Brain Imaging and Behavior DOI 10.1007/s11682-014-9342-8
SI: DEVELOPING BRAIN
Relationship between receptive vocabulary and the neural substrates for story processing in preschoolers M. Claire Sroka & Jennifer Vannest & Thomas C. Maloney & Tzipi Horowitz-Kraus & Anna W. Byars & Scott K. Holland & CMIND Authorship Consortium
# Springer Science+Business Media New York 2014
Abstract A left-lateralized fronto-temporo-parietal language network has been well-characterized in adults; however, the neural basis of this fundamental network has hardly been explored in the preschool years, despite this being a time for rapid language development and vocabulary growth. We examined the functional imaging correlates associated with vocabulary ability and narrative comprehension in 30 preschool The CMIND (Cincinnati MR Imaging of NeuroDevelopment) Authorship Consortium Scott K. Holland, Ph.D.1,6,9,10 Jennifer Vannest, Ph.D.1,5 Vincent J. Schmithorst, Ph.D.1,2 Mekibib Altaye, Ph.D.1,7 Gregory Lee, Ph.D.1,6 Luis Hernandez-Garcia, Ph.D.3 Michael Wagner, Ph.D.1,8 Arthur Toga, Ph.D. 12,13 Jennifer Levitt, MD14 Anna W. Byars, Ph.D1,5 Andrew Dimitrijevic, Ph.D.9,10 Nicolas Felicelli8 Darren Kadis, Ph.D.1,5 James Leach, MD1,6 Katrina Peariso, MD, Ph.D.5 Elena Plante, Ph.D.4 Akila Rajagopal, M.S.1 Andrew Rupert, M.S.8 Mark Schapiro, MD1,5 Ronald Ly14 Petros Petrosyan12 JJ Wang, Ph.D.11 Lisa Freund, Ph.D.15 1 Pediatric Neuroimaging Research Consortium 5 Div. of Neurology, Dept. of Pediatrics 6 Dept. of Radiology 7 Div. of Biostatistics and Epidemiology, Dept. of Pediatrics 8 Div. of Biomedical Informatics, Dept. of Pediatrics 9 Dept. of Otolaryngology 10 Communication Sciences Research Center Cincinnati Children’s Hospital Medical Center University of Cincinnati
children ages 3 to 5. Bilateral auditory cortex and superior temporal activation as well as left angular and supramarginal gyrus activation were observed during a passive listening-tostories task. Boys showed greater activation than girls in the right anterior cingulate and right superior frontal gyrus (SFG). Finally, children with higher vocabulary scores showed increased grey matter left-lateralization and greater activation in bilateral thalamus, hippocampus, and left angular gyrus. This study is novel in its approach to relate left-hemisphere language regions and vocabulary scores in preschool-aged children using fMRI. Keywords Functional MRI . Language development . Preschool language function . Vocabulary
Introduction Brain function for language processing in the adult brain has been mapped during the past decade using modern neuroimaging and modeling methods (Price 2000; Poeppel and Hickok 2004; Hickok 2009; Price 2010; Price et al. 2011; Poeppel et al. 2012; Price 2012). Emergence of brain networks supporting language development during childhood is less well characterized (Karunanayaka et al. 2007; 2011), and there is a particular gap in our knowledge during rapid brain and language development in early childhood. Speech perception abilities begin to develop prenatally (CheourLuhtanen et al. 1995), and a few studies have shown that some specialized brain mechanisms in the left hemisphere may already be in place (Chi et al. 1977; Dehaene-Lambertz et al. 2002; Pena et al. 2003; Kuhl et al. 2006). Between 7 and 12 months, children begin to respond to their names, recognize the names of familiar objects, and respond to simple commands. By the second year of life, children’s vocabularies will expand to hundreds of words (Bloom 2000). In the
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preschool years, a rapidly expanding vocabulary is integrated with grammatical knowledge, and typically-developing children produce and comprehend multiclause expressions by 5 years of age (for a review, see Conti-Ramsden and Durkin 2012). Even as these higher-level language functions develop, vocabulary remains a crucial aspect of language development, and Verbal IQ (WPPSI; (Wechsler 1989) has been associated with general intelligence and academic success (Naglieri and Bornstein 2003; Marchman and Fernald 2008). It defines the foundation for future technical reading and reading comprehension abilities (Qian 1999; Muter et al. 2004; Durand et al. 2013). Here we provide new data illustrating the relationship between functional brain development and early vocabulary skills in children from 3 to 5 years of age. By adulthood, receptive and expressive language function, very generally, relies on a left-dominant fronto-temporal network, including inferior frontal gyrus (IFG), and superior and middle temporal gyri, along with structural connections between the two (see Friederici and Gierhan 2013 for a review). Across development, this network appears to transition from a more distributed, bilateral representation to a more specialized left-lateralized one (Brauer and Friederici 2007). During multiple language tasks, left-lateralization has been shown to increase from ages 5–25 (Holland et al. 2001; Szaflarski et al. 2006; Brauer and Friederici 2007; Holland et al. 2007). At ages 5–7, mechanisms for receptive language appear to be less specialized: in one recent fMRI study (Brauer and Friederici 2007), adults and children ages 5–7 heard correct sentences, syntactically incorrect sentences, and semantically incongruous sentences. Children activated the inferior and middle frontal cortex bilaterally in all conditions, a phenomenon also observed in other studies (Horowitz-Kraus et al. 3333 Burnet Ave. Cincinnati, OH 45229 2 Pediatric Imaging Research Center, Dept. of Radiology Children’s Hospital of Pittsburgh of UPMC, Pittsburgh, PA 3 Functional MRI Laboratory, Dept. of Biomedical Engineering University of Michigan, Ann Arbor, MI 4 Dept. of Speech, Language, and Hearing Sciences University of Arizona, Tucson, AZ 11 Dept. of Neurology, UCLA, Los Angeles, CA 12 Laboratory of Neuroimaging, Keck School of Medicine of USC, Los Angeles, CA 13 Departments of Ophthalmology, Neurology, Psychiatry, and the Behavioral Sciences, Radiology and Engineering, Keck School of Medicine of USC, Los Angeles, CA 14 Psychiatry and Biobehavioral Sciences, UCLA, Los Angeles, CA 15 Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD M. C. Sroka : J. Vannest (*) : T. C. Maloney : T. Horowitz-Kraus : A. W. Byars : S. K. Holland Pediatric Neuroimaging Research Consortium, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Ave. ML 5033, Cincinnati, OH 45229, USA e-mail: [email protected]
2013). In contrast, adults engaged more localized networks, depending on the semantic or syntactic violation. For example, adults showed left anterior frontal operculum activation in the syntactically incorrect condition, whereas children showed this activation in all conditions. A relationship between language skill in children and a more specialized language network has also been demonstrated. Children ages 4–7 who were high performing on an independent grammar test showed similar activation to adults in the left IFG and left superior temporal gyrus (STG)/superior temporal sulcus (STS) when presented with more complex sentences, whereas average-performing children showed a more widespread activation (Knoll et al. 2012). The authors suggest that children with higher syntactic skills have strengthened and specialized functional neural networks responsible for receptive language. In addition, age-related changes in the brain for a number of cognitive abilities may be different for boys and girls, and it is important to consider the effects of sex on the developing brain (Schmithorst and Holland 2006, 2007; Wilke et al. 2007; Wang et al. 2012). There is some evidence that boys and girls have different specializations in the language network (Plante et al. 2006; Schmithorst et al. 2008), although consistent results remain to be seen. Young girls have shown superior language skills to boys early in childhood, which may be reflected in the neural correlates of language; however, these differences tend to disappear with age (Morisset et al. 1995; Bornstein et al. 2000; Bauer et al. 2002). Across several language tasks, girls have shown greater overall activation of language areas than boys (bilateral inferior frontal and superior temporal gyri and left fusiform gyrus), after controlling for age and performance accuracy (Burman et al. 2008). The differences between boys and girls may not solely be due to disparities in the language networks but also to differences in other processes such as executive function. Indeed, working memory, an important executive function, has been shown to correlate with vocabulary knowledge (for a review, see Baddeley 2003). The frontal lobe undergoes considerable changes during childhood and adolescence (Giedd et al. 1999; Casey et al. 2000; Sowell et al. 2001, 2002, 2004) as executive functions develop and refine (Diamond 2002). Certain executive functions (inhibition and impulse control) have been shown to mature earlier in girls (Klenberg et al. 2001; Unterrainer et al. 2013). Therefore, we speculate that utilization of executive functions may be more automatic for young girls, and boys may need to engage executive function-related areas of the prefrontal cortex to a greater degree in order to perform a cognitively engaging activity such as a language task. Other than studies of speech perception in very young infants (e.g. Dehaene-Lambertz et al. 2002), the neural basis of language function has not been characterized using fMRI methods in children younger than age 4. In the present study, we used fMRI during a passive story processing task to
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examine receptive language function and lateralization in children ages 3:0–5:11. This task has previously been shown to engage bilateral, but left-lateralized activation in the STG and superior frontal gyrus (SFG) as well as left IFG and angular gyrus activation in children 5–18 years old (Schmithorst et al. 2006; Karunanayaka et al. 2007; Schmithorst et al. 2007; Vannest et al. 2009; HorowitzKraus et al. 2013). Because vocabulary during toddler and preschool years has been associated with cognitive skills (Marchman and Fernald 2008) and reading comprehension (Muter et al. 2004; Durand et al. 2013) later in childhood, we also examined the relationship between activation during the story processing task and behavioral vocabulary scores (from the PPVT-4 battery; Dunn and Dunn 2007). We hypothesized that increased age, as well as higher vocabulary scores, would be associated with greater engagement of left-hemisphere fronto-temporo-parietal regions supporting receptive language function. Based on previous reports of sex differences in developing language networks, we also hypothesize that regions supporting receptive language function will be more active in girls and that there will be greater involvement of brain regions supporting executive function in boys during story processing.
Methods Participants Thirty participants were selected from a national database of functional neuroimaging and behavioral data from typically developing children recently released by the Pediatric Functional Neuroimaging Research Network. The Cincinnati MR Imaging of NeuroDevelopment (C-MIND) database is publically accessible online at http://research.cchmc.org/c-mind. To ensure that the C-MIND database contains data from normally developing children, the following inclusion criteria were: 1) negative history and family history (in first-degree relatives) of neurological or psychiatric disease; 2) Body Mass Index between the 5 and 95th percentile for age and gender and; 3) normal neurological exam. Exclusion criteria included: 1) chronic illness; 2) gestation less than 37 weeks or greater than 42 weeks; 3) birth weight less than the 10th percentile; 4) history of head trauma with a loss of consciousness; 5) special education; 6) orthodontic braces or other metallic implants, and; 7) standard MRI contraindications. Informed consent was obtained from the parent or guardian. Informed consent procedures were approved by the Institutional Review Board of the Cincinnati Children’s Hospital Medical Center. C-MIND participants first completed a structural MRI (physiological session) and were invited to return for a functional imaging session following successful
completion of the first session (details of the two sessions can be found in Vannest et al. 2014). The current study focused on participants ages 3:0 to 5:11 who returned for neuropsychological testing and who completed the second functional imaging session while awake. 42 participants in this age range completed a physiological session (approximately 65 % of children in this age range successfully complete at least 30 min of scanning in their first session, see Vannest et al. 2014 for details) and 38 returned for a functional session. The success rate for this group of 38 participants was higher than average for this age group because they had already completed the physiological session with success. Of the participants who returned for the functional session, one (1) boy was unable to complete the scan, one (1) boy had excessive motion artifacts that rendered the fMRI data unusable, two (2) participants had data with other image artifacts due to technical problems, three (3) did not receive neuropsychological testing, and one (1) had an unanticipated imaging finding that resulted in exclusion from the study (criteria for describing unanticipated findings are included in the article by Kaiser et al. in this issue of Brain Imaging and Behavior). Excluding these eight participants from the current analysis yielded a total of 30 participants (17 girls) with a mean age of 4.22 years, see Table 1 for a distribution of age and gender. Participants were native English speakers (17 Caucasian, 11 African-American, 1 Multi-ethnic, 1 unknown) with an average household income of $35,000–$50,000.
Neuropsychological testing All children participated in a battery of neuropsychological tests assessing general intellectual function, vocabulary, fine motor skill and other domains (details of the battery can be found at https://research.cchmc.org/c-mind/neuropsychologicalbattery). Specifically, the current study examined scores on the Peabody Picture Vocabulary Test, Fourth Edition (PPVT-4; Dunn and Dunn 2007). The PPVT-4 is a reliable and valid norm-referenced test with standardized scoring, designed to evaluate the receptive vocabulary of children and adults. The examinee must select the picture that best illustrates the meaning of a word spoken by the examiner from four pictures arranged on a page. Testing for this study was performed by study staff trained and supervised by a board-certified neuropsychologist.
Table 1 Number of participants by gender and age in years
Age (years)
3
4
5
Girls Boys
9 7
4 1
4 5
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MRI acquisition in young children Prior to study visits, the parents and child watched a video describing the MRI as an adventure in space in order to prepare and excite the child for the study visits. This video is available on the C-MIND website at https://research.cchmc. org/c-mind/visitors/preparing. Specific procedures were used at each visit to acclimate the child to the scanner environment (see Vannest et al. 2014 for a detailed description). The child explored the scanner environment, moved the scanner bed up and down, sat on the bed, and finally practiced holding “as still as a statue.” Communication was established between the child and study coordinator through headphones equipped with a built-in microphone. Once the child was comfortable, he or she was positioned within the scanner bore, began watching a movie via MRI-compatible audiovisual system, and image acquisition began. Verbal communication and positive reinforcement was maintained with the child throughout the scan. Scanning was terminated immediately if the child did not wish to continue. All children were awake for the entire duration of the scan. Story processing fMRI task The fMRI paradigm involved a passive story processing task in which participants listened to natural speech stories in a female voice during the stimulated condition. The baseline condition included non-speech broadband noise sweep with center frequencies from 200 to 400 Hz and durations of 0.5–2.0 Hz. The task began with a stories block followed by the non-speech noise block. Each block was 64 s in duration and there was a total of 5 cycles through the two conditions. The story processing task was presented to participants through Avotec audiovisual systems equipped with Silent Scan 3100 systems. Functional MRI acquisition methods MRI data was obtained using a Philips 3 T Achieva system and a 32-channel head coil. A new concurrent whole-brain functional arterial spin labeled/blood oxygenation level dependent (ASL/BOLD) acquisition method was used with a double-excitation approach (Schmithorst et al. 2014); however, only standard BOLD acquisitions were included in the present analysis. Acquisition parameters were: TR = 4000 ms, TE1=11 ms, TE2=35 ms, matrix=64×64, FOV= 25.6×25.6 cm, slice thickness=5 mm, 25 slices acquired covering the whole brain. The ASL and BOLD image volumes were split in pre-processing and submitted to separate pre-processing pipelines, specific to the image types. For the current analysis we have used only the BOLD fMRI data from the story processing task. The ASL images are not included in the results presented here. In addition, the coregistration and alignment of the fMRI data make use of a 3D, T1-weighted
1 mm isotropic anatomical MRI image of the participant, acquired during the same functional imaging session. Data analysis First-level fMRI analysis First-level fMRI data processing was carried out using FEAT (FMRI Expert Analysis Tool) Version 6.0, part of FSL (FMRIB’s Software Library, www. fmrib.ox.ac.uk/fsl). After motion correction and spatial smoothing, fMRI data were coregistered to an ageappropriate pediatric template, created from C-MIND data for 2 to 4 years old, that was then normalized to 2 mm MNI standard space using symmetric diffeomorphic image normalization (SyN, Avants et al. 2008), as implemented in ANTs (Advanced Normalization Tools, stnava.github.io/ANTs/). Motion correction of the BOLD time-series (to a common reference frame) was carried out using MCFLIRT (Jenkinson et al. 2002). In an initial run, the central time point was used as the reference frame. Based on the derived motion parameters, the time point with the minimal displacement from the average position of the brain over the time-series was determined. Motion correction was then restarted, using this minimal displacement time point as the reference frame. Following motion correction, spatial smoothing using a Gaussian kernel of FWHM 8 mm and high-pass temporal filtering (cutoff of 104 s) was applied. Grand-mean intensity normalization by a single multiplicative factor was applied to each 4D dataset. A general linear model with autocorrelation correction was then used to compute BOLD activation at the single-subject level. For the present analysis, only BOLD data was considered (comparison with ASL is beyond the scope of this paper). Data quality assurance Raw image data from the MRI scan acquisition was reviewed for image quality by a trained expert prior to being included in the C-MIND database. Image quality was rated on a scale from 0 to 3 (zero being the best quality and three being the poorest quality) according to predefined criteria previously validated and published (Yuan et al. 2009). fMRI data with a rating of three were excluded from analysis (only one participant in the present analysis). After the preprocessing steps were applied to the fMRI time-series data and first level analysis was completed to generate the contrast maps for story processing > noise, correction for multiple comparisons was performed and the resulting contrast maps were again inspected for image quality. No data was excluded at this stage of the study. Criteria used to assign ratings are included in Table 2. Group composites and comparisons A general linear model was used to identify brain regions associated with story processing in all participants and regions that differed between boys and girls. Group comparison of boys versus girls was performed by selecting two age-matched groups, 13 boys
Brain Imaging and Behavior Table 2
Image quality rating criteria for structural and functional data
Structural imaging 0 Perfect data, no discernable artifacts, homogeneous signal intensity across field of view and clear contrast between tissue types. 1 Good image quality and contrast. Some artifacts where all slices contain a variation in intensity including variation in homogeneity or discrete artifacts such as zippers, ringing, wrap-around, etc. 2 Serious artifacts caused by motion, B0 or B1 non-uniformity. All slices contain a severe intensity variation across FOV. Poor contrast between tissue types but discernable tissue boundaries. 3 Excessive image artifacts due to motion or other factors affecting all slices. No visible tissue contrast or discernable tissue boundaries. Data should clearly be discarded. Functional imaging 0 Excellent data, no discernable motion. Intensity modulation may be present in some slices. 1 Some minimal motion where all slices contain a change in intensity and/or position. Degree of motion does not pose a threat to the integrity of the data. 2 3
Continuous, moderate motion where all slices contain a change in intensity and position. Degree of motion may pose a threat to the integrity of the data. Continuous, excessive motion where all slices contain a change in intensity and position; data should clearly be discarded.
(mean age 4.26, SD 1.00 years) and 13 girls (mean age 4.27, SD 1.03 years), and examining the differences in activation patterns between these groups. For display purposes, the group composite map and difference map for boys versus girls were thresholded with an initial z>2.3 and corrected for multiple comparisons using FSL’s cluster based inference to p noise) and receptive vocabulary skills and age. BOLD contrast for each participant was submitted to a correlation analysis with PPVT-4 standard scores and on a voxel-wise basis using participant age as a regressor of no interest (see Results: Behavioral Data below). For display purposes, correlation maps were thresholded with an initial z>2.3 and corrected for multiple comparisons using FSL’s cluster based inference to p noise in a functionally-defined region of interest (ROI) in the left angular/supramarginal gyrus that was significantly correlated with PPVT-4 score. This correlation was examined separately for boys and girls. Lateralization index A hemispheric lateralization index (LI) was calculated for each participant based on a grey matter mask extracted from a template created from the 30 participants, using a template creation script available as part of ANTs. Prior to the template creation, the T1-weighted anatomical images were bias corrected using the N4 algorithm (Tustison et al. 2010); non-brain removal was performed using BET (Smith 2002). The template was normalized to
MNI standard space as described above. By using a study specific template to extract the grey matter mask, we were able to account for left-right asymmetries in grey matter volume that are present in children in this age range (Giedd et al. 1996; Matsuzawa et al. 2001; Shaw et al. 2008). Voxels with zscores greater than or equal to the median z-score (from the unthresholded contrast maps for stories > noise) within a mask for each individual participant were used to calculate the LI for that individual. Voxels above the median z-score threshold were counted, and a lateralization index was defined as the difference in the number of activated voxels, summed independently for the left and right, divided by the sum of active voxels on the left plus the right. This procedure yields lateralization indices ranging from −1 (right) to 1 (left) (Holland et al. 2007). We then examined the relationship between LI, age, and PPVT-4 score.
Results Behavioral results The mean PPVT-4 standard score was 108.5 (SD 17.1; range 78 to 138). Scores did not differ between girls and boys [t(28)=−0.10, p>0.9], and did not correlate with age (r= −0.31, p=0.098). An additional test comparing the 10 youngest participants (mean PPVT-4=110) with the 10 oldest (mean PPVT-4=100) confirmed no relationship between PPVT-4 and age [t(18)=1.30, p>0.2]. However, while the relationship between age and PPVT-4 scores was not significant, there was a non-significant trend toward higher PPVT-4 scores in younger participants (p=0.098). This motivated our use of age as a covariate of no interest in the correlation analysis of imaging data.
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Neuroimaging results
Discussion
Group composite maps
In the present study, we used fMRI during a story processing task to examine receptive language function and lateralization in preschool children ages 3:0–5:11. We also examined the relationship between activation during the story processing task and PPVT-4 scores. We hypothesized that increased age, as well as higher vocabulary scores, would be associated with greater engagement of left hemisphere regions supporting receptive language function. We also hypothesized that regions supporting receptive language function would be more active in girls and that there would be greater involvement of brain regions supporting executive function in boys during story processing. We found that story processing resulted in bilateral superior temporal activation extending into the temporal poles, and activation of left angular/supramarginal gyrus, consistent with other studies in children 5 years of age and up (Schmithorst et al. 2006; Karunanayaka et al. 2007; Schmithorst et al. 2007). Task-negative patterns of activation (more active during the baseline noise condition than during stories) were found in regions associated with the “default mode” network (Fox et al. 2005; Dosenbach et al. 2007; Fox and Raichle 2007). Higher PPVT-4 scores correlated with activation in the left angular/supramarginal gyri. Whereas this region is not part of the “canonical” language network, a number of studies have found involvement of the angular and/or supramarginal gyri (SMG) in semantic processing (Ahmad et al. 2003; Binder et al. 2005; Lee et al. 2007; Price 2010); this suggests that children with higher vocabulary scores have a more developed semantic processing mechanism that would typically be acquired later in development. Along with activation of the angular/supramarginal gyri, higher PPVT-4 scores were correlated with activation of the thalamus. While thalamic structures were formerly thought to simply relay sensory information to cortical regions, there is increasing evidence for thalamic involvement in linguistic capacities (Klostermann et al. 2013; Crosson 2013). The Selective Engagement Model posits a cortico-thalamic network in which thalamic nuclei control the functional connectivity between frontal and temporal cortices for the integration of syntactic and semantic information (Crosson 1985; Nadeau
Regions of significant group activation during story processing relative to noise included bilateral auditory cortex and superior temporal activation extending into the temporal poles bilaterally, and left angular/supramarginal gyrus. These areas are highlighted in hot colors in Fig. 1a. Tasknegative activation, labeled in cold colors in Fig. 1a, is found bilaterally in ventral prefrontal cortex, cuneus/precuneus, and inferior parietal lobule; and right supramarginal gyrus. Some regions were more active during story processing in boys compared to girls: right anterior cingulate and right superior frontal gyrus. Areas exhibiting greater BOLD contrast (stories > noise) for the age-matched group of boys (n= 13) compared to girls (n=13) are highlighted in hot colors in Fig. 1b. The location of centroids of activation clusters and mean z-scores are listed in Table 3. Correlation of neuroimaging data with PPVT-4 scores PPVT-4 standard scores (with age included as a covariate of no interest) were positively correlated with bilateral activation in the thalamus extending into hippocampus/parahippocampal gyrus, and left angular gyrus (Fig. 2). Correlation of neuroimaging data with age No regions of significant correlations were observed between age and task-positive or task-negative activation during story processing. Region-of-interest analysis: left supramarginal/angular gyrus As described above, we selected the region of left supramarginal/angular gyrus as a region of interest to further examine the relationship between mean z-score and PPVT-4 scores in boys and girls. A significant positive correlation with PPVT-4 score was observed for both boys (r=0.63; p noise for all 30 participants (17 girls) ages 3:0 to 5:11; B Activation difference map showing regions where the BOLD contrast for story processing > noise is greater in 13 boys (n=13, mean age 4.26, SD 1.00 years) than 13 agematched girls (n=15, mean age 4.27, SD 1.03 years). Both images are thresholded at z>2.3 with correction for multiple comparisons via cluster based inference to p noise for all 30 participants. B. MNI coordinates of regions with task-negative activation for story processing > noise for all 30 participants. C. MNI coordinates of regions with positive activation for
Region A. Positive activation during story processing relative to noise Cortical L Superior/Middle/Inferior Temporal Gyrus R Superior/Middle/Inferior Temporal Gyrus L Precentral/Postcentral/L Angular Gyrus Bilateral Anterior Cingulate Subcortical Bilateral Midbrain/Hippocampus/Thalamus/Basal Ganglia Cerebellum
story processing > noise that were more active for boys (n=13) than agematched girls (n=13). D. MNI coordinates of regions with positive activation for story processing > noise that were positively correlated with scores on PPVT-4 Cluster Volume (cm3)
Center of gravity X (mm)
Center of gravity Y (mm)
Center of gravity Z (mm)
100.34 64.98 14.65 0.36
−48.20 43.80 −39.80 −7.84
−21.90 −7.06 −25.00 10.20
−2.99 −8.47 50.00 23.80
3.65 3.66 2.91 2.59
49.08 3.49
−3.95 13.70
−18.40 -75.00
−7.93 -19.00
2.73 2.59
7.92 −35.50 37.40
−57.10 49.20 44.60
36.90 11.80 11.60
−2.99 −2.89 −2.83
20.80
25.60
28.40
2.66
−46.00
−65.10
19.70
2.70
−1.89 −46.00
−36.80 −65.10
2.16 19.70
2.79 2.70
B. Negative activation during story processing relative to noise Cortical R Precuneus/ Bilateral Inferior Parietal Lobule 70.26 L Middle Frontal Gyrus 17.26 R Middle Frontal Gyrus 15.04 C. Activation greater in boys than girls during story processing relative to noise Cortical R Middle Frontal Gyrus, Anterior Cingulate 11.82 D. Activation with greater PPVT-4 scores during story processing relative to noise Cortical L Angular/Supramarginal Gyrus 14.00 Subcortical L Anterior Cerebellum, Bilateral Thalamus 19.31 L Angular/Supramarginal Gyrus 14.00
and Crosson 1997), and support for this has been found in a more recent study (Wahl et al. 2008). Growing neuroimaging evidence for the involvement of the thalamus in semantic processes comes from studies that observed thalamic activation when participants engaged in the retrieval of an object from semantic memory (Kraut et al. 2002a, b, 2003; Assaf et al. 2006). This provides additional support for the idea that children with greater receptive vocabulary scores may have a more developed semantic processing network that is typical later in development. Mesial temporal regions known to support memory encoding and retrieval (see Rugg et al. 2012 for a recent review), including vocabulary learning (Shtyrov 2012), were also more active during story processing in children with higher PPVT-4 scores. We speculate that children with greater receptive vocabulary may engage circuitry needed to comprehend the linguistic material presented to them during the stories, accessing memory representations, not only for single
Mean Z-score
vocabulary items, but of episodic memories associated with these vocabulary items. Children with higher receptive vocabulary scores also showed greater left-lateralization during story processing, as determined by global grey-matter lateralization indices. This finding further supports the idea that children with higher receptive vocabularies have language networks more similar to adults, as language lateralization has been shown to increase with age (Holland et al. 2001; Szaflarski et al. 2006; Brauer and Friederici 2007; Holland et al. 2007). This result is also similar to previous studies that have shown an association between cognitive domains and increased left-lateralization of language specific brain regions. Individuals with leftlateralization of the arcuate fasciculus, a subdivision of the superior longitudinal fasciculus white matter tract which connects frontal and temporal language areas, performed better than right-lateralized individuals on tests of verbal intelligence and phonological processing (Lebel and Beaulieu 2009). In a
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Fig. 2 Activation correlation map for all 30 participants (17 girls) showing regions where the BOLD contrast for story processing > noise is positively correlated with higher PPVT-4 scores; thresholded at z>2.3
and corrected via cluster based inference to p
SI: DEVELOPING BRAIN
Relationship between receptive vocabulary and the neural substrates for story processing in preschoolers M. Claire Sroka & Jennifer Vannest & Thomas C. Maloney & Tzipi Horowitz-Kraus & Anna W. Byars & Scott K. Holland & CMIND Authorship Consortium
# Springer Science+Business Media New York 2014
Abstract A left-lateralized fronto-temporo-parietal language network has been well-characterized in adults; however, the neural basis of this fundamental network has hardly been explored in the preschool years, despite this being a time for rapid language development and vocabulary growth. We examined the functional imaging correlates associated with vocabulary ability and narrative comprehension in 30 preschool The CMIND (Cincinnati MR Imaging of NeuroDevelopment) Authorship Consortium Scott K. Holland, Ph.D.1,6,9,10 Jennifer Vannest, Ph.D.1,5 Vincent J. Schmithorst, Ph.D.1,2 Mekibib Altaye, Ph.D.1,7 Gregory Lee, Ph.D.1,6 Luis Hernandez-Garcia, Ph.D.3 Michael Wagner, Ph.D.1,8 Arthur Toga, Ph.D. 12,13 Jennifer Levitt, MD14 Anna W. Byars, Ph.D1,5 Andrew Dimitrijevic, Ph.D.9,10 Nicolas Felicelli8 Darren Kadis, Ph.D.1,5 James Leach, MD1,6 Katrina Peariso, MD, Ph.D.5 Elena Plante, Ph.D.4 Akila Rajagopal, M.S.1 Andrew Rupert, M.S.8 Mark Schapiro, MD1,5 Ronald Ly14 Petros Petrosyan12 JJ Wang, Ph.D.11 Lisa Freund, Ph.D.15 1 Pediatric Neuroimaging Research Consortium 5 Div. of Neurology, Dept. of Pediatrics 6 Dept. of Radiology 7 Div. of Biostatistics and Epidemiology, Dept. of Pediatrics 8 Div. of Biomedical Informatics, Dept. of Pediatrics 9 Dept. of Otolaryngology 10 Communication Sciences Research Center Cincinnati Children’s Hospital Medical Center University of Cincinnati
children ages 3 to 5. Bilateral auditory cortex and superior temporal activation as well as left angular and supramarginal gyrus activation were observed during a passive listening-tostories task. Boys showed greater activation than girls in the right anterior cingulate and right superior frontal gyrus (SFG). Finally, children with higher vocabulary scores showed increased grey matter left-lateralization and greater activation in bilateral thalamus, hippocampus, and left angular gyrus. This study is novel in its approach to relate left-hemisphere language regions and vocabulary scores in preschool-aged children using fMRI. Keywords Functional MRI . Language development . Preschool language function . Vocabulary
Introduction Brain function for language processing in the adult brain has been mapped during the past decade using modern neuroimaging and modeling methods (Price 2000; Poeppel and Hickok 2004; Hickok 2009; Price 2010; Price et al. 2011; Poeppel et al. 2012; Price 2012). Emergence of brain networks supporting language development during childhood is less well characterized (Karunanayaka et al. 2007; 2011), and there is a particular gap in our knowledge during rapid brain and language development in early childhood. Speech perception abilities begin to develop prenatally (CheourLuhtanen et al. 1995), and a few studies have shown that some specialized brain mechanisms in the left hemisphere may already be in place (Chi et al. 1977; Dehaene-Lambertz et al. 2002; Pena et al. 2003; Kuhl et al. 2006). Between 7 and 12 months, children begin to respond to their names, recognize the names of familiar objects, and respond to simple commands. By the second year of life, children’s vocabularies will expand to hundreds of words (Bloom 2000). In the
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preschool years, a rapidly expanding vocabulary is integrated with grammatical knowledge, and typically-developing children produce and comprehend multiclause expressions by 5 years of age (for a review, see Conti-Ramsden and Durkin 2012). Even as these higher-level language functions develop, vocabulary remains a crucial aspect of language development, and Verbal IQ (WPPSI; (Wechsler 1989) has been associated with general intelligence and academic success (Naglieri and Bornstein 2003; Marchman and Fernald 2008). It defines the foundation for future technical reading and reading comprehension abilities (Qian 1999; Muter et al. 2004; Durand et al. 2013). Here we provide new data illustrating the relationship between functional brain development and early vocabulary skills in children from 3 to 5 years of age. By adulthood, receptive and expressive language function, very generally, relies on a left-dominant fronto-temporal network, including inferior frontal gyrus (IFG), and superior and middle temporal gyri, along with structural connections between the two (see Friederici and Gierhan 2013 for a review). Across development, this network appears to transition from a more distributed, bilateral representation to a more specialized left-lateralized one (Brauer and Friederici 2007). During multiple language tasks, left-lateralization has been shown to increase from ages 5–25 (Holland et al. 2001; Szaflarski et al. 2006; Brauer and Friederici 2007; Holland et al. 2007). At ages 5–7, mechanisms for receptive language appear to be less specialized: in one recent fMRI study (Brauer and Friederici 2007), adults and children ages 5–7 heard correct sentences, syntactically incorrect sentences, and semantically incongruous sentences. Children activated the inferior and middle frontal cortex bilaterally in all conditions, a phenomenon also observed in other studies (Horowitz-Kraus et al. 3333 Burnet Ave. Cincinnati, OH 45229 2 Pediatric Imaging Research Center, Dept. of Radiology Children’s Hospital of Pittsburgh of UPMC, Pittsburgh, PA 3 Functional MRI Laboratory, Dept. of Biomedical Engineering University of Michigan, Ann Arbor, MI 4 Dept. of Speech, Language, and Hearing Sciences University of Arizona, Tucson, AZ 11 Dept. of Neurology, UCLA, Los Angeles, CA 12 Laboratory of Neuroimaging, Keck School of Medicine of USC, Los Angeles, CA 13 Departments of Ophthalmology, Neurology, Psychiatry, and the Behavioral Sciences, Radiology and Engineering, Keck School of Medicine of USC, Los Angeles, CA 14 Psychiatry and Biobehavioral Sciences, UCLA, Los Angeles, CA 15 Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD M. C. Sroka : J. Vannest (*) : T. C. Maloney : T. Horowitz-Kraus : A. W. Byars : S. K. Holland Pediatric Neuroimaging Research Consortium, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Ave. ML 5033, Cincinnati, OH 45229, USA e-mail: [email protected]
2013). In contrast, adults engaged more localized networks, depending on the semantic or syntactic violation. For example, adults showed left anterior frontal operculum activation in the syntactically incorrect condition, whereas children showed this activation in all conditions. A relationship between language skill in children and a more specialized language network has also been demonstrated. Children ages 4–7 who were high performing on an independent grammar test showed similar activation to adults in the left IFG and left superior temporal gyrus (STG)/superior temporal sulcus (STS) when presented with more complex sentences, whereas average-performing children showed a more widespread activation (Knoll et al. 2012). The authors suggest that children with higher syntactic skills have strengthened and specialized functional neural networks responsible for receptive language. In addition, age-related changes in the brain for a number of cognitive abilities may be different for boys and girls, and it is important to consider the effects of sex on the developing brain (Schmithorst and Holland 2006, 2007; Wilke et al. 2007; Wang et al. 2012). There is some evidence that boys and girls have different specializations in the language network (Plante et al. 2006; Schmithorst et al. 2008), although consistent results remain to be seen. Young girls have shown superior language skills to boys early in childhood, which may be reflected in the neural correlates of language; however, these differences tend to disappear with age (Morisset et al. 1995; Bornstein et al. 2000; Bauer et al. 2002). Across several language tasks, girls have shown greater overall activation of language areas than boys (bilateral inferior frontal and superior temporal gyri and left fusiform gyrus), after controlling for age and performance accuracy (Burman et al. 2008). The differences between boys and girls may not solely be due to disparities in the language networks but also to differences in other processes such as executive function. Indeed, working memory, an important executive function, has been shown to correlate with vocabulary knowledge (for a review, see Baddeley 2003). The frontal lobe undergoes considerable changes during childhood and adolescence (Giedd et al. 1999; Casey et al. 2000; Sowell et al. 2001, 2002, 2004) as executive functions develop and refine (Diamond 2002). Certain executive functions (inhibition and impulse control) have been shown to mature earlier in girls (Klenberg et al. 2001; Unterrainer et al. 2013). Therefore, we speculate that utilization of executive functions may be more automatic for young girls, and boys may need to engage executive function-related areas of the prefrontal cortex to a greater degree in order to perform a cognitively engaging activity such as a language task. Other than studies of speech perception in very young infants (e.g. Dehaene-Lambertz et al. 2002), the neural basis of language function has not been characterized using fMRI methods in children younger than age 4. In the present study, we used fMRI during a passive story processing task to
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examine receptive language function and lateralization in children ages 3:0–5:11. This task has previously been shown to engage bilateral, but left-lateralized activation in the STG and superior frontal gyrus (SFG) as well as left IFG and angular gyrus activation in children 5–18 years old (Schmithorst et al. 2006; Karunanayaka et al. 2007; Schmithorst et al. 2007; Vannest et al. 2009; HorowitzKraus et al. 2013). Because vocabulary during toddler and preschool years has been associated with cognitive skills (Marchman and Fernald 2008) and reading comprehension (Muter et al. 2004; Durand et al. 2013) later in childhood, we also examined the relationship between activation during the story processing task and behavioral vocabulary scores (from the PPVT-4 battery; Dunn and Dunn 2007). We hypothesized that increased age, as well as higher vocabulary scores, would be associated with greater engagement of left-hemisphere fronto-temporo-parietal regions supporting receptive language function. Based on previous reports of sex differences in developing language networks, we also hypothesize that regions supporting receptive language function will be more active in girls and that there will be greater involvement of brain regions supporting executive function in boys during story processing.
Methods Participants Thirty participants were selected from a national database of functional neuroimaging and behavioral data from typically developing children recently released by the Pediatric Functional Neuroimaging Research Network. The Cincinnati MR Imaging of NeuroDevelopment (C-MIND) database is publically accessible online at http://research.cchmc.org/c-mind. To ensure that the C-MIND database contains data from normally developing children, the following inclusion criteria were: 1) negative history and family history (in first-degree relatives) of neurological or psychiatric disease; 2) Body Mass Index between the 5 and 95th percentile for age and gender and; 3) normal neurological exam. Exclusion criteria included: 1) chronic illness; 2) gestation less than 37 weeks or greater than 42 weeks; 3) birth weight less than the 10th percentile; 4) history of head trauma with a loss of consciousness; 5) special education; 6) orthodontic braces or other metallic implants, and; 7) standard MRI contraindications. Informed consent was obtained from the parent or guardian. Informed consent procedures were approved by the Institutional Review Board of the Cincinnati Children’s Hospital Medical Center. C-MIND participants first completed a structural MRI (physiological session) and were invited to return for a functional imaging session following successful
completion of the first session (details of the two sessions can be found in Vannest et al. 2014). The current study focused on participants ages 3:0 to 5:11 who returned for neuropsychological testing and who completed the second functional imaging session while awake. 42 participants in this age range completed a physiological session (approximately 65 % of children in this age range successfully complete at least 30 min of scanning in their first session, see Vannest et al. 2014 for details) and 38 returned for a functional session. The success rate for this group of 38 participants was higher than average for this age group because they had already completed the physiological session with success. Of the participants who returned for the functional session, one (1) boy was unable to complete the scan, one (1) boy had excessive motion artifacts that rendered the fMRI data unusable, two (2) participants had data with other image artifacts due to technical problems, three (3) did not receive neuropsychological testing, and one (1) had an unanticipated imaging finding that resulted in exclusion from the study (criteria for describing unanticipated findings are included in the article by Kaiser et al. in this issue of Brain Imaging and Behavior). Excluding these eight participants from the current analysis yielded a total of 30 participants (17 girls) with a mean age of 4.22 years, see Table 1 for a distribution of age and gender. Participants were native English speakers (17 Caucasian, 11 African-American, 1 Multi-ethnic, 1 unknown) with an average household income of $35,000–$50,000.
Neuropsychological testing All children participated in a battery of neuropsychological tests assessing general intellectual function, vocabulary, fine motor skill and other domains (details of the battery can be found at https://research.cchmc.org/c-mind/neuropsychologicalbattery). Specifically, the current study examined scores on the Peabody Picture Vocabulary Test, Fourth Edition (PPVT-4; Dunn and Dunn 2007). The PPVT-4 is a reliable and valid norm-referenced test with standardized scoring, designed to evaluate the receptive vocabulary of children and adults. The examinee must select the picture that best illustrates the meaning of a word spoken by the examiner from four pictures arranged on a page. Testing for this study was performed by study staff trained and supervised by a board-certified neuropsychologist.
Table 1 Number of participants by gender and age in years
Age (years)
3
4
5
Girls Boys
9 7
4 1
4 5
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MRI acquisition in young children Prior to study visits, the parents and child watched a video describing the MRI as an adventure in space in order to prepare and excite the child for the study visits. This video is available on the C-MIND website at https://research.cchmc. org/c-mind/visitors/preparing. Specific procedures were used at each visit to acclimate the child to the scanner environment (see Vannest et al. 2014 for a detailed description). The child explored the scanner environment, moved the scanner bed up and down, sat on the bed, and finally practiced holding “as still as a statue.” Communication was established between the child and study coordinator through headphones equipped with a built-in microphone. Once the child was comfortable, he or she was positioned within the scanner bore, began watching a movie via MRI-compatible audiovisual system, and image acquisition began. Verbal communication and positive reinforcement was maintained with the child throughout the scan. Scanning was terminated immediately if the child did not wish to continue. All children were awake for the entire duration of the scan. Story processing fMRI task The fMRI paradigm involved a passive story processing task in which participants listened to natural speech stories in a female voice during the stimulated condition. The baseline condition included non-speech broadband noise sweep with center frequencies from 200 to 400 Hz and durations of 0.5–2.0 Hz. The task began with a stories block followed by the non-speech noise block. Each block was 64 s in duration and there was a total of 5 cycles through the two conditions. The story processing task was presented to participants through Avotec audiovisual systems equipped with Silent Scan 3100 systems. Functional MRI acquisition methods MRI data was obtained using a Philips 3 T Achieva system and a 32-channel head coil. A new concurrent whole-brain functional arterial spin labeled/blood oxygenation level dependent (ASL/BOLD) acquisition method was used with a double-excitation approach (Schmithorst et al. 2014); however, only standard BOLD acquisitions were included in the present analysis. Acquisition parameters were: TR = 4000 ms, TE1=11 ms, TE2=35 ms, matrix=64×64, FOV= 25.6×25.6 cm, slice thickness=5 mm, 25 slices acquired covering the whole brain. The ASL and BOLD image volumes were split in pre-processing and submitted to separate pre-processing pipelines, specific to the image types. For the current analysis we have used only the BOLD fMRI data from the story processing task. The ASL images are not included in the results presented here. In addition, the coregistration and alignment of the fMRI data make use of a 3D, T1-weighted
1 mm isotropic anatomical MRI image of the participant, acquired during the same functional imaging session. Data analysis First-level fMRI analysis First-level fMRI data processing was carried out using FEAT (FMRI Expert Analysis Tool) Version 6.0, part of FSL (FMRIB’s Software Library, www. fmrib.ox.ac.uk/fsl). After motion correction and spatial smoothing, fMRI data were coregistered to an ageappropriate pediatric template, created from C-MIND data for 2 to 4 years old, that was then normalized to 2 mm MNI standard space using symmetric diffeomorphic image normalization (SyN, Avants et al. 2008), as implemented in ANTs (Advanced Normalization Tools, stnava.github.io/ANTs/). Motion correction of the BOLD time-series (to a common reference frame) was carried out using MCFLIRT (Jenkinson et al. 2002). In an initial run, the central time point was used as the reference frame. Based on the derived motion parameters, the time point with the minimal displacement from the average position of the brain over the time-series was determined. Motion correction was then restarted, using this minimal displacement time point as the reference frame. Following motion correction, spatial smoothing using a Gaussian kernel of FWHM 8 mm and high-pass temporal filtering (cutoff of 104 s) was applied. Grand-mean intensity normalization by a single multiplicative factor was applied to each 4D dataset. A general linear model with autocorrelation correction was then used to compute BOLD activation at the single-subject level. For the present analysis, only BOLD data was considered (comparison with ASL is beyond the scope of this paper). Data quality assurance Raw image data from the MRI scan acquisition was reviewed for image quality by a trained expert prior to being included in the C-MIND database. Image quality was rated on a scale from 0 to 3 (zero being the best quality and three being the poorest quality) according to predefined criteria previously validated and published (Yuan et al. 2009). fMRI data with a rating of three were excluded from analysis (only one participant in the present analysis). After the preprocessing steps were applied to the fMRI time-series data and first level analysis was completed to generate the contrast maps for story processing > noise, correction for multiple comparisons was performed and the resulting contrast maps were again inspected for image quality. No data was excluded at this stage of the study. Criteria used to assign ratings are included in Table 2. Group composites and comparisons A general linear model was used to identify brain regions associated with story processing in all participants and regions that differed between boys and girls. Group comparison of boys versus girls was performed by selecting two age-matched groups, 13 boys
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Image quality rating criteria for structural and functional data
Structural imaging 0 Perfect data, no discernable artifacts, homogeneous signal intensity across field of view and clear contrast between tissue types. 1 Good image quality and contrast. Some artifacts where all slices contain a variation in intensity including variation in homogeneity or discrete artifacts such as zippers, ringing, wrap-around, etc. 2 Serious artifacts caused by motion, B0 or B1 non-uniformity. All slices contain a severe intensity variation across FOV. Poor contrast between tissue types but discernable tissue boundaries. 3 Excessive image artifacts due to motion or other factors affecting all slices. No visible tissue contrast or discernable tissue boundaries. Data should clearly be discarded. Functional imaging 0 Excellent data, no discernable motion. Intensity modulation may be present in some slices. 1 Some minimal motion where all slices contain a change in intensity and/or position. Degree of motion does not pose a threat to the integrity of the data. 2 3
Continuous, moderate motion where all slices contain a change in intensity and position. Degree of motion may pose a threat to the integrity of the data. Continuous, excessive motion where all slices contain a change in intensity and position; data should clearly be discarded.
(mean age 4.26, SD 1.00 years) and 13 girls (mean age 4.27, SD 1.03 years), and examining the differences in activation patterns between these groups. For display purposes, the group composite map and difference map for boys versus girls were thresholded with an initial z>2.3 and corrected for multiple comparisons using FSL’s cluster based inference to p noise) and receptive vocabulary skills and age. BOLD contrast for each participant was submitted to a correlation analysis with PPVT-4 standard scores and on a voxel-wise basis using participant age as a regressor of no interest (see Results: Behavioral Data below). For display purposes, correlation maps were thresholded with an initial z>2.3 and corrected for multiple comparisons using FSL’s cluster based inference to p noise in a functionally-defined region of interest (ROI) in the left angular/supramarginal gyrus that was significantly correlated with PPVT-4 score. This correlation was examined separately for boys and girls. Lateralization index A hemispheric lateralization index (LI) was calculated for each participant based on a grey matter mask extracted from a template created from the 30 participants, using a template creation script available as part of ANTs. Prior to the template creation, the T1-weighted anatomical images were bias corrected using the N4 algorithm (Tustison et al. 2010); non-brain removal was performed using BET (Smith 2002). The template was normalized to
MNI standard space as described above. By using a study specific template to extract the grey matter mask, we were able to account for left-right asymmetries in grey matter volume that are present in children in this age range (Giedd et al. 1996; Matsuzawa et al. 2001; Shaw et al. 2008). Voxels with zscores greater than or equal to the median z-score (from the unthresholded contrast maps for stories > noise) within a mask for each individual participant were used to calculate the LI for that individual. Voxels above the median z-score threshold were counted, and a lateralization index was defined as the difference in the number of activated voxels, summed independently for the left and right, divided by the sum of active voxels on the left plus the right. This procedure yields lateralization indices ranging from −1 (right) to 1 (left) (Holland et al. 2007). We then examined the relationship between LI, age, and PPVT-4 score.
Results Behavioral results The mean PPVT-4 standard score was 108.5 (SD 17.1; range 78 to 138). Scores did not differ between girls and boys [t(28)=−0.10, p>0.9], and did not correlate with age (r= −0.31, p=0.098). An additional test comparing the 10 youngest participants (mean PPVT-4=110) with the 10 oldest (mean PPVT-4=100) confirmed no relationship between PPVT-4 and age [t(18)=1.30, p>0.2]. However, while the relationship between age and PPVT-4 scores was not significant, there was a non-significant trend toward higher PPVT-4 scores in younger participants (p=0.098). This motivated our use of age as a covariate of no interest in the correlation analysis of imaging data.
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Neuroimaging results
Discussion
Group composite maps
In the present study, we used fMRI during a story processing task to examine receptive language function and lateralization in preschool children ages 3:0–5:11. We also examined the relationship between activation during the story processing task and PPVT-4 scores. We hypothesized that increased age, as well as higher vocabulary scores, would be associated with greater engagement of left hemisphere regions supporting receptive language function. We also hypothesized that regions supporting receptive language function would be more active in girls and that there would be greater involvement of brain regions supporting executive function in boys during story processing. We found that story processing resulted in bilateral superior temporal activation extending into the temporal poles, and activation of left angular/supramarginal gyrus, consistent with other studies in children 5 years of age and up (Schmithorst et al. 2006; Karunanayaka et al. 2007; Schmithorst et al. 2007). Task-negative patterns of activation (more active during the baseline noise condition than during stories) were found in regions associated with the “default mode” network (Fox et al. 2005; Dosenbach et al. 2007; Fox and Raichle 2007). Higher PPVT-4 scores correlated with activation in the left angular/supramarginal gyri. Whereas this region is not part of the “canonical” language network, a number of studies have found involvement of the angular and/or supramarginal gyri (SMG) in semantic processing (Ahmad et al. 2003; Binder et al. 2005; Lee et al. 2007; Price 2010); this suggests that children with higher vocabulary scores have a more developed semantic processing mechanism that would typically be acquired later in development. Along with activation of the angular/supramarginal gyri, higher PPVT-4 scores were correlated with activation of the thalamus. While thalamic structures were formerly thought to simply relay sensory information to cortical regions, there is increasing evidence for thalamic involvement in linguistic capacities (Klostermann et al. 2013; Crosson 2013). The Selective Engagement Model posits a cortico-thalamic network in which thalamic nuclei control the functional connectivity between frontal and temporal cortices for the integration of syntactic and semantic information (Crosson 1985; Nadeau
Regions of significant group activation during story processing relative to noise included bilateral auditory cortex and superior temporal activation extending into the temporal poles bilaterally, and left angular/supramarginal gyrus. These areas are highlighted in hot colors in Fig. 1a. Tasknegative activation, labeled in cold colors in Fig. 1a, is found bilaterally in ventral prefrontal cortex, cuneus/precuneus, and inferior parietal lobule; and right supramarginal gyrus. Some regions were more active during story processing in boys compared to girls: right anterior cingulate and right superior frontal gyrus. Areas exhibiting greater BOLD contrast (stories > noise) for the age-matched group of boys (n= 13) compared to girls (n=13) are highlighted in hot colors in Fig. 1b. The location of centroids of activation clusters and mean z-scores are listed in Table 3. Correlation of neuroimaging data with PPVT-4 scores PPVT-4 standard scores (with age included as a covariate of no interest) were positively correlated with bilateral activation in the thalamus extending into hippocampus/parahippocampal gyrus, and left angular gyrus (Fig. 2). Correlation of neuroimaging data with age No regions of significant correlations were observed between age and task-positive or task-negative activation during story processing. Region-of-interest analysis: left supramarginal/angular gyrus As described above, we selected the region of left supramarginal/angular gyrus as a region of interest to further examine the relationship between mean z-score and PPVT-4 scores in boys and girls. A significant positive correlation with PPVT-4 score was observed for both boys (r=0.63; p noise for all 30 participants (17 girls) ages 3:0 to 5:11; B Activation difference map showing regions where the BOLD contrast for story processing > noise is greater in 13 boys (n=13, mean age 4.26, SD 1.00 years) than 13 agematched girls (n=15, mean age 4.27, SD 1.03 years). Both images are thresholded at z>2.3 with correction for multiple comparisons via cluster based inference to p noise for all 30 participants. B. MNI coordinates of regions with task-negative activation for story processing > noise for all 30 participants. C. MNI coordinates of regions with positive activation for
Region A. Positive activation during story processing relative to noise Cortical L Superior/Middle/Inferior Temporal Gyrus R Superior/Middle/Inferior Temporal Gyrus L Precentral/Postcentral/L Angular Gyrus Bilateral Anterior Cingulate Subcortical Bilateral Midbrain/Hippocampus/Thalamus/Basal Ganglia Cerebellum
story processing > noise that were more active for boys (n=13) than agematched girls (n=13). D. MNI coordinates of regions with positive activation for story processing > noise that were positively correlated with scores on PPVT-4 Cluster Volume (cm3)
Center of gravity X (mm)
Center of gravity Y (mm)
Center of gravity Z (mm)
100.34 64.98 14.65 0.36
−48.20 43.80 −39.80 −7.84
−21.90 −7.06 −25.00 10.20
−2.99 −8.47 50.00 23.80
3.65 3.66 2.91 2.59
49.08 3.49
−3.95 13.70
−18.40 -75.00
−7.93 -19.00
2.73 2.59
7.92 −35.50 37.40
−57.10 49.20 44.60
36.90 11.80 11.60
−2.99 −2.89 −2.83
20.80
25.60
28.40
2.66
−46.00
−65.10
19.70
2.70
−1.89 −46.00
−36.80 −65.10
2.16 19.70
2.79 2.70
B. Negative activation during story processing relative to noise Cortical R Precuneus/ Bilateral Inferior Parietal Lobule 70.26 L Middle Frontal Gyrus 17.26 R Middle Frontal Gyrus 15.04 C. Activation greater in boys than girls during story processing relative to noise Cortical R Middle Frontal Gyrus, Anterior Cingulate 11.82 D. Activation with greater PPVT-4 scores during story processing relative to noise Cortical L Angular/Supramarginal Gyrus 14.00 Subcortical L Anterior Cerebellum, Bilateral Thalamus 19.31 L Angular/Supramarginal Gyrus 14.00
and Crosson 1997), and support for this has been found in a more recent study (Wahl et al. 2008). Growing neuroimaging evidence for the involvement of the thalamus in semantic processes comes from studies that observed thalamic activation when participants engaged in the retrieval of an object from semantic memory (Kraut et al. 2002a, b, 2003; Assaf et al. 2006). This provides additional support for the idea that children with greater receptive vocabulary scores may have a more developed semantic processing network that is typical later in development. Mesial temporal regions known to support memory encoding and retrieval (see Rugg et al. 2012 for a recent review), including vocabulary learning (Shtyrov 2012), were also more active during story processing in children with higher PPVT-4 scores. We speculate that children with greater receptive vocabulary may engage circuitry needed to comprehend the linguistic material presented to them during the stories, accessing memory representations, not only for single
Mean Z-score
vocabulary items, but of episodic memories associated with these vocabulary items. Children with higher receptive vocabulary scores also showed greater left-lateralization during story processing, as determined by global grey-matter lateralization indices. This finding further supports the idea that children with higher receptive vocabularies have language networks more similar to adults, as language lateralization has been shown to increase with age (Holland et al. 2001; Szaflarski et al. 2006; Brauer and Friederici 2007; Holland et al. 2007). This result is also similar to previous studies that have shown an association between cognitive domains and increased left-lateralization of language specific brain regions. Individuals with leftlateralization of the arcuate fasciculus, a subdivision of the superior longitudinal fasciculus white matter tract which connects frontal and temporal language areas, performed better than right-lateralized individuals on tests of verbal intelligence and phonological processing (Lebel and Beaulieu 2009). In a
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Fig. 2 Activation correlation map for all 30 participants (17 girls) showing regions where the BOLD contrast for story processing > noise is positively correlated with higher PPVT-4 scores; thresholded at z>2.3
and corrected via cluster based inference to p
