- Email: [email protected]
Determination of cortical language dominance using functional transcranial Doppler sonography in left-handers
Clinical Neurophysiology 115 (2004) 154–160 www.elsevier.com/locate/clinph
Determination of cortical language dominance using functional transcranial Doppler sonography in left-handers Silvio Basic*, Sanja Hajnsek, Zdravka Poljakovic, Marela Basic, Viktor Culic, Ivana Zadro Department of Neurology, University Hospital Zagreb, Kispaticeva 12, 10000 Zagreb, Croatia Accepted 5 August 2003
Abstract Objective: Verbal analytical functions are primarily related to the left hemisphere in right-handers, but there is yet no agreement about cortical language dominance in left-handers. Also, there are some contradictory reports about sex differences in cortical language lateralization. The aim of this study is to investigate cortical language dominance in left-handers and to explore gender influence on cortical language representation. Methods: We performed functional transcranial Doppler sonography (previous validated for determination of cerebral language lateralization) during a word generation task, measuring changes in mean cerebral blood flow velocity (BFVmean) in both middle cerebral arteries (MCA) in 150 healthy subjects (75 left-handers and 75 right-handers). In left-handers we observed significant increase BFVmean in right MCA in 58 (77.3%) subjects. Bilateral increase was observed in 11 (14.7%) subjects and increase in left MCA in 6 (8%) subjects. In right-handed group 93.3% subjects showed left cortical dominance, while 6.7% showed bilateral language representation. Results: Current results showed significant (P , 0:0001) right hemispheric language dominance in healthy left-handed subjects. Conclusions: Our results showed significant difference in hemispheric dominance for verbal function between righthanders and lefthanders. Also there is statistically insignificant female gender tendency for bilateral hemispheric language representation in both handedness. q 2004 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved. Keywords: Cortical language dominance; Functional transcranial Doppler sonography; Middle cerebral arteries
1. Introduction Handedness is an example of many forms of behavioral lateralization seen in humans. Left-handedness has existed in a small subset of the human population (approximately 8%) (Reiss and Reiss, 1999). There is a strong evidence that the dominance of language functions in the cerebral cortex is not equal in left-handed and in right-handed people (van der Kallen et al., 1998b; Ramsey et al., 2001; Knecht et al., 2000a). There is general consent that the verbal analytical functions are primarily related to the left hemispheres in right-handed, but there is yet no such confirm about cortical language dominance in left-handed individuals (Lishman and McMeekan, 1977; Keane, 1999; Pujol et al., 1999; Saffran, 2000; Szaflarski et al., 2002; Khedr et al., 2002; Hund-Georgiadis et al., 2002; Sabbah et al., 2003; Ramsey et al., 2001b). Previous results showed different percentage * Corresponding author. Tel.: þ 385-1-9888-8100. E-mail address: [email protected] (S. Basic).
of right cortical dominance in left-handers, from 10% to about 55%, probably because of small investigated groups, and because of age differences between subjects. These discrepancies could conceivably be due to any of several differences in methodology among the different studies, which included differences in task demands, image acquisition techniques, data analysis methods and statistical thresholds. One of the most important reasons why former results differ between each other so much is that the results are often derived from studies of patients with brain lesions and thus possible secondary reorganization of cerebral functions. Also, there is a suggestion that language lateralization in human occurs along a graded continuum (Knecht et al., 1996, 2000b; Springer et al., 1999; Calabrese et al., 2001). To determinate cerebral language lateralization, we used functional transcranial Doppler sonography (fTCD). TCD was introduced in 1982 for non-invasive and continuous monitoring of blood flow velocity in the basal cerebral arteries. Since then, the TCD technique has been widely
1388-2457/$30.00 q 2004 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved. doi:10.1016/S1388-2457(03)00281-5
S. Basic et al. / Clinical Neurophysiology 115 (2004) 154–160
used to evaluate regional cerebral blood flow changes in both physiological and pathological conditions (Newell and Aaslid, 1992; Rihs et al., 1995; Markus and Boland, 1992; Bay-Hansen et al., 1997; Vingerhoets and Stroobant, 1999; Silvestrini et al., 1994). Functional TCD research examines blood flow velocity (BFV) changes during the performance of mental tasks. The technique of fTCD is based on the linkage of cerebral activation and perfusion, a principle also underlying functional magnetic resonance imaging (fMRI) and oxygen-15 positron emission tomography. Assuming that the diameter and perfusion territory of the basal cerebral arteries remains unchanged with time, BFV changes under successive mental conditions are related to volume flow changes and reflect changes in cerebral metabolism due to cerebral activation (Klingelho¨fer et al., 1994; Stoll et al., 1999; Hartje et al., 1994; Droste et al., 1989). The main aim of this study is to investigate cortical language dominance in left-handed individuals. The second aim is to explore possible gender influence on cortical language representation, since previous published papers showed contradictory reports about sex differences in cortical language lateralization.
2. Subjects and methods One hundred and fifty healthy subjects (75 left-handers and 75 right-handers; 84 (56%) men and 66 (44%) women; mean ^ SD age 34 ^ 6; range 20– 46 years) participated in the study. None of the subjects took psychoactive medication, had an active medical disease, or had a history of cardiovascular, neurological or psychiatric disorder. Inclusion criteria included also presence of acoustic temporal skull window for insonation of the middle cerebral arteries (MCA) on both sides. Handedness was established and graded by Edingbourgh Handedness Inventory (Oldfield, 1971). To ensure validity of results, during experiment observer did not know handedness of the subjects. Previous works validated fTCD as non-invasive, suitable and very robust tool for determination of cerebral language lateralization as well for clinical as for investigative purposes (Knecht et al., 1998a,b; Rihs et al., 1999; Schmidt et al., 1999). For determination of hemispheric language dominance we used a word generation task previously shown to activate lateralized language areas in normal adults (Knecht et al., 1998a; Frith et al., 1991; Cuenod et al., 1995). Continuous measurement of blood flow velocity in MCA was achieved by a commercially available 2-MHz pulsed-wave TCD unit (MultiDopX, DWL inc). Both MCA were insonated through left and right temporal scull window, starting from an insonation depth of 50 mm. Depth and angles of insonation were adjusted to obtain the highest signal intensity of the M1 segment of MCA (insonation depth ranged from 42 to 56 mm). Signals were identified by means of the spectral screen display and as audible pitch. Details of the insonation technique, and
155
the correct insonation of the MCA have been described elsewhere (Ringelstein et al., 1990). The BFVmean were calculated by the standard algorithm implemented on the instrument with use of a fast Fourier transform. All tests were performed in a quiet room without any visual or auditory stimulation and with illumination held constant. Before the examination the basic principles of the equipment were demonstrated and during the examination subjects were resting in the supine position, also they were requested to close their eyes, relax, and ‘think of nothing’. Following an initial 15-min rest phase, subjects performed the language task, which consisted of silently finding as many words as possible starting with the presented letter. Letters were presented by observer in random order. After 15 s following the presentation of the letter, subjects were requested to articulate the words they had found to control cooperation in the task. We performed fTCD measuring changes in BFVmean during the 3 successive cycles without interruption. Each cycle consisted of alternating epochs of rest and activation – one epoch of 15 min of resting and one epoch of 15 s of activity (word generation task). Relative increase of BFVmean was calculated from the end of the resting phase (baseline value) to the 15 s following activation. Only the last 30 s of the rest period served as the baseline measurement for the subsequent activation phase. Because TCD cannot detect the difference between real asymmetries in BFV and differences caused by slightly different insonation angles on the left and right sides of one subject, the measured velocities expressed in centimetres per second do not represent the real blood flow velocities. Therefore, for data evaluation all velocity changes were transformed into changes of FVmean percentages from the rest phase to task performance, and then the data of all 3 cycles were averaged. If the percentage of velocity changes from the rest phase to task performance in the one MCA was more than 5% than in the contralateral MCA, we considered it like significant difference of increased velocities between left and right MCA. If the difference of increased velocities from the baseline values between left and right MCA was less than 5% we considered it as a bilateral pattern of cortical language organization. The SPSS 10.0 for Windows software package was used for descriptive analyzes and analyzes of significance. To compare mean percentage changes in left and right MCA between lefthanders and right-handers we used Student’s t test for independent samples, and to analyze gender influence on hemispheric language lateralization we used One-way analysis of variance. Results were considered statistically significant for P , 0:05.
3. Results In left-handers we observed significant increase BFVmean in right MCA in 58 (77.3%) subjects and bilateral increase
156
S. Basic et al. / Clinical Neurophysiology 115 (2004) 154–160
4. Conclusion and further work
Fig. 1. Differences of significant increase of BFVmean in the MCA between left- and right-handers.
in 11 (14.7%) subjects. The predominance of left-hemisphere activation, however, was weak in these cases; only in 6 (8%) left-handed subjects was observed significant increase in left MCA representing left cortical language dominance. In the right-handed group 70 (93.3%) subjects showed significant increase BFVmean in left MCA, while 5 (6.7%) showed only small differences between left and right MCA, possibly reflecting bilateral language representation. In this group, there was no significant increase BFVmean in right MCA (Fig. 1). In both left-handed and right-handed there was insignificant tendency in females for bilateral hemispheric language representation. Almost 92% (91.7%; 33 subjects) of righthanded female subjects showed significant BFV mean increase in left MCA, whereas 8.3% (3 subjects) showed a bilateral activation pattern. None of right-handed females showed right language cortical dominance. In contrast, right-hemisphere lateralization occurred in 22 (73.3%) lefthanded females, bilateral activation in 6 (20%), and significant BFVmean increase in left MCA in the remaining 2 (6.7%). Increase in left MCA was observed in 37 (94.1%) right-handed male subjects, and in two (5.1%) right-handed males increase were bilateral. In the male left-handers group 36 (80%) subjects showed increase BFVmean in right MCA, 5 (11.1%) bilateral, and in 4 (8.9%) male subject increase were observed in left MCA (Fig. 2).
Fig. 2. Differences of significant increase of BFVmean in the MCA according to gender.
There is general consent that the left and right human hemispheres differ in anatomy and function: verbal analytical functions are primarily related to the dominant hemisphere, while non-verbal integrative visuoperceptive and visuocognitive functions are related to the nondominant hemisphere (Ingvar, 1976; Hassler, 1990; Kashiwagi et al., 1990; Ahern et al., 1991; Rey et al., 1988). Results are based mostly on the population of right-handed people, and a generally accepted view is that there is a left sided cortical preference for speech in such a population. However controversial findings exist about the speech dominance in left-handed people. Language dominance is also very close associated with the laterality of temporal and spatial movement representations (i.e. ideomotor praxis dominance) even more than the hand preference is. Patients with atypical language dominance exhibit more bilateral cerebral distribution of both, language and praxis function (Polemikos and Papaeliou, 2000; Floel et al., 2001; Day and MacNeilage, 1996; Sussman, 1982; Strauss and Wada, 1983; Searleman, 1980; Strauss, 1986). It was suggested that in the normal population, handedness and footedness are relevant factors in predicting cerebral speech dominance. Recent advances in functional neuroimaging techniques have prompted an increase in the number of studies investigating lateralization of language functions. One of the problems in relating findings of various studies to one another is the diversity of reported results. Differences in the tasks that are used to stimulate language processing regions and in the control tasks, as well as differences in the way imaging data are analyzed, in particular the threshold for significance of signal change, can be a reason of this discrepancies. It has been proved that there are task-specific language region in the brain (Roux and Tremoulet, 2002). So there is a possibility that different activation mechanisms can activate different brain regions, which has been indirectly proved in former studies. They namely showed that different stimulation techniques could induce different cortical centres. Beside that, just differently designed studies and ways of result evaluations (by using the same technique) brought up controversial results. For instance, there is a disagreement of the authors about cortical language representation according to sex preference and they used same technique (fMRI for example). We can present several studies whose results speak in favor, but also against sex difference in cortical language presentation (Vikingstad et al., 2000; Frost et al., 1999; Shaywitz et al., 1995; Phillips et al., 2001; van der Kallen et al., 1998a). Another reason can also be a small number of individuals in the investigation group, so statistically significant data could not be obtained from these groups. Furthermore, the investigations have mostly been performed on patients with neurological illnesses or disorders (like patients with epilepsy, candidates for neurosurgical treatment, or patients
S. Basic et al. / Clinical Neurophysiology 115 (2004) 154–160
suffering from stroke). By such a group there is a possibility of cortical reorganization of language function, so the data can not be relevant. Investigations which were performed on larger number of patients who were older, could also be misinterpreted according their possible vascular changes in the cerebral circulation and possible unrecognized microinfarcts of the brain in the past, which could have had influence of the reorganization of cerebral functions. Therefore, such results must also be analyzed with a precaution. Recent results of cortical language representation showed a right sided domination in left-handed people in 10 –55% of investigated population, depending on author and used techniques, design of the study or used investigation group. Basso et al. had, on a small group of 24 non-right-handed patients with stroke 21% of right sided dominance, while Risse found a very small number of patients with right sided preference in a group of both left- and right-handed patients with epilepsy who were candidates for neurosurgical treatment (Basso et al., 1990; Risse et al., 1997). However those results are questionable because chronic vascular lesions of the brain, as well as epilepsy are associated with varying degrees of brain dysfunction and tissue damage, and thus possible secondary reorganization of cerebral (language) functions may occur relatively often in such patients. Anatomic studies show a different cortical language organization in left-handers. Foundas et al., in a small sample of right- and left-handed adults have demonstrated that right-handers had a significant leftward planar asymmetry, whereas the left-handers were more likely to have symmetric or reversed planar measures (Foundas et al., 1995). Later, they have found (2002) reduced leftward planar (planum temporale) asymmetry in the left handers relative to the right handers. They found atypical planar anatomy in 44.5% consistent left handers (Foundas et al., 2002). This anatomy difference of posterior cortical language areas between left and right-handers suggest different pattern of language processing in left-handers and right-handers. Steinemtz reported atypical rightward planar asymmetries in 42% of the left handers (Steinemtz, 1995). Also, Pieniadz and Naeser has demonstrated computed tomography anatomy differences between right and left handers, and similar results were published by other authors (Pieniadz and Naeser, 1984; Habibet al., 1995). The same conclusion is suggested by investigations of previously normal patients with unilateral lesions secondary to stroke, which showed that left-handed aphasic patients tend to have incomplete and unusual aphasic syndromes (Brown and Hecaen, 1976) and to recover more rapidly (Hecaen and Sauguet, 1971) then right-handers (Brown and Hecaen, 1976; Hecaen and Sauguet, 1971). In another study (Rey et al., 1988a), right hemispheric dominance was found in 50% of left handed patients and in none of right handed patients. Bilateral speech functions were observed in 7% of
157
right-handers, 13% of left-handers, and 35% of ambidextrous (Rey et al., 1988b). Unlike intracarotid amobarbital procedure and lesion methods, which are based on the inference of language localization from observation of language deficits, activation imaging techniques such as positron emission tomography and fMRI provide direct observation of brain activity during language processes. However, inferring language dominance from such data requires consideration of two critical issues. First, the activation task used may engage a number of brain systems not specifically related to language, including sensory, motor and attentional systems. Measurement of language lateralization with such techniques thus requires activation of these systems to be controlled by a contrast or baseline task. Secondly, even when such controls are used, it is conceivable that some areas engaged specifically by the language task might not be critically necessary for normal language performance. Thus, the extent to which activation imaging data correlate with conventional measures of language dominance based on lesion methods must be determined empirically for each language activation task. Pujol et al. showed bilateral activation in 14%, and righthemisphere lateralization in the 10% of normal left-handed people studied by functional MRI. Their conclusion was that silent word generation lateralizes to the left cerebral hemisphere in both handedness groups, but right-hemisphere participation is frequent in normal left-handed subjects (Pujol et al., 1999). In contrast, Sabbah et al. showed by functional MRI right hemispheric language dominance in 55% left-handers, but it was small group of epileptic patients (Sabbah et al., 2003). A serious limitation of fMRI is that at the same moment only small cortical areas can be seen and analyzed, so we can not tell what is happening in other regions, which are much bigger than the analyzed section. Furthermore, inspite of very sophistic technical possibilities of a fMRI technique, it is not a realtime representation like fTCD is. fTCD shows at the same time a possible activation of a larger part of the hemispheric region, namely in the whole irrigation area of the investigated blood vessel. In our investigation this is a case for the arteria cerebri media, and therefore it shows much bigger area than it can be showed on fMRI and is in the same time a ‘real-time’ presentation. Interpreting results of Pujol et al., we also must consider that they have included some ‘reserve’ patients in the study. The results of Andreou also speak in favor of different cortical organization in left and right handed people. He used event related potentials (ERPs) and found a bilateral pattern of lateralization in left-handed males for both their native and foreign language, in all of study population (100% of healthy young bilingual left-handed males, a sample of 30 people) (Andreou and Karapetsas, 2001). These results clearly demonstrate that the relationship between handedness and language dominance is not an artifact of cerebral pathology but a natural phenomenon.
158
S. Basic et al. / Clinical Neurophysiology 115 (2004) 154–160
The possible reason why former fTCD studies did not show higher dominance of the right brain hemisphere in left-handed people could also be their design, namely the time of the activation epoques that has been analyzed. Knecht used a longer epoque and analyzed both 15 s of baseline as well as 30 s (and even more) after the activation. In our work we observed also a significant and abrupt raise in blood flow velocity immediately after the activation, but which showed the tendency to baseline values (or same values as in the contralateral hemisphere) already after 15 or 20 s. The possible reason for this may be that most of the investigation population after 15 – 20 s lacks another words for generating, so other cortical centers tend to be activated. Several studies have shown that diameter of large cerebral arteries remains constant and does not change significantly under a variety of physiological stimuli, and that alterations of flow velocity are related to the diameter of the small vessels (Schmidt et al., 1999; Huber and Handa, 1967; Giller et al., 1993; Kontos, 1989). According to the fact that changes in cerebral perfusion are consequence of cerebral activation, changes (increase) of flow velocity observed in our study during language task can be interpreted as an increase of neural activity in the MCA supplied brain regions. In our study we examined changes in cerebral blood flow velocities during the rest and during language task trying to find different hemodynamic patterns in right and lefthanders. We found significant differences in the hemodynamic patterns of the left-handers and the right-handers during language task. Our results proved significant difference in hemispheric dominance for verbal function between right- and left-handers. In right-handed individuals we found expected strong left hemispheric dominance, while in lefthanders we showed significant right hemispheric dominance, but also a stronger tendency for bilateral cortical language representation. Current results showed significant (t ¼ 217:369, P , 0:0001) right hemispheric language dominance in healthy left-handed subject, but also approve that there is no ‘mirror image’ cortical language organization in left-handers. Also there is insignificant female gender tendency for bilateral hemispheric language representation in both handedness, which cannot approve assumption of gender influence on cortical language organization (t ¼ 21:081, P ¼ 0:281). Our data agree with previous suggestion that different stimulation techniques can induce intense tonic emotional arousal, high enough for hemisphere asymmetry, which can be registered and measured by TCD. Our results show the possibilities of fTCD in clinical practice or research. This method is simple, non-invasive, relatively cheap, very easy to perform and to repeat in every-day conditions, so it gives new possibilities in research of cognitive cerebral functions, but also in clinical practice. We can presume that the usefulness of fTCD will be growing, so the indication field can be even bigger. For Instance fTCD might become even
now or in the near future, an alternative non-invasive or complementary tool to the Wada test, particularly in patients to whom the Wada test gives inconclusive results or is impractical. However, a very strong limitation of fTCD is that some subjects lack an acoustic temporal bone window for insonation of MCA, fortunately, in only small percentage of population. In our study only one subject could not enter inclusion criteria for this reason. Small differences between left and right MCA during the language task in some subjects possibly reflects bilateral language representation and approves theory of graded continuum in cortical language organization in humans. But, luck of hemisphere asymmetry in those subjects can also be due to bad response to used stimulation technique. Previous studies showed that different stimulation techniques induce different regional cortical activation, more or less high enough for registration by fTCD. That’s why is strongly recommended to find stimulation technique which will be able to induce stronger hemisphere lateralization response, before clinical use in determination of cortical language dominance and possible replacement of Wada test. Our results incline towards the result of the group of authors which showed significant difference between leftand right-handers. The reason for such a big percentage of right-sided dominance may lie in the attributes of the investigation group (young, healthy population, same number of male and female population). The next reason can also be the design of the study, namely long enough period of rest between to interrogation periods, which tried to exclude the influence of other cortical center on the final results, so that only the activation of language cortical centers can be evaluated. Still, our results must surely be confirmed in further studies, which have the same design and a larger investigation group. It would be interesting to compare the results of Wada test and fMRI in our investigational population. Only having all this results we could get relevant data about cortical language organization in left handed people but also confirm or exclude the possibility of replacing Wada test with fTCD in presurgical evaluation of the language centers, especially in patients with epilepsy who are candidates for neurosurgical operation. References Ahern GL, Schomer DL, Kleefield J, Blume H, Cosgrove GR, Weintraub S, Mesulam MM. Right hemisphere advantage for evaluating emotional facial expressions. Cortex 1991;27:193–202. Andreou G, Karapetsas A. Hemispheric asymmetries of visual ERPs in lefthanded bilinguals. Brain Res Cogn Brain Res 2001;12(2):333–5. Basso A, Farabola M, Grassi MP, Laiacona M, Zanobio ME. Aphasia in left-handers. Comparison of aphasia profiles and language recovery in non-right-handed and matched right-handed patients. Brain Lang 1990; 38(2):233–52. Bay-Hansen J, Ravn T, Knudsen GM. Application of interhemispheric index for transcranial doppler sonography velocity measurements and evaluation of recording time. Stroke 1997;28:1009– 14.
S. Basic et al. / Clinical Neurophysiology 115 (2004) 154–160 Brown JW, Hecaen H. Lateralization and language representation. Neurology 1976;26(2):183– 9. Calabrese P, Neufeld H, Falk A, Markowitsch HJ, Muller C, Heuser L, Gehlen W, Durwen HF. Word generation in bilinguals-fMRI study with implications for language and memory processes. Fortschr Neurol Psychiatr 2001;69(1):42–9. Cuenod CA, Bookheimer SY, Hertz-Pannier L, Zeffiro TA, Theodore WH, Le Bihan D. Functional MRI during word generation using conventional equipment. Neurology 1995;29:1821–7. Day LB, MacNeilage PF. Postural asymmetries and language lateralization in humans (Homo sapiens). J Comp Psychol 1996;110(1):88–96. Droste DW, Harders AG, Rastogi E. Two transcranial doppler studies on blood flow velocity in both middle cerebral arteries during rest and the performance of cognitive tasks. Neuropsychologia 1989;27(10): 1221–30. Floel A, Knecht S, Lohmann H, Deppe M, Sommer J, Drager B, Ringelstein EB, Henningsen H. Language and spatial attention can lateralize to the same hemisphere in healthy humans. Neurology 2001; 57(6):1018– 24. Foundas AL, Leonard CM, Heilman KM. Morphologic cerebral asymmetries and handedness. The pars triangularis and planum temporale. Arch Neurol 1995;52(5):501–8. Foundas AL, Leonard CM, Hanna-Pladdy B. Variability in the anatomy of the planum temporale and posterior ascending ramus: do right- and lefthanders differ? Brain Lang 2002;83(3):403–24. Frith C, Friston KJ, Liddle PF, Frackowiak RS. A PET study of word finding. Neuropsychologia 1991;29:1137 –48. Frost JA, Binder JR, Springer JA, Hammeke TA, Bellgowan PS, Rao SM, Cox RW. Language processing is strongly left lateralized in both sexes. Evidence from functional MRI. Brain 1999;122(Pt 2):199–208. Giller CA, Browman G, Dyer H, Mootz L, Krippner W. Cerebral arterial diameters during changes in blood pressure and carbon dioxide during craniotomy. Neurosurgery 1993;32:737–47. Habib M, Robichon F, Levrier O, Khalil R, Salamon G. Diverging asymmetries of temporo-parietal cortical areas: a reappraisal of Geschwind/Galaburda theory. Brain Lang 1995;48(2):238– 58. Hartje W, Ringelstein EB, Kistinger B, Fabianek D, Willmes K. Transcranial doppler assessment of middle cerebral artery blood flow velocity changes during verbal and visuospatial cognitive tasks. Neuropsychologia 1994;32(12):1443–52. Hassler M. Functional cerebral asymmetries and cognitive abilities in musicians, painters, and controls. Brain Cogn 1990;13:1–17. Hecaen H, Sauguet J. Cerebral dominance in left-handed subjects. Cortex 1971;7(1):19–48. Huber P, Handa J. Effects of contrast material, hypercapnia, hyperventilation, hypertonic glucose and papaverine on the diameter of the cerebral arteries: angiographic determination in man. Invest Radiol 1967;2: 17–32. Hund-Georgiadis M, Friederici ULA, von Cramon DY. Non-invasive regime for language lateralization in right- and left-handers by means of functional MRI and dichotic listening. Exp Brain Res 2002;145: 166–76. Ingvar DH. Functional landscapes of the dominant hemisphere. Brain Res 1976;176:181 –97. Kashiwagi A, Kashiwagi T, Nishikawa T, Tanabe H, Okuda J. Hemispatial neglect in a patient with callosal infarction. Brain 1990;113:1005– 23. Keane AM. Cerebral organization of motor programming and verbal processing as a function of degree of hand preference and familial sinistrality. Brain Cogn 1999;40(3):500–15. Khedr EM, Hamed E, Said A, Basahi J. Handedness and language cerebral lateralization. Eur J Appl Physiol 2002;87(4–5):469–73. Klingelho¨fer J, Matzander G, Sander D, Conrad B. Bilateral changes of middle cerebral artery blood flow velocities in various hemispherespecific brain activities. J Neurol 1994;241:264 –5. Knecht S, Henningsen H, Deppe M, Huber T, Ebner A, Ringelstein EB. Successive activation of both cerebral hemispheres during cued word generation. Neuroreport 1996;7(3):820–4.
159
Knecht S, Deppe M, Ebner A, Henningsen H, Huber T, Jokeit H, Ringelstein EB. Non-invasive determination of language lateralization by functional transcranial doppler sonography. A comparison with the Wada test. Stroke 1998a;29:82–6. Knecht S, Deppe M, Ringelstein EB, Wirtz M, Lohmann H, Dra¨ger B, Huber T, Henningsen H. Reproducibility of functional transcranial doppler sonography in determining hemispheric language lateralization. Stroke 1998b;29:1155–9. Knecht S, Drager B, Deppe M, Bobe L, Lohmann H, Floel A, Ringelstein EB, Heinningsen H. Handedness and hemispheric language dominance in healthy humans. Brain 2000a;12:2512 –8. Knecht S, Deppe M, Drager B, Bobe L, Lohmann H, Ringlestein E, Henningsen H. Language lateralization in healthy right-handers. Brain 2000b;123(1):74– 81. Kontos HA. Validity of cerebral arterial blood flow calculations from velocity measurements. Stroke 1989;20:1– 3. Lishman WA, McMeekan ER. Handedness in relation to direction and degree of cerebral dominance for language. Cortex 1977;13(1): 30– 43. Markus HS, Boland M. ‘Cognitive activity’ monitored by non-invasive measurement of cerebral blood flow velocity and its application to the investigation of cerebral dominance. Cortex 1992;28:575–81. Newell DW, Aaslid R. Transcranial doppler: clinical and experimental use. Cerebrovasc Brain Metab Rev 1992;4:122–43. Oldfield RC. The assessment and analysis of handedness: the Edinburgh inventory. Neuropsychologia 1971;9(1):97 –113. Phillips MD, Lowe MJ, Lurito JT, Dzemidzic M, Mathews VP. Temporal lobe activation demonstrates sex-based differences during passive listening. Radiology 2001;220(1):202–7. Pieniadz JM, Naeser MA. Computed tomographic scan cerebral asymmetries and morphologic brain asymmetries. Correlation in the same cases post mortem. Arch Neurol 1984;41(4):403–9. Polemikos N, Papaeliou C. Sidedness preference as an index of organization of laterality. Percept Mot Skills 2000;91(3 Pt 2): 1083–90. Pujol J, Deus J, Losilla JM, Capdevila A. Cerebral lateralization of language in normal left-handed people studied by functional MRI. Neurology 1999;52(5):1038 –43. Ramsey NF, Sommer IE, Rutten GJ, Kahn RS. Combined analysis of language tasks in fMRI improves assessment of hemispheric dominance for language function in individual subjects. Neuroimage 2001a;13(4): 719– 33. Ramsey NF, Sommer IE, Rutten GJ, Kahn RS. Combined analysis of language tasks in fMRI improves assessment of hemispheric dominance for language function in individual subjects. Neuroimage 2001b;13(4): 719– 33. Reiss M, Reiss G. Current aspects of handedness. Wien Klin Wochenschr 1999;111(24):1009–18. Rey M, Dellatolas G, Bancaud J, Talairach J. Hemispheric lateralization of motor and speech functions after early brain lesion: study of 73 epileptic patients with intracarotid Amytal test. Neuropsychologia 1988a;26: 167– 72. Rey M, Dellatollas G, Bancaud J, Talairach J. Hemispheric lateralization of motor and speech functions after early brain lesion: study of 73 epileptic patients with intracarotid amytal test. Neuropsychologia 1988b;26: 167– 72. Rihs F, Gutbrod K, Gutbrod B, Steiger HJ, Sturzenegger M, Mattle HP. Determination of cognitive hemispheric dominance by ‘stereo’ transcranial doppler sonography. Stroke 1995;26:70 –3. Rihs F, Sturzenegger M, Gutbrod K, Schroth G, Mattle HP. Determination of language dominance: Wada test confirms functional transcranial doppler sonography. Neurology 1999;52(8):1591 –6. Ringelstein EB, Kahlscheuer B, Niggemeyer E, Otis SM. Transcranial doppler sonography: automatical landmarks and normal velocity values. Ultrasound Med Biol 1990;16:745 –61.
160
S. Basic et al. / Clinical Neurophysiology 115 (2004) 154–160
Risse GL, Gates JR, Frangman MC. A reconsideration of bilateral language representation based on the intracarotid amobarbital procedure. Brain Cogn 1997;33(1):118–32. Roux FE, Tremoulet M. Organization of language areas in bilingual patients: a cortical stimulation study. J Neurosurg 2002;97(4): 857– 64. Sabbah P, Chassoux F, Leveque C, Landre E, Baudoin-Chial S, Devaux B, Mann M, Godon-Hardy S, Nioche C, Ait-Ameur A, Sarrazin JL, Chodkiewicz JP, Cordoliani YS. Functional MR imaging in assessment of language dominance in epileptic patients. Neuroimage 2003;18(2): 460– 7. Saffran EM. Aphasia and the relationship of language and brain. Sem Neurol 2000;20(4):409– 18. Schmidt P, Krings T, Willmes K, Roessler F, Reul J, Thron A. Determination of cognitive hemispheric lateralization by functional transcranial doppler cross-validated by functional MRI. Stroke 1999; 30:939–45. Searleman A. Subject variables and cerebral organization for language. Cortex 1980 Aug;16(2):239–54. Shaywitz BA, Shaywitz SE, Pugh KR, Constable RT, Skudlarski P, Fulbright RK, Bronen RA, Fletcher JM, Shankweiler DP, Katz L, et al. Sex differences in the functional organization of the brain for language. Nature 1995;373(6515):607– 9. Silvestrini M, Troisi E, Cupini LM, Matteis M, Pistolese GR, Bernardi G. Transcranial doppler assessment of the functional effects of symptomatic carotid stenosis. Neurology 1994;44:1910–4. Springer JA, Binder JR, Hammeke TA, Swanson SJ, Frost JA, Bellgowan PS, Brewer CC, Perry HM, Morris GL, Muller WM. Language dominance in neurologically normal and epilepsy subjects: a functional MRI study. Brain 1999;122(11):2013–4.
Steinemtz H. Anatomical asymmetry is normally distributed, associated with handedness, and develops before birth: other predictions from the right shift theory. Curr Psychol Cogn 1995;14:610– 4. Stoll M, Hamann GF, Mangold R, Huf O, Winterhoff-Spurk P. Emotionally evoked changes in cerebral hemodynamics measured by transcranial doppler sonography. J Neurol 1999;246:127–33. Strauss E. Hand, foot, eye and ear preferences and performance on a dichotic listening test. Cortex 1986;22(3):475 –82. Strauss E, Wada J. Lateral preferences and cerebral speech dominance. Cortex 1983;19(2):165– 77. Sussman HM. Contrastive patterns of intrahemispheric interference to verbal and spatial concurrent tasks in right-handed, left-handed and stuttering populations. Neuropsychologia 1982;20(6):675–84. Szaflarski JP, Binder JR, Possing ET, McKiernan KA, Ward BD, Hammeke TA. Language lateralization in left-handed and ambidextrous people: fMRI data. Neurology 2002;59(2):238– 44. van der Kallen BF, Morris GL, Yetkin FZ, van Erning LJ, Thijssen HO, Haughton VM. Hemispheric language dominance studied with functional MR: preliminary study in healthy volunteers and patients with epilepsy. Am J Neuroradiol 1998a;19(1):73–7. Van der Kallen BFW, Morris GL, Yetkin Z, van Erning L, Thijssen H, Haughton V. Hemispheric language dominancy studied with functional MR: preliminary study in healthy volunteers and patients with epilepsy. Am J Neuroradiol 1998b;19:73–7. Vikingstad EM, George KP, Johnson AF, Cao Y. Cortical language lateralization in right handed normal subjects using functional magnetic resonance imaging. J Neurol Sci 2000;175(1):17 –27. Vingerhoets G, Stroobant N. Lateralization of cerebral blood flow velocity changes during cognitive tasks. A simultaneous bilateral transcranial doppler study. Stroke 1999;30:2152–8.
Determination of cortical language dominance using functional transcranial Doppler sonography in left-handers Silvio Basic*, Sanja Hajnsek, Zdravka Poljakovic, Marela Basic, Viktor Culic, Ivana Zadro Department of Neurology, University Hospital Zagreb, Kispaticeva 12, 10000 Zagreb, Croatia Accepted 5 August 2003
Abstract Objective: Verbal analytical functions are primarily related to the left hemisphere in right-handers, but there is yet no agreement about cortical language dominance in left-handers. Also, there are some contradictory reports about sex differences in cortical language lateralization. The aim of this study is to investigate cortical language dominance in left-handers and to explore gender influence on cortical language representation. Methods: We performed functional transcranial Doppler sonography (previous validated for determination of cerebral language lateralization) during a word generation task, measuring changes in mean cerebral blood flow velocity (BFVmean) in both middle cerebral arteries (MCA) in 150 healthy subjects (75 left-handers and 75 right-handers). In left-handers we observed significant increase BFVmean in right MCA in 58 (77.3%) subjects. Bilateral increase was observed in 11 (14.7%) subjects and increase in left MCA in 6 (8%) subjects. In right-handed group 93.3% subjects showed left cortical dominance, while 6.7% showed bilateral language representation. Results: Current results showed significant (P , 0:0001) right hemispheric language dominance in healthy left-handed subjects. Conclusions: Our results showed significant difference in hemispheric dominance for verbal function between righthanders and lefthanders. Also there is statistically insignificant female gender tendency for bilateral hemispheric language representation in both handedness. q 2004 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved. Keywords: Cortical language dominance; Functional transcranial Doppler sonography; Middle cerebral arteries
1. Introduction Handedness is an example of many forms of behavioral lateralization seen in humans. Left-handedness has existed in a small subset of the human population (approximately 8%) (Reiss and Reiss, 1999). There is a strong evidence that the dominance of language functions in the cerebral cortex is not equal in left-handed and in right-handed people (van der Kallen et al., 1998b; Ramsey et al., 2001; Knecht et al., 2000a). There is general consent that the verbal analytical functions are primarily related to the left hemispheres in right-handed, but there is yet no such confirm about cortical language dominance in left-handed individuals (Lishman and McMeekan, 1977; Keane, 1999; Pujol et al., 1999; Saffran, 2000; Szaflarski et al., 2002; Khedr et al., 2002; Hund-Georgiadis et al., 2002; Sabbah et al., 2003; Ramsey et al., 2001b). Previous results showed different percentage * Corresponding author. Tel.: þ 385-1-9888-8100. E-mail address: [email protected] (S. Basic).
of right cortical dominance in left-handers, from 10% to about 55%, probably because of small investigated groups, and because of age differences between subjects. These discrepancies could conceivably be due to any of several differences in methodology among the different studies, which included differences in task demands, image acquisition techniques, data analysis methods and statistical thresholds. One of the most important reasons why former results differ between each other so much is that the results are often derived from studies of patients with brain lesions and thus possible secondary reorganization of cerebral functions. Also, there is a suggestion that language lateralization in human occurs along a graded continuum (Knecht et al., 1996, 2000b; Springer et al., 1999; Calabrese et al., 2001). To determinate cerebral language lateralization, we used functional transcranial Doppler sonography (fTCD). TCD was introduced in 1982 for non-invasive and continuous monitoring of blood flow velocity in the basal cerebral arteries. Since then, the TCD technique has been widely
1388-2457/$30.00 q 2004 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved. doi:10.1016/S1388-2457(03)00281-5
S. Basic et al. / Clinical Neurophysiology 115 (2004) 154–160
used to evaluate regional cerebral blood flow changes in both physiological and pathological conditions (Newell and Aaslid, 1992; Rihs et al., 1995; Markus and Boland, 1992; Bay-Hansen et al., 1997; Vingerhoets and Stroobant, 1999; Silvestrini et al., 1994). Functional TCD research examines blood flow velocity (BFV) changes during the performance of mental tasks. The technique of fTCD is based on the linkage of cerebral activation and perfusion, a principle also underlying functional magnetic resonance imaging (fMRI) and oxygen-15 positron emission tomography. Assuming that the diameter and perfusion territory of the basal cerebral arteries remains unchanged with time, BFV changes under successive mental conditions are related to volume flow changes and reflect changes in cerebral metabolism due to cerebral activation (Klingelho¨fer et al., 1994; Stoll et al., 1999; Hartje et al., 1994; Droste et al., 1989). The main aim of this study is to investigate cortical language dominance in left-handed individuals. The second aim is to explore possible gender influence on cortical language representation, since previous published papers showed contradictory reports about sex differences in cortical language lateralization.
2. Subjects and methods One hundred and fifty healthy subjects (75 left-handers and 75 right-handers; 84 (56%) men and 66 (44%) women; mean ^ SD age 34 ^ 6; range 20– 46 years) participated in the study. None of the subjects took psychoactive medication, had an active medical disease, or had a history of cardiovascular, neurological or psychiatric disorder. Inclusion criteria included also presence of acoustic temporal skull window for insonation of the middle cerebral arteries (MCA) on both sides. Handedness was established and graded by Edingbourgh Handedness Inventory (Oldfield, 1971). To ensure validity of results, during experiment observer did not know handedness of the subjects. Previous works validated fTCD as non-invasive, suitable and very robust tool for determination of cerebral language lateralization as well for clinical as for investigative purposes (Knecht et al., 1998a,b; Rihs et al., 1999; Schmidt et al., 1999). For determination of hemispheric language dominance we used a word generation task previously shown to activate lateralized language areas in normal adults (Knecht et al., 1998a; Frith et al., 1991; Cuenod et al., 1995). Continuous measurement of blood flow velocity in MCA was achieved by a commercially available 2-MHz pulsed-wave TCD unit (MultiDopX, DWL inc). Both MCA were insonated through left and right temporal scull window, starting from an insonation depth of 50 mm. Depth and angles of insonation were adjusted to obtain the highest signal intensity of the M1 segment of MCA (insonation depth ranged from 42 to 56 mm). Signals were identified by means of the spectral screen display and as audible pitch. Details of the insonation technique, and
155
the correct insonation of the MCA have been described elsewhere (Ringelstein et al., 1990). The BFVmean were calculated by the standard algorithm implemented on the instrument with use of a fast Fourier transform. All tests were performed in a quiet room without any visual or auditory stimulation and with illumination held constant. Before the examination the basic principles of the equipment were demonstrated and during the examination subjects were resting in the supine position, also they were requested to close their eyes, relax, and ‘think of nothing’. Following an initial 15-min rest phase, subjects performed the language task, which consisted of silently finding as many words as possible starting with the presented letter. Letters were presented by observer in random order. After 15 s following the presentation of the letter, subjects were requested to articulate the words they had found to control cooperation in the task. We performed fTCD measuring changes in BFVmean during the 3 successive cycles without interruption. Each cycle consisted of alternating epochs of rest and activation – one epoch of 15 min of resting and one epoch of 15 s of activity (word generation task). Relative increase of BFVmean was calculated from the end of the resting phase (baseline value) to the 15 s following activation. Only the last 30 s of the rest period served as the baseline measurement for the subsequent activation phase. Because TCD cannot detect the difference between real asymmetries in BFV and differences caused by slightly different insonation angles on the left and right sides of one subject, the measured velocities expressed in centimetres per second do not represent the real blood flow velocities. Therefore, for data evaluation all velocity changes were transformed into changes of FVmean percentages from the rest phase to task performance, and then the data of all 3 cycles were averaged. If the percentage of velocity changes from the rest phase to task performance in the one MCA was more than 5% than in the contralateral MCA, we considered it like significant difference of increased velocities between left and right MCA. If the difference of increased velocities from the baseline values between left and right MCA was less than 5% we considered it as a bilateral pattern of cortical language organization. The SPSS 10.0 for Windows software package was used for descriptive analyzes and analyzes of significance. To compare mean percentage changes in left and right MCA between lefthanders and right-handers we used Student’s t test for independent samples, and to analyze gender influence on hemispheric language lateralization we used One-way analysis of variance. Results were considered statistically significant for P , 0:05.
3. Results In left-handers we observed significant increase BFVmean in right MCA in 58 (77.3%) subjects and bilateral increase
156
S. Basic et al. / Clinical Neurophysiology 115 (2004) 154–160
4. Conclusion and further work
Fig. 1. Differences of significant increase of BFVmean in the MCA between left- and right-handers.
in 11 (14.7%) subjects. The predominance of left-hemisphere activation, however, was weak in these cases; only in 6 (8%) left-handed subjects was observed significant increase in left MCA representing left cortical language dominance. In the right-handed group 70 (93.3%) subjects showed significant increase BFVmean in left MCA, while 5 (6.7%) showed only small differences between left and right MCA, possibly reflecting bilateral language representation. In this group, there was no significant increase BFVmean in right MCA (Fig. 1). In both left-handed and right-handed there was insignificant tendency in females for bilateral hemispheric language representation. Almost 92% (91.7%; 33 subjects) of righthanded female subjects showed significant BFV mean increase in left MCA, whereas 8.3% (3 subjects) showed a bilateral activation pattern. None of right-handed females showed right language cortical dominance. In contrast, right-hemisphere lateralization occurred in 22 (73.3%) lefthanded females, bilateral activation in 6 (20%), and significant BFVmean increase in left MCA in the remaining 2 (6.7%). Increase in left MCA was observed in 37 (94.1%) right-handed male subjects, and in two (5.1%) right-handed males increase were bilateral. In the male left-handers group 36 (80%) subjects showed increase BFVmean in right MCA, 5 (11.1%) bilateral, and in 4 (8.9%) male subject increase were observed in left MCA (Fig. 2).
Fig. 2. Differences of significant increase of BFVmean in the MCA according to gender.
There is general consent that the left and right human hemispheres differ in anatomy and function: verbal analytical functions are primarily related to the dominant hemisphere, while non-verbal integrative visuoperceptive and visuocognitive functions are related to the nondominant hemisphere (Ingvar, 1976; Hassler, 1990; Kashiwagi et al., 1990; Ahern et al., 1991; Rey et al., 1988). Results are based mostly on the population of right-handed people, and a generally accepted view is that there is a left sided cortical preference for speech in such a population. However controversial findings exist about the speech dominance in left-handed people. Language dominance is also very close associated with the laterality of temporal and spatial movement representations (i.e. ideomotor praxis dominance) even more than the hand preference is. Patients with atypical language dominance exhibit more bilateral cerebral distribution of both, language and praxis function (Polemikos and Papaeliou, 2000; Floel et al., 2001; Day and MacNeilage, 1996; Sussman, 1982; Strauss and Wada, 1983; Searleman, 1980; Strauss, 1986). It was suggested that in the normal population, handedness and footedness are relevant factors in predicting cerebral speech dominance. Recent advances in functional neuroimaging techniques have prompted an increase in the number of studies investigating lateralization of language functions. One of the problems in relating findings of various studies to one another is the diversity of reported results. Differences in the tasks that are used to stimulate language processing regions and in the control tasks, as well as differences in the way imaging data are analyzed, in particular the threshold for significance of signal change, can be a reason of this discrepancies. It has been proved that there are task-specific language region in the brain (Roux and Tremoulet, 2002). So there is a possibility that different activation mechanisms can activate different brain regions, which has been indirectly proved in former studies. They namely showed that different stimulation techniques could induce different cortical centres. Beside that, just differently designed studies and ways of result evaluations (by using the same technique) brought up controversial results. For instance, there is a disagreement of the authors about cortical language representation according to sex preference and they used same technique (fMRI for example). We can present several studies whose results speak in favor, but also against sex difference in cortical language presentation (Vikingstad et al., 2000; Frost et al., 1999; Shaywitz et al., 1995; Phillips et al., 2001; van der Kallen et al., 1998a). Another reason can also be a small number of individuals in the investigation group, so statistically significant data could not be obtained from these groups. Furthermore, the investigations have mostly been performed on patients with neurological illnesses or disorders (like patients with epilepsy, candidates for neurosurgical treatment, or patients
S. Basic et al. / Clinical Neurophysiology 115 (2004) 154–160
suffering from stroke). By such a group there is a possibility of cortical reorganization of language function, so the data can not be relevant. Investigations which were performed on larger number of patients who were older, could also be misinterpreted according their possible vascular changes in the cerebral circulation and possible unrecognized microinfarcts of the brain in the past, which could have had influence of the reorganization of cerebral functions. Therefore, such results must also be analyzed with a precaution. Recent results of cortical language representation showed a right sided domination in left-handed people in 10 –55% of investigated population, depending on author and used techniques, design of the study or used investigation group. Basso et al. had, on a small group of 24 non-right-handed patients with stroke 21% of right sided dominance, while Risse found a very small number of patients with right sided preference in a group of both left- and right-handed patients with epilepsy who were candidates for neurosurgical treatment (Basso et al., 1990; Risse et al., 1997). However those results are questionable because chronic vascular lesions of the brain, as well as epilepsy are associated with varying degrees of brain dysfunction and tissue damage, and thus possible secondary reorganization of cerebral (language) functions may occur relatively often in such patients. Anatomic studies show a different cortical language organization in left-handers. Foundas et al., in a small sample of right- and left-handed adults have demonstrated that right-handers had a significant leftward planar asymmetry, whereas the left-handers were more likely to have symmetric or reversed planar measures (Foundas et al., 1995). Later, they have found (2002) reduced leftward planar (planum temporale) asymmetry in the left handers relative to the right handers. They found atypical planar anatomy in 44.5% consistent left handers (Foundas et al., 2002). This anatomy difference of posterior cortical language areas between left and right-handers suggest different pattern of language processing in left-handers and right-handers. Steinemtz reported atypical rightward planar asymmetries in 42% of the left handers (Steinemtz, 1995). Also, Pieniadz and Naeser has demonstrated computed tomography anatomy differences between right and left handers, and similar results were published by other authors (Pieniadz and Naeser, 1984; Habibet al., 1995). The same conclusion is suggested by investigations of previously normal patients with unilateral lesions secondary to stroke, which showed that left-handed aphasic patients tend to have incomplete and unusual aphasic syndromes (Brown and Hecaen, 1976) and to recover more rapidly (Hecaen and Sauguet, 1971) then right-handers (Brown and Hecaen, 1976; Hecaen and Sauguet, 1971). In another study (Rey et al., 1988a), right hemispheric dominance was found in 50% of left handed patients and in none of right handed patients. Bilateral speech functions were observed in 7% of
157
right-handers, 13% of left-handers, and 35% of ambidextrous (Rey et al., 1988b). Unlike intracarotid amobarbital procedure and lesion methods, which are based on the inference of language localization from observation of language deficits, activation imaging techniques such as positron emission tomography and fMRI provide direct observation of brain activity during language processes. However, inferring language dominance from such data requires consideration of two critical issues. First, the activation task used may engage a number of brain systems not specifically related to language, including sensory, motor and attentional systems. Measurement of language lateralization with such techniques thus requires activation of these systems to be controlled by a contrast or baseline task. Secondly, even when such controls are used, it is conceivable that some areas engaged specifically by the language task might not be critically necessary for normal language performance. Thus, the extent to which activation imaging data correlate with conventional measures of language dominance based on lesion methods must be determined empirically for each language activation task. Pujol et al. showed bilateral activation in 14%, and righthemisphere lateralization in the 10% of normal left-handed people studied by functional MRI. Their conclusion was that silent word generation lateralizes to the left cerebral hemisphere in both handedness groups, but right-hemisphere participation is frequent in normal left-handed subjects (Pujol et al., 1999). In contrast, Sabbah et al. showed by functional MRI right hemispheric language dominance in 55% left-handers, but it was small group of epileptic patients (Sabbah et al., 2003). A serious limitation of fMRI is that at the same moment only small cortical areas can be seen and analyzed, so we can not tell what is happening in other regions, which are much bigger than the analyzed section. Furthermore, inspite of very sophistic technical possibilities of a fMRI technique, it is not a realtime representation like fTCD is. fTCD shows at the same time a possible activation of a larger part of the hemispheric region, namely in the whole irrigation area of the investigated blood vessel. In our investigation this is a case for the arteria cerebri media, and therefore it shows much bigger area than it can be showed on fMRI and is in the same time a ‘real-time’ presentation. Interpreting results of Pujol et al., we also must consider that they have included some ‘reserve’ patients in the study. The results of Andreou also speak in favor of different cortical organization in left and right handed people. He used event related potentials (ERPs) and found a bilateral pattern of lateralization in left-handed males for both their native and foreign language, in all of study population (100% of healthy young bilingual left-handed males, a sample of 30 people) (Andreou and Karapetsas, 2001). These results clearly demonstrate that the relationship between handedness and language dominance is not an artifact of cerebral pathology but a natural phenomenon.
158
S. Basic et al. / Clinical Neurophysiology 115 (2004) 154–160
The possible reason why former fTCD studies did not show higher dominance of the right brain hemisphere in left-handed people could also be their design, namely the time of the activation epoques that has been analyzed. Knecht used a longer epoque and analyzed both 15 s of baseline as well as 30 s (and even more) after the activation. In our work we observed also a significant and abrupt raise in blood flow velocity immediately after the activation, but which showed the tendency to baseline values (or same values as in the contralateral hemisphere) already after 15 or 20 s. The possible reason for this may be that most of the investigation population after 15 – 20 s lacks another words for generating, so other cortical centers tend to be activated. Several studies have shown that diameter of large cerebral arteries remains constant and does not change significantly under a variety of physiological stimuli, and that alterations of flow velocity are related to the diameter of the small vessels (Schmidt et al., 1999; Huber and Handa, 1967; Giller et al., 1993; Kontos, 1989). According to the fact that changes in cerebral perfusion are consequence of cerebral activation, changes (increase) of flow velocity observed in our study during language task can be interpreted as an increase of neural activity in the MCA supplied brain regions. In our study we examined changes in cerebral blood flow velocities during the rest and during language task trying to find different hemodynamic patterns in right and lefthanders. We found significant differences in the hemodynamic patterns of the left-handers and the right-handers during language task. Our results proved significant difference in hemispheric dominance for verbal function between right- and left-handers. In right-handed individuals we found expected strong left hemispheric dominance, while in lefthanders we showed significant right hemispheric dominance, but also a stronger tendency for bilateral cortical language representation. Current results showed significant (t ¼ 217:369, P , 0:0001) right hemispheric language dominance in healthy left-handed subject, but also approve that there is no ‘mirror image’ cortical language organization in left-handers. Also there is insignificant female gender tendency for bilateral hemispheric language representation in both handedness, which cannot approve assumption of gender influence on cortical language organization (t ¼ 21:081, P ¼ 0:281). Our data agree with previous suggestion that different stimulation techniques can induce intense tonic emotional arousal, high enough for hemisphere asymmetry, which can be registered and measured by TCD. Our results show the possibilities of fTCD in clinical practice or research. This method is simple, non-invasive, relatively cheap, very easy to perform and to repeat in every-day conditions, so it gives new possibilities in research of cognitive cerebral functions, but also in clinical practice. We can presume that the usefulness of fTCD will be growing, so the indication field can be even bigger. For Instance fTCD might become even
now or in the near future, an alternative non-invasive or complementary tool to the Wada test, particularly in patients to whom the Wada test gives inconclusive results or is impractical. However, a very strong limitation of fTCD is that some subjects lack an acoustic temporal bone window for insonation of MCA, fortunately, in only small percentage of population. In our study only one subject could not enter inclusion criteria for this reason. Small differences between left and right MCA during the language task in some subjects possibly reflects bilateral language representation and approves theory of graded continuum in cortical language organization in humans. But, luck of hemisphere asymmetry in those subjects can also be due to bad response to used stimulation technique. Previous studies showed that different stimulation techniques induce different regional cortical activation, more or less high enough for registration by fTCD. That’s why is strongly recommended to find stimulation technique which will be able to induce stronger hemisphere lateralization response, before clinical use in determination of cortical language dominance and possible replacement of Wada test. Our results incline towards the result of the group of authors which showed significant difference between leftand right-handers. The reason for such a big percentage of right-sided dominance may lie in the attributes of the investigation group (young, healthy population, same number of male and female population). The next reason can also be the design of the study, namely long enough period of rest between to interrogation periods, which tried to exclude the influence of other cortical center on the final results, so that only the activation of language cortical centers can be evaluated. Still, our results must surely be confirmed in further studies, which have the same design and a larger investigation group. It would be interesting to compare the results of Wada test and fMRI in our investigational population. Only having all this results we could get relevant data about cortical language organization in left handed people but also confirm or exclude the possibility of replacing Wada test with fTCD in presurgical evaluation of the language centers, especially in patients with epilepsy who are candidates for neurosurgical operation. References Ahern GL, Schomer DL, Kleefield J, Blume H, Cosgrove GR, Weintraub S, Mesulam MM. Right hemisphere advantage for evaluating emotional facial expressions. Cortex 1991;27:193–202. Andreou G, Karapetsas A. Hemispheric asymmetries of visual ERPs in lefthanded bilinguals. Brain Res Cogn Brain Res 2001;12(2):333–5. Basso A, Farabola M, Grassi MP, Laiacona M, Zanobio ME. Aphasia in left-handers. Comparison of aphasia profiles and language recovery in non-right-handed and matched right-handed patients. Brain Lang 1990; 38(2):233–52. Bay-Hansen J, Ravn T, Knudsen GM. Application of interhemispheric index for transcranial doppler sonography velocity measurements and evaluation of recording time. Stroke 1997;28:1009– 14.
S. Basic et al. / Clinical Neurophysiology 115 (2004) 154–160 Brown JW, Hecaen H. Lateralization and language representation. Neurology 1976;26(2):183– 9. Calabrese P, Neufeld H, Falk A, Markowitsch HJ, Muller C, Heuser L, Gehlen W, Durwen HF. Word generation in bilinguals-fMRI study with implications for language and memory processes. Fortschr Neurol Psychiatr 2001;69(1):42–9. Cuenod CA, Bookheimer SY, Hertz-Pannier L, Zeffiro TA, Theodore WH, Le Bihan D. Functional MRI during word generation using conventional equipment. Neurology 1995;29:1821–7. Day LB, MacNeilage PF. Postural asymmetries and language lateralization in humans (Homo sapiens). J Comp Psychol 1996;110(1):88–96. Droste DW, Harders AG, Rastogi E. Two transcranial doppler studies on blood flow velocity in both middle cerebral arteries during rest and the performance of cognitive tasks. Neuropsychologia 1989;27(10): 1221–30. Floel A, Knecht S, Lohmann H, Deppe M, Sommer J, Drager B, Ringelstein EB, Henningsen H. Language and spatial attention can lateralize to the same hemisphere in healthy humans. Neurology 2001; 57(6):1018– 24. Foundas AL, Leonard CM, Heilman KM. Morphologic cerebral asymmetries and handedness. The pars triangularis and planum temporale. Arch Neurol 1995;52(5):501–8. Foundas AL, Leonard CM, Hanna-Pladdy B. Variability in the anatomy of the planum temporale and posterior ascending ramus: do right- and lefthanders differ? Brain Lang 2002;83(3):403–24. Frith C, Friston KJ, Liddle PF, Frackowiak RS. A PET study of word finding. Neuropsychologia 1991;29:1137 –48. Frost JA, Binder JR, Springer JA, Hammeke TA, Bellgowan PS, Rao SM, Cox RW. Language processing is strongly left lateralized in both sexes. Evidence from functional MRI. Brain 1999;122(Pt 2):199–208. Giller CA, Browman G, Dyer H, Mootz L, Krippner W. Cerebral arterial diameters during changes in blood pressure and carbon dioxide during craniotomy. Neurosurgery 1993;32:737–47. Habib M, Robichon F, Levrier O, Khalil R, Salamon G. Diverging asymmetries of temporo-parietal cortical areas: a reappraisal of Geschwind/Galaburda theory. Brain Lang 1995;48(2):238– 58. Hartje W, Ringelstein EB, Kistinger B, Fabianek D, Willmes K. Transcranial doppler assessment of middle cerebral artery blood flow velocity changes during verbal and visuospatial cognitive tasks. Neuropsychologia 1994;32(12):1443–52. Hassler M. Functional cerebral asymmetries and cognitive abilities in musicians, painters, and controls. Brain Cogn 1990;13:1–17. Hecaen H, Sauguet J. Cerebral dominance in left-handed subjects. Cortex 1971;7(1):19–48. Huber P, Handa J. Effects of contrast material, hypercapnia, hyperventilation, hypertonic glucose and papaverine on the diameter of the cerebral arteries: angiographic determination in man. Invest Radiol 1967;2: 17–32. Hund-Georgiadis M, Friederici ULA, von Cramon DY. Non-invasive regime for language lateralization in right- and left-handers by means of functional MRI and dichotic listening. Exp Brain Res 2002;145: 166–76. Ingvar DH. Functional landscapes of the dominant hemisphere. Brain Res 1976;176:181 –97. Kashiwagi A, Kashiwagi T, Nishikawa T, Tanabe H, Okuda J. Hemispatial neglect in a patient with callosal infarction. Brain 1990;113:1005– 23. Keane AM. Cerebral organization of motor programming and verbal processing as a function of degree of hand preference and familial sinistrality. Brain Cogn 1999;40(3):500–15. Khedr EM, Hamed E, Said A, Basahi J. Handedness and language cerebral lateralization. Eur J Appl Physiol 2002;87(4–5):469–73. Klingelho¨fer J, Matzander G, Sander D, Conrad B. Bilateral changes of middle cerebral artery blood flow velocities in various hemispherespecific brain activities. J Neurol 1994;241:264 –5. Knecht S, Henningsen H, Deppe M, Huber T, Ebner A, Ringelstein EB. Successive activation of both cerebral hemispheres during cued word generation. Neuroreport 1996;7(3):820–4.
159
Knecht S, Deppe M, Ebner A, Henningsen H, Huber T, Jokeit H, Ringelstein EB. Non-invasive determination of language lateralization by functional transcranial doppler sonography. A comparison with the Wada test. Stroke 1998a;29:82–6. Knecht S, Deppe M, Ringelstein EB, Wirtz M, Lohmann H, Dra¨ger B, Huber T, Henningsen H. Reproducibility of functional transcranial doppler sonography in determining hemispheric language lateralization. Stroke 1998b;29:1155–9. Knecht S, Drager B, Deppe M, Bobe L, Lohmann H, Floel A, Ringelstein EB, Heinningsen H. Handedness and hemispheric language dominance in healthy humans. Brain 2000a;12:2512 –8. Knecht S, Deppe M, Drager B, Bobe L, Lohmann H, Ringlestein E, Henningsen H. Language lateralization in healthy right-handers. Brain 2000b;123(1):74– 81. Kontos HA. Validity of cerebral arterial blood flow calculations from velocity measurements. Stroke 1989;20:1– 3. Lishman WA, McMeekan ER. Handedness in relation to direction and degree of cerebral dominance for language. Cortex 1977;13(1): 30– 43. Markus HS, Boland M. ‘Cognitive activity’ monitored by non-invasive measurement of cerebral blood flow velocity and its application to the investigation of cerebral dominance. Cortex 1992;28:575–81. Newell DW, Aaslid R. Transcranial doppler: clinical and experimental use. Cerebrovasc Brain Metab Rev 1992;4:122–43. Oldfield RC. The assessment and analysis of handedness: the Edinburgh inventory. Neuropsychologia 1971;9(1):97 –113. Phillips MD, Lowe MJ, Lurito JT, Dzemidzic M, Mathews VP. Temporal lobe activation demonstrates sex-based differences during passive listening. Radiology 2001;220(1):202–7. Pieniadz JM, Naeser MA. Computed tomographic scan cerebral asymmetries and morphologic brain asymmetries. Correlation in the same cases post mortem. Arch Neurol 1984;41(4):403–9. Polemikos N, Papaeliou C. Sidedness preference as an index of organization of laterality. Percept Mot Skills 2000;91(3 Pt 2): 1083–90. Pujol J, Deus J, Losilla JM, Capdevila A. Cerebral lateralization of language in normal left-handed people studied by functional MRI. Neurology 1999;52(5):1038 –43. Ramsey NF, Sommer IE, Rutten GJ, Kahn RS. Combined analysis of language tasks in fMRI improves assessment of hemispheric dominance for language function in individual subjects. Neuroimage 2001a;13(4): 719– 33. Ramsey NF, Sommer IE, Rutten GJ, Kahn RS. Combined analysis of language tasks in fMRI improves assessment of hemispheric dominance for language function in individual subjects. Neuroimage 2001b;13(4): 719– 33. Reiss M, Reiss G. Current aspects of handedness. Wien Klin Wochenschr 1999;111(24):1009–18. Rey M, Dellatolas G, Bancaud J, Talairach J. Hemispheric lateralization of motor and speech functions after early brain lesion: study of 73 epileptic patients with intracarotid Amytal test. Neuropsychologia 1988a;26: 167– 72. Rey M, Dellatollas G, Bancaud J, Talairach J. Hemispheric lateralization of motor and speech functions after early brain lesion: study of 73 epileptic patients with intracarotid amytal test. Neuropsychologia 1988b;26: 167– 72. Rihs F, Gutbrod K, Gutbrod B, Steiger HJ, Sturzenegger M, Mattle HP. Determination of cognitive hemispheric dominance by ‘stereo’ transcranial doppler sonography. Stroke 1995;26:70 –3. Rihs F, Sturzenegger M, Gutbrod K, Schroth G, Mattle HP. Determination of language dominance: Wada test confirms functional transcranial doppler sonography. Neurology 1999;52(8):1591 –6. Ringelstein EB, Kahlscheuer B, Niggemeyer E, Otis SM. Transcranial doppler sonography: automatical landmarks and normal velocity values. Ultrasound Med Biol 1990;16:745 –61.
160
S. Basic et al. / Clinical Neurophysiology 115 (2004) 154–160
Risse GL, Gates JR, Frangman MC. A reconsideration of bilateral language representation based on the intracarotid amobarbital procedure. Brain Cogn 1997;33(1):118–32. Roux FE, Tremoulet M. Organization of language areas in bilingual patients: a cortical stimulation study. J Neurosurg 2002;97(4): 857– 64. Sabbah P, Chassoux F, Leveque C, Landre E, Baudoin-Chial S, Devaux B, Mann M, Godon-Hardy S, Nioche C, Ait-Ameur A, Sarrazin JL, Chodkiewicz JP, Cordoliani YS. Functional MR imaging in assessment of language dominance in epileptic patients. Neuroimage 2003;18(2): 460– 7. Saffran EM. Aphasia and the relationship of language and brain. Sem Neurol 2000;20(4):409– 18. Schmidt P, Krings T, Willmes K, Roessler F, Reul J, Thron A. Determination of cognitive hemispheric lateralization by functional transcranial doppler cross-validated by functional MRI. Stroke 1999; 30:939–45. Searleman A. Subject variables and cerebral organization for language. Cortex 1980 Aug;16(2):239–54. Shaywitz BA, Shaywitz SE, Pugh KR, Constable RT, Skudlarski P, Fulbright RK, Bronen RA, Fletcher JM, Shankweiler DP, Katz L, et al. Sex differences in the functional organization of the brain for language. Nature 1995;373(6515):607– 9. Silvestrini M, Troisi E, Cupini LM, Matteis M, Pistolese GR, Bernardi G. Transcranial doppler assessment of the functional effects of symptomatic carotid stenosis. Neurology 1994;44:1910–4. Springer JA, Binder JR, Hammeke TA, Swanson SJ, Frost JA, Bellgowan PS, Brewer CC, Perry HM, Morris GL, Muller WM. Language dominance in neurologically normal and epilepsy subjects: a functional MRI study. Brain 1999;122(11):2013–4.
Steinemtz H. Anatomical asymmetry is normally distributed, associated with handedness, and develops before birth: other predictions from the right shift theory. Curr Psychol Cogn 1995;14:610– 4. Stoll M, Hamann GF, Mangold R, Huf O, Winterhoff-Spurk P. Emotionally evoked changes in cerebral hemodynamics measured by transcranial doppler sonography. J Neurol 1999;246:127–33. Strauss E. Hand, foot, eye and ear preferences and performance on a dichotic listening test. Cortex 1986;22(3):475 –82. Strauss E, Wada J. Lateral preferences and cerebral speech dominance. Cortex 1983;19(2):165– 77. Sussman HM. Contrastive patterns of intrahemispheric interference to verbal and spatial concurrent tasks in right-handed, left-handed and stuttering populations. Neuropsychologia 1982;20(6):675–84. Szaflarski JP, Binder JR, Possing ET, McKiernan KA, Ward BD, Hammeke TA. Language lateralization in left-handed and ambidextrous people: fMRI data. Neurology 2002;59(2):238– 44. van der Kallen BF, Morris GL, Yetkin FZ, van Erning LJ, Thijssen HO, Haughton VM. Hemispheric language dominance studied with functional MR: preliminary study in healthy volunteers and patients with epilepsy. Am J Neuroradiol 1998a;19(1):73–7. Van der Kallen BFW, Morris GL, Yetkin Z, van Erning L, Thijssen H, Haughton V. Hemispheric language dominancy studied with functional MR: preliminary study in healthy volunteers and patients with epilepsy. Am J Neuroradiol 1998b;19:73–7. Vikingstad EM, George KP, Johnson AF, Cao Y. Cortical language lateralization in right handed normal subjects using functional magnetic resonance imaging. J Neurol Sci 2000;175(1):17 –27. Vingerhoets G, Stroobant N. Lateralization of cerebral blood flow velocity changes during cognitive tasks. A simultaneous bilateral transcranial doppler study. Stroke 1999;30:2152–8.