Functional Brain Mri Mapping of Epileptic Foci: A Literature Review

Vito Masagus Junaidy

Department of Neurosurgery, Hasan Sadikin, Faculty of Medicine, Padjadjaran University,
Bandung 40161, Indonesia.

Abstract
Functional MRI (fMRI) is increasingly being used in the presurgical evaluation of
patients with intractable epilepsy. In the clinical setting, real-time fMRI is a simple diagnostic
technique. For eloquent cortex mapping and language lateralization, it has become a noninvasive
alternative to intraoperative cortical stimulation and the Wada test. It is being recognized for its
role in predicting postsurgical memory outcome and localizing ictal activity. This review article
describes the biophysical basis of BOLD fMRI and the methodology used, including the design,
paradigms, fMRI setup, and data analysis. Illustrative cases were discussed in which the fMRI
results influenced the seizure team's decisions on diagnosis and therapy.

Keywords: functional MRI; epilepsy; diagnosis

Introduction
Functional MRI (fMRI) is a technique that maps the physiological or metabolic
consequences of changes in brain electrical activity. Unlike positron emission tomography
(PET), a similar brain mapping technique that has been used for many years to study brain
function, fMRI does not use ionizing radiation and can thus be repeated as many times as needed
in patients or healthy volunteers. 1 The electrical activity in the brain is mapped using
electroencephalography (EEG) and magnetoencephalography (MEG). EEG and MEG have high
temporal resolution (10-100 milliseconds), but poor spatial resolution (one to several
centimeters). The spatial resolution of the blood-oxygen-level-dependent (BOLD) fMRI
technique is a few millimeters and the temporal resolution is a few seconds. 2

Biophysical Basis of BOLD fMRI

The stimulation of neurons causes a local increase in energy and oxygen consumption in
functional areas. fMRI measures the subsequent local hemodynamic changes transmitted via
neurovascular coupling. Roy and Sherrington first described the 'activation flow coupling' (AFC)
between regional changes in brain metabolism and regional cerebral blood flow (CBF) in 1890.
The BOLD technique is based on the magnetic properties of oxygenated and deoxygenated
hemoglobin. Thulborn and colleagues demonstrated in 1982 that the ferrous iron on the heme
moiety of deoxy-Hb is paramagnetic. In the measurable range of MRI, paramagnetic deoxy-Hb
causes local field inhomogeneities, resulting in a signal decrease in susceptibility-weighted MRI-
sequences (T2*), whereas diamagnetic oxy-Hb does not interfere with the external magnetic
field. 2,3
When neurons are stimulated, local oxygen consumption increases, resulting in an initial
decrease in oxy-Hb and an increase in deoxy-Hb in the functional area. Perfusion in capillaries
and draining veins is increased within seconds to provide oxygenated blood to active neurons.
The initial decrease in local oxy-Hb is equalized and then overcompensated as a result of this
process. The deoxy-Hb is gradually washed out. This reduces local field inhomogeneity while
increasing the BOLD signal in T2*W MRI images [Figure 1]. Although the 'initial dip'
corresponds to neuronal activity both temporally and spatially, measuring it in clinical settings is
more difficult. 3

2
 Figure 1. BOLD signal shows initial dip and then a more prolonged ‘positive’ signal

Most fMRI studies use a block design, in which tasks are alternated to generate brain
responses in different states, to elicit the activated functional areas in the brain using the BOLD
signal effectively and robustly (in the simplest form, two states: rest versus activation). In recent
years, event-related designs have also been used to investigate language function and
lateralization. 3,4 In contrast to a block design, in which conditions are alternated within a block
(resting, task1, resting, task2) with each block having a fixed duration, events of different types
are randomly intermixed in an event-related design. Some studies have found that event-related
design paradigms activate language areas more strongly than block design paradigms. 5
Because of its quick acquisition time, echo planar imaging (EPI) is the most commonly
used imaging sequence in fMRI studies. However, because it takes some time to produce
detectable hemodynamic changes after stimulus onset, the temporal resolution of such a
sequence is in the order of several seconds, and the spatial resolution is usually significantly
lower than that of anatomical MRI. Another disadvantage is that EPI is sensitive to field
inhomogeneities, which causes geometric distortion of images in specific brain regions. 5
Because the BOLD signal is extremely sensitive to motion, subject motion is a common
issue during any fMRI experiment and can jeopardize the entire experiment. The cardioballistic
effect refers to the minimal brain motion associated with cardiac or respiratory cycles, as
opposed to the gross head movement. Individual images are commonly realigned and
coregistered before any subsequent analysis to minimize the motion effect. Following that,

3
statistical modeling is used to correlate the signal time course in each voxel of the images and the
time course of different tasks. 6,7

Figure 2. fMRI activation map overlaid on anatomical images.

Data Analysis
Each fMRI experiment generates a massive amount of data, which must be thoroughly
analyzed in order to obtain the best results. As previously stated, real-time fMRI processing will
aid in simple analysis. 6,7 Previously, we demonstrated that real-time fMRI analysis using a
vendor-provided fMRI processing tool can provide clinically useful information comparable to
time-tested postprocessing tools [Figure 3]. We currently use real-time fMRI processing for the
majority of our fMRI studies. The fMRI data is then coregistered with 3D-FLAIR images. We
found that coregistering on 3D-FLAIR was more useful than coregistering on T1W 3D spoiled
gradient images (3D FLASH/3D SPGR). 8

4
Figure 3. Real-time fMRI (provided by the vendor - Inline BOLD) versus offline processing
with statistical parametric mapping (SPM). Inline BOLD fMRI coregistered on 3D-FLASH
images with a time-activity curve of a patient with seizures due to a frontal mass lesion is
compared to fMRI results with a time-activity curve after offline processing of the same data set
using SPM2 and subsequent coregistration onto 3D-FLASH images using MRIcro software.
Take note of the activation similarities between real-time processing with inline BOLD and
offline processing techniques with SPM2.

Extensive computation may be required for event-related paradigms and more complex
boxcar paradigms involving more than two states using any of the free or commercial softwares,
such as statistical parametric mapping (SPM) (www.fil.ion.ucl.ac.uk/spm), FSL
(www.fmrib.ox.ac.uk/fsl), or Brain Voyager ( www.brainvoyager.de). The basic idea behind
functional imaging data analysis is to find voxels that exhibit signal changes that vary with
changes in the given cognitive or motor state of interest over the course of the experiment. This
is a difficult problem because fMRI signal changes are very small (of the order of 0.5-5%),
resulting in a high likelihood of false negative results. 9
The most difficult issue in any fMRI experiment is subject motion. The BOLD signal is
extremely sensitive to motion, which can derail the experiment entirely. Motion can refer to
either gross head movement or the minor brain movement associated with cardiac or respiratory
cycles. 7,9 To minimize motion effects, most analysis software includes some realignment and
coregistration programs. Another step is to reduce the noise in the data using spatial smoothing
and temporal filtering. After that, the images can be normalized to a common brain space [for
example, the Montreal Neurological Institute (MNI) template]. This procedure is mostly used in
research studies and is not required for individual patients in the clinical setting. 10

5
Clinical Applications in Patients with Epilepsy

fMRI has been used to study patients with a wide variety of neurological disorders and at
various stages of disease severity. The findings have shed light on disease mechanisms as well as
normal brain function. The vast majority of published studies were conducted in research
settings. 8,9 The clinical utility of fMRI is becoming more widely recognized. Presurgical
assessment of brain function in patients with brain tumors and epilepsies was and continues to be
one of the earliest and most well-validated clinical applications of fMRI. A substantial body of
evidence suggests that functional MRI is an effective technique for localizing different body
representations in the primary motor and somatosensory cortex, as well as for localizing and
lateralizing language function prior to surgery. 11

Mapping the Eloquent Cortex

Intraoperative cortical stimulation in awake patients, implantation of a subdural grid, or

intraoperative recording of sensory-evoked potentials can all be used to map eloquent areas.
These data can be obtained preoperatively and noninvasively using fMRI. fMRI can define the
relationship between the margin of a lesion and any adjacent functionally significant brain tissue,
in addition to its high sensitivity for visualizing brain lesions. 6,7 fMRI has the potential to predict
potential deficits in motor and sensory perceptual functions, as well as language, that may result
from intrinsic lesion expansion or therapeutic interventions such as surgery. This aids decision
making during patient care. The relative risks of intervention versus nonintervention can be
discussed and explained to the patient and his or her family. 8–10
Eloquent cortex mapping was performed on epilepsy patients who had a tumor, gliosis, or
cortical development malformation in or near the eloquent cortex. Our neurosurgeons have
discovered that fMRI for eloquent cortex mapping is most useful in patients with gliosis, where
the anatomy distortion makes predicting the eloquent cortex extremely difficult. 12 Gliotic lesions
typically attract functionally active areas. Lesions that take up a lot of space, like brain tumors,
primarily displace the functional cortex. As a result, resection within the boundaries of a lesion
should not directly harm the eloquent cortex and cause a significant deficit. In contrast,

6
functional reorganization may or may not occur within the dysplastic cortex in cortical
development malformations. 13

Figure 4. Three patients had seizures as a result of a gliotic area. The gliosis in the first patient
was caused by an old healed granuloma. The coregistration of axial FLAIR and inline BOLD on
3D-FLASH (A, B) images obtained after left hand movement vs rest shows that the right motor
hand area is well away from the gliotic area (white arrow). The gliosis in the second patient was
postsurgical. Inline BOLD fMRI coregistered on 3D-FLASH images obtained after bilateral
hand movement vs rest and tongue movement vs rest (C, D) show that the left hand area is closer
to the gliotic area, whereas the left face area is not visible. The activation area of the left hand is
being drawn towards the gliotic area. The third patient had gliosis in the occipital cortex, which
was most likely caused by perinatal hypoglycemia. After visual stimulation, sagittal FLAIR and
inline BOLD fMRI coregistered on axial FLAIR images show minimal activation in the gliotic
left occipital cortex. The right side of the brain is responsible for the majority of visual
activation. All three patients in whom fMRI assisted in surgical planning underwent gliotic
resection without developing neurological deficits.

Eloquent cortex mapping was performed on epilepsy patients who had a tumor, gliosis, or
cortical development malformation in or near the eloquent cortex. Our neurosurgeons have
discovered that fMRI for eloquent cortex mapping is most useful in patients with gliosis, where
the anatomy distortion makes predicting the eloquent cortex extremely difficult. Gliotic lesions
typically attract functionally active areas. 12 Lesions that take up a lot of space, like brain tumors,
primarily displace the functional cortex. As a result, resection within the boundaries of a lesion
should not directly harm the eloquent cortex and cause a significant deficit. In contrast,
functional reorganization may or may not occur within the dysplastic cortex in cortical
development malformations. 11–13
7
 Conclusion
During the presurgical workup of patients with epilepsy, mapping sensorimotor, visual,
language, and memory function using fMRI can identify the eloquent cortex and predict
postoperative deficits of specific functions. EEG-correlated fMRI has the potential to identify the
cortical areas involved in generating the discharges in selected patients with frequent interictal
epileptiform discharges. Better and better techniques are gradually evolving to address clinical
fMRI challenges. With the availability of higher Tesla magnets, faster sequences, and improved
paradigms and postprocessing tools, the clinical application of this technique in epilepsy patients
will grow in the coming years.

References

1. Kesavadas C, Thomas B, Kesavadas C. Clinical applications of functional MRI in epilepsy [Internet]. Vol.
18, Indian J Radiol Imaging. 2008. Available from: www.brainvoyager.

2. Nakai Y, Nishibayashi H, Donishi T, Terada M, Nakao N, Kaneoke Y. Regional abnormality of

functional connectivity is associated with clinical manifestations in individuals with intractable
focal epilepsy. Sci Rep. 2021 Dec 1;11(1).
3. Centeno M, Tierney TM, Perani S, Shamshiri EA, StPier K, Wilkinson C, et al. Optimising
EEG-fMRI for localisation of focal epilepsy in children. PLoS One. 2016 Feb 1;11(2).
4. Sadjadi SM, Ebrahimzadeh E, Shams M, Seraji M, Soltanian-Zadeh H. Localization of Epileptic
Foci Based on Simultaneous EEG–fMRI Data. Vol. 12, Frontiers in Neurology. Frontiers Media
S.A.; 2021.
5. Wang A, Peters TM, de Ribaupierre S, Mirsattari SM. Functional Magnetic Resonance Imaging
for Language Mapping in Temporal Lobe Epilepsy. Epilepsy Res Treat. 2012 Jul 25;2012:1–8.
6. Nedic S, Stufflebeam SM, Rondinoni C, Velasco TR, dos Santos AC, Leite JP, et al. Using
network dynamic fMRI for detection of epileptogenic foci. BMC Neurol. 2015 Dec 21;15(1).
7. Walz JM, Pedersen M, Omidvarnia A, Semmelroch M, Jackson GD. Spatiotemporal mapping of
epileptic spikes using simultaneous EEG-functional MRI. Brain. 2017 Apr 1;140(4):998–1010.
8. Shi Y, Zhang X, Yang C, Ren J, Li Z, Wang Q. A review on epileptic foci localization using
resting-state functional magnetic resonance imaging. Vol. 17, Mathematical Biosciences and
Engineering. American Institute of Mathematical Sciences; 2020. p. 2496–515.

8
9. de Ciantis A, Lemieux L. Localisation of epileptic foci using novel imaging modalities. Vol. 26,
Current Opinion in Neurology. 2013. p. 368–73.
10. Salmenpera TM, Duncan JS. Imaging in epilepsy. Vol. 76, Neurology in Practice. 2005.
11. Bernasconi A, Bernasconi N. The Role of MRI in the Treatment of Drug-Resistant Focal
Epilepsy. European Neurology. S. Karger AG; 2022.
12. Xiao F, An D, Zhou D. Functional MRI-based connectivity analysis: A promising tool for the
investigation of the pathophysiology and comorbidity of epilepsy. Vol. 44, Seizure. W.B.
Saunders Ltd; 2017. p. 37–41.
13. Shaikh Z, Torres A, Takeoka M. Neuroimaging in pediatric epilepsy. Brain Sci. 2019 Aug
1;9(8).