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Epilepsia, 49(Suppl. 3):1522, 2008

doi: 10.1111/j.1528-1167.2008.01506.x

SUPPLEMENT - MERRITT PUTNAM SYMPOSIUM

Molecular and diffusion tensor imaging

of epileptic networksAimee F. Luat and Harry T. Chugani

Carman and Ann Adams Department of Pediatrics, and the Departments of Neurology and Radiology,

Childrens Hospital of Michigan, Wayne State University, Detroit, Michigan, U.S.A.

SUMMARYSeveral studies have shown that seizure-induced

cellular and molecular changes associated with

chronic epilepsy can lead to functional and struc-

tural alterations in the brain. Chronic epilepsy,when medically refractory, may be associated with

an expansion of the epileptic circuitry to involve

complex interactions between cortical and subcor-

tical neuroanatomical substrates. Progress in neu-

roimaging has led not only to successful identifica-

tion of epileptic foci for surgical resection, but also

to an improved understanding of the functional and

microstructural changes in long-standing epilepsy.

Positron emission tomography (PET), functional

magnetic resonance imaging (fMRI) and diffusion

tensor imaging (DTI) are all promising tools that

can assist in elucidating the underlying patho-

physiology in chronic epilepsy. Studies using PET

scanning have demonstrated dynamic changes as-

sociated with the evolution from acute to chronic

intractable epilepsy. Among these changes are datato support the existence of secondary epileptoge-

nesis in humans. MRI with DTI is a powerful tool

which has the ability to characterize microstruc-

tural abnormalities in epileptic foci, and to demon-

strate the white matter fibers and tracts partici-

pating in the epileptic network. In this review, we

illustrate how PET and DTI can be applied to de-

pict the functional and microstructural alterations

associated with chronic epilepsy.

KEY WORDS: Epileptic networks, Secondary

epileptogenesis, PET, DTI.

There has been a growing body of evidence to indicate

that seizure-induced neuronal injury in chronic epilepsy

can cause alterations in synaptic reorganization and con-

nectivity (Sutula et al., 1998; Lehmann et al., 2000;

Cavazos et al., 2004). It has been shown in animal models

that seizures may produce long-term alterations in neuronal

structures extending beyond the epileptic focus (Brener

et al., 1991; Hagemann et al., 1998) so that there may

be an expansion of the epileptic network with repeated

seizures. For example, autoradiography studies of glucosemetabolism in electrically kindled rats showed progressive

recruitment of cortical and subcortical limbic structures as

the stages of kindling increased (Handforth & Ackermann,

1988; 1995). Similarly, after systemic injection of kainic

acid in rat, propagation of seizures in limbic and nonlim-

bic structures occurred (Lothman & Collins, 1981). Thus,

Address correspondence to Harry T. Chugani, M.D., Pediatric Neurol-ogy/PET Center, Childrens Hospital of Michigan, 3901 Beaubien Blvd.,Detroit, MI 48201, U.S.A. E-mail: [email protected]

Blackwell Publishing, Inc.C 2008 International League Against Epilepsy

metabolic activation was noted initially in the hippocampus

prior to the appearance of motor seizures. During limbic

seizures, increased glucose consumption is seen in regions,

such as the amygdala, entorhinal and pyriform cortices, and

thalamic nuclei. With repeated seizures, metabolic activa-

tion progresses to involve many other structures, including

the substantia nigra. The crucial role of subcortical struc-

tures in the propagation and behavioral manifestations of

epileptic seizures has also been shown in various experi-

mental animal models and in humans (reviewed in Norden& Blumenfeld, 2002). Taken together, these findings sug-

gest that epileptic seizures involve widespread network

interactions between cortical and subcortical structures,

which contribute to the epileptic circuitry.

Although advances in both structural and functional neu-

roimaging have led to improved localization of the epilep-

tic focus for presurgical planning in refractory cases, novel

imaging techniques can also provide a better understanding

of the underlying mechanisms in epilepsy and the func-

tional consequences of chronic epilepsy. Positron emis-

sion tomography (PET), functional magnetic resonance

imaging (fMRI) and diffusion tensor imaging (DTI) can

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A. F. Luat and H. T. Chugani

all be utilized as powerful tools in the study of epileptic

networks.

PET IMAGING IN EPILEPSY

In addition to conventional MRI, functional neuroimag-ing using PET and single photon emission computed to-

mography (SPECT) can provide complementary informa-

tion to help localize the epileptic focus and often provides

additional information that cannot be obtained from con-

ventional MRI sequences. Indeed, PET scanning using var-

ious tracers has been utilized in the identification of the

primary epileptic focus and dysfunctional areas outside the

primary focus (Juhasz et al., 2000; Sood & Chugani, 2006).

The most widely available PET tracer used in epilepsy is

2-deoxy-2-[18F]fluoro-D-glucose (FDG), which allows the

rates of regional brain glucose utilization to be estimated.

FDG-PET can detect focal areas of decreased glucosemetabolism that are generally concordant with the epileptic

cortex even in patients with normal MRI (Chugani et al.,

1990; da Silva et al., 1997). In addition, there are sev-

eral other tracers that have been applied in epilepsy. For

example, [11C]-flumazenil (FMZ), which binds to gamma

aminobutyric acid (GABAA) receptors (Savic et al., 1988;

Henry et al., 1993), has been shown to improve localization

of epileptic foci in patients with intractable epilepsy of both

medial temporal and neocortical origin, including those

with normal conventional MRI (Savic et al., 1988; Henry

et al., 1993; Savic et al., 1993, 1995; Richardson et al.,

1996; Ryvlin et al., 1998; Muzik et al., 2000; Juhasz et al.,

2000, 2001). [11C] -methyl-L-tryptophan (AMT) which

is a tracer of tryptophan metabolism (Muzik et al., 1997;

Chugani et al., 1998a) has been utilized in epilepsy surgery

evaluation, particularly in the identification of epileptic

tubers in children with intractable epilepsy and tuberous

sclerosis complex (TSC) (Chugani et al., 1998b; Asano

et al., 2000). In addition, AMT PET appears to be use-

ful in the identification of the epileptic focus in children

with intractable neocortical epilepsy without TSC who

had malformations of cortical development with abnormal

(Fedi et al., 2001) and normal MRI (Juhasz et al., 2003).

Other PET tracers with the potential capability of detecting

epileptic brain regions include radiolabeled ligands whichbind to opioid receptors (Frost et al., 1988), histamine

H1 receptors (Iinuma et al., 1993), N-methyl-D-aspartate

receptors (Kumlien et al., 1999) and peripheral benzo-

diazepine receptors (Sauvageau et al., 2002), although

these tracers have not yet been validated for presurgical

evaluation.

SECONDARY EPILEPTIC FOC I

Morrell coined the word secondary epileptic foci as

trans-synaptic and long-lasting alterations in nerve cell

behavior characterized by paroxysmal electrographic man-

ifestations and clinical seizures induced by seizures from

a primary epileptic focus (Morrell, 1985; 1989). He de-

scribed three stages in the formation of secondary epilep-

tic foci. In the first stage, epileptiform activity in the new

brain region is dependent on a trigger from a primary fo-cus. In the second stage, epileptiform activity occurs spon-

taneously in the new focus. At this time, the removal or

ablation of the primary focus will still lead to resolution of

the epileptiform activity at the secondary site, but the re-

covery takes place over time. If this dependent focus is not

removed, electrographic spikes and electrographic seizures

begin to develop independently at the second site leading

to the third stage, when the epileptiform activity in the

secondary focus has become irreversible (independent sec-

ondary focus).

Much of our knowledge on secondary epileptogene-

sis was derived from experimental animal studies. Boththe kindling and kainate animal models have been uti-

lized for studying this phenomenon (Cibula & Gilmore,

1997; Dudek & Spitz, 1997). Recently, in vitro demonstra-

tion of the formation of a secondary epileptogenic focus

was described (Khalilov et al., 2003). Although the con-

cept of secondary epileptogenesis in animals is well es-

tablished, its existence in humans remains controversial.

Nevertheless, there is evidence to support the notion that

secondary epileptogenesis may occur in human epilepsy.

For example, patients with unilateral brain lesions and

epilepsy may have bilateral interictal foci (Gupta et al.,

1973; Hughes, 1985; Morrell, 1985; Gilmore et al., 1994;

McCarthy et al., 1997). In a long-term follow-up study on

60 patients who underwent standard anterior temporal lobe

resection for lesions associated with chronic, medically

intractable seizures, Eliashiv et al. (1997) observed late

seizure recurrence in three patients; two had been seizure-

free for 10 years and one for 15 years after surgery, before

recurrence of seizures in the absence of tumor recurrence.

These investigators suggested that a prolonged history of

seizures prior to surgery may be associated with poor sur-

gical outcome. Similarly, in a long-term follow-up study

by Foldvary et al. (2000) on 79 patients with unilateral

intractable medial temporal lobe epilepsy who underwent

temporal lobectomy, 55% of the patients had at least onepost-operative partial-onset seizure and 30 of them (38% of

the total) experienced multiple seizures during an average

of 14-years follow-up suggesting that partial seizures can

be generated elsewhere in the brain of individuals who have

suffered intractable mesial temporal lobe epilepsy. These

findings suggest that secondary epileptogenesis at various

sites distant to the lesion may develop with years of un-

controlled seizures and may contribute to the recurrence of

seizures even after successful resection of the primary fo-

cus. Therefore, identification of these secondary epileptic

foci during preoperative evaluation is imperative to allow

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Molecular and Diffusion Tensor Imaging of Epileptic Networks

modification of surgical treatment in order to achieve a

good surgical outcome.

PET EVIDENCE OF THE EXISTENCEOF SECONDARY EPILEPTOGENIC

FOCI IN HUMAN EPILEPSY

It is well-known that the extent of brain glucose hy-

pometabolism shown on PET scans of patients with

epilepsy is not static but undergoes dynamic changes de-

pending upon the chronicity and intractability of epilepsy.

For example, PET scans of glucose metabolism in pa-

tients with new onset partial epilepsy rarely show focal

abnormalities (Matheja et al., 2001; Gaillard et al., 2002).

Recently, Gaillard et al. (2007) were not able to demon-

strate progression of hypometabolism in a short longitudi-

nal study over 23 years. On the other hand, patients withchronic partial epilepsy often exhibit areas of glucose hy-

pometabolism not only in the primary epileptic focus, but

also in remote yet interconnected cortical areas (da Silva

et al., 1997; Jokeit et al., 1997; Juhasz et al., 2000; Takaya

et al., 2006).

Longitudinal changes in the extent of glucose hy-

pometabolism using sequential PET scans in children with

partial epilepsy have been demonstrated by our group

(Benedek et al., 2006). In this longitudinal study of 15

children with partial epilepsy and normal MRI scans, two

FDG-PET scans were performed 744 months apart and

the extent of hypometabolic cortex on the side of elec-

troencephalography (EEG)-verified epileptic focus and its

changes between the two PET scans were measured and

Figure 1.

(A) Transaxial 2-deoxy-2-

[18F]fluoro-D-glucose positron

emission tomography (FDG

PET) image of a 15-year-old

child, whose seizure frequency

increased between the two

scans from one per day to more

than 10 seizures per day. Notethe expansion of the areas of

the left temporal and frontal

lobe hypometabolism (arrows).

(B) Three-dimensional surface

rendering of the objectively

marked FDG PET abnormali-

ties showing the hemispheric

expansion of cortical glucose

hypometabolism.

Epilepsia C ILAE

correlated to clinical seizure variables. It was noted that

the change in seizure frequency between the two PET

scans correlated positively with the change in the ex-

tent of the cortical glucose hypometabolism. Most patients

with persistent or increased seizure frequency showed en-

largement of the cortical areas of glucose hypometabolism(Fig. 1A and B). On the other hand, the extent of glu-

cose hypometabolism remained stable or even decreased

if seizures came under control. This observation suggests

that the extent of glucose metabolism alterations correlates

with major changes in clinical seizure frequency suggest-

ing that clinical progression or persistence of severe, in-

tractable epilepsy can lead to involvement of progressively

larger cortical areas of neuronal dysfunction, as reflected

by the size of the cortical glucose hypometabolism. Con-

versely, at least some of the cortical hypometabolism seen

on PET scans may represent reversible changes in neuronal

function. These findings are consistent with the observa-tions of other investigators who have shown that some foci

of glucose hypometabolism disappear after seizure control

achieved either medically (Matheja et al., 2000) or with

surgery (Akimura et al., 1999; Spanaki et al., 2000; Joo

et al., 2005).

All together, these observations support the notion that

intractable epilepsy in children is a progressive condition,

and that the areas of focal glucose hypometabolism un-

dergo dynamic changes related to seizure activity. Persis-

tent epilepsy in children may recruit progressively larger

areas of brain into the seizure network. Whether this pro-

cess is linked etiologically with the development of an

epileptic encephalopathy in some children remains to be

determined.


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Figure 2.

2-deoxy-2-[18F]fluoro-D-glucose positron emission to-

mography (FDG PET) (A) showed areas of glucose hy-

pometabolism in the right frontal and parietal cortex

(arrows). Flumazenil (FMZ) PET (B) disclosed a smaller

area of decreased FMZ binding involving the right

frontal cortex. Electrocorticography captured seizures

of right frontal onset overlapping with the area of de-

creased FMZ binding.

Epilepsia C ILAE

PET USING [11C] FLUMAZENIL(FMZ)

Based on the observation of altered gamma-

aminobutyric acid (GABA) inhibitory mechanisms in

the epileptic focus demonstrated in experimental and

human epilepsy (Craig & Colasanti, 1986; Lloyd et al.,

1986; Pitkanen et al., 1987), several investigators have

explored the use of PET scanning with FMZ in the iden-

tification of the epileptic focus. FMZ is a benzodiazepinereceptor antagonist that binds to the alpha subunit of

the GABAA receptors. PET scanning with [11C] FMZ is

sensitive in detecting mesial temporal sclerosis (Savic

et al., 1988; Henry et al., 1993), but has also been used in

the identification of epileptogenic cortex in extratemporal

lobe epilepsy (Savic et al., 1995; Richardson et al., 1996;

Ryvlin et al., 1998; Muzik et al., 2000). Compared with

FDG-PET, the cortical area showing decreased FMZ

binding is usually smaller than the cortical region of

glucose hypometabolism (Fig. 2) and has been found to

be a better indicator of the seizure focus and areas of

frequent spiking on electrocorticography (Fig. 3) (Savic

et al., 1993; Muzik et al., 2000; Juhasz et al., 2001).

Furthermore, cortical regions remote from the presumed

epileptic focus (as indicated by scalp EEG), detected

as areas of decreased FMZ binding are often identified

(Juhasz & Chugani, 2003). In the study of Juhasz et al.

(2001) on patients with intractable localization-relatedepilepsy with MRI-verified brain lesions, remote areas of

FMZ-PET abnormalities were noted in areas having direct

corticocortical connections with the primary lesional

region suggesting that well-established corticocortical

pathways (e.g., superior longitudinal fasciculus, inferior

longitudinal fasciculus, and arcuate fasciculus) may be

involved in propagation of epileptic discharges to cause

alterations in remote areas. On the other hand, some of

the FMZ-binding abnormalities outside the primary focus

may disappear following surgical removal of the primary

epileptic focus (Savic et al., 1998). These observations

suggest that such FMZ abnormalities beyond the primaryepileptic focus may represent areas of secondary epileptic

foci, and that some of these changes may be potentially

reversible, as predicted by Morrell (1985, 1989).

THE USE OF DIFFUSION TENSORIMAGING IN EPILEPSY

DTI is a new MRI technique, which is based upon the

ability of MRI to assess the direction and magnitude of

water diffusion in tissues in vivo by utilizing the prin-

ciple of anisotropic diffusion of water molecules in the

white matter tracts of the brain (Le Bihan et al., 1986).

DTI measurements reflect the random thermal displace-

ment of water molecules and the technique is more sen-

sitive than conventional MRI in detecting microstructural

changes in the brain. Two important parameters: the appar-

ent diffusion coefficient (ADC), which measures the over-

all magnitude of diffusion, and the fractional anisotropy

(FA), which measures the directional preference of the dif-

fusion motion, can be calculated using DTI. By detecting

these changes, DTI provides tissue information about mi-

croscopic barriers, which can be affected by various dis-

ease processes. Furthermore, it has the capability of track-

ing the white matter fibers by assessing the connectivity ofthe main fiber direction.

The use of DTI in epilepsy has great potential value.

Studies on experimentally induced status epilepticus

showed reductions in ADC in various brain regions in-

volving both limbic and extralimbic structures including

the medial thalamus, suggesting that sustained epileptic

activity is associated with complex interactions involv-

ing both cortical and subcortical structures (Zhong et al.,

1993; Nakasu et al., 1995; Fabene et al., 2003). The de-

creased ADC was attributed to the presence of cytotoxic

edema which may be due to a shift of extracellular water

into the intracellular space, resulting in a reduction of free


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Figure 3.

Flumazenil-positron emission tomography (FMZ PET) of a 7.2-year-old girl with intractable epilepsy projected on a

3-dimensional brain surface. Areas of>10% decreased FMZ binding are seen in black. Seizure onset was noted in

the right inferior temporal cortex (yellow diamond) and areas of frequent (>10/min) interictal spiking (orange circle)

were noted in the right temporal and frontal cortex. Both the seizure onset zone and the area of rapid seizure

spread (circle with cross) were overlapping and/or adjacent to the areas of decreased FMZ binding. Scalp ictal EEG

showed an anterior temporal focus but did not disclose epileptiform activity in the frontal region.

Epilepsia C ILAE

diffusion. A similar observation was noted in patients

with new onset prolonged seizure and acute symptomatic

seizures (Farina et al., 2004; Parmar et al., 2006) where de-

creased ADC in the hippocampus corresponded to the side

of the EEG focus.

Interictal DTI has been utilized to further character-

ize the microstructural abnormalities of epileptic foci

(Wieshmann et al., 1999; Rugg-Gunn et al., 2001, 2002;

Assaf et al., 2003; Thivard et al., 2005). Increases in diffu-

sivity (ADC) and reductions in anisotropy (FA) likely re-

lated to neuronal loss, gliosis and structural disorganization

were noted not only in patients with acquired partial epilep-

sies but also in subjects with cryptogenic partial epilep-

sies, thus indicating a higher sensitivity of this modality

to detect epilepsy-related changes as compared with con-

ventional MRI (Rugg-Gunn et al., 2001).

Since subcortical brain structures have been implicated

in the propagation of seizure spread through cortico

subcortical epileptic circuitries (Morillo et al., 1982; Gale,

1992; Chugani et al., 1994), we evaluated DTI changes

in the hippocampus and subcortical brain structures in

14 children with temporal lobe epilepsy: seven with and

seven without secondary generalization (Kimiwada et al.,

2006). Five patients had MRI signs of hippocampal scle-

rosis. None of the subjects showed any structural or signal

changes on conventional MRI in the thalamus or basal gan-

glia. Decreased FA (p < 0.001) and increased ADC (p =

0.003) values were found in the hippocampi ipsilateral to

the seizure focus. Significant decreases of FA (p = 0.002)

were also seen in the contralateral hippocampi, despite uni-

lateral seizure onset and excellent surgical outcome in pa-

tients who underwent surgery. FA and ADC values of pa-

tients with generalized versus partial seizures did not show

significant differences in this preliminary study involving

relatively few patients. However, there was a weak trend

for increased FA in the ipsilateral thalami of children with

generalized seizures (p = 0.12). In addition, a trend for in-

creased ADC was also found in the ipsilateral thalami of

children with generalized seizures (p = 0.09) but not in

those with partial epilepsy only (p = 0.46). Our observa-

tions added evidence for the existence of microstructural

changes of the hippocampus and perhaps, the ipsilateral

thalamus in children with temporal lobe epilepsy suggest-

ing that further, detailed characterization of the structural


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Figure 4.(A) 2-deoxy-2-[18F]fluoro-D-glucose positron emission tomography (FDG PET) image of a child with tuberous

sclerosis complex (TSC) showing multiple areas of cortical glucose hypometabolism representing multiple cortical

tubers (thin arrows). (B) Alpha [11C] methyl-L-tryptophan positron emission tomography (AMT PET) of the same

child showing a single tuber which showed increased AMT uptake (thick arrow). The patient underwent left temporo-

parietal resection, including the tuber with increased AMT uptake. He became seizure-free for 15 months. After 4

years of follow-up, he achieved Engel class IIA outcome.

Epilepsia C ILAE

and functional changes in brain regions beyond the epilep-

tic temporal lobe can be obtained by DTI.

THE USE OF DTI IN THEIDENTIFICATION OF EPILEPTOGENIC

TUBERS IN TS C

Whereas, FDG-PET is not able to distinguish between

epileptogenic and nonepileptogenic tubers, AMT-PET

scanning has proven to be a useful tool in the identifica-

tion of epileptogenic tubers and has improved the outcome

of epilepsy surgery in TSC (Kagawa et al., 2005). Cortical

tubers on FDG PET are typically seen as areas of glucose

hypometabolism. AMT-PET, on the other hand, is able to

highlight epileptogenic tubers as areas of increased AMTuptake interictally while nonepileptogenic tubers show de-

creased uptake of AMT (Fig. 4) (Chugani et al., 1998;

Asano et al., 2000).

With recognition of the potential role of DTI in the lo-

calization of epileptogenic cortex in partial epilepsy, its po-

tential use in the identification of the epileptogenic tuber

has also been explored. Jansen et al. (2003), in a study

of four patients, found increased ADC values in epilep-

togenic tubers, based on interictal spiking (derived from

high-resolution magnetoencephalography and scalp EEG).

They noted that while all tubers showed high ADC val-

ues compared to the surrounding cortex, the increase in

ADC was much higher in the epileptogenic tubers. The

high ADC values in cortical tubers are reflective of the

loss of the structural barrier in water motion, perhaps due

to looser integrity of the tissues, presence of hypomyelina-

tion, gliosis, or loss of neurons.

Since DTI-fiber tractography can noninvasively evalu-

ate the tissue microenvironment of cerebral white mat-

ter tracts, it can be applied to evaluate the integrity and

connectivity of the white matter tracts connecting cortical

and subcortical brain structures. With the growing body of

evidence suggesting the involvement of subcortical struc-

tures in the epileptic network, DTI-fiber tractography can

potentially be used to detect and define the epileptic cir-

cuitry as it evolves with chronicity and increasing sever-

ity of epilepsy. We have explored the use of DTI-fiber

tractography in identifying epileptogenic tubers. Based onour preliminary data, some of the epileptogenic tubers (de-

fined as ictal onset zone by electrocorticography) showed

thalamic connectivity with significantly higher FA values

when compared with the contralateral homotopic side sug-

gesting that this may represent an aberrant connectivity to

the thalamus. Whether this observation is related to the

involvement of the thalamus in the epileptic circuitry or

to the phenomenon of thalamo-cortical retargetting sec-

ondary to reorganization following early brain injury as

has been observed in experimentally induced cerebro-

cortical microgyria (Rosen et al., 2000) remains to be

elucidated.Epilepsia, 49(Suppl. 3):1522, 2008doi: 10.1111/j.1528-1167.2008.01506.x

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CONCLUSION

Provocative evidence exists to suggest that epileptic

networks may undergo dynamic changes as a result of per-

sistent seizures, particularly in the immature brain, thus re-

cruiting more structures into the epileptic network. In chil-dren, expansion of an epileptic network may be related to

the development of an epileptic encephalopathy or the es-

tablishment of secondary epileptic foci that, if independent,

also must be identified and resected in epilepsy surgery.

Currently, we do not have adequate methods of distinguish-

ing dependent from independent secondary epileptic

foci. However, advances in neuroimaging using PET scan-

ning, DTI, and functional MRI have the potential capabil-

ity of delineating and defining the epileptic network thus

contributing to improved outcomes in epilepsy surgery.

ACKNOWLEDGMENTSThis work was supported by NIH grant RO1 NS/RR38324 (to H.C.).

We are grateful to the staff of the PET Center at Childrens Hospital ofMichigan, Wayne State University for the collaboration and assistance inperforming the studies described above.

Conflict of interest: The contributing authors to this article have declaredno conflicts of interest.

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