Diffusion Tensor Imaging and Its Application to...

named after the English botanist Robert Brown, who in 1827observed the constant movement of minute particles sus-pended within grains of pollen.* We now know that molecularmotion is affected by the properties of the medium in which itoccurs and that diffusion within biological tissues reflectsboth tissue structure and architecture at the microscopiclevel. Equal, or isotropic, diffusion occurs when a mediumdoes not restrict molecular motion, as would be the case withcerebrospinal fluid. Skewed, or anisotropic, diffusion, seen incrystals and polymer films, is not equal in all directions. DTI

REVIEW

Diffusion Tensor Imaging and Its Applicationto Neuropsychiatric Disorders

Marek Kubicki, MD, PhD, Carl-Fredrik Westin, PhD, Stephan E. Maier, MD, PhD, Hatsuho Mamata, MD, PhD,Melissa Frumin, MD, Hal Ersner-Hershfield, BA, Ron Kikinis, MD, Ferenc A. Jolesz, MD, Robert McCarley, MD,

and Martha E. Shenton, PhD

Magnetic resonance diffusion tensor imaging (DTI) is a new technique that can be used tovisualize and measure the diffusion of water in brain tissue; it is particularly useful for evalu-ating white matter abnormalities. In this paper, we review research studies that have ap-plied DTI for the purpose of understanding neuropsychiatric disorders. We begin with a dis-cussion of the principles involved in DTI, followed by a historical overview of magneticresonance diffusion-weighted imaging and DTI and a brief description of several differentmethods of image acquisition and quantitative analysis. We then review the applicationof this technique to clinical populations. We include all studies published in English fromJanuary 1996 through March 2002 on this topic, located by searching PubMed and Medlineon the key words “diffusion tensor imaging” and “MRI.” Finally, we consider potential fu-ture uses of DTI, including fiber tracking and surgical planning and follow-up. (HARVARD REV

PSYCHIATRY 2002;10:324–336.)

From the Clinical Neuroscience Division, Laboratory of Neuroscience,Boston VA Health Care System—Brockton Division, Brockton, Mass.(Drs. Kubicki, Frumin, McCarley, and Shenton; Mr. Ersner-Hershfield); the Department of Radiology, Brigham and Women’sHospital, Boston, Mass. (Drs. Kubicki, Westin, Maier, Mamata, Kiki-nis, Jolesz, and Shenton); and the Departments of Psychiatry (Drs.Kubicki, Frumin, McCarley, and Shenton) and Radiology (Drs. Ku-bicki, Westin, Maier, Mamata, Kikinis, Jolesz, and Shenton), Har-vard Medical School, Boston, Mass.

Original manuscript received 14 February 2002; revised manuscriptreceived 29 May 2002, accepted for publication 6 June 2002.

This work was supported, in part, by grants from the National Al-liance for Research on Schizophrenia and Depression (Drs. Kubickiand Frumin), the Grable Foundation (Dr. Kubicki), the National In-stitutes of Health (K02 MH 01110 and R01 MH 50747 to Dr. Shenton,R01 NS 39335 to Dr. Maier, R01 MH 40799 to Dr. McCarley), andthe National Center for Research Resources (R01 RR 11747 to Dr. Kiki-nis, P41 RR 13218 to Drs. Jolesz and Westin); Department of Veter-ans Affairs Merit Awards (Drs. Shenton and McCarley); and a VAPsychiatry/Neuroscience Research Fellowship Award (Dr. Frumin).

324

Diffusion tensor imaging (DTI) is an exciting recent techniquein neuroimaging that affords a unique opportunity to quan-tify the diffusion of water in brain tissue. It is based upon thephenomenon of water diffusion known as Brownian motion,

Reprint requests: Martha E. Shenton, PhD, Department of Psychiatry–116A, VA Boston Healthcare System—Brockton Division, 940 BelmontSt., Brockton, MA 02301 (e-mail: [email protected]).

© 2002 President and Fellows of Harvard College

*It was long thought that Brown observed the movement of pollengrains suspended in water. Many now believe that he observed themovement of particles suspended within the grains of pollen. See, forexample, BJ Ford, Brownian movement in Clarkia pollen: a repriseof the first observations. The Microscope 1992;40:235–41 (avail-able on the World Wide Web at: http://www.sciences.demon.co.uk/wbbrowna.htm).

measures diffusion properties and consequently allows spa-tial description of the medium under study.

Taking advantage of the fact that diffusion is not uniformthroughout the brain (differing, for example, between graymatter, white matter, and cerebrospinal fluid), researcherscan employ DTI to evaluate tissue characteristics. The tech-nique is particularly useful in the study of white matter tractsin the brain since the mobility of water is restricted perpen-dicular to the axons oriented along the fiber tracts (aniso-tropic diffusion). This is due to the concentric structure ofmultiple tightly packed myelin membranes wrapped aroundthe axon fibers. Although myelination is not essential for dif-fusion anisotropy of nerves (see studies on nonmyelinatedgarfish olfactory nerves1 and on neonate brains prior to theappearance of myelin2,3), myelin is generally assumed to bethe major barrier to diffusion in white matter tracts.

DTI evolved from earlier studies using diffusion-weightedimaging (DWI), a magnetic resonance imaging (MRI) tech-nique in which a single field gradient pulse is applied duringimage acquisition, allowing quantitative measurement of wa-ter diffusion.4 Displacement of water molecules (diffusion)causes randomization of the nuclear magnetic resonance spinphase, which, in turn, results in signal reduction. The amountof reduction provides a quantitative measure of the diffusionin the gradient direction; thus, only diffusion in the directionof this particular gradient can be detected. Since diffusion isa three-dimensional process, three orthogonal measures areneeded to calculate the mean diffusivity for each voxel.

DTI was developed for true multidimensional assessmentof diffusion data in vivo.5,6 In contrast to DWI, DTI measuresat least six different gradient directions. The diffusion datafor each voxel, represented as a 3 × 3 matrix, comprise a dif-fusion tensor (see Figure 1). In isotropic media, where diffu-sion along the three main axes is equal, the diffusion tensor issymmetrical in all directions and is visualized as a sphere. Inanisotropic media, where the diffusion is different along eachaxis, the diffusion tensor is visualized as an ellipsoid, withits longest axis indicating the greatest of the so-called prin-cipal directions of diffusion. The shape of the tensor ellipsoiddepends on the strength of the diffusion along the three prin-cipal directions (i.e., its eigenvectors). Within myelinatedwhite matter fiber tracts, the greatest principal direction ofdiffusion will always indicate the axonal trajectory, since per-pendicular diffusion is restricted by myelin sheathing. Theshape of the tensor ellipsoid therefore provides qualitativeand quantitative measures of white matter tracts withinthe brain.

DWI AND ITS ACQUISITION IN THE BRAIN

DWI was introduced in 1986 by Le Bihan and colleagues.4

From the beginning, however, the widespread application ofthis technique to clinical studies was greatly impeded by tech-

nical constraints, the most important being motion sensitiv-ity, which can cause severe ghosting artifacts or complete sig-nal loss. In attempts to observe molecular displacement inmicrometers, it is no surprise that motion of any sort, evenunavoidable involuntary head movements or pulsations ofblood in the brain tissue, interfere with measurement. Theproblem is even more serious when scans must be obtainedfrom, for example, a disoriented and confused stroke victim,who may move his or her head excessively. These limitationswere a major incentive for the development of faster se-quences that are more robust in the face of bulk motion.

The development of diffusion-sensitive pulse sequencesfollowed two basic directions: echo-planar imaging methods,7

which capture a complete image within a single shot, andnavigator methods,8 which acquire images in multiple shots,with each shot employing “navigator MR signals” to detectand correct the bulk motion. Although single-shot methodsare extremely robust, the elevated sensitivity to magneticfield inhomogeneities inherent in these techniques may leadto image-distortion artifacts, such as susceptibility artifacts,occurring in areas exhibiting large variations in magneticsusceptibility (e.g., interfaces between air, bone, and braintissue), and chemical shift artifacts, caused by the differencein chemical properties of fat and water. Moreover, spatial res-olution is limited, and signal averaging may be necessary.Navigator methods, on the other hand, permit excellent spa-tial resolution with a minimum of image-distortion artifactsand high signal-to-noise ratio, but they are not as robust andrequire acquisition times of 10 minutes or more. Further-more, cardiac gating—that is, synchronization of slice acqui-sition with heart rate—must be used, which makes the tech-nique less attractive in a routine clinical setting. Recently,

Harvard Rev Psychiatry

Volume 10, Number 6 Kubicki et al. 325

FIGURE 1. Difference between unrestricted (isotropic) and restric-ted (anisotropic) diffusion within the brain. The shape of the tensorellipsoid is determined by the strength of the diffusion along threeprincipal directions (its eigenvectors). In nonrestrictive media suchas cerebrospinal fluid, where diffusion is equal in all directions, thetensor can be visualized as a sphere. In restrictive media such aswhite matter, where diffusion is different in all directions, the tensorcan be visualized as an ellipsoid.

researchers have proposed several new techniques (diffusion-weighted radial acquisition of data,9 line-scan diffusion im-aging,10 slab-scan diffusion imaging13) that avoid susceptibil-ity and chemical shift artifacts and allow for resolution higherthan that obtained with echo-planar imaging.

QUANTITATIVE REPRESENTATION OF DIFFUSION IN DWI

As noted previously, the measurement of water diffusion intissues is based on probing the movement of water moleculeswithin the tissue environment. In pure liquids, such as wa-ter, individual molecules are in constant motion in everydirection due to random (Brownian) motion. In tissues, how-ever, various tissue components (larger molecules, intra-cellular organs, membranes, cell walls, and so on) restrict theBrownian motion. In cerebrospinal fluid and many tissues(liver and cerebral gray matter, for example), when averagedover the macroscopic scale of image voxels, this restriction isidentical in every direction—the diffusion is isotropic. In somevery structured tissues, however, such as muscle or cerebralwhite matter, cellular arrangement shows a preferred direc-tion of water diffusion that is largely uniform across the en-tire voxel—the diffusion is anisotropic. The diffusion coeffi-cient is a measure of this molecular motion, and it can bedetermined by applying consecutive magnetic field gradientpulses and then measuring the change between the imagesacquired. Each gradient is typically applied for several tens ofmilliseconds, during which time the average water moleculein brain tissues may migrate 10 or more micrometers in arandom direction. The irregularity of the motion entails a sig-nal loss that can be used to quantify the diffusion constant.This MR measurement, however, fails to differentiate diffu-sion-related motion from blood flow, perfusion, bulk tissue,or tissue pulsation motions. Thus, the diffusion value ob-tained with this technique is not an actual diffusion coeffi-cient, but only an apparent diffusion coefficient (ADC).

DIFFUSION TENSOR IMAGING

The concept of a diffusion tensor was introduced to the field ofMR diffusion imaging by Basser and colleagues in 1994.6 Itis a construct adapted from physics and engineering, where itis employed to describe tension forces in solid bodies with anarray of three-dimensional vectors.

The particular tensors used to describe diffusion can befurther conceptualized and visualized as ellipsoids. The threemain axes of the ellipsoid describe an orthogonal coordinatesystem. The directions of the main axes represent the so-called eigenvectors; their length, the so-called eigenvalues ofthe tensor. In DTI, a tensor that describes diffusion in all spa-tial directions is calculated for each voxel. The longest mainaxis of the diffusion ellipsoid represents the value and the di-rection of maximum diffusion, whereas the shortest axis rep-

resents the value and direction of minimum diffusion. If thethree eigenvalues are equal, then the diffusion is said to beisotropic, and the diffusion tensor can be visualized as asphere. If they are unequal, then the diffusion is said to beanisotropic, and the diffusion tensor can be visualized moreas an ellipsoid, as would be the case for myelin sheaths (seeFigure 1). To estimate the diffusion tensor, at least six mea-surements (taken from different gradient directions) areneeded, in addition to the baseline image data.

White matter fiber tracts consist of a large number ofdensely packed myelinated axons. Because the movement ofwater molecules within this myelinated white matter is sub-stantially restricted perpendicular to the longitudinal axesof the axons, the longest main axis of the diffusion ellipsoidis much larger than the other two and coincides with thedirection of the fibers. Following Westin and colleagues’ geo-metric classification of the diffusion tensor using linear,planar, and spherical measures,12 this type of anisotropicallyrestricted diffusion is termed “linear diffusion.” “Planar dif-fusion” refers to diffusion restricted in one direction only andunrestricted in the other two—for example, between layersof tissue.

The above-mentioned basic ellipsoid model is idealized anddoes not necessarily reflect the true diffusion behavior en-countered in real tissues. For example, at nerve-fiber-tractcrossings, the ellipsoid tensor model fails, since each fibertract registers a principal direction of diffusion. Acquisitionprotocols that measure diffusion in a large number of direc-tions allow for a better description of the complex directionaldiffusion behavior at fiber-tract crossings and in other het-erogeneously organized tissue structures.

Data from DTI can be analyzed in several ways. The mostgeneral approach is to characterize the overall displacement ofthe molecules (average ellipsoid size) by determining mean dif-fusivity. To do so, the trace of the diffusion tensor,4 which is cal-culated as the sum of the eigenvalues of the tensor, is employed.This sum is divided by three to calculate mean diffusivity.

Several measures have been introduced to describeanisotropic diffusion. To be useful, such measures must be in-dependent of the orientation of the diffusion ellipsoid andthus provide information relevant to the specific tissue type.The most commonly used measures, proposed by Basser andPierpaoli,13 are relative anisotropy (RA), a normalized stan-dard deviation representing the ratio of the anisotropic partof the tensor to its isotropic part; fractional anisotropy (FA), ameasure of the fraction of the magnitude of the tensor thatcan be ascribed to the anisotropic diffusion; and volume ra-tio, a measure representing the ratio of the ellipsoid volumeto the volume as a sphere of radius l. These and otheranisotropy indices are summarized in Table 1. Such indicesmeasure the diffusion within each voxel (intravoxel diffusion)separately. A second type of anisotropy measure has been in-troduced to describe the intervoxel coherence of the tensors in

326 Kubicki et al.Harvard Rev Psychiatry

November/December 2002

the neighboring voxels. The latter measures, summarized inTable 2, better reflect fiber organization and orientation atthe macroscopic level.

Like quantifying diffusion tensor anisotropy, displayingtensors in three dimensions also poses a problem. Severalmethods have been proposed for visualizing the three-dimensional information contained in DTI data. These in-clude using the octahedra in each pixel;14 color maps,15 wheredifferent intensities of the three colors indicate the size andthe ADC in each of the three Cartesian directions;16 and bluelines to represent the in-plane component of the principal dif-fusion direction, along with a color-coded out-of-plane com-ponent17 (see Figure 2).

Clinical Applications in Neuropsychiatric DisordersThe phenomenon of restricted diffusion is of particular inter-est to studies that evaluate the integrity of white matter fibertracts, as noted above. Based on geometry and the degree ofanisotropy loss, white matter tract pathology, such as dislo-cation, swelling, infiltration, and disruption, can be docu-mented. In addition, the cross-sectional sizes of these path-ways yield a quantitative measure of connectivity betweendifferent brain regions. For example, disruptions in connec-tivity—and, in some cases, subsequent reorganizationof nerve pathways—resulting from physical trauma or is-chemia, brain tumor, multiple sclerosis (MS), infection withhuman immunodeficiency virus (HIV), schizophrenia, or de-generative or metabolic diseases might be visualized and

quantified. A loss of connectivity between brain regions asmeasured by DTI could indicate developmental pathology, ax-onal damage, demyelination, and/or disruption of fiber tracts.

Brain ischemia. Evaluation of ischemia is one of the earli-est, most important, and most widely used clinical applica-tions of DWI. So far, DWI is the most sensitive in vivo methodfor detecting acute ischemia.18,19 It also allows for the dis-tinction between old and new strokes19,20 and helps to differ-entiate early stroke from other focal brain processes mimick-ing stroke on conventional MRI.21,22 DWI studies23–25 showthat diffusion parameters decrease in the acute stage,“pseudonormalize” in the subacute phase, and increase in thechronic stage of the stroke. Unfortunately, because DWI doesnot reflect the spatial organization of the fiber tracts, it fails todetect long-term white matter changes, either in the closevicinity of the lesion or remote from it.

DTI, on the other hand, is more sensitive to the organi-zation and orientation of the fiber tracts, and research26 al-ready shows better correlation between clinical status andanisotropy indices (e.g., diffusion anisotropy remains de-creased in the subacute stage, even after diffusion coefficientnormalization [between 1 and 3 weeks.]). DTI data are moresensitive to changes in fiber-tract organization (i.e., axonalloss, degeneration, or incomplete remyelination) followinga stroke. Moreover, changes in anisotropy can be detectedseveral months after the stroke—and within the fiber tractsremote from the stroke (e.g., in the corticospinal tract)—



TABLE 1. Anisotropy Indices Used in Clinical Studies

Index Study Description

Anisotropy minor, anisotropy major Shimony et al.77 Measures describing the variation in ellipsoid shape along the majorand minor axes

Eccentricity Tievsky et al.41 Measure describing the ellipsoid nature of the principal and minoraxes with reference to a sphere

Fractional anisotropy Basser & Pierpaoli13 Measure of the fraction of the magnitude of the tensor that can be ascribed to anisotropic diffusion

Geometric measures of anisotropy Westin et al.78 Measures classifying the ellipsoid’s closeness to a line, a plane, or asphere (linear, planar, or spherical diffusion)

Gamma variate anisotropy Armitage & Bastin79 A measure formulated in relation to noise (less sensitive to noise thanother anisotropy indices)

Relative anisotropy Basser & Pierpaoli13 Normalized standard deviation representing the ratio of theanisotropic portion of the tensor to its isotropic portion

Total anisotropy Shimony et al.77 Coefficient of variation determined on the basis of the second moment(variance) of diffusion; similar to relative anisotropy except for ascaling factor of 21⁄2, which places total anisotropy on the absoluteanisotropy scale

Ultimate anisotropy Ulug & Van Zihl76 Ratio of the diffusion ellipsoid’s volume to its surface area; does notrequire tensor diagonalization (as opposed to relative and fractionalanisotropy, which do)

Volume ratio Basser & Pierpaoli13 Measure representing the ratio of the ellipsoid volume to the volume asa sphere with a radius of 1

presumably marking fiber-tract degeneration (walleriandegeneration).27,28

A recent DTI study29 has also demonstrated that ischemicstroke damage in white matter occurs earlier and is more se-vere than previously inferred from DWI investigations. Table3 summarizes all clinical DTI studies published throughMarch 2002 on stroke and other neuropsychiatric conditions.

Traumatic brain injury. As with stroke, DWI has playeda major role in the early detection of brain changes following

traumatic injury. The early increase in ADC seen on DWI isusually attributable to vasogenic edema, whereas later de-creases in ADC (despite ongoing increase of intracranial pres-sure) are usually attributable to cytotoxic edema,30 believed toplay a major role in posttraumatic brain swelling.31

DTI allows a closer investigation of the specific fiber tractsaffected, as well as the ability to monitor the degenerationprocess following injury. Specifically, DTI performed severalmonths after an internal capsule focal brain injury32 demon-strated full recovery and preservation of the structural in-tegrity and orientation in the posterior capsular limb and dis-rupted structure in the anterior limb on the injured side,which correlated with the functional motor deficits revealedby the functional MRI. Moreover, in another DTI study33 apatient who had right frontotemporal brain injury and im-paired memory revealed increased diffusion traces in rightfrontal, temporal, and occipital lobes as well as diffusion



TABLE 2. Intervoxel Diffusion Indices Describing Local Coherence between Tensors

Index Study Description

Correlation measure of Basser & Pierpaoli13 A measure assessed by applying the convolution averaging procedure, organization weighting the scalar matrix products in neighboring voxels more heavily than

those in distant onesGeometric measures of Westin et al.12 Measures obtained by locally averaging the tensors with a low-pass filter and

weighted average tensor applying Westin’s geometric measuresIntervoxel coherence Pfefferbaum et al.50 A measure obtained by averaging the angle between the eigenvector of the largest

eigenvalue of a given voxel and those of its eight neighborsLattice index of anisotropy Pierpaoli & Basser16 A measure that averages diffusion tensors in neighboring voxels, decreasing the

bias and variance of estimated diffusion anisotropy

FIGURE 3. Three-dimensional tractography of a normal subject,showing the anterior (white) and posterior (blue) portions of the cor-pus callosum as well as the left and right (yellow and green) corti-cospinal tracts. These tracts pass through an axial section of the lat-eral ventricles.FIGURE 2. Visualization of diffusion tensors. The blue lines repre-

sent the in-plane component of the principal diffusion direction; theother colors show the magnitude of the out-of-plane component, withorange/red indicating maximal diffusion. The white and green ar-rows point to the corpus callosum and the anterior commissure, re-spectively, two major fiber tracts with the largest in-plane diffusioncomponent, while the blue and pink arrows indicate the cingulateand uncinate fasciculi, fibers with the biggest out-of-plane diffusioncomponent.



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changes in myelinated structures, including the right opticradiation and the forceps major of the corpus callosum, whichcorresponded with clinically predictable symptoms. Thesecase studies suggest that DTI is a powerful new technologyfor investigating functional deficits caused by brain injury,as well as for predicting prognosis.

Brain tumors. DWI has not been particularly useful inbrain tumor differentiation, although it is helpful in detectingthe cystic components of tumors, early edema around thetumor, and ischemic lesions within the pathological mass. Incontrast, DTI can be implemented for modeling fiber-tractdisruptions or displacement caused by the tumor34,35 andcould be useful for early detection of spine metastases, aswell as for detection of corticospinal-tract disruptions ordisplacement.

Seizure disorders. Compared with its use in the detectionand differentiation of early stroke from brain tumor, DWI hasso far played only a minor role in routine interictal imaging.In rats, severe, acute focal damage (expressed in animals ascytotoxic edema, which causes a drop in diffusion) after pro-longed induced seizures can be detected with DWI, especiallywithin the amygdala and piriform cortex.35 These resultshave not been replicated in humans, presumably becausethey show a different mechanism of brain injury (vasogenicedema, which causes an increase in diffusion, coexists withthe cytotoxic edema).

A few existing DTI studies already demonstrate highersensitivity of DTI compared to structural MRI in detectingmalformations of cortical development. Such malformationsdisturb the orientation of the fiber tracts and are a commoncause of epilepsy. Rugg-Gunn and colleagues,37 for example,have shown that changes within the white matter of the lefttemporal lobe can be identified with DTI but not with struc-tural MRI.

Other Conditions Affecting White Matter. DWI has beenshown to be superior in detecting white matter abnormali-ties in MS—abnormalities that are not as readily observedin conventional structural MRI (“normal-appearing whitematter”).38–40 It is hoped that DTI will be of even greatervalue in detecting fiber-tract alterations due to demyelina-tion and axonal loss. DTI studies in patients with MS haveshown an increase in mean diffusivity and a decrease in dif-fusion anisotropy within acute lesions,41 as well as within thenormal-appearing white matter,42 most likely attributable toedema. In addition, DTI has been found to be useful in dif-ferentiating between two types of MS,43 secondary progres-sive and relapsing-remitting, which have different clinicalcourses.

Finally, DTI has demonstrated white matter fiber tractpathology in Krabbe’s disease,44 HIV infection,45,46 amy-

otrophic lateral sclerosis,47 cerebral autosomal dominant ar-teriopathy with subcortical infarcts and leukoencephalopa-thy,48 leukoencephalopathy,49 and chronic alcohol depend-ence.50 In such studies, DTI was able to detect and quantifytherapeutic responses to treatment that are believed to bethe result of decreased edema during the acute phase of in-flammation.44,46 The potential of DTI as an exploratory tool issuggested by a study of patients with chronic alcohol de-pendence50 that revealed a correlation between loss of work-ing memory and attention and a decrease in diffusionanisotropy within the corpus callosum.

Alzheimer’s disease. The early to moderate stages ofAlzheimer’s disease are characterized by impaired cognitionwith preserved mobility.51 Although the disease is believedmainly to affect gray matter, postmortem studies52,53 have re-vealed loss of axons and oligodendrocytes within the whitematter as well. Of note, a recent DWI study54 has shown re-duced diffusion within the splenium and body of the corpuscallosum, findings consistent with previous reports of atro-phy in the corpus callosum in patients with Alzheimer’s dis-ease.55,56 In addition, DTI studies conducted in the earlystages of the disease57,58 have revealed significant connectiv-ity disruptions within the association white matter fibertracts, including the temporal stem (uncinate fasciculus), cin-gulate fasciculus, corpus callosum, and superior longitudinalfasciculus, as well as the hippocampus. Thus, DTI studiesmay improve our ability to track progressive changes inAlzheimer’s disease and could possibly be used in the futureto evaluate changes in response to treatment.

Schizophrenia. Schizophrenia is a disorder of unknownetiology. Although many subtle brain abnormalities havebeen observed in this disorder (see review in reference 59),no brain lesions have been definitively correlated with manyof the functional deficits found in these patients. Of note, how-ever, are several DTI reports of decreased diffusion aniso-tropy in the white matter of persons with schizophrenia. Lossof orientation and organization of fiber tracts has beendetected in the whole white matter60 and in frontal whitematter,61 but also in particular fiber tracts such as the corpuscallosum62,63 and the uncinate fasciculus.64 Further DTIinvestigation of white matter fiber-tract abnormalities inschizophrenia may change how we view this disorder, partic-ularly in providing access to in vivo developmental studiesacross time.

Other possible uses in psychiatric disorders. To date,there are no studies using DTI to investigate white matterabnormalities that have been reported in other psychiatricconditions. MRI has revealed white matter hyperintensitiesin deep and periventricular white matter in patients with af-fective disorders;65 it has also shown deep white matter



lesions to be correlated with poor outcome in bipolar dis-order66 and with degree of residual dysfunction following asevere episode of depression.67 MRI studies in patientswith posttraumatic stress disorder have revealed nonspecificwhite matter lesions, as well as some functional deficits thatmight be attributed to the disconnection of specific corticalregions (i.e., the amygdala, Broca’s region, and the cingulatecortex).68 Correlations between psychiatric symptoms andwhite matter lesions could be further evaluated using DTI.Such testing might be able to determine the specificity of theparticular fiber tracts affected, as well as the extent of theirinvolvement.

Developmental StudiesDevelopmental DTI studies are only just beginning. Investi-gation of normal and abnormal brain development, however,should lead to a better understanding of brain maturation.DWI has, in fact, already revealed greater water diffusion inneonates than in adults,69,70 and there is evidence to suggestthat anisotropic diffusion is higher in full-term neonates thanin preterm neonates,3 a difference most likely due to themyelination of white matter fiber tracts. Such findings sug-gest that diffusion-imaging techniques can detect an increasein myelination during normal development.

In addition, anisotropic diffusion has been observed to de-cline as a result of age-related degenerative processes in-volving white matter fibers and myelin sheaths.71 Whetherthis change is due to normal aging or pathological aging re-mains to be determined. Table 4 summarizes all neurodevel-opmental studies utilizing DTI published through March2002.

Diffusion imaging offers the opportunity to evaluate bothnormal and pathological changes in white matter and brainconnectivity over the life span. Such changes may be impor-tant for understanding not only normal development but alsodifferences in cognitive abilities over time.

Future ApplicationsPotential future applications of DTI include visualization ofthe anatomical connections among different parts of thebrain. Diffusion tensor tractography (see Figure 3), proposedby several authors,72–75 uses the principal diffusion directionmeasured with DTI to compute the pathways of completenerve fiber tracts. The tracing is performed by first definingregions of interest. Then, starting from points (“seed points”)selected within this region and following the spatially inter-polated direction of maximum diffusion in neighboring voxels,the path of fibers within a fiber tract is defined. Such tracking,which is done repetitively with multiple seed points, createsa contiguous path that defines the fiber tract of interest.

Visualization is then performed in three dimensions to de-pict the white matter fiber tract. Progressing from an exam-ination of anisotropy to a more elaborate analysis of the re-lationship between neighboring diffusion ellipsoids opens thepossibility for assessing, in vivo, axonal fiber connectivity andfunctional links among brain regions.

A slightly different approach to tensor tractography, de-scribed by Westin and colleagues,14 attempts to reduce prob-lems encountered when tracing fibers in complex regions(such as where fiber tracts merge, branch, or cross within avoxel) by defining the direction of the trace path in a novelway. Rather than following the direction of the maximum dif-fusivity (the direction of the major axis of the diffusion ellip-soid), this approach “bends” the trace with a strong bias to-ward this direction. Another approach regularizes the tracepath based on its curvature—that is, fixes the curve accordingto a predefined parameter.

Diffusion tensor tractography, combined with informationfrom conventional and functional MR imaging, can provide apowerful tool for neurosurgical planning, especially when sur-gery occurs in the vicinity of vital nerve fiber tracts. Tracingand mapping the passage of functionally relevant fiber tractsalong the tumors is as important as mapping cortical func-



TABLE 4. Neurodevelopmental Studies Utilizing DTI

Study n Measure(s) Findings*

Hüppi et al.3 24 infants: 17 preterm, Diffusivity, RA Anisotropy was higher the closer birth was to term7 full-term

Klingberg et al.91 7 children, 5 adults FA, Tr Anisotropy in frontal white matter was lower in children than in adults

Pfefferbaum et al.71 31 healthy men, ages Diffusivity, FA, IC Anisotropy declined with age in all regions except the splenium 23–76 y of the corpus callosum

Nusbaum et al.92 20 healthy volunteers, RA, diffusivity Anisotropy decreased significantly with increasing age in ages 20–91 y histograms periventricular white matter, frontal white matter, and the

genu and splenium of the corpus callosum

FA, fractional anisotropy; IC, intervoxel coherence; RA, relative anisotropy; Tr, diffusion trace.*All findings reported are significant at p ≤ 0.05.

tions adjacent to tumors. The information gathered withthese complementary techniques helps the neurosurgeon todecide where tumor tissue can be excised without permanentneurological consequences.

In addition, DTI, as mentioned above, can be used to followup surgical and neurological treatment (by assessing the re-generation and/or remyelination of the affected fiber tracts),as well as to monitor the effects of medication. Finally, in dis-orders such as schizophrenia, where gross brain abnormali-ties are not evident, DTI may offer an opportunity to evaluatesubtle changes in white matter fiber tracts that are relatedto neurocognitive abnormalities observed in this disorder.Such information might further our knowledge of brain-connectivity abnormalities and lead to more-targeted phar-macological treatments as well as to a better understandingof brain-behavior links in this devastating disorder.

In summary, DTI has opened up new research possibili-ties in areas that previously relied largely upon postmortemstudies. For the first time, the intricate connective architec-ture of the most complex human organ can be studied nonin-vasively. Other potentially important applications for thistechnique, such as characterization of cardiac muscle tissuearchitecture, diagnosis of liver disease, mapping of tissuetemperature, and diffusion spectroscopy, are beyond the scopeof this article. It is clear that DTI could revolutionize what isknown in many different domains of medicine and disease.The ability to visualize white matter fiber tracts in the hu-man brain, in vivo, will likely be critical to a new under-standing of brain structure and function, both in normal in-dividuals and in those with a neuropsychiatric disorder.

The authors would like to thank Marie Fairbanks for her admin-istrative assistance.

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