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Abnormal functional lateralization and activity of language brain areas in typical specific language impairment (developmental dysphasia)

Clément de Guibert, Camille Maumet, Pierre Jannin, Jean-Christophe Ferré, Catherine Tréguier, Christian Barillot, Elisabeth Le Rumeur, Catherine Allaire, Arnaud Biraben
DOI: http://dx.doi.org/10.1093/brain/awr141 3044-3058 First published online: 30 June 2011

Summary

Atypical functional lateralization and specialization for language have been proposed to account for developmental language disorders, yet results from functional neuroimaging studies are sparse and inconsistent. This functional magnetic resonance imaging study compared children with a specific subtype of specific language impairment affecting structural language (n = 21), to a matched group of typically developing children using a panel of four language tasks neither requiring reading nor metalinguistic skills, including two auditory lexico-semantic tasks (category fluency and responsive naming) and two visual phonological tasks based on picture naming. Data processing involved normalizing the data with respect to a matched pairs paediatric template, groups and between-groups analysis, and laterality indices assessment within regions of interest using single and combined task analysis. Children with specific language impairment exhibited a significant lack of left lateralization in all core language regions (inferior frontal gyrus-opercularis, inferior frontal gyrus-triangularis, supramarginal gyrus and superior temporal gyrus), across single or combined task analysis, but no difference of lateralization for the rest of the brain. Between-group comparisons revealed a left hypoactivation of Wernicke’s area at the posterior superior temporal/supramarginal junction during the responsive naming task, and a right hyperactivation encompassing the anterior insula with adjacent inferior frontal gyrus and the head of the caudate nucleus during the first phonological task. This study thus provides evidence that this subtype of specific language impairment is associated with atypical lateralization and functioning of core language areas.

  • specific language impairment
  • functional MRI
  • cerebral lateralization
  • cerebral function
  • language development

Introduction

Some children fail to develop typical language for no obvious reason. Their impairment typically reflects difficulties with producing and understanding oral language, and cannot be attributed to sensorimotor, intellectual deficits or other developmental impairment, especially autistic spectrum disorders, and is not the consequence of evident brain lesion or socio-affective deprivation (Bishop, 1997; Rapin et al., 2003). It usually leads to literacy difficulties (Bishop and Snowling, 2004) and, in a substantial number of cases, to persistent language difficulties through adolescence (Stothard et al., 1998). This condition is known as developmental dysphasia (Parisse and Maillart, 2009), developmental language disorder (Rapin et al., 2003) or specific language impairment (Bishop, 1997).

The current optimal diagnostic procedure of specific language impairment involves both psychometric assessment and clinical appraisal and expertise (Rapin et al., 2003; Bishop and Hayiou-Thomas, 2008), since psychometric criteria alone do not provide sufficient sensitivity, specificity and clinical congruence (Dunn et al., 1996; Bishop, 2004). Psychometric criteria may include a normal non-verbal intelligence quotient and abnormal language scores (Tomblin et al., 1996). Non-word repetition, sentence repetition and syntactic manipulation are known to be more sensitive and specific than other tests (Conti-Ramsden, 2003; Bishop, 2004).

Specific language impairment is known to be heterogeneous, encompassing distinct clinical profiles that may reflect distinct underlying deficits. A convergent trend distinguishes structural impairments affecting the core components of language (especially morphosyntax and phonology), from those affecting language reception, articulation or social use (auditory verbal processing, oromotor verbal gesture and pragmatics) (Rapin and Allen, 1983; Conti-Ramsden et al., 1997; Rapin et al., 2003; Bishop, 2004). Structural impairments are referred to as grammatical specific language impairment (van der Lely, 2005), linguistic dysphasia (Parisse and Maillart, 2009) or typical specific language impairment (Bishop, 2004).

The aetiology of specific language impairment remains largely unknown. There is growing evidence that it has a genetic component and can be inherited, but a complex picture is emerging of interaction between several genes and environmental risk factors (Fisher et al., 2003; Bishop, 2006). This interaction may affect the anatomo-functional development and organization of the brain language network (Bates, 1997; Bishop, 2000; Rapin et al., 2003; Friederici, 2006a). In addition, given the left lateralization of language in most typically developing individuals, atypical language lateralization has been hypothesized to explain literacy and language developmental disorders (Annett, 1985; Geshwind and Galaburda, 1985). Moreover, as acquired childhood aphasias show that unilateral lesion of the dominant hemisphere in childhood rarely leads to a persistent deficit (van Hout, 2003), the abnormality of brain development in specific language impairment is suspected to be bilateral (Vargha-Khadem et al., 1998; Rapin et al., 2003).

Although some studies have reported morphometric and functional brain anomalies in specific language impairment, the results remain inconsistent and heterogeneous (Webster and Shevell, 2004; Friederici, 2006a; Herbert and Kenet, 2007).

Volumetric studies have reported abnormal volume and/or asymmetries of the perisylvian frontotemporoparietal region (Plante et al., 1991), inferior frontal region (Jernigan et al., 1991) and posterior perisylvian region or planum temporale (Jernigan et al., 1991; Leonard et al., 2002). However, other studies have reported normal (Gauger et al., 1997; Preis et al., 1998) and even exaggerated (De Fossé et al., 2004; Herbert et al., 2005) asymmetry of the planum temporale. Furthermore, voxel-based morphometry studies have reported no differences of grey matter for core language areas (Jäncke et al., 2007) and grey matter increase in the right posterior superior temporal gyrus (STG; Soriano-Mas et al., 2009).

Studies using single photon emission computed tomography (SPECT) have also detected perisylvian functional anomalies, including hypoactivation of the anterior perisylvian region at rest (Lou et al., 1984) and the left inferior parietal region during phoneme discrimination (Tzourio et al., 1994), as well as Broca’s area during a dichotic verbal task (Chiron et al., 1999). However, Ors et al. (2005) reported hypoactivation at rest affecting the right parietal region and a right hyperactivation with lower left asymmetry involving the temporal lobes.

To our knowledge, three studies have investigated specific language impairment using functional MRI. In a study of eight adolescents with specific language impairment, Ellis-Weismer et al. (2005) reported hypoactivation in the left parietal region and precentral gyrus during sentence comprehension, as well as in the left insular portion of the inferior frontal gyrus (IFG) during final word recognition, without any difference of lateralization. Dibbets et al. (2006), in a study of four adolescents with specific language impairment, found hyperactivations in frontal, temporal and angular regions during a non-verbal executive paradigm. Finally, based on listening to speech sounds in five members of the same family, Hugdhal et al. (2004) reported a leftward but smaller and weaker temporal activation than in controls.

Thus, the results from neuroimaging studies of specific language impairment remain inconsistent, which may be partly due to the heterogeneity of specific language impairment (Rapin et al., 2003; Friederici, 2006a; Herbert and Kenet, 2007; Whitehouse and Bishop, 2008). In addition, although functional MRI is promising for investigating developmental language disorders (Friederici, 2006a; Gaillard et al., 2006), there are as yet very few functional MRI studies.

One issue of functional MRI language mapping is its sensitivity and specificity, i.e. the ability to draw a comprehensive and selective picture of the essential language network (Medina et al., 2007; Tie et al., 2008). Since any single language task is unlikely to engage all aspects of language, and be limited to language processing alone, one strategy is to use several tasks targeting distinct aspects of language (Deblaere et al., 2002; Roux et al., 2003; Gaillard et al., 2004). This makes it possible to focus separately on parts of the network that are distinctly recruited by the tasks, while combined tasks analysis provides a more robust laterality assessment (Ramsey et al., 2001; Rutten et al., 2002).

Functional MRI in children requires special precautions due to the risk of movement, attentional constraints, task design and preparation of the child (O'Shaughnessy et al., 2008; Leach and Holland, 2010). The procedure may be even more problematic with young and language-disordered children, who may not be able to do classical tasks involving reading or verbs-to-words and words-to-letter generation, which have been used with typically developing children. Similar difficulty arises with metalinguistic tasks, which, in addition, require explicit forced-choice analysis and are likely to involve undesired executive effects (Blank et al., 2002; Crinion et al., 2003).

Following functional MRI studies that developed task panels for language mapping in children (Gaillard et al., 2004; Wilke et al., 2006; Holland et al., 2007), we developed and tested with typically developing children a four-task panel that was specifically designed to be feasible for use with young and language-disordered children (de Guibert et al., 2010). The whole procedure avoids reading, metalinguistic or complex executive requirements. It makes use of auditory and visual stimuli, and involves language comprehension and production.

In the present functional MRI study, we use this task panel to compare a group of children with typical specific language impairment to a matched group of typically developing children. All children with typical specific language impairment were referred to a hospital specialized centre and diagnosed on both psychometric and clinical grounds. Data processing includes single task, group and between-group analysis, as well as laterality indices assessment and comparison within regions of interest using single tasks and combined tasks analysis.

Methods

Participants

The study was approved by the regional ethics committee of the University Hospital. Parents and children were informed about the experiment; parents signed the informed consent and children gave their verbal assent.

Children with typical specific language impairment were native French speakers recruited among children referred to the Centre for Language and Learning Disorders (University Hospital). They were diagnosed on psychometric and clinical grounds by the interdisciplinary team, after neuropaediatric, neuroradiological, neuropsychological and language examinations. Out of the 25 children initially recruited, four were finally excluded because of associated attention-deficit hyperactivity disorder (n = 1), non-verbal index within the deficit range (i.e. <70; n = 1) and fear (n = 1) or teeth braces (n = 1) preventing the MRI session. This resulted in a group of 21 children with typical specific language impairment aged from 7 to 18 years (mean age = 11.4 ± 3.3), with nine males (mean age = 11.4 ± 3.7) and 12 females (mean age = 11.4 ± 3.1). Three children were left handed (14.3%), as assessed by the Edinburgh inventory (Oldfield, 1971), which is within the estimation of 8–15% left-handers for the general population (Hardyck and Petrinovitch, 1977). None exhibited any neurological anomalies or auditory deficit, or was affected by communication, behavioural or attentional disorders. The visual inspection of anatomical 3D T1 and fluid attenuated inversion recovery images by an experienced neuroradiologist showed no significant abnormalities.

A matched group of typically developing children was recruited excluding non-French native language speakers, previous or current neurological, developmental or psychiatric illness, as well as learning disability or abnormal academic performance. They did not undergo psychometric testing. This resulted in a group of 18 children aged from 8.7 to 17.7 years (mean age = 12.7 ± 3), with nine males (mean age = 12.3 ± 3.2) and nine females (mean age = 13 ± 3). Two children (11.1%) were left handed.

The typical specific language impairment and control groups were similar for sex and handedness, and no significant between-group difference was found for age (P = 0.22).

Neuropsychological and language assessment

Neuropsychological assessment includes achievement of the full Wechsler Intelligence Scale for Children–Fourth edition (WISC-IV; Wechsler, 2003). This version provides a Verbal Comprehension Index and a Perceptual Reasoning Index replacing the previous verbal and non-verbal intelligence quotients. Two subjects older than 16 years performed the full Wechsler Adult Intelligence Scale–Third edition (WAIS-III; Wechsler, 1997).

Children with typical specific language impairment as a group showed a discrepancy between low verbal (Verbal Comprehension Index) and higher non-verbal (Perceptual Reasoning Index) indices (Table 1). Individually, non-verbal scores were all above the intellectual deficit range (i.e. Perceptual Reasoning Index ≥70).

View this table:
Table 1

Groups characteristics

Control group (n = 18)
    Age (years)12.7 ± 3 (8.7 to 17.7)
    Gender (male:female)9:9
    Handedness (left:right)2:16
Typical specific language impairment group (n = 21)
    Age (years)11.4 ± 3.3 (7 to 18)
    Gender (male:female)9:12
    Handedness (left:right)3:18
    Intellectual indices (WISC-IV)
     Verbal index (VCI)77.0 ± 15.7 (45 to 112)
     Non-verbal index (PRI)90.0 ± 13.1 (73 to 121)
    Language z-scores (L2MA)a
     Phonology (complex unfamiliar word repetition)−2.4 ± 1.7 (−6.9 to 0.4)
     Vocabulary (picture naming)−0.3 ± 1.0 (−2.6 to 1.3)
     Morphosyntactic integration (sentence completion)−1.2 ± 1.5 (−5.0 to 1.3)
     Complex instructions comprehension−0.2 ± 1.1 (−2.2 to 1.7)
     Morphosyntax-comprehension (sentence–picture match)−0.5 ± 1.0 (−2.5 to 1.1)
     Sentence repetition−1.4 ± 0.8 (−2.5 to 0.8)
  • Ranges are reported in brackets. Bold font indicates language scores <1 SD below the normal mean.

  • a Including scores of the four youngest children who performed equivalent subtests from the Nouvelles Epreuves pour l’Evaluation du Langage (N-EEL; see text).

  • L2MA = battery Langage oral, Langage écrit, Mémoire, Attention; WISC-IV = Wechsler Intelligence Scale for Children-Fourth version; VCI and PRI = Verbal Comprehension and Perceptual Reasoning Indexes.

The language assessment included subtests from the ‘Langage oral, Langage écrit, Mémoire, Attention’ battery (L2MA; Chevrie-Muller et al., 1997). Since the L2MA is standardized from 8 years and 7 months onwards, four children below this age performed analogous subtests from the Nouvelles Epreuves pour l’Examen du Langage, standardized for younger children (N-EEL; Chevrie-Muller and Plaza, 2001). All children performed the six following subtests: phonology (repetition of complex unfamiliar words); vocabulary (picture naming); morphosyntactic integration and comprehension (sentence completion; sentence–picture matching); comprehension of complex instructions; and sentence repetition.

Children with typical specific language impairment as a group showed scores <1 SD below the normal mean for phonology (repetition of complex unfamiliar words), sentence repetition and morphosyntactic integration (sentence completion) (Table 1). Individually, all children performed <1.5 SD below the normal mean for at least one of these subtests. Thus, all children demonstrated impairments of the phonological or morphosyntactic components of language, or both, which is characteristic of typical specific language impairment. No child was diagnosed with developmental verbal dyspraxia, verbal auditory agnosia or pragmatic language impairment.

Functional MRI protocol and task panel

The protocol has been previously described (de Guibert et al., 2010) and is summarized here. The session includes four language tasks separately implemented with the same parameters, aiming to minimize attentional complications: a simple block design involves alternating a rest condition with a task, starting with rest. Each paradigm comprises three 27 s blocks of each condition and has a total duration of 2 min 48 s. The session has duration of 30–35 min, including the anatomical acquisition and the four tasks. All subjects perform the tasks in the same order, as during the preparation step, to avoid the mixing of auditory and visual tasks. During the rest condition, children are asked ‘not to work’, to listen to the noise of the scanner, while fixing their attention on a red cross displayed on the screen.

The panel of tasks does not involve reading, metalinguistic (i.e. explicit analysis of language) or high-executive skills, and targets anterior and posterior core language areas. It uses auditory and visual stimuli delivery, solicits language comprehension and production, and involves lexico-semantic and phonological processing.

Two auditory lexico-semantic tasks were chosen from the literature because of their distinct and selective activations of either the left IFG (word generation from categories, Gaillard et al., 2003; hereafter ‘category task’) or the left STG (auditory responsive naming, Balsamo et al., 2002; hereafter ‘definition task’).

In the category task adapted from Gaillard et al. (2003), children hear category names (e.g. animals, colours) and have to silently generate examples of these categories. A category name is delivered every 9 s, with three categories per block and nine categories for the whole task.

In the definition task adapted from Balsamo et al. (2002), children hear definitions of concepts (e.g. ‘a big animal with a trunk’) and have to find and silently name the corresponding word (e.g. elephant). Definitions are delivered every 9 s, with three definitions per block and nine definitions for the whole task.

Two new visual phonological tasks are based on picture naming and require the child to silently name three objects repetitively (i.e. triplets) one-by-one. Within the triplets, the names are semantically unrelated, but exhibit a minimal phonological change, either, for the first task, a phonological minimal difference (hereafter ‘phon-diff task’), or, for the second task, a change in segmentation (hereafter ‘phon-seg task’). These tasks are adapted from so-called minimal pairs in linguistics and from procedures used in the assessment and remediation of phonological disorders. The repetitive evocation of just three familiar but phonologically close words attenuates the lexico-semantic requirements, while stressing the phonological constraints.

In both tasks, line drawings of objects from each triplet are displayed every 1.4 s, successively and randomly (without any picture being delivered twice in succession), so that the child could not predict the upcoming picture. Three distinct triplets (one per block) are used for each task.

In the phon-diff task, children name objects such as poule, boule and moule [/pul/–/bul/–/mul/; (hen, ball, tin)]. In the triplets, a difference of distinctive feature occurs in the first phoneme, e.g. the voicing feature of /p/ and /b/ (voiceless versus voiced) for poule and moule. Concretely, children may successively name, for example: ‘poule, moule, boule, moule, poule …’ in a first block, then: ‘banc, dent, gant, dent, banc …’ [/bã/, /dã/, /gã/…; (bench, tooth, glove)] in a second block, and so on.

In the phon-seg task, children name objects such as ‘car, car-te and car-t-on’ [/kar/–/kart/–/kartõ/; (car, card, cardboard box)]. In the triplets, there is a change of segmentation, with phoneme addition (car and then carte or carton) or subtraction (carton and then carte or car). Concretely, children may successively name, for example: ‘car, carte, carton, carte, car …’ in a first block, then: ‘croix, roi, oie, roi, croix …’ [/krwa/, /rwa/, /wa/…; (cross, king, goose)] in a second block, and so on.

For all tasks, children were prepared extensively prior to entering the scanner, with each task being thoroughly explained and practiced several times, using original task material and both aloud and silently, to check for comprehension and achievement by the child.

Data acquisition

Acquisitions were performed on a 3 T whole-body scanner (Achieva, Philips Medical Systems) using a 8-channel head coil. Anatomical 3D T1-weighted images were acquired with a Fast Field Echo sequence. The acquisition parameters were as follows: echo time/repetition time/flip angle = 4.6 ms/9.9 ms/8°; acquired matrix size: 256 × 256 mm; field of view: 256 mm; voxel size: 1 × 1 × 1 mm; volume: 160 sagittal 1-mm thickness slices; acquisition time: 3 min 56 s. Functional images were acquired using a single-shot T2* weighted gradient-echo echo planar imaging sequence. Twenty-four 4-mm slices were acquired with the following parameters: echo time/repetition time/flip angle: 35 ms/3000 ms/90°; acquired matrix size: 80 × 80; reconstructed matrix size: 128 × 128; field of view: 230 × 230; acquired voxel size: 2.9 × 2.9 × 4 mm; reconstructed voxel size: 1.8 × 1.8 × 4 mm. Slices were positioned parallel to the anterior commissure–posterior commissure line, with no gap, and were interleaved from bottom to top. Each functional run consisted of 56 series of image acquisitions for the 24 slices covering the entire brain volume separated by a 3000 ms delay, with a total acquisition time of 2 min 48 s. Children were positioned supine in the system. The subject’s head motion was minimized using straps and foam padding.

Visual stimuli were delivered through a screen placed within the head-coil (IFIS-SA functional MRI system, Invivo) just in front of the face and synchronized with the scanner. If necessary, the children wore corrective glasses compatible with the high-magnetic field environment. Auditory verbal stimuli were delivered by an experienced member of the staff using the machine microphone, via specially converted high-fidelity stereo headphones.

Data processing

MRI data were preprocessed and analysed using the General Linear Model (Friston et al., 1995) with SPM5 (Statistical Parametric Mapping; Wellcome Department of Imaging Neuroscience, University College London; www.fil.ion.ucl.ac.uk). The first two volumes of functional MRI data were discarded to allow for signal stabilization. Slice timing and motion correction were applied to the remaining 54 volumes. Data were excluded if associated with excessive motion (>3 mm of translation in any direction or 3° of rotation throughout the session). To prevent bias caused by the normalization of paediatric data on adult templates (Wilke et al., 2003a), we used the match pair option of the Template-O-Matic toolbox (Wilke et al., 2008) to generate a customized paediatric template based on the age and sex of our 39 subjects. Structural MRI were segmented using unified segmentation (Ashburner and Friston, 2005), and then normalized. Functional MRI data were registered on structural images, normalized and then smoothed using an isotropic 8-mm full width at half maximum 3D Gaussian kernel.

Statistical activation maps were obtained using a mixed effects analysis. At the subject level, a high-pass filter was applied to functional MRI data to remove slow signal drifts due to undesired effects. The haemodynamic response was modelled by the Informed Basis Set (Friston et al., 1998) to account for possible delay and dispersion of the response from the canonical haemodynamic response function. For each task, group activations were identified by contrasting out the effect of temporal and dispersion derivative, focusing on the canonical variable, at a threshold of P < 0.05 Family-wise-error corrected for multiple comparisons at the cluster level with a cluster-defining threshold of P < 0.001. Between-group comparisons were considered significant at the cluster level at a threshold of P < 0.05 family-wise-error corrected, with a cluster-defining threshold of P < 0.005.

For regional analyses, regions of interest covering brain areas involved in language were selected from the literature: the IFG-opercularis, IFG-triangularis, STG, SMG and insula. For laterality assessment, the following extended regions of interest were also computed: frontal language (IFG-opercularis, IFG-triangularis, insula), temporoparietal language (STG, SMG), language (i.e. combining the two previous regions) and non-language (i.e. all brain regions of interest except the ‘language region of interest’). Left and right regions of interest as delineated in the Automated Anatomical Labelling atlas (Tzourio-Mazoyer et al., 2002) were adapted to our customized paediatric template using an approach by Wilke et al. (2003b). To match our template, we performed a non-linear deformation of the structural image on which the Automated Anatomical Labelling regions were delineated. The deformation parameters were then applied to the region of interests.

Laterality indices were estimated using the lateralization index toolbox (Wilke and Lidzba, 2007). For each subject, the average t-value within each region of interest was measured and voxels smaller than this threshold were discarded. The laterality index was then calculated with the remaining voxels as follows: Embedded Image where Embedded Image and Embedded Image denote the sum of the remaining voxels in the left and right parts of the region of interest, respectively.

The lateralization index was calculated for each single task and also using combined task analysis (Ramsey et al., 2001), the latter being known to yield more robust lateralization index when dealing with a panel of tasks (Rutten et al., 2002). Box plots based on these values were created for each region and each task. T-tests were performed on each region of interest to determine significant group lateralization (i.e. left or right if lateralization index significantly greater or less than zero, respectively; otherwise bilateral). Correlation with age was assessed using covariance analysis including the factors group, age and interaction. When the effect of interaction and age were non-significant, and based on current hypotheses about specific language impairment, a one-tailed two-sample t-test was performed to highlight laterality differences in language region of interests, while a two-sided two-sample t-test was performed in non-language regions of interest.

Results

The results are reported successively for each single task, focusing on language areas, including group analysis (Fig. 1), between-group comparisons (Fig. 2), as well as lateralization index measurements and comparison (Fig. 3). Finally, comparison of lateralization indices using the combined task analysis is reported (Fig. 4).

Figure 1

Functional MRI group effects for each language task (P < 0.05 family-wise-error corrected). The functional maps are superimposed onto an individual brain normalized with respect to our customized paediatric template, with x-coordinates in Montreal Neurological Institute space. Left slices are left hemisphere. T-SLI = typical specific language impairment.

Figure 2

Functional MRI between-group comparisons for definition and phon-diff tasks (P < 0.05 family-wise-error corrected). Blue and yellow colours indicate the hypo- and hyperactivations, respectively, for the typical specific language impairment group compared with the control group. The 3D view focuses on the peak contrasts. Functional maps are superimposed on an individual brain normalized with respect to our customized paediatric template. Coordinates are in Montreal Neurological Institute space. T-SLI = typical specific language impairment.

Figure 3

Laterality indices, significant group lateralizations and between-group comparisons within the region of interests for each single language task. The box plots depict group lateralization for each region of interest, with positive and negative lateralization indices reflecting left and right, respectively, and with significant left or right lateralizations (P < 0.05) outlined by bold lines. The P-values of between-group comparisons are indicated, with significant between-group differences outlined by a square bracket with an asterisk. aP-value of group factor from analysis of covariance with factors age and group.

Figure 4

Lateralization indices, significant group lateralizations and between-group comparisons using combined tasks analysis within single (right) and extended (left) regions of interest. The box plots depict group lateralization for each region of interest, with positive and negative lateralization indices reflecting left and right, respectively, and with significant left or right lateralizations (P < 0.05) outlined by bold lines. The P-values of between-group comparisons are indicated, with significant between-group differences outlined by a square bracket with an asterisk. ROI = region of interest. aP-value from two-sided two sample t-test. Temporoparietal language region of interest = STG and SMG; frontal language region of interest = IFG (opercularis and triangularis) and insula; language region of interest = frontal language and temporoparietal language regions of interest; non-language region of interest = whole brain (i.e. all Automated Anatomical Labelling regions of interest) except language region of interest.

Auditory language tasks

Category task

The control group showed left-only activations in the dorsal IFG as well as in the posterior STG with, as expected, a predominance of the former. A left-dominant activation was situated in the anterior insula and extended into the ventral IFG. According to the lateralization indices, the left lateralization was significant in the IFG-opercularis and -triangularis.

In contrast, the typical specific language impairment group showed small activations in the left dorsal IFG, and no activation in the most posterior STG. The activation of the anterior insula was right dominant and extended into the ventral IFG on the right. According to the lateralization indices, no region of interest was significantly lateralized.

The between-group analysis did not reveal any significant between-group differences. However, the lateralization index comparison revealed a significant lack of left lateralization of the IFG-opercularis in the typical specific language impairment group (Fig. 3).

Definition task

The control group shows left-only activations in the posterior STG/adjacent SMG, and in the dorsal IFG, with an expected predominance of the former. A left-dominant activation occurred in the anterior insula and extended into the adjacent ventral IFG. According to the lateralization indices, the SMG and IFG-opercularis were significantly left lateralized.

In contrast, the typical specific language impairment group showed no activation in the posterior STG/adjacent SMG or in the dorsal IFG. A bilateral activation was centred on the anterior insula and extended, superiorly on the right, into the ventral IFG. According to the lateralization indices, no region of interest was significantly lateralized, although the IFG and the SMG tended towards the right.

The between-group analysis highlighted a left hypoactivation centred on the posterior STG/SMG junction in the typical specific language impairment group (Fig. 2; k = 304; T = 4.42; P = 0.03). According to the lateralization index comparison, there was a significant lack of left lateralization of the SMG, IFG-opercularis and IFG-triangularis in the typical specific language impairment group (Fig. 3).

Visual language tasks

Phonological minimal difference task

The control group showed left-only activations in the ventral and dorsal IFG and in the anterior insula, without activation in the STG. According to the lateralization indices, the IFG-opercularis was significantly left lateralized.

In contrast, the typical specific language impairment group showed right-only activation in the IFG and a right-dominant activation in the anterior insula. According to the lateralization indices, the IFG-triangularis was significantly right lateralized.

Between-group analysis highlighted a right hyperactivation centred on the anterior insula, extending into the adjacent ventral IFG (opercularis and triangularis) and into the head of the caudate nucleus in the typical specific language impairment group (Fig. 2; k = 362; T = 4.34; P = 0.02). According to comparison of the lateralization indices, there was a significant lack of left lateralization of the IFG-opercularis in the typical specific language impairment group (Fig. 3). A positive effect of age on lateralization index was found in the SMG (P = 0.024), but no group difference was detected in this region.

Phonological change in segmentation task

The control group showed a left-dominant activation in the ventral and dorsal IFG-opercularis, as well as left-only activations in the posterior STG/adjacent SMG and in the anterior insula. According to the lateralization indices, no region was significantly lateralized.

In contrast, the typical specific language impairment group showed no activation in the IFG, STG, SMG or the insula. According to the lateralization indices, no region of interest was significantly lateralized.

The between-group analysis did not reveal any significant between-group differences. However, the lateralization index comparison highlighted a significant lack of left lateralization of the IFG-opercularis in the typical specific language impairment group (Fig. 3).

Lateralization index assessment and comparison using combined task analysis

According to the assessment of lateralization indices using combined task analysis, the control group exhibited a left lateralization of the SMG and STG. This was not observed with the typical specific language impairment group, where no region of interest was lateralized. According to the between-group comparison, the lack of left lateralization in the typical specific language impairment group was significant for the SMG and STG (Fig. 4).

Subsequently, combined task analysis was carried out using extended regions of interest: frontal language, temporoparietal language, language (i.e. combining the two latter) and non-language region of interest (i.e. all Automated Anatomical Labelling regions of interest except the latter). In the control group, lateralization indices from the combined task analysis show a left lateralization in all these extended regions of interest. This is not the case for the typical specific language impairment group, where no lateralization appears, despite a right trend for the frontal language and language region of interests.

The between-group comparison of the lateralization indices highlights a significant lack of left lateralization in all extended language regions of interest (i.e. temporoparietal language, frontal language and language), while, inversely, there is no significant difference for the non-language region of interest (Fig. 4).

In summary, our main results highlight a left hypoactivation centred on the posterior STG/SMG junction (definition task), a right hyperactivation of the anterior insula including the adjacent IFG and extending into the head of caudate (phon-diff task) and a lack of left lateralization of core language areas in the typical specific language impairment group. The lack of left lateralization is found for the IFG-opercularis (all tasks), the IFG-triangularis (definition task), the SMG (definition task and combined tasks), the STG (combined tasks), and in all extended language region of interests when using combined tasks. On the contrary, there is no difference of lateralization for the rest of the brain when the language regions are excluded.

Discussion

Although functional neuroimaging may have an expanding role in the investigation of development language disorders, functional MRI studies of specific language impairment are sparse and available results from functional studies remain inconsistent, in parallel with heterogeneous morphometric findings. Based on a comparison with typically developing children, we studied a group of 21 children with typical specific language impairment, a main form of specific language impairment affecting structural aspects of language, which was diagnosed on psychometric and clinical grounds. To apply an appropriate procedure and to improve the mapping by using several tasks, we set up a panel of tasks without reading, metalinguistic or high attentional requirements. Three main interesting results arise from our study: (i) the lack of left lateralization of core language areas; (ii) the left hypoactivation centred on the posterior STG/SMG junction (definition task); and (iii) the right hyperactivation of the anterior insula including the adjacent IFG and extending into the head of caudate (phon-diff task).

Lack of left lateralization of core language areas

The study reveals a lack of left functional lateralization for all single language regions of interest across single or combined tasks, i.e. in the IFG-opercularis (all tasks), the IFG-triangularis (definition task), the SMG (definition and combined tasks) and the STG (combined tasks). In addition, when using combined tasks analysis, this lack also applies to larger frontal and temporoparietal language regions of interest, while interestingly, no significant difference appears for the whole brain when language regions of interest are excluded. Thus, our study provides evidence that typical specific language impairment is associated with atypical lateralization of language function in core language areas.

No anomaly of lateralization was found or reported in previous functional MRI studies of specific language impairment (Hugdhal et al., 2004; Ellis Weismer et al., 2005; Dibbets et al., 2006), including a study of orofacial verbal dyspraxia (Liégeois et al., 2003), which could be due to reduced sample sizes, distinct activation tasks and/or distinct clinical subtypes. However, single-photon emission CT studies at rest have reported a reversed asymmetry in Wernicke’s area (Chiron et al., 1999) and a more symmetric activation in the temporal lobe (Ors et al., 2005). Furthermore, one study using functional transcranial Doppler ultrasonography during words-to-letter generation reported a lack of leftward dominance of blood flow in adults with persisting specific language impairment, a condition more associated with structural language impairment than transient specific language impairment (Whitehouse and Bishop, 2008).

Our results support the hypothesis of atypical cerebral dominance for literacy and language developmental disorders, although atypical lateralization is not in itself either abnormal or specific. Atypical functional lateralization has been reported in 5% of right-handed and 73–80% of non-right-handed normal subjects (Szaflarski et al., 2002) and in other developmental clinical conditions including speech delay (Bernal and Altman, 2003), stuttering (Brown et al., 2005), autism spectrum disorder (Kleinhans et al., 2008; Knaus et al., 2008) and dyslexia (Maisog et al., 2008; Heim et al., 2010).

Therefore, our study shows that a well-defined form of specific language impairment affecting structural aspects of language is more associated with atypical functional lateralization of core language areas, but we cannot yet affirm that it is a specific marker of typical specific language impairment. As argued by Whitehouse and Bishop (2008), atypical cerebral lateralization may be an indicator, albeit imperfect, of some causal factor that leads together to atypical cerebral lateralization and language impairment.

Left hypoactivation of the posterior superior temporal gyrus/supramarginal gyrus junction

The second result, provided by the definition task, is the left hypoactivation centred on the junction of the posterior supratemporal plane (STG) and the SMG, extending laterally, deeply into the Sylvian fissure, and superiorly in the parietal operculum and parietal inferior lobule. This region is crucial for language, belonging to the so-called ‘Wernicke’s area’ or ‘territory’ (Blank et al., 2002; Catani et al., 2005).

The central location of the hypoactivation corresponds to the posterior planum temporale/ventral SMG region (Price, 2010) or ‘area sylvian parietal-temporal’ (Hickok and Poeppel, 2007), which may be a sensorimotor interface translating acoustic speech signals from the posterior temporal sulcus into articulatory representation for the premotor cortex and posterior IFG. This region is involved in both complex speech perception and production (e.g. Hickok et al., 2003; Price, 2010), and its lesion may be associated with conduction aphasia, which exhibits phonemic paraphasias with better preserved comprehension (Hillis, 2007). Therefore, on the whole, the putative function of this region is in agreement with the task used here involving both speech reception and (covert) production, and with the linguistic deficit inherent to typical specific language impairment.

In line with our result, single-photon emission CT studies of specific language impairment have reported bilateral posterior perisylvian hypoactivation at rest (Lou et al., 1984) and no activation of the left inferior parietal region during phonological discrimination (Tzourio et al., 1994). One functional MRI study has also reported a hypoactivation in the left parietal lobe during sentence comprehension (Ellis Weismer et al., 2005). In contrast, using single-photon emission CT at rest, Ors et al. (2005) reported a hypoactivation of the right parietal region.

One question is whether our result can be linked to morphological anomalies. Volumetric studies of specific language impairment have shown a reduced volume of the perisylvian temporoparietal region (Jernigan et al., 1991) and reduced left asymmetry of the planum temporale when compared with reading disability (Leonard et al., 2002). However, other authors report normal volume and asymmetry for the planum temporale (leftward) and for the parietal ascending ramus (rightward) (Gauger et al., 1997; Preis et al., 1998), and even an exaggerated leftward asymmetry for the planum temporale (De Fossé et al., 2004; Herbert et al., 2005), without any difference for the parietal opercule and the SMG (De Fossé et al., 2004). Using voxel-based morphometry, Jäncke et al. (2007) found no grey matter differences for core language areas, and Soriano-Mas et al. (2009) reported an increase in grey matter at the right temporoparietal junction. Apart from methodological differences, this heterogeneity may result from the heterogeneity of specific language impairment.

In summary, the left hypoactivation of the posterior STG/SMG junction found in children with typical specific language impairment during the auditory responsive naming task could reflect a dysfunction of a core region considered as an interface between complex language reception and production (Hickok and Poeppel, 2007; Price, 2010). This result converges with a single-photon emission CT study of specific language impairment using a discrimination task involving phonologically close words (Tzourio et al., 1994).

Right hyperactivation of the anterior insula, adjacent inferior frontal gyrus and head of caudate

The third main result of this study is the right hyperactivation centred on the anterior insula and extending into the adjacent IFG (opercularis and triangularis), as well as into the head of caudate, during the phon-diff task. The anterior insula and adjacent IFG is an important region for language, in continuity with the frontal operculum and, at the left side, Broca’s area (Keller et al., 2009). The head of caudate has already been highlighted in a developmental speech disorder, orofacial verbal dyspraxia (Vargha-Khadem et al., 2005).

The anterior insula is involved in motor aspects of speech, although its specific role for speech remains unclear. Overall, this region has been linked with coordination and motor control of speech articulation, vocal tract and mimic muscles, as well as non-speech orofacial gestures, swallowing and respiratory voluntary regulation (Brown et al., 2005, 2009; Ackermann and Riecker, 2010; Price, 2010). Clinical studies have yielded some controversial results, with one study based on lesion overlap reporting a correlation of left insular lesion with deficits in motor programming of speech (Dronkers, 1996), which was not replicated using neuroimaging at stroke onset (Hillis et al., 2004). Single clinical cases and brain stimulation studies involving the insula have reported aphasic, dysarthric, speech initiation and/or non-speech oromotor disturbances, and functional neuroimaging studies have revealed the involvement of the anterior insula, predominantly on the left, in motor aspects of speech (Ackermann and Riecker, 2010; Price, 2010). Interestingly, Bohland and Guenther (2006) found increased bilateral activation of the insula/IFG junction in proportion to phonological complexity by requiring triads of syllables of varying complexity (ta-ta-ta/ka-ru-ti/stra-stra-stra/kla-stri-splu), which suggests a function of integration of low-level motor aspects, abstract speech sounds and prosodic components in speech planning. The right anterior insula/frontal operculum may specifically mediate suprasegmental aspects of speech (prosody, intonation contour), as well as vocal imitation and musical melodies (Brown et al., 2005; Ackermann and Riecker, 2010).

Therefore, the hyperactivation in the right anterior insula/adjacent IFG during our phonological task could reflect an articulatory and/or prosodic compensatory mechanism of defective structural phonological function in typical specific language impairment. Such a compensation could be interhemispheric (i.e. left to right) and possibly intrahemispheric (i.e. lateral IFG to insula). Compensatory interhemispheric recruitment of the right inferior frontal region is well known after the left acquired lesions associated with aphasia (Crinion and Leff, 2007), and the recruitment of the right insula may compensate dysfunction of the left counterpart (Duffau et al., 2001). An intrahemispheric shift of frontal response towards the anterior insula/frontal operculum, at the right side, has also been reported in subjects with left temporal lobe epilepsy (Voets et al., 2006). If further corroborated, this suggests that the insular structure might be involved in the compensation of speech/language function (Ackermann and Riecker, 2010).

Previous functional neuroimaging studies of specific language impairment yield results that are heterogeneous with respect to the insula. A right hyperactivation has been highlighted in the anterior part during speech sound listening (Hugdhal et al., 2004) and in the posterior part during a non-verbal executive paradigm (Dibbets et al., 2006). This contrasts with hypoactivation on the left during word recognition (Ellis Weismer et al., 2005). While one volumetric study reports a volume reduction of the left insula (Jernigan et al., 1991), no anomaly of the insula has been observed using voxel-based morphomtery (Jäncke et al., 2007; Soriano-Mas et al., 2009).

In our study, the right hyperactivation extends into the head of caudate. The caudate nucleus participates in sensorimotor coordination including response selection and initiation, in executive-related processes, and may support the planning and execution of correct strategies required for complex goals (Grahn et al., 2008). As regards to speech, the caudate nucleus is involved in the control and selection of articulatory motor sequences, and may initiate cortical phonological and controlled processes when automatic processes are not well-suited (Friederici, 2006b; Booth et al., 2007). Furthermore, the bilateral head of caudate is involved in language-based conflict, suggesting that it participates in the suppression of inappropriate responses in a competitive context (Price, 2010). Similarly, the hyperactivation of the right head of caudate during the phon-diff task in our study could reflect higher compensatory attempts of initiation of phonological processes in the context of phonological conflict (e.g. the minimal difference between pain/bain/main).

Regarding previous neuroimaging studies of specific language impairment, the right caudate has been found to be hyperactive during a non-verbal switch paradigm in four children (Dibbets et al., 2005). Moreover, it was bilaterally reduced in the volumetric study by Jernigan et al. (1991), but increased on the left in the voxel-based morphometry study by Soriano-Mas et al. (2009).

In summary, the right hyperactivation of the anterior insula/adjacent IFG and the head of caudate in typical specific language impairment, which is highlighted when requiring phonological differentiation, could reflect compensatory recruitments of non-language-specific functions resulting from the structural phonological deficit. This could be associated with higher recruitment of orofacial and intonative motor functions for the anterior insula/adjacent IFG, and response initiation and selection in the context of interferences for the head of caudate.

Comparison with other developmental disorders

Another question is whether the functional abnormalities reported in our study are specific to structural language disorder (i.e. typical specific language impairment) compared with disorders affecting other aspects of language such as communication, reading or speech.

With regards to the left temporoparietal hypoactivation, in autistic spectrum disorder, in contrast, hyperactivation has been detected in the posterior temporal region during a responsive naming task (Knaus et al. 2008) and other language tasks (Just et al., 2004; Harris et al., 2006). On the other hand, left temporoparietal hypoactivation appears to be a ‘neural signature’ of dyslexia (Shaywitz and Shaywitz, 2008), as obtained during reading, rhyme or semantic tasks (Paulesu et al., 1996; Schulz et al., 2008; Richlan et al., 2009). Phonological disturbances in dyslexia nevertheless concern metalinguistic tasks (i.e. phonological awareness) rather than direct oral language, likely reflecting a phonological-access deficit (Ramus and Szenkovits, 2008), and the differentiation from specific language impairment remains clinically and aetiologically justified (Bishop and Snowling, 2004). Finally, as regards speech disorders, developmental stuttering has been associated with hypoactivation of the auditory cortices, but not of the temporoparietal junction (Brown et al., 2005; Watkins et al., 2008), while orofacial verbal dyspraxia in Family KE was associated with hypoactivation near the left posterior STG/SMG junction during covert verb generation (Liégeois et al., 2003). Although the core deficit in this family is dyspraxic, affected members also exhibit phonological and grammatical impairments, so linguistic deficits cannot be ruled out (Vargha-Khadem et al., 2005).

As regards the right hyperactivation of the anterior insula/adjacent IFG, in autistic spectrum disorder, the insula has been found to be hypoactive during tasks involving social processing (Uddin and Menon, 2009). In dyslexia, hyperactivation of the anterior insula has been observed during reading tasks, either on the left or on the right (Maisog et al., 2008; Richlan et al., 2009). However, one study reports a bilateral hypoactivation in parallel to higher activation of the adjacent frontal operculum during click and speech sound listening (Steinbrink et al., 2009). As regards speech disorders, the anterior insula has been found to be hyperactive at the left side during overt words repetition in orofacial verbal dyspraxia (Liégeois et al., 2003). Nevertheless, it is noteworthy that hyperactivation of the right frontal operculum/anterior insula during speech production is considered as a ‘neural signature’ of developmental stuttering (Brown et al., 2005; Watkins et al., 2008). This suggests that lower skills for speech result in compensatory hyperactivation of vocal–motor areas, which are right lateralized because of left dysfunction of the normal dedicated regions (Preibish et al., 2003; Brown et al., 2005).

As regards the right hyperactivation of the caudate, no functional anomaly of the caudate has been found either in autistic spectrum disorder during language tasks (Harris et al., 2006; Knaus et al., 2008) or in dyslexia (Maisog et al., 2008; Richlan et al., 2009). Nevertheless, in studies of orofacial verbal dyspraxia in Family KE, the caudate was found to be both bilaterally morphologically reduced (Varkha-Khadem et al., 1998; Watkins et al., 2002; Belton et al., 2003), and functionally hyperactive on the left (Vargha-Khadem et al., 1998). In this context, these anomalies come under the hypothesis of a dysfunction of the frontostriatal network (Vargha-Khadem et al., 2005). Finally, the activity of the caudate on both sides has been positively correlated with the severity of developmental stuttering (Giraud et al., 2008), and a dysfunction of the basal ganglia has been speculated to underlie the deficit in the timing of speech motor initiation (Alm, 2004), or to reflect a secondary dysfunction resulting from a left inferior frontal anomaly (Kell et al., 2009).

In summary, the left temporoparietal hypoactivation associated with typical specific language impairment is similar to results obtained by studies of dyslexia (Richlan et al., 2009) and by one study of orofacial verbal dyspraxia (Liégeois et al., 2003). Moreover, in developmental stuttering, the hyperactivation of the right anterior insula is regarded as a ‘neural signature’ (Brown et al., 2005) and the activity of the right caudate is correlated with the severity of impairment (Giraud et al., 2008). As these disorders and the activation tasks used are distinct, further studies are needed to elucidate whether these similarities reflect common dysfunctions, common atypical compensatory modes of resolution of language tasks and/or more task-specific effects.

Methodological considerations

As described previously (de Guibert et al., 2010), to optimize the feasibility of the procedure for young disordered children, and minimize motion artefacts as well as attentional complications, we implemented four identical block-designed paradigms with a low-level condition as baseline (listening to the noise and fixing a red cross) and without requiring motor responses. These choices reduced the heterogeneity and complexity of the protocol, as the child did not have to understand and achieve supplementary control tasks and also give motor responses. Furthermore, although requiring motor responses is well suited for metalinguistic tasks (i.e. judgement tasks with explicit analysis), which may involve additional non-language functions (Blank et al., 2002; Crinion et al., 2003), it is not appropriate for investigations under more natural conditions such as word production.

However, these choices have some drawbacks. First, the achievement of the tasks cannot be directly assessed. Requiring overt responses would allow online performance monitoring, but speech increases the risk of movement, which is crucial in the case of children, and especially with disordered children (O'Shaughnessy et al., 2008). Therefore, children were intensively prepared before the scanner session using the same order of tasks and stimuli, allowing us to check that they understood and were able to achieve the tasks, and were also questioned after the session. Thus, the design of the tasks and the preparation aimed to ensure high performance for each child during the scanner session. Secondly, low-level control conditions involve more non-language-specific coactivations (Wilke et al., 2006; Holland et al., 2007) and, in some research contexts, it may be important to use high-level control tasks to target more specific functions. Nevertheless, together with the use of several tasks, a low-level control condition makes it possible to map a comprehensive and specific left-lateralized language network in normal children or adults (Ramsey et al., 2001; Tie et al., 2008; de Guibert et al., 2010), and was appropriate in our study for the comparison with language-impaired children. Furthermore, we used a combined tasks analysis to provide a robust assessment of language lateralization.

Moreover, to select a representative sample of the general population, close to the clinical context for language-disordered children, we did not solely recruit right-handed children. In this study, the proportions of left handed in the typical specific language impairment and control groups are similar and within the normal range estimate. Furthermore, additional analyses excluding left-handed children (n = 5) were carried out, which showed no major change of results [e.g. out of 11 lateralization index differences for the whole group, 8 remained significant and 2 were nearly significant (P = 0.057) when eliminating left-handers]. Moreover, to avoid distortions due to normalization of the childrens’ data with respect to an adult template, we used a tool dedicated to the creation of pair- and group-matched normalized templates based on normative brain data (Wilke et al., 2008).

Finally, a well-known issue with the category of specific language impairment is its clinical heterogeneity, since it encompasses impairments reflecting structural rule-like deficits (i.e. mainly phonology and morphosyntax), as well as impairments of articulatory, auditory receptive or pragmatic aspects of language. Since this heterogeneity may be a crucial source of inconsistency in the neuroimaging results, we focus here on structural language impairments, known as typical specific language impairment or linguistic dysphasia. Future studies need to investigate whether distinct subtypes of specific language impairment are associated with distinct brain functional anomalies. Secondly, since the current psychometric diagnostic tools are not totally adequate when used in isolation, because they lack clinical congruence, we selected typical specific language impairment children on both psychometric and clinical grounds. The typical specific language impairment children, as a group, failed three subtests (repetition of unfamiliar words, sentence completion and sentence repetition) that are acknowledged as being especially sensitive to specific language impairment, and all the subjects had an early history of selective language impairment and had been diagnosed in our specialized hospital centre.

In conclusion, by using functional MRI with a panel of distinct language tasks, this study provides evidence that a well-defined type of specific language impairment affecting structural components of language is associated with a lack of left functional lateralization in core language areas (pars opercularis and triangularis of the IFG, STG and SMG), with hypoactivation of the left superior temporoparietal junction, within Wernicke’s area, as well as with hyperactivation of the right anterior insula, adjacent inferior frontal gyrus and head of caudate. These results are similar to some findings from studies of developmental disorders involving other aspects of language such as dyslexia, stuttering or orofacial verbal dyspraxia, which will require further comparisons.

Funding

‘Programme Hospitalier de Recherche Clinique’ (PHRC–2007; University Hospital, Pontchaillou, Rennes, France); ‘Association pour la Recherche Clinique sur l’Epilepsie’. This work benefited from a research delegation from Institut National de Recherche en Informatique et Automatique (INRIA) granted to C.dG.

Acknowledgements

We would like to thank the children who participated in the study and their parents, as well as the teams at the Regional Centre for Language and Learning Disorders and at the Department of Neuroradiology, for their contribution.

Abbreviations
IFG 
 inferior frontal gyrus
SMG 
 supramarginal gyrus
STG 
 superior temporal gyrus

References

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