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Human Brain Mapping 36:2580–2591 (2015)

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Effective Connectivity of Brain Regions Related to Visual Word Recognition: An fMRI Study of Chinese Reading Min Xu,1,2,3 Tianfu Wang,1,2 Siping Chen,1,2 Peter T. Fox,1,4,5* and Li Hai Tan1,2* 1

Department of Biomedical Engineering, School of Medicine, Shenzhen University, Shenzhen, China 2 Guangdong Key Laboratory of Biomedical Information Detection and Ultrasound Imaging, Shenzhen, China 3 School of Humanities, The University of Hong Kong, Pokfulam Road, Hong Kong 4 Research Imaging Institute, University of Texas Health Science Center at San Antonio, San Antonio, Texas 5 South Texas Veterans Health Care System, San Antonio, Texas r

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Abstract: Past neuroimaging studies have focused on identifying specialized functional brain systems for processing different components of reading, such as orthography, phonology, and semantics. More recently, a few experiments have been performed to look into the integration and interaction of distributed neural systems for visual word recognition, suggesting that lexical processing in alphabetic languages involves both ventral and dorsal neural pathways originating from the visual cortex. In the present functional magnetic resonance imaging study, we tested the multiple pathways model with Chinese character stimuli and examined how the neural systems interacted in reading Chinese. Using dynamic causal modeling, we demonstrated that visual word recognition in Chinese engages the ventral pathway from the visual cortex to the left ventral occipitotemporal cortex, but not the dorsal pathway from the visual cortex to the left parietal region. The ventral pathway, however, is linked to the superior parietal lobule and the left middle frontal gyrus (MFG) so that a dynamic neural network is formed, with information flowing from the visual cortex to the left ventral occipitotemporal cortex to the parietal lobule and then to the left MFG. The findings suggest that cortical dynamics is constrained by the differences in how visual orthographic C 2015 V symbols in writing systems are linked to spoken language. Hum Brain Mapp 36:2580–2591, 2015. Wiley Periodicals, Inc.

Key words: connectivity; functional magnetic resonance imaging; reading; Chinese reading; dynamic causal modeling; ventral pathway; dorsal pathway; writing systems r

Contract grant sponsor: National Strategic Basic Research Program (“973” Program) of the Ministry of Science and Technology of China; Contract grant number: 2012CB720701; Contract grant sponsor: National Natural Science Foundation of China; Contract grant number: 61372006. *Correspondence to: Li Hai Tan, Department of Biomedical Engineering, School of Medicine, Shenzhen University, Shenzhen 518060, China. E-mail: [email protected] or Peter T. Fox, 8407 C 2015 Wiley Periodicals, Inc. V

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Floyd Curl Dr., San Antonio, TX 78229, USA. E-mail: fox@ uthscsa.edu Received for publication 8 January 2015; Revised 10 March 2015; Accepted 11 March 2015. DOI: 10.1002/hbm.22792 Published online 18 March 2015 in Wiley Online Library (wileyonlinelibrary.com).

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Effective Connectivity of Brain Regions

INTRODUCTION Reading involves the associations of written symbols (i.e., orthography) with sounds (i.e., phonology) and meaningful concepts. Neurobiological models of reading have identified specialized brain regions for the processing of these linguistic components. The left occipitotemporal cortex (vOT) is known to be responsible for extracting visualorthographic information of printed words [Ben-Shachar et al., 2007; Cohen and Dehaene, 2004; Paulesu et al., 2000; Price, 2012; Schlaggar and McCandliss, 2007; Shaywitz et al., 2008; Wandell et al., 2012], while the left temporoparietal regions and the dorsal portion of left inferior frontal gyrus (IFG) are proposed to be involved in letter-sound transformation and phonological processing [Booth et al., 2002; Cohen et al., 2008; Eden et al., 2004; Gabrieli, 2009; He et al., 2013; Hoeft et al., 2006; Paulesu et al., 2000; Poldrack et al., 1999]. Processing of lexicosemantics encompasses a more widespread set of cortical sites, such as the ventral portion of the left IFG, the left anterior temporal cortex, and the posterior superior temporal region [Bookheimer, 2002; Devlin et al., 2003; Gabrieli et al., 1998; Katzev et al., 2013; Petersen et al., 1988; Poldrack et al., 1999; Richardson et al., 2011]. More recently, great emphasis has been placed on integration and interaction of distributed neural systems for complex brain functions and there has been a rapid growth of studies investigating the neural pathways for visual word recognition [Friston, 2011; Horwitz et al., 1998; Park and Friston, 2013; Price, 2012; Schlaggar and Church, 2009]. It is suggested that visual word processing in alphabetic languages involves both ventral and dorsal neural pathways originating from visual cortex [Booth et al., 2008; Carreiras et al., 2014; Levy et al., 2009; Price, 2012; Richardson et al., 2011; Seghier et al., 2012]. Using dynamic causal modeling (DCM), Richardson et al. [2011] found that during silent reading of English words and sentences, there were multiple routes from the left inferior occipital cortex (iO) to the left anterior superior temporal sulcus (aSTS), one via vOT and the other via the left posterior superior temporal sulcus (pSTS). Hypothetically, the iO!pSTS and vOT!pSTS connections are involved in linking orthography and phonology, the pSTS!aSTS connection is involved in linking phonology and semantics, and the iO!vOT!aSTS connection is involved in linking orthography and semantics. In a functional magnetic resonance imaging (fMRI) study, Levy et al. [2009] used a passive view paradigm with French words and conducted structural equation modeling analyses among four left-hemisphere regions, including middle occipital gyrus, posterior vOT, posterior parietal cortex, and IFG. They found that reading real words involved both a ventral pathway from the middle occipital gyrus to the posterior vOT and a dorsal pathway to the posterior parietal cortex. Using DCM and an English spelling task, Booth et al. [2008] showed multiple connections from visual cortex to higher-order language areas,

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including vOT, superior temporal gyrus, inferior parietal lobule, and IFG in the left hemisphere. Accumulating evidence has shown that reading of different orthographies places different weights on the ventral and dorsal systems [Duncan et al., 2013; Goswami, 2006; Paulesu et al., 2000; Price, 2012]. For example, in a study using positron emission tomography, Paulesu et al. [2000] compared brain activation in Italian and English readers during explicit (reading aloud words and nonwords) and implicit (feature detection task) reading tasks. They found that reading shallow orthographies such as Italian engaged the dorsal system (i.e., the left temporoparietal regions) to a greater extent, reflecting greater reliance on phonological analysis, while reading deep orthographies such as English recruited the ventral system (i.e., the left vOT) to a greater extent, which might reflect more reliance on retrieving phonology from the orthography of the whole word. In a recent fMRI study, Duncan et al. [2013] compared effective connectivity between lexical decision of Japanese Kanji and syllabographic Hiragana. They found that Kanji, a deeper orthography than Hiragana, increased bidirectional connections between primary visual cortex and left vOT, whereas reading Hiragana increased connection from left IFG to left inferior parietal cortex in the dorsal pathway, which was assumed to reflect a top-down modulation to guide processes of phonological assembly. Together, these findings suggest that reading deeper orthographies relies more on the ventral pathway, with less involvement of the dorsal pathway. Written Chinese is among extremely deep orthographies, and thus, it represents an important case for any attempts to test the multiple pathways model for visual word recognition. The Chinese logographic system maps graphic forms (characters) onto morphemes (meanings), rather than phonemes. Chinese characters are defined at the monosyllabic level, with no parts of a character corresponding to phonemes. Hence, there is no such rule as grapheme-to-phoneme correspondence rules in Chinese. Visually, Chinese characters are formed with intricate strokes filled in square configurations and the visual complexity increases as the stroke number increases, which is in sharp contrast to the linear structure of alphabetic words [Perfetti et al., 2005; Siok et al., 2004]. Neuroimaging studies have highlighted both similarities and differences in neural systems for reading Chinese and alphabetic languages [Cao et al., 2009; Chen et al., 2008; Ge et al., 2015; Hu et al., 2010; Liu et al., 2015; Perfetti and Tan, 2013; Schlaggar and McCandliss, 2007; Tan et al., 2003, 2005; Wu et al., 2012; Xue et al., 2006; Zhao et al., 2014; Zhang et al., 2014; Zhu et al., 2014]. For example, in a meta-analysis study, Tan et al. [2005] showed that phonological processing of Chinese and alphabetic languages shared the left ventral prefrontal system and the left vOT, whereas the left temporoparietal cortex uniquely contributed to the grapheme–phoneme conversions in alphabetic languages and the left middle frontal gyrus (MFG) is critically involved in Chinese reading. The left MFG is

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proposed to serve a crucial role in syllable-based phonological processing and the coordination of orthographic, phonological, and semantic information during Chinese reading [Kuo et al., 2001, 2003; Li et al., 2010; Perfetti et al., 2006; Siok et al., 2004, 2008; Tan et al., 2003, 2005; Wu et al., 2012; Zhu et al., 2014]. However, it remains largely unknown as to how the neural systems dynamically interact with one another to support Chinese reading, and whether the ventral and dorsal visual pathways are equally involved in printed word recognition in Chinese and alphabetic languages. In this fMRI study, we used DCM and family-level Bayesian model selection [BMS; Friston et al., 2003; Penny et al., 2010] to examine this question. Bayesian model averaging (BMA) was applied over the wining families of models to examine the effective connectivity among the key regions supporting Chinese reading. We used a phonological task and focused on the process of orthography–phonology mapping by varying the visual-orthographic complexity of Chinese characters, indexed by the number of strokes. There were behavioral studies showing an effect of stroke number in Chinese character recognition [Coney, 1998; Leong et al., 1987; Hsiao and Cheng, 2013; Yu and Cao, 1992]. We expected that in a phonology-related task, the “load” of mapping from orthography to phonology becomes heavier as the visual-orthographic complexity of Chinese characters increases, and this change should be reflected in the change of information flow from visual cortex to other brain regions for higher-order processing.

MATERIALS AND METHODS Subjects Eighteen healthy subjects (9 males) participated in our experiment. All were native Mandarin Chinese speakers and primarily familiar with simplified characters. One subject failed to complete the experiment and the data from this subject were excluded for further analyses. The remaining 17 subjects (9 males), ranging in age from 17 to 23 years (mean age 5 20.5 years, SD 5 1.28), were strongly right-handed, as assessed by the handedness inventory [Snyder and Harris, 1993], and had normal or corrected-tonormal vision. They were physically healthy and free of neurological disease, head injury and psychiatric disorder. Subjects were paid for their participation and gave informed consent prior to scanning.

Design and Materials The experimental task in the scanner was a phonologybased tone judgment task, in which the subjects were asked to decide whether or not a visually exposed character was pronounced as the 4th tone (i.e., the falling tone). We used a tone judgment task because tonal information is part of a phonological code [Spinks et al., 2000], and no

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component of the characters corresponds to a lexical tone. An arrow direction judgment task was used as a control task, in which subjects judged whether the direction of an arrow was upward or downward. A blocked design was used, with eight blocks of tone judgment (four blocks with characters of low number of strokes and four blocks with characters of high number of strokes) alternated with eight blocks of arrow judgment. Condition order was counterbalanced. Each experimental block consisted of a 2-second task instruction and 12 trials, and each arrow-direction judgment block consisted of a 2second task instruction and six trials. On each trial, a black stimulus (character or arrow) was displayed on the center of a white background for 1,000 ms, followed by a 1,000ms blank interval. For the tone judgment task, subjects were instructed to press the first button with the righthand index finger for positive response and press the second button with the right-hand thumb for negative response. For the arrow judgment task, they pressed the first button with the index finger for an upward arrow and pressed the second button with the thumb for a downward arrow. All subjects had some practice before scanning. During practice session, the subjects performed the tasks for at least 10 trials to ensure that they understood the task and performed well enough (no less than 90% accuracy). Chinese characters used in the practice session were different from those in the in-scanner task. The subjects were instructed to perform as quickly and accurately as possible. Chinese character as a salient visual unit is formed with intricate strokes filled in a square configuration. A stroke, either straight or curved, like “ ” and “ ,” is the smallest structural unit in the character A total of 96 characters were used in this study, including 48 characters of low number of strokes (8–10 strokes, mean 5 9.4, SD 5 0.74; e.g., , /chuan1/, meaning to pass through/to wear/to thread; , /pa4/, meaning to fear), and 48 characters of high number of strokes (12–17 strokes, mean 5 14.2, SD 5 1.27; e.g., , /xu1/, meaning to require/necessity/ need; , /yan2/, meaning color/countenance). The characters were either in top-down or left-right structure and the structures of characters were matched across conditions. All of the selected characters consisted of two components.

MRI Acquisition Experiment was performed on a 3 T Siemens MRI scanner, using a T2*-weighted gradient-echo echo plannar imaging (EPI) sequence (echo time [TE] 5 30 ms, repetition time [TR] 5 2 s, flip angle 5 90 , field of view 5 21 cm, slice thickness 5 4 mm, and the image matrix 5 64 3 64). Thirty axial slices were acquired to cover the whole brain. Visual stimuli were presented through a projector onto a translucent screen and subjects viewed the screen through a mirror attached to the head coil.

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fMRI Data Analysis Statistical Parametric Mapping software package (SPM8; http://www.fil.ion.ucl.ac.uk/spm/) was used for preprocessing and analysis of imaging data. Functional images were first slice timing corrected to correct differences in acquisition time between slices, and then realigned to remove movement artifact. No subject had >2 mm translation or >2 rotation. The images were then spatially normalized to an EPI template based on the the International Consortium for Brain Mapping (ICBM-152) stereotactic space. Voxels were resampled at a voxel size of 2 3 2 3 2 mm3. An isotropic Gaussican kernel (8 mm full width at half-maximum) was applied for spatial smoothing. Each time series was high-pass filtered with a cutoff period set at 128 s to remove low-frequency drifts. Realignment parameters were included in the first-level statistical model to regress out movement-related variance. Contrast images were generated for each subject and were then used to create group contrast images at the second level. Corrections for multiple comparisons across the whole brain were applied (P < 0.05, false discovery rate [FDR] corrected), with an extent threshold of 10 contiguous voxels. Brain regions are estimated from Talairach and Tournoux [1988], after adjustments for differences between MNI and Talariach coordinates with a nonlinear transform.

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connectivity induced by the experimental manipulations [Friston, 2011; Friston et al., 2003].

Extracting regional time series Subject-specific regions of interest (ROIs; 6-mm sphere) were defined as the local maxima of the contrast of tone judgment (collapsing high- and low-stroke conditions) > arrow judgment, with a liberal threshold of P < 0.05 uncorrected. To ensure that the functional regions were consistent across subjects, ROI selection was guided by group results. We first identified group peak voxel of the four ROIs based on group analyses and then extracted time series from each subject’s activation map at the closest maxima within a distance of 8 mm of the group peak voxel [for a similar rationale, see Leff et al., 2008; Seghier et al., 2011]. Because brain activation associated with our task was predominantly left lateralized, only lefthemisphere regions were included in the effective connectivity analyses. Four left-hemisphere regions were included, that is, left cuneus (mean coordinates: [217 290 5]), left vOT (mean coordinates: [241 255 214]), left superior parietal lobule (SPL, mean coordinates: [224 264 44]), and left MFG (mean coordinates: [247 12 35]). The mean coordinates of the four left-hemisphere regions are specified as MNI coordinates. The principle eigenvariate was extracted for each ROI and adjusted to the effect of interest.

Effective Connectivity Analyses Effective connectivity rests on models of the directed causal influence among regions [Friston, 2011]. We used DCM10, as implemented in SPM8, to explore effective connectivity. Different from other approaches, such as Granger causality and structural equation modeling, which operate at the level of the measured signals, DCM combines a neurobiological model of neural dynamics and a biophysical forward model that links neuronal activity to the measured signals [Friston et al., 2003; Stephan and Friston, 2010]. In DCM analyses, BMS tests a set of alternative models (or families of models) and identifies the most likely model given empirical data. The BMS procedure takes into account both model accuracy and model complexity to determine the best model and is not confounded by multiple comparisons [Penny et al., 2004]. Bayesian estimation is used to make inferences about the parameters, which are expressed as the rate or speed of change (in Hz) of activity in one region that is associated with activity in another. Three sets of parameters are estimated, including (1) input parameters that allow influence on specific regions by external stimuli (e.g., sensory stimulation); (2) the intrinsic parameters that describe couplings among regions and can be viewed as the “baseline” connectivity that is present in the system in the absence of external input; and (3) modulatory parameters that capture the changes in the

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The DCM model space and family comparisons The aim of our DCM analyses was to examine whether the ventral (cuneus!vOT), the dorsal pathways (cuneus!SPL), or both pathways were modulated by visual-orthographic load during orthography–phonology mapping. We performed two-step analyses. In the firststep analysis, we constructed models with the four lefthemispheric regions (i.e., cuneus, vOT, SPL, and MFG) and specified the left cuneus as a region receiving driving input. To keep a reasonable size for the model space and on the basis of previous studies [Duncan et al., 2013], direct connections between cuneus and frontal region were not included. Thus, there were 10 intrinsic connections in the models. The competing models varied as to which connections were modulated by visualorthographic load. We compared three families of models, which differed in whether the ventral pathway only, the dorsal pathway only, or both pathways were modulated by experimental manipulation (Fig. 3A). Each family contained 256 models (5 28) and thus resulted in 768 models in total. Family-level random-effect BMS was used to compare the three families [Penny et al., 2010]. Exceedance probability (xp), that is, the possibility one family being more likely than the other families to generate the observed data, was used to index the relative superiority of families.

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In the second-step connectivity analysis, we included only three left-hemispheric regions (i.e., vOT, SPL, and MFG) and tested whether the ventral (i.e., vOT) or the dorsal (i.e., SPL) neural system receive driving input. This analysis would help to further elucidate whether the ventral or the dorsal neural system or both of them would be involved in relaying information from early visual area and drive the connectivity within the network. We compared three families of models that differed in where the inputs enter the model, that is, the vOT only, the SPL only, or both vOT and SPL (Fig. 3B). The models contained six intrinsic connections that reciprocally connected the three ROIs. Each model contained one to six modulatory input on the connections, resulting in 63 possible models in each family. Therefore, a total of 189 models were specified for each subject. BMA within the wining family was used to make inferences on the connection parameters within the three-region models. BMA provides a weighted average of each parameter based on the posterior probability of each model, such that the model with the highest probability makes the greatest contribution to the estimates [Penny et al., 2010]. With the BMA procedure, 10,000 data points are sampled to generate posterior distribution for each parameter. Significance is assessed by the proportion of samples that are different from zero, with threshold set at 0.90 [for a similar procedure, see Lee and Noppeney, 2011; Richardson et al., 2011; Seghier et al., 2011].

essing of alphabetic words were not seen in our study, consistent with many of previous studies of Chinese reading [Booth et al., 2006; Dong et al., 2005; Siok et al., 2003, 2004, 2008; Tan et al., 2001]. Direct contrast between the high-stroke and low-stroke conditions found greater activation for characters with the high number of strokes in regions including bilateral middle frontal gyri (BA 9), left dorsal portion of IFG (BA 44/45), left cingulate gyrus (BA32), bilateral posterior parietal cortex (BA 7/40), bilateral fusiform gyri (BA37/ 18), and bilateral inferior/middle occipital areas (BA18/ 19) (Fig. 2 and Table II). Though many of these regions showed bilateral activation, they were activated more prominently in the left hemisphere. There was no greater activation for the low-stroke condition than the highstroke condition. We also conducted ROI analysis on six regions exhibiting significantly greater activation for the characters of the high number of strokes than the characters of the low number of strokes. Six sphere ROIs (8-mm radius) were defined, including bilateral vOT (coordinate: left [228 260 210]; right [36 276 210]), bilateral MFG (left [248 32 28]; right [40 12 32]) and bilateral SPL (left [220 260 48]; right [28 260 46]). Parameter estimates (beta values) were extracted for each subject from these regions. Figure 2B showed mean beta values for the high-stroke and the lowstroke conditions.

RESULTS

DCM Results

Behavior Results

In the first-step connectivity analysis, we used a family-level random-effect BMS procedure and compared three families of models, which differed in whether the ventral pathway only, the dorsal pathway only, or both pathways were modulated by visual-orthographic load during orthography–phonology mapping (Fig. 3A). We found that the family of models with modulation on the ventral pathway only (cuneus!vOT) showed overwhelming evidence (family xp 5 0.95) relative to the other two families. In the second-step family comparison, we constructed models with three left-hemispheric regions (i.e., vOT, SPL, and MFG) and compared three families of models that differed in whether inputs entered the model via the vOT only, the SPL only, or both (Fig. 3B). Results showed that driving input most likely entered via left vOT only, with xp being 0.98. Results from BMA analysis of model parameters over the winning family are shown in Table III for intrinsic connectivity and in Figure 4 for modulatory connections. There were significant modulatory effects of visual-orthographic load on the connections from left vOT to left SPL (0.14 Hz), from left SPL to left MFG (0.048 Hz), and from left MFG to left vOT (20.47 Hz). These results indicated that when the characters had a high number of strokes, information flow from left vOT to left SPL and

After excluding trials where participants pressed the wrong key, the average reaction time was 844 ms (SD 5 116) for the high-stroke condition, 825 ms (SD 5 120) for the low-stroke condition, and 476 ms (SD 5 52) for the control condition. Paired t-test analysis showed no reliable difference of reaction time for high- versus low-stroke condition (t(16) 5 1.97, P > 0.05). Mean accuracy was 0.88 (SD 5 0.08) for the high-stroke condition, 0.95 (SD 5 0.06) for the low-stroke condition, and 1.00 (SD 5 0.006) for arrow judgment. Paired t-tests indicated higher accuracy for the low-stroke condition than the high-stroke condition (t(16) 55.26, P < 0.01).

Imaging Results Brain activations related to phonological conditions contrasted with control condition overlap to a great extent for high-stroke and low-stroke conditions, with peak activation in the left inferior and middle frontal gyri, right superior frontal gyrus, cingulate cortex, left posterior parietal cortex, bilateral cuneus, bilateral lingual gyri, left fusiform gyrus and so on (see Fig. 1 and Table I). Interestingly, the left temporoparietal regions critical for phonological proc-

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Figure 1. Lateral and axial view of cortical activation associated with tone judgment contrasted with control condition. The significant threshold is P < 0.05 FDR-corrected. (A) The low-stroke condition minus the control condition. (B) The high-stroke condition minus the control condition. L 5 left hemisphere; R 5 right hemisphere.

from left SPL to left MFG increased, whereas information flow from left MFG to left vOT decreased.

DISCUSSION Previous neuroimaging studies have found that visual word recognition in alphabetic languages engages both ventral and dorsal neural pathways from visual cortex to higher-order language areas [Booth et al., 2008; Levy et al., 2009; Richardson et al., 2011; Seghier et al., 2012], and that reading deep orthographies relies more on the ventral pathway compared to shallow orthographies [Duncan et al., 2013; Paulesu et al., 2000; Price, 2012]. This study directly tested the involvement of the ventral and dorsal pathways during reading of Chinese, an extremely deep orthography. Our results

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from the two-step family comparisons converged to suggest that the ventral pathway, but not the dorsal pathway, was critically involved in Chinese visual word processing. First, we found overwhelming evidence that only the ventral pathway (rather than only the dorsal pathway or both ventral and dorsal pathways) was modulated by the visual-orthographic load. Second, when vOT, SPL, and MFG were included in the models, there was unequivocal evidence suggesting that the driving input entered the models via the ventral system (i.e., vOT) rather than only the dorsal system (i.e., SPL) or both. These findings reveal a significant variation of the neural pathways for reading across writing systems. Writing systems differ in how the graphic unit maps onto the phonological unit of language. In alphabetic languages, phonology can be represented by different levels

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TABLE I. Coordinates of activation peaks Coordinates (MNI) Regions activated

BA

X

Characters of low number of stroke > Control Frontal lobe L inferior frontal gyrus 47 232 46 246 L middle frontal gyrus 6/9 252 L medial frontal gyrus 6 24 6 210 L precentral gyrus 6 248 L cingulate gyrus 24 220 R cingulate gyrus 32 12 L insula 226 230 234 Parietal lobe L precuneus 7 224 7 226 L inferior parietal lobule 40 248 40 250 40 256 Occipital lobe L cuneus 17 222 L middle occipital gyrus 18 226 18 228 R middle occipital gyrus 18 20 L lingual gyrus 17 212 R lingual gyrus 18 24 18 26 17 16 Subcortical regions L thalamus 220 226 214 R thalamus 20 18 24 28 L caudate 212 R caudate tail 30 L medial globus pallidus 218 R medial globus pallidus 14 R cerebellum 20 Characters of high number of stroke > Control Frontal lobe L inferior frontal gyrus 47 228 46 244 R inferior frontal gyrus 44/45 32 L middle frontal gyrus 46 236 R middle frontal gyrus 9/10 42 9 40 L medial frontal gyrus 8 24 6 24 R superior frontal gyrus 6 26 R insula 28 22 Parietal lobe L precuneus 7 220 R superior parietal lobule 7 30

Y

Z

TABLE I. (continued). Z score

26 36 6 12 2 24 22 18 26 26 26

2 16 48 52 66 52 42 40 16 14 12

5.46 4.98 3.52 5.35 5.13 3.52 3.75 4.79 5.28 4.92 4.84

262 254 238 238 234

40 38 44 60 54

4.81 4.57 4.09 3.73 4.09

286 280 280 288 292 282 276 286

4 0 212 8 24 22 0 24

6.58 6.01 5.86 6.25 6.04 5.82 5.72 5.52

220 234 210 212 220 230 228 22 238 210 26 266

16 0 0 18 16 10 22 22 2 28 22 248

5.58 4.9 3.38 4.42 4.24 3.67 3.96 5.06 3.79 4.24 3.75 4.84

24 36 8 28 46 12 16 12 24 22 26

22 14 24 20 28 30 48 52 74 22 2

5.71 5.51 3.95 5.41 3.58 4.89 5.63 5.51 4.22 5.66 5.39

264 264

46 44

5.24 4.67

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Coordinates (MNI) Regions activated L inferior parietal lobule Occipital lobe L cuneus R cuneus L lingual gyrus L middle occiptial gyrus R inferior occipital gyrus Temporal lobe L fusiform gyrus

Y

40

244

238

44

18 17 17 17 18/19 19 19

218 220 24 216 228 36 34

292 288 284 290 282 276 278

8 6 6 0 212 24 212

6.58 6.56 6.73 6.13 6.6 6.02 5.53

37 37

240 240

256 248

210 214

6.51 6.11

226 28 18 12

228 232 212 26

24 2 0 0

5.79 4.82 4.01 3.75

Subcortical regions L thalamus R thalamus R medial globus pallidus

Z

Z score

X

BA

5.2

L, left; R, right; BA, Brodmann’s area.

of orthographic structures: letters, onset/rimes, syllables, and the whole words [Ziegler and Goswami, 2005]. In deep alphabetic languages like English, inconsistent correspondence between graphemes and phonemes may lead to the development of both dorsal pathway for processing smaller grain size (e.g., phonemes) and ventral pathway for processing larger grain size [e.g., syllables or whole words; Richardson et al., 2011]. In contrast, the logographic Chinese uses characters to represent morphosyllabic but not phonemic information, such that small grain-size correspondences are not available for Chinese. Such characteristics in written Chinese have led to the suggestion that phonological activation in Chinese characters exhibited threshold-style activation, in which a full orthographic specification is needed before the activation of word-level phonology [Perfetti et al., 2005]. Therefore, different relationships between orthography and phonology may explain why reading of logographic Chinese has to go through the left vOT in the ventral pathway, which serves to extract orthographic information of whole words for lexical processing [Dehaene et al., 2005; Shaywitz et al., 2008], whereas alphabetic reading can also be accomplished with the dorsal pathway for serial letter-sound conversion [Booth et al., 2002; Cohen et al., 2008; Gabrieli, 2009; Paulesu et al., 2000]. In addition, our results highlighted the importance of the connections from vOT to SPL and from SPL to MFG in Chinese reading. As stroke number increased, the left SPL may come to play a more important role in finegrained orthographic analysis of the characters. The left MFG was proposed to support coordination of different

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Figure 2. Brain regions significantly activated for high-stroke condition in comparison with low-stroke condition, with significant threshold at P < 0.05 FDR-corrected. (A) Lateral view. (B) Axial sections and parameter estimates (beta values) extracted for high-stroke and low-stroke conditions from six ROIs: left vOT (in dark green), right vOT (in blue), left MFG (in yellow),

right MFG (in cyan), left SPL (in light green), and right SPL (in orange). Error bars depict standard error of mean (SEM). L5 left hemisphere; R 5 right hemisphere; high 5 high-stroke condition; low 5 low-stroke condition; vOT 5 ventral occipitotemporal cortex; MFG 5 middle frontal gyrus; SPL 5 superior parietal lobule.

aspects of linguistic information and the phonological processing at a syllable level during Chinese reading [Kuo et al., 2001, 2003; Liu et al., 2006; Perfetti et al., 2006; Siok et al., 2004, 2008; Song et al., 2013; Tan et al., 2001, 2003, 2005; Wu et al., 2012]. In our study, the left MFG might be more engaged to integrate visualorthographic and phonological information when the

visual-orthographic load became heavier. We also noted a strong negative modulation effect on the backward connection from left MFG to left vOT. Such top-down inhibitory connectivity may enable more efficient information processing in the lower-level areas that conformed to the processing in higher-level areas [Cardin et al., 2011; Carreiras et al., 2009].

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TABLE II. Coordinates of activation peaks: The high-stroke condition minus the low-stroke condition Coordinates (MNI) Regions activated

BA

Frontal lobe L middle frontal gyrus R middle frontal gyrus L inferior frontal gyrus

R inferior frontal gyrus Cingulate gyrus Parietal lobe L superior parietal lobule R superior parietal lobule L inferior parietal lobule Occipital lobe L middle occipital gyrus R middle occipital gyrus L inferior occipital gyrus R inferior/middle occipital gyrus Temporal lobe L fusiform gyrus R fusiform gyrus Subcortical regions R caudate

X

Y

Z

Z score

9 9 44 45 47 47 47 32

248 40 240 236 224 232 28 26

32 12 4 22 26 36 22 22

28 32 28 24 22 28 22 44

4.45 3.63 4.33 4.47 4.28 3.99 3.68 3.3

7 7 40

220 28 232

260 260 248

48 46 50

3.77 3.84 3.46

19 18 19 18/19

232 26 238 28

286 282 280 282

12 6 24 22

4.27 4.07 4.07 3.93

37 18

228 36

260 276

210 210

4.24 3.85

28 34

6 0

3.39 3.14

16 18

L, left; R, right; BA, Brodmann’s area.

Figure 3. Results from BMS analyses. (A) Family comparison at the firststep BMS analysis. Solid black arrows indicate the connections used to partition model space into three competitive families that differed in whether the ventral pathway only, the dorsal pathway only, or both pathways were modulated by visualorthographic load. The bar graph shows the exceedance probability (xp) for the three families. (B) Family comparison at the second-step BMS analysis. Three competitive families differed in the location the inputs entered the model, via the vOT only, the SPL only, or both. The bar graph shows the xp for the three families.

mation flowing from the visual cortex (cuneus) to vOT to SPL and to MFG. This dynamic system reinforces wholecharacter-based phonology, which is related to visualorthographic complexity. It represents sharp contrast to alphabetic languages in which both ventral and dorsal pathways are critically involved during word recognition. Cortical dynamics is constrained by the differences in how graphic symbols are linked to spoken language in writing systems.

TABLE III. Strengths of intrinsic connectivity for the three-region model (probability values shown in parentheses) From To

To conclude, this study provides important evidence suggesting that visual word recognition of Chinese characters engages the ventral pathway from visual cortex to vOT, but not the dorsal pathway from visual cortex to the left superior temporal or parietal regions. The ventral pathway, however, is linked to the SPL and the left MFG, so that a dynamic neural network is built, with infor-

r

vOT

vOT

/

SPL

0.87 (1.00) 1.22 (1.00)

MFG

2588

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SPL

MFG

20.51 (0.99) /

20.14 (0.74) 20.17 (0.94) /

20.48 (1.00)

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Effective Connectivity of Brain Regions

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Figure 4. Results from BMA parameter analysis for the three-region model. The average strength of significant modulatory connection parameters (in Hz) are shown above the thicken lines, with probability values shown in parentheses. The distribution of the 10,000 samples of the posterior densities generated during BMA is presented for the significant modulatory effects.

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