From the Department of Neurology, University of Münster (S.K., M.D.,
H.H., T.H., E.-B.R.), and Epilepsie-Zentrum Bethel (A.E., H.J.), Münster,
Germany.
Correspondence to Stefan Knecht, MD, Department of Neurology, University of Münster, Albert-Schweitzer-Straße 33, D-48129 Münster, Germany. E-mail knecht{at}uni-muenster.de
Methods—fTCD and the Wada test were performed in 19 patients
evaluated for epilepsy surgery. By the Wada test, 13 patients were
classified as left-hemisphere dominant and 6 as right-hemisphere
dominant for language. fTCD was based on the continuous bilateral
measurements of blood flow velocities in the middle cerebral arteries
and event-related averaging during a cued word generation task
previously shown to activate lateralized language areas in
normal adults.
Results—In 4 patients fTCD assessment was not possible because of
lack of an acoustic temporal bone window. In the remaining 15
candidates, determination of language dominance was concordant with the
Wada test in every case. Moreover, the correlation of the
lateralization measures from both procedures was highly significant
(r=.92, P<.0001).
Conclusions—This strong correlation validates fTCD as a
noninvasive and practical tool for the determination of language
lateralization that can be applied for clinical and investigative
purposes.
The changes in cerebral perfusion during cognitive tasks that underlie
fMRI result in corresponding alterations of blood flow velocities in
the feeding basal arteries. These alterations can be noninvasively and
conveniently assessed by fTCD.7 8 9 10 11 12 13 14 15 16 17 18 The technique involves
the continuous bilateral measurement of blood flow velocities in both
MCAs during repeated performance of a task. Successive,
event-related changes of blood flow in both arteries relative to the
respective pre-event baseline are averaged, and averages from each
hemisphere are then subtracted from each other. The calculation of mean
relative blood flow differences makes the technique very robust, even
allowing for intermittent moving and speaking. Moreover, it renders
fTCD insensitive to global changes of perfusion due to modulations in
PCO2 or PO2 that affect
blood flow velocities in both insonated arteries equally.18
Thus, fTCD can even be applied in patients unsuitable for examinations
by fMRI and can easily be repeated for follow-up. Its only limitation
is that some subjects lack an acoustic temporal bone window for
insonation of the MCA. In a previous study we demonstrated that fTCD
during cued word generation in healthy right-handed subjects was
associated with a significantly higher blood flow increase to the left
relative to the right hemisphere in every subject.16 In the
present study we directly compared fTCD with the Wada test in
patients evaluated for epilepsy surgery to test the validity of fTCD as
a tool for determination of language dominance.
Functional TCD
To measure CBFV changes in the basal arteries as an indicator of a
downstream increase of regional metabolic activity during
the language task, a commercially available dual TCD device (Multi-Dop
T, DWL) was used. The MCAs were insonated at a depth of 50 mm with
two 2-MHz transducer probes attached to a headband and placed at the
temporal skull windows bilaterally (Fig 1
where V(t) is the CBFV over time. Relative
CBFV changes from repeated presentations of letters (on the
average 20 runs) were averaged time-locked to the cueing tone.
Differences in the velocity changes in the two MCAs in every patient
were statistically evaluated by the Wilcoxon test for each time
point. This nonparametric test is less sensitive to
outliers when only a limited number of epochs can be averaged. The
number of repetitions was less than 22 because no letter was
presented more than once during the word generation task. An
fTCD LIfTCD was calculated by the following formula (the
integral was substituted by the corresponding sum over the sampled data
points representing the velocity curve):
Wada Method
A Wada LI (LI Wada) was calculated by the formula: LI
Wada=(Pleft-Pright), where P is the language
score after left and right internal carotid artery injection,
respectively. This formula yields Wada indices between -104 for strong
left-hemispheric language dominance and +104 for strong
right-hemispheric language dominance.
Functional TCD
While attending the screen for an upcoming letter, ie, after the first
cueing tone and before the actual display of a letter on the screen
occurred, patients with left-hemisphere language dominance often showed
a relative right-hemispheric CBFV increase. Patients with
right-hemisphere language dominance showed either a relative CBFV
increase in the right hemisphere or, in one case, in the left
hemisphere. In most cases, however, these attention-related activations
did not reach significance.
The LIs for language determined with the Wada test (LI Wada) revealed a
highly significant correlation with the LIs measured by fTCD (LI fTCD)
(r=.92, P<.0001) (Fig 2
The Wada test, although a proven standard for determination of language
dominance, has several substantial disadvantages.3 4 23 The
required intracarotid angiography necessitates hospitalization, is
distressing to the patients, and has a morbidity risk reported as high
as 5%.24 Obtundation after injection of amobarbital can
make the distinction between attention-related and language-related
deficits difficult. Results can be influenced by cross flow of
anesthetic from the injected internal carotid artery to the
contralateral hemisphere via the circle of Willis25 or by
carryover effects from the first to the second injection when both
carotid arteries are injected on the same day.26 The very
restricted time for testing after amobarbital injection and the
unavailability of test-retest reliability data constitute further
limitations.
Because of the risks and shortcomings associated with the Wada test,
various attempts have been made to find alternatives to this technique.
Speech localization has been performed with the use of repetitive
transcranial magnetic stimulation.27 Repetitive
magnetic stimulation of the brain, however, carries a small but
definite risk for seizures, particularly in epileptic
patients.28 Moreover, it can induce facial and laryngeal
muscle contractions interfering with speech performance.
Positron emission tomography is another technique that allows
localization of cerebral language functions29 30 31 32 but is in
itself invasive because of radiation exposure.
Functional MRI offers another noninvasive alternative for the
determination of hemispheric language dominance.5 6 In
patients with refractory epilepsy, however, fMRI can be difficult to
perform. It requires maximal cooperation because the technique is very
sensitive to movement artifacts.33 It cannot be used in
patients with claustrophobia, gross obesity, metallic implants near to
or in the head, or cardiac pacemakers. Here fTCD holds promise as a
complementary technique, since the perfusional changes assessed by fTCD
are similar to those detected by fMRI but without the above
restrictions.12
The physiological information obtained by either
fTCD or the Wada test depends on the arterial distribution
under study. While the amobarbital injection during the Wada test
impairs cerebral function within the territory of the internal carotid
artery, fTCD operates more selectively by pinpointing the distribution
of a specific pial artery, eg, the MCA. Functional TCD imposes no time
or space restraints and is associated with no distress and little to no
inconvenience to the patient. Furthermore, TCD is a mobile and
comparatively inexpensive technique, available in most neurological
departments. It can be performed on an outpatient basis and may easily
be repeated for follow-up purposes. It allows control regarding patient
cooperation during every task without jeopardizing the
recording in toto due to movement artifact, as is sometimes the
case in fMRI studies. This makes it a practical tool for the
determination of language dominance in the clinical setting. Functional
TCD is, however, dependent on its ability to acoustically penetrate the
temporal bone. In our series this was not always feasible because 4 of
19 patients lacked a "window." In these patients, determination of
language dominance by fTCD was not possible with our technology.
However, auxiliary techniques are now becoming available that allow TCD
assessment even in the presence of thicker bones.34
Full use of the potential of fTCD has in the past been hampered by the
fact that the CBFV signal displays large fluctuations of the mean in
the range of ±30% due to heart rate or changes in
PCO2. This makes detection of small functional
changes on the order of 2% to 5% difficult. During cognitive tasks,
triphasic modulations of heart rate and cardiac ejection fraction add
to fluctuations of CBFV.35 36 It was not before the
introduction of bilateral simultaneous TCD that mean
lateralized increases of the CBFV relative to these global fluctuations
could be assessed by comparison between sides. This comparison between
sides also allows for detection of bilateral language
representation characterized by CBFV increases in both MCAs
with small differences, ie, a low LI. In some series the reported
incidence of bilateral language function determined by multiple
language tasks applied during Wada testing is almost
20%.37 In our series only one patient17 had a
low LI by both the Wada test and fTCD. Given the limited sample size,
this study does not lend itself to establish a
representative incidence of hemispheric language
dominance. Although patients had not been specifically selected for the
purpose of our study, the 20% incidence of right-hemispheric dominance
was far higher than in amobarbital studies based on several hundred
patients.38
The word generation task during fTCD corresponds to paradigms used in
other studies involving functional imaging.39 40 41
Conversely, the Wada test, as used in the present study, assesses a
wider variety of language functions. Time restraints during the
intracarotid amobarbital procedure did not allow us to perform an
additional word generation task identical to the one used for fTCD.
Thus, there were not only methodological differences between fTCD
(involving activation) and the Wada test (involving
anesthesia) but also differences in the behavioral task. In
the literature, impairments in word generation capabilities are linked
to damage in the left frontal lobe but can also be seen in nonfrontal
lobe lesions.42 43 Activation studies indicate that lexical
retrieval involves multiple regions of one hemisphere, many of which
are located outside the classic language areas.44 Moreover,
many of the patients in this study had long-standing cerebral lesions.
Thus, there was an increased likelihood of functional reorganization of
language areas and involvement of atypical anatomic
locations.45 However, the strong correlation between the
results from fTCD based on the word generation task and from the Wada
test based on multiple language tasks indicates that there was a
substantial overlap of brain regions involved in the respective
behavioral tasks. Nevertheless, further fTCD studies involving
different activation paradigms and direct comparison with postoperative
language performance should be performed to better delineate
the potential role of this new technique in epilepsy surgery and in
other investigational fields of language lateralization.
Received August 18, 1997;
revision received September 26, 1997;
accepted September 29, 1997.
© 1998 American Heart Association, Inc.
Original Contributions
Noninvasive Determination of Language Lateralization by Functional Transcranial Doppler Sonography
A Comparison With the Wada Test
Abstract
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
References
Background and Purpose—Functional
transcranial Doppler ultrasonography (fTCD) can assess
event-related changes in cerebral blood flow velocities and, by
comparison between sides, can provide a measure of hemispheric
perfusional lateralization. It is easily applicable, insensitive to
movement artifacts, and can be used in patients with less than perfect
cooperation. In the present study we investigated the validity of
fTCD in determining the hemispheric dominance for language by direct
comparison of fTCD with intracarotid amobarbital anesthesia
(Wada test).
Key Words: cerebral dominance • laterality • ultrasonography, Doppler • Wada test
Introduction
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
References
In most epilepsy
surgery programs, hemispheric dominance for language is assessed by
intra-arterial administration of amobarbital by means of a
transfemoral catheter placed into the cerebral arteries (Wada
test).1 2 Although of proven value in predicting the
potential risk of language impairment after resective surgery, the Wada
test has several inherent limitations, most importantly its
invasiveness.3 4 Recently, fMRI has been used to measure
cerebral perfusional changes noninvasively during language tasks in
patients capable of avoiding movement artifacts during MRI scanning.
The technique has been found to correlate closely with the outcome of
the Wada test.5 6
Subjects and Methods
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
References
Subjects
We studied 19 patients (12 males, 7 females) aged 17 to 45 years
(mean age, 29 years) who underwent comprehensive evaluation for
surgical treatment of medically intractable epilepsy at our department
in Münster and the Epilepsie-Zentrum Bethel (Germany). The
assessment included neurological examination, ictal semiology, video
monitoring with continuous interictal and ictal
electrophysiological recording,
MRI, neuropsychological evaluation, fTCD, and the Wada test. Subjects
gave informed consent to participate in the study. All were native
German speakers. Thirteen were right handed and six left handed by the
Edinburgh Handedness Inventory19 (Table
). Wada and fTCD
evaluations were performed by two different examiners blinded to the
results obtained with either technique.
View this table:
[in a new window]
Table 1. Patient Characteristics, Duration of Epilepsy, Handedness, and
Results of Wada Test and fTCD
Determination of hemispheric language dominance by fTCD was
performed as previously described by our group.16 Subjects
were seated in front of a computer screen where, 5 seconds after a
cueing tone, a letter was presented for 2.5 seconds (Fig 1). Subjects silently had to find as many
German words as possible starting with the displayed letter. To control
the performance of the task, subjects were instructed to report
the words after a second auditory signal 15 seconds after
presentation of the letter. All words had to be reported
within a 5-second time period. Afterward, a relaxation period of 60
seconds was given. Then the next letter was presented in the
same way. Letters were presented in random order.
Q,. X, and Y were excluded because
very few German words have these letters as initials. No letter was
displayed more than once.
View larger version (34K):
[in a new window]
Figure 1. Experimental setup of language dominance
assessment by fTCD. Displayed data represent the averaged
results from 20 letter presentations in a single subject.
Note the delay of approximately 4 to 7 seconds before the maximal
hemispheric difference is reached. dV indicates relative CBFV
changes. 
). Details of the insonation
technique, particularly the correct identification of the MCA, have
been published elsewhere.20 The angles of insonation were
adjusted to obtain the maximal signal intensity at the predetermined
insonation depth. The spectral envelope curves of the Doppler
signal were recorded with a rate of 28 sample points per second and
stored for off-line analysis with custom-tailored software that
had been programmed by one of the authors (M.D.). Artifacts like those
elicited by probe displacement were automatically detected by
comparison of the number of pulses per time unit of the entire
recording session with the frequency of peaks in a given
segment. Frames of recordings were rejected when these
frequencies differed by more than one third. Additionally, epochs
containing CBFV values outside the range of 30% to 200% of the mean
flow velocity were rejected. The remaining data were integrated over
the corresponding cardiac cycles, segmented into epochs that related to
the cueing tone, and were then averaged. The epochs were set to begin
15 seconds before and to end 35 seconds after the cueing tone. The mean
velocity in the 15-second precueing interval
(Vpre.mean) was taken as the baseline value. The
relative CBFV changes (dV) during cerebral activation were
calculated by the
formula dV=[V(t)-Vpre.mean]*100/Vpre.mean
where
V(t)=dV(t)left-dV(t)right
is the difference between the relative velocity changes of the left and
right MCAs. tmax represents the latency
of the absolute maximum of V(t) during an
interval of 7 to 27 seconds after cueing, ie, during verbal processing.
For integration a time period of tint=2 seconds
was chosen. The test-retest reproducibility of this procedure in
determining hemispheric language lateralization based on the Pearson
product moment correlation coefficient was r=.95,
P<.0001 (S.K. et al, unpublished data, 1997). Results of
the language lateralization by fTCD LIfTCD and
Wada test LIWADA were compared by linear
regression of the respective LIs.
The Wada procedure corresponded to the one described by Jokeit
et al.21 22 Briefly, angiography was performed by a
transfemoral approach with patients in a supine position. A single
bolus of 150 mg amobarbital was injected over a 4-second interval into
the internal carotid artery under study. First the side of suspected
seizure focus and, 30 minutes later, the contralateral side were
assessed. Immediately after injection, numerical ratings were performed
for the following language tasks. Following simple commands such as
"Lift your arm" (maximal score, 4); reporting his/her first and
second names (maximal score, 2); naming the days of the week (maximal
score, 8; 1 point per day listed with an additional point for the
correct sequence); reading simple words (maximal score, 15); reading
complex words (maximal score, 10); naming colors, objects, and numbers
presented visually (maximal score, 10 each); repeating
sentences (maximal score, 10); describing concrete drawings (maximal
score, 15); and explaining the meaning of words (maximal score, 10).
The performance in tasks having maximal scores of 10 or 15
points was rated with the use of a scale between 0 and 5 for each of
two or three items: 0 indicated no response, 1 meant that the response
was unintelligible, 2 indicated that the response was incorrect, 3 that
only repetition of an answer spoken aloud was possible, 4 that a
correct response was possible only after verbal priming, and 5 that a
correct answer was given spontaneously.
Results
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
References
Of 19 patients who underwent successful Wada testing, fTCD could
be performed in 15 patients. In the remaining 4 candidates no adequate
acoustic temporal bone window for insonation of the MCAs could be
found. There were no dropouts due to distress, movement artifacts, or
lack of cooperation. The Table
presents details of the patients,
duration of epilepsy, handedness, and results on the Wada test and the
fTCD.
During the examined task, 8% (mean; range, 0% to 20%) of the
recorded CBFV epochs were rejected because of artifacts. Mean CBFV
data from the remaining epochs showed a bilateral biphasic CBFV
augmentation. A first CBFV increase was seen approximately 1 second
after the cueing tone but before letter presentation. This
increase peaked on average at the time when the letter was expected,
ie, 5 to 7 seconds later. A second CBFV augmentation began during
letter presentation and, on average, peaked 4 seconds
later. During actual word generation, ie, from letter
presentation to the second tone, a significant
(P
.05, Wilcoxon test) relative predominance of
CBFV increase in the left hemisphere was seen in 11 patients and in the
right hemisphere in 4 patients. The extent of relative hemispheric CBFV
predominance, ie, the difference between the mean CBFV increase from
the baseline in one hemisphere relative to the other, varied from 1.3%
to 6.3% (median, 3.2%; quartile, 2.6% to 4.0%) (left greater than
right) in patients with left-hemisphere language dominance, and it
varied from 1.3% to 5.7% (median, 3.6%; quartile, 2.2% to 4.9%)
(right greater than left) in patients with right-hemisphere language
dominance. In every case the determination of language lateralization
by fTCD was concordant with the Wada test. ).
View larger version (19K):
[in a new window]
Figure 2. Correlation between lateralization by the Wada
test and the fTCD (r=.92045, P<.0001)
(Wada= -1.594+ 16.892*fTCD). Dashed lines indicate 95% confidence
intervals; 
, individual patients with right- or left-hemispheric
dominance for language.
Discussion
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
References
The main finding of this study was that determination of
hemispheric language dominance by fTCD was concordant with the result
of the Wada test in every case. Moreover, even the quantitative measure
of lateralization assessed by both techniques correlated closely
(r=.92, P<.0001). Obviously, the
activated cerebral areas during the employed word generation
task, which led to a lateralization on fTCD, correspond closely to
those areas underlying the hemispheric dominance as assessed by the
Wada test. Unlike the Wada test, however, fTCD is without any risk or
inconvenience to the patient. The statistical technique of averaging
relative blood flow differences provides a very reliable indicator of
the language lateralization and the extent of this lateralization in
individual patients. The findings in the present study, obtained on
this basis, corroborate the suggestion that language lateralization
occurs along a graded continuum.6
Selected Abbreviations and Acronyms
CBFV
=
cerebral blood flow velocity
fMRI
=
functional magnetic resonance imaging
fTCD
=
functional transcranial Doppler ultrasonography
LI
=
laterality index
MCA
=
middle cerebral artery
TCD
=
transcranial Doppler ultrasonography
Acknowledgments
This study was supported by the Bennigsen-Foerder grant from the
Ministry of Science and Research of Nordrhein-Westfalen, Germany.
Footnotes
Presented in part at the Third International Conference on Functional Mapping of the Human Brain, May 19–23, Copenhagen, Denmark.
References
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
References
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