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Epilepsia, 49(2):189200, 2008

doi: 10.1111/j.1528-1167.2007.01378.x

CRITICAL REVIEW AND INVITED COMMENTARY

Diffusion-based magnetic resonance imaging and

tractography in epilepsyMahinda Yogarajah and John S. Duncan

Department of Clinical and Experimental Epilepsy and National Society for Epilepsy, Institute of Neurology,

University College London, Queen Square, London, United Kingdom

SUMMARYDiffusion-based imaging is an advanced MRI tech-

nique that is sensitive to the movement of water

molecules, providing additional information on the

micro-structural arrangement of tissue. Qualita-tive and quantitative analysis of peri, post and in-

terictal diffusion images can aid the localization of

seizure foci. Diffusion tensor tractography is an ex-

tension of diffusion-based imaging, and can provide

additional information about white matter path-

ways. Both techniques are able to increase under-

standing of the effects of epilepsy on the structural

organization of the brain, and can be used to opti-

mize presurgical planning of patients with epilepsy.

This review focuses on the basis, applications, lim-

itations, and future directions of diffusion imagingin epilepsy.

Literature search strategy: We searched Pubmed

using the terms diffusion MRI or diffusion tensor

MRI or tractography and epilepsy.

KEY WORDS: Diffusion, Diffusion tensor, MRI,

Tractography, Ictal, Postictal.

Magnetic resonance imaging (MRI) is central to the as-

sessment of individuals with refractory epilepsy, enabling

the identification of the underlying epileptogenic substrate,and if surgical treatment is considered, depicting the rela-

tionship of the epileptogenic lesion and zone to eloquent

areas of the brain such as the motor, language, or memory

areas.

Diffusion-based MRI and tractography can provide valu-

able information in the evaluation of an individual with

epilepsy. Diffusion-based MRI has the potential to identify

potentially epileptogenic abnormalities, including those

that appear normal on standard MRI sequences. Tractog-

raphy may be used to map white matter tracts, and their

relationship to epileptogenic tissue and eloquent cortex.

This information may be used to improve surgical plan-ning in order to minimize postoperative deficits including

memory, language, and visual field loss. Furthermore, it

also has the potential to aid understanding of the acute

Accepted August 31, 2007; Online Early publication October 18, 2007.

Address correspondence to Prof J. S. Duncan, Department of Experi-mental and Clinical Epilepsy, Institute of Neurology, University CollegeLondon, Queen Square, London WC1N 3BG, United Kingdom E-mail:

[email protected]

Blackwell Publishing, Inc.C 2008 International League Against Epilepsy

and chronic pathophysiological effects of seizures on the

brain.

THE BIOLOGICAL AND PHYSICALBASIS OF DIFFUSION IMAGING

In a free medium the molecular diffusion of water refers

to the random translational motion (Brownian motion)

of molecules resulting from the thermal energy carried

by these molecules. In the brain, diffusion is restricted

by intra- and extracellular boundaries, and represents the

effects of several variable, independent factors. These

include the presence of impermeable or semipermeable

membranes (Hansen, 1971), macromolecules that hinderthe diffusion of small molecules, and intra- and extracel-

lular microcirculatory effects (Le Bihan et al., 1992; Le

Bihan & Turner, 1992). The measurement of water dif-

fusion therefore provides a means of probing cellular in-

tegrity and pathology (Le Bihan, 2003).

The principles of diffusion MRI were first developed in

vivo in the mid 1980s (see Le Bihan, 1995 for review).

In diffusion-weighted imaging (DWI), images are sensi-

tized to the diffusional properties of water by the incorpora-

tion of pulsed magnetic field gradients into a standard spin

echo sequence (Merboldt et al., 1985; Taylor & Bushell,

1985). By taking measurements in at least three directions,

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M. Yogarajah and J. S. Duncan

it is possible to characterize the mean diffusion properties

within a voxel in the image by way of a single scalar ap-

parent diffusion coefficient (ADC). Early diffusion studies

discovered that ADC measurements depended on a sub-

jects orientation relative to the magnet and gradient coils

(Hajnal et al., 1991). White matter tracts parallel to an ap-plied gradient had the greatest ADC whereas those lying

oblique or transverse to a gradient had smaller ADC val-

ues. This gave rise to the concept of asymmetry of diffusion

of molecules in three directions, or anisotropy (Basser,

1995).

Diffusion tensor imaging (DTI) enables not only the

quantification of water molecule diffusion, but also the

characterization of the degree and direction of anisotropy

(see Le Bihan et al., 2001 for review). The diffusion tensor

is a mathematical construct that can be calculated from a

nondiffusion-weighted image plus six or more diffusion-

weighted measurements along noncollinear directions. Thetensor can be diagonalized to give three eigenvectors, 1,2, and 3 representing the principal directions of diffu-

sion, and three eigenvalues 1, 2, and 3 representing the

magnitude of diffusion (or the corresponding ADC values)

along these directions. Furthermore, a number of diffusion

parameters can be derived in each voxel, which are insensi-

tive to subject positioning and fiber tract alignment within

the diffusion gradients of the MRI scanner (Basser et al.,

1994; Pierpaoli et al., 1996). Mean diffusivity (MD) is a

summary measure of the average diffusion properties of a

voxel and is equivalent to the estimated ADC over three

Figure 1.

(A) Axial diffusion-weighted image. The dark end of the gray scale represents areas of increased diffusion, and the

bright end areas of restricted diffusion. Diffusion is greatest in the CSF, which therefore appears dark. Diffusion-

weighted images are T2 sensitive, such that bright regions of high T2 signal that are not diffusion restricted persist

in the diffusion-weighted images (T2 shine through). For this reason the calculation of an ADC map that is

independent of this effect is useful. Bright T2 signal and decreased ADC drive DWI signal intensity up whereas low

T2 signal and high ADC drive DWI signal intensity down. (B) Axial ADC map describing the ADC value in each

voxel. The bright end of the gray scale represents increased diffusion, and the dark end areas of decreased diffusion.

Diffusion is greatest in the CSF, which therefore appears bright. (C) Fractional anisotropy map describes the degree

of diffusion anisotropy in each voxel. In white matter where anisotropy is high the bright end of the gray scale is

assigned. In gray matter where anisotropy is low, the dark end of the gray scale is applied.

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orthogonal directions. Fractional anisotropy (FA) on the

other hand is an estimate of what proportion of the mag-

nitude of the diffusion tensor is due to anisotropic diffu-

sion. Quantitative maps of these parameters can also be

constructed, and used to make comparisons between indi-

viduals or populations (Fig. 1).Diffusion anisotropy in cerebral tissue is highly hetero-

geneous due to several factors including, the concentration

of macromolecules and intracellular organelles, regional

differences in the density of nerve fibers, the degree of

myelination, fiber diameter and the density of neuroglial

cells (Beaulieu, 2001). Anisotropy in white matter results

from the organization of tissue as bundles of axons and

myelin sheaths run in parallel, and the diffusion of water

is freer and quicker in the long axis of the fibers, than in

the perpendicular direction (Beaulieu, 2001). Malforma-

tions or acquired insults cause disruption to the microstruc-

tural environment, and more often than not, a subsequentreduction in anisotropy. Such abnormalities may also lead

to a reduction in cell density and/or expansion of the extra

cellular space, resulting in an increase in MD/ADC.

PER I- AN D POSTICTAL CHANGES INDIFFUSION

Seizure-associated changes in diffusion parameters are

not static, but have a dynamic profile. These changes are

observed in both animal and human studies, and generally

show a pattern of early postictal depression, followed by

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Diffusion-based MRI and Tractography in Epilepsy

normalization, and then transient or chronic elevation of

the ADC/MD (Righini et al., 1994).

Animal studies

A considerable body of animal data has shown that

diffusion-weighted MRI can visualize the histopathologi-cal changes that result from seizures in animal models. The

first reported study, by Zhong et al., demonstrated a fall of

15% in the ADC in bicuculline-induced status epilepticus

in rats (Zhong et al., 1993). Other models have shown sim-

ilar reductions in ADC values that are in proportion to the

severity of seizure activity (Prichard et al., 1995; Zhong

et al., 1995, 1997).

The ictal and postictal changes seen in the ADC are sim-

ilar to those seen in cerebral ischaemia, and both share a

common biological basis, namely the loss of membrane

function and ion homeostasis. Cerebral ischaemia leads

to a failure of energy metabolism, membrane dysfunction,and cell death. Sustained seizures on the other hand lead

to an increased metabolic rate. This is coupled to an in-

crease in cerebral blood flow (Szabo et al., 2005), so that

cellular energy values are close to normal, though in pro-

longed ictal activity, the increased metabolic activity may

not be matched by enhanced blood flow (Bruehl et al.,

1998). The early ADC decline seen in prolonged seizures

is thought to reflect cytotoxic oedema (Wang et al., 1996),

and a decrease in the extra cellular space volume frac-

tion of up to 30% at the area of maximum neuronal activ-

ity in the cortex (Lux et al., 1986). This in turn leads to

increased extracellular tortuosity and decreased diffusiv-

ity. Seizures cause increased membrane ion permeability

(McNamara, 1994) leading to an influx of sodium, cal-

cium, and water along the osmotic gradient (Wang et al.,

1996), which cannot be compensated for by an energy de-

ficient sodiumpotassium ion ATP pump. Intracellular cy-

toskeletal fragmentation that increases intracellular tortu-

osity and viscosity, may also contribute to restricted diffu-

sion (van der Toorn et al., 1996).

While cytotoxic oedema is the most common patho-

physiological effect of seizures found in cortical gray mat-

ter, vasogenic oedema has also been reported less com-

monly in subcortical white matter (Tanaka et al., 1992).

Animal studies have demonstrated that seizures can alsotrigger acidosis and the breakdown of the blood brain bar-

rier (Nitsch & Klatzo, 1983). This, together with local va-

sodilatory effects, can give rise to vasogenic oedema and

an increase in intercellular space and diffusivity (Nedelcu

et al., 1999).

Though cytotoxic oedmatous changes are not necessar-

ily irreversible, with prolonged seizures, diffusivity and the

ADC can change permanently (Nedelcu et al., 1999). Ex-

citotoxic mechanisms mediated by excitatory amino acids,

calcium influx, ATP depletion, and lactate accumulation

eventually lead to cell atrophy and death (Wasterlain et al.,

1993). This cell lysis results in an increase in extracellu-

Figure 2.

(Adapted with permission from Wieshmann et al., 1997)

DWI in a patient with complex partial status epilepticus

affecting the right leg. Decreased diffusion is visible in

the motor cortex, and increased diffusion is visible inthe subcortical white matter. This corresponded to

a relative decrease in ADC of 27% and increase in

ADC of 31% in the cortical and subcortical tissue,

respectively.

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lar space and an increase in diffusion above normal values,

which correlates with histopathological changes in both the

seizure focus and secondarily affected areas (Pitkanen et

al., 2002; Hasegawa et al., 2003).

Clinical studies

Status epilepticus

Early clinical studies assessed diffusion-weighted imag-

ing in patients with status epilepticus. In a patient with

focal motor status epilepticus consisting of clonic jerking

of the right leg, a 27% relative decrease in the ADC was

demonstrated in the motor cortex of the right leg (Wiesh-

mann et al., 1997). There was also a 31% relative increase

in the ADC of the subcortical white matter (Fig. 2). This

finding was thought to represent a shift of water into corti-

cal cells at the seizure focus, and a shift of water into ex-

tracellular space in remote white matter due to vasogenicoedema (Lux et al., 1986). Similar findings in other case

reports hint at the complex osmotic relationship between

epileptogenic and surrounding areas, and cytotoxic and va-

sogenic oedema (Kim et al., 2001; Hong et al., 2004).

Other studies have broadly corroborated these results in-

cluding a small case series, where cortical ADC reductions

of up to 36% were found during partial status epilepticus

(Lansberg et al., 1999).

Early clinical reports also suggested that there were

significant correlations between the areas of diffusion

abnormalities, and increased perfusion and electrocortico-

graphic abnormalities (Diehl et al., 1999; Flacke et al.,Epilepsia, 49(2):189200, 2008

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2000; Calistri et al., 2003). In a study of 10 patients with

complex partial status epilepticus there was correlation

between focal swelling and hyperintensity on T2-weighted

images and increased signal on DWI images (Szabo et

al., 2005). ADC values were reduced by 11 to 37%, and

there was a close spatial correlation of diffusion weightedand perfusion imaging (PI) changes, hyperperfusion on

SPECT, and localization of EEG focus. These abnormal-

ities normalized in most patients by day 14. In many cases

however, DWI revealed abnormalities in several different

regions, and it was problematic to differentiate changes in

areas of seizure focus, and changes in the epileptic corti-

cal and subcortical networks that underlie seizure spread

(Lansberg et al., 1999; El Koussy et al., 2002). The authors

therefore concluded that it would be difficult to locate the

epileptogenic focus using DWI and PI alone.

Single seizuresThere have also been several studies of diffusion imag-

ing following single seizures (Table 1). The interpretation

of these studies is limited by a number of factors. These

include, small numbers of heterogeneous patients, varying

methods of analysis (including a priori region of interest

(ROI) and whole brain voxel-based methods), lack of con-

trol groups or follow-up scanning, and wide variability in

the duration of both seizure, and interval from seizure to

scan.

Salmenpera et al. (2006b) used DWI to study changes

in diffusivity after single seizures. In 21 patients with in-

tractable focal epilepsy, postictal decreases were found in

52% seizures, but in 17% of seizures there were increases

Table 1. Postictal diffusion studies

Authors Findings

Diehl et al., 2001 1/7 had significant ADC compared with contralateral side after a single seizure

Areas of diffusion change maximal adjacent to hippocampus (unclear if seizure onset or seizure spread zone)

Hufnagel et al., 2003 2/9 patients had significant ADC postictally compared to interictally

Changes colocalized with postulated seizure focus

Konermann et al., 2003 10 patients with TLE scanned before and after injection with flumazenil

Significant ADC in all patients postictally compared with interictally

Changes colocalized with postulated seizure focusOh et al., 2004 9/14 patients had significant ADC postictally compared to interictally

Changes colocalized with postulated seizure focus

Significant difference seen only in patients with neocortical ictal onset zones or in neocortical portion of temporal

lobeauthors hypothesize this is due to interictal chronic ADC in hippocampus of mTLE patients masking any

postictal decrease

Diehl et al., 2005 8/18 patients had significant MD postictally compared with interictally which were focal in seven patients

(including one with MD)

In 3 patients presumed epileptogenic zone colocalized with the area of MD decrease

No changes in FA seen suggesting that single short seizures cause changes in cell hydration but not the

directionality of diffusion

Salmenpera et al., 2006b 21 patients scanned after 23 seizures

Focal diffusion changes (significant or in MD) seen in 52% of seizures postictally compared with interictally

Changes colocalized with postulated seizure focus in 4 patients

in MD. The analysis used voxel-based methods to include

data from the whole brain, and the resulting spatial dis-

tribution of diffusion changes was complex, with postictal

changes in MD often being found distant to the putative

seizure focus. This implied involvement of a widespread

epileptic network, and not a single focus (Fig. 3). Theincreases in MD, which were detected together with the

decreases in postictal scans that were acquired soon af-

ter seizures, were thought to be due to vasogenic oedema.

Concordance with the presumed epileptogenic focus was

seen in only four patients, all of whom had postictal scans

within 45 min of seizure onset. Repeated postictal scans

showed a gradual return to baseline for both the increases

and decreases in MD.

In an effort to minimize the delay between seizure and

scan, Konermann et al. administered intravenous flumaze-

nil, during scanning. They consistently demonstrated sig-

nificantly reduced ADC in hippocampi and parahippocam-pal gyri, ipsilateral to the seizure onset, in a series of 10 pa-

tients with refractory TLE (Konermann et al., 2003). Fur-

ther work by the same group without the use of flumazenil,

identified diffusion changes postictally in only two out of

nine patients, in whom complex partial seizures were of du-

ration greater than 60 s, and seizure to scan time was less

than 15 min. Generalized seizures were associated with

global ADC change (Hufnagel et al., 2003).

These studies suggest that the diffusion changes visu-

alized with MRI after single seizures are more transient

than those after status epilepticus, and are complex in terms

of their distribution and evolution of change. The inher-

ent difficulties in scanning patients directly after seizures,

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Figure 3.

(Adapted with permission from

Salmenpera et all. 2006b)

Difference analysis (areas of de-creased diffusivity postictally are

compared with interictal values) of

a patient with left temporal lobe

epilepsy scanned 40 min after a

complex partial seizure. The areas

of change are overlaid in color on

the patients normalized b0 image,

and this shows decreased mean

diffusivity postictally in the bilat-

eral cingulate cortex compared to

the interictal image. Red arrows

refer to the mean diffusivity val-ues measured from the areas of

change at different time points

(II = interictal, PI = postictal).

Epilepsia C ILAE

the evident involvement of a cerebral network and not of

a single focus, and the physical limitations of spatial res-

olution limit the sensitivity of the technique in the local-

ization of seizure foci. Technological advancements such

as, real time motion correction, open access scanners, and

fast acquisitions may overcome these limitations and re-sult in postictal diffusion MRI becoming a useful clinical

tool.

Interictal studies

Early interictal diffusion imaging studies of patients

with epilepsy concentrated on temporal lobe epilepsy

(TLE) and hippocampal Sclerosis (HS) and found in-

creased average ADC values in sclerotic hippocampi, com-

pared with the contralateral side and control subjects. This

suggested structural disorganization and an expansion of

extra cellular space, and was thought to reflect neuronal

loss, reduction of dendritic branching, and microstruc-tural changes associated with epileptogenesis (Hugg et al.,

1999; Wieshmann et al., 1999a; Kantarci et al., 2002; Yoo

et al., 2002; Assaf et al., 2003; Hakyemez et al., 2005).

Furthermore, in those patients who undergo surgery, ADC

measures may be a useful postoperative prognostic indi-

cator (Goncalves Pereira et al., 2006). Studies using high-

resolution DTI have also found abnormal anisotropy val-

ues in the hippocampus compared to healthy control sub-

jects, though to a lesser magnitude than mean diffusivity

changes (Salmenpera et al., 2006a). Abnormalities in the

diffusion parameters of hippocampi ipsilateral to seizure

onset, which are normal on conventional MRI have also

been found. This suggests that diffusion MRI may be more

sensitive in identifying abnormal cerebral tissue than stan-

dard MRI sequences (Assaf et al., 2003; Londono et al.,

2003). Wehner et al. assessed 22 patients with TLE, and

found that in the 14 patients with MRI defined hippocam-

pal sclerosis, the ADC was significantly greater in the ipsi-lateral HC compared with the contralateral side, and could

be used to lateralize the seizure focus (Wehner et al., 2007).

In the remaining patients without HS, the ADC of the hip-

pocampi were not significantly different to the contralateral

side, but were significantly less than in controls. Analysis

of the resected specimens confirmed hippocampal sclero-

sis in those MR positive patients, but revealed gliosis only

without any apparent neuron loss or hippocampal sclerosis

in the MR negative group. The authors postulated that bi-

lateral temporal lobe abnormalities in some patients with

TLE might explain why diffusivity did not provide later-

alizing information in patients with nonlesional MRI, andthis appears to be have been borne out by other studies (Lee

et al., 2004). Diffusion-based studies that have specifically

assessed normal looking tissue, beyond ipsilateral mesial

temporal lobe structures in TLE patients, have demon-

strated bilateral changes together with extratemporal ab-

normalities (Arfanakis et al., 2002; Thivard et al., 2005b;

Gross et al., 2006). This suggests that structural or func-

tional abnormalities (metabolic changes, subtle structural

lesions) may extend beyond the seizure onset zone in uni-

lateral mesial TLE associated with HS.

Diffusion imaging is also sensitive to patients with

epilepsy and nonprogressive acquired lesions such as

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Figure 4.

(Adapted with permission from Dumas et al., 2005)

(AC) Frontal lobe dysplasia in a 31-year-old patient. (A) FLAIR sequences showing subtle hyperintensity of the

left frontal lobe (arrow). (B) Fractional anisotropy (FA) map. Area of decreased FA of the left frontal lobe, more

extensive than the area of FLAIR signal abnormality. (C) Superposition of FA (using a color scale) and FLAIR images.

Epilepsia C ILAE

cerebral ischaemic lesions and perinatal hypoxia (Wiesh-

mann et al., 1999b, 1999c, Rugg-Gunn et al., 2001). Ar-

eas of increased MD and decreased FA correlate with

abnormalities identified on visual inspection of conven-

tional MR imaging, and are concordant with neuronal loss,

gliosis, and structural disorganization. Moreover, diffusion

imaging can often pick up areas of pathology beyond the

conventional margins of acquired lesions seen on stan-

dard MRI, again suggesting additional sensitivity from DTI

(Rugg-Gunn et al., 2001).

Patients with epilepsy and malformations of cortical de-velopment (MCD) have also been studied with diffusion-

based MRI (Wieshmann et al., 1999b). Eriksson et al. used

a voxel-based method to assess the whole brains of 22 pa-

tients with several types of MCD (Eriksson et al., 2001).

Fifteen and eight patients had reduced anisotropy and in-

creased diffusivity within the MCD respectively, which

suggests a loss of directional organization and relatively

preserved cell density. Moreover, diffusion abnormalities

were also found beyond the margins of the evident MCD

in areas that appeared normal on conventional MRI. Con-

sistent with these findings, Dumas et al. used a ROI-based

method to assess both areas of MR visible abnormality, and

normal appearing cerebral tissue in 15 patients (Dumas etal., 2005). They identified significantly reduced anisotropy

in normal appearing white matter adjacent to, and 23

cm distant from several types of cerebral lesion, includ-

ing MCDs (Fig. 4). Histological examination of resected

normal looking tissue revealed the presence of occult ab-

normalities such as gliosis, infiltrative tumor cells, and ax-

onal loss. Together these findings suggest that diffusion

imaging can often pick up areas of pathological abnormal-

ity beyond the conventional margins seen on standard MR

images, which has implications for the surgical resection

margins of these areas.

Interictal DTI is also able to identify focal abnormali-

ties in patients with focal epilepsy, and unremarkable con-

ventional MRI (Fig. 5). In one of the earliest studies, in-

creased diffusivity was found in eight patients and reduced

anisotropy was found in two patients out of a total of 30

patients with refractory focal epilepsy, and unremarkable

conventional MRI (Rugg-Gunn et al., 2001). In seven, the

areas of abnormal diffusion corresponded with the local-

ization of EEG focus. A group analysis of the nine patients

with electroclinical seizure onset localizing to the left tem-

poral region revealed a significant increase in diffusivity,and reduction in anisotropy within the white matter of the

left temporal lobe. The areas of abnormal diffusion were

postulated to be caused by disruption in the microstruc-

tural environment due to etiological factors such as occult

dysgenesis, or acquired damage, or as a result of repeated

seizures leading to neuron loss, gliosis, and expansion of

the extra cellular space. This study suggested that diffu-

sivity is a more sensitive diffusion index than anisotropy

for identifying occult abnormalities in patients with nor-

mal, conventional MRI. This may represent expansion of

the extra cellular space but retention of the overall struc-

tural organization of the white matter tracts. A patient from

this study, with cryptogenic frontal lobe epilepsy, had fo-cally increased MD in the right frontal lobe. Subsequent in-

tracranial EEG concluded that this was the area of seizure

onset, and led to a resection. Histopathologic examination

of the resected specimen showed marked white matter glio-

sis, associated with structural disorganization, and expan-

sion of the extra cellular space (Rugg-Gunn et al., 2002).

Six years following surgery, seizures have been reduced by

more than 50% the preoperative rate.

Subsequent studies have corroborated these findings,

and investigated the correlation between DTI mea-

surements and stereo-electroencephalographic (SEEG)

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Figure 5.

(Adapted with permission from Thivard et al., 2006)

View of a 3D representation of the brain of a patient with occipital lobe epilepsy and reported normal conven-

tional MRI. Diffusion imaging revealed a region of increased ADC (red) in the left temporo-occipital junction. This

corresponded to the onset zone (blue) and irritative zone (green) as delineated by intracranial EEG.

Epilepsia C ILAE

recordings in patients with cryptogenic focal epilepsy

(Thivard et al., 2006; Guye et al., 2007). These studies havefound good spatial concordance between epileptiform ac-

tivity on EEG and diffusion abnormalities in nearly 50%

(6/13 and 4/9, respectively) patients. They also found that

diffusivity, rather than anisotropy measures, correlated bet-

ter with electroclinical data. Furthermore, in those patients

who have undergone surgery for their epilepsy, this has of-

ten translated into a good postoperative outcome, suggest-

ing that DTI can provide additional information over con-

ventional MRI in the identification of occult abnormalities.

Despite the encouraging nature of these results, it is

important to note that in several of the aforementioned

studies, details of the conventional MRI sequences used

were not available. Tertiary referral centers can increasetheir diagnostic yield in patients with refractory epilepsy,

with the use of epilepsy-specific, high-resolution volumet-

ric imaging (Von Oertzen et al., 2002). In those cases that

remain MR negative after such imaging, interictal diffu-

sion imaging has a role to play. The derivation of quanti-

tative ADC/MD/FA maps and their analysis either by ROI

or VBM methods provides a useful tool in the localiza-

tion of subtle structural abnormalities, as part of a multi-

modality evaluation that should include interictal and ictal

EEG recordings, neuro psychiatric and psychological eval-

uations and other imaging modalities such as PET, SPECT,

or magnetoencephalography (MEG).

TRACTOGRAPHY AND EPILEPSY

Knowledge of the anatomy of white matter connections

is crucial to the understanding of normal and abnormal

brain function (Ffytche & Catani, 2005). With conventional

MRI variations in white matter signal are subtle, and white

matter tracts cannot be accurately parcellated. In most stud-

ies, DTI quantitative measures have been assessed using

either region of interest or voxel-based analysis. The for-

mer has limitations in that it is user dependent, and has a

possibility of error that other fiber tracts, gray matter and

CSF or other white matter structures may be included. The

latter, though observer independent, has problems associ-

ated with the need for spatial normalization and smoothingdue to anatomical variations in ventricular size, gyral pat-

terns, etc. Both methods have limited ability to quantify

specific white matter pathways along their entire trajecto-

ries. Tractography is an extension of DTI, whereby the di-

rectional information obtained in each voxel is used to gen-

erate virtual, three-dimensional white matter maps. These

maps are based on similarities between the diffusion prop-

erties of neighboring voxels in terms of shape (quantita-

tive diffusion anisotropy measures) and orientation (princi-

pal eigenvector map), and several mathematical algorithms

have been devised to generate white matter tracts (Mori &

van Zijl, 2002).Epilepsia, 49(2):189200, 2008

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Tractography does not therefore trace fibers in the sense

that injected tracers do; rather it demonstrates the path of

least resistance to water diffusion. The size of typical imag-

ing voxels is a 23 mm3 so a single voxel could contain

thousands of axons. In addition most methods assume that

fibers at each voxel are well described by a single orienta-tion estimate. This can lead to tracking difficulties in areas

of fiber kissing or crossing. As methodological develop-

ments occur in orientational (Tuch et al., 2002) and spatial

resolution (Nunes et al., 2005), and in diffusion model-

ing (Tournier et al., 2004; Tuch, 2004; Alexander, 2005;

Perrin et al., 2005) and tractography algorithms (Parker &

Alexander, 2005), these limitations should prove less of a

problem.

Despite these limitations tractography is the only tech-

nique available for tracing the white matter pathways in the

living brain. By isolating specific pathways from adjacent

gray and white matter and CSF, tract-specific qualitativeand quantitative information such as volume, anisotropy,

and connectivity indices can also be derived (Ciccarelli

et al., 2003a). Tracts can also be normalized and combined

to generate group maps that indicate how reproducible a

given tract or connection is across a group of subjects (Ci-

ccarelli et al., 2003b). This information can be used to lo-

cate and assess the pathophysiological effects of chronic

epilepsy on the white matter anatomy, including the struc-

tural reorganization of higher cortical functions such as

language and memory. The technique can also be used

to investigate white matter anatomy (Catani et al., 2002),

which can aid preoperative planning, and prevent damage

to eloquent cortical functions, particularly when combined

with functional activation studies (Guye et al., 2003).

Reorganization of language and memory networks

Refractory TLE due to HS has a good outcome follow-

ing anterior temporal lobe resection (ATLR). TLE may be

associated with disrupted lateralization of language and

material specific memory, and these functions may be fur-

ther impaired by ATLR. Significant, selective language

deficits have been reported in up to 40% of patients fol-

lowing dominant ATLR (Davies et al., 1998). Patients un-

dergoing unilateral ATLR for refractory TLE also typically

show a decline in verbal memory following surgery involv-ing the language-dominant hemisphere (Ivnik et al., 1987)

and deficits in topographical memory following nondom-

inant temporal lobe resection (Spiers et al., 2001). Func-

tional MRI studies have demonstrated the reorganization

of both memory (Powell et al., 2007b) and language func-

tions in TLE patients (Adcock et al., 2003; Thivard et

al., 2005a). DTI tractography has the potential to demon-

strate the structural reorganization of networks involved in

memory and language, which mirror changes in cerebral

function.

Powell et al. (Powell et al., 2007a) combined fMRI

and tractography in patients with unilateral TLE, and

in controls. Verb generation and reading comprehension

paradigms were used to define functional regions that were

used to generate starting regions for tractography. Trac-

tography was carried out using diffusion images acquired

with a high angular resolution technique, and a proba-

bilistic algorithm. This technique is thought to cope betterwith crossing or kissing fibers (Parker & Alexander, 2003).

Controls and right TLE patients had a left-lateralized pat-

tern of both language-related activations, and associated

white matter organization. Left TLE patients showed more

symmetrical language activations, along with reduced left

hemisphere and increased right hemisphere white matter

pathways, in comparison with both controls and right TLE

patients (see Fig. 6). Correlations between measures of

structure and function in both groups were found, with

subjects with more lateralized functional activation having

more lateralized white matter pathways.

Other tractography studies have assessed memory-related structures within the limbic system. Concha et

al. found that patients with unilateral TLE have bilateral

changes in the fornix and cingulum bundle, characterized

by impaired tracking of these pathways, and increased

mean diffusivity and reduced FA along them. This was

thought to be consistent with the degeneration of path-

ways connecting to the hippocampus (Concha et al., 2005).

Other studies have assessed the progression of Wallerian

degeneration in the limbic structures in patients with re-

fractory epilepsy who have undergone surgical procedures

such as corpus callostomy (Concha et al., 2006) and tem-

poral lobe resections (Concha et al., 2007). Together, these

results suggest that the use of tractography-derived quanti-

tative measures may have a significant role to play in the

longitudinal evaluation of the effects of epilepsy on the

brain, and on cognitive functions such as memory and lan-

guage, particularly when correlated with neuropsychologi-

cal measures (Lui et al., 2005).

Visual pathways and preoperative planning

ATLR can also cause visual field defects (VFD) in up

to 10% of patients. Indeed, in 5% it can be severe enough

to render the patient ineligible for a driving license, de-

spite being seizure-free (Manji & Plant, 2000). Typically,

VFDs after ATLR occur in the superior homonymous fieldcontralateral to the resection and are due to disruption of

fibers of Meyers loop. The anterior extent of the Meyer

loop is not visualized on conventional imaging and varies

from person to person (Ebeling & Reulen, 1988). As a con-

sequence the occurrence and extent of a postoperative VFD

cannot be accurately predicted by conventional MRI, or

from the extent of resection performed. Tractography has

been used to demonstrate the optic radiation in normal sub-

jects (Yamamoto et al., 2005), and has been applied to pre-

and postoperative surgical patients with AV malformations

and tumors in and around the visual pathways. Kikuta et

al. (Kikuta et al., 2006) carried out pre- and postoperativeEpilepsia, 49(2):189200, 2008doi: 10.1111/j.1528-1167.2007.01378.x

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Figure 6.

(Adapted with permission from Powell et al., 2007a)

Group variability maps of the connecting paths tracked

from left and right functionally defined frontal ROIs for

each of the three groups controls, left TLE and right

TLE patients. Each image shows the maximum inten-

sity of the commonality maps in each plane of view

as a brain surface rendering. The color scale indicates

the degree of overlap among subjects (expressed as

commonality value); for example, a value of 1 (pure

red) represents 100% subject overlap (i.e., every sub-

jects identified tract contains the voxel in question).

Controls and right TLE patients show a similar pattern

of connections with greater SLF connections to the

temporal lobe on the left (arrowed) than the right. In

the left TLE group the opposite pattern is seen with

greater temporal lobe connections on the right.Epilepsia C ILAE

tractography in 10 such patients, and were able to predict

the magnitude of pre- and postoperative visual field loss

from the geometrical relationship between the optic radi-

ation and AV malformation. A recent study demonstrated

application to temporal lobe surgery for epilepsy (Fig. 7).

The optic radiation was visualized before and after ATLR,

and disruption of Meyers loop was demonstrated in a pa-

tient who developed a quadrantanopia (Powell et al., 2005).

In a similar vein, other studies have demonstrated the util-

Figure 7.

(Adapted with permission from Powell et al., 2005)

Tractography of the optic radiation in two patients

who underwent anterior temporal lobe resections,

superimposed on each subjects sagittal non diffusion

weighted (b = 0) MR image. Preoperative images on

the left and postoperative images on the right. Patient

A suffered a quadrantic field deficit postoperatively due

to surgical interruption of the optic radiation (arrow).

The visual fields of patient B remained intact.

Epilepsia C ILAE

ity of tractography in the resection of neoplasms that are in

close proximity to eloquent subcortical white matter tracts

(Yu et al., 2005). There are, however, technical challenges

to be overcome to enable the coregistration of preopera-

tive tractography with the T1-weighted MR images used

to guide neurosurgical interventions. When these are sur-

mounted, preoperative tractography of the optic radiation

and other vital white matter connections, will be able to

be displayed when planning and undertaking surgical pro-

cedures (Kamada et al., 2005). Further, the advent of per-

operative MRI will allow the correction of the movement

of tracts caused by craniotomy, and will improve the ac-

curacy of the data, to aid surgical planning and result in a

lower risk of postoperative deficits.

CONCLUSION

The advent of diffusion-based MRI and tractography

heralds an exciting period in the neuroimaging of epilepsy

patients. The interpretation of peri- and postictal diffusion

changes remains complex, but has the potential to improve

understanding of seizure physiology. Interictal diffusion

MRI studies have some localizing value in patients with fo-

cal epilepsy, but normal conventional MRI scans. The use

of quantitative maps derived from diffusion imaging, es-

pecially within the context of a multimodality assessment,

is a powerful tool to search for subtle lesions. Furthermore

this technique may also have advantages for delineating theEpilepsia, 49(2):189200, 2008

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extent of a structural abnormality, and have a particularly

important role in the planning of intracranial EEG and tis-

sue resection.

The place of tractography in the imaging armory avail-

able to epileptologists remains to be determined. Its find-

ings need to be interpreted with a degree of caution due tothe limitations described above. Despite this, it has already

demonstrated its potential in increasing our understand-

ing of the structural and functional plasticity that occurs

in chronic TLE. Further studies are needed to evaluate the

role of tractography in presurgical planning, particularly

studies incorporating postoperative findings. We anticipate

that as data acquisition and tracking algorithms improve,

and tractography data are combined with EEG and fMRI

data, these improvements will be forthcoming. Ultimately,

it may be possible to visualize white matter organization

with tractography, such that potentially novel approaches

to functionally disconnect the seizure focus from the sur-rounding brain can be developed.

ACKNOWLEDGEMENTSWe are grateful to the Welcome Trust for supporting our work (Pro-

gramme Grant No 067176) and The Big lottery Fund, Wolfson Trust, andthe National Society for Epilepsy for supporting The NSE MRI scanner.

Conflict of interest: We confirm that we have read the Journals positionon issues involved in ethical publication and affirm that this report is con-sistent with those guidelines.

M. Yogarajah nilJ. Duncan nil

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