J Neurosurg 121:827–838, 2014
©AANS, 2014

Intraoperative cortico-cortical evoked potentials for theevaluation of language function during brain tumor
resection: initial experience with 13 cases
Clinical article
Taiichi Saito, M.D., Ph.D.,1,5,7 Manabu Tamura, M.D., Ph.D.,1,2,5
Yoshihiro Muragaki, M.D., Ph.D.,1,2,5 Takashi Maruyama, M.D., Ph.D.,1,2,5
Yuichi Kubota, M.D., Ph.D.,1 Satoko Fukuchi, R.T., 3 Masayuki Nitta, M.D., Ph.D.,1,2,5
Mikhail Chernov, M.D., D.Med.Sci.,1,2 Saori Okamoto, M.D., 2
Kazuhiko Sugiyama, M.D., Ph.D., 6 Kaoru Kurisu, M.D., Ph.D.,7
Kuniyoshi L. Sakai, Ph.D., 4,5 Yoshikazu Okada, M.D., Ph.D.,1
and Hiroshi Iseki, M.D., Ph.D.1,2
Department of Neurosurgery; 2Faculty of Advanced Techno-Surgery; 3Central Clinical Laboratory, Tokyo
Women’s Medical University; 4Department of Basic Science, Graduate School of Arts and Sciences, The
University of Tokyo; 5CREST, Japan Science and Technology Agency, Tokyo; and Departments of 6Cancer
Chemotherapy and 7Neurosurgery, Hiroshima University, Hiroshima, Japan
1

Object. The objective in the present study was to evaluate the usefulness of cortico-cortical evoked potentials(CCEP) monitoring for the intraoperative assessment of speech function during resection of brain tumors.
Methods. Intraoperative monitoring of CCEP was applied in 13 patients (mean age 34 ± 14 years) during theremoval of neoplasms located within or close to language-related structures in the dominant cerebral hemisphere.
For this purpose strip electrodes were positioned above the frontal language area (FLA) and temporal language area
(TLA), which were identified with direct cortical stimulation and/or preliminary mapping with the use of implanted
chronic subdural grid electrodes. The CCEP response was defined as the highest observed negative peak in either
direction of stimulation. In 12 cases the tumor was resected during awake craniotomy.
Results. An intraoperative CCEP response was not obtained in one case because of technical problems. In theother patients it was identified from the FLA during stimulation of the TLA (7 cases) and from the TLA during stimulation of the FLA (5 cases), with a mean peak latency of 83 ± 15 msec. During tumor resection the CCEP response
was unchanged in 5 cases, decreased in 4, and disappeared in 3. Postoperatively, all 7 patients with a decreased orabsent CCEP response after lesion removal experienced deterioration in speech function. In contrast, in 5 cases withan unchanged intraoperative CCEP response, speaking abilities after surgery were preserved at the preoperative level,
except in one patient who experienced not dysphasia, but dysarthria due to pyramidal tract injury. This difference wasstatistically significant (p < 0.01). The time required to recover speech function was also significantly associated withthe type of intraoperative change in CCEP recordings (p < 0.01) and was, on average, 1.8 ± 1.0, 5.5 ± 1.0, and 11.0 ±3.6 months, respectively, if the response was unchanged, was decreased, or had disappeared.
Conclusions. Monitoring CCEP is feasible during the resection of brain tumors affecting language-related cerebral structures. In the intraoperative evaluation of speech function, it can be a helpful adjunct or can be used in its
direct assessment with cortical and subcortical mapping during awake craniotomy. It can also be used to predict the
prognosis of language disorders after surgery and decide on the optimal resection of a neoplasm.
(http://thejns.org/doi/abs/10.3171/2014.4.JNS131195)

S

Key Words
brain tumor••

awake craniotomy•
cortico-cortical evoked potentials • surgery•
oncology•
language function • diagnostic and operative techniques

urgical removal of intraaxial brain tumors locatedwithin or close to language-related cerebral structures represents a significant challenge. To minimize the risk of permanent postoperative speech dysfunction, detailed localization of the frontal language

Abbreviations used in this paper: CCEP = cortico-cortical evoked
potentials; ECoG = electrocorticography; FLA = frontal language
area; TLA = temporal language area.

J Neurosurg / Volume 121 / October 2014

area (FLA) and temporal language area (TLA), as well as
their subcortical connections, is critical. At present it canbe more or less precisely done with advanced neuroimaging techniques, such as functional MRI,2,5,12,13,22,29–31,33 diffusion tensor imaging,4–6,9,22,37 magnetoencephalography,4and PET.4,29 However, the most effective and precise
method is direct brain mapping using electrical stimulation, which can be accomplished either after implantationof chronic subdural grid electrodes4,5,20,21,36,37 or during
awake craniotomy.1,5,6,13,16,22,27,29,31,34,35,37,40
827

T. Saito et al.
Nevertheless, despite its proven effectiveness andwidespread acceptance, direct intraoperative brain mapping has some limitations. First, not all patients are suitable for awake craniotomy or can tolerate the procedure.27,31,37 Second, intraoperative evaluation of the verbal
response is generally subjective and can be significantly
influenced by the level of consciousness and cooperativeness of the patient, as well as by the parameters of cortical stimulation. Third, negative intraoperative corticalmapping does not fully prevent postoperative deterioration of speech function, which can be observed immediately after surgery in 4%–23% of such cases.16,34 Fourth,
intraoperative evaluation of language can be difficult inpatients with a preexisting speech deficit.22 Fifth, despite
the high reliability of intraoperative cortical mapping for
anatomical localization of language-related areas, thefunctional interconnections of these areas generally remain obscured. Sixth, intraoperative mapping of corticaland subcortical structures with electrical stimulation canbe performed only at some time points before or between
different stages of tumor removal, but is not suitable forconstant monitoring during the whole procedure. Finally,
while the appearance of durable speech disorders during
surgery generally leads to reluctance to perform further
tumor resection, the postoperative prognosis of such disorders is hardly predictable. For these reasons, further
searches for novel methods of objectively assessing language during awake craniotomy seem reasonable.
The objective in the present study was to evaluate therecording of intraoperative cortico-cortical evoked potentials (CCEP) as an adjunctive method of assessing speech
function during the resection of intraparenchymal brain
neoplasms. To the best of our knowledge, there have beenno previous reports on the application of this neurophysiological technique for brain tumor surgery.

Methods

Between February 2006 and July 2012, intraoperative
monitoring of CCEP was applied in 13 patients (11 men
and 2 women; mean age 34 ± 14 years) during removalof intraparenchymal brain neoplasms located within or
close to language-related structures (FLA, TLA, arcuate
fasciculus, and superior longitudinal fasciculus) in thedominant cerebral hemisphere. Detailed characteristicsof the patients are shown in Table 1. The ethics committee of the Tokyo Women’s Medical University approved
the study protocol, and each patient provided informed
consent before surgery.
Preoperative Evaluation

Preoperatively 11 of 13 patients had normal language
function, whereas mild dysphasia was noted in 2. The neoplasms were predominantly located within the middle orinferior frontal gyrus (6 cases), inferior parietal lobule (4cases), or insula (3 cases) of the left cerebral hemisphere.
In all cases the diagnosis was based on multimodal MRI,
which included pre- and postcontrast T1-weighted, T2weighted, FLAIR, diffusion-weighted, diffusion tensor,
and spectroscopic images. Additionally, PET scanningwith 11C-methionine, 11C-choline, and 18F-FDG was per-828

formed. In all patients the intracarotid amobarbital test
revealed that the left cerebral hemisphere was language
dominant.
Extraoperative Cortical Mapping

For detailed cortical mapping before tumor removal, 9 of 13 patients underwent subdural implantation ofchronic grid electrodes over the cortical area of interest.
This technique was usually applied in cases presenting
with seizures for precise localization of the epileptic focus relative to the neoplasm and eloquent cortical areas.
Each grid (60 × 40 mm) contained 24 electrodes with adiameter of 3 mm and a distance of 10 mm between thecenters (Unique Medical Co.). Usually two grids were
implanted in each individual to cover a sufficient area ofthe cortex. Three-dimensional localization of electrodes
relative to the brain surface was achieved using Leksell
GammaPlan (Elekta Instruments AB), whereas matchingof the cortical sulci and gyri was done with BrainVISA
software.38,39 Patients underwent continuous (2–3 weeks)
electrocorticography (ECoG) videomonitoring for detection of seizure activity.
Additionally, extraoperative cortical mapping was
performed. For this purpose repetitive square wave biphasic current of alternating polarity (pulse width 0.5 msec,
frequency 20 or 50 Hz, duration 1–2 seconds) was appliedin a bipolar fashion to adjacent pairs of electrodes so that
all electrodes were used. Continuous digital ECoG activity was monitored through nonstimulated electrodes to detect seizures and afterdischarges. The stimulus intensity
increased steadily from 2 mA using stepwise incrementsof 1 mA until the effect was attained or abnormalities
on ECoG were noted. The maximum stimulus intensity
was 6 mA, which corresponds to 12 mA if a monophasic
pulse were used. Of note, the maximum stimulus intensity recommended by guidelines of The Japan Awake Surgery Conference15 for cortical stimulation with the use of
subdural electrodes is 16 mA. Cortical stimulations were
performed using an Ojemann cortical stimulator (OCS1, Integra Radionics, Inc.), whereas all recordings weremade with a dedicated multimodal neuromonitor (Neuromaster Mee-1000, Nihon Kohden Corp.).
Regions of cerebral cortex were defined as language
related if their stimulation consistently interrupted, disturbed, or slowed the patient’s ability to name a pictured
object, to pronounce a written familiar Japanese word,
and/or to generate an action verb during the picture-naming task in the absence of seizures, afterdischarges, andpositive and negative motor responses of the tongue (defined as involuntary contraction and impairment of rapid
alternating movements, respectively). For confirmation of
reproducible results, each cortical area was stimulated atleast twice, although never in succession. The testing wasrecorded on video for subsequent reanalysis.
In our experience, extraoperative cortical mapping
significantly reduces the time required for intraoperative localization of eloquent cortical areas (particularly incases of dominant parietal lobe tumors) and for the overall operation, but cannot substitute for awake craniotomy
with direct electrical stimulation particularly aimed at theidentification of functionally important subcortical strucJ Neurosurg / Volume 121 / October 2014

J Neurosurg / Volume 121 / October 2014

12, M lt middle frontal
29, M lt middle frontal
31, M lt middle frontal

21, F

33, M lt inferior parietal

26, M lt insula

41, M lt insula

32, F lt inferior frontal
31, M lt inferior parietal

58, M lt inferior parietal

4
5
6

7

8

9

10

11
12

13

AO

AO
AOA

O

AOA

O

OA

CM
O
GBM

AOA

local (awake)

local (awake)
local (awake)

local (awake)

local (awake)

local (awake)

local (awake)

generallocal (awake)
local (awake)

local (awake)

local (awake)
local (awake)Type ofAnesthesia

6

4
3

4

4

4

6

6
6
6

6

6
8

Stimulus
Intensity(mA)†

FLA→TLA

TLA→FLAFLA→TLA

TLA→FLA
TLA→FLA
TLA→FLA

TLA→FLA

TLA→FLA
TLA→FLA

Direction of
Stimulation

disappeared

disappeared

unchanged
unchanged
unchanged

unchanged

unchanged
disappeared

40

95
95

60

85

95

95

100
95
75

30

98
80

ChangesDuring Tumor % Lesion
RemovalResection

decreased (upto 20%)
92
FLA→TLA decreased (upto 40%)§
no response no response NA
80
FLA→TLA decreased (upto 20%)
48
FLA→TLA decreased (upto 20%)§

94

66

94

73
94
98

90

70
91

Peak
Latency(msec)

Intraop CCEP

Intraopdysarthria
paraphasia, dysar­
thria
mild dys­ mild dysphasia, simi­
phasialar to preop levelnormalNA
normalnormalmild dys­ mild dysphasia, simi­
phasialar to preop levelnormalparaphasia, repeti­tion failurenormalparaphasia, repeti­tion failure, dys­arthria
normalparaphasia, repeti­tion failurenormalparaphasia, repeti­tion failurenormalnormalnormalnaming failure,
repetition failurenormalparaphasia, repeti­tion failurenormalnormal

Preop

yes

no
yes

yes

yes

yes

yes, similar topreop levelnonoyes, similar topreop level
yes

yes‡
yes

Presence

4

NA
6

6

6

15

10

NA
NA
1.5

3

1
8

Time toRecovery (mos)Language Function
Postop Speech Prod Disorder* AO = anaplastic oligodendroglioma; AOA = anaplastic oligoastrocytoma; CM = cavernous malformation; GBM = glioblastoma multiforme; NA = not applicable; O = oligodendroglioma; OA = oligoas­
trocytoma; Prod = production.
† Electrical stimulus was applied with biphasic current; therefore, actual stimulus intensities are 2 times greater.
‡ Caused by dysarthria due to pyramidal tract injury.
§ In these cases some recovery of CCEP was noted after termination of tumor removal.

lt inferior parietal

62, M lt inferior frontal

3

AO
O

Tumor
Tumor Location Histology

35, M lt middle frontal
27, M lt insulaAge(yrs),
Sex

1
2

Case
No.

TABLE 1: Summary of clinical characteristics in 13 patients*

Cortico-cortical evoked potentials

829

T. Saito et al.
tures, such as the arcuate fasciculus and superior longitudinal fasciculus.
Surgery

Surgery was performed according to the previously
described concept of the information-guided brain tumor
removal, presuming maximum possible resection of theneoplasm with minimal risk of permanent postoperative neurological complications.23–26 Intraoperative MRI(AIRIS II, Hitachi Medical Corp.), updated neuronavigation, comprehensive neurophysiological monitoring, anddetailed histopathological characterization of resected
tissue obtained at various stages of the procedure wereused routinely. In cases of malignancy, neurochemical
guidance of lesion resection with 5-aminolevulinic acidwas applied as well. In cases of high-grade gliomas, surgery was generally directed at the maximum possible
removal of the contrast-enhanced area visualized on
T1-weighted MRI; for low-grade gliomas, surgery was
focused on maximum removal of the hyperintense area
demonstrated on T2-weighted MRI. Histopathologicaldiagnosis of tumors was based on the current criteria of
the WHO.19
Intraoperative Brain Mapping

In all but one patient, tumor removal was done during awake craniotomy and was guided by positive mapping of cortical language areas and subcortical structures.
These procedures followed dedicated guidelines of The
Japan Awake Surgery Conference.15 Before surgery, patients were familiarized with the tasks used during intraoperative language mapping.15,37
For intraoperative brain mapping, electrical stimulation of the cortex was applied with repetitive square wave
biphasic current of alternating polarity (pulse width 0.5
msec, frequency 50 Hz, duration 1–2 seconds) using a bipolar electrode probe with an interpolar distance of 5 mm
and tip diameters of 1 mm. Stimulation was performed
in a systematic manner every 8–10 mm of the corticalsurface. Continuous digital ECoG activity was monitored
to detect seizures and afterdischarges. The stimulus intensity increased steadily from 2 mA using stepwise increments of 1 mA until the effect was obtained or abnormalities on ECoG were noted. The maximum stimulus
intensity was 6 mA, which is in concert with the experience and recommendations of others.1,5,16,22,34,40 The maximum stimulus intensity in this study corresponded to 12
mA if a monophasic pulse were used, which is in concordance with guidelines of The Japan Awake Surgery
Conference.15 Cortical stimulations were performed using
an Ojemann cortical stimulator, and all recordings weredone with a dedicated multimodal Neuromaster Mee1000 neuromonitor.
To demonstrate language assessment tasks to the patient, the dedicated intraoperative examination monitor
for awake craniotomy23,24 was used, which allows realtime visualization, integration and recording of a wide
spectrum of data, including a view of the patient’s faceduring response, the type of test provided, the position of
the cortical stimulator in the surgical field, and so forth.
830

Cortical stimulation immediately preceded task presentation for the patient and continued for 1–2 seconds.15 As in
extraoperative brain mapping, regions of the cerebral cortex were defined as language-related areas if their stimulation consistently interrupted, disturbed, or slowed thepatient’s ability to name a pictured object, to pronounce a
written familiar Japanese word, and/or to generate an action verb during the picture-naming task in the absence of
seizures, afterdischarges, and positive and negative motor
responses of the tongue. For confirmation of the reproducible results, each cortical area was stimulated at least
3 times, although never twice in succession. The stimulated sites were initially marked with sterile tags, whereas
eloquent cortical areas were delineated with the surgical
pen upon the completion of mapping. One centimeter ofbrain tissue close to the defined borders was preserved
during tumor resection. Removal of the neoplasm was accompanied by subcortical stimulation through the resection cavity directed at identifying the language pathways.
The devices used for this purpose and the parametersof stimulation, including intensity, were similar to thoseused for cortical mapping.15
During the entire procedure under awake conditions,the patient’s ability to speak freely was constantly monitored through continuous conversation with a memberof the treatment team who was specialized in assessing
language function and provided specific tasks to evaluate
recalling, counting, fluency, and comprehension.37
Intraoperative CCEP Monitoring

Intraoperative CCEP monitoring was performed continuously before, during, and after tumor resection, withspecial attention on assessing response during removalof the deep part of the neoplasm adjacent to the arcuate
fasciculus and superior longitudinal fasciculus. For thispurpose the strip electrodes (diameter 3 mm, distance
between centers 10 mm, Unique Medical Co.) were positioned above the FLA and TLA, which were identified
with cortical stimulation (Fig. 1). Additionally, recordings
through the resection cavity were tried occasionally. Twoadjacent electrodes were stimulated in a bipolar fashion
with a constant-current square wave of alternating polarity (pulse width 0.3 msec, frequency 1 Hz). Continuous
digital ECoG activity was recorded to detect seizures andafterdischarges. The stimulus intensity increased steadily
from 2 mA using stepwise increments of 1 mA until the
response was attained or abnormalities on ECoG werenoted. Actual stimulus intensities in the present study
varied from 3 to 8 mA, which is lower than the 10–15
mA used in previous studies of extraoperative CCEP
recordings in patients with epilepsy.4,7,8,21 The referenceelectrode was placed in the area of the contralateral mastoid process. The bandpass filter for data acquisition was
set at 5–1500 Hz with a sampling rate of 5000 Hz foreach channel.
In each case the stimulus was applied to the FLA withrecordings from the TLA and vice versa, and the CCEP
response was defined as the highest observed negative
peak in either direction. During each stimulation session
two or more trials of 100 responses were averaged using
the stimulus onset as the trigger and a delay of 10 msec to
J Neurosurg / Volume 121 / October 2014

Cortico-cortical evoked potentials

Fig. 1. Case 5. Intraoperative photograph showing strip electrodes
for CCEP monitoring, located above the TLA (black arrow) and FLA(white arrow) and within the resection cavity (gray arrow) during remov­
al of the left frontal glioma.

avoid artifacts caused by the stimulation itself. The complete CCEP response was obtained in 100 seconds, but
it usually stabilized after the application of 30 stimuli;
therefore, the changes, if presented, could be identified
in 30–40 seconds. A decrease in the CCEP response wasconsidered to occur when its amplitude reduced approximately 20% or more. All stimulations and recordingsof CCEP were performed with a dedicated multimodal
neuromonitor (Neuromaster Mee-1000). Patients in theawake condition were not specifically requested to perform any task during CCEP evaluation.
Postoperative Evaluation

Tumor resection rate was assessed with contrastenhanced MRI performed within 48 hours after surgery.
Speech function was evaluated initially after the patient
awoke from anesthesia and subsequently on a daily basis
until discharge from the hospital. Thereafter all patientswere regularly followed up in the outpatient clinic by anattending neurosurgeon. In cases of high-grade gliomas,
adjuvant radiochemotherapy was administered as appropriate.

Statistical Analysis

Nonparametric statistical tests were applied to evaluate factors associated with speech disturbances in theearly postoperative period and with the time required
to recover speech. For statistical analysis, in cases withnormal postoperative speech function, the time to speech
recovery was considered as 0. Statistical significance wasdefined at p < 0.05.

Results

Intraoperative brain mapping was successfully accomplished in all 12 patients who underwent awake craniotomy. In all cases the FLA and TLA were identified
J Neurosurg / Volume 121 / October 2014

within the posterior part of the inferior frontal gyrus andthe posterior part of the superior temporal gyrus, respectively. Additionally, in one patient (Case 13) the middle
part of the superior temporal gyrus also contained theTLA.
In 10 of these 12 patients, intraoperative speech dysfunction persisted to the end of surgery. However, in 2
(Cases 3 and 6) of the 10 patients mild dysphasia waspresent before surgery and was not aggravated during lesion resection, whereas in another patient (Case 1) dysarthria caused by pyramidal tract injury was observed, butdysphasia was not. Among 7 other patients paraphasias
and repetition failures were mainly encountered.
An intraoperative CCEP response was not obtainedin one patient (Case 11), presumably because of technicalproblems. In 4 patients (Cases 4 and 6–8) a clear bidirectional response was evident, whereas in 8 others (Cases
1–3, 5, 9, 10, 12, and 13) a definite CCEP response wasobserved in only one direction. Overall, the best response
was identified from the FLA during stimulation of the
TLA (7 cases) and from the TLA during stimulation of
the FLA (5 cases) with a mean latency of 83 ± 15 msec
(range 48–98 msec, median 91 msec). Attempts to detect
the CCEP response with strip electrodes located within
the resection cavity were not successful in any case.
During removal of the neoplasm the CCEP response
was unchanged in 5 cases, decreased (up to 20%–40%) in
4, and disappeared in 3. In all cases changes in the CCEP
response abruptly appeared during removal of the deeppart of the tumor in the presence of speech dysfunction,
but the occurrence of the latter was not always accompanied by alterations in response. In 2 patients (Cases 10 and13) some recovery of CCEP was noted within 20–30 minutes and was not accompanied by improvement in speech.
Limits for tumor removal were identified throughsubcortical stimulation of language or motor pathways(Cases 1, 3, 5, 6, and 11), decrease or disappearance of
the CCEP response (Cases 7, 8, and 12), or both of thesefactors (Cases 2, 9, 10, and 13). The median resection rate
was 95% (range 30%–100%). Histopathological examination revealed 7 high-grade gliomas, 5 low-grade gliomas,
and 1 cavernous malformation. The mean duration of surgery, including two intraoperative MRI sessions, was 8.2± 1.7 hours (range 5–10 hours).
Postoperative Course

During the early postoperative period, impairmentof speech was noted in 10 of 13 patients. However, as
mentioned above, in 2 patients (Cases 3 and 6) the mild
dysphasia had been present before surgery and was notaggravated during lesion resection; in another patient(Case 1) dysarthria caused by pyramidal tract injury wasobserved, but dysphasia was not.
All 7 patients with a decreased or absent CCEP response after tumor removal experienced deteriorationin speech function compared with its preoperative level.
In contrast, in 5 cases with an unchanged intraoperative
CCEP response, including 2 with preexisting mild dysphasia, speaking abilities were preserved at the preoperative level, except in the patient in Case 1, who experienced
dysarthria due to pyramidal tract injury. The difference831

T. Saito et al.
was statistically significant (p < 0.01, chi-square test with
continuity correction).
Speech function recovered in all patients within,on average, 6.1 ± 4.2 months after surgery (range 1–15
months, median 6 months). The time to speech recovery
was significantly associated with the type of intraoperative change in CCEP recordings (p < 0.01, Kruskal-Wallistest) and was, on average, 1.8 ± 1.0, 5.5 ± 1.0, and 11.0 ±3.6 months, respectively, if the response was unchanged,
was decreased, or had disappeared. In this way, the absence of intraoperative CCEP changes had 100% sensitivity, specificity, and positive predictive value for the recovery of language function within 3 months after surgery.
Additionally, the time to speech recovery was significantly associated with lesion location, taking, on average, 1.8± 1.0, 6.7 ± 1.2, and 8.8 ± 4.9 months, respectively, incases of frontal, insular, and parietal neoplasms (p < 0.02,
Kruskal-Wallis test).
Other evaluated factors, namely patient age, sex, tumor histopathological grade, lesion resection rate, maximum stimulus intensity, peak latency, and direction of
stimulation during CCEP recording, did not demonstrate
a statistically significant association with postoperative
impairment of speech function and the time to its recovery.
Case 8Illustrative Cases

History and Examination. A 33-year-old man experienced several episodes of generalized seizures. He
had no other neurological symptoms or signs, and his
speech function was normal. Magnetic resonance imaging demonstrated a nonenhancing intraaxial brain tumor
centered in the left inferior parietal lobule, which had ahypointense signal on T1-weighted images and a slightly
heterogeneous hyperintense signal on FLAIR images. Intracarotid amobarbital test revealed that the left cerebral
hemisphere was language dominant.

Operation. Tumor removal was performed during
awake craniotomy and continuous CCEP monitoringwith stimulation of the TLA and recordings from theFLA. In total 95% resection of the lesion was attained
under the guidance of cortical and subcortical mappingof language-related structures. During removal of theneoplasm, paraphasia, repetition failure, and dysarthria
were noted, whereas an initially normal CCEP response
demonstrated an abrupt decrease in amplitude and occasionally disappeared (Fig. 2). The histopathological diagnosis was oligodendroglioma.
Postoperative Course. After surgery the patient experienced the same speech disorders as intraoperatively, which recovered very slowly but became normal 15
months later. He did not have epileptic seizures duringfollow-up.

Case 13

History and Examination. A 58-year-old generally
healthy man experienced generalized seizures. Magnetic resonance imaging revealed nonenhancing intraaxial
832

brain tumor in the left parietal lobe. There were no otherneurological symptoms, and the patient was initially followed up with anticonvulsants and regular neuroimaging
at another hospital. Two years later, however, the appearance and gradual enlargement of a contrast-enhanced
area at the peripheral part of the lesion was noted. Malignant transformation was suspected, and the patient wassent to our clinic for surgical treatment. On admission thepatient was neurologically intact, and his speech function was normal. Magnetic resonance imaging revealed atumor centered in the left inferior parietal lobule, which
had hypointense signal on T1-weighted images and heterogeneous hyperintense signal on FLAIR images. The
contrast-enhanced lesion was located within the left insula. Intracarotid amobarbital test revealed that the left
cerebral hemisphere was language dominant.
First Operation. Two-stage surgical removal of thetumor was planned. Initially, the contrast-enhanced insular tumor was totally resected with the patient under general anesthesia. Histopathological examination revealed
anaplastic oligodendroglioma. At the end of surgery
chronic grid electrodes were implanted subdurally for detailed cortical mapping before resection of the residual
neoplasm.
First Postoperative Course. The postoperative course
was uneventful. The patient’s speech function remained
normal. Cortical mapping using grid electrodes identified
the FLA in the posterior part of the inferior frontal gyrus
and the inferior part of the precentral gyrus. The TLA
was located in the middle and posterior parts of the superior temporal gyrus and in the inferior parietal lobule.

Second Operation. Three weeks later the secondstage awake craniotomy was performed. Intraoperative
brain mapping revealed the same location of the FLA as
was defined with cortical stimulation using chronic gridelectrodes; however, the TLA was identified only in the
middle and posterior parts of the superior temporal gyrus. Continuous CCEP monitoring was performed withstimulation of the FLA and recordings from the TLA.
During resection of the deep part of the neoplasm, paraphasia and repetition failure were noted, whereas subcortical electrical stimulation resulted in short-term speecharrest. It was accompanied by a decrease in the CCEP
response in the posterior part of the superior temporal gyrus up to 20% and an increase in peak latency, althoughthese parameters were stable in the middle part of thegyrus (Fig. 3). Approximately 30 minutes later partial recovery of the CCEP response was noted. Nevertheless, toavoid an irreversible deterioration in language function,
further resection of the neoplasm was abandoned. In total
40% tumor removal was attained.
Second Postoperative Course. The postoperative
course was uneventful. Despite the presence of speech
production disorders in the early postoperative period,
language function gradually recovered and became normal by 4 months after surgery. The patient received acourse of fractionated radiotherapy (60 Gy) with concomitant and adjuvant chemotherapy (nimustine hydrochloride), which resulted in stabilization of the residual tumor.

J Neurosurg / Volume 121 / October 2014

Cortico-cortical evoked potentials

Fig. 2. Case 8. Oligodendroglioma in a 33-year-old man. Preoperative MR images (A) demonstrated tumor in the left inferiorparietal lobule. The neoplasm was resected during awake craniotomy, and intraoperative CCEP monitoring was performed withstimulation of the TLA and recordings from the FLA. During surgery, paraphasia, repetition failure, and dysarthria were noted. An
initially normal CCEP response demonstrated a decrease in amplitude and occasionally disappeared (B). The resection rate was
95% (C). After surgery, the patient experienced prolonged speech dysfunction with slow recovery within 15 months of follow-up.

Discussion

The technique of CCEP monitoring is based onelectrical stimulation of one cortical area and recording the averaged response from another, which permits
evaluation of their functional interconnections.4,7,8,17,20,21
Previous reports have demonstrated that this neurophysiological method can be useful for assessing the language
network in patients with epilepsy and that the evolved response is well correlated with the location of the FLA and
TLA.4,7,21 In the present study we showed for the first timethat CCEP recordings can be effectively performed durJ Neurosurg / Volume 121 / October 2014

ing awake craniotomy for brain tumors and are feasible
for the evaluation of language, since the evolved response
was closely related to intraoperative and postoperative
speech function, as well as to its prognosis after surgery.
Direct comparison of the results of CCEP monitoring
presented herein with those previously reported by othergroups is difficult. To the best of our knowledge, all previous studies have been based on recordings performed
after subdural implantation of chronic grid electrodes inpatients with seizures, whereas in the present study CCEP
monitoring was applied during the resection of brain neoplasms. Moreover, the quantitative and qualitative differ833

T. Saito et al.

Fig. 3. Case 13. Anaplastic oligodendroglioma in a 58-year-old man. A neoplasm in the inferior parietal lobule (A) was re­sected during a second-stage awake craniotomy and intraoperative CCEP monitoring with stimulation of the FLA and recordings
from the TLA. During removal of the deep part of the tumor, language function was impaired, whereas subcortical electricalstimulation resulted in short-term speech arrest (B, black arrow). It was accompanied by a decrease in CCEP response (C) in theposterior part of the superior temporal gyrus (P) up to 20% and an increase in peak latency, whereas these parameters recorded
from the middle part of the gyrus (M) were stable. Approximately 30 minutes later some recovery of the CCEP response wasnoted. However, only partial resection of the tumor was attained (D) to avoid permanent postoperative speech dysfunction. After
surgery the patient experienced paraphasias and repetition failures, with gradual recovery within 4 months of follow-up. Curved
arrows (C) show the directions of stimulation, presumably along dorsal and ventral language pathways, and arrowheads (C)indicate peak corresponding to CCEP response. F = FLA.

ences in subcortical fibers interconnecting evaluated cortical areas, as well as the distance between stimulating
and recording electrodes, are reflected in the intersubject
variability of latency and amplitude of CCEP responses3,4
and may differ in cases of nonstructural brain pathology
and tumors adjacent to the area of interest, particularly
834

because of the invasive and compressive effects of the latter. In their original study, Matsumoto et al.21 investigatedlanguage-related CCEP in 8 patients with epilepsy. The
response typically consisted of an early (N1) and late (N2)
negative peak with latencies of 22–36 msec and 113–164
msec, respectively, during stimulation of the FLA andJ Neurosurg / Volume 121 / October 2014

Cortico-cortical evoked potentials
recordings from the TLA, and 23–39 msec and 90–161
msec in the opposite direction. Recordings were successfully accomplished in the posterior language area after
stimulation of the anterior language area in 7 of 8 patients,
and in 3 of 4 patients when it was done in the opposite direction. Therefore, interconnections between anterior andposterior cortical language areas were considered bidirectional21 in contrast to the classic model of language.11
In our cases CCEP response frequently consisted of two
negative peaks, but only the highest one evoked in any
direction was evaluated because it was considered to be
more suitable for the purpose of intraoperative monitoring. Since the median peak latency was 91 msec, it probably corresponded to N2, which mainly reflects the direct
arrival of slow multisynaptic volleys via the cortico-subcortico-cortical pathway.21 Moreover, in the present study
the intraoperative CCEP response strongly depended on
the direction of stimulation and was clearly bidirectionalin only 4 patients. In Cases 9, 10, 12, and 13, responses
could not be reliably observed in the FLA during stimulation of the TLA, while they were clearly identified in
the opposite direction. It has been previously remarked
that the CCEP response in the anterior language area during stimulation of the posterior language area is less welldefined, because of the more scattered distribution of the
projecting neurons within the latter and the subsequent
activation of the smaller number of projecting neurons at
one time with the stimulation technique applied.21 Additionally, the degree of evoked response may be related tothe size of pyramidal neurons, which are smaller in theposterior language area and may require greater stimulation intensity.21 On the other hand, the strip electrodes
for intraoperative CCEP recordings in our patients werepositioned in the cortical areas, whose direct electricalstimulation resulted in speech abnormalities, while thebest response in the TLA during stimulation of the FLA
can be presented in spatially different areas.21 In someway it can explain the unidentified CCEP response in the
TLA after stimulation of the FLA in our Cases 1–3 and 5.
Finally, the absence of a noted response from white matter within the resection cavity may be particularly caused
by a predetermined delay in recordings of 10 msec after
trigger, since subcortical CCEP responses usually haveshort latencies.8
It is evident that the intraoperative evaluation of
CCEP may provide new insights into the neurophysiological organization of speech function. For example,
according to the traditional model, the FLA and TLA are
interconnected via a single neuronal pathway involving
the arcuate fasciculus and superior longitudinal fasciculus.11 However, this model cannot explain the different
CCEP responses observed during speech impairment
accompanying the removal of the deep part of the left
inferior parietal glioma in Case 13: deterioration of peaklatency and amplitude was noted in the posterior part ofthe superior temporal gyrus but not in its middle part.
On the other hand, such a finding may favor the recently
described dorsal and ventral pathways of the language
network.1,10,14,35 The former involves the arcuate fasciculus and superior longitudinal fasciculus and interconnects
the FLA with the TLA and parietal cortex,9 whereas the
J Neurosurg / Volume 121 / October 2014

latter includes the uncinate fasciculus and inferior frontooccipital fasciculus and interconnects the FLA with the
TLA and occipital cortex.1,10,35 In such a way, in our patient isolated deterioration of the CCEP response in theposterior part of the superior temporal gyrus may havebeen caused by alterations of the dorsal pathway but preservation of the ventral one.
Moreover, the application of intraoperative CCEP
monitoring may have definite clinical importance. During awake craniotomy the majority of patients in thepresent study demonstrated speech dysfunction, whichusually appeared during removal of the deep part of thetumor that affected the subcortical language pathways.
Trinh et al.40 noted that the presence of language and/or
motor abnormalities not resolved by the end of surgery
is associated with an 88% probability of a neurologicaldeficit in the immediate postoperative period and that patients in such cases are more than 6 times more likely tohave dysfunction at the 3-month follow-up.40 In our series the changes in CCEP were constantly observed in
the presence of intraoperative speech abnormalities, but
the appearance of the latter was not always accompaniedby alterations in the CCEP response. Changes in CCEP
were variable and ranged from complete disappearance
to a more or less prominent decrease followed by somerecovery, which was associated with the time interval torestore language function. Of note, the absence of any intraoperative CCEP change had 100% positive predictive
value for the recovery of speech function within 3 months
after surgery. Additionally, monitoring CCEP facilitatedintraoperative evaluation of speech in patients with a preexisting deficit (Cases 3 and 6) and was helpful in differentiating dysarthria caused by pyramidal tract injury
from dysphasia (Case 1). Therefore, CCEP recording canbe considered as a useful adjunct for assessing language
during surgery and predicting its postoperative prognosis.
Decision making in regard to the optimal resection
rate for glioma, whose removal under awake conditions isaccompanied by the appearance of speech disturbances,is always difficult. It is evident that complete elimination of the neoplasm can be beneficial to patient survival,
but its attainment at the cost of permanent postoperative
speech dysfunction is hardly acceptable.22 The majority of persistent neurological deficits after awake craniotomy for glioma removal is related to the dissection of
eloquent subcortical structures,40 which can be identified
with diffusion tensor imaging or intraoperative electrical stimulation. The former imaging technique, however,is susceptible to known inaccuracies, even if performed
intraoperatively,28,32,37 whereas positive subcortical mapping through the resection cavity is associated with theimmediate postoperative appearance or aggravation of
speech dysfunction in 67%–100% of patients.1,6 In thepresent study tumor removal was guided by intraoperative CCEP recording. Unless subcortical stimulation
caused speech arrest, the resection continued even in
the presence of language disturbances until a prominent
decrease in or disappearance of the CCEP response wasobserved. This strategy can be criticized since, like any
neurophysiological technique based on the evaluation of
an averaged response, intraoperative CCEP monitoring835

T. Saito et al.
may be susceptible to the temporary gap between structural injury and its detection. However, it seems that the
100 seconds required for recording the complete CCEP
response is comparable with the time required for intraoperative neurophysiological methods of proven efficacy
such as somatosensory evoked potentials (56.2 seconds
for averaging 500 stimuli at 8.9 Hz) and auditory brainstem response (99 seconds for averaging 1000 stimuli
at 10.1 Hz). It should be noted that the median resection
rate in the current series was 95%, and in no cases werepermanent speech production disorders remarkable after
surgery, although they are encountered in approximately
2% of patients undergoing awake craniotomy with direct
intraoperative brain mapping.1,34 Therefore, intraoperative CCEP monitoring can facilitate decision making as
regards the optimal resection of gliomas located in thevicinity of language-related structures, although further
studies on this important issue are definitely needed.
As was pointed out by Matsumoto et al., 21 CCEP recordings are task free and do not require any cooperationfrom the patient, which facilitates its use in persons who
are not candidates for awake craniotomy or who cannot tolerate this procedure. In fact, in one of our patients(Case 4), removal of the neoplasm was done under general anesthesia. During surgery CCEP monitoring did notreveal any changes in the evoked response, and no postoperative language disorders were noted. While before
making any solid conclusions, any beneficial outcome
should be reproduced in additional cases, this observation pointed out the possibility of speech function control
during brain tumor removal under general anesthesia. In
such a way, the FLA and TLA can be localized with cortical mapping in patients undergoing surgery according
to an awake-asleep strategy, through cortical mapping
after initial implantation of the chronic subdural gridelectrodes (as it was done in our patient), or by meansof advanced neuroimaging. In particular, functional MRI
provides 59%–100% sensitivity and 0%–97% specificity
for correct identification of language-related cortical areas12,33 and is generally considered to be fairly good fordemonstrating the FLA but less effective for demonstrating the TLA.
Possible disadvantages of the proposed techniqueof intraoperative CCEP monitoring include an increasein operation time and the requirement of a large craniotomy to provide access to the tumor, FLA, and TLA. It
has been suggested that glioma resection guided by positive cortical mapping can, by itself, be associated witha greater risk of postoperative neurological deterioration,
and a “tailored” craniotomy without intentional exposureof the eloquent cortex has been advocated.16,34,40 However,
the mentioned drawbacks should not be overemphasized.
While a larger craniotomy and intraoperative brain mapping have certainly led to some increase in the durationof surgery (roughly 1.5 hours per patient), the mean operation time in the present study (8.2 hours) corresponds
well with our general experience with surgery for gliomas using intraoperative MRI.23–26 Recently, Leuthardt
et al.18 reported an average operating room time of 7.9
hours (range 5.9–9.7 hours) in 12 patients treated withthe combined use of awake craniotomy, intraoperative836

cortical mapping, and intraoperative MRI, which seems
concordant with time in the present study. It should be
noted that neither a more extensive surgical approach nor
a relative prolongation of the surgical procedure resulted
in additional morbidity in our patients.
There are several limitations to the present study.
First, it was conducted at a single institution, includes
a small number of highly selected cases, and does notcontain a control group, which do not permit detailed
statistical evaluation of the predictive value of the presented technique for postoperative speech dysfunction
and its prognosis, particularly in comparison with direct
intraoperative assessment of language during awake craniotomy. Second, the exact threshold of CCEP decrease,which can be used for the termination of tumor resection
to avoid permanent postoperative language dysfunction,
was not determined. Third, the location of stimulating
and recording electrodes used for intraoperative CCEP
monitoring corresponded to rather restricted sites within
the cortical language-related areas, which (especially, theTLA) can be distributed rather widely.21,29,34 Fourth, onlyinterconnections between the FLA and the TLA were
evaluated, although it is known that other cortical areas,
especially the inferior parietal lobule, and their subcortical pathways are playing very important roles in speaking
abilities.1,3,6,21,22,34,35 Fifth, while diffusion tensor imaging
and subcortical stimulation were routinely performed in
our patients, the correspondence between identified language pathways and CCEP response was not specificallyaddressed. Finally, the detailed neurophysiology of theevolved response, especially as related to the direction of
stimulation, should be clarified further. Therefore, despite
the rather promising results presented herein, evaluationof CCEP recordings for the assessment of speech function during brain tumor surgery definitely needs additional investigation.

Conclusions

Results of the present study demonstrate the feasibility of CCEP monitoring during the resection of intracranial tumors affecting language-related cerebral structures.
This neurophysiological method can be useful in the objective evaluation of speech function as well as its direct
assessment during awake craniotomy. Moreover, it can be
helpful in predicting the prognosis of intraoperative andpostoperative deteriorations in language and for deciding
on the optimal resection of a neoplasm. Further experience with intraoperative CCEP recordings may open thepossibility of monitoring speech function during neurosurgical procedures performed under general anesthesia.
DisclosureThis study was supported by grants from the Japan National
Cancer Research and Development Fund and Core Research for
Evolutional Science and Technology (CREST), Japan Science andTechnology Agency. The authors report no conflict of interest concerning the materials or methods used in this study or the findings
specified in this paper.
Author contributions to the study and manuscript preparationin­clude the following. Conception and design: Muragaki, Saito, Ku­-

J Neurosurg / Volume 121 / October 2014

Cortico-cortical evoked potentials
bota. Acquisition of data: Saito, Tamura, Maruyama, Fukuchi, Nitta,
Okamoto. Analysis and interpretation of data: Saito, Tamura, Maru­yama, Kubota, Fukuchi, Chernov, Sugiyama, Kurisu. Drafting thearticle: Saito. Critically revising the article: all authors. Reviewed
submitted version of manuscript: all authors. Approved the finalver­sion of the manuscript on behalf of all authors: Muragaki. Sta­tistical analysis: Chernov. Administrative/technical/material support:
Muragaki, Tamura, Maruyama, Fukuchi, Okamoto, Sakai. Studysupervision: Muragaki, Sakai, Okada, Iseki.
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Manuscript submitted July 7, 2013.
Accepted April 22, 2014.
Please include this information when citing this paper: published online May 30, 2014; DOI: 10.3171/2014.4.JNS131195.
Address correspondence to: Yoshihiro Muragaki, M.D., Ph.D.,
Faculty of Advanced Techno-Surgery, Institute of Advanced Biomedical Engineering and Science, Tokyo Women’s Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan. email:ymuragaki@abmes.twmu.ac.jp.

J Neurosurg / Volume 121 / October 2014