie of the beating heart is obtained
(for a review of the subject, see Glover and Pelt
[94]). Applications of the technique include the
quantification of cardiac function involving the
measurements of ventricular ejection fraction [95,96].
As previously pointed out, the signal in FLASH
and its derivatives is sensitive to magnetic field
inhomogeneity. Any intrinsic gradients such as
those originating from local variations in magnetic
susceptibility, cause an imbalance in the gradient
moments which leads to local signal loss. While
such effects can be detrimental, there are clinical
situations where gradients are caused by pathology.
We have already seen that hemorrhage constitutes
such a case. Gradient echo imaging thus was found
to be exquisitely sensitive to small hemorrhagic
lesions [97,98]. Similarly, calcification causes a
local perturbation in the magnetic field, presum-
ably because calcium phosphate is more diamag-
netic than normal tissue [99]. The latter finding is
particularly revealing since MRI, during the early
stages of clinical evaluation, was alleged to be
unable to detect calcium (while CT, of course, is
extremely sensitive to calcium). Another promising
application is quantitative imaging of trabecular
bone density [lOO,lOl] for the diagnosis of osteo-
porosis [ 1021. Very recently, Chung et al. [ 1031
showed that the induced magnetic fields resulting
from the greater diamagnetic susceptibility of bone
cause line broadening of the protons in the bone
marrow cavities. Further, the line broadening, Ri,
was found to scale with Young’s modulus for com-
pressive loading, thus providing a means of asses-
sing the elastic properties of bones (Fig. 20).
The ultimate scan speed achievable with FLASH
and its derivatives is determined by the gradients’
amplitude, slew rates and duty cycle, and the data
sampling frequency. Collecting a partial, rather
than the full echo, further shortens the pulse
sequence cycle duration, but of course, entails a
SNR penalty. In this manner, TR can be reduced
to 5 ms, or so, resulting in scan times of less than 1 s
for a 128 x 128 data array [104]. Rather than oper-
ating in a steady-state mode, the pulse sequence can
be preceded by a preparation pulse such as an
inversion pulse [ 104,105] or a DEFT preparation
cycle [ 1061.For a review of the principles and appli-
cations of gradient-echo imaging techniques the
reader is referred to a recent review by Haacke
et al. [107] and a text by Wehrli [108].
10.2 Multi-line scanning techniques
Potentially much higher scan rates can be
attained by methods in which the magnetization
 F. W. WehrliJProgress in Nuclear Magnetic Resonance Spectroscopy 28 (1995) 87-135 115

is recalled in the form of repeated echoes which are

individually encoded. This is what underlies
Mansfield’s idea of collecting a train of recalled
Phase echoes by periodically reversing a gradient, say
Encoding
G,, in the presence of a second constant gradient
GY [34,109]. In this manner, it was shown that the
entire encoding process could be completed during
b- Npx NfSamples -4
a single FID. It is readily seen that Mansfield’s
original approach consists of traversing half of
k-space in a zig-zag trajectory. The difficulties in
reconstructing images, from only half of the data
and non-orthogonal sampling grids were remedied
with the introduction of pre-encoding gradients
and discontinuous phase-encoding [ 1 10,l 111.
Figs. 21(a) and 21(b) illustrate the two different
approaches of scanning k-space.
* In addition, Pykett and Rzedzian inserted a 180”
phase reversal pulse such that the center of k-space
(a)
is scanned at the location of the spin echo. With
this significant modification, which they dubbed
‘instascan’, they succeeded in obtaining entire
images of 64 x 128 data arrays of the heart and
abdomen in as little as 50 ms at 2 T field strength
[1 11,112] (Fig. 22). For an in-depth discussion of
Phase
the subject the reader should consult the recent
Encoding u-“-- l ==‘=‘= - review by Cohen and Weisskoff [113].
An interesting corollary of single-shot EPI is that
the pulse repetition time loses its meaning since the
data are collected in a single sequence cycle. The
k spin system is in equilibrium and image contrast
f thus has no Ti dependence. Further, since the sig-
nal is derived from the full magnetization, weighted

----l--
only by e- TE’TZ,the SNR is higher than in a high-
speed gradient echo. On the other hand, repeated
acquisitions for the purpose of generating movies,
underlay the same restrictions as the conventional
,
, FLASH method, demanding adjustment of the r.f.
/
, flip angle to control saturation. Cohen and
, (
I 1 Weisskoff showed 16-frame cardiac movies obtained
/
Y I by acquiring complete images every 67 ms within a
(b)
single heart beat [113]. Unlike gated techniques
Fig. 21. (a) Mansfield’s original EPI approach: the read or fre- where each image data set, or fraction thereof, is
quency-encoding gradient is oscillated in the presence of a con- collected during consecutive heart beats, the
stant orthogonal gradient (‘phase-encoding’), top, resulting in a method is insensitive to variations in heart rate.
zig-zag trajectory across half of k-space. (b) By discretizing the
In contrast to the high-speed FLASH-type
phase-encoding gradient in the form of brief ‘blips’ and negative
pre-encoding gradients, both halves of k-space are scanned in a method, however, echoplanar imaging puts far
rectilinear fashion, thus permitting Fourier processing of the more stringent demands on instrumentation, in
raw data as in spin warp imaging. particular to amplitudes and slew rates of the
11 F. W. WehrlijProgress in Nuclear Magnetic Resonance Spectroscopy 28 (1995) 87 13s

(a

Fig. 22. Array of images obtained by the single-shot instascan technique from 16 different levels of the abdomen at 2 T field strength.
The total data acquisition for each 64 x 128 image was 40 ms. The voxel size was 0.06 cm3 and the SNR for muscle about 30 : 1. (a) Pulse
repetition time Ta = infinity; (b) Tn = 0.9 s. Echo times (left to right: 30,48,66 and 84 ms). Increased SNR and contrast in the images of
(a) are evident (from Ref. [ill], with permission).

gradients. Some of these conditions are relaxed if
only a fraction of k-space is scanned from a single
echo train, e.g. by interleaving multiple trajectories,
which are combined prior to reconstruction
[114,115].
In 1986 Hennig introduced the spin-echo coun-
terpart of EPI [I 16,117], initiating a development
which would have a significant impact on clinical
imaging, though the work did not elicit broad
interest initially. The perception that the images
emphasized structures with long T,, thereby
producing significantly T2-weighted images,
prompted Hennig to dub his technique “RARE”,
(rapid acquisition with relaxation enhancement).
Early RARE images from Hennig and colleagues’
original work are shown in Fig. 23.
Besides scan time reduction by up to an order of
magnitude, one of RARE’s salient features is its
insensitivity to magnetic field inhomogeneities
since spin echoes rather than gradient echoes are
collected. Equally important, however, as Hennig
and colleagues showed, is the almost unlimited
latitude in image contrast offered by the technique.
The latter is possible if the method is implemented
in a hybrid mode with only a fraction of k-space
covered per echo train. By appropriately assigning
the echoes to the low spatial frequency signals
(which contain most of the signal energy) Melki
and coworkers [ 118,119] demonstrated that
virtually any arbitrary contrast is possible. For
example, phase-encoding early echoes with low
gradient moments, de-emphasizes T2 weighting.
Hennig showed that the per-unit-time SNR can
be up to a factor of 100 higher in single-shot
RARE, which again emphasizes what we have
seen for EPI, i.e. that increased scan speed does
not inevitably penalize SNR. Therefore, the
improved efficiency can be traded for improved
resolution (by a factor of four in linear resolution)
without adversely affecting SBR when compared to
single-line spin-echo imaging. Further, it enables
3D imaging with all its benefits such as retrospec-
tive data rearrangement with image display in
secondary planes, which hitherto was impractical
due to excessive scan time. Finally, it has also been
shown that RARE and EPI principles can be com-
bined in such a manner that gradient echoes are
interleaved into a spin-echo train [120,121] thus
further augmenting efficiency.
An alternative k-space scanning technique
 F. W. WehrlijProgress in Nuclear Magnetic Resonance Specfroscopy 28 (1995) 87-135 117

(b)

Fig. 23. RARE images from Hennig and co-workers’ 1986 work: (a) single-excitation image obtained by individually phase-encoding a
train of 256 echoes, showing essentially only structures with long Tl (brain tumor and cerebrospinal fluid). (b) RARE image obtained
from 16 trains of 16 echoes each. Due to the reduced echo train length structures with shorter T? such as the brain parenchyma become
more prominent (from Ref. [I 161, with permission).

which, like EPI uses oscillating gradients, is spiral Spiral scans require different reconstruction
scanning. As implied by the term, the k-space algorithms. Fourier transformation along the
trajectory in this case is a spiral originating at the radial coordinate affords a series of projections
k-space center. In 1986 Ahn et al. [122] reported the from which the image is obtained by filtered back
first spiral scan images while most of the more projection [122]. Alternatively, the data can be
recent work has been carried out in the Electrical rearranged into a rectilinear grid by interpolation,
Engineering Department at Stanford University, making it amenable to Fourier reconstruction
by Macovski and colleagues. They use constant- [123]. -
velocity interleaved k-space spirals (as opposed to We have thus seen that during the past two
constant angular frequency) [123], which has the decades since its inception, a wide spectrum of
advantage that k-space is covered more uniformly technical approaches has evolved for scanning
and that the amplitude of the oscillating gradients data space and optimizing data acquisition
is constant. Compared to EPI the gradient ampli- efficiency. We find that scan speed is a continuum
tude and slew rate requirements in spiral scanning ranging from milliseconds to minutes with trade-
are less demanding and the technique has been found offs between temporal resolution, SNR and spatial
to be tolerant to flow-related dephasing. The latter resolution. The rate at which k-space can be
observation has been attributed to the low gradient scanned is significantly determined by the available
moments near the k-space center and the periodic hardware, in particular the achievable amplitudes
simultaneous return to zero of all moments [123]. of the spatial encoding gradients and their
118 F. W. WehrlijProgress in Nuclear Magnetic Resonance Spectroscopy 28 (1995) 87-135
switching rates, and the bandwidth of the receiver.
Besides intrinsic SNR, the ultimate scan speed may
be limited by potentially harmful bioeffects,
notably peripheral nerve stimulation caused at
increased dB/dt of the switched gradients [ 1241.
11. Imaging of blood flow, organ perfusion and
neurologic function
We shall now turn to another development in
MRI with very significant clinical benefit: imag-
ing of the vascular system and quantification of
blood flow. The study of fluid motion by NMR
began well before imaging and, in fact, is almost
as old as NMR in condensed phase itself.
Suryan, in 1951, noted that the signal from
spins in a fluid flowing through a coil first
increased as the fluid velocity increased and sub-
sequently decreased [125]. The increase was
attributed to replacement of partly saturated by
fully polarized spins. Much of the early work on
blood flow by means of NMR is owed to Singer
who devised the method of radiofrequency
demagnetization tagging and performed the first
blood flow measurements in a living system
[126]. In the 1970s Battocletti and coworkers
conceived a real-time limb flow meter [127,128].
In the preferred embodiment the protons are
polarized in a large enough magnet encompass-
ing the entire limb. The spins are excited and
detected in the continuous-wave mode at the
site of measurement. During slow diastolic flow
the signal is reduced due to saturation whereas
during fast systolic flow there is sufficient inflow
of unsaturated magnetized spins to give rise to
enhancement. Using such a device, flow rates
were measured in human subjects, including
patients with peripheral vascular disease [ 1291.
An entirely different manifestation of moving
spins is their effect on spin phase. In their classic
paper Carr and Purcell found the echo amplitude
obtained from a train of 180” r.f. pulses attenuated
on odd-numbered echoes in the presence of con-
vection currents [7]. They predicted that spins
moving along a gradient magnetic field G with
constant velocity ~1, when subjected to a 90”
(--7-180°--7), pulse train, refocus on alternate
(even) echoes. This result can readily be verified
by evaluating the phase integral at the time of the
nth echo, with n = 2,4,6, . . . , and assuming that
x(t) = vt holds.
2nr
4(x) = 71; Gx(t)dt = yGv tdt (18)
J0
Singer studied the effect of unidirectional motion in
the presence of magnetic field gradients [130] and
Hemminga and D. Jager used this technique to
measure flow in capillaries [131].
All of the above work preceded imaging. Pre-
sumably the first documented observation of a
time-of-flight flow effect in an NMR image is
found in the work by Hinshaw et al. [49] who
observed signal enhancement for the vessels in the
wrist. Crooks et al. [72,132] described the enhance-
ment for slowly flowing blood orthogonal to the
slice arising from inflow of unsaturated spins.
They found the effect to be absent for fast flow,
an observation which they attributed to the
increasing fraction of spins entering the slice during
the defocusing period (time between the 90” and
180” pulses). An early illustration of vascular signal
enhancement in spin-echo spin warp images of the
superior sagittal sinus (a large vein at the surface of
the brain along the head’s midline) is found in
Ref. [72]. Manifestations of the ‘even-echo rephas-
ing’ effect, as Carr and Purcell’s observation later
was called, were reported in modulus MR images
[133,134] for blood flow occurring along the read
gradient. Of course, as shown by Wehrli et al. [ 1331
a reduction in the pixel signal intensities is possible
only if there is a distribution of velocities such as in
the case of laminar flow, which leads to destructive
interference of the spin isochromats.
I I .l. MR angiography and quantitative flow imagitig
While NMR’s potential for non-invasive assess-
ment of blood flow dynamics was recognized early,
it is clearly not practical without some form of
image-based localization. In 1982 Moran [135]
proposed an experiment capable of producing
images providing both spatial and dynamic infor-
mation. His idea was to encode velocity in a man-
ner analogous to spatial phase-encoding. It can
readily be shown that a bipolar balanced gradient
 F. W. Wehr1iJProgre.u in Nuclear Magnetic Resonance Spectroscopy 28 (1995) 87-135
(i.e. a gradient which consists of two lobes of equal
area but opposite polarity) encodes for velocity
whilst, as we have seen previously, does not impart
phase shifts on stationary spins. It is easy to show
that such a gradient pair induces a phase shift
$ = yvAT where A = 1 G(t)dt is the time integral
of each gradient lobe, T the time difference between
the two lobes, and TJthe spins’ velocity in the direc-
tion of the field gradient. Stepping this gradient
analogous to the spatial phase-encoding gradient
yields, after Fourier transformation, a spectrum
of velocities. Of course, encoding in all three spatial
directions for both spatial spin density and velo-
city, would require a six-dimensional data set,
which would demand excessive scan time and
thus is impractical. However, the dimensionality
can be reduced, for example, to one spatial and
one velocity dimension, as shown by Redpath et
al. in a phantom [136] and in vivo by Feinberg
and Mark [137] who applied the technique to the
measurement of cerebrospinal fluid dynamics, and
later by Hennig et al. [ 1381and Merboldt et al. [ 1391
who measured blood flow in the vessels of the neck.
The motion-induced spin dephasing phenom-
enon is the basis of the first angiographic images
reported in 1985 [140]. The idea underlying the
technique of Wedeen et al. 11401 was to produce
two sets of image data, with one set gated to sys-
tole, and the second set to diastole. During the
diastolic phase, arterial flow velocities are low
with a relatively narrow distribution. Hence the
isochromats within a volume element maintain
their phase coherence. By contrast, during systole
the velocities are much higher and the distribution
wider, leading, according to Eq. (18) to greater
phase dispersion and thus attenuation of the vas-
cular signal. Since the phase of stationary protons
is not dependent on the cardiac phase, subtraction
of the two data sets will lead to cancellation of the
stationary background while highiighting the sig-
nal from arterial water (Fig. 24).
Instead of exploiting phase shifts caused by the
imaging gradients (the readout gradient in the
above technique), better control of the induced
phase shifts is achieved by resorting to velocity-
encoding gradients, for example, by subjecting
the spins to bipolar balanced gradients which affect
the phase of moving spins only, akin to the method
119
proposed by Moran [135]. However, rather than
stepping this gradient, it is held constant. Pairs of
data, obtained with and without a motion sensitiz-
ing gradient, can be processed to afford a phase
difference which is proportional to blood flow
velocity, as shown by Bryant et al. [141], Nayler
et al. [93], and also O’Donnell [142]. A significant
improvement was the introduction of gradient
waveforms which compensate for phase shifts
caused by constant-velocity flow [93,143,144]. It
can readily be seen from the integral of Eq. [lS]
that for a gradient of three lobes such as shown
in Fig. 25(a) the phase is exactly nulled for spins
moving at constant velocity in the direction of the
gradient, provided that the three lobes have an area
ratio of 1 : 2 : 1 and the middle lobe has opposite
polarity. If, on the other hand, the third lobe is
offset by a time increment A, a phase shift propor-
tional to velocity and A is produced. A phase dif-
ference image can then be displayed with zero
phase shift in intermediate grey, and positive and
negative phase shifts (corresponding to forward
and reverse flow) in brighter and darker shades of
grey, respectively. Fig. 25 illustrates the phase con-
trast flow imaging method by Nayler et al. [93],
together with images processed to display magni-
tude and phase difference. From the latter, velocity
and flow rates during the cardiac cycle can be eval-
uated (Fig. 25(d)). A more efficient encoding strat-
egy entails acquisition of two data sets which are
both velocity encoded by means of bipolar gradi-
ents with reversed polarity. These techniques
permit measurement of flow velocities and volume
flow as a function of cardiac phase and have been
discussed in detail by Pelt et al. [ 1451and by Firmin
et al. [146].
The concept of bipolar flow-sensitizing gradients
is the basis of phase contrast angiography. a tech-
nique generally attributed to Dumoulin and
coworkers [147,148]. Just as in quantitative flow
velocimetry, the flow-encoding gradients are
applied in pairs for each k-space line k,, with
alternately reversed polarity. Complex subtraction
of the two data sets then yields an image in which
signal from moving spins, proportional to sin $, is
retained, while all other signals cancel. Since flow is
multidirectional. encoding has to occur in all three
spatial directions. By suitably combining the data,
120 F. W. WehrlilProgress in Nuclear Magnetic Resonance Specrroscopy 28 (1995) 87-135

Fig. 24. A, During diastole flow velocities are low and the dis-
tribution is small. In the presence of a gradient, such as the
readout gradient, applied parallel to the direction of flow,
phase coherence is maintained. By contrast, during systole,
flow velocities are higher, resulting in a broader distribution
and thus loss of phase coherence. B and C, Projection spin-
echo images acquired during systole (B) and diastole (C); D,
difference C - B (images, courtesy Dr Van Wedeen, with
permission).

between successive excitations. This technique

does not require special flow-encoding gradients
and can, in principle, be practiced with ordinary
spin warp gradient-echo imaging. Gullberg et al.
[149] first showed that by reprojecting a set of
contiguous gradient-echo images acquired such
that flow is essentially perpendicular to the
plane of section, an angiographic image can be
obtained. By presaturating the water in venous
blood (which typically flows in a direction oppo-
site to that of arterial blood) arterial and venous
flow can be distinguished. By means of a ray
tracing algorithm [ 1501 which retains the highest
signal the projection rays hit while traversing the
a set of tomographic vascular images is obtained imaging volume, Keller et al. obtained arterio-
which can be reprojected to yield a projection grams of the vessels of the neck [151]. Other
angiogram analogous to X-ray contrast angiography. versions of the technique whereby instead of a
Another class of angiographic imaging tech- stack of 2D images a 3D volume is collected, are
niques exploits the earlier mentioned time-of-flight being practiced as well [152,153]. For a compre-
effect, i.e. the inflow of fully polarized spins hensive discussion of blood flow imaging, the
F. W. WehrlijProgress in Nuclear Magnetic Resonance Spectroscop_v 28 (1995) 87-135

0 200 Go ’ -6M
1-X’

(4
Time Imsec)

Fig. 25. Principle of the phase difference flow measurement

technique by Nayler et al. [93], illustrated for measuring flow
perpendicular to the plane of section. (a) A slice-selection gra-
dient which produces zero phase shift in the presence of constant
velocity flow (solid line). By offsetting the third lobe by a time
increment A (shaded line), the phase from spins Rowing with
velocity 11 in the direction of the gradient will be shifted by
4 = QUA J G(f)dt. (b) Magnitude image showing major vessels
in the chest; (c) phase difference images obtained from the same
data. Static material is displayed in intermediate gray, flow in
cranial direction is black, flow toward the feet white. Flow is
seen in the ascending aorta (AA), descending aorta (DA), pul-
monary artery (PA), and superior vena cava (WC). (d) Plots of
volume Row rate for the vessels depicted in (b) and (c). as a
function of cardiac phase. (Parts (b)-(d) from Ref. [93], with
permission.)

interested reader may consult the recent text by

Potchen et al. [154].

11.2. Imaging of tissue perfusion

Of perhaps even greater significance than bulk

flow rates is the assessment of regional blood flow
by microcirculation, also denoted ‘perfusion’
which is associated with energy metabolism.
Positron emission tomography (PET) and single
photon emission tomography (SPECT) have been
the classic modalities for image-based perfusion
measurements. Since both use ionizing radiation
and suffer from relatively poor resolution, MRI
was soon recognized as potentially superior. Simi-
lar to SPECT and PET, most MRI perfusion
measurements are based on exogenously adminis-
tered tracers, typically relaxation agents and rest
on the premise that the differential relaxation rate
AR,,1is proportional to the concentration of the
122 F. W. WehrlilProgress in Nuclear Magnetic Resonance Spectroscopy 28 (1995) 87-135
(4
o+
10 20 30
@I ’ SECONDS
Fig. 26. (a) Sixteen sequential gradient echo-planar images of
canine brain, sampled at l-s intervals during bolus contrast
injection of 0.2 mM kg-’ DY(DTPA)~-. The images show the
time course of the transit of the contrast, manifesting in a tran-
sient reduction in signal intensity due to spin dephasing caused
by the paramagnetic susceptibility of the agent in the intravas-
cular compartment. (b) Signal vs. time curve from regions of
interest pertaining to white and grey matter (from Ref. [212],
with permission).
agent (for a review of the subject, see, for example
Ref. [ 1551).
Of particular interest are relaxation agents which
affect T;. Due to its paramagnetic susceptibility,
an agent such as gadolinium or dysprosium-III
chelate (e.g. gadolinium diethylenetriammine-
penta-acetate, Gd-DTPA), when injected into the
blood stream, induces an inhomogeneous magnetic
field which is a function of the shape of the com-
partment (see, for example, Ref. [156]). Villringer
et al. [157] first showed that confinement of the
susceptibility agent to the capillaries, which in the
brain is the case due to the blood-brain barrier,
causes an inhomogeneous field in the vicinity of
the capillaries and thus shortened T;. Since the
induced field gradients extend well beyond the
capillaries, the spins in the entire brain parenchyma
sense the inhomogeneous field as the bolus transits
the capillary bed. We have seen previously that a
pulse sequence involving a gradient echo is sensi-
tive to magnetic field inhomogeneity. Hence, as the
bolus passes the pixel signal intensity first decreases
and increases thereafter. With the bolus transit
time being on the order of 10 s, mapping of the
signal pixel by pixel requires high temporal resolu-
tion which can be achieved with techniques such as
EPI. From the integral of the signal vs. time curve
the relative blood volume can be determined
[155,158]. Fig. 26 shows an array of images
obtained following administration of a bolus of
contrast material, along with signal intensity-
time curves. The larger area obtained from a grey
matter region is consistent with a capillary volume
which is greater in grey than in white matter.
Other ,approaches not relying on externally
administered tracers have been reported as well.
t Williams et al. [159] reported a technique whereby
they labeled arterial spins in a slice of tissue proxi-
mal to the slice of interest by means of an inversion
or saturation pulse. Inflow of partially saturated
arterial water causes a small reduction in signal
amplitude which depends on blood flow, the appar-
ent relaxation rate in the presence of saturation or
inversion, l/T,,,,,, and the brain-blood partition
coefficient. By means of this technique perfusion
maps were obtained in the brain of small animals
at high field. While the technique has been shown
to afford quantitative results, it requires high SNR
since the differential signal is obtained from arterial
water only, which accounts for less than 5% of all
spins present.
Another endogenous tracer is deoyhemoglobin
which, as we have seen earlier, plays a critical
role in the diagnosis of hemorrhage. Analogous
to a paramagnetic tracer, deoxyhemoglobin in
 F. W. WehrlijProgress in Nuclear Magnetic Resonance Spectroscopy 28 (1995) 87-135
Motor Response Time
stim rest
rest
I I
2010-1
0 64 128
Seconds
Fig. 27. A, Activation of motor cortex obtained by subtracting
two gradient-echo images recorded with and without contra-
lateral hand squeezing. B, Temporal response obtained by plot-
ting region-of-interest signal changes in images acquired at a
rate of 0.5 SC’ (from Ref. [213], with permission).
venules, by virtue of its paramagnetic susceptibility
and confinement in the capillaries, induces a small
inhomogeneous field near the boundaries of the
capillaries. Ogawa showed that the gradient-echo
signal intensity in the brain is dependent on the
blood oxygen level and denoted this form of con-
trast ‘blood oxygen level dependent’ or BOLD
[ 1601.At high oxygenation level hemoglobin is pre-
dominantly in its diamagnetic oxy state and thus
the magnetic susceptibility inside and outside the
capillaries is the same. On the other hand, in its
paramagnetic deoxy state, the difference in volume
susceptibility, Ax, is sufficient to produce a field
shift [85]. For a cylindrical capillary of radius a,
oriented perpendicular to the magnetic field, the
induced field AH/H, outside the capillary is
given by
AH/H,, = 27rAx(~/r)~(2cos~ 0 - 1)
where r( 2 a) is the radial distance and 0 is the angle
123
of the position vector r relative to the direction of
the applied magnetic field. The induced field is thus
inhomogeneous and causes a dispersion of the
phase of the spin isochromats, analogous to the
effect of an exogenous paramagnetic agent such
as a lanthanide chelate, discussed above.
The discovery of the BOLD effect represents a
major biophysical milestone providing the basis of
functional brain imaging. Ogawa et al. [ 1611found
Course that BOLD contrast could be altered by physiolo-
gic challenges which alter blood flow. By means of
stim
gradient echoplanar imaging, Turner et ai. [162]
showed that oxygenation in the cat brain can be
monitored on the basis of the BOLD effect.
In 1991 Belliveau et al. [ 1631 reported the first
detection of the response to a change in cognitive
state by MRI. Specifically, they produced blood
volume maps in the manner described earlier, i.e.
by administering a bolus of Gd(DTPA) and
I recording the signal-time curve. By calculating
I
192 256 the difference between sets of images taken with
and without visual stimulus, they found up to
24% increase in blood volume in the visual cortex.
Shortly thereafter, three research groups reported
task activation in the human brain on the basis of
the BOLD effect [ 164- 1661in the visual and motor
cortex. The pattern observed in consistent and has
since been corroborated in at least 100 labora-
tories: an increase in parenchymal signal intensity
in the pertinent cortical areas during stimulation.
At 1.5 T the signal increase in gradient-echo images
is on the order of 2-5%, but can be considerably
larger at higher field [167,168]. The effect has been
ascribed to an increase in blood flow and thus
replacement of venous by oxygenated blood. Func-
tional maps of brain activity may then be produced
by subtracting image data from one another, taken
in the presence and absence of a stimulus and
superimposing the difference data onto higher-
resolution anatomic images, though more sophisti-
cated processing strategies have been reported as
well [169]. Fig. 27 illustrates the effect of cortical
activation and the time course of the observed
signal changes.
11.3. D$fusion and magnetization transfer contrast
(19)
We have seen earlier that the NMR image
124 F. W. WehrlilProgress in Nuclear Magnetic Resonance Spectroscopy 28 (1995) 87-135

Fig. 28. 2 T images of cat brain, 1 h following stroke induced by occlusion of the middle cerebral artery: (a) Tz weighted image (no
diffusion weighting, b = 0); (b) same pulse sequence parameters as (a), but with diffusion weighting, b = 1.413 s mm-*; (c) calculated
diffusion image, from (a) and ib) (from M.E. Moseley, Ref. [214], p 24, with permission).

typically is a map of spin density modulated by the
relaxation parameters and, possibly, the chemical
shift of the particular chemical species selected.
While in relaxation-weighted images the signal
amplitude is sensitive to rotational diffusion,
Le Bihan et al. [170] first showed that images can
be obtained in which the signal is modulated by
translational diffusion. For this purpose, they
incorporated a pair of balanced gradients sym-
metrically disposed on either side of a 180” phase
reversal pulse into the conventional spin warp
imaging sequence, analogous to the Stejskal-
Tanner pulsed field gradient experiment [171]. Of
course, in the absence of molecular displacements,
the phase at the time of the echo is nulled. How-
ever, in the presence of random motion, phase dis-
persion occurs, with a concomitant attentuation of
the transverse magnetization. For a pair of diffu-
sion sensitizing gradients of duration S, separated
by A milliseconds, the transverse magnetization, in
the presence of a gradient G, is given by
MXY= M&exp[-y2G2DS2(A - S/3) -t TE/T2]
(20)
the term b = y2G2b2(A - S/3) is called the gradi-
ent factor and its exact form depends on the nature
of the diffusion sensitizing gradient. It is thus
readily recognized from Eq. (20) that by varying
6, the diffusion coefficient can be evaluated pixel
by pixel as the slope of ln(M,YY)vs. b.
The technique as described is laborious as it
requires collection of a multitude of images.
More importantly, however, the images are sensi-
tive to bulk motion resulting from physiologic
motion such as pulsatile blood flow, cerebrospinal
fluid motion and involuntary patient motion. Suffi-
cient diffusion sensitivity requires either large
gradients, not until recently available on whole-
body imagers, or large A values and thus
intolerable T2 signal losses. Dedicated high-power
gradient inserts and the incorporation of the diffu-
sion gradients into an echoplanar readout scheme
remedied both problems [ 1721.
An interesting though not unexpected finding
was the observation of anisotropic diffusion in tis-
sues. In neural white matter, Moseley et al. found
the diffusion coefficients to be reduced for myelin
fiber tracts oriented perpendicular to the diffusion
sensitizing gradients [173]. A finding of substantial
clinical importance reported by the same group
of researchers [ 174,175], showed that diffusion-
weighted images are sensitive to brain ischemia,
in that the ischemic territory exhibits reduced
diffusivity, a phenonemon usually attributed to
cellular swelling and thus reduced extracellular
volume. The technique thus offers a new diagnostic
tool for evaluating early stroke (Fig. 28).
Another more recently discovered contrast
mechanism with clinical potential is magnetization
transfer (MT) imaging [64,176]. Wolff and Balaban
[64] showed that irradiation off-resonance from the
tissue water protons causes a signal reduction.
They postulated the effect to arise from cross
 F. W. WehrlilProgress in Nuclear Magnetic Resonance Spectroscopy .?H (1995) X7-135 125

relaxation, i.e. a dipolar interaction with protons early work by Richards and Moon [ 1801 who first
bound to macromolecules (e.g. proteins). Such an reported high-resolution 3’P NMR spectra of
effect was previously described by Edzes and intact red blood cells in which the various phos-
Samulski for hydrated collagen and muscle [18] phorus metabolites could be identified. The idea
and Koenig et al. for protein solutions [177]. The of sampling signal from a small volume of tissue
saturation of the protons in the macromolecular by means of what became the surface coil [ 1811
matrix is carried over to the observable protons made spectroscopic NMR in live animals and ulti-
via chemical exchange and other processes such mately humans possible. Britton Chance at the
as spin diffusion. The concomitant signal attenua- University of Pennsylvania and George Radda at
tion is tissue-specific and is typically expressed in Oxford University used 3’P NMR extensively to
terms of the magnetization transfer ratio study cellular metabolism in vivo. Much of the
r = (1 - 1,/Z,), where Z, and I,, represent the signal work reported during the first decade of in vivo
measured with and without off-resonance irradia- spectroscopy is summarized in a review article by
tion. Since the efficiency of cross relaxation Bottomley [182].
increases with increasing correlation time of the The field of in vivo NMR is so vast that even a
cross-relaxing species (decreased rate for reorienta- cursory coverage of its history is not within the
tional motion), the MT ratio parallels this behavior. intended scope of this article. I will, however,
MT images are typically generated by either attempt, to briefly delineate the major technologi-
continuous-wave [64] or pulsed [ 1781 irradiation cal milestones that led to the current state of art of
off resonance. The interpretation of contrast in metabolic MRI. Much of the early work is dis-
MT images is complicated in that intensity varia- cussed in a text by Gadian [ 1831. For a more recent
tions may represent differences in exchange rates as discussion of the subject, the reader may consult
well as relaxation times and proton densities. The the recent treatise by Gillies [184].
development of models for a detailed quantitative It was recognized early that in order to be prac-
understanding of the MT effect in tissues is a field tical, some form of spatial localization would be
of intense current research. The clinical applica- needed. The conceptionally simplest approach is
tions of MT imaging have recently been reviewed based on the distance-dependent sensitivity profile
by Baiaban and Ceckler [ 1791. of surface coils, first described by Ackerman et al.
[ 18 I]. Other related approaches not requiring static
spatial encoding gradients make use of the spatial
12. Localized spectroscopy and spectroscopic dependence of the flip angle in the presence of a B,
imaging gradient produced by a surface coil, exploiting the
previously discussed rotating frame zeugmato-
In vivo spectroscopy was for a long time graphy principle [32]. Garwood et al. [185] applied
regarded as a discipline separate from imaging this method as a means of obtaining localized
and the development of the technology thus spectra of “‘P metabolites.
initially proceeded on parallel paths and there An early localization scheme utilizing magnetic
was little communication between in vivo spectro- field gradients is described by Gordon et al. [I861
scopists and the medical imaging community. In who showed that by shaping the field with a non-
good part this separate evolution is cultural in linear gradient of cylindrical symmetry, a relatively
origin. In vivo spectroscopy, now referred to by homogeneous spot along the axis of a supercon-
the acronym MRS (magnetic resonance spectro- ducting magnetic is produced. While straight-
scopy, in distinction to MRI) is a tool for probing forward to implement, the major shortcoming of
cellular metabolism, rather than morphology. It is this approach is that the hot spot is not easily
thus understandable that MRS initially had more movable. More advanced techniques, suited to
appeal to the biochemist and physiologist than to select a volume at arbitrary location on the basis
the traditional user of imaging, the radiologist. of an anatomic image-based prescription, rely on
Spectroscopy of living systems dates back to the linear imaging gradients. The first among these is
Fig. 29. Multislice proton spectroscopic images of the normal brain. The images labeled GRASS, NAA, Cr and Cho correspond to the
bulk proton image (obtained by a gradient echo imaging technique,
resonance signal amplitudes from N-acetyl aspartate, creatine and choline, respectively (from Ref. [i94], with permission).
‘depth-resolved surface coil spectroscopy’ (DRESS)
which uses slice selection in the presence of a linear
gradient analogous to 2D imaging. Other, more
elaborate approaches seek selection of a parallele-
piped-shaped volume [ 1871; ‘point-resolved spec-
troscopy’ (PRESS) [188] and ‘stimulated echo
acquisition’ (STEAM) [189]. The principle of the
latter two approaches is to generate an echo from
three spatially selective r.f. pulses, each adminis-
tered in the presence of a slice-selective gradient
applied in one of the three orthogonal planes. Var-
iants of these techniques are currently practiced,
often in conjunction with water and lipid suppres-
sion as well as some form of spectral editing.
Inherent to the single-voxel localized spectro-
scopy experiment is its relative inefficiency since
data are gathered from a fraction of the total tissue
volume only. A radically different approach is
based on the principles of spin warp imaging, i.e.
by encoding spatial information into the phase of
the r.f. signal by modulating the static field. In this
manner it was shown that chemically shifted
species can be imaged. Instead of reading the signal
in the presence of a frequency-encoding gradient
(which would provide additional frequency dis-
persion), it is collected in the absence of any gra-
dient [190-1921. The result, following Fourier
transformation along the three time coordinates,
are anatomic maps of spatial spin density as a func-
tion of chemical shift, i.e. images of individual
metabolites. Alternatively, entire spectra from
individual voxels may be displayed [193]. Fig. 29
shows recently published proton images of specific
metabolites in the human brain [194].
referred to as ‘GRASS’), and images displaying the methyl
The most commonly used nuclei for probing
cellular metabolism in vivo are ‘H, 3’P and 13C.
Metabolic constituents amenable to proton spec-
troscopy are N-acetyl aspartate, which has been
invoked as a marker of neuronal integrity, choline,
creatine, glutamate and lactic acid, the last occurring
primarily in ischemic insults. 31P NMR is suited for
measuring the levels of high-energy phosphates
adenosine triphosphate and phosphocreatine, inor-
ganic phosphate and membrane phospholipids.
Applications of spectroscopic imaging to the
neurologic system and body in humans are dis-
cussed in a recent book chapter by Meyerhoff [ 1951.
A significant challenge for NMR spectroscopic
imaging (SI) - versus radionuclide scanning such
as positron emission tomography (PET) or single
photon emission tomography (SPECT)-is detec-
tion sensitivity. We need to be cognizant of the fact
that most metabolites of interest are present at
millimolar concentration only, compared with cel-
lular water which has a concentration of about 40
molar. Hence, the intrinsic SNR in metabolic
imaging is reduced by a factor of lo4 relative to
tissue water, which can be offset in practically
only one way, i.e. by trading spatial resolution
for sensitivity. Given a typical lower limit of
about 1Op4cm3 for bulk proton imaging in humans
at 1.5 T field strength and further that SNR is pro-
portional to voxel size, one would predict voxel
sizes for SI on the order of about 1 cm3, consistent
with a linear resolution of about 1 cm. This order
of resolution has indeed been attained at 1.5 T field
strength (e.g. Ref. [ 1941)and is likely to be surpassed
with the advent of higher field whole-body
 F. W. WehrlilProgress in Nuclear Magnetic Resonance Spectroscopy 28 (1995) 87-135
(b)
Fig. 30. (a) First NMR micrograph from a single cell (ovum of
African clawed toad, Xetropus laevis) obtained at 360 MHz using
a spin-echo technique. The in-plane pixel size was IO x I3 pm*,
the slice thickness 250 pm (from Aguayo et al. [199], with per-
mission). (b) NMR micrograph at 4 pm in-plane pixel size and
100-300 pm slice thickness obtained by a gradient-echo
warp imaging technique in which essentially only the descending
portion of the echo is sampled as a means of minimizing dif-
fusion-induced signal attenuation, showing human
suspended in glycerin, from 25- and 60-year old males, corre-
sponding to diameters of about 20 and 70 /Am, respectively (from
Ref. [201], with permission).
instrumentation (see, for example, Hetherington
et al. [196]). Such resolution, however, is still inferior
by about a factor of 223 to state-of-the-art PET.
13. NMR microscopy
Besides the enormous impact MRI had so far
127
and will continue to have in the future on medical
diagnosis, its microscopic version, typically denoted
NMRmicroscopy (NMRM), now plays a significant
role in the basic biological and medical sciences.
Applications pursued include the study of the
response to experimental drugs in animal models,
histology, plant biology and physiology, food tech-
nology and the material sciences - both synthetic
and biological. For a discussion of specific applica-
tions the reader is referred to the book, edited by
Bliimich and Kuhn [197]. The theory and applica-
tions of NMR microscopy have been extensively
treated in Callaghan’s erudite 1991 book [ 1981.
Though already mentioned as a possible exten-
sion of large-scale zeugmatography by Lauterbur
[lo] in 1973 and also by Mansfield and Grannell in
1975 [9], NMRM began in earnest only ten years
ago. Callaghan defines NMR microscopy as
MRI at a linear resolution of less than 100
pm. Perhaps the first truly microscopic image
meeting this criterion was reported by Aguayo
et al. in 1986 [199] with NMR micrographs
from an intact single cell (ovum from Xenopus
leavis, the African clawed toad), at a resolution
of 10 x 13 pm* (Fig. 30(a)).
We have seen earlier that resolution in MRI is
determined by the maximum spatial frequencies
sampled. Since the spatial frequency is propor-
tional to the time integral of the spatial encoding
gradients (Eq. (4)) and the limited life time of the
NMR signal leaves little room for extending
gradient on-time, gradient amplitudes typically
limit the achievable resolution in MRI. The resolu-
spin tion limit in NMRM has been addressed in detail
by Callaghan and Eccles [200] and Cho et al. [201].
For a summary discussion of this work the reader
hairs
may consult the book chapter by Zhou and
Lauterbur [202].
For frequency-encoded methods it is obvious
that in order to separate two neighboring pixels
of length Ar, the bandwidth per pixel, yGAr/27r
has to exceed the line width 6~ = l/rT,. For bio-
logical systems T2 = 50 ms, so this criterion is
easily satisfied for a resolution of 2 pm at the
modest gradient strength of about 10 G cm-‘.
However, for phase encoding, this is not the case.
Cho et al. [201] showed that it is the phase
uncertainty, A& which limits resolution, according
128 F. W. Wehrli/Progress in Nuclear Magnetic Resonance Spectroscopy 28 f 199Sj X7-135
to
A4 = yG,TAr
(21)
where G, and T represent the phase encoding gra-
dient amplitude and its duration, respectively.
Considering further that the Nyquist criterion has
to be satisfied in Fourier imaging (demanding
A$ = rr), Eq. (21) would require a gradient ampli-
tude of 1174 G cm-’ in order to achieve a 1 pm
pixel size! The gradient requirements in Fourier
NMRM are thus far more stringent than in PR
NMRM. This treatment, however, ignores phase
jitter arising from diffusion. Cho et al. [201]
obtained a relationship for the diffusion-limited
minimal pixel size, as
Ar> ZDT (22)
d--
with D being the diffusion coefficient and T the
duration of the phase encoding gradient. For
T = 1.5 ms and D M 10-j cm2 s-*, Eq. (21) yields
a resolution limit of 1 pm.
The highest resolution reported so far, albeit in
two dimensions only, is 4 pm [201], of human hair
specimens (Fig. 30(b)), though NMR micrographs
from smaller voxels have been reported (for a com-
pilation, see, for example, Table 1, in Ref. [202]).
The practical limitation to achieving higher spatial
resolution, of course, is the available SNR which
scales as ( Ar)3. Therefore, increasing resolution,
from say 100 to 1 pm, would demand an increase
in SNR by six orders of magnitude, which seems to
impose insurmountable barriers to approaching
the theoretical resolution limit. However, recent
work by Black et al. who constructed a receiver
coil made of YBazCu307 high-temperature super-
conductor with a quality factor (Q) of 50000 at a
field of 7 T [203] indicates that the prospects for
1 pm imaging are not entirely unrealistic. They
showed that by eliminating the principal source
of noise, which arises from the resistance of the
coil (rather than from the sample, as in large-
scale imaging (cf. Eq. (12)) SNR can be improved
sixty-fold over a comparable copper coil.
For most of the applications mentioned above,
far more modest resolution regimes, on the order of
20-80 pm, suffice. In fact, for in vivo applications
in small animals, physiologic motion is usually the
limiting factor. By means of synchronization of
both heart motion and electronically paced lung
ventilation to data acquisition, Gewalt et al. [204]
obtained superb high-resolution images of the rat
thorax.
Though perhaps never achieving the resolution
of optical microscopy, NMRM is far more versa-
tile. It shares all of the intrinsic properties with its
large-scale counterpart, MRI, i.e. it is non destruc-
tive and inherently three-dimensional. Acquisition
of a 3D data set permits retrospective slicing across
the imaging volume or, alternatively, by means of
image processing techniques, permits display of
surface-rendered 3D images. However, perhaps
the most significant aspect is the latitude it offers
to the user for contrast manipulation. Images can
be made sensitive to specific chemical constituents,
relaxation times, diffusion, or flow.
14. Current state-of-the-art and beyond
Two decades after its inception and 15 years
after the beginning of clinical trials in humans,
MRI has reached a level of sophistication which
makes it difficult to foresee further advances. We
are now in a position to acquire images of human
anatomy that rival the detail seen in anatomic sec-
tions. Fig. 31 shows a comparison of two images
from comparable anatomic locations, one obtained
at the University of Nottingham in about 1980, the
other more recently, by means of the RARE tech-
nique. In an attempt to quantify the improvement
in image quality, we may resort to the notion that
image quality can be evaluated in terms of an
index, expressed as the product of per-unit-time
SNR and the reciprocal of voxel volume (the latter
representing some figure of merit of spatial resolu-
tion). Being generous, we may estimate the historic
image to have SNR M 10, a voxel volume of
2 x 2 x 10 mm3, as opposed to SNR z 100, voxel
volume of 0.4 x 0.4 x 2 mm3, with both images
having been obtained in about 5 min. The corre-
sponding improvement in image quality is thus
about a factor of 103!
We can only speculate on forthcoming innova-
tions beyond the next few years; but it is likely that
MRI will continue to evolve well into the 21st
 F. W. WehrlilProgress in Nuclear Magnetic Resonance Spectroscopy 28 (1995) 87-135 129

century. One of the conceivable applications of

real-time ultrafast imaging is whole-body screen-
ing. Clearly, this would give MRI an enormous
impetus which could result in hundreds of millions
of studies per year. Examination times are likely to
approach a few minutes per patient within the next
5- 10 years, achieved by incorporating and perfect-
ing high-speed imaging techniques and enhanced
efficiency of the imager’s patient and operator
interface. The prospect of MRI eventually even
displacing chest film radiography seems far-
fetched, yet not unrealistic. The technology for
rapid tomographic imaging of the entire torso in
seconds is clearly feasible with today’s technology.
An entirely new development is the integration
of real-time MRI as a means for monitoring inter-
ventional procedures. During the past decades sur-
gery has become less invasive. Among the emerging
surgical methods are ablative procedures by means
of lasers and cryoprobes inserted into tumors and,
(a) in the near future, focused ultrasound which is
completely noninvasive as its application does not
require surgical incision. MRI is uniquely suited
for on-line monitoring because of the temperature
sensitivity of the signal. Interventional MRI sys-
tems incorporating new technology such as open
cryogen-free superconducting magnets, are already
undergoing clinical trials and are predicted to radi-
cally alter the ways surgical procedures will be per-
formed in the 21st century (see, for example, a
recent review article by Jolesz and Blumenfield
P-m.
The emergence of new superconducting materials
with higher current-carrying capacity will facilitate
the construction of magnets at field strengths well
beyond the current technological limits. Already
now, using conventional superconductors, whole-
body NMR magnets have been constructed,
operating at field strengths up to 4 T [206,207]
and the design of such magnets with field strengths
up to 10 T by means of niobium-tin superconductors
(b) appears to be within reach of current technology,
albeit at a cost that will limit their diffusion. The
Fig. 3 1. Improvement in NMR image quality, achieved during increase in signal-to-noise ratio, brought about by
the past 15 years: (a) early low-field image, about 1980, com-
the higher magnetic field, should make it possible
pared with state-of-the-art high-resolution image, corresponds
to improvement by three orders of magnitude in terms of an to perform chemical shift imaging at much
image quality index defined as the product of per-unit-time improved spatial resolution on such biological
SNR and the reciprocal of voxel volume (for details see, text). nuclei as carbon-l 3, sodium-23, phosphorus-3 1,
130 F. W. WehrlilProgress in Nuclear Magnetic Resonance Spectroscopy 28 (1995) 87-135
deuterium, potassium-39, etc. Moreover, higher
field strengths enhance the sensitivity to detecting
stimulus response in neurologic studies based on
the BOLD effect, discussed earlier [ 1671.
MRI has inherent limitations as well. Compared
to X-ray and radionuclide-based modalities, NMR
is relatively insensitive. Hence any substantial
future enhancement of the technology will critically
hinge on our ability to improve detection
sensitivity. A quantum leap in detection sensitivity
is theoretically possible by electron-nuclear double
resonance in a situation where electron spins are
dipolar coupled to nuclear spins. Irradiation at
the electron spin resonance (ESR) frequency then
induces an electron-nuclear Overhauser effect
[208] which increases the nuclear spin polarization
several hundred-fold. The exploitation of this effect
for selective local signal enhancement, first proposed
in 1980 by Raymond Andrew, has recently been
reported by Lurie et al. [209]. By Injecting a targetable
paramagnetic molecule, irradiation at the ESR fre-
quency would cause strong local signal enhancement.
The hurdles to practical implementation of this idea
seem insurmountable. For example, the power
required to keep the fast relaxing electron spins satu-
rated may well be orders of magnitude beyond what
the human body can tolerate, except at very low field
strength. Nevertheless, if it could be made to work
and non-toxic targetable agents could be developed,
the diagnostic potential of the method would be enor-
mous. For example, we might be able to diagnose
early malignancies well before they become sympto-
matic, thus providing a tool for screening popula-
tions who, on the basis of their genetics, are at risk.
A fascinating new approach to NMR detection,
not relying on Faraday’s law of induction, has
recently been reported by Rugar et al. [210]. The
experiment exploits the force exerted on the mag-
netization by a field gradient (it is thus the same
effect Stern and Gerlach used to split an atomic
beam of silver atoms in their famous 1924
experiment to prove the spatial quantization of
the magnetic moment [21 I]). By cyclically inverting
the magnetization at some frequency, the force
changes direction, causing a vibration of the canti-
lever on which the sample is mounted. Though only
in the femtonewton range, the force causing the
vibration could be measured interferometrically.
In this manner Rugar and colleagues succeeded in
detecting 1013 spins in a gradient field of about
6 x IO4 G cm-‘, which resulted in a resolution in
one dimension of 2.6 pm. We shall know in the near
future whether this experiment is a precursor for
imaging microscopic objects at the subcellular level.
In conclusion, we see from the few examples of
recent innovations quoted here that NMR, a half
century after its first detection in condensed phase
and nearly twenty-five years after the first image
was produced, is far from having reached its ulti-
mate potential. History has taught us that we can-
not be bold enough in the pursuit of new ideas. It
will be left to future generations of scientists to
look back on NMR’s hundredth anniversary and
assess the progress achieved between now and then.
They are likely to conclude that our crystal ball
gazing in 1995 was hopelessly conservative.
Glossary of terms
BOLD, blood oxygen level dependent (contrast);
NMR contrast phenomenon resulting from physio-
logic changes in blood oxygen level.
Cardiac Cine Imaging, gradient echo imaging tech-
nique producing a series of images taken at dif-
ferent phases of the cardiac cycle. When displayed
in succession, a movie of the beating heart is
obtained.
CSI, Chemical Shift Imaging; family of spectro-
scopic imaging techniques from which spatial
maps of individual metabolites can be generated.
CT, Computed Tomography; medical imaging
technique for the generation of images of sections,
based on the mathematics of filtered back-
projection of an array of angular projection
signals.
DEFT, Driven Equilibrium Fourier Transform;
90”~r-180”~r-(90”) r.f. pulse sequence.
DRESS, Depth Resolved Surface Coil Spectroscopy;
spectroscopic localization technique based on slice
selection by means of field gradients, analogous to
imaging.
EPI, Echo-planar Imaging; high-speed NMR
imaging technique, characterized by an oscillating
read-out gradient, generating a train of echoes
which are encoded in a second dimension.
 F. W. WehrlijProgress in Nuclear Magnetic Resonance Spectroscopy 28 (1995) 87-135
FISP, Fast Imaging with Steady State Precession;
embodiment of the FLASH experiment, character-
ized by balancing the phase-encoding gradient to
avoid phase variations between successive pulse
sequence cycles.
FLASH, Fast Low Angle Shot; embodiment of the
spin warp experiment whereby the pulse repetition
time is shortened and the flip angle for the excita-
tion r.f. pulse is adjusted to minimize saturation.
FONAR, Field focusing NMR; single-point imag-
ing technique whereby the subject is incrementally
moved through a spot of homogeneous magnetic
field so as to obtain an array of signals which can
be arranged to form an image.
Fourier Zeugmatography (see also zeugmato-
graphy); imaging technique based on successive
application of at least two orthogonal imaging
gradients of which the first is incremented in time,
to afford a 2D array of time domain data. The
image is obtained as the 2D Fourier transform of
the time domain data.
GRASS, Gradient-Recalled Acquisition in the
Steady State; embodiment of the FLASH experi-
ment, analogous to FISP.
k-Space; spatial frequency domain or reciprocal
space. k-space and image data are Fourier
transforms.
MRA, Magnetic Resonance Angiography; com-
prises a family of imaging techniques from which
projection images of blood vessels can be created,
analogous to X-ray based contrast angiography.
MT, Magnetization Transfer; although the term
has a more general meaning, in imaging MT refers
to a signal modulation caused by cross relaxa-
tion, involving transfer of magnetization from
unobservable macromolecular protons to obser-
vable water protons, effected by means of off-
resonance saturation.
PET, Positron Emission Tomography; tomographic
technique based on positron emitting tracers.
Phase Contrast Imaging; technique which exploits
the phase difference of moving relative to station-
ary spins as a means to generate angiographic
images of blood vessels or for measuring blood
flow velocities.
PRESS, Point Resolved Spectroscopy; spectral
localization technique whereby a 3D volume is
selected from a second spin echo obtained in the
131
presence of three spatially selective r.f. pulses.
RARE, Rapid Acquisition with Relaxation
Enhancement; fast imaging technique whereby a
train of spin echoes is generated, which are indi-
vidually phase and frequency encoded so as to
cover multiple k-space lines following creation of
transverse magnetization.
Spin Warp imaging; modification of Fourier
zeugmatography, whereby a position dependent
phase twist (or ‘warp’) is applied on the magnetiza-
tion, achieved by incrementally stepping the ampli-
tude of a phase-encoding gradient prior to signal
read out.
Spiral Scan Imaging; imaging technique character-
ized by oscillating the spatial encoding gradients in
such a manner that k-space is traversed in a spiral
fashion.
STEAM, Stimulated Echo Acquisition Mode; in
the context of in vivo spectroscopy, refers to a
spatial localization method, characterized by three
successive r.f. pulses, applied in the presence of
mutually orthogonal gradients, for the purpose of
generating a stimulated echo from a parallelepiped-
shaped volume of the object.
Zeugmatography; term introduced by Lauterbur to
characterize an NMR imaging method whereby
spatial information is encoded into the signal by
means of field gradients.
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