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Interictal High Gamma Oscillation Regularity as a Marker for Presurgical

Epileptogenic Zone Localization

Article in Operative Neurosurgery · April 2022

DOI: 10.1227/ons.0000000000000245

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 CONCEPTS, INNOVATIONS AND TECHNIQUES

Interictal High Gamma Oscillation Regularity

Yosuke Sato, MD, PhD
Yoshihito Tsuji, MD, PhD‡
Madoka Yamazaki, PhD§
Downloaded from http://journals.lww.com/onsonline by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCywCX1AWnYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC1y0abggQZXdgGj2MwlZLeI= on 05/05/2022
as a Marker for Presurgical Epileptogenic Zone
Localization
* BACKGROUND: To ensure that epilepsy surgery is effective, accurate presurgical localization
of the epileptogenic zone is essential. Our previous reports demonstrated that interictal high
gamma oscillation (30-70 Hz) regularity (GOR) on intracranial electroencephalograms is re-

Yoshihisa Fujii, PhD||
Atsushi Shirasawa¶
Katsuhiko Harada#
Tohru Mizutani, MD, PhD*
*Department of Neurosurgery, Showa
University School of Medicine, Tokyo,
Japan; ‡Department of Neurosurgery,
Matsubara Tokushukai Hospital, Osaka,
Japan; §Grand Coeur Lab, LLC, Saitama,
Japan; ||EFken Inc., Tokyo, Japan; ¶Miyuki
Giken Co., Ltd, Tokyo, Japan; #Nihonko-
den Co., Tokyo, Japan
Correspondence:
Yosuke Sato, MD, PhD,
Department of Neurosurgery,
Showa University School of Medicine,
1-5-8 Hatanodai, Shinagawa-ku,
Tokyo 142-8666, Japan.
Email: yanda2011@gmail.com
Received, November 4, 2021.
Accepted, February 12, 2022.
Published Online, April 29, 2022.
lated to epileptogenicity.
OBJECTIVE: To examine whether preoperative GOR analysis with interictal high-density
electroencephalography (HD-EEG) improves the accuracy of epileptogenic focus locali-
zation and enhances postoperative seizure control.
METHODS: We calculated GOR from 20 seconds of HD-EEG data for 21 patients with
refractory focal epilepsy (4 with nonlesional temporal lobe epilepsy) scheduled for ep-
ilepsy surgery. Low-resolution brain electromagnetic tomography was used to analyze the
high GOR source. To validate our findings, we made comparisons with other conventional
localization methods and postoperative seizure outcomes.
RESULTS: In all patients, the areas of interictal high GOR were identified and resected. All
patients were seizure-free after the operation. The concordance between the results of in-
terictal high GOR on HD-EEG and those of source estimation of interictal discharge was fully
overlapping in 10 cases, partially overlapping in 8 cases, and discordant in 3 cases. The
concordance between the results of interictal high GOR on HD-EEG and those of interictal
123
I-iomazenil single-photon emission computed tomography was fully overlapping in 8
cases, partially overlapping in 11 cases, and discordant in 2 cases. In 4 patients with non-
lesional temporal lobe epilepsy, the interictal high GOR on HD-EEG was useful in confirming
the epileptogenic zone.
CONCLUSION: The interictal high GOR on HD-EEG is an excellent marker for presurgical
epileptogenic zone localization.
KEY WORDS: Epileptic focus, Epilepsy surgery, Gamma oscillation regularity, High-density EEG, Sample entropy

© Congress of Neurological Surgeons Operative Neurosurgery 00:1–10, 2022 https://doi.org/10.1227/ons.0000000000000245

2022. All rights reserved.

locating this zone.2 Interictal epileptiform dis-

T
o perform surgery for intractable focal
epilepsy safely and accurately, reliable,
simple, and minimally invasive presurgical
localization of the epileptogenic zone is required.
The epileptogenic zone is defined as the area whose
surgical resection can prevent seizures.1 Electro-
encephalography (EEG) plays an important role in
ABBREVIATIONS: ECoG, electrocorticography; EEG,
electroencephalography; ESI, electrical source
imaging; GOR, gamma oscillation regularity; HD, high
density; HD-EEG, high-density electroencephalography;
IED, interictal epileptiform discharge; IMZ-SPECT,
123
I-iomazenil single-photon emission computed
tomography; LORETA, low-resolution electromagnetic
tomography.
charge (IED), as represented by spikes in EEG, is a
useful marker of the irritative zone,3 and electrical
source imaging (ESI) of IEDs based on high-
density (HD)-EEG is particularly effective in lo-
calizing the epileptic focus.4-7 Ictal ESI can also
provide useful information in the absence of
IEDs.8 There are 2 types of IEDs: “red spikes”
reveal focal epileptogenicity occurring in and
around the seizure onset zone while “green spikes”
reflect peripheral inhibition, the green spikes can
be distinguished from the red spikes because they
exhibit more pronounced peripheral slow waves,
more pronounced positive baseline shifts, and
more frequent propagation pathways’ shifts.9
However, in practice, there may be IEDs that

OPERATIVE NEUROSURGERY VOLUME 00 | NUMBER 00 | MONTH 2022 | 1

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SATO ET AL
are not clearly distinguishable. In addition, in cases without IEDs,
the localization of the epileptic focus can be difficult. Although ESI
studies have made considerable progress in epileptic focus locali-
zation, many issues remain to be addressed.8
We have recently shown that interictal gamma oscillation
regularity (GOR), which may reflect epileptic synchronous ac-
tivities of interneurons associated with focal epileptogenicity,10-14
can be quantified using the sample entropy method for ac-
curate assessment of the epileptogenic zone from intracranial
EEG data.15-17 The GOR can be accurately measured from
HD-EEG. The presence of markedly localized areas of sig-
nificantly high GOR in patients without IEDs suggests that
GOR analysis detects subtle and focal interneuronal hyper-
synchronization associated with epileptogenicity, which is
undetectable as IEDs on EEG. Furthermore, GOR is con-
sidered capable of reflecting diffusion data that decay with
distance from their source; this feature is consistent with the
fact that the range of high GOR on HD-EEG is further refined
by high GOR on electrocorticography (ECoG).
Although the effectiveness of interictal ESI with scalp EEG
for presurgical assessment of the epileptogenic zone has been
documented,18-20 the combination of HD-EEG6 and ictal ESI8 can
reportedly provide an even more accurate assessment. 123I-iomazenil
single-photon emission computed tomography (IMZ-SPECT) can
detect the epileptogenic focus with superior sensitivity.21 Finding
concordance between interictal IMZ-SPECT and 2-[18F]fluoro-2-
deoxy-D-glucose positron emission tomography, a recent study
reported that the epileptogenic zone is identified 6 times more
accurately than by each examination alone among patients with
nonlesional findings on MRI.22
This study aimed to examine whether preoperative GOR
analysis with HD-EEG could improve the accuracy of epi-
leptogenic focus localization relative to other conventional
techniques, including interictal ESI and IMZ-SPECT. A
confirmation of the relative superiority of GOR analysis with
HD-EEG could ultimately help improve postoperative seizure
control.
METHODS
Patients
We analyzed 21 patients undergoing HD-EEG recording as a part of
the routine epilepsy practice for presurgical evaluation of medically re-
fractory focal epilepsy who underwent epilepsy surgery in the Department
of Neurosurgery at Showa University School of Medicine. These 21
patients were selected to match the following 3 criteria from all the other
patients operated in our hospital: (1) habitual seizures were captured on
preoperative long-term video-EEG monitoring, providing information
on the seizure onset zone; (2) symptomatic epilepsy with structural
abnormalities on MRI or if there were no structural abnormalities, the
epileptic focus was determined based on the results of long-term EEG
monitoring; and (3) informed consent was obtained after a detailed ex-
planation. The postoperative seizure outcomes were evaluated according to
the International League Against Epilepsy classification system.23
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This study was approved by the Research Ethics Board at the Showa
University School of Medicine. All procedures adhered to the tenets of the
latest version of the Declaration of Helsinki.
HD-EEG Recordings
All patients underwent HD-EEG with the 128-channel (patient #21) or
256-channel Geodesic Sensor Net (Electrical Geodesics, Inc), which
covered the face, neck, and cranium, with electrodes positioned 20 to
25 mm apart. The recordings were performed for more than 90 minutes,
sampled at 1 kHz, referenced to electrode Cz, and bandpass-filtered at 0.5
and 70 Hz.
All recordings were performed by a certified EEG technologist. We
randomly selected a 20-second epoch consisting of the interictal
background EEG for GOR analysis for each patient. All selected
epochs were inspected by a board-certified clinical epileptologist to
ensure the absence of significant artifacts. The epileptologist was
blinded to the results of other localization methods used on the patients
and to the patient’s clinical history and symptoms at the time of
inspection.
GOR Analysis With HD-EEG
The detailed algorithm for GOR analysis using the sample entropy
method has been described previously.15 The HD-EEG data were
downsampled to 200 Hz, where the timescale factor τ = 3 to 7 corre-
sponded to the gamma frequency (28.6-66.7 Hz). A time series of length
of 200 Hz × 20 seconds has been applied as it provides stable results in
preceding EEG study.24 It has been also reported that an EEG data point
of 200 Hz × 20 seconds provides a reliable assessment of GOR.15 We
quantified the GOR for the selected 20-second epoch and calculated the
mean and SD of the measured GOR in a given patient. Z-values were
calculated using the following equation:
ðindividual GORÞ-ðmean GORÞ
Z ¼ :
ðSD of GORÞ
Calculations were performed for each electrode placed on each pa-
tient. Z-values of less than 2 were defined as significant, as previously
described.16 Lower Z-values represented higher GOR. These procedures
were performed using a custom program developed in cooperation with
EFken Inc. We used the inverse method, low-resolution electromagnetic
tomography (LORETA),25 for significantly high GOR to reveal the
epileptogenic zone. LORETA demonstrates the synchronous neuronal
activities underlying EEG data by computing their cortical localization
from the scalp distribution of the electric field.26 We used LORETA
to limit our selection to areas where the GOR was significantly
high (Z < 2) and identified the center of the GOR source as the
epileptogenic zone.
GOR Analysis With Intraoperative ECoG
In all patients, we performed GOR analysis with intraoperative ECoG
to evaluate the results of GOR analysis with HD-EEG. Intraoperative
ECoG was recorded under the following conditions: 2.5% sevoflurane
under maintaining partial pressure of carbon dioxide in arterial blood at
30 to 35 mm Hg. Because this method is very sensitive and accurate in
locating the epileptogenic zone,17 the area identified by this method was
resected. The data processing methods were the same as those mentioned
above.
operativeneurosurgery-online.com
 OPERATIVE NEUROSURGERY
TABLE 1. Patient Characteristics
© Congress of Neurological Surgeons 2022. Unauthorized reproduction of this article is prohibited.

Age Preoperative Intraoperative

Follow-up
At Interictal high length
Patient seizure At GOR High GOR with after Outcome
no. Sex onset surgery MRI findings Seizure type with HD-EEG Interictal ESI IMZ-SPECT ECoG ECoG (spikes) Operation surgery (Engel)

1 F 24 y 31 y Left temporal Focal impaired Left mesial Left mesial Left anterior Left lateral Left lateral Cavernoma removal + 3 y 10 mo I
cavernoma awareness seizure temporal temporal temporal temporal + left temporal + left hippocampal transection
hippocampus hippocampus
2 F 45 y 47 y Left occipitoparietal Visual hallucination Left superior Undetectable Left Left superior None Cavernoma removal + 3 y 5 mo I
cavernoma occipital occipitoparietal occipital focal resection
3 M 37 y 42 y Lett frontal cavernoma Focal to bilateral Left premotor Left prefrontal Left premotor‒ Left premotor Left premotor Cavernoma removal + 3 y 7 mo I
tonic-clonic seizure prefrontal focal resection
4 M 23 y 24 y Left frontal cavernoma Aphasic seizure Left dorsolateral Left Left prefrontal Left dorsolateral None Cavernoma removal + 3 y 1 mo I
prefrontal frontopolar prefrontal focal resection
5 F 44 y 45 y Right parietal Focal sensory seizure Right superior Right parietal Right parietal Right superior Right parietal Cavernoma removal + 2 y 10 mo I
cavernoma parietal parietal focal resection
6 M 52 y 56 y Right temporal Focal impaired Right mesial Right mesial Right mesial Right lateral Right lateral Cavernoma removal + 2 y 7 mo I
cavernoma awareness seizure temporal temporal temporal temporal + right temporal + right transsylvian
hippocampus hippocampus hippocampectomy
7 F 30 y 32 y Left postcentral tumor Focal sensory seizure Left postcentral Left parietal Left parietal Left postcentral Left parietal Tumor removal + focal 2 y 9 mo I
resection
8 F 71 y 72 y Right frontal tumor Focal motor seizure Right prefrontal Right Right prefrontal Right prefrontal Right prefrontal Tumor removal + focal 2 y 5 mo I
prefrontal resection
9 F 44 y 49 y Left postcentral tumor Focal sensory seizure Left postcentral Undetectable Left parietal Left postcentral None Tumor removal + focal 2 y 4 mo I
resection
10 M 49 y 69 y Left parietal tumor Focal sensory seizure Left superior Left parietal Left parietal Left superior Left superior Tumor removal + focal 2 y 2 mo I
parietal parietal parietal resection
11 F 20 y 26 y Left precentral tumor Supplementary Left Left primary Left premotor Left Left Tumor removal + focal 2 y 1 mo I
motor seizure supplementary motor supplementary supplementary resection
motor area motor area motor area
12 M 20 y 25 y Left frontal Focal motor seizure Left premotor Left prefrontal Left prefrontal Left premotor Left premotor Tumor removal + focal 4 y 9 mo I
postoperative scar resection
13 M 5y 26 y Normal Focal impaired Left mesial Left anterior Left anterior Left Left Transsylvian hippocampal 3 y 4 mo I
awareness seizure temporal temporal temporal hippocampus hippocampus transection
14 M 16 y 22 y Normal Focal impaired Left mesial Left anterior Left anterior Left Left Transsylvian hippocampal 2 y 7 mo I
awareness seizure temporal temporal temporal hippocampus hippocampus transection
15 M 8y 69 y Normal Focal impaired Right mesial Bilateral Right anterior Right Right Transsylvian hippocampal 2 y 2 mo I
awareness seizure temporal temporal temporal hippocampus hippocampus transection/partial
hippocampectomy

INTERICTAL HIGH GOR AS EPILEPTIC ZONE MARKER

16 F 19 y 27 y Normal Focal impaired Left mesial Left anterior Left anterior Left Left Transsylvian hippocampal 2 y 7 mo I
awareness seizure temporal temporal temporal hippocampus hippocampus transection
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17 F 19 y 29 y Left parietooccipital Visual hallucination Left superior Left parietal Left Left superior Left superior Focal resection 2 y 9 mo I
postoperative scar + focal to bilateral parietal parietooccipital parietal parietal
tonic-clonic seizure
18 F 38 y 40 y Right postcentral Focal sensory seizure Right Right parietal Right rolandic Right postcentral Right postcentral Focal resection 2 y 7 mo I
postoperative scar postcentral
19 M 20 y 43 y Right precentral Focal motor seizure Right precentral Right Right premotor Right precentral Right precentral Focal resection 2 y 3 mo I
postoperative scar + focal to bilateral frontopolar
tonic-clonic seizure
20 M 30 y 33 y Left temporal Focal to bilateral Left anterior Left anterior Left anterior Left anterior Left anterior Meningoencephalocele 3 y 8 mo I
meningoencephalocele tonic-clonic seizure temporal temporal temporal temporal temporal repair + focal resection
21 F 1 y 2 mo 2 y 6 mo Left precentral focal Focal motor seizure Left precentral‒ Left Left premotor‒ Left precentral‒ Left precentral‒ Focal resection 3 y 2 mo I
cortical dysplasia premotor precentral‒ prefrontal premotor premotor
premotor
123
ECoG, electrocorticography; HD-EEG, high-density electroencephalography; GOR, gamma oscillation regularity; ESI, electrical source imaging; IMZ-SPECT, I-iomazenil single photon emission computed tomography; M, male; F, female
SATO ET AL
TABLE 2. Concordance Between Interictal High GOR With HD-EEG and Other Methods
Interictal ESI
Fully Partially Fully
overlapping overlapping Discordant overlapping
No. of 10 (48%) 8 (38%) 3 (14%) 8 (38%)
cases (%)
ESI, electrical source imaging; GOR, gamma oscillation regularity; HD-EEG, high-density electroencephalography; IMZ-SPECT,
tomography.
ESI
We compared the ESI with the GOR analysis in all patients. The
interictal spikes seen in HD-EEG were visually identified by a certified
EEG technologist and confirmed by a board-certified clinical epileptologist.
Electrical source localization was conducted at the rising phase for spikes
detected on HD-EEG with a linear inverse method using the GeoSource
software package (https://www.egi.com/research-division/electrical-source-
imaging/geosource) within the space of a 3D head model derived from the
Montreal Neurological Institute’s average adult MRI.27
Statistical Analysis
The concordance between the results of interictal GOR analysis and
HD-EEG with those of interictal ESI, IMZ-SPECT, and postoperative
MRI was evaluated. Concordance was defined as fully overlapping,
partially overlapping, or discordant.
Data Availability Statement
The raw data supporting this article will be made available by the
authors without undue reservation.
RESULTS
The results of all patients (10 men; mean age, 37.8 years; age
range, 2-72 years) are summarized in Table 1.
Of all patients, 6 had cavernomas (patients #1-6), 6 had tumors
(patients #7-12), 4 had temporal lobe epilepsy (patients #13-16), 3
had postoperative scars (patients #17-19), one had meningoence-
phalocele (patient #20), and one had focal cortical dysplasia (patient
#21). Preoperatively, the interictal GOR analysis with HD-EEG
allowed for the localization of the epileptogenic zone in all cases, and
these results were consistent in terms of laterality and brain lobe level,
with the results of the interictal ESI in all but 3 cases. The con-
cordance between the results of interictal high GOR on HD-EEG
and those of source estimation of interictal discharge was fully
overlapping in 10 cases (48%), partially overlapping in 8 cases
(38%), and discordant in 3 cases (14%). The concordance between
the results of interictal high GOR on HD-EEG and those of IMZ-
SPECT was fully overlapping in 8 cases (38%), partially overlapping
in 11 cases (52%), and discordant in 2 cases (10%). The concor-
dance between the results of interictal high GOR on HD-EEG and
those of postoperative MRI was fully overlapping in 14 cases (67%),
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IMZ-SPECT Postoperative MRI
Partially Fully Partially
overlapping Discordant overlapping overlapping Discordant
11 (52%) 2 (10%) 14 (67%) 7 (33%) 0
123
I-iomazenil single-photon emission computed
partially overlapping in 7 cases (33%), and no discordant cases
(Table 2).
In particular, interictal high GOR with HD-EEG was useful in
confirming the epileptogenic zone in 4 cases with nonlesional
temporal lobe epilepsy (patients #13-16). Intraoperative high
GOR with ECoG localized the epileptogenic zone in complete
concordance with preoperative interictal high GOR with HD-
EEG and in even greater detail in cases of temporal cavernomas
(patients #1 and #6). Intraoperative ECoG showed no significant
spikes in 3 cases (patients #2, #4, and #9), thus making high GOR
a definitive marker of the epileptogenic zone.
Focal resection was performed in all cases where the intraoperative
GOR was significantly high. All patients were seizure-free post-
operatively, and no complications were observed. The preoperative
MRI findings; results of interictal high GOR with HD-EEG, in-
terictal ESI, IMZ-SPECT, intraoperative ECoG, and high GOR
with ECoG; postresectional photographs of the brain surface; and
postoperative MRI findings of the representative 4 cases (patients
#4, #11, #15, and #19) are illustrated in Figures 1-4.
DISCUSSION
We used GOR analysis with HD-EEG to accurately predict the
epileptogenic zone preoperatively. In our 17 cases with apparent
lesions on MRI, GOR analysis with HD-EEG successfully revealed
the epileptogenic zone when used along with other conventional
methods. Contrarily, in our 4 cases with nonlesional temporal lobe
epilepsy (patients #13-16), conventional methods did not provide any
preoperative data that could help predict the epileptogenic zone. In
such cases of nonlesional temporal lobe epilepsy, long-term video-
EEG monitoring with intracranial electrodes was necessary to identify
the precise location of the epileptogenic zone. Our preoperative GOR
analysis with HD-EEG could indicate the laterality of the focus in
patients with nonlesional temporal lobe epilepsy and help identify
precise location of the epileptogenic zone in the temporal cortex
without requiring the invasive placement of intracranial electrodes.
Our experience suggests that preoperative GOR analysis with HD-
EEG can successfully contribute to localizing seizures, particularly in
cases of nonlesional temporal lobe epilepsy and can help avoid
complications from invasive surgery for EEG monitoring in patients.
operativeneurosurgery-online.com
 INTERICTAL HIGH GOR AS EPILEPTIC ZONE MARKER

FIGURE 1. Illustrative results of a patient with aphasic seizure due to a cavernoma in the left frontal lobe (patient #4). A, Preoperative MRI findings.
B, Interictal GOR with high-density electroencephalography reveals significantly high GOR in the left dorsolateral prefrontal region. C, Interictal
electrical source imaging shows that the spikes are localized to the left frontopolar region. D, 123I-iomazenil single-photon emission computed to-
mography shows decreased uptake in the left prefrontal region (arrow). E, Intraoperative ECoG shows no significant epileptic discharges. F, In-
traoperative GOR with ECoG reveals significantly high GOR in the left dorsolateral prefrontal region (electrodes #2 and #6: red dotted circle). G,
Intraoperative photograph of the brain surface after resection (resection area: red dotted circle). H, Postoperative MRI findings. ECoG, electro-
corticography; GOR, gamma oscillation regularity; ref, referential electrode.

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SATO ET AL

FIGURE 2. Illustrative results of a patient with supplementary motor seizure due to a left precentral tumor (patient #11). A,
Preoperative MRI findings. B, Interictal GOR with high-density electroencephalography reveals significantly high GOR in the left
supplementary motor area. C, Interictal electrical source imaging shows that the spikes are localized to the left primary motor area. D,
123
I-iomazenil single-photon emission computed tomography shows decreased uptake in the left premotor region (arrow). E, Intraoperative
ECoG shows the spikes in the left supplementary motor area (electrodes #7, #8, #12, and #13). F, Intraoperative GOR with ECoG
reveals significantly high GOR in the left supplementary motor area in a more localized distribution (electrodes #8, #12, and #13: red
dotted circle). G, Intraoperative photograph of the brain surface after resection (resection area: red dotted circle). H, Postoperative MRI
findings. ECoG, electrocorticography; GOR, gamma oscillation regularity; ref, referential electrode.

6 | VOLUME 00 | NUMBER 00 | MONTH 2022 operativeneurosurgery-online.com

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 INTERICTAL HIGH GOR AS EPILEPTIC ZONE MARKER

FIGURE 3. Illustrative results of a patient with focal impaired awareness seizure due to the nonlesional temporal lobe
epilepsy (patient #15). A, Preoperative MRI findings. B, Interictal GOR with high-density electroencephalography
reveals significantly high GOR in the right mesial temporal region. C, Interictal electrical source imaging shows the
spike sources that were detected in the bilateral temporal regions. D, 123I-iomazenil single-photon emission computed
tomography shows decreased uptake in the right anterior temporal region (arrow). E, Intraoperative ECoG shows spikes
in all electrodes on the right hippocampus. F, Intraoperative GOR with ECoG reveals significantly high GOR in the
posterior part of the body and tail of the right hippocampus (electrodes #3 and #4: red dotted circle). G, Intraoperative
photograph after hippocampal resection (resection area: red dotted circle). H, Postoperative MRI findings. ECoG,
electrocorticography; GOR, gamma oscillation regularity; ref, referential electrode.

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SATO ET AL

FIGURE 4. Illustrative results of a patient with focal motor seizure and focal to bilateral tonic-clonic seizure due to the right precentral
postoperative scar (patient #19). A, Preoperative MRI findings. B, Interictal GOR with high-density electroencephalography reveals
significantly high GOR in the right precentral region. C, Interictal electrical source imaging shows that the spikes are localized to the right
frontopolar region. D, 123I-iomazenil single-photon emission computed tomography shows decreased uptake in the right premotor region
(arrow). E, Intraoperative ECoG shows the spikes in the right precentral region (electrodes #9, #10, #17, #18, and #35). F, Intraoperative
GOR with ECoG reveals significantly high GOR in the right precentral region with a relatively more localized distribution (electrodes #17,
#18, #19, and #25: red dotted circle). G, Intraoperative photograph of the brain surface after resection (resection area: red dotted circle).
H, Postoperative MRI findings. ECoG, electrocorticography; GOR, gamma oscillation regularity; ref, referential electrode.

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In lesion cases, the addition of GOR analysis with HD-EEG to
conventional preoperative evaluation methods may increase di-
agnostic accuracy. Furthermore, intraoperative GOR analysis will
allow us to provide minimally invasive epilepsy surgery. In
nonlesional cases, the diagnosis of epileptogenic focus may be
made on the basis of GOR analysis with HD-EEG becasuse it
cannot be fully evaluated by conventional preoperative methods.
If that does not provide a clear diagnosis, invasive placement of
intracranial electrodes should be considered. The evaluation
methods should be chosen in order of less invasiveness.
Although the effectiveness of intraoperative GOR assessment with
ECoG for the resection of cavernomas surrounding the epileptogenic
focus has been reported previously,17 whether this method could
facilitate planning for resection of the seizure focus caused by other
diseases was unclear. Although intraoperative ECoG failed to show
IEDs in three of our cases (patients #2, #4, and #9), we could resect
the focus using intraoperative GOR analysis and ECoG with good
seizure-related outcomes. In the remaining patients with clear IEDs,
intraoperative GOR provided more precise and targeted information
of the focus than did standard ECoG, making the surgery less in-
vasive. Taken together, these results indicate that intraoperative GOR
measurement may be widely applicable to preoperative planning in
future epilepsy-related surgical practice.
A large-scale network of studies demonstrated that coherent
gamma oscillations are generated through increased synchronous
activities of local cortical neurons and that such local interneuron
connectivity is related to the long-range synchrony of gamma
oscillations.10,28 This may explain how the results of preoperative
GOR analysis with HD-EEG can be further refined by intra-
operative GOR analysis and ECoG. Furthermore, a study of
postsurgical tissue from a patient with temporal lobe epilepsy
demonstrated that IEDs are preceded by interneuronal firing.12
Because IEDs are basically markers of the irritative zone and GOR
may represent the localized epileptogenic zone overlapping the
irritative zone, the concordance between interictal GOR and
interictal ESI might have been moderate. Although SPECT is
reliable when ictal scans are subtracted from interictal baseline
scans to increase the detection rate of the epileptogenic zone, in
this study, interictal IMZ-SPECT was performed instead of such a
method, which may be one of the reasons for the fair concordance
between interictal GOR and interictal IMZ-SPECT. Comparison
of interictal GOR with subtraction ictal SPECT will be inves-
tigated in the near future.
The sample entropy method is originally a coarse graining of
time series data, and it is a method to calculate the average value of
time series data in a window of length τ, averaging the time series
data in order without regard to each other. τ = 1 is the original
time series without coarse graining, and τ = N (≥2) is the value
obtained by averaging the original time series data in order N from
the beginning by N. When the sampling ratio is high (1000 Hz),
each divided frequency become too much detailed. If coarse
graining with a high sampling frequency picks up a lot of τ, the
regularity of the frequency to be analyzed tends to vary, which
does not necessarily result in a high-resolution analysis. A time
OPERATIVE NEUROSURGERY
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INTERICTAL HIGH GOR AS EPILEPTIC ZONE MARKER
series of length N = 4000 (ie, 20-seconds × 200 Hz) has been
applied because it provides stable results in preceding EEG
study.24 It has been also reported that an EEG data point of
200 Hz × 20 seconds provides a reliable assessment of GOR.15
This is the reason why we down-sampled to 200 Hz.
Limitations
This study used a highly diverse patient cohort in terms of
etiology. In epilepsy due to focal cortical dysplasia, the efficacy of
GOR analysis in ECoG data has been previously reported.15,16 In
those studies, it has been discussed that hypersynchronization of
interneuron, which may play a role of inhibiting the epileptogenic
focus during interictal periods, could be detected as GOR high. In
poststroke epilepsy such as cavernoma, it has been suggested
that epileptogenesis may be acquired by bleeding-induced neu-
ronal excitotoxicity and synaptic plasticity.29 In addition, iron
deposition has been suggested to inhibit glutamate uptake and
glutamine synthetase.30 It is possible that the hemosiderin
deposition near cavernomas causes impaired glutamate uptake,
which allows interneuronal hypersynchronization, and such
hypersynchronization is detected as high GOR.16 In tumor-
induced epileptogenesis, a variety of factors have been suggested,
including peritumoral edema, metabolic imbalances, pH changes,
and so on.31 Because of many variations of tumor types, it is
difficult to comprehensively explain those epileptogenic mecha-
nisms. Although much information about epileptogenicity is
missing in other etiologies including MRI negative temporal lobe
epilepsy, we speculate that interneuronal hypersynchonization,
which may be common in focal epilepsy, may correspond to GOR
high. Future statistical comparisons between techniques will also
help address the other limitations of this study, such as the small
cohort size, consecutive case–series design, and lack of randomi-
zation with a control group to evaluate outcome measures.
CONCLUSION
Interictal high GOR analysis with HD-EEG could be an ef-
fective diagnostic aid for presurgical epileptogenic zone locali-
zation and particularly useful in the treatment of our patients,
especially those with nonlesional temporal lobe epilepsy.
Funding
This study was supported by research grants from the JSPS KAKENHI Grant
No. JP 20K09356.
Disclosures
The authors have no personal, financial, or institutional interest in any of the
drugs, materials, or devices described in this article.
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Acknowledgments
We thank Dr Tohru Mizutani, Department of Neurosurgery, Showa Uni-
versity School of Medicine, for providing training in neurosurgical skills to Dr
Yosuke Sato. We also appreciate the assistance and support provided by Dr
Yoshihito Tsuji, Department of Neurosurgery, Matsubara Tokushukai Hospital,
Osaka, Japan.
operativeneurosurgery-online.com