1. Participants
Seventy-nine (79) participants were included in this study. All participants were left-handed (n=67) or ambidextrous (n=12) according to the Edinburgh Handedness Inventory/EHI (Oldfield 1971; Bryden 1977). The hemispheric language lateralization of participants was calculated following the completion of an fMRI verb generation task based on which the participants were categorized as left-lateralized (n=41), right-lateralized (n=17), or ambilateral (n=21) for language. There were no statistically significant differences between the groups in terms of age (F = 1.60; P = .21), sex (χ2 = 4.88; P = .78), or EHI (F = 2.72, P = .07). A slightly significant difference (F = 3.13, P = .049) was detected in fluid intelligence (measured via WAIS-IV matrix reasoning subtest; Wechsler, 2012) between the left-lateralized and right-lateralized groups (Bonferroni’s pair-wise P = .053). Descriptive statistics of the lateralization groups can be found in Table 1.
Participants were recruited following a screening fMRI session in which language lateralization was roughly assessed using real-time data (BrainWave software, GE HealthCare Technologies Inc.), hence the high proportion of right-lateralized and ambilaterals. None of the participants reported any history of head injury resulting in the loss of consciousness or psychiatric or neurological disorders. All participants signed an Informed Consent Form prior to participating in the study, following a protocol approved by the Universitat Jaume I Ethics Committee. All methods and procedures were carried out in accordance with the approved guidelines and current regulations.
Table 1 Descriptive statistics for the left-lateralized, right-lateralized and ambilateral groups according to hemispheric lateralization of language
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Left-lateralized (n = 41)
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Ambilateral (n = 21)
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Right-lateralized (n = 17)
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Sex
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20 male, 21 female
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11 male, 10 female
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7 male, 10 female
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Age (years)
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22.46 ± 4.81
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24.76 ± 5.74
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24.71 ± 7.22
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EHI (score)
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41.24 ± 5.56
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44.14 ± 4.78
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43.65 ± 4.43
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WAIS-IV (score)
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12.49 ± 2.13
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11.71 ± 2.22
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11 ± 2
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aAge, EHI and WAIS-IV are expressed as mean ± standard deviation
2. Verb generation task
Expressive language function was measured by way of fMRI verb generation task (Sanjuán et al. 2010) that consisted of a block design paradigm with activation and control conditions. During the activation condition, participants were presented with a series of nouns and were requested to say the first verb that came to mind when seeing each word. During the control condition, participants were asked to read aloud visually presented pairs of letters. The task was administered using E-prime 2.0 (https://pstnet.com/products/e-prime) and included 6 activation and 6 control blocks. Each block lasted 30 seconds with each stimulus duration of 1500 ms and with a blank inter-stimulus interval of 1500 ms. Prior to performing the task in the scanner, each participant received detailed instructions on performing the task and completed a practice trial that lasted 2 minutes. Stimuli were presented using MRI-compatible googles (VisuaStim Digital, Resonance Technology Inc.) and verbal responses were recorded with a noise-cancelling microphone (FOMRI III+, Optoacoustics Ltd.) to ensure task compliance.
3. Landmark task
Visuospatial processing was examined by fMRI line bisection judgement task, known as the landmark task (Ciçek et al. 2009). During this task, participants were presented with a series of horizontal lines pre-bisected with a short vertical line and were required to respond by pressing the index button on the left response grip if the line was bisected correctly (task condition) and the thumb button if not. In this condition, the lines were bisected correctly in 40% of the trials or deviated to the right or left of the midline by 2.5% (hardest difficulty), 5% (medium difficulty) or 7.5% (easiest difficulty) of the line’s length, each deviation presented in 10% of the trials (see Fig 1). During the control condition, the participants were required to respond whether the presented horizontal line and the bisection mark touched (index button) or not (thumb button). In this condition, the lines were touching in 40% of the trials, and not touching in 60% of the trials. The task was administered using E-prime 2.0 (https://pstnet.com/products/e-prime) and included 7 activation and 7 control blocks. Each block lasted 22 seconds and started with a 4-second instruction, followed by a 215 ms blank inter stimulus interval and a 1.6-second presentation of a total of 12 line images. To avoid the use of the screen center as reference during the activation trials, and to ensure that participants correctly engaged in visuospatial processing, line images were not centered on the screen but slightly tilted to the left or right, alternating between trials. Prior to performing the task in the scanner, each participant received detailed instructions and completed a practice trial that consisted of 1 activation and 1 control block. Stimuli were presented using MRI-compatible goggles (VisuaStim Digital, Resonance Technology Inc.), and goggles-adapted corrective lens were available to ensure perfect visual perception for all participants. During the task, data on accuracy (% of correct responses) across all types of trials was recorded to measure task performance. Responses were registered with an MRI-compatible response grip (ResponseGrips, NordicNeuroLab).
4. Image acquisition
Images were acquired on a 3T General Electric Signa Architect magnetic resonance imaging (MRI) scanner using a 32-channel head coil. All slices were acquired in the sagittal plane. A 3D structural MRI was acquired for each subject using a T1-weighted magnetization-prepared rapid gradient-echo sequence (TR/TE = 8.5/3.3 ms; flip angle = 12; matrix = 512 × 512 × 384; voxel size = 0.47 × 0.47 × 0.5). For the functional images, a gradient-echo T2*-weighted echo-planar imaging sequence was used to acquire 150 functional volumes for the verb generation task (TR/TE = 2500/30 ms; flip angle = 70; matrix = 64 × 64 × 30; voxel size = 3.75 × 3.75 × 4). A different gradient-echo T2*-weighted echo-planar imaging sequence was used to acquire 185 functional volumes for the landmark task (TR/TE = 2000/30 ms; flip angle = 70; matrix = 64 × 64 × 27; voxel size = 3.75 × 3.75 × 4.5).
5. Image processing
The processing of the functional images was carried out using the Statistical Parametric Mapping software package (SPM12; Wellcome Trust Centre for Neuroimaging, London, UK) and MATLAB (version R2018b, MathWorks, Natick, MA). The default pipeline was followed during preprocessing steps that included: a) aligning the functional data to the AC‐PC plane by using the anatomical image; (b) head motion correction, realigning and reslicing the functional images to the mean functional image; (c) coregistration of the anatomical image to the mean functional image; (d) re‐segmentation of the anatomical image; (e) spatial normalization of the functional images to the MNI (Montreal Neurological Institute, Montreal, Canada) space with a 3 mm3 resolution; followed by (f) spatial smoothing with a 4-mm full-width-at-half-maximum (FWHM) Gaussian kernel. The general linear models (GLM) for both the verb generation task and the landmark tasks were defined for each participant by contrasting activation > control blocks. For both tasks, the BOLD (Blood‐Oxygen‐Level‐Dependent) signal was estimated by convolving each task’s block/trial onsets with the canonical hemodynamic response function (HRF). Six motion realignment parameters were included as nuisance regressors, and a high‐pass filter (128 s) was applied to the contrast images to account for low-frequency drifts.
6. Individual functional lateralization and group distribution
Functional lateralization for each task was assessed by obtaining the Laterality index (LI) using the bootstrap method implemented in the LI-toolbox for SPM12 (Wilke and Lidzba 2007). The LI is computed by calculating the proportion of activation differences between the two hemispheres for each individual subject. For the verb generation task, we explored the LI of the areas of the inferior frontal gyrus responsible for language production, specifically, pars opercularis and pars triangularis (Harvard-Oxford atlas). For the landmark task, the LI calculation centered on the posterior areas involved in visuospatial attention during this task (Fink et al. 2001; Ciçek et al. 2009; Cavézian et al. 2012; Cai et al. 2013; Zago et al. 2016), specifically: supramarginal gyrus, angular gyrus, and the superior division of the lateral occipital cortex (Harvard-Oxford atlas). The LI ranges from +100 (total left functional lateralization) to -100 (total right functional lateralization), thus providing information about the direction and degree of hemispheric lateralization during a given task. The participants were thus categorized as left-lateralized if their LI was > 40, right-lateralized if their LI was < −40, and ambilateral if their LI was in between −40 and 40.
7. Statistical analyses
A series of analyses were performed to test the hypothesis of crossed dominance of the parietal network involved in visuospatial processing in individuals with atypical language lateralization. First, a Kruskal-Wallis test was computed to check if significant differences existed in landmark LI between the left, right and ambilateral groups according to language. Post hoc pair-wise comparisons were calculated using the Dunn test. Next, Spearman’s correlation was used to study the linear relationship between the LIs for the verb generation and the landmark tasks.
Voxel-wise whole-brain activations during the landmark task were also explored in relation to language lateralization groups. One-sample t-tests were computed to describe the activation pattern during the ‘activation > control’ condition across the whole sample (voxel-wise P < .001; FWE cluster-corrected at P < .05). Then, voxel-wise two-sample t-tests were used to examine activation differences between the groups with left, right, and ambilateral language lateralization according to the verb generation task (voxel-wise P < .001; FWE cluster-corrected at P < .05).
We also studied behavioral performance during the landmark task in relation to hemispheric lateralization. First, accuracy (%) when correctly detecting the bisected lines was compared across all groups using two separate ANOVA designs (one for language-based groups, and one for visuospatial-based groups), including age and fluid intelligence (WAIS-IV score) as covariates of control. Then, two separate repeated-measures ANOVAs (one for language-based groups, and one for visuospatial-based groups) were also computed exploring the trials requiring the detection of incorrectly bisected lines. These models included difficulty (easy, medium, hard) as within-subject factor, lateralization group (left, right, or ambilateral) as between-subject factor, and the accuracy rate as a dependent variable. Age, fluid intelligence (WAIS-IV score), and accuracy rate during correctly bisected trials were used as covariates of control.