Degree of language lateralization determines susceptibility to unilateral brain lesions

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1 Degree of language lateralization determines susceptibility to unilateral brain lesions S. Knecht 1, A. Flöel 1, B. Dräger 1, C. Breitenstein 1, J. Sommer 1, H. Henningsen 1, E. B. Ringelstein 1 and A. Pascual-Leone 2 1 Department of Neurology, University of Münster, Albert-Schweitzer-Straβe 33, D Münster, Germany 2 Laboratory for Magnetic Brain Stimulation, Harvard Medical School, 33 Brookline Avenue, Kirstein Building KS 454, Boston, Massachusetts 2215, USA Correspondence should be addressed to S.K. (knecht@uni-muenster.de) Published online: 1 June 22, doi:1.138/nn868 Language is considered a function of either the left or, in exceptional cases, the right side of the brain. Functional imaging studies show, however, that in the general population a graded continuum from left hemispheric to right hemispheric language lateralization exists. To determine the functional relevance of lateralization differences, we suppressed language regions using transcranial magnetic stimulation (TMS) in healthy human subjects who differed in lateralization of language-related brain activation. Language disruption correlated with both the degree and side of lateralization. Subjects with weak lateralization (more bilaterality) were less affected by either leftor right-side TMS than were subjects with strong lateralization to one hemisphere. Thus in some people, language processing seems to be distributed evenly between the hemispheres, allowing for ready compensation after a unilateral lesion. Language impairments are most frequently seen after lesions to the left side of the brain, and occasionally after lesions to the right side. The mechanisms involved in the recovery of language after a one-sided brain lesion are uncertain. The undamaged hemisphere or undamaged parts of the injured hemisphere may take over language representation. If so, it is unclear why certain patients overcome initial deficits, whereas many others remain impaired. One possibility is that individual differences in the organization of language render some people more able to recover function after unilateral brain damage. Functional imaging has provided a wealth of information on brain activity during language processing. Studies with large numbers of subjects often show individuals with weak lateralization, or bihemispheric activation, during language tasks 1 3. Bihemispheric increases in blood flow can be artifacts of methodology in some cases, rather than reflections of a truly bilateral language organization 4,5. Data from epilepsy patients who underwent temporary inactivation of each hemisphere by injection of anesthetics indicate that both hemispheres can be involved in the processing of language 6. However, such patients have abnormal brains because of their medication-resistant epilepsy, and their bilaterality of language representation may reflect disorganization resulting from longstanding lesions. It remains unclear whether true bihemispheric representation of language occurs in healthy subjects, accounts for bihemispheric activation in functional imaging data and offers resistance to language deficits after unilateral brain lesions. To assess the functional relevance of lateralization of language-related brain activation in healthy subjects, we used transient focal virtual lesions 7 induced by transcranial magnetic stimulation (TMS). Subjects were selected from a cohort of 324 to represent the continuum of language lateralization from left- to righthemisphere dominance 3 (Table 1). We assessed language lateralization by measuring hemispheric perfusion differences during a word generation task using functional transcranial Doppler sonography (ftcd) and functional magnetic resonance imaging (fmri) 8. Then, using TMS, we suppressed brain regions 9 to test their causal relation to performance on a picture word verification task (Methods). To test for nonspecific effects, TMS was also applied over a midline occipital control site (Oz) and during a control task involving matching of geometric objects. We found that both the side and the degree of lateralization of language-related brain activation correlated with a person s susceptibility to language disruption by neural deactivation in one hemisphere. In addition, greater bilaterality of the language system, as indicated by low lateralization, allowed for autonomous verbal processing within each hemisphere. RESULTS We analyzed our data by dividing subjects into two groups: right language dominant (laterality index (LI), Methods) and left language dominant (LI > ). Each subject was stimulated with TMS, in different trials, in the left hemispheric Wernicke s language region (CP5) and its right hemispheric homologue (CP6). A repeated-measures analysis of variance (ANOVA) showed a significant interaction for stimulation side group (F 1,18 = 7.74, P <.1). Simple main effects of group, analyzed for each stimulation side separately, showed that subjects with left language dominance were significantly slower nature neuroscience volume 5 no 7 july

2 Table 1. Subject characteristics. Subject Gender Age Handedness* LI based on ftcd** 1 m f f m f (f) 25 (22) 13 (6) 3.68 (4.2) 6 m f m f (f) 3 (33) 1 (9).67 (1.25) 1 m (m) 27 (26) 2 (1).66 (1.23) 11 f f (f) 22 (23) 73 (1).5 (.61) 13 f (f) 22 (26) 8 ( ( 5.1) 14 f (f) 22 (24) 6 ( 9) 2.3 ( 2.3) 15 f (f) 24 (28) 9 ( 1) 2.4 ( 2.2) 16 m f (f) 27 (22) 9 (8) 3.58 ( 3.52) 18 f f m f, female; m, male (values for exchange subjects who took part in the control task). * Handedness was assessed by the Edinburgh Handedness Inventory 31 spanning a range from 1 for strong left-handedness to +1 for strong right-handedness. ** Positive values indicate lateralization to the left; negative values indicate lateralization to the right hemisphere. than were subjects with right language dominance after TMS over CP5; the reverse pattern (right dominant > left dominant) was seen for stimulation over CP6 (unpaired t-tests, both t (18) > 2.19, P <.5). Furthermore, simple main effects of stimulation side, analyzed for each group separately, showed that response times (RTs) after CP6 stimulation were slower than they were after CP5 stimulation for subjects with right language dominance (paired t-test, t (8) = 2.16, P =.6). A tendency for the reverse pattern (TMS over CP5 > TMS over CP6) was seen in subjects with left language dominance (paired t- test, P =.1). Thus, we found a double dissociation between the side of language lateralization and the side of TMS-induced disruption in verbal processing (Fig. 1). Changes in verbal processing speed after TMS of CP5 and CP6 correlated with the degree of language lateralization as assessed by ftcd (Fig. 2). Subjects with strong lateralization of language-related brain activation showed strong effects from interference by left or right hemispheric TMS; those with low lateralization showed only minor effects. The graded effect of TMS was similar when only disruption of the dominant (left or right) hemisphere was considered (Fig. 3). Pooled data from all subjects examined with TMS of the control site Oz (n = 12, Methods) showed no effect of this control TMS on mean RT (628 ms before TMS, 629 ms after TMS; Fig. 1. Mean changes (± s.e.m.) in verbal processing speed as assessed by reaction time. Interaction between left (CP5) and right (CP6) hemispheric stimulation and left dominant (n = 11) and right dominant (n = 9) hemispheric language dominance. Also shown are changes in reaction time (RT) after TMS pulses to the midline occipital control site (Oz). Note that only 6 left and 6 right hemisphere dominant subjects were stimulated at the control site. P =.9, paired t-test, Fig. 1), confirming the topographic specificity of our results. The accuracy of responses during the picture word task was not significantly affected by TMS at either CP5 or CP6 (paired t-tests), and the before after change scores did not correlate with language lateralization for any of the stimulation sites. Differences in RT between hands were small (mean difference, 1.5 ms). TMS had no significant effect on this parameter (3 ms after inhibitory TMS at CP5; 1 ms after inhibitory TMS at CP6). There was no statistically significant interaction between side of language dominance (determined by ftcd) and effect of TMS on processing speed during the non-linguistic control task. There was a nonsignificant correlation between results on the object matching task and language lateralization, which showed the inverse pattern to that of the linguistic task (Fig. 2). After right-hemispheric TMS, there was a tendency for slowed geometric object matching with increasing leftside language lateralization (r =.24, P =.3), whereas the inverse pattern was seen after TMS of the left hemisphere (r =.38, P =.1). DISCUSSION In subjects with left-side language dominance, verbal processing was slowed during transient disruption of the left but not the right hemisphere. The opposite pattern was seen in subjects with right-sided language dominance. This double dissociation attests to the cross-method validity of perfusion-sensitive functional imaging and TMS, although different language tasks had to be used (word generation for ftcd and picture word verification for TMS). The word generation task used for the initial recruitment of subjects by ftcd is predominantly expressive in nature, whereas the picture word verification task used for TMS is mostly receptive (Methods). Interhemispheric dissociations of expressive and receptive language functions have so far been shown only in patients with preexisting brain lesions 1,11. Activation studies usually show a concordant lateralization of brain regions involved in expressive and receptive language 12,13. Inhibition of verbal processing after TMS over the left hemisphere has been shown in several studies So far, no data have been reported on TMS in healthy subjects with righthemispheric language representation. Verbal slowing after right-hemisphere TMS in subjects with right-hemisphere language dominance, as shown here, accords with clinical observations of crossed aphasias, that is, aphasias after right hemisphere lesions 19. After disruption of the non-dominant hemisphere in subjects with either left or right hemisphere language dominance, Change in RT post TMS (ms) acceleration slowing Left dominant Right dominant CP5 (left) Oz CP6 (right) TMS site 696 nature neuroscience volume 5 no 7 july 22

3 Functional transcranial Doppler sonography (ftcd). Twenty subjects (Table 1) were selected from a cohort of 324 healthy volunteers previarticles Fig. 2. Correlations between the degree of language lateralization and degree of language disruption by TMS. Top, three example fmri images from subjects with left, bilateral and right language dominance (red, maximal activation). Middle and bottom, lateralization was estimated by functional transcranial Doppler sonography (ftcd, x-axis), and disruption of language processing is shown on the y-axis (black circles). TMS was done over the left hemisphere (middle) and over the right hemisphere (bottom). Orange triangles represent the effect of TMS on the non-linguistic control task involving matching of geometric objects. Positive values on the y-axis indicate an increase, and negative values a decrease, in response time (RT). we found an acceleration of verbal processing another example of paradoxical functional improvement by a focal brain disruption 7,2. At first glance, it could be taken to reflect interhemispheric disinhibition, with the non-dominant hemisphere inhibiting the dominant one during normal, pre-tms verbal processing. Faster verbal processing could also result from a narrowing of the lexical search. The picture word verification task in this study consisted of accessing the literal meaning of concrete nouns. It did not require more complex semantic analyses, a function attributed to the non-dominant hemisphere 5,21,22. Inhibition of the nondominant hemisphere by TMS may have prevented such a complex and time-consuming contextual analysis. Four subjects (two with left and two with right hemisphere dominance) who became faster after TMS of the non-dominant hemisphere felt that their verbal performance had markedly deteriorated. These subjects may have noticed difficulties in accessing associative semantic information after disruption of their non-dominant hemisphere. Matching of geometric objects during the control task was affected differently by TMS than was picture word matching. There was a nonsignificant tendency for slowed processing after TMS of the nondominant hemisphere. The discrepancy in results for the linguistic and non-linguistic tasks implies that modulation of language processing by TMS was language-specific and not related to a memory component common to both tasks. A slowing of object matching after suppression of the rostral part of the superior temporal cortex in the nondominant hemisphere would also be compatible with the prominent role of this region in extrapolation of object-related and space-related information 23. Change in RT (ms) post-tms of dominant hemisphere acceleration slowing Pearson r =.51 P = Absolute degree of language lateralization (%) The focus of our study was on language performance in individuals lacking marked hemispheric lateralization of language processing. After TMS of either hemisphere, such subjects showed almost no slowing of verbal processing. To the extent that repetitive TMS is a valid model of focal lesions and hence of cerebrovascular stroke, this finding suggests that individuals with a more bilateral language representation will remain relatively unaffected in verbal functioning after stroke to either the right or left hemisphere. We propose that such hemispheric autonomy does not result from simple duplication of the brain s language processing hardware. Rather, in humans with weak language lateralization, the partially redundant neural network supporting language may be more evenly distributed between both hemispheres than it is in subjects with strong lateralization. METHODS The study was approved by the Ethics Committee of the Medical Faculty of the University of Münster, Germany. Informed consent was obtained from all subjects. Fig. 3. Effect of functional lesion by TMS of only the dominant (left or right) hemisphere relative to the absolute degree of language lateralization by ftcd. nature neuroscience volume 5 no 7 july

4 Behavioral tasks. Different language tasks had to be used for ftcd and TMS. To produce consistent regional blood flow increases amenable to detection by fmri or ftcd, neural activations of several seconds in duration are required. To quantify effects of TMS on neural processing speed, linguistic tasks with homogenous material and of short duration are required. Verbal processing speed was assessed by measuring RT in a picture word verification task (Fig. 5). Thirty black-and-white drawings of concrete objects, selected for name agreement and complexity, were presented in a randomized order on a computer screen with correct or incorrect subtitles. Incorrect subtitles were randomly chosen and were not matched with the correct subtitles for semantic or phonematic features or word length. Pictures and words in this no-match condition were taken from the same pool as the matching picture word pairs. Incorrect pairs were correctly rejected in over 95% of trials. Subjects indicated right or wrong pairings by bimanual key presses. Each subject received eight practice blocks to overtrain performance and achieve a plateau of RTs. For training, the same material was used as during the TMS intervention. Verbal RTs before TMS were subtracted from those after TMS. A post-hoc control experiment was done to examine whether effects were linguistic. Twelve of the original subjects and eight new subjects matched for language lateralization (Table 1, parentheses) participated. The task involved matching two geometric objects with two identical or different objects of the same size in a lower row (Fig. 5, lower left). A set of 3 correct and 3 incorrect pairings were used for training and testarticles ously assessed for language dominance by ftcd (Münster Functional Imaging Study on the Variability of Hemispheric Specialization in Health and Disease) (Fig. 4) 3,8,24,25. Language lateralization had been determined with ftcd by measuring relative hemispheric perfusion increases during word generation 3,8,24,25. Subjects were presented a letter on a computer screen 5 s after a cueing tone. They were asked to silently find as many words as possible starting with the displayed letter. Task compliance was controlled by instructing subjects to report the words after a second auditory signal that was delivered 15 s after presentation of the letter. All words had to be reported in a 5-s time window. The next letter was presented in the same way after a rest period of 6 s. Letters were presented in random order. Q, X and Y were excluded because very few words begin with these letters. No letter was displayed more than once. Changes in the cerebral blood flow velocity (CBFV) in the basal arteries, an indicator of the downstream increase of the regional metabolic activity during the language task, were measured by dual transcranial Doppler ultrasonography of the middle cerebral arteries (MCAs). Ultrasonography was done with two 2-MHz transducer probes attached to a headband and placed at the temporal skull windows bilaterally. After automated artifact rejection, data were integrated over the corresponding cardiac cycles, segmented into epochs that related to a cueing tone before the language task and were then averaged. The epochs were set to begin 15 s before, and to end 35 s after, the cueing tone. The mean velocity in the 15-s interval before cueing (V pre.mean ) was taken as the baseline value. The relative CBFV changes (dv) during cerebral activation were calculated using the formula: dv =(V(t) V pre.mean ) * 1/V pre.mean where V(t) is the CBFV over time. Relative CBFV changes from repeated presentations of letters (on the average 2 runs) were averaged time-locked to the cueing tone. The functional TCD laterality index (LI) was calculated using the formula: 1 LI = t int tmax +.5tint t max.5t int V (t) dt Fig. 4. Distribution of lateralization indices (LIs). LIs were based on ftcd for all 324 healthy subjects, 111 subjects with negative (or zero) and 213 subjects with positive handedness values in the Edinburgh inventory (based on previously published data 3 ). The percentage perfusion difference (x-axis) between the left and the right hemisphere, or, more specifically, the territory of the middle cerebral artery, was measured during word generation. coefficient was r =.95, P <.1 (ref. 25). ftcd has been validated by direct comparison with the intracarotid amobarbital injection protocol and functional magnetic resonance imaging 8,24. Left-hemispheric language dominance was assumed in all cases with a positive lateralization index. Right-hemispheric language dominance was defined accordingly. Subjects were divided into five categories of lateralization. Within each category, those subjects who had been examined last were contacted and invited to participate in the present study. Thus, subjects with bilateral and right-hemispheric language representation were overrepresented relative to the general population (Fig. 4). Although moderate to strong left-hemispheric language lateralization is the epidemiological rule, the focus here was on the continuum of lateralization and susceptibility that could explain why patients with similar brain lesions can differ markedly with respect to language impairments 26. where V(t) = dv(t) left dv(t) right is the difference between the relative velocity changes of the left and right MCAs. t max represents the latency of the absolute maximum of V(t)during an interval of 1 18 s after cueing (during verbal processing). For integration, a time period of t int = 2 s was chosen. The test-to-retest reproducibility of this procedure based on the Pearson product moment correlation Training of picture word verification Time Mouse Lion Reaction time and accuracy pre-tms Reaction time and accuracy post-tms Mouse Fig. 5. Experimental design. A set of 6 pictures (3 different drawings with correct subtitles and 3 identical drawings with incorrect subtitles) was presented in randomized sequence pre- and post-tms. Response times and accuracy of response were compared pre- and post-tms (paired t-test). In a control task (lower left), subjects matched geometric objects in an upper row with those in a lower row (left, correct pairs; right, incorrect pairs). Samples from object matching control task: Random order of pictures TMS coil over CP5 Random order of pictures 698 nature neuroscience volume 5 no 7 july 22 CP6 Midline occipital control site (Oz) Time Banana

5 ing in a manner identical to the linguistic task. TMS protocol and RT assessment were as in the original task. Transcranial magnetic stimulation (TMS). TMS was applied using a Magstim Rapid Stimulator (Magstim, Whitland, UK) with a focal figureof-eight coil positioned over CP5 or CP6 according to the international 1 2 electrode system. These sites are considered to reflect the approximate locations of Wernicke s area and its contralateral homologue, respectively 15. They were targeted because of their established role in receptive language tasks and thus their likely involvement in picture word verification 27. A midline occipital stimulation site (Oz) served as the control site. TMS was applied at 1 Hz for 6 s at 11% intensity of the motor threshold 28. This TMS protocol has been shown to cause a disruption of the function of the targeted brain region and behavioral effects that last for several minutes after the stimulation 2,29. Each TMS administration was followed by a 3-min rest before the next administration to avoid carryover effects 28,3. For each picture, RTs and accuracy of responses were assessed (Fig. 5). The relationship between the extent of RT changes after TMS (over CP5 and CP6) and the extent of language lateralization as determined by ftcd was assessed by Pearson product correlation. ANOVA and post-hoc analysis were used to test for a double dissociation between the side of TMS and the side of language lateralization as measured by ftcd. For a subset of subjects (2, 3, 5, 6, 7, 9, 12, 13, 14, 15, 17, 18), RTs before and after TMS at Oz were also compared using paired t- tests. To assess possible interference of TMS with motor performance, we measured RTs for each hand separately. We analyzed with paired t-tests whether differences in RT between hands changed from before to after TMS. Acknowledgments This work was supported by Nachwuchsgruppen-Förderung, Innovative Medizinische Forschung, and Deutsche Forschungsgemeinschaft. Competing interests statement The authors declare that they have no competing financial interests. RECEIVED 13 MARCH; ACCEPTED 8 MAY Binder, J. R. et al. Determination of language dominance using functional MRI: a comparison with the Wada test. Neurology 46, (1996). 2. Pujol, J., Deus, J., Losilla, J. M. & Capdevila, A. Cerebral lateralization of language in normal left-handed people studied by functional MRI. Neurology 52, (1999). 3. Knecht, S. et al. Handedness and hemispheric language dominance in healthy humans. Brain 123, (2). 4. Just, M. A., Carpenter, P. A., Keller, T. A., Eddy, W. F. & Thulborn, K. R. Brain activation modulated by sentence comprehension. Science 274, (1996). 5. George, M. S. et al. Understanding emotional prosody activates right hemisphere regions. Arch. Neurol. 53, (1996). 6. Risse, G. L., Gates, J. R. & Fangman, M. C. A reconsideration of bilateral language representation based on the intracarotid amobarbital procedure. Brain Cogn. 33, (1997). 7. Rafal, R. Virtual neurology. Nat. Neurosci. 4, (21). 8. Deppe, M. et al. Assessment of hemispheric language lateralization: a comparison between fmri and ftcd. J. Cereb. Blood. Flow. Metab. 2, (2). 9. Walsh, V. & Cowey, A. Transcranial magnetic stimulation and cognitive neuroscience. Nat. Rev. Neurosci. 1, (2). 1. Baynes, K., Eliassen, J. C., Lutsep, H. L. & Gazzaniga, M. S. Modular organization of cognitive systems masked by interhemispheric integration. Science 28, (1998). 11. Kurthen, M. et al. Interhemispheric dissociation of expressive and receptive language functions in patients with complex-partial seizures: an amobarbital study. Brain Lang. 43, (1992). 12. Vigliocco, G. The anatomy of meaning and syntax. Curr. Biol. 1, 78 8 (2). 13. Embick, D., Marantz, A., Miyashita, Y., O Neil, W. & Sakai, K. L. A syntactic specialization for Broca s area. Proc. Natl. Acad. Sci. USA 97, (2). 14. Pascual-Leone, A., Gates, J. R. & Dhuna, A. Induction of speech arrest and counting errors with rapid-rate transcranial magnetic stimulation. Neurology 41, (1991). 15. Jennum, P., Friberg, L., Fuglsang-Frederiksen, A. & Dam, M. Speech localization using repetitive transcranial magnetic stimulation. Neurology 44, (1994). 16. Epstein, C. M. Transcranial magnetic stimulation: language function. J. Clin. Neurophysiol. 15, (1998). 17. Flitman, S. S. et al. Linguistic processing during repetitive transcranial magnetic stimulation. Neurology 5, (1998). 18. Wassermann, E. M. et al. Repetitive transcranial magnetic stimulation of the dominant hemisphere can disrupt visual naming in temporal lobe epilepsy patients. Neuropsychologia 37, (1999). 19. Bakar, M., Kirshner, H. S. & Wertz, R. T. Crossed aphasia. Functional brain imaging with PET or SPECT. Arch. Neurol. 53, (1996). 2. Hilgetag, C. C., Theoret, H. & Pascual-Leone, A. Enhanced visual spatial attention ipsilateral to rtms-induced virtual lesions of human parietal cortex. Nat. Neurosci. 4, (21). 21. Bottini, G. et al. The role of the right hemisphere in the interpretation of figurative aspects of language. A positron emission tomography activation study. Brain 117, (1994). 22. Gazzaniga, M. S. et al. Collaboration between the hemispheres of a callosotomy patient. Emerging right hemisphere speech and the left hemisphere interpreter. Brain 119, (1996). 23. Karnath, H. O., Ferber, S. & Himmelbach, M. Spatial awareness is a function of the temporal not the posterior parietal lobe. Nature 411, (21). 24. Knecht, S. et al. Non-invasive determination of hemispheric language dominance using functional transcranial Doppler sonography: a comparison with the Wada test. Stroke 29, (1998). 25. Knecht, S. et al. Reproducibility of functional transcranial Doppler sonography in determining hemispheric language lateralization. Stroke 29, (1998). 26. Willmes, K. & Poeck, K. To what extent can aphasic syndromes be localized? Brain 116, (1993). 27. Lichtheim, L. On aphasia. Brain 7, (1884). 28. Chen, R. et al. Depression of motor cortex excitability by low-frequency transcranial magnetic stimulation. Neurology 48, (1997). 29. Kosslyn, S. M. et al. The role of area 17 in visual imagery: convergent evidence from PET and rtms [published erratum appears in Science 284, 197 (1999)]. Science 284, (1999). 3. Muellbacher, W., Ziemann, U., Boroojerdi, B. & Hallett, M. Effects of lowfrequency transcranial magnetic stimulation on motor excitability and basic motor behavior. Clin. Neurophysiol. 111, (2). 31. Oldfield, R. C. The assessment and analysis of handedness: the Edinburgh inventory. Neuropsychologia 9, (1971). nature neuroscience volume 5 no 7 july