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59i

Review

Diffusion Denis

MR Imaging:

Le Bihan,1

Robert

Turner,2

Clinical

Philippe

Douek,3

Applications

and

Nicholas

Water self-diffusion, a recently discovered source of contrast on MR images, has already shown promise for some clinical applications. Most studies have been of the brain, essentially for technical reasons. Diffusion is useful in distinguishing the different components of brain tumors (cystic regions, edema, necrosis) from

the

tumor

core

itself.

Recent

studies

fusion is anisotropic in brain white matter fiber tract’s orientation in space), offering disorders. Diffusion is also dramatically following

ischemic

injury

in the

cat

have (i.e., new

shown

insights

altered

brain,

that

dependent

dif-

myelin

in the minutes

which

may

have

tre-

mendous impact for the diagnosis and management of hyperacute stroke. With ultrafast acquisition schemes, diffusion imaging has also been used outside the CNS, for instance, in the eye and kidney. copy

Future and

gress

applications

temperature

in this

field

and

include imaging.

diffusion-localized

This

suggests

article

potential

spectros-

reviews

recent

Patronas1’4

tively immobile tissues and of having favorable MR characteristics, such as long Ti and T2 relaxation times. Body studies are far more difficult, although preliminary results of diffusion imaging of the kidneys have been reported and are shown here. Also, the possibility of applying to perfusion imaging techniques similar to those used in diffusion imaging has been suggested [2, 3]. However, technical difficulties have limited application of such perfusion imaging. Also, the feasibility of using diffusion imaging in vivo was not demonstrated overnight. The initial technique, based on spin-echo two-dimensional Fourier transform (2DFT) imaging [4, 5], was slow, sensitive to motion artifacts, and implemented on MR units with imperfect gradient systems, so that some researchers

on the into

pro-

expressed

applications.

ment and transport

of diffusion

in biological

MR imaging,

tissues

water

move-

have become

attrac-

reprint requests to D. Le Bihan. 2 National Heart, Lung and Blood 3 4

Biomedical Department

AJR i59:59i-599,

Institute,

National

28, 1992. The Warren

Institutes

of Health,

amazing

of several

1992 0361-803X/92/1

593-0591

the meaning technical

capability

of determining

of the improve-

molecular

have

occurred

that

have

Background Principles

of Diffusion

MR Imaging

The principles of diffusion MR imaging have been outlined recently in several review articles [2, 7] and are only sum-

G. Magnuson

Clinical

Bethesda,

MO 20892.

© American

about important

millimeters)

Center,

National

Institutes

Engineering and Instrumentation Program, National Institutes of Health, Bethesda, MO 20892. of Radiology, Georgetown University Hospital, 3800 Reservoir Rd. NW., Washington, DC 20007. September

then,

proved the feasibility of diffusion imaging in vivo. The basic principles of diffusion imaging are reviewed only briefly, as the main object of this article is to survey the current and potential clinical applications of this technique.

studies were of the CNS. Besides beings of compelling clinical interest, the CNS has the advantages of consisting of rela-

after revision February Bldg. 10, Rm. 1 C660,

the

an amplitude

of the tissue insights about

water exchanges between these compartments in various normal or disease states [2]. Although diffusion MR imaging is a recently developed technique, some studies have already shown the clinical value of the method. Most of these clinical

Received July 15, 1992; accepted 1 Diagnostic Radiology Department,

(e.g.,

concerns

[6]. Since

displacements in the micrometer range from images that have a millimeter resolution and depict organs that may move with

tive topics for in vivo MR imaging investigations [i ]. Studies of molecular displacements over distances comparable to a cell’s dimensions can be expected to provide information

about the geometry and spatial organization compartments, as well as some functional

justifiable

measurements ments

With the introduction

Article

Roentgen

Ray Society

of Health,

Bethesda,

MO 20892.

Address

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592

LE

BIHAN

manzed here. Diffusion imaging is based on the natural sensitivity of MR to motion, which serves, for instance, as the basis of MR phase-contrast angiography. In the presence of a magnetic field gradient, protons carried by moving water molecules undergo a phase shift of their transverse magnetization (Fig. 1). As diffusion is characterized by the random (brownian) displacements of molecules, these phase shifts are widely dispersed, interfering with each other and finally resulting in attenuation of the MR signal. This attenuation directly depends on the amplitude of the molecular displacements (related to the diffusion coefficient) and on the intensity of the magnetic field gradient. Diffusion effects are extremely small and are usually invisible on conventional MR images. In practice, diffusionweighted images are obtained by incorporating strong magnetic field gradient pulses within any imaging pulse sequence (Fig. 2). The degree of diffusion weighting is set by the strength and duration of the gradient pulses (integrated in the so-called gradient factor [2, 7]), as the degree of T2 weighting in a spin-echo sequence is defined by the echo time. In a diffusion-weighted image (Fig. 3A), structures with fast (large)

diffusion are dark, because they are subject to greater signal attenuation, whereas structures with slow (low) diffusion are bright. Calculated (quantitative) diffusion images can also be generated from a series of diffusion-weighted images by using adequate software. In those images (Fig. 3B), diffusion is the only variable responsible for the contrast (and not Ti and T2). Usually, contrast is such that structures with high (fast) dif-

fusion are bright, and those with low (slow) diffusion

ET

AL.

AJR:159,

September

90

180

Echo

.IL

A

A

1992

-1r---------------lr--------------#{149}1r--Tag

Untag Diffusion

Time

j’-

/1,,_

71k

, Lia -

r’

“i

ri\14 L

---

y_

Fig. 2.-Principles of diffusion MR imaging. Effects of motion and diffusion become visible when an MR sequence, such as spin echo, is sensitized by magnetic field gradients. Suppose Zia and Zib are positions of two molecules when first (tagging) gradient pulse G is applied. Because of this pulse, molecules in time will acquire a phase shift that is a function of their position with respect to the gradient After a given interval (diffusion time), a second (untagging) pulse is applied. For “static” molecules, the second phase shift is identical to that produced by the first pulse, so that pulses cancel each other out (Initial phase shift is reversed by 180#{176} RF pulse). For diffusing molecules, position changes between the two pulses (Z2a and Z2b). A net phase shift is then observable, a function of displacement, Z2 - ZI, of the molecules during diffusion time. Phase shifts acquired by all molecules interfere with each other, resulting in imperfect refocusing of echo (i.e., attenuation of an echo depends directly on molecular mobility rate [diffusion coefficient]).

are dark.

Calculated diffusion images are somewhat dependent on postprocessing power. They generally have a noisier appearance than diffusion-weighted images, and therefore may be preferred for clinical use. However, only calculated images provide the quantitative information necessary for validation

of new results. Moreover, as other kinds of intravoxel incoherent motion (IVIM), such as capillary perfusion, may produce effects similar to those of true diffusion, the term apparent diffusion coefficient (ADC) has been suggested to describe quantitatively the results of diffusion imaging experiments in

vivo [3, 5]. Clinical use of diffusion MR imaging has been limited by the technique’s high sensitivity to motion artifacts and by available

3

Phase

Random

motion

distribution

hardware on conventional MR systems. Diffusion imaging has benefited from recent technical improvements. Among these are the use of shielded gradient coils [8-i 0], which reduce eddy currents generated by the switching of the diffusion-

1)

sensitizing Echo

attenuation

gradient

Fig.

1.-Intravoxel incoherent motion and signal attenuation. For a of randomly moving molecules, as in diffusion, motion along the direction of the magnetic field gradient is different for each molecule, resulting In a distribution of phase shifts that reflects distribution of molecular motion. In the case of diffusion, the average phase shift is zero, because the average molecular displacement is zero. Dispersion of the phase shifts depends on the variance of the displacements (square of the diffusion distance), which is related to the diffusion coefficient. This dispersion of phase shifts finally results in an attenuation of the signal amplitude, which depends on the diffusion coefficient and the gradient

population

waveform.

coils,

amplitudes.

implementation

diffusion Gradient

gradient

low-inductance

imaging

pulses,

and the use of small dedicated

which

allow

rapid

switching

This latter innovation

of echoplanar

has benefited

imaging

[i i -i 4], from

enormously.

in Biological

which

The use of such

a single-shot technique has greatly reduced the artifacts and has increased the accuracy of diffusion coefficients, because many differently fusion images can now be obtained in short patible with a clinical protocol (Fig. 4).

Diffusion

of large

has also enabled

risk of motion the measured sensitized difintervals corn-

Tissues

Many diffusion studies in isolated biological tissues were conducted in the i 970s [1 5-i 9]. The diffusion coefficient of water in tissues was found to be two to i 0 times less than

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AJR:i59,

September

DIFFUSION

1992

MR

IMAGING

593

Fig. 3.-A, Coronal diffusion-weighted MR image (50-msec acquisition time, 10-mm slice thickness, 2.5 mm2 in-plane resolution, i00-msec TE) was obtained directiy by using echoplanar imaging sequence sensitized to diffusion by additional gradient pulses. Gradient pulses (20-msec duration, 30 mT/ m amplitude) were set along z axis (superior-inferior). White matter tracts where fibers are perpendicular to the z axis, as in corpus callosum (arrows), present lower diffusion and therefore less signal attenuation than gray matter and white matter tracts parallel to z axis and appear brighter than these structures. Contrast between gray matter and parallel white matter is otherwise pooc Diffusion in gray matter is less than in parallel white matter, but T2 is longer in gray matter, so that diffusion and T2 effects cancel each other. B, Calculated diffusion MR image was obtained from a set of eight different diffusion-weighted images acquired as in A, while amplitude of gradient pulse was varied from 0 to 38 mT/m. Brightness of each pixel is now directly proportional to diffusion coefficient and depends only on this variable. Fiber tracts perpendicular to z axis now appear dark (corpus callosum, straight arrows); tracts parallel to z axis are bright (curved arrows). Excellent contrast is achieved, because Ti and T2 effects have been removed.

that of pure water

(Table

i). This is understandable,

given

that water molecules must move tortuously around obstructions presented by fibers, intracellular organelles, and macromolecules [20]. In addition, a continual exchange occurs

between

free

water

molecules

and

water

molecules

that

spend some of their time associated with the much more slowly moving macromolecules [2i , 22]. Diffusion coefficients are thus expected to vary according to a tissue’s microstructune or physiologic state, a potential source of tissue contrast for characterization or functional studies. As the diffusion range of water during typical MR diffusion times (i 00 msec) is on the order of a few micrometers, in the size range of many cells, microdynamic studies can be done at a scale that is much smaller than the resolution of current MR images. By comparing diffusion measurements obtained with sufficiently short and sufficiently long diffusion times, it may be possible to estimate cell diameters, provided diffusion is restricted by cell membranes. This effect has been shown in vegetable tissues, in which the cell wall is essentially impermeable to water transport [i 9], or by measuring diffusion of metabolites that remain inside the intracellular compartment [23]. In living

animal tissues, and rapid

cell membranes

exchanges

occur

are permeable

between

different

to water

[24],

compartments,

such as intra- and extracellular spaces. The result is that diffusion is expected to be more likely “hindered” by random

TABLE

1:

Tissues,

Diffusion

Tissue Fig. 4.-Set of eight diffusion-weighted echoplanar MR images (diffusion gradient pulses along z axis; gradient factor is 0-800 sec/mm2 from upper left to bottom right). Signal attenuation is important in structures containing CSF (ventricular cavities, subarachnoid spaces), because of fast diffusion and CSF circulation. Note changes in gray/white matter contrast between first and last images. White matter in upper frontal lobe becomes much darker on heavily diffusion-weighted images, because of faster diffusion along myelin fiber in direction parallel to z axis. In tumor, attenuation is less at bottom (core of tumor, arrows) than in remaining part, which contains more free water (edema).

Coefficients

Normalized

Liver [15] Brain [18] 20-msec

in Some

Diffusionts4Diffusionwat

[Ref.]

Muscle [17] Parallel to fibers Perpendicular

of Water

to fibers

time

0.45

0.10

[15]

diffusion

0.61 0.44 0.25-0.30

60-msec diffusion time Heart

Excised

to Pure Water, at Room Temperature

0.34-0.37

Rat

LE BIHAN

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594

obstacles than strictly “restricted” in closed spaces by walls. In these conditions, MR diffusion measurements could be used to determine the permeability of cell membranes to water [i 5]. This new possibility of evaluating molecular displacements in vivo, without compromising tissue integrity, metabolism, and function, has given an impulse to clinical MR diffusion imaging. Some discrepancies may be expected with results obtained about 20 years ago with excised, dead tissues at room temperature and with older hardware.

ET

AL.

Imaging

Diffusion Matter

in the Normal

Brain;

Anisotropic

Diffusion

in White

Diffusion of water was measured previously in excised brain tissue [i 8]. Recent in vivo studies have shown that the diffusion coefficient of water in the normal brain does not vary much among subjects, if measurements are made with great care [7]. Diffusion of water in CSF is similar to the diffusion of pure water at the same temperature (Table 2). Indeed, the apparent diffusion coefficient in some locations, such as the foramina of Monro or the fourth ventricle, sometimes may be

surprisingly

larger (3-6

x i 03/mm2/sec),

which seems physi-

cally impossible, but which is understandable considering that CSF is flowing incoherently in some locations. In MR imaging (Fig. i), the distribution of velocities in a voxel will produce a signal attenuation (flow-void effect) that is similar to that of diffusion but larger (Fig. 4). This finding has been used to map and evaluate CSF [5, 25]. In gray matter, diffusion is isotropic and roughly 2.5-fold lower than in pure water at the same temperature (Table 2). In white matter, diffusion apparently is extremely variable. Indeed, the value of the diffusion coefficient directly depends on the relative orientation of the fibers and the magnetic field gradients; this is known as anisotropic diffusion. It is expected that, in some tissues, hindrance or restriction in molecular water motion may not be the same for different directions of motion, so that the measured diffusion coefficients may vary according to the direction of measurement. Examples have been shown in muscle [1 7] and more recently in the white matter of cat [26] and human [1 2, 27, 28] brains. Water diffusion in gray matter is not anisotropic [26, 28] and is not completely restricted by impermeable walls [28, 29]. By contrast, diffusion in white matter is extremely anisotropic;

TABLE

2:

Diffusion

Coefficients

This has been clearly demonstrated

2.94

Gray matter

0.76 callosum

Axial fibers Transverse

mm2/s) ± 0.05 ± 0.03

of fibers

0.22 ± 0.22

1 .07 fibers

as compared

with diffusion

in other brain structures.

±

0.06

0.64 ± 0.05

refers to z axis (vertical).

tion have low diffusion

coefficients

3B and 5), contrast is to the gradient direc-

and now appear dark, and

fibers parallel to the gradient direction are bright. Color-coded maps of the myelin fiber orientation can be generated on the basis of diffusion anisotropy [30]. Although there is no doubt that diffusion is anisotropic in

white matter, controversies

about the origin of this anisotropy

remain. Techniques that use radiotracers or ion-selective microelectrodes [2i] have shown that slow and anisotropic diffusion of compounds in extracellular spaces could occur because of the tortuosity of the diffusion pathways between

tissue microscopic

substructures,

such as myelin fibers. How-

ever, most MR-visible water is in the axons. A simple model would be to consider that water molecules are enclosed in the axonal spaces and that water diffusion outside the axons is prevented by the myelin sheath [26-3i ]. When diffusion measurements are made parallel to the direction of the fibers,

diffusion is not restricted, resulting in higher measured diffusion coefficients. Indeed, the situation is more complex, as it has been

shown

sheath is somewhat

by MR dispersion

permeable

studies

that

the

myelin

to water [32]. In recent diffu-

Brain

matter

Corpus

with diffusion-weighted

MR images (Fig. 3A). White matter structures in which fibers are perpendicular to the diffusion-gradient direction appear bright on such images, because diffusion is slow in this

Coefficient

(x 10

CSF

Note-Direction are given in [12].

in Human

Diffusion

Tissue

White

of Water

1992

at each different image location. It appears that diffusion coefficients are significantly decreased when the myelin fiber tracts are perpendicular to the direction of the magnetic field gradient used to measure molecular displacements (Fig. 3).

On calculated diffusion images (Figs. opposite: Fibers that are perpendicular

in the CNS

September

the results of the measurements depend on the respective orientation of the myelin fiber tracts and the gradient direction

direction, Diffusion

AJR:159,

Experimental

parameters

Fig. 5.-Anisotropic diffusion in white matter. Calculated diffusion MR image from a set of eight different diffusion-weighted images was acquired as in Fig. 4; amplitude of gradient pulse was varied from 0 to 38 mT/m. Brightness of each pixel is now directly proportional to diffusion coefficient and depends only on this variable. Fiber tracts perpendicular to z axis appear dark; tracts parallel to z axis are bright Excellent contrast is achieved, because TI and T2 effects have been removed. Corpus callosum and temporal white matter fibers, which are horizontal, are dark; vertical corona radiata frontal fibers and internal capsule fibers are bright In brainstem, vertical fast-conducting motor and somatosensory tracts are also bright These orientation patterns correlate well with anatomy.

AJR:i59,

September

DIFFUSION

1992

MR

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sion experiments [28, 29], no restricted diffusion pattern could be observed in white matter. In particular, the diffusion coefficient remained constant with the variations in diffusion time and did not decrease as would be expected in the case of

restricted diffusion diffusion coefficient

in one direction. The reduced value of the across myelin fibers thus likely reflects a

decreased water mobility through the successive lipid layers [28] or water exchanges limited to nodes of Ranvier. The low

permeability

of myelin to water apparently

does not prevent

water molecules from being exchanged between axons within a rather short time. Such diffusion studies could provide an estimation of the permeability of myelin to water [33]. Another possible explanation is that water in myelin sheaths is in a liquid crystalline environment in which anisotropic, but free,

diffusion

can be observed.

On the other hand, the enhanced

value of diffusion measured parallel to the axoplasm could arise from a facilitated transport favored by the highly oriented intraaxonal microstructures, such as microtubules or microfil-

aments,

in relation

to axoplasmic

transport

[28]. This trans-

port is not a diffusional process, but could be seen as an incoherent motion at the voxel scale. The measurement of anisotropic diffusion in white matter offers exciting potential applications. Mapping the orientation of myelin fibers might be useful for a better understanding of white matter diseases

such as multiple sclerosis, wallerian degeneration, or delayed white matter myelination in neonates [34, 35]. The coupling between

the degree

white matter

of diffusion

myelination

anisotropy

an argument to justify that diffusion is related to the myelin sheath.

Diffusion

Imaging

Subacute

ischemia, abnormal in white

in Brain

anisotropy

of

[35] is also

in white

matter

matter

increases

lschemia

about

normal value [36]. This is probably edema,

in which

space is an important

Fig. 6.-Diffusion

in subacute

595

showed that edema could be easily recognized on diffusion images. Typically, vasogenic edema is visible as a large homogeneous area that has an increased diffusion coefficient (Fig. 6). In some instances of chronic ischemia, abnormalities in brain parenchyma (low diffusion) have been seen on diffusion images, although conventional Ti - or T2-weighted images appeared normal [3]. Diffusion may also help detect encephalomalacic cysts, which have a diffusion coefficient sim-

ilar to that of pure water. Acute

lschemia.-The

most

promising

application

of diffu-

sion imaging in stroke has been suggested by the finding that diffusion imaging can be used to detect brain ischemia at an early stage. Recently, MR diffusion imaging model of ischemia showed that the diffusion

water is significantly emic

injury,

decreased

a time when

ing conventional The mechanism

all other

in a cat brain coefficient of

within minutes imaging

after an isch-

techniques,

includ-

MR, do not show any change (Fig. 7) [37]. of this decrease in water mobility is still

unclear. It is unlikely that this finding is related to nondiffusion phenomena, such as a decrease in bulk tissue pulsatility caused by the microcirculatory arrest. The decrease in diffusion is not instantaneous; it appears progressively within the first hour [37]. It is also difficult to explain on the basis of a decrease in temperature. A 30% decrease in the diffusion coefficient would imply a temperature decrease of about i 0#{176} C [38], which is unrealistic. This decrease in diffusion more likely reflects a modification of the water balance or transport

between spaces.

tissue compartments, such as intra- and extracellular It is known that ischemia is responsible for the

massive entry of ions and accompanying water into the intracellular space, accompanied by an increase in osmolanity [39]. A modern, but still under debate, theory of cytotoxic

and chronic ischemia.-At the stage of subacute when findings on conventional MR images appear (showing an increase in T2), the diffusion coefficient

of vasogenic

cellular

and the degree

during CNS maturation

IMAGING

two-

or threefold

because

bulk water

stroke.

A, T2-weighted MR image (1799/140 [TRITE]) shows small infarcted area (arrows) in left temporal lobe. B, Calculated diffusion MR image shows infarcted area has a large diffusion coefficient similar to that found in ventricles. This high water mobility typically accompanies vasogenic edema, in which water diffusion is relatively free and additional microscopic motion may occur.

its

of the presence

motion

phenomenon.

above

in the extra-

Earlier work [5]

edema is that the calcium channels open because of the excitation of N-methyl-D-aspartate receptors by the release and accumulation such as glutamate,

changes

in terms of microvacuolation

20 mm after complete of

of neurotoxic dicarboxylic in the extracellular spaces

potassium

ions

ischemia. and

the

are visible as early as

This results massive

amino acids, [39]. Cytologic

entry

in the cell release of

sodium

ions,

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596

LE

BIHAN

ET AL.

AJR:159,

September1992

Fig. 7.-Diffusion in hyperacute cerebral ischemia. MR images obtained on a 2-T C51 unit 1, 2.5, and 4 hr after occlusion of middle cerebral artery of a cat brain. (Courtesy of M. E. Moseley, San Francisco). Top row, T2-weighted images (gradient factor = 0 sec/mm2) show no evidence of abnormality, even 4 hr after occlusion. Bottom row, Diffusion-weighted images (gradient factor = 1413 sec/mm2) dramatically show ischemlc territory as a bright area, indicating decreased water mobility as soon as 1 hr after occlusion. lschemic area is cleariy enlarging with time (arrows).

which quickly overtake the capacity of the ionic transrnembrane pumps. An interesting finding in favor ofthis mechanism is that calcium blockers prevent or lessen the decrease in diffusion [40]. Furthermore, artificially induced cytotoxic edema in animals also produces a decrease in the diffusion coefficient [4i ]. Diffusion imaging could also reflect various intracellular active transport mechanisms that cease operating when energy metabolites are no longer available.

Diffusion

imaging

thus

offers

the unique

opportunity

to

address, noninvasively and in a clinical setting, fundamental issues about the response of brain tissue to ischemia at different stages that may not be possible with other techniques, including conventional MR and MR spectroscopy [42].

Early detection

of stroke, at a stage when tissue damage

is still reversible, may provide justification for more aggressive and controversial reperfusion or other therapies designed to protect CNS tissues. It will be of extreme interest to find out if diffusion can be used as a reliable marker of tissue damage and of its potential reversibility.

Brain

Tumors

So far, only modest results have been obtained with the use of diffusion imaging in a clinical context [3, 5, 43-45]. The most pertinent finding is that diffusion coefficients are significantly higher in structures in which diffusion is free, such as cysts (where the diffusion coefficient is close to that of pure water, depending only slightly on the viscosity of the cystic fluid [46]). This feature becomes clinically useful when, because of a high paramagnetic protein content, Ti and T2 are not as long as expected for a liquid, so that some

complicated

cystic lesions have the same Ti and T2 appear-

ances as a solid tumor [47]. In these cases, diffusion imaging clearly shows the liquid nature of the lesion [2, 5] (Fig. 8). On the other hand, the extension of the concept of diffusion to other kinds of IVIM can be clinically valuable, at least in some

situations. tumors,

For instance, such

the ADC is different

as epidermoid

tumors,

and

between

pulsatile

solid

cisternal

or even

CSF

static

fluid

collections.

Diffusion

imaging,

or

rather IVIM [3, 5] imaging, has been found useful in improving the detection, characterization, and therapeutic management of extraaxial

brain tumors

Perfusion-sensitized

obtained

in clinical

3].

IVIM

With

pseudodiffusion

practice

imaging,

network is considered circulation can thus niques.

[43]. of the brain have also been by applying the IVIM concept [2,

images

microcirculatory

and imaged

Use of echoplanar

by using diffusion MR imaging

motion artifacts and allows collection numerous images in order to separate bulk water

fraction

diffusion

flow in the capillary

to be random at the voxel level. Microbe modeled as a type of macroscopic

in the tissues

of normal brain occupied

imaging

eliminates

tech-

the risk of

in a short interval of microcirculation from

[7, i 2]. However,

by flowing

the small

blood (typically

a

few percent) makes this separation difficult, requiring high signal-to-noise ratios. Therefore, the accuracy and sensitivity of the method are limited, especially in the low perfusion range [48]. Furthermore, the link between the information

provided by IVIM measurements and actual blood flow requires some modeling [49, 50]. It remains that, with IVIM imaging, highly perfused tumors have been detected because they have patterns different from those of poorly perfused tumors or tissues. Potentially, distinction between tumor recurrence and radiation damage in patients previously irradiated for brain tumors could be made. IVIM images show high perfusion in tumor recurrence, whereas radiation damage causes low perfusion and apparently decreased diffusion [5i]. These results are well correlated with those obtained

from metabolic

data produced

by positron

emission

tomog-

raphy with ‘8F-fluorodeoxyglucose [52]. Diffusion/perfusion images have also shown abnormalities that regular Ti - and

T2-weighted done to depicted how such flow and ages for

images have not shown [3]. Work remains

to be

characterize the way capillary microcirculation/ is when gradient sensitization techniques are used and results correlate with measurements of actual blood to establish the reliability of diffusion/perfusion imobtaining accurate, reliable, and reproducible data.

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AJR:159,

DIFFUSION

September1992

MR

IMAGING

597

Fig. 8.-Diffusion in a cystic lesion. A and B, Coronal Ti-weighted (400/26 [TRITE]) and T2-weighted (1000/140) MR images show a lesion (arrows) at upper extremity of a pituitary adenoma. Ti and T2 values are nonspecifically elevated, but are not as high as in CSF. C, Intravoxel incoherent motion MR image of same slice strongly suggests lesion (arrows) is cystic, because of its high apparent diffusion coefficient, similar to diffusion coefficient of free water, as found in nearby ventricular cavities. (In some parts of ventricles, apparent diffusion coefficient is even higher, because of CSF flow). Using diffusion MR images to distinguish solid from cystic lesions is more reliable than using Ti or T2 images because diffusion is insensitive to proteins or other paramagnetic substances in cystic fluid. Such substances may alter Ti and T2, and cause cysts to have appearance of solid lesions.

Diffusion

Imaging

Diffusion

Imaging

Outside

the CNS

application of diffusion imaging. The kidney is an interesting organ for diffusion/perfusion imaging, because of the impor-

of the Eye

tant contribution

Many eye diseases involve disorders in fluid circulation in different parts of the eye (glaucoma) or in blood microcirculation in the choroid (diabetes, uveitis). Therefore, diffusion

exchanges

of perfusion

between

and the crucial

the different

role of water

segments

of the nephron and interstitial tissue. Encouraging results have been obtained in the dog kidney [54] with a spin-echo 2DFT diffusion imaging

and pseudodiffusion imaging of the eye could be extremely useful. Unfortunately, these studies are not easy owing to the mobility of the eye in vivo.

High-resolution esthetized

tures,

diffusion-weighted

rabbits

[53]

have

images

shown

some

such as the lens and the choroid,

barely visible with subjects, ultrafast MR imaging, are be kept constant tunately, without spatial resolution

obtained anatomic

in anstruc-

that otherwise

are

conventional MR imaging (Fig. 9). In human imaging techniques, such as echoplanar required, because the direction of gaze must during acquisition of the MR images. Unforhigh-performance digitization hardware, high is not possible with echoplanar imaging,

and, owing to the vulnerability of echoplanar imaging to susceptibility artifacts, the shape of the eye and internal structures may be distorted. Further improvements include the use of surface coils to increase the signal-to-noise ratio and

a smaller

shown

field

the feasibility

vivo. Besides used to study

Imaging

of view.

These

preliminary

of using diffusion

imaging

its clinical potential, this method animal models of eye disease.

also could

be

The

motion,

main

to

diffusion imaging is sensitive, and to the relatively short of body tissues, which require much shorter echo than brain tissues do. By “freezing” motion in a single echoplanar MR imaging has broadened the scope of

T2 values

times shot,

have

of the Kidney

Diffusion imaging in the body is a challenge. difficulties are related to organ and respiratory which

results

of the eye in

Fig. 9.-Diffusion-weighted MR images (1000/46 [TR/TE]) of a rabbit eye were obtained in vivo by using a 4.7-T CSI instrument and a twodimensional Fourier transform spin-echo diffusion imaging sequence (4mm slice thickness, 230-sm in-plane resolution; gradient factors = 14, 32, 89, 128, 227, 355, 51 1, and 600 sec/mm2. Some structures, such as cortex of lens and choroid, are more visible on heavily diffusion-weighted Images (arrows).

598

LE BIHAN

sequence, in rabbit kidneys (Fig. i 0), and in human volunteers [55] with echoplanar imaging.

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Future Diffusion

Recent progress in in vivo localized MR spectroscopy allows the extension of diffusion measurements to molecules other than water. MR can resolve different nuclear species because of the species’ different Larmor frequencies, such as phosphorous-3i , fluorine-i 8, hydrogen-2, or carbon-i 3. For a given species, the chemical shift can be used to determine the diffusion coefficients of the different compounds in complex mixtures [56]. Diffusion of phosphocreatine, for instance, can be studied by using 31P spectroscopy [23, 57]. Measurement of phosphocreatine is a true probe of intracellular space; in contrast to phosphocreatine, water does not diffuse across cell membranes, so true restricted diffusion can be observed. Phosphocreatine (or N-acetyl aspartate in neurons, which can be studied by using H spectroscopy) can be used to provide exclusive information on the intracellular as its viscosity

or geometry.

Monitoring

of

exchanges of metabolites or drugs through cell membranes could also benefit from similar techniques designed to measure molecular flow [58]. Interventional

AJR:159,

September

1992

and are worth reporting. These results are based on the sensitivity of diffusion to temperature. Temperature changes induced within the magnet bore when a dedicated hyperthermia device or laser beams are used have been shown and measured with diffusion MR imaging [38, 59, 60]. Combined with fast imaging, temperature-diffusion rn-

Spectroscopy

such

AL.

been encouraging

Developments

medium,

ET

MR Imaging

It is premature to describe the future role of MR imaging in interventional radiology, but some pioneering results have

aging

may play a significant

role in the real-time

monitoring

of

interventional or neurosurgical procedures performed within the magnet bore, especially by giving information on tissues not directly visible. Conclusions Diffusion

appears

to be a promising

source

of contrast

for

MR imaging. No correlation exists between the diffusion coefficient and Ti and T2 relaxation times. Ti and T2 may be normal or elevated in diseased states while diffusion is lowered, as shown in early brain ischemia. Whereas Ti and T2 essentially provide anatomic pictures in the context of a long history of clinical imaging techniques, the information brought by diffusion has no real clinical antecedents, so diffusion MR imaging falls into a new territory in the field of radiology.

Furthermore,

diffusion

is not simply

an MR param-

eter; it has a much wider significance independent of MR. However, MR imaging is the only available method for evaluating diffusion in vivo with good accuracy and spatial resolution. With improvements in gradient hardware to produce very large gradient strengths, and continued regard for safety concerns, significant improvements in diffusion accuracy may be expected. It remains that diffusion imaging is not an easy technique. Good immobilization and cooperation of the patient, and sometimes cardiac gating, are essential, even when

echoplanar imaging is used, to avoid misregistration problems. The gradient unit must be of excellent quality to avoid eddy currents or instability-related artifacts. Plenty of work remains

to understand

this phenomenon

fully

the

meaning

and

usefulness

of

for clinical applications.

REFERENCES

Fig. 10.-Series of diffusion-sensitized echoplanar MR images (4000/ 70 [TR/TE]) of rabbit kidneys (128 x 64 pixels, 5-mm thickness, 50-msec acquisition time per image, gradient factors of 0-550 sec/mm2) shows good-quality high-resolution intravoxel inherent-motion-sensitized echoplanar Images can be obtained in body. No motion artifact or blumng is visible. Note that cortex has a greater signal attenuation than medulla when amplitude of diffusion gradient pulses is increased (higher diffusion/ perfusion rate). (Obtained in collaboration with P. Choyke, J. A. Frank, and M. Girton, Bethesda, MD.)

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