Cortical organization for receptive language functions in Chinese, English, and Spanish: a cross-linguistic MEG study

Neuropsychologia 42 (2004) 967–979

Cortical organization for receptive language functions in Chinese, English, and Spanish: a cross-linguistic MEG study C. E. Valaki a,b , F. Maestu a,c , P. G. Simos d , W. Zhang d , A. Fernandez a , C. M. Amo a , T. M. Ortiz a,∗ , A. C. Papanicolaou d a

d

Facultad de Medicina, Centro de Magnetoencefalografia Dr. Perez Modrego, Universidad Complutense de Madrid, Pabellon No. 8, Avendia Complutense s/n, 28040 Madrid, Spain b Brain and Cognitive Science Division, Department of Methodology and Theory of Science, National University of Athens, Athens, Greece c Department of Basic Psychology II, Cognitive Processes UCM, Madrid, Spain Department of Neurosurgery, Vivian Lee Smith Center for Neurologic Research, University of Texas Health Science Center, Houston, TX, USA Received 3 June 2003; received in revised form 1 October 2003; accepted 11 November 2003

Abstract Chinese differs from Indo–European languages in both its written and spoken forms. Being a tonal language, tones convey lexically meaningful information. The current study examines patterns of neurophysiological activity in temporal and temporoparietal brain areas as speakers of two Indo–European languages (Spanish and English) and speakers of Mandarin–Chinese were engaged in a spoken-word recognition task that is used clinically for the presurgical determination of hemispheric dominace for receptive language functions. Brain magnetic activation profiles were obtained from 92 healthy adult volunteers: 30 monolingual native speakers of Mandarin–Chinese, 20 Spanish-speaking, and 42 native speakers of American English. Activation scans were acquired in two different whole-head MEG systems using identical testing methods. Results indicate that (a) the degree of hemispheric asymmetry in the duration of neurophysiological activity in temporal and temporoparietal regions was reduced in the Chinese group, (b) the proportion of individuals who showed bilaterally symmetric activation was significantly higher in this group, and (c) group differences in functional hemispheric asymmetry were first noted after the initial sensory processing of the word stimuli. Furthermore, group differences in the degree of hemispheric asymmetry were primarily due to greater degree of activation in the right temporoparietal region in the Chinese group, suggesting increased participation of this region in the spoken word recognition in Mandarin–Chinese. © 2004 Elsevier Ltd. All rights reserved. Keywords: Magnetoencephalography; Temporal lobe; Laterality; Chinese; Functional brain imaging; Language

1. Introduction There is a wealth of data (Breier et al., 2001), cortical stimulation (Ojemann, 1993), and non-invasive functional brain imaging studies (Binder et al., 1997; Maestu et al., 2002; Papanicolaou et al., 1999) regarding the cortical mechanisms that support receptive language functions in native speakers of Indo–European languages (Simos et al., 2001). Little is known, however, about the lateralization of brain mechanisms involved in linguistic processing in the context of other language groups, with distinct features in both their written or spoken forms, like the Chinese. The prosodic features (mainly variations in the fundamental frequency, or tone, over the course of a single word) of ∗ Corresponding author. Tel.: +34-91-394-22-92; fax: +34-91-394-22-94. E-mail address: [email protected] (T.M. Ortiz).

0028-3932/$ – see front matter © 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.neuropsychologia.2003.11.019

Mandarin Chinese are used to distinguish among words that are—otherwise—phonologically identical. In addition to being a tonal language, Mandarin Chinese operates with special prosodic rules that influence the processing strategies of the listener. Since in Chinese, unlike in Indo–European languages, tones convey lexically meaningful information, native speakers of tone languages may process combinations of segmental (i.e. syllabic) and supra-segmental (i.e. prosodic) information differently (Lee & Nusbaum, 1993). The presence of fundamentally distinct features in Mandarin Chinese raise the question of whether the cerebral mechanisms involved in language functions in native Chinese speakers are different from those used by speakers of non-tonal languages. One such obvious difference may involve increased participation of the right-hemisphere (RH). Early studies, reported single cases of aphasia after right cerebral infarction (April & Han, 1980; April & Tse, 1977), hinting for a higher incidence of right-hemisphere

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involvement in language functions among members of the Han group, which represents the majority of people in China (Hu et al., 1990). Along the same lines is evidence from a larger study with 309 Chinese who suffered a leftor right-hemisphere (RH) cerebral infarction. Ninety-seven percent of these patients developed aphasia after a left cerebral damage and only 3% developed aphasia after a right-hemisphere infarction (Wang, 1996). A closer look at the data, however, reveals that the proportion of patients who did not develop aphasia after left-hemisphere stroke was comparable to the proportion of patients who did not develop aphasia after right-hemisphere stroke (23% versus 27%, respectively). Brain imaging studies with bilingual Chinese volunteers have shown greater activity in the left inferior and middle frontal areas in both English and Chinese languages, failing to find differences in the cortical representation of each language (Klein et al., 1999; Pu et al., 2001). Findings suggest that all linguistic information signaled by prosodic cues engages left-hemisphere circuits (Hsieh et al., 2001). In a PET study, Mandarin- and English-speaking subjects showed common regions of increase in blood flow, but only Mandarin speakers showed additional activation in frontal, parietal, and parieto-occipital regions of the left-hemisphere (LH). In contrast, only the English-speaking group showed activity in the right inferior frontal cortex, consistent with greater right-hemisphere involvement in pitch perception (Klein et al., 2001). Mandarin tones appear to be predominantly processed in the left-hemisphere by native Mandarin speakers, whereas they are bilaterally processed by American English speakers with no prior tone experience (Wang et al., 2001). There have been no studies, however, specifically addressing the issue of hemispheric dominance for receptive language functions in Chinese. Functional imaging methods have a number of advantages over traditional tools in neuropsychology: they are non-invasive, they afford a greater spatial scope, and can be repeated to establish reliability. Nevertheless, they are capable only of pointing to the brain regions involved in a particular function, rather than those areas necessary for that function. This inherent uncertainty in interpreting imaging data can be partially alleviated by using activation and data reduction protocols, the concurrent validity of which has been established through direct comparisons with the results of invasive techniques considered as the “Gold Standards” in the field. One of the modern functional brain imaging techniques for which there is ample validity confirmation is magnetoencephalography (MEG) (Papanicolaou et al., 1999). MEG is based on recordings of magnetic flux produced by intracellular currents in neuronal populations that show increased levels of signaling, time-locked to the presentation of an external stimulus. In addition to providing a more direct measure of neuronal signaling, MEG-derived activation profiles provide information regarding locally elevated levels of neuronal activity in real time. The reliability and validity of a MEG testing and data

reduction protocol for determining hemispheric dominance for language has been established empirically in a series of normative studies involving English speakers (Breier et al., 1999; Simos et al., 1998). Subsequently, the concurrent validity of this protocol for determining hemispheric dominance for receptive language functions has been established for native English and Spanish speakers in comparison with the results of the Wada test (Breier et al., 2001; Maestu et al., 2002) or the results of direct cortical stimulation mapping (Papanicolaou et al., 1999; Simos et al., 1999). The MEG activation protocol for which sufficient validity and reliability data exist, consists of a simple word recognition task. The activation profiles obtained in the context of this task feature initial activation of the primary auditory cortex, bilaterally, within 200 ms after stimulus onset, followed by activity in auditory association areas in the superior and middle temporal gyri, and also in mesial temporal cortex. The degree of activity in non-primary sensory cortex is strongly lateralized to the left-hemisphere in the great majority of right-handed, healthy participants. In addition to providing quantitative information regarding the degree of laterality in regional brain activation during spoken language processing, a judgment can be made regarding hemispheric dominance for this function on a case by case basis. Thus the proportion of individuals classified in each hemispheric dominance subgroup group (left- or right-hemisphere dominance or bi-hemispheric representation of language functions) can be estimated. In the present study, we used the Chinese version of this task to gain a better understanding of the brain mechanisms supporting auditory comprehension functions in native speakers of Mandarin–Chinese. Specifically, we examined language-specific differences in (a) the degree of hemispheric asymmetry in brain activity within each group and (b) the distribution of individual participants with respect to hemispheric dominance subgroups.

2. Subjects and methods 2.1. Subjects Brain activation profiles were obtained from the following groups of neurologically intact volunteers, using identical protocols: 30 monolingual native speakers of Mandarin–Chinese (16 men and 14 women, age range: 14–45 years, mean: 30 years), 20 Spanish-speaking (10 men and 10 women, age range: 21–36 years, mean: 28 years), and 42 native speakers of American English (21 men and 21 women, age range: 21–50 years, mean: 31 years). Participants had no history of psychiatric disorder, hearing impairment, or learning disability. All participants were right-handed based on a score of 0.40 or greater on the Edinburgh Handedness Inventory and all signed a consent form after the nature of the procedures involved had been explained to them.

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Table 1 Participant’s linguistic background Participants’ native language Spanish Formal training in second language (years) (mean, S.D., range) Everyday exposure/use of second language (years)

English

(0.0)a

Chinese 0–6b

6.0 0.3 (0.2) 0–0.5

2.7 (1.0) 1–5c 1.4 (1.3) 0–4

2.1 (1.5) 1.9 (1.3) 1–3d

a

The National Educational System in Spain offers a course in a foreign language (typically English or French) throughout Middle and High School. The course usually consists of two teaching hours per week during the school year and provides only rudimentary knowledge of a second language. b Nearly all participants (40/42) had Spanish as a second language. French was the second language in the remaining two participants. c All participants tested at the Houston site had English as their second language. Participants in Madrid were prospective students at Complutense University and did not have any formal training in a second language at the time of their testing. d Typically, occasional use in the course of daily transactions with the community’s large Hispanic population.

In order to establish the generalizability of the results activation scans were acquired in two different whole-head MEG systems using identical testing protocols: a system equipped with first-order gradiometer sensors (WH3600 scanner; n = 14 Chinese and n = 14 English speakers) and a second system equipped with magnetometer sensors in Houston, Texas (WH2500 scanner; n = 28 English speakers) and finally a system equipped with magnetometer sensors in Madrid, Spain (WH2500 scanner; n = 16 Chinese and n = 20 Spanish speakers). A summary of the linguistic background for each group of participants is presented in Table 1. 2.2. Procedures 2.2.1. Stimuli and task A detailed account of the assumptions that underlie the MEG procedures for receptive language mapping can be found in previous reports (9, 28,20) and will be briefly summarized here. Language-specific brain activity was elicited using an auditory word recognition task. A list of 63 abstract Chinese–Mandarin, English, or Spanish words were recorded by a native (male) speaker of Chinese–Mandarin, English, or Spanish, respectively, with a flat intonation and stored on a Macintosh G4 computer. A continuous word recognition task was constructed using each list using Superlab Pro as follows: word stimuli were arranged in three lists of 43 words: 33 “target” words that were the same in all three lists, and 10 distractors that were unique in each list, for a total 129 auditory events. Prior to the onset of the recording session, participants were presented with the list of targets (at the same rate as during the recognition phase) and were asked to pay attention to the stimuli in order to be able to recognize them later. A second sequence of 129 events was also created, using the same targets, in different random ordering in each block, and a different set of distractors, permitting replication of the task in the same participant. The recorded words were presented binaurally via two 5 m long plastic tubes terminating in ear inserts. The intensity was set at 80 dB sound pressure level measured at the participant’s outer ear. The subjects were then asked to lift their right index finger whenever they recog-

nize a target word (i.e. a word repeated in all three lists) (Table 2). 2.3. MEG recording and analyses 2.3.1. MEG signal processing In all three systems the neuromagnetometer device was manufactured by 4D Neuroimaging, San Diego, CA. and was housed in a magnetically shielded room designed to reduce environmental magnetic noise that might interfere with biological signals. The typical recording session requires the participant to lie motionless on a bed with their head inside the helmet-like magnetometer for approximately 10 min. The signal was filtered online with a band pass between 0.1 and 50 Hz, digitized for 950 ms (254 Hz sampling rate) including a 150 ms pre-stimulus period, and subjected to an adaptive filtering procedure that is part of the 4D Neuroimaging signal analysis package. These steps are necessary to minimize the amount of low frequency magnetic noise that is typically present in MEG recordings. The single trial event-related field records (ERFs) elicited by target stimuli were then averaged together after removing those during which an eye movement or blink had occurred (as indicated by a peak to peak amplitude in the electro-oculogram channel in excess of 50 ␮V). A minimum of 80 ERF epochs were collected to calculate each averaged waveform. Finally, the averaged epochs were digitally filtered with a low pass 20 Hz filter.

Table 2 Stimulus characteristics Spanish Frequency Number of syllables Duration Concreteness a

English (3.07)a

5.39 2.50 (0.70) 450 ms (6.4) <4.0c

Chinese (2.5)b

4.8 – 3.1 (0.6) 1.9 (0.1) 450 ms (10.4) 520 ms (0.33) <3.0d –

Occurrences per million (Algarabel, 1996). Occurrences per million (Kucera & Francis, 1967). c Based on Nacher’s concreteness scale (N´ acher et al., 1998). d Based on Paivio’s concreteness scale (Paivio, Yuille, & Madigan, 1969). b

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2.3.2. MEG-based measures of regional activation The intracranial generators of the observed ERFs (henceforth referred to as “activity sources”) were modeled as single equivalent current dipoles and fitted at successive 4 ms intervals by using the non-linear Levenberg–Marquardt algorithm. For a given point in time, the source fitting algorithm was applied to the magnetic flux measurements obtained from a group of 34–38 sensors, always including both magnetic flux extremes. Source computation was restricted to latency periods during which a single pair of magnetic flux extremes dominated the left and/or the right half of the head surface. The algorithm used in this study searched for the source that was most likely to have produced the observed magnetic field distribution at a given point in time. Source solutions were considered satisfactory after meeting two criteria: (1) a correlation coefficient of at least 0.9 between the observed and the “best” predicted magnetic field distribution, and (2) a goodness of fit of at least 0.9 or higher. Satisfactory source solutions can be described on the basis of four complementary measures: (a) location (i.e., coordinates on the MEG Cartesian coordinate system defined by the ear canals and the nasion), (b) estimated current moment of the net neuronal population response (in nano-Amperes per meter (nA/m)), (c) global field power or root mean square (RMS) of the measured magnetic flux used to calculate the corresponding activity source (in femtoTesla (fT)), and (d) latency or delay after stimulus onset at which point a given source is estimated (in milliseconds (ms)). In our previous studies with health volunteers and patients, the metric that produced the most conclusive results as an index of the degree of regional activation was the total number of successive activity sources in a particular area or group of areas (Breier et al., 1999, 2001; Maestu et al., 2002). In principle, this metric reflects the amount of time (in milliseconds) during which dipolar neurophysiological activity is present in a particular brain region. The potential utility of information regarding the strength of each activity source (both with respect to the intracranial electrical current and the ensuing magnetic flux recorded at the head surface) was also considered in the present study when appropriate (specified in more detail in the following paragraphs). In order to determine the anatomical regions corresponding to each activity source, source locations, which were initially computed in reference to the MEG Cartesian coordinate system mentioned above, were coregistered on T1-weighted, magnetic resonance (MR) images (TR 13.6 ms; TE 4.8 ms; recording matrix 256 × 256 pixels, 1 excitation, 240 mm field of view, and 1.4 mm slice thickness) obtained from each participant. Transformation of the MEG coordinate system into MRI-defined space was achieved with the aid of three lipid capsules inserted into the ear canals and attached to the nasion which could be easily visualized on the MRIs, using the STAR software which is part of the 4D Neuroimaging software. As in our previous studies using the English and Spanish versions of this task, activity sources were found in all

participants in the posterior third of the superior temporal gyrus which includes cortex in and around Heschl’s gyrus, extending posteriorly into the superior temporal plane and the supramarginal gyrus and ventrally into the superior temporal sulcus. In the left-hemisphere, this extended region encompasses Wernicke’s area and will henceforth be referred to as area Tmp. Activity sources were also found in the posterior third of the middle temporal gyrus and the underlying mesial temporal cortex (hippocampus and parahippocampal gyrus) in 97% of the brains studied (labeled Mtg). Finally activity sources in the vicinity of Broca’s area (including premotor cortex) were found in 70% of the brains studied (labeled Ifg). Regions of interest were defined empirically as those brain areas where activity sources were found in a significant majority (P < 0.01 binomial distribution) of hemispheres for each group, i.e. in 21/30, 28/41, and 15/20 hemispheres in the Chinese, English, and Spanish groups. 2.3.3. Statistical analyses of MEG data Three sets of analyses were performed. First, statistical analyses were performed on the number of successive activity sources localized in perisylvian regions (Tmp, Mtg, and Ifg regions) during the late portion of the ERF record (i.e. between approximately 200 and 800 ms after stimulus onset). In previous studies that directly compared MEG-derived activation maps with the results of the Wada test, this measure showed the highest concordance with the Wada (Breier et al., 1999, 2001; Maestu et al., 2002). The selected time window extended from the offset of the N1m response (at ∼200 ms after stimulus onset), which is accounted for primarily by activity in and around Heschl’s gyrus, to the end of the recorded segment of magnetic flux (800 ms after stimulus onset). The rationale for this selection was that early components of the ERF reflect activity in primary auditory cortices, which is typically bilaterally symmetric. In contrast, late components account for activity in nearby association cortices, and show consistent inter-hemispheric asymmetries, reflecting the dominant role of one hemisphere (usually the left) for language functions (Papanicolaou et al., 1999). Using this metric we computed a laterality index (LI) for each participant and brain region based on the following formula: (LH − RH)/(LH + RH), where LH represents the number of activity sources in the left-hemisphere and RH the number of activity sources in the right-hemisphere. The second set of analyses examined time-dependent changes in regional activation as measured by the total number of activity sources in perisylvian regions. These were assessed by dividing the entire post-stimulus ERF record of 800 ms into three different time windows: the first between ∼40 and ∼200 ms, the second between ∼200 and 400 ms, and the third between 400 and 800 ms after stimulus onset. Given that the average reaction time to comparable word recognition tasks is approximately 600 ms (a delay that includes the time necessary for preparation of the manual response and conduction of the efferent neural signal to the hand muscles), the first two intervals correspond roughly

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to the pre-recognition phase of stimulus processing. As the first window represented neurophysiological activity that took place in the vicinity of the primary auditory cortex, bilaterally, it was activity in the second window that was more likely to reflect activity associated with linguistic processing of the word stimuli that preceded recognition. Evidence from ERP and MEG studies suggests that cortical activity associated with the detection of lexical/semantic anomalies (an indication that lexical/semantic access is under way) is first evident around 200 ms after the onset of spoken word stimuli (e.g., Halgren et al., 2002; Helenius et al., 2002; Van Petten et al., 1999). The later window reflects neurophysiological activity that takes place in the post-recognition phase. Additional tests were performed on the RMS of magnetic flux sampled at the N1m peak, and the current dipole moment (Q) associated with the activity source accounting for the N1m peak. The purpose of these analyses was to ascertain that hemispheric asymmetries observed during processing of each word stimulus were not caused by systematic asymmetries in the initial response of the auditory cortex to the stimuli. The third set of analyses addressed the issue of nonsystematic variance in the precise spatial extent of activation profiles, a problem that is common to all functional imaging methods. The data for these analyses were collected at the Houston site using a higher-density neuromagnetometer equipped with gradiometer sensors. This system features drastically improved signal-to-noise ratio and affords the recording of complete event-related field data sets based on as few as 20 single-trial magnetic flux recordings (as compared to over 80 ERF data segments required with older systems). Taking advantage of this technical improvement, we constructed four whole-brain activation profiles for each subject. These profiles, which represented successive replications of the same task and consisted of late activity sources (>200 ms post-stimulus onset) for reasons explained above, were then compared within individuals and any sources that were not repeatably observed in all four scans were eliminated. Reliable sources were defined as those that occurred within a spherical volume of 1 cm from each other with a latency difference of less than 50 ms. This approach results in a discreet area of activation, which invariably includes the posterior portion of the left superior temporal gyrus in left-hemisphere dominant subjects and patients (Simos et al., 1998). We have shown that electrical stimulation of this region selectively produces transient deficits in receptive language functions and can be used to identify the location and extent of Wernicke’s area in surgical patients (Simos et al., 1999). Four measures, computed across the four replication data sets, were used to describe activity in this area: (a) the mean number activity sources for the entire duration of detectable activity in this region, (b) the mean root-mean-square (RMS or global field power) of the magnetic flux across all time slices when satisfactory activity sources were computed, (c) the mean current dipole moment (Q) for the same set of sources,

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and finally (d) the mean onset latency of activity in this region. All follow up tests were examined against critical P-values adjusted using the Bonferoni method to maintain family-wise Type I error at <0.05. Type of scanner (magnetometer or gradiometer) was entered in the ANOVA models as a covariate to ensure that language group effects on hemispheric asymmetries of activation were not due to the fact that subgroups of subjects were tested in different MEG systems.

3. Results Visual inspection of individual activation profiles (see Fig. 1) clearly indicated differences among the language groups: although the great majority of native speakers of Spanish and English showed the expected pattern of left-hemisphere predominant perisylvian activity, the majority of native Chinese speakers showed little or no hemispheric asymmetry in the degree of perisylvian activity. These trends were explored in more detail in the context of the three sets of analyses the rationale for which was explained in Section 2. 3.1. Laterality profiles regardless of latency Mean laterality indices for each group are shown in Fig. 2, which also plots the distribution of individual scores. In view of the fact that data were collected at different sites, with different systems, it was crucial to ensure that no difference due to extra-experimental factors—better yet factors irrelevant to the purpose of the study—interfered with the procedure. For this purpose, an ANCOVA with group (Spanish, English, Chinese) as the between subjects variable and type of scanner (magnetometer or gradiometer) as a covariate was performed on the LI values computed for the number of activity sources in the entire perisylvian region (Tmp, Mtg, and Ifg combined). This test revealed a main effect of group, F(2, 88) = 38.43, P < 0.00001, and pairwise comparisons confirmed the impression that Chinese speakers showed significantly less positive (or more negative) LI scores than both the Spanish, t(48) = 9.19, P < 0.0001 and English-speaking participants, t(70) = 7.30, P < 0.0001, which were not significantly different from each other (P > 0.05). In our previous studies with English- and Spanishspeaking patients, adopting a cutoff LI value of 0.25 was associated with the highest concordance with judgments of hemispheric dominance derived from the Wada test. Adopting the same criterion, the proportions of participants who would be classified as left-hemisphere dominant for language were: 100% for the Spanish, 80% (20% bilateral) for the English, and 14% (7% RH “dominant” and 79% bilateral) for the Chinese group. The proportion of Chinese speakers with significant left-leaning asymmetries was different than the corresponding proportions in

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Fig. 1. Typical activation profiles from a Chinese- (left column), an English- (middle column), and a Spanish-speaking participant (right-hand column). Each series of coronal MRI slices displays a complete set of activity sources computed after the initial sensory activation (>200 ms post-stimulus onset).

the English (Mann–Whitney U = 5.31, P < 0.0001) and Spanish groups (Mann–Whitney U = 5.94, P < 0.00001). Adopting a less stringent criterion of 0.0 on the LI metric, corresponding rates for left-hemisphere dominant individuals were: 100, 100, and 65% (7% bilateral and 29% RH “dominant”) (Mann–Whitney U = 4.68, P < 0.0001 for English versus Chinese and Mann–Whitney U = 3.39, P < 0.0001 for Spanish versus Chinese). Next, we examined group differences in the degree of hemispheric asymmetry for specific perisylvian regions. An ANOVA performed on LI scores with group as the

between subjects factor and area (Tmp, Mtg, Ifg) as the within-subjects factor showed a group by area interaction, F(4, 178) = 4.96, P < 0.001. Follow-up one-way ANOVAs showed group simple main effects for activity sources in Tmp, F(2, 89) = 31.55, P < 0.00001 and Mtg, F(2, 38) = 28.61, P < 0.00001. Fig. 3 indicates greater left-leaning asymmetries between the Chinese and both the Spanish and English groups with respect to the degree of activity in Tmp, t(48) = 7.29, P < 0.0001 (Chinese versus Spanish) and t(70) = 6.76, P < 0.0001 (Chinese versus English). However, only the Spanish group was different from the

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tivity sources in Tmp and Mtg, combined (activity sources during the early time window were restricted to these regions). The test revealed a Time by group interaction, F(4, 168) = 9.02, P < 0.000001. Follow up univariate ANCOVAs revealed that group differences were restricted to the middle, F(2, 82) = 8.31, P < 0.0005, and last latency windows, F(2, 82) = 20.89, P < 0.0000001, which are clearly evident in Fig. 4 (all subsequent tests were evaluated at alpha = 0.05/12 = 0.004). The degree of hemispheric asymmetry was significantly lower in the Chinese than both the Spanish, t(48) = 4.17, P < 0.0001, and English groups, t(70) = 3.88, P < 0.0002, during the middle window, and again during the late window, t(48) = 6.20, P < 0.0000001,

Fig. 2. Top: Laterality indices (LIs) for late activity sources in perisylvian regions (superior, middle temporal, supramarginal, and inferior frontal gyri). Significant group differences (P < 0.0001) are indicated with symbols (“*” or “ˆ”) and vertical bars represent 95% confidence intervals. Bottom: The distribution of individual LIs in each language group. Positive values indicated left-leaning hemisphere asymmetries and negative values indicate greater number of activity sources in the right over the left perisylvian region.

Chinese group on the degree of activity in Mtg, t(48) = 5.14, P < 0.0001. Next, we examined whether the effects described above were specific to particular time windows of the event-related magnetic response waveform. 3.2. Latency-dependent laterality profiles To examine if group differences in hemispheric asymmetries in activation were time-dependent, an ANCOVA with group (Spanish, English, Chinese) as the between subjects variable, Time Window (∼40–200, 200–400, and 400–800 ms) as the within-subjects factor, and type of scanner (magnetometer or gradiometer) as a covariate was performed on the LI values computed for the number of ac-

Fig. 3. Laterality Indices for late activity sources in the posterior portion of the superior temporal gyrus and adjacent supramarginal gyrus (top) and the posterior portion of the middle temporal gyrus and underlying mesial temporal cortex (bottom). Significant group differences (P < 0.0001) are indicated with symbols (“*” or “ˆ”) and vertical bars represent 95% confidence intervals.

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Fig. 4. Hemispheric asymmetries in the number of activity sources in Tmp and Mtg computed during three consecutive time windows: an early window (∼40–200 ms after stimulus onset, representing primarily activity in the vicinity of primary auditory cortices), and two late windows (200–400 ms and 400–800 ms after stimulus onset), reflecting activity in auditory association cortices.

and t(70) = 5.12, P < 0.000003, respectively. Examining Time Window effects for each group, we found main effects for the Spanish, F(2, 38) = 51.41, P < 0.000000001, and English groups, F(2, 82) = 27.97, P < 0.000000001, but not for the Chinese group (P > 0.7). The degree of hemispheric asymmetry in Tmp and Mtg activity increased between the early and middle windows for both the Spanish, t(19) = 6.61, P < 0.000002, and English groups, t(42) = 5.25, P < 0.000005. On average LI scores showed a further increase through the last time window (see Fig. 4), for the English and Spanish groups, but this trend did not reach statistical significance. Finally, a MANOVA performed on LI values computed on two additional measures of the degree of early activity (i.e., peak RMS and Q of the N1m response measured between ∼40 and 200 ms after stimulus onset) did not reveal significant effects involving group (P > 0.1). Consistent with this finding was the fact that these measures of early cortical activity were poor predictors of hemispheric asymmetries involving the number of late activity sources, R2 = 0.003, P > 0.9. Visual inspection of the brain activation profiles indicated that the distinguishing feature of the activation profiles of Chinese speakers was greater degree of late activity (i.e. after ∼200 ms post-stimulus onset) in the right posterior superior temporal and temporoparietal region. To examine this issue we performed an ANCOVA with group as the between subjects factor, hemisphere (left, right), area (Tmp, Mtg, Ifg), and time window (200–400, 400–800 ms) as the within-subjects factors, and type of scanner (magnetometer, gradiometer) as a covariate. The test revealed an area by hemisphere by group interaction, F(4, 176) = 5.74, P < 0.0001. Follow up tests (evaluated with alpha set at

0.05/6 = 0.0083), revealed simple main group effects for the left Tmp, F(2, 61) = 12.14, P < 0.00004, left Mtg, F(2, 61) = 7.38, P < 0.001, and right Tmp, F(2, 61) = 5.38, P < 0.007, for the data collected with magnetometer systems, and the right Tmp, F(1, 26) = 8.12, P < 0.008, for the data collected with the gradiometer system. Pairwise comparisons (adjusted for inequality of group variances when necessary) indicated greater left Tmp activity in the English as compared to the Chinese, t(37, 39) = 4.49, P < 0.00006, and even the Spanish group, t(36.26) = 4.02, P < 0.0003, Greater activity in the left Mtg was found in the Spanish as compared to the Chinese group, t(34) = 3.98, P < 0.0004, whereas the converse was true for activity in the right Mtg, t(34) = 3.22, P < 0.003 (Chinese > Spanish). Finally, degree of activity in the right Tmp region was greater in the Chinese as compared to the English group on both systems, but attained statistical significance only in the data from the gradiometer system, F(1, 26) = 8.12, P < 0.008 (see Fig. 5). 3.3. Laterality profiles for activity in the vicinity of Wernicke’s area As explained in Section 2, data sets from each of the subjects scanned in the high-density gradiometer system at the Houston site, were split into four segments, enabling construction of an equal number of whole-brain activation profiles for each of the 28 subjects (14 Chinese and 14 English speakers). Applying a spatiotemporal clustering approach to each set of eight maps (one for each hemisphere and replication of the task) resulted in clusters of activity sources that were consistently observed over time in the same anatomical location and at the same latency (with a 1 cm and 50 ms tolerance limits, respectively). Representative activation profiles are shown in Fig. 6. Four measures were extracted from each cluster for each subject (number of activity sources, mean RMS, mean Q, and onset latency), and entered into a MANOVA with hemisphere as the within-subjects variable and group (English-speaking versus Chinese-speaking) as the between-subjects variable. The analysis revealed a main effect of hemisphere for Q (LH > RH), F(1, 26) = 9.00, P < 0.006, and a hemisphere by group interaction for the number of activity sources, F(1, 26) = 4.60, P < 0.041. The latter was due to a simple main effect of hemisphere (LH > RH) for the English-speaking group, F(1, 13) = 49.08, P < 0.00001. The hemisphere effect did not reach statistical significance for the Chinese-speaking group (P > 0.9). A laterality index was then computed for the number of activity sources, mean RMS, and mean Q (using the formula described in Section 2), whereas a simple left–right difference was computed on latency. The four measures were then entered into a MANOVA with group as the between-subjects variable, which revealed a main effect for the total number of activity sources, F(1, 26) = 13.29, P < 0.001. The results indicate that group differences in the degree of LH-predominant asymmetries held only for

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Fig. 5. Plots of the degree of activity (expressed by the number of late activity sources) in each brain area. Significant group differences are indicated with symbols (“*” or “ˆ”) and vertical bars represent standard error.

Fig. 6. Regions that show reproducible neurophysiological activity in a representative Chinese (left) and English-speaking participant (right). Clusters of late activity sources (>200 ms after stimulus onset) that correspond to a single replication of the activation task (see Section 2) appear in the same color (green, yellow, red, or blue).

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Fig. 7. Hemisphere asymmetries in activity in temporoparietal regions indexed by four complementary measures (standard error values in vertical bars). ∗∗ P < 0.001, ∗ P < 0.05.

the number of activity sources (or duration of activity) in Wernicke’s area. The proportions of participants who would be classified as left-hemisphere dominant for language using the +0.25 LI cutoff for the number of activity sources were 80% for the English and 21% for the Chinese group (0.7% RH “dominant” and 78% bilateral), Mann–Whitney U = 2.97, P < 0.009. The group difference retained statistical significance even when the less stringent criterion of 0.0 on the LI scale was adopted. In this case corresponding estimated rates for left-hemisphere dominant individuals were: 86% (0.07% bilateral, and 14% RH “dominant” for the English) and 43% (21% bilateral, and 36% RH “dominant” for the Chinese), Mann–Whitney U = 2.78, P < 0.024. Partial correlation coefficients between corresponding measures of early activity in primary auditory cortex and late activity in the vicinity of Wernicke’s area were also non-significant (P > 0.2) ranging between 0.26 and 0.19. These results corroborate earlier findings that hemispheric asymmetries in association cortex activity cannot be ac-

counted for by hemispheric differences in the initial cortical response to the spoken word stimuli (Fig. 7).

4. Discussion Our results show notable differences between speakers of two Indo–European languages (English and Spanish) and native speakers of Mandarin–Chinese in the activation profiles associated with performance of a simple spoken-word processing task. While Spanish and English speakers showed a strong lateralization of activity sources to the left-hemisphere, the Chinese showed greater individual variability in the degree and direction of hemispheric asymmetries, so that a bilaterally symmetric profile emerged in the group data. Interestingly, the atypical activation profile displayed by the Chinese speakers was more prominent when the duration of regional activity (or number of successive activity sources) in temporoparietal cortices was examined. This measure has been validated in functional

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imaging studies using MEG through direct comparisons with the Wada procedure in both Spanish and English speakers, and via direct comparison with electrocortical stimulation mapping in English-speaking patients (Breier et al., 2001; Maestu et al., 2002; Papanicolaou et al., 1999; Simos et al., 1999). Complementary measures of the degree of regional activation, indicating the net magnetic flux recorded at the surface of the head (RMS) and the estimated strength of the electrical dipoles used to model successive sources of neurophysiological activity (Q), generally correlate with the number of activity sources, at least on a group basis. In the present study, however, there was a dissociation between duration and intensity measures of regional activity during processing of Mandarin–Chinese by native speakers of that language. Although, temporoparietal cortex in both hemispheres was engaged for approximately the same amount of time in response to each spoken word, the net neurophysiological activity in the left-hemisphere was stronger than activity in the right-hemisphere, suggesting recruitment of a larger neuronal population in the vicinity of Wernicke’s area. There is substantial evidence that cortex in the left temporoparietal region is intimately involved in the phonetic and phonological elaboration of speech in healthy individuals who are native English speakers. In a recent MEG study, for instance, strong hemispheric asymmetries in the number of activity sources in the posterior portion of the superior temporal gyrus, were observed during performance of a simple phonetic discrimination task (Papanicolaou et al., 2003). These asymmetries, which were observed consistently across participants, were significantly reduced during processing of non-speech sounds, regardless of whether the later were perceived in a speech-like manner, or not. These findings are in agreement with the results of lesion (Blumstein et al., 1977), electrocortical stimulation (Boatman et al., 1995) and other functional brain imaging studies, that utilize hemodynamic measures of regional activation (Binder et al., 2000; Burton et al., 2000; Vouloumanos et al., 2001). Temporoparietal cortex, which largely overlaps with Wernicke’s area may also be involved in accessing stored representations of spoken words (Wise et al., 2001). If the left temporoparietal region plays a crucial role in language-specific operations, what is known about the functional role of the right temporoparietal region? There is currently a growing body of evidence suggesting that this region plays a role in: (a) the perception of rapid changes in pitch (Zatorre, 1988, 2001; Zatorre et al., 1992; Johnsrude et al., 2000), (b) the perception of suprasegmental pitch variations, such as those conveying the emotional prosody (Blumstein & Cooper, 1974; Bryan, 1989; Dykstra et al., 1995; Lalande et al., 1992; Schirmer et al., 2001; Stiller et al., 1997; Van Lancker, 1980; Van Lancker & Sidtis, 1992; Weintraub et al., 1981), and (c) the perception of sound amplitude modulation (Clarke et al., 1996). Incidentally, Mandarin–Chinese, unlike in Indo–European languages, employs suprasegmen-

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tal pitch and amplitude variations, in the form of tones, to convey lexically meaningful information (Lee & Nusbaum, 1993; Whalen & Xu, 1992). In addition to the role of supra-segmental features for lexical discriminations, there are differences between Mandarin–Chinese and all other western languages in the use of phonetic cues. For instance, the voiced/voiceless distinction has little relevance, whereas aspiration plays an important role. Perceptual discriminations of voiced and voiceless consonants require efficient processing of rapidly changing spectral acoustic cues and appear to depend largely upon left-hemisphere circuits (Laguitton et al., 2000; Papanicolaou et al., 2003), whereas the perception of aspiration-related cues requires predominantly frequency distinctions, which appear to be mediated largely by right-hemisphere circuits (e.g., Zatorre et al., 1992). It should be noted that hemodynamic brain imaging techniques cannot capture systematic variations in the temporal course of regional activity in the sub-second range such as those revealed in the present study. Assuming that the brain circuits specialized for complex auditory processing are similar, at least qualitatively, in native Chinese and English speakers, it is tempting to speculate that the prolonged participation of the right temporoparietal region in the former group reflects the engagement of neurophysiological processes that serve the analysis of lexical tones. Although the present study was not designed to isolate processes involved in phonological and lexical processes, both types of processes are regularly involved in the recognition of spoken words in Chinese. On the other hand, the finding of increased net electrical current, associated with neuronal signaling, in the left temporoparietal region is consistent with earlier reports of an increased hemodynamic response in left temporoparietal regions in Chinese volunteers during performance of a lexical tone discrimination task (Klein et al., 2001). Based on this and other functional imaging studies (e.g., Gandour et al., 2002), it was surmised that pitch patterns carrying a greater linguistic load (e.g. lexical tones) are processed predominantly by left-hemisphere cortical circuits, while those carrying less linguistic load (e.g. intonation patterns signaling affective mood or pitch patterns that occur in melodies) are processed predominantly by right-hemisphere circuits (Zatorre, 2001). Another pivotal issue that emerges from our results is whether the laterality profiles during single word processing in the Chinese group are valid indicators of corresponding patterns of hemispheric dominance for language functions. Results from both the Spanish and English groups are in close agreement with our expectations, based on prior knowledge, regarding the distribution of hemispheric asymmetries in the population and, also, on the results of previous studies using identical activation protocols in healthy volunteers and in patients where these same asymmetry estimates were directly compared with the results of the Wada test. In these groups, there was a consistent pattern of increased duration of activity in left-hemisphere temporoparietal regions as compared to homologous regions in the right-hemisphere,

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during late portions of the event-related magnetic response to spoken word stimuli (i.e. after 200 ms post-stimulus onset). Using similar criteria for classifying individual Chinese participants, the rate of atypical hemispheric dominance (i.e. the proportion of individuals who do not show clear left-hemisphere dominance) would be estimated to as high as 43%. Although there have been reports of crossed aphasia in Mandarin–Chinese, there is no evidence to suggest that the incidence of aphasia after right-hemisphere stroke is indeed higher. An alternative possibility would be that, simply, it is the rate of bi-hemispheric language representation that is higher in Chinese. This type of functional brain organization can be associated with two phenotypes: (a) presence of brain circuits in both hemispheres that are each specialized, and indispensable, for particular linguistic functions and (b) presence in both hemispheres of redundant circuits, capable of performing the same linguistic functions with similar degree of proficiency. The latter possibility implies that left-hemisphere cortical circuits are capable of supporting most, if not all, component processes necessary for spoken word recognition and comprehension, including both phonological and tonal aspects of this function. The obvious prediction stemming from the former hypothesis is that the incidence of crossed aphasia would be higher in this population, a conjecture that we discounted already. The prediction derived from the second hypothesis is that the incidence of aphasia following left-hemisphere stroke would be lower in the Chinese population as compared to Indo–European language groups. However, although some indications do exist in support of this prediction, they do not constitute strong evidence. For instance, the incidence of aphasia following right-hemisphere stroke in a relatively large sample of patients approached the proportion of patients who did develop aphasia after left-hemisphere stroke (Wang, 1996). A non-mutually exclusive alternative, that is supported by the dissociation between duration and intensity of activity measures reported here, is that the intensity and/or spatial spread of neurophysiological activity associated with spoken word processing in Chinese shows a left-hemisphere predominance, similar to that observed in speakers of Indo–European languages. Prolonged engagement of the right temporoparietal region simply reflects the need for processing of suprasegmental cues which, in the case of Chinese–Mandarin is crucial for word recognition. In conclusion, our results indicate an atypical pattern of regional cerebral activation associated with spoken word comprehension in this sample of Mandarin–Chinese speakers. This pattern consists of increased strength of neurophysiological activity in the left temporoparietal region which, however, follows a similar time course in both hemispheres. This is in sharp contrast with the increased strength and prolonged duration of neurophysiological activity found for English speakers. These findings indicate a fundamentally different organization of the brain mechanism that is involved in spoken word recognition in Chinese. The data underline the necessity for better controlled-functional

imaging studies, with adequate temporal resolution, performed in conjunction with invasive brain mapping methods such as the Wada test or intra-operative electrocortical stimulation. Moreover, it is important to assess other aspects of linguistic function, such as expressive language, in this population, and in parallel examine brain activation profiles in the context of tasks design to tap into specific components of speech processing that are unique to Mandarin–Chinese.

Acknowledgements This study was supported in part by NINDS grant NS37941 to A.C. Papanicolaou, NICHD grant HD30885 to P.G. Simos, and by a 4D Neuroimaging grant to C.E. Valaki.

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