The neuroanatomy of developmental language disorder: a systematic review and meta-analysis.

Developmental language disorder (DLD) is a common neurodevelopmental disorder with adverse impacts that continue into adulthood. However, its neural bases remain unclear. Here we address this gap by systematically identifying and quantitatively synthesizing neuroanatomical studies of DLD using co-localization likelihood estimation, a recently developed neuroanatomical meta-analytic technique. Analyses of structural brain data (22 peer-reviewed papers, 577 participants) revealed highly consistent anomalies only in the basal ganglia (100% of participant groups in which this structure was examined, weighted by group sample sizes; 99.8% permutation-based likelihood the anomaly clustering was not due to chance). These anomalies were localized specifically to the anterior neostriatum (again 100% weighted proportion and 99.8% likelihood). As expected given the task dependence of activation, functional neuroimaging data (11 peer-reviewed papers, 414 participants) yielded less consistency, though anomalies again occurred primarily in the basal ganglia (79.0% and 95.1%). Multiple sensitivity analyses indicated that the patterns were robust. The meta-analyses elucidate the neuroanatomical signature of DLD, and implicate the basal ganglia in particular. The findings support the procedural circuit deficit hypothesis of DLD, have basic research and translational implications for the disorder, and advance our understanding of the neuroanatomy of language.

Functional near-infrared spectroscopy measures of neural activity in children with and without developmental language disorder during a working memory task.

INTRODUCTION: Children with developmental language disorder (DLD) exhibit cognitive deficits that interfere with their ability to learn language. Little is known about the functional neuroanatomical differences between children developing typically (TD) and children with DLD. METHODS: Using functional near-infrared spectroscopy, we recorded oxygenated hemoglobin (O2 hb) concentration values associated with neural activity in children with and without DLD during an auditory N-back task that included 0-back, 1-back, and 2-back conditions. Analyses focused on the left dorsolateral prefrontal cortex (DLPFC) and left inferior parietal lobule (IPL). Multilevel models were constructed with accuracy, response time, and O2 hb as outcome measures, with 0-back outcomes as fixed effects to control for sustained attention. RESULTS: Children with DLD were significantly less accurate than their TD peers at both the 1-back and 2-back tasks, and they demonstrated slower response times during 2-back. In addition, children in the TD group demonstrated significantly greater sensitivity to increased task difficulty, showing increased O2 hb to the IPL during 1-back and to the DLPFC during the 2-back, whereas the DLD group did not. A secondary analysis revealed that higher O2 hb in the DLPFC predicted better task accuracy across groups. CONCLUSION: When task difficulty increased, children with DLD failed to recruit the DLPFC for monitoring information and the IPL for processing information. Reduced memory capacity and reduced engagement likely contribute to the language learning difficulties of children with DLD.

Structural language impairment in Autism Spectrum Disorder versus Loss of Autism Diagnosis: Behavioral and neural characteristics.

This study probed for structural language impairment using behavioral and functional neuroimaging methods in individuals with Autism Spectrum Disorder (ASD) and those diagnosed with ASD in childhood who no longer meet criteria for ASD, referred to as Loss of Autism Diagnosis (LAD1). Participants were drawn from Fein et al. (2013): ASD (n = 35), LAD (n = 31), and Neurotypical (NT; n = 34). Criteria for structural language impairment were: Scores ≤ 82 on Clinical Evaluation of Language Fundamentals-4 (CELF) Core Language, an omnibus measure of language; and scores ≤ 7 on CELF Recalling Sentences, a clinical marker of structural language impairment. Task-based fMRI examined lateralization of significantly activated language-related brain regions in groups with structural language impairment (LI2) versus normal-range language (LN3), collapsed across ASD, LAD1, and NT status. Results showed no ASD versus LAD group differences in the proportion of participants with structural language impairment according to either metric (Recalling Sentences or Core Language). Functional MRI results indicated greater left hemisphere lateralization within significantly activated regions in the LI2 group. Structural language abilities were not meaningfully associated with either social abilities or lifetime ADHD symptoms in LI2 subgroups, further suggesting the presence of structural language impairment. Findings indicate the presence of persistent structural language difficulty even in the absence of ASD symptoms in some individuals within the LAD1 group and unique patterns of language-related neural specialization for language function in LI2 relative to LN3.

Inherited cases of CNOT3-associated intellectual developmental disorder with speech delay, autism, and dysmorphic facies.

De novo pathogenic variants in CNOT3 have recently been reported in a developmental delay disorder (intellectual developmental disorder with speech delay, autism, and dysmorphic facies [IDDSADF, OMIM: #618672]). The patients present with a variable degree of developmental delay and behavioral problems. To date, all reported disease-causing variants occurred de novo and no parent-child transmission was observed. We report for the first time autosomal dominant transmissions of the CNOT3-associated developmental disorder in two unrelated families. The clinical characteristics in our patients match the IDDSADF features reported so far and suggest substantial variability of the phenotype within the same family.

Procedural and declarative memory brain systems in developmental language disorder (DLD).

The aim of the current study was to examine microstructural differences in white matter relevant to procedural and declarative memory between adolescents/young adults with and without Developmental Language Disorder (DLD) using diffusion tensor imaging (DTI). The findings showed atypical age-related changes in white matter structures in the corticostriatal system, in the corticocerebellar system, and in the medial temporal region in individuals with DLD. Results highlight the importance of considering the age factor in research on DLD. Future studies are needed to examine the developmental relationship between long-term memory and individual differences in language development and learning.

Altered brain structures in the dorsal and ventral language pathways in individuals with and without developmental language disorder (DLD).

Developmental Language Disorder (DLD) is a neurodevelopmental disorder characterized by difficulty learning and using language, and this difficulty cannot be attributed to other developmental conditions. The aim of the current study was to examine structural differences in dorsal and ventral language pathways between adolescents and young adults with and without DLD (age range: 14-27 years) using anatomical magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI). Results showed age-related structural brain differences in both dorsal and ventral pathways in individuals with DLD. These findings provide evidence for neuroanatomical correlates of persistent language deficits in adolescents/young adults with DLD, and further suggest that this brain-language relationship in DLD is better characterized by taking account the dynamic course of the disorder along development.

The neural basis of nonword repetition in children with developmental speech or language disorder: An fMRI study.

Developmental language disorder (DLD) and developmental speech disorder (DSD) are highly prevalent childhood conditions. An impaired ability to repeat nonsense words ("nonword repetition"), is claimed to be a robust behavioural marker for these conditions. Yet how brain function is altered during this task remains poorly understood. Previous research suggests that DLD or DSD may be associated with reduced brain activation in the inferior frontal and posterior temporal regions when compared to controls. However, this research is limited by within and between group variability in age, speech/language phenotype, and comorbidities. Here, we used functional MRI to examine brain activation during nonword repetition. As anticipated, behavioural findings confirmed that the DLD and DSD groups had poorer nonword repetition performance compared to typical controls. In contrast, fMRI revealed no statistically significant differences in brain activation, despite the groups appearing to engage slightly different regions when compared at identical thresholds. Therefore, whilst nonword repetition is a sensitive clinical marker for DLD and DSD, the findings from this study suggest that this task is not a sensitive brain MRI marker for children with these disorders, unlike for individuals with single gene mutations like FOXP2 mutations.

Grey matter volume in developmental speech and language disorder.

Developmental language disorder (DLD) and developmental speech disorder (DSD) are common, yet their etiologies are not well understood. Atypical volume of the inferior and posterior language regions and striatum have been reported in DLD; however, variability in both methodology and study findings limits interpretations. Imaging research within DSD, on the other hand, is scarce. The present study compared grey matter volume in children with DLD, DSD, and typically developing speech and language. Compared to typically developing controls, children with DLD had larger volume in the right cerebellum, possibly associated with the procedural learning deficits that have been proposed in DLD. Children with DSD showed larger volume in the left inferior occipital lobe compared to controls, which may indicate a compensatory role of the visual processing regions due to sub-optimal auditory-perceptual processes. Overall, these findings suggest that different neural systems may be involved in the specific deficits related to DLD and DSD.

The value of diffusion tensor imaging for differentiating autism spectrum disorder with language delay from developmental language disorder among toddlers.

BACKGROUND: Impaired language function is frequently observed as an initial sign in people with autism spectrum disorder (ASD). However, clinically, the early stages of ASD are difficult to distinguish from those of developmental language disorder (DLD). OBJECTIVE: To evaluate the ability of diffusion tensor imaging (DTI) parameters for language-related white matter tracts (arcuate fasciculus) to differentiate ASD from DLD among toddlers. MATERIALS AND METHODS: We included 16 ASD toddlers with language delay and 18 DLD toddlers in this study. Magnetic resonance imaging sequences included T2-weighted imaging (T2WI), T1 3-dimensional magnetization-prepared rapid acquisition gradient-echo (3D MP-RAGE), and DTI. Tractography was performed using Neuro 3D in the Siemens Syngo Workstation, and fractional anisotropy (FA), average fiber length (AFL), tract volume (TV), and number of voxels (NV) were automatically calculated. Data were then analyzed using IBM SPSS Statistics 22. RESULTS: The ASD group exhibited significantly lower FA values, as well as significantly higher TV and NV values compared with the DLD group. With age as the covariate, analysis of covariance revealed different significances in TV and NV. Analysis of variance for AFL revealed no significant differences between the 2 groups. CONCLUSION: DTI parameters of arcuate fasciculus were useful for differentiating ASD with language delay from DLD among toddlers. DTI has the potential to provide an objective and effective method for aiding early diagnosis, early intervention and improving long-term outcomes of ASD.

The mis-wired language network in children with developmental language disorder: insights from DTI tractography.

This study aims to detect the neural substrate underlying the language impairment in children with developmental language disorder (DLD) using diffusion tensor imaging (DTI) tractography. Deterministic DTI tractography was performed in a group of right-handed children with DLD (N = 17; mean age 10;07 ± 2;01 years) and a typically developing control group matched for age, gender and handedness (N = 22; mean age 11;00 ± 1;11 years) to bilaterally identify the superior longitudinal fascicle, arcuate fascicle, anterior lateral segment and posterior lateral segment (also called dorsal language network) and the middle and inferior longitudinal fascicle, extreme capsule fiber system and uncinate fascicle (also called ventral language network). Language skills were assessed using an extensive, standardized test battery. Differences in language performance, white matter organization and structural lateralization of the language network were statistically analyzed. Children with DLD showed a higher overall volume and higher ADC values for the left-hemispheric language related WM tracts. In addition, in children with DLD, the majority (88%; 7/8) of the studied language related WM tracts did not show a significant left or right lateralization pattern. These structural alterations might underlie the language impairment in children with DLD.

White matter alterations and tract lateralization in children with dyslexia and isolated spelling deficits.

The present study investigated whether children with a typical dyslexia profile and children with isolated spelling deficits show a distinct pattern of white matter alteration compared with typically developing peers. Relevant studies on the topic are scarce, rely on small samples, and often suffer from the limitations of conventional tensor-based methods. The present Constrained Spherical Deconvolution study includes 27 children with typical reading and spelling skills, 21 children with dyslexia and 21 children with isolated spelling deficits. Group differences along major white matter tracts were quantified utilizing the Automated Fiber Quantification software and a lateralization index was calculated in order to investigate the structural asymmetry of the tracts. The two deficit groups mostly displayed different patterns of white matter alterations, located in the bilateral inferior longitudinal fasciculi, right superior longitudinal fasciculus, and cingulum for the group with dyslexia and in the left arcuate fasciculus for the group with isolated spelling deficits. The two deficit groups differed also with respect to structural asymmetry. Children with dyslexia did not show the typical leftward asymmetry of the arcuate fasciculus, whereas the group with isolated spelling deficits showed absent rightward asymmetry of the inferior fronto-occipital fasciculus. This study adds evidence to the notion that different profiles of combined or isolated reading and spelling deficits are associated with different neural signatures.

Altered gray matter volumes in language-associated regions in children with developmental language disorder and speech sound disorder.

Developmental language disorder (DLD) and speech sound disorder (SSD) are common, and although scientific evidence for structural and functional alterations in DLD/SSD is accumulating, current neuroimaging studies provide an incongruent picture. Here, we hypothesized that children affected by DLD and SSD present with gray matter (or gray matter asymmetry) aberrations in brain areas associated with language processing compared to typically developing (TD) children. To assess this hypothesis, we enhanced MRI-based information with microscopically defined cytoarchitectonic probabilities of Broca's area (BA 45, BA 44) as well as an auditory area (TE 3.0). We detected a larger rightward gray matter asymmetry in BA 45 in children with DLD (n = 13) and with SSD (n = 18) compared to TD children (n = 18), albeit only on a trend level. Interestingly though, we observed significantly larger gray matter volumes in right BA 45 in DLD compared to SSD children (and also compared to TD children).

Language Regression in an Atypical SLC6A1 Mutation.

Recent technological advances in exome sequencing or targeted gene sequencing with epilepsy panels have allowed clinicians to better understand the pathogenesis and clinical presentation of children with epilepsy. We present a child with a SLC6A1 mutation with language delay and autistic spectrum disorder and remind the reader that the identification of specific mutations in these conditions increase the likelihood of identification of potential therapeutic targets.

A Brain Marker for Developmental Speech Disorders.

OBJECTIVE: To characterize the organization of speech- and language-related white matter tracts in children with developmental speech and/or language disorders. STUDY DESIGN: We collected magnetic resonance diffusion-weighted imaging data from 41 children, ages 9-11 years, with developmental speech and/or language disorders, and compared them with 45 typically developing controls with the same age range. We used probabilistic tractography of diffusion-weighted imaging to map language (3 segments of arcuate fasciculus, extreme capsule system) and speech motor (corticobulbar) tracts bilaterally. The corticospinal and callosal tracts were used as control regions. We compared the mean fractional anisotropy and diffusivity values between atypical and control groups, covarying for nonverbal IQ. We then examined differences between atypical subgroups: developmental speech disorder (DSD), developmental language disorder, and co-occurring developmental speech and language disorder. RESULTS: Fractional anisotropy in the left corticobulbar tract was lower in the DSD than in the control group. Radial and mean diffusivity were higher in the DSD than the developmental language disorder, co-occurring developmental speech and language disorder, or control groups. There were no group differences for any metrics in the language or control tracts. CONCLUSIONS: Atypical development of the left corticobulbar tract may be a neural marker for DSD. This finding is in line with reports of speech disorder after left corticobulbar damage in children and adults with brain injury. By contrast, we found no association between diffusion metrics in language-related tracts in developmental language disorder, and changes for language disorders are likely more complex.

Does shape affect function? Articulatory skills in babbling of infants with deformational plagiocephaly.

PURPOSE: The purpose of this study was to quantitatively analyse pre-speech/early language skills in healthy full-term infants with moderate or severe deformational plagiocephaly (DP) and in infants without any skull asymmetry. METHODS: At 6 and 12 months, 51 children with DP (41 moderate, 10 severe cases) were studied, along with 15 infants serving as control. Deformational plagiocephaly (DP) was objectively determined based on cranial vault asymmetry (CVA) using 3D stereophotogrammetry (3dMDhead System® and Analytics 4.0, Cranioform®). Articulatory skills in babbling were assessed using the articulatory skill (ART-index) and mean syllable number (MSN). At 12 months, standardized parental questionnaires were used to evaluate early language outcomes. RESULTS: Overall, 3546 vocalizations were studied. Statistical tests did not reveal any significant differences of the ART-index between the three groups (ANOVA, F[2,63] = 0.24, p = 0.24). MSN likewise did not differ between the three shape groups (Kruskal-Wallis, p = 0.84). Among the children assigned to the at-risk group for language outcomes at 12 months were seven members of the symmetrical shape group (vs. seven assigned to the normally developing group), nine of the moderate DP group (vs. 27), and one of the severe DP group (vs. six). Fisher's exact test was used to analyse whether helmet therapy in the moderate DP group affected the results by influencing language outcomes, but did not reveal any significant influence (p = 0.712). CONCLUSIONS: The results of this study do not support arguments suggesting that DP is a cognitive risk condition. The suggestion that a direct neurophysiological relationship exists between a DP condition and a cognitive developmental delay remains controversial.

Atypical Callosal Morphology in Children with Speech Sound Disorder.

Speech sound disorder (SSD) is common, yet its neurobiology is poorly understood. Recent studies indicate atypical structural and functional anomalies either in one hemisphere or both hemispheres, which might be accompanied by alterations in inter-hemispheric connectivity. Indeed, abnormalities of the corpus callosum - the main fiber tract connecting the two hemispheres - have been linked to speech and language deficits in associated disorders, such as stuttering, dyslexia, aphasia, etc. However, there is a dearth of studies examining the corpus callosum in SSD. Here, we investigated whether a sample of 18 children with SSD differed in callosal morphology from 18 typically developing children carefully matched for age. Significantly reduced dimensions of the corpus callosum, particularly in the callosal anterior third, were observed in children with SSD. These findings indicating pronounced callosal aberrations in SSD make an important contribution to an understudied field of research and may suggest that SSD is accompanied by atypical lateralization of speech and language function.

Early changes in brain structure correlate with language outcomes in children with neonatal encephalopathy.

Global patterns of brain injury correlate with motor, cognitive, and language outcomes in survivors of neonatal encephalopathy (NE). However, it is still unclear whether local changes in brain structure predict specific deficits. We therefore examined whether differences in brain structure at 6 months of age are associated with neurodevelopmental outcomes in this population. We enrolled 32 children with NE, performed structural brain MR imaging at 6 months, and assessed neurodevelopmental outcomes at 30 months. All subjects underwent T1-weighted imaging at 3 T using a 3D IR-SPGR sequence. Images were normalized in intensity and nonlinearly registered to a template constructed specifically for this population, creating a deformation field map. We then used deformation based morphometry (DBM) to correlate variation in the local volume of gray and white matter with composite scores on the Bayley Scales of Infant and Toddler Development (Bayley-III) at 30 months. Our general linear model included gestational age, sex, birth weight, and treatment with hypothermia as covariates. Regional brain volume was significantly associated with language scores, particularly in perisylvian cortical regions including the left supramarginal gyrus, posterior superior and middle temporal gyri, and right insula, as well as inferior frontoparietal subcortical white matter. We did not find significant correlations between regional brain volume and motor or cognitive scale scores. We conclude that, in children with a history of NE, local changes in the volume of perisylvian gray and white matter at 6 months are correlated with language outcome at 30 months. Quantitative measures of brain volume on early MRI may help identify infants at risk for poor language outcomes.

An fMRI study of implicit language learning in developmental language impairment.

Individuals with developmental language impairment can show deficits into adulthood. This suggests that neural networks related to their language do not normalize with time. We examined the ability of 16 adults with and without impaired language to learn individual words in an unfamiliar language. Adults with impaired language were able to segment individual words from running speech, but needed more time to do so than their normal-language peers. ICA analysis of fMRI data indicated that adults with language impairment activate a neural network that is comparable to that of adults with normal language. However, a regional analysis indicated relative hyperactivation of a collection of regions associated with language processing. These results are discussed with reference to the Statistical Learning Framework and the sub-skills thought to relate to word segmentation.

Comparison of brain MRI findings with language and motor function in the dystroglycanopathies.

OBJECTIVE: To describe the spectrum of brain MRI findings in a cohort of individuals with dystroglycanopathies (DGs) and relate MRI results to function. METHODS: All available brain MRIs done for clinical indications on individuals enrolled in a DG natural history study (NCT00313677) were reviewed. Reports were reviewed when MRI was not available. MRIs were categorized as follows: (1) cortical, brainstem, and cerebellar malformations; (2) cortical and cerebellar malformations; or (3) normal. Language development was assigned to 1 of 3 categories by a speech pathologist. Maximal motor function and presence of epilepsy were determined by history or examination. RESULTS: Twenty-five MRIs and 9 reports were reviewed. The most common MRI abnormalities were cobblestone cortex or dysgyria with an anterior-posterior gradient and cerebellar hypoplasia. Seven individuals had MRIs in group 1, 8 in group 2, and 19 in group 3. Language was impaired in 100% of those in MRI groups 1 and 2, and degree of language impairment correlated with severity of imaging. Eighty-five percent of the whole group achieved independent walking, but only 33% did in group 1. Epilepsy was present in 8% of the cohort and rose to 37% of those with an abnormal MRI. CONCLUSIONS: Developmental abnormalities of the brain such as cobblestone lissencephaly, cerebellar cysts, pontine hypoplasia, and brainstem bowing are hallmarks of DG and should prompt consideration of these diagnoses. Brain imaging in individuals with DG helps to predict outcomes, especially language development, aiding clinicians in prognostic counseling.

Quantitative assessment of white matter injury in preterm neonates: Association with outcomes.

OBJECTIVE: To quantitatively assess white matter injury (WMI) volume and location in very preterm neonates, and to examine the association of lesion volume and location with 18-month neurodevelopmental outcomes. METHODS: Volume and location of WMI was quantified on MRI in 216 neonates (median gestational age 27.9 weeks) who had motor, cognitive, and language assessments at 18 months corrected age (CA). Neonates were scanned at 32.1 postmenstrual weeks (median) and 68 (31.5%) had WMI; of 66 survivors, 58 (87.9%) had MRI and 18-month outcomes. WMI was manually segmented and transformed into a common image space, accounting for intersubject anatomical variability. Probability maps describing the likelihood of a lesion predicting adverse 18-month outcomes were developed. RESULTS: WMI occurs in a characteristic topology, with most lesions occurring in the periventricular central region, followed by posterior and frontal regions. Irrespective of lesion location, greater WMI volumes predicted poor motor outcomes (p = 0.001). Lobar regional analysis revealed that greater WMI volumes in frontal, parietal, and temporal lobes have adverse motor outcomes (all, p < 0.05), but only frontal WMI volumes predicted adverse cognitive outcomes (p = 0.002). To account for lesion location and volume, voxel-wise odds ratio (OR) maps demonstrate that frontal lobe lesions predict adverse cognitive and language development, with maximum odds ratios (ORs) of 78.9 and 17.5, respectively, while adverse motor outcomes are predicted by widespread injury, with maximum OR of 63.8. CONCLUSIONS: The predictive value of frontal lobe WMI volume highlights the importance of lesion location when considering the neurodevelopmental significance of WMI. Frontal lobe lesions are of particular concern.